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1.  Weight loss is associated with plasma free amino acid alterations in subjects with metabolic syndrome 
Nutrition & Diabetes  2016;6(2):e197-.
Objectives:
The prevalence of metabolic syndrome is increasing worldwide, especially in Asian populations. Early detection and effective intervention are vital. Plasma free amino acid profile is a potential biomarker for the early detection for lifestyle-related diseases. However, little is known about whether the altered plasma free amino acid profiles in subjects with metabolic syndrome are related to the effectiveness of dietary and exercise interventions.
Methods:
Eighty-five Japanese subjects who fulfilled the Japanese diagnostic criteria for metabolic syndrome were enrolled in a 3-month diet and exercise intervention. The plasma free amino acid concentrations and metabolic variables were measured, and the relationships between plasma free amino acid profiles, metabolic variables and the extent of body weight reduction were investigated. Those who lost more than 3% of body weight were compared with those who lost less than 3%.
Results:
Baseline levels of most amino acids in the subset that went on to lose <3% body weight were markedly lower compared with the counterpart, although both groups showed similar proportional pattern of plasma amino acid profiles. The weight loss induced by the diet and exercise intervention normalized plasma free amino acid profiles. For those with a high degree of weight loss, those changes were also associated with improvement in blood pressure, triglyceride and hemoglobin A1c levels.
Conclusions:
These data suggest that among Japanese adults meeting the criteria for metabolic syndrome, baseline plasma free amino acid profiles may differ in ways that predict who will be more vs less beneficially responsive to a standard diet and exercise program. Plasma free amino acid profiles may also be useful as markers for monitoring the risks of developing lifestyle-related diseases and measuring improvement in physiological states.
doi:10.1038/nutd.2016.5
PMCID: PMC4775824  PMID: 26926588
2.  Predicting the characteristics of the aetiological agent for Kawasaki disease from other paediatric infectious diseases in Japan 
Epidemiology and Infection  2015;144(3):478-492.
SUMMARY
Although Kawasaki disease (KD), which was first reported in the 1960s, is assumed to be infectious, its aetiological agent(s) remains unknown. We compared the geographical distribution of the force of infection and the super-annual periodicity of KD and seven other paediatric infectious diseases in Japan. The geographical distribution of the force of infection, which was estimated as the inverse of the mean patient age, was similar in KD and other paediatric viral infections. This similarity was due to the fact that the force of infection was determined largely by the total fertility rate. This finding suggests that KD shares a transmission route, i.e. sibling-to-sibling infection, with other paediatric infections. The super-annual periodicity, which is positively associated with the sum of an infectious disease's incubation period and infectious period, was much longer for KD and exanthema subitum than other paediatric infectious diseases. The virus for exanthema subitum is known to persist across the host's lifespan, which suggests that the aetiological agent for KD may also be capable of persistent infection. Taken together, these findings suggest that the aetiological agent for KD is transmitted through close contact and persists asymptomatically in most hosts.
doi:10.1017/S0950268815001223
PMCID: PMC4714300  PMID: 26201398
Emerging infections; epidemiology; infectious disease epidemiology; Kawasaki disease; mathematical modelling
3.  P14.05INCIDENCE OF GLIOMA IN KUMAMOTO PREFECTURE IN SOUTHERN JAPAN: A 25 YEARS STUDY 
Neuro-Oncology  2014;16(Suppl 2):ii72-ii73.
BACKGROUND: In Western countries, the incidence of gliomas increases with advancing age. However, no accurate population-based epidemiological survey of gliomas in Japan has been reported. METHODS: We examined the incidence of glioma in a well- defined population residing in Kumamoto prefecture (population 1.86 million in 2001) in southern Japan. RESULTS: During the period from 1989 to 2013, 1,382 patients harboring gliomas were diagnosed; 1,027(74.3 %) tumors were confirmed microscopically. The age-adjusted incidence rate was 2.9 (males, 3.3; females, 2.5) per 100,000 population per year. During the 25 years from 1989 and 2013 there was an increase in the incidence of glioma; the number of gliomas diagnosed in the last 5 years was almost twice that of the first 5 years. Its incidence increased with age; the highest rate was observed in males and females older than 80-years and the age-specific incidence per 100,000 per year was 9.1 for males and 6.0 for females. Although the number of elderly individuals doubled during this study period, the number of malignant gliomas in this group showed a five-fold increase. CONCLUSION: Although the incidence of glioma remains lower in Japan than in Western countries, it is on the increase. Besides the aging of the population, environmental changes may account for the increase in the incidence of malignant gliomas in Japan.
doi:10.1093/neuonc/nou174.277
PMCID: PMC4185635
4.  Diffuse Liver Metastasis of Small-Cell Lung Cancer Presenting as Acute Liver Failure and Diagnosed by Transjugular Liver Biopsy: A Rare Case in Whom Nodular Lesions Were Detected by Enhanced CT Examination 
Small-cell lung cancer (SCLC) is a subgroup of lung cancer with a high frequency of liver metastasis, which is a predictor of poor prognosis. Diffuse liver metastases of SCLC with no visible nodular lesions in the liver when examined using computed tomography (CT) are relatively rare; however, a few cases with rapid progression to acute liver failure that were diagnosed after death have been reported. In this paper, we report a 63-year-old man with diffuse liver metastases of SCLC that were histologically diagnosed using a transjugular liver biopsy while the patient was alive, even though no lesions were visible during a contrast-enhanced CT examination.
doi:10.1159/000381140
PMCID: PMC4427142  PMID: 25969674
Diffuse liver metastasis; Acute liver failure; Small-cell lung cancer
5.  Compact laser accelerators for X-ray phase-contrast imaging 
Advances in X-ray imaging techniques have been driven by advances in novel X-ray sources. The latest fourth-generation X-ray sources can boast large photon fluxes at unprecedented brightness. However, the large size of these facilities means that these sources are not available for everyday applications. With advances in laser plasma acceleration, electron beams can now be generated at energies comparable to those used in light sources, but in university-sized laboratories. By making use of the strong transverse focusing of plasma accelerators, bright sources of betatron radiation have been produced. Here, we demonstrate phase-contrast imaging of a biological sample for the first time by radiation generated by GeV electron beams produced by a laser accelerator. The work was performed using a greater than 300 TW laser, which allowed the energy of the synchrotron source to be extended to the 10–100 keV range.
doi:10.1098/rsta.2013.0032
PMCID: PMC3900035  PMID: 24470414
X-ray phase contrast imaging; laser wakefield acceleration; plasma acceleration
6.  Plasma amino acid profiles are associated with insulin, C-peptide and adiponectin levels in type 2 diabetic patients 
Nutrition & Diabetes  2014;4(9):e133-.
Objectives:
Plasma-free amino acid (PFAA) profiles have been associated with a future risk of developing diabetes or cardiovascular disease in nondiabetic subjects. These PFAA alterations might predominantly result from the metabolic shift caused by insulin resistance and visceral fat deposition. The variety of PFAA profiles within diabetic subjects is not well researched. In this study, we focused on type 2 diabetic subjects and examined the association between PFAA profiles and insulin- and glucose-related variables.
Methods:
Fifty-one Japanese subjects diagnosed with type 2 diabetes were recruited from an outpatient clinic. The plasma concentrations of 21 amino acids; glucose-related markers including glucose, hemoglobin A1c (HbA1c), glycoalbumin and 1,5-anhydroglucitol; insulin-related markers including insulin, C-peptide, and the homeostasis model assessment of insulin resistance; and adipocytokines including adiponectin and leptin were determined. The association of PFAA and other metabolic profiles were analyzed, and stratified analyses of the PFAAs and clinical characteristics were performed according to the fasting plasma insulin and HbA1c levels. In addition, the PFAA indices that correlate to visceral fat obesity were evaluated.
Results:
Although strong correlations between PFAAs and glucose-related markers were not observed, several amino acids (branched-chain amino acids, tryptophan, alanine, tyrosine, glutamate and proline) and PFAA indices that evaluate visceral obesity were highly correlated with insulin-related markers and adiponectin (P<0.001). In the group of diabetic patients with hyperinsulinemia, the amino acid levels were significantly increased, which generally demonstrated good concordance with insulin-related markers and adiponectin levels.
Conclusions:
The PFAA profiles in diabetic patients were strongly associated with hyperinsulinemia and hypoadiponectinemia, which might become risk evaluation factors for the development of cardiovascular diseases.
doi:10.1038/nutd.2014.32
PMCID: PMC4183973  PMID: 25177913
7.  Focal macular photopic negative response in patients with optic neuritis 
Eye  2011;25(3):358-364.
Purpose
To investigate, by focal macular electroretinography (ERG), the change of photopic negative response (PhNR) in the recovery of visual function in patients with optic neuritis.
Methods
Focal macular ERG was recorded from nine patients with acute optic neuritis (38.6±10.2 years). The photostimulator device projected 15° visual angle spotlight onto the macula. Focal macular ERG recording was performed at the onset and at 1 month and 6 months after the onset of optic neuritis. The results were compared between each recording for seven of the patients.
Results
All patients decreased in the vision below 20/100 and had central scotoma. Vision improved more than 20/20 within 1 month and full-visual field recovered within 6 months after the onset in all patients. The amplitude of the a-wave, b-wave, and PhNR of focal macular ERG at the onset was significantly attenuated in eyes with optic neuritis (66.8±15.5, 65.8±17.7, and 65.2±14.4% of normal control, respectively). The amplitude of the a-wave and b-wave increased gradually after steroid pulse therapy. The increase in a-wave amplitude was significant at 6 months (P=0.046), whereas the PhNR amplitude did not show any significant change over 6 months after the onset of optic neuritis.
Conclusions
Our results suggest that inflammation at the onset of optic neuritis leads to functional deficits that extend to at least the inner nuclear layers of the retina, and that all but the ganglion cell layers of retina recover.
doi:10.1038/eye.2010.205
PMCID: PMC3171782  PMID: 21212800
focal electroretinogram; photopic negative response; optic neuritis; macula
8.  Hepatoma-derived growth factor and its role in keloid pathogenesis 
Abstract
Hepatoma-derived growth factor (HDGF) is a novel mitogenic growth factor that has been implicated in many different carcinomas. Its role in keloid biology has not yet been investigated. The present study is aimed at examining the role of HDGF in keloid pathogenesis. Immunohistochemical staining and Western blot analyses were used to examine in vivo localization and expression of HDGF in keloid and normal skin tissue. This was followed by the detection of HDGF expression in fibroblasts cultured in vitro and fibroblasts exposed to serum. To investigate the effect of epithelial–mesenchymal interactions, a two-chamber system was employed in which keratinocytes on membrane inserts were co-cultured with the fibroblasts. HDGF expression levels in all cell extracts and conditioned media were assayed through Western blot analysis. In another set of experiments, the effect of exogenous recombinant HDGF on keloid fibroblasts (KF) and normal fibroblasts (NF) was examined. Cell proliferation was assessed by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and by quantifying proliferating cell nuclear antigen (PCNA) expression. Downstream targets of HDGF were identified by detecting their expression through Western blot analysis. Our results indicate that there was an increase in HDGF expression in the dermis of keloid compared with normal skin tissue. The application of serum and epithelial–mesenchymal interactions did not seem to have any effect on intracellular HDGF expression levels. However, co-culturing keloid keratinocytes with KFs resulted in increased HDGF secretion when compared with monoculture or normal controls. Furthermore, treatment with exogenous recombinant HDGF was found to increase the proliferation of KFs, activate the extracellular signal-regulated kinase (ERK) pathway and up-regulate the secretion of vascular endothelial growth factor (VEGF).
doi:10.1111/j.1582-4934.2009.00779.x
PMCID: PMC3828849  PMID: 19432814
hepatoma-derived growth factor; keloid fibroblast; proliferation; ERK; epithelial–mesenchymal interaction; wound healing; vascular endothelial growth factor
10.  The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials 
Objectives To investigate whether statins reduce all cause mortality and major coronary and cerebrovascular events in people without established cardiovascular disease but with cardiovascular risk factors, and whether these effects are similar in men and women, in young and older (>65 years) people, and in people with diabetes mellitus.
Design Meta-analysis of randomised trials.
Data sources Cochrane controlled trials register, Embase, and Medline.
Data abstraction Two independent investigators identified studies on the clinical effects of statins compared with a placebo or control group and with follow-up of at least one year, at least 80% or more participants without established cardiovascular disease, and outcome data on mortality and major cardiovascular disease events. Heterogeneity was assessed using the Q and I2 statistics. Publication bias was assessed by visual examination of funnel plots and the Egger regression test.
Results 10 trials enrolled a total of 70 388 people, of whom 23 681 (34%) were women and 16 078 (23%) had diabetes mellitus. Mean follow-up was 4.1 years. Treatment with statins significantly reduced the risk of all cause mortality (odds ratio 0.88, 95% confidence interval 0.81 to 0.96), major coronary events (0.70, 0.61 to0.81), and major cerebrovascular events (0.81, 0.71 to 0.93). No evidence of an increased risk of cancer was observed. There was no significant heterogeneity of the treatment effect in clinical subgroups.
Conclusion In patients without established cardiovascular disease but with cardiovascular risk factors, statin use was associated with significantly improved survival and large reductions in the risk of major cardiovascular events.
doi:10.1136/bmj.b2376
PMCID: PMC2714690  PMID: 19567909
11.  The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials 
The BMJ  2009;338:b2376.
Objectives To investigate whether statins reduce all cause mortality and major coronary and cerebrovascular events in people without established cardiovascular disease but with cardiovascular risk factors, and whether these effects are similar in men and women, in young and older (>65 years) people, and in people with diabetes mellitus.
Design Meta-analysis of randomised trials.
Data sources Cochrane controlled trials register, Embase, and Medline.
Data abstraction Two independent investigators identified studies on the clinical effects of statins compared with a placebo or control group and with follow-up of at least one year, at least 80% or more participants without established cardiovascular disease, and outcome data on mortality and major cardiovascular disease events. Heterogeneity was assessed using the Q and I2 statistics. Publication bias was assessed by visual examination of funnel plots and the Egger regression test.
Results 10 trials enrolled a total of 70 388 people, of whom 23 681 (34%) were women and 16 078 (23%) had diabetes mellitus. Mean follow-up was 4.1 years. Treatment with statins significantly reduced the risk of all cause mortality (odds ratio 0.88, 95% confidence interval 0.81 to 0.96), major coronary events (0.70, 0.61 to0.81), and major cerebrovascular events (0.81, 0.71 to 0.93). No evidence of an increased risk of cancer was observed. There was no significant heterogeneity of the treatment effect in clinical subgroups.
Conclusion In patients without established cardiovascular disease but with cardiovascular risk factors, statin use was associated with significantly improved survival and large reductions in the risk of major cardiovascular events.
doi:10.1136/bmj.b2376
PMCID: PMC2714690  PMID: 19567909
12.  Extracellular thioredoxin levels are increased in patients with acute lung injury 
Thorax  2006;61(6):521-527.
Background
Acute lung injury (ALI) and its extreme manifestation the acute respiratory distress syndrome (ARDS) complicate a wide variety of serious medical and surgical conditions. Thioredoxin is a small ubiquitous thiol protein with redox/inflammation modulatory properties relevant to the pathogenesis of ALI. We therefore investigated whether thioredoxin is raised extracellulary in patients with ALI and whether the extent of any increase is dependent upon the nature of the precipitating insult.
Methods
Bronchoalveolar lavage (BAL) fluid and plasma samples were collected from patients with ALI (n = 30) and healthy controls (n = 18, plasma; n = 14, BAL fluid). Lung tissue was harvested from a separate group of patients and controls (n = 10). Thioredoxin was measured by ELISA in fluids and by immunohistochemistry in tissue. Interleukin (IL)‐8 levels were determined by ELISA. Disease severity was assessed as APACHE II and SOFA scores.
Results
BAL fluid levels of thioredoxin were higher in patients with ALI than in controls (median 61.6 ng/ml (IQR 34.9–132.9) v 16.0 ng/ml (IQR 8.9–25.1), p<0.0001); plasma levels were also significantly higher. When compared with controls, sections of wax embedded lung tissue from patients with ALI showed greater positive staining for thioredoxin in alveolar macrophages and type II epithelial cells. BAL fluid levels of thioredoxin correlated with IL‐8 levels in BAL fluid but not with severity of illness scores or mortality. BAL fluid levels of thioredoxin, IL‐8, and neutrophils were significantly greater in patients with ALI of pulmonary origin.
Conclusions
Extracellular thioredoxin levels are raised in patients with ALI, particularly of pulmonary origin, and have a significant positive association with IL‐8. Extracellular thioredoxin levels could provide a useful indication of inflammation in ALI.
doi:10.1136/thx.2005.053041
PMCID: PMC2111226  PMID: 16601094
acute lung injury; acute respiratory distress syndrome; interleukin‐8; inflammation; thioredoxin
13.  Survival impact of epidermal growth factor receptor overexpression in patients with non‐small cell lung cancer: a meta‐analysis 
Thorax  2005;61(2):140-145.
Background
It is thought that overexpression of epidermal growth factor receptor (EGFR) in non‐small cell lung cancer (NSCLC) might compromise patient survival, presumably by promoting tumour growth by an autocrine mechanism. However, conflicting results have been reported from various laboratories, and the clinical importance of EGFR overexpression remains unsettled.
Methods
A meta‐analysis of previous studies was performed to quantitatively review the effects of EGFR overexpression on survival in patients with NSCLC using a DerSimonian‐Laird random effects model. Eighteen studies including 2972 patients were subjected to final analysis.
Results
Overall, positivity for EGFR overexpression differed between histological types: 39% in adenocarcinomas, 58% in squamous cell carcinomas, 38% in large cell carcinomas, and 32% in cancers in a miscellaneous category (p<0.0001). The combined hazard ratio (HR) was 1.14 (95% CI 0.97 to 1.34; p = 0.103), indicating that EGFR overexpression has no significant impact on survival. When only the 15 immunohistochemistry based studies were considered, the combined HR was 1.08 (95% CI 0.92 to 1.28; p = 0.356), again suggesting that EGFR overexpression has no impact on survival. Heterogeneity testing indicated that there was heterogeneity between studies but publication bias was absent, which suggests that the summary statistics obtained may approximate the actual average.
Conclusions
EGFR overexpression was not associated with poorer survival in patients with NSCLC. Specific mutations of the EGFR gene will need further study in terms of survival implications.
doi:10.1136/thx.2005.042275
PMCID: PMC2104592  PMID: 16284218
epidermal growth factor receptor; lung cancer; overexpression; survival
14.  Early prediction of rheumatoid arthritis by serological variables and magnetic resonance imaging of the wrists and finger joints: results from prospective clinical examination 
Annals of the Rheumatic Diseases  2006;65(1):134-135.
doi:10.1136/ard.2005.043075
PMCID: PMC1797983  PMID: 16344501
early stage rheumatoid arthritis; anti‐cyclic citrullinated peptide antibody; magnetic resonance imaging; bone marrow oedema; bone erosion
15.  The presence of anti‐cyclic citrullinated peptide antibody is associated with magnetic resonance imaging detection of bone marrow oedema in early stage rheumatoid arthritis 
Annals of the Rheumatic Diseases  2006;65(1):133-134.
doi:10.1136/ard.2005.04138
PMCID: PMC1797979  PMID: 16344500
early stage rheumatoid arthritis; anti‐cyclic citrullinated peptide antibodies; magnetic resonance imaging; bone marrow oedema
16.  RS3PE syndrome presenting as vascular endothelial growth factor associated disorder 
Annals of the Rheumatic Diseases  2005;64(11):1653-1655.
Methods: Vascular endothelial growth factor165 (VEGF165), tumour necrosis factor α (TNFα), and interleukin 1ß (IL1ß) were measured by enzyme linked immunosorbent assay (ELISA) in serum samples from three patients with RS3PE syndrome. As controls, serum samples from 26 healthy volunteers, 12 patients with rheumatoid arthritis, 10 patients with systemic lupus erythematosus, 13 patients with polymyositis/dermatomyositis, 13 patients with vasculitis syndrome, and 6 patients with mixed connective tissue disease were also analysed. Synovial hypervascularity of patients with RS3PE syndrome was estimated by rate of enhancement (E-rate) in a dynamic MRI study.
Results: Serum concentrations of VEGF165 (mean (SD) 2223.3 (156.3) pg/ml) were significantly higher in patients with active RS3PE syndrome than in controls before corticosteroid treatment. TNFα and IL1ß levels were similar in patients and controls. Synovial hypervascularity in affected joints and subcutaneous oedema decreased during corticosteroid treatment, in parallel with the fall in serum VEGF165.
Conclusions: VEGF promotes synovial inflammation and vascular permeability in patients with RS3PE syndrome, suggesting that RS3PE can be classified as a VEGF associated disorder.
doi:10.1136/ard.2004.032995
PMCID: PMC1755286  PMID: 16227418
17.  Histopathological and immunohistochemical studies of lenticules after epikeratoplasty for keratoconus 
Aims: To examine histopathological and immunohistochemical changes in lenticules and host of corneal buttons from patients who previously underwent epikeratoplasty for keratoconus.
Methods: 12 penetrating keratoplasty specimens from patients with keratoconus who had previously undergone epikeratoplasty, eight keratoconus, and seven normal corneas were examined. Immunostaining for Sp1, α1-proteinase inhibitor (α1-PI), and α2-macroglobulin (α2M) were performed.
Results: In nine of the 12 lenticules, the keratoconus-like disruptions were found in Bowman’s layer. Peripheral and posterior keratocyte repopulation of the lenticules was observed in all cases. Keratocyte repopulation in the anterior and mid-stromal regions of the lenticules appeared related to the time since epikeratoplasty. Sp1 nuclear staining of the basal and wing epithelial cells was more intense in lenticules and keratoconus corneas than in normal corneas. Lenticular, host, and keratoconus keratocytes showed positive Sp1 staining, whereas staining was absent in normal corneas. Compared to normal corneas, α1-PI and α2M immunostaining was lower in the lenticules, host, and keratoconus specimens.
Conclusions: The epithelial cells and keratocytes repopulated in the lenticules retain keratoconus-like biochemical abnormalities such as upregulation of Sp1 and downregulation of α1-PI and α2M. The authors speculate that both keratocytes and the corneal epithelium may participate in the development of keratoconus.
doi:10.1136/bjo.2004.054684
PMCID: PMC1772740  PMID: 15965163
keratoconus; epikeratoplasty; Bowman’s layer disruption; keratocyte repopulation; Sp1
18.  Ten year recurrence after first ever stroke in a Japanese community: the Hisayama study 
Background: Very few population based cohort studies have focused on the long term recurrence of stroke.
Objective: To examine 10 year cumulative recurrence rates for stroke in a Japanese cohort according to pathological type and clinical subtype of brain infarction.
Methods: During a 32 year follow up of 1621 subjects ⩾40 years of age, 410 developed first ever stroke. These were followed up prospectively for 10 years after stroke onset.
Results: During follow up, 108 (26%) experienced recurrent stroke. The cumulative recurrence rates were 35.3% at five years and 51.3% at 10 years. The 10 year recurrence rates of subarachnoid haemorrhage (SAH), brain haemorrhage, and brain infarction were 70.0%, 55.6%, and 49.7%, respectively; the difference between SAH and brain infarction was significant (p = 0.004). Most recurrent episodes after SAH or brain haemorrhage happened within a year after the index stroke, whereas recurrence of brain infarction increased consistently throughout the observation period. Cardioembolic stroke had a higher recurrence rate (75.2%) than lacunar infarction (46.8%) (p = 0.049). The 10 year risk of stroke recurrence increased with age after lacunar or atherothrombotic brain infarction, but not after the other types or subtypes. After atherothrombotic brain infarction, cardioembolic stroke, or SAH, the type and subtype of most recurrent strokes were the same as for the index stroke, but recurrence after lacunar infarction or brain haemorrhage showed divergent patterns.
Conclusions: Japanese people have higher recurrence rates of stroke than other populations. Recurrence rate after a first brain infarct increases consistently through the next 10 years.
doi:10.1136/jnnp.2004.038166
PMCID: PMC1739549  PMID: 15716529
19.  External Manual Carotid Compression is Effective in Patients with Cavernous Sinus Dural Arteriovenous Fistulae 
Interventional Neuroradiology  2007;13(Suppl 1):115-122.
Summary
External manual carotid compression is a non-invasive method to treat patients with cavernous sinus dural arteriovenous fistulae (CS-DAVF). We studied a group of patients with CS-DAVF to identify factors that made cure by compression therapy possible.
We treated 23 patients with CS-DAVF without cortical venous drainage or a recent decline in visual acuity by compression therapy. All were followed up by magnetic resonance angiography (MRA) at one, three, six, and 12 months after treatment and the characteristics of the imaging findings, their neurological symptoms, and the patterns of symptom improvement were examined.
In group A (n=8), cure was achieved by manual carotid compression; in the other 15 patients (group B), cure was not obtained. Group B manifested significantly higher ocular pressure and a significantly longer interval between symptom onset and treatment by manual carotid compression. In group A, venous drainage was via the superior orbital vein (SOV) with/without involvement of the inferior petrosal sinus (IPS); closure of the CS-DAVF occurred within 4.1 months after the start of treatment. In three patients symptom improvement progressed steadily and gradually. The other five cured patients experienced transient worsening of their symptoms at two to four months after the start of treatment, these resolved within four to seven months
Manual carotid compression was effective in patients without retrograde venous CS-DAVF drainage or a severe decline in visual acuity. The factors that rendered cure by compression therapy possible were lower ocular pressure and a shorter interval between symptom onset and the start of treatment. Venous drainage in those patients was exclusively via the SOV without involvement of the IPS.
PMCID: PMC3345454  PMID: 20566088
cavernous sinus, carotid artery, dural arteriovenous fistulae, external compression
20.  Characterisation of cartilage intermediate layer protein (CILP)-induced arthropathy in mice 
Annals of the Rheumatic Diseases  2004;63(3):252-258.
Objectives: To characterise cartilage intermediate layer protein (CILP)-induced arthropathy in mice.
Methods: The first and second halves of the nucleotide triphosphate pyrophosphohydrolase (NTPPHase) non-homologous region of human CILP were prepared as recombinant proteins (C1 and C2, respectively), including three overlapping fragments of C2 (C2F1, C2F2, and C2F3). C57BL/6 mice were immunised with these proteins to induce arthritis. In addition, a separate group of mice were immunised repeatedly with the mixture of C1 and C2 to see the effect of chronic immunisation. Arthritis developed in the mice, and cellular and humoral immune responses against CILP were analysed.
Results: Immunisation with C2 and with the mixture C2F1/C2F2/C2F3 caused the severest arthritis to develop in mice. Immunisation with one of C1, C2F1, C2F2, or C2F3 caused milder arthritis, even though each of the fragments carried T cell epitopes. Immunisation either with C1 or C2 alone evoked cellular and humoral immune responses to both the C1 and C2 proteins. Further, the repeated immunisation with the C1/C2 mixture caused tendon calcification and bone irregularity, together with decreased NTPPH activity.
Conclusions: The results show that multiple T cell epitopes are needed for the development of CILP-induced arthritis, and present the characteristic new model of mild arthropathy accompanied by extra-articular calcifications. An immune response to putative murine CILP/NTPPH may be involved in the ectopic calcifications in the arthritic mice.
doi:10.1136/ard.2003.008045
PMCID: PMC1754905  PMID: 14962958
21.  Diagnosis of Vertebral Artery Dissection by Basi-parallel Anatomical Scanning (BPAS) MRI 
Interventional Neuroradiology  2006;12(Suppl 1):129-132.
Summary
To diagnose VA dissection, MRA or cerebral angiography, which provides information regarding intra-vascular space, has been performed. We report the acquisition of various information about VA dissection using MRI-BPAS, which is a new diagnostic method.
PMCID: PMC3387939  PMID: 20569617
vertebral artery dissection, MRI-BPAS
22.  Cerebralod Flow Change Before and After Carotid Angioplasty and Stenting (CAS) in Cases with Contralateral Carotid Artery Occlusion 
Interventional Neuroradiology  2006;12(Suppl 1):201-204.
Summary
Contralateral carotid artery occlusion is thought to represent a significant risk factor in carotid endarterectomy (CEA). There is also evidence that intraoperative and postoperative hypotention may cause contralateral hemodynamic ischemia. As such, contralateral carotid artery occlusion is regarded as a risk factor for carotid angioplasty and stenting (CAS). In this paper, we report on five cases of severe ICA stenosis with contralateral carotid artery occlusions. Cerebral blood flow(CBF) and cerebral vasoreactivity(CVR) of the contralateral carotid artery occlusions were measured before and after CAS. Additionally, the influence that ipsilateral CAS exerted on the occluded side was examined.
123I-IMP SPECT was performed before and after CAS, both at rest and at the time of acetazoramide administration. The CBF was evaluated quantitatively using the ARG method. The mean CBF of the treated side rose from 30.0 ± 7.1 ml/100g/min to 34.4 ± 8.3 ml/100g/min (p<0.05), and the mean CBF of the occluded side similarly rose from 28.3 ± 6.1 ml/100g/min to 31.7 ± 6.4 ml/100g/min (p<0.05). Correspondingly, the regional CVR (rCVR) increased from 5.9% ± 16.3% to 35.0% ± 16.4%(p<0.05) on the treated side, and from 3.7% ± 14.7% to 10.7% ± 16.9% (p<0.05) on the occluded side.
This demonstrates that ipsilateral CAS seems to improve both CBF and CVR on the contralateral occluded side. The fact that some cases developed cross flow from the anterior communicating artery was both remarkable and significant. Where there was poor cross flow from the anterior communicating artery, improvement in cerebral vaso reactivity was limited.
PMCID: PMC3387953  PMID: 20569632
CAS, contralateral carotid artery occlusion, CBF.
23.  Association of CYP2A6 deletion polymorphism with smoking habit and development of pulmonary emphysema 
Thorax  2003;58(7):623-628.
Methods: 203 current or ex-smokers (lifelong cigarette consumption (CC) ≥10 pack years) with subclinical and established COPD phenotypes were clinically evaluated and pulmonary function tests and a chest CT scan were performed (smoker group). The non-smoker group consisted of 123 healthy volunteers. CYP2A6 genotypes were determined in both groups.
Results: The percentage of subjects with a CYP2A6del allele (genotype D) was lower in heavy smokers (20.5%, n=88, CC ≥60 pack years) than in light smokers (37.4%, n=115, CC 10–59 pack years, χ2=6.8, p=0.01) or non-smokers (36.1%, n=122, χ2=6.0, p=0.01); lower in ex-smokers (20.7%, n=111) than in current smokers (41.3%, n=92, χ2=10.1, p<0.01); and lower in smokers with a high LAA (low attenuation area) score on the chest CT scan (18.4%, n=76, LAA ≥8.0) than in those with a low LAA score (37.0%, n=127, LAA <8.0, χ2=7.8, p<0.01).
Conclusions: Subjects with the CYP2A6del allele tend not to be heavy habitual smokers but can be light habitual smokers. The CYP2A6del polymorphism may inhibit smokers from giving up smoking, but appears to function as a protective factor against the development of pulmonary emphysema independent of smoking habit.
doi:10.1136/thorax.58.7.623
PMCID: PMC1746722  PMID: 12832682
25.  Risk factors for age related maculopathy in a Japanese population: the Hisayama study 
Aims: To examine the risk factors for age related maculopathy (ARM) in a sample Japanese population.
Methods: In 1998, a cross sectional community survey was conducted among residents of Hisayama. A total of 596 men and 886 women living in Hisayama, Japan, aged 50 years or older consented to participate in the study. Each participant underwent a comprehensive examination that included an ophthalmic examination. The presence of ARM was determined by grading from fundus examination by indirect ophthalmoscopy, slit lamp examination, and colour fundus photographs. Using these cross sectional data, logistic regression analyses were performed to determine the risk factors for ARM. The following 10 possible risk factors were used: age, cataract, hypertension (history), hypertension (history or examination), diabetes, hyperlipidaemia, current smoker, alcohol intake, BMI, and WBC.
Results: ARM was detected in 19.5% of men and 14.9% of women. Men were found to have a significantly higher prevalence of ARM than women. Multiple logistic regression analysis showed that age and hypertension (history or examination) were significantly associated with ARM in men, whereas only age was a significant risk factor for ARM in women.
Conclusions: This study suggests that higher age and male sex are relevant risk factors for ARM in Japan. In addition, hypertension is a relevant risk factor in men.
PMCID: PMC1771615  PMID: 12642312
age related maculopathy; Japanese population; risk factor; population based study

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