Satoko Mitani

Intracranial deep white matter lesions (DWLs) are associated with chronic kidney disease (CKD) and cognitive impairment: a 5-year follow-up magnetic resonance imaging (MRI) study.

Stroke incidence and cognitive decline are related to progression of arteriosclerosis in intracranial DWLs. However, the relationships between DWLs and factors associated with their progression, including CKD, have not been fully elucidated using longitudinal MRI. Of 291 individuals (184 males, 107 females; age 66.9 ± 6.1 years) who had voluntarily participated in a hospital-based health check-up and underwent repeated brain MRI scans in 2003 and 2008, 273 were evaluated in this study. The DWL group included those having DWL without progression, and the DWL progression (DWLP) group included those having an increase in grade number according to the Fazekas classification. Unimpaired age-matched subjects with no brain MRI abnormalities constituted Group C. The Mini-Mental State Examination (MMSE) and verbal fluency tasks were used for objective cognitive evaluations according to the MR evaluation schedule in 2008. Associations between DWLs and vascular risk factors were examined. DWLP occurred in 9.2% of subjects. Compared to Group C subjects, DWL and DWLP group subjects had high odds ratios (ORs) for hypertension (HT) (2.23 and 2.92, respectively) and CKD (1.40 and 2.41, respectively). After adjustment for potential confounders, the ORs of CKD for DWLs remained significant (1.13 and 1.43, p<0.05). DWLs and DWLP were associated with low cognitive scale scores and increased CKD. In conclusion, CKD was associated with DWLs and DWLP as an independent risk factor and a lower level of cognitive function 5 years after CKD was identified. Successful CKD therapy may be expected to prevent DWLP.

Depressive symptoms as a side effect of Interferon-α therapy induced by induction of indoleamine 2,3-dioxygenase 1.

Depression is known to occur frequently in chronic hepatitis C viral (HCV) patients receiving interferon (IFN)-α therapy. In this study, we investigated whether indoleamine 2,3-dioxygenase1 (IDO1)-mediated tryptophan (TRP) metabolism plays a critical role in depression occurring as a side effect of IFN-α therapy. Increases in serum kynurenine (KYN) and 3-hydroxykynurenine (3-HK) concentrations and in the ratios of KYN/TRP and 3-HK/kynurenic acid (KA) were much larger in depressive HCV patients than in non-depressed patients following therapy. Furthermore, transfection of a plasmid continuously expressing murine IFN-γ into normal mice significantly increased depression-like behavior. IFN-γ gene transfer also resulted in a decrease in serum TRP levels in the mice while KYN and 3-HK levels were significantly increased in both serum and frontal cortex. Genetic deletion of IDO1 in mice abrogated both the increase in depression-like behavior and the elevation in TRP metabolites’ levels, and the turnover of serotonin in the frontal cortex after IFN-γ gene transfer. These results indicate that the KYN pathway of IDO1-mediated TRP metabolism plays a critical role in depressive symptoms associated with IFN-α therapy.

Determinants of brachial-ankle pulse wave velocity in a Japanese population: a cohort study.

Abstract Arterial stiffness is one of the biggest predictors of coronary heart disease (CHD). We evaluated whether brachial–ankle pulse wave velocity (baPWV) and augmentation index (AI) are correlated with risk factors of CHD. All of the 528 participants (270 males and 258 females) in this study were healthy workers aged from 36 to 69 (mean age: 47.9 ± 8.1 years). The Framingham Risk Score (FRS) showed a good correlation with baPWV (r = 0.53, p < 0.01), indicating that FRS is also applicable as an index of arterial stiffness in Japanese people. Blood pressures were well controlled in patients with medical treatment for hypertension; however, vessels remained relatively still stiff, whereas the AI was considerably low. Multivariate linear regression analysis showed that factors of such as FRS, body mass index, alcohol consumption and AI P75 were significantly correlated with baPWV.

Effect of Histone Acetylation on N-Methyl-D-Aspartate 2B Receptor Subunits and Interleukin-1 Receptors in Association with Nociception-Related Somatosensory Cortex Dysfunction in a Mouse Model of Sepsis.

ABSTRACT Whole-body inflammation (i.e., sepsis) often results in brain-related sensory dysfunction. We previously reported that interleukin (IL)-1 resulted in synaptic dysfunction of septic encephalopathy, but the underlying molecular mechanisms remain unknown, as do effective treatments. Using mice, we examined immunohistochemistry, co-immunoprecipitation, enzyme-linked immunosorbent assay, and behavior analyses, and investigated the role of the N-methyl-D-aspartate 2B subunit (NR2B) of NMDA receptor, IL-1 receptor, and histone acetylation in the pathophysiology underlying sensory dysfunction induced by lipopolysaccharide (LPS). Mice groups of sham-operated, LPS, LPS with an NR2B antagonist, or LPS with resveratrol (a histone acetylation activator) were analyzed. We found that LPS increased NR2B and interleukin-1 receptor (IL-1R) immunoreactivity. The expression of Iba1, a marker for microglia and/or macrophages, increased more significantly in the brain than in the spinal cord, implicating NR2B and IL-1R in brain inflammation. Immunoprecipitation with NR2B and IL-1R revealed related antibodies. Blood levels of IL-1&bgr; (i.e., the IL-1R ligand) increased, though not significantly, suggesting that inflammation peaked at 20 h. Behavioral assessments of central (CNS) and peripheral sensory (PNS) function indicated that LPS delayed CNS but not PNS escape latency. Finally, NR2B antagonist or resveratrol in the lateral ventricle antagonized the effects of LPS in the brain and improved animal survival. In summary, histone acetylation may control expression of NR2B and IL-1R, alleviating inflammation-induced sensory neuronal dysfunction caused by LPS.

L/T-type and L/N-type calcium-channel blockers attenuate cardiac sympathetic nerve activity in patients with hypertension

Abstract Sympathetic nerve activity is augmented by calcium-channel blocker treatment as a result of decreased blood pressure. Dihydropyridine calcium-channel blockers are divided into three different types. The purpose of the present study was to investigate whether treatment effects on hemodynamics, cardiac autonomic nerve activity and plasma norepinephrine levels differ among amlodipine (L type), efonidipine (L + T type) and cilnidipine (L + N type). We enrolled 14 hypertensive patients (seven males, seven females, 70 ± 6 years old) undergoing a monotherapy of amlodipine, efonidipine or cilnidipine into this prospective, open-labeled, randomized, crossover study. At baseline and every 6 months of the treatment period, we repeated the evaluation of hemodynamics, spectral analysis of heart rate variability and plasma norepinephrine levels. Blood pressure and pulse rate were comparable among the three treatments. The low-frequency (LF)/high-frequency (HF) power ratio, an index of cardiac sympathovagal balance, was significantly lower with efonidipine and cilnidipine than with amlodipine, while the HF/total power ratio, an index of cardiac vagal activity, revealed the opposite results. There was no significant correlation between the LF/HF ratio and plasma norepinephrine levels. Antihypertensive monotherapy with efonidipine or cilnidipine attenuates cardiac sympathetic nerve activity more effectively than amlodipine monotherapy.

TGF-beta1 is associated with the progression of intracranial deep white matter lesions: a pilot study with 5 years of magnetic resonance imaging follow-up

Abstract Objectives: Elevated expression of transforming growth factor (TGF)-beta1 has been reported in hereditary cerebral small-vessel (HCSV) disease. The aim of this study was to clarify whether TGF-beta1 is a risk factor for intracranial deep white matter lesions (DWLs) and their progression in a general elderly population. Methods: The subjects included 81 participants (Groups DWL, DWLP, and C) who had voluntarily undergone a health examination and brain magnetic resonance imaging (MRI) in 2003 and 2008 and 43 age-matched patients with previous symptomatic brain infarctions. Deep white matter lesions were graded from Grade 0 to 3 according to the Fazekas classification. Group DWL (23 subjects) was defined as DWLs with no progression in the grade level, and Group DWLP (progression of DWL) (12 subjects) was defined as DWLs with an increase in one or more grade number and an apparent worsening of Grade 3. Forty-six age-matched control subjects with consistent normal brain MRI were included in Group C. The associations between DWLs and various vascular risk factors, including peripheral blood TGF-beta1 levels, were examined. Results: In addition to the classical risk factors, the highest TGF-beta1 levels were found in Group DWLP. The TGF-beta1 levels were significantly higher in Group DWLP than in Group DWL, and DWLP was significantly correlated with elevated TGF-beta1 levels (odds ratio [OR]  =  1·72). Conclusions: The present data suggest that TGF-beta1 may be important in the pathogenesis and progression of DWLs, and it is expected to be useful as a clinical indicator reflecting the presence of intracranial white matter lesions.

Matrix Metalloproteinase-9 Triggers the Gap Junction Impairment and Somatosensory Neuronal Dysfunction in Septic Encephalopathy

Although septic encephalopathy leads to be the devastating neurological symptoms including sensory dysfunction, cognitive impairment and unconsciousness, potent substrates and their effects inducing the synaptic dysfunction remain obscure. In this study, we successfully characterized the sensory dysfunction with immunohistochemistry, immunoblotting and electrophysiology. A mouse model of septic encephalopathy was examined at 20 hrs after cecal ligation and puncture or intraperitoneal injection of lipopolysaccharide (1 mg). We found several effects of active enzyme of matrix metalloproteinases-9 (active MMP-9) on the somatosensory cortex, thalamus and prefrontal cortex related to the sensory functions in septic encephalopathy. At first, active MMP-9 was up-regulated. Second, both of the occludin, tight junction protein composing blood brain barrier, and the connexin-43, transmembrane protein of gap junction, which were potent substrate of active MMP-9, were disrupted. Third, the evoked local field potentials in cortical and thalamic neurons were impeded during sensory neuronal stimulation. Conversely, matrix metalloproteinase inhibitor GM6001 significantly protected the reduction of occludin, connexin-43 and the regression of neuronal activities. In conclusion, MMP-9 is a prerequisite candidate for protection of the junction proteins reduction and for the potent therapeutics in the sensory dysfunction in septic encephalopathy.

Ensuring Adequate Human Medical Resources during an Avian Influenza A/H5N1 Pandemic

INTRODUCTION When countermeasures are taken against an avian influenza (AI) pandemic in a hospital, it is essential to know the potential number of staff who would choose to be absent. The purpose of this study was to clarify how many medical staff would be willing to work during a pandemic, and requirements to secure adequate human resources. METHODS From September to December 2008, a total of 3,152 questionnaires were sent to five private hospitals and one public hospital, which represent the core hospitals in the regions of Kyoto, Osaka, and Hyogo Prefectures. Participants consisted of hospital staff including: (1) physicians; (2) nurses; (3) pharmacists; (4) radiological technologists (RTs); (5) physical therapists (PTs); (6) occupational therapists (OTs); (7) clinical laboratory technologists (CLTs); (8) caregivers; (9) office clerks; and (10) others. They were queried about their attitude toward pandemics, including whether they would come to the hospital to work, treat patients, and what kinds of conditions they required in order to work. RESULTS A total of 1,975 persons (62.7%) responded. A total of 204 persons (10.6%) would not come to the hospitals during a pandemic, 363 (18.8%) would perform their duties as usual, unconditionally, 504 (26.1%) would come to hospitals but not treat AI patients, and 857 (44.5%) would report to the hospital and treat AI patients with some essential conditions. These essential conditions were: (1) personal protective equipment (PPE) (80.0%); (2) receipt ofworkmens compensation (69.3%); (3) receipt of anti-virus medication (58.2%); and (3) receipt of pre-pandemic vaccination (57.8%). CONCLUSION During a pandemic, all types of health professionals would be lacking, not only physicians and nurses. This study indicates that ensuring sufficient medical human resources would be difficult without the provision of adequate safety and compensation measures.

In Vivo Imaging of Septic Encephalopathy

Septic encephalopathy is a devastating symptom of severe sepsis. Many studies have been performed to uncover the pathophysiological mechanisms of septic encephalopathy; however, novel technical approaches are still required to overcome this complex symptom. Because patients are suffering from severe cognitive impairment, coma, or delirium, which burden not only patients but also caregivers, overcoming septic encephalopathy is still a major social problem worldwide, especially in the intensive care. Septic encepha‐ lopathy seems to be caused by cytokine invasion and/or oxidative stress into the brain, and this pathological state leads to imbalance of neurotransmitters. In addition to this pathophysiology, septic encephalopathy causes complicated symptoms (e.g., ischemic stroke, edema, and aberrant sensory function). For these pathophysiological mecha‐ nisms, electrophysiology using animal models, positron emission tomography (PET), computed tomography, and magnetic resonance imaging for septic patients has provided important clues. However, the research for septic encephalopathy is currently confronted with the difficulty of complex symptoms. To overcome this situation, in this chapter, we introduce our novel methods for in vivo imaging of septic encephalopathy using near infrared (NIR) nanoparticles, quantum dots. In addition to our recent progress, we propose a strategy for the future approach to in vivo imaging of septic encephalopathy.

A Cross-Sectional Study of Familial Clustering in Hyperhomocysteinemia

Background: Hyperhomocysteinemia is correlated with diseases and lifestyle habits. However, there is no epidemiological evidence concerning the distribution and prevalence of hyperhomocysteinemia in a local community. Objective: The purpose of this study was to clarify the distribution and prevalence of hyperhomocysteinemia and the existence or nonexistence of familial clustering. Methods: The subjects were participants in the Basic Health Check Service 1999. We administered a questionnaire and obtained blood samples from 865 subjects (306 men, 559 women) who agreed to participate in our study. Results: Hyperhomocysteinemia was present in 52 men (17.0%) and 25 women (4.5%). Ten subjects who had hyperhomosysteinemia ha a family member who also had hyperhomocysteinemia. The odds ratio for hyperhomocysteinemia adjusted for age and sex was 4.77 (p < 0.01, 95% CI = 1.95–11.65). Conclusion: Hyperhomocysteinemia shows familial clustering. Men and elderly persons were more likely to have hyperhomocysteinemia.