The death due to liver diseases accounts for more the 35,000 cases every year in Japan for decades. Among these liver diseases, the Ministry of Health, Labor, and Welfare of Japan has named both fulminant hepatitis and primary biliary cirrhosis (PBC) as intractable liver diseases, since the precise mechanism of these diseases are unclear. Accordingly, there are no effective medical treatments other than liver transplantation toward these diseases. However, still the number of the liver transplantation performed in Japan is small. Thus, we have focused on the pathogenesis of these two intractable conditions. The fulminant hepatitis is a distinct form of acute hepatitis, and hepatitis B virus infection accounts for 20~30% of this lethal condition. Only tiny proportions of patients with acute HBV infection develop fulminant hepatitis (less than 10%). It has been widely believed both viral and host factors contribute for fulminant hepatitis, although still unknown factors are expected to be involved. On the other hand, PBC is a chronic progressive cholestatic liver disease. Clinical features of PBC include female predominance (80 to 90%), the presence of antimitochondrial antibody (up to 95%), and elevated serum levels of immunoglobulin M. Eventually, patients with PBC will develop liver failure due to biliary cirrhosis in spite of medical interventions. Immune-mediated processes are believed to be responsible for the pathogenesis, although the precise mechanism is yet to be determined. In this review article, our endeavors to understand the mechanism of these intractable liver diseases are discussed.
Rapid eye movement (REM) sleep behavior disorder (RBD) is parasomnia characterized by REM sleep without atonia (RWA) and elaborate motor activity in association with dream mentation. Periodic leg movement during sleep (PLMS) is observed in a large share of patients with RBD, suggesting a common pathology: dopaminergic dysfunction. This study was undertaken to evaluate the effectiveness and mechanism of action of pramipexole, a dopamine agonist, on RBD symptoms. Fifteen patients (57-75 years old) with RBD with a PLMS index of more than 15 events/h shown by nocturnal polysomnography were enrolled. Sleep variables, the score of severity for RBD symptoms, REM density, and PLM index were compared before and after one month or more of consecutive pramipexole treatment. Correlation analysis was conducted between the rate of change in RBD symptoms and the rate of reduction of REM density. Fourteen patients with RBD (80.0%) achieved symptomatic improvement of RBD with pramipexole treatment, which reduced REM density and PLM index during non-REM sleep despite the unchanged amount of RWA. The rate of change in RBD symptoms correlated positively with the rate of REM density reduction. Significant reduction of the PLM index was observed in non-REM sleep but not in REM sleep. Pramipexole can improve RBD symptoms, possibly because of changes in dream contents or its amount manifested as the reduction of REM density. The restricted influence of pramipexole on PLMS only during non-REM sleep suggests that other factors may affect the pathophysiology of PLMS during the REM sleep period in RBD.
Epicardial adipose tissue (EAT), localized beneath the visceral pericardium, is a metabolically active endocrine and paracrine organ with possible interactions within the heart. Recent studies identified possible roles of uric acid (UA)-induced oxidative stress and increased inflammatory status in the pathogenesis of ascending aortic dilatation. The aim of this study was to investigate whether EAT is an independent factor for ascending aortic dilatation. The patients were evaluated by a complete transthoracic echocardiographic examination including measurements of EAT and aortic dimensions. Serum levels of UA and C-reactive protein and EAT thicknesses were compared in 38 patients with dilated ascending aorta (DAA) (the diameter ≥ 37 mm) vs. 107 subjects with normal aortic diameter (AD) of < 37 mm. EAT thickness was significantly higher in DAA group compared to normal AD group (8.3 ± 2.7 vs. 5.4 ± 2.2 mm, p < 0.001) as well as age (53 ± 10 vs. 48 ± 9 years, p = 0.004), the presence of hypertension (54% vs. 30%, p = 0.009) and UA levels (6.0 ± 1.4 vs. 5.2 ± 1.1 mg/dL, p < 0.001). There was a strong correlation between EAT thickness and ascending aortic diameter (r = 0.521, p < 0.001). In multiple logistic regression analysis, EAT thickness (OR: 1.429, p = 0.006), body mass index (OR: 1.169, p = 0.014) and UA levels (OR: 1.727, p = 0.023) were independently correlated to ascending aortic dilatation. We therefore propose that increased EAT thickness is an independent predictor of ascending aortic dilation.
Hashimoto thyroiditis (chronic autoimmune thyroiditis) is the most common form of thyroiditis in childhood. Previous studies have found autonomic dysfunction of varying magnitude in patients with autoimmune diseases, which is considered a cardiovascular risk factor. We aimed to evaluate the heart rate variability (HRV), a measure of cardiac autonomic modulation, in children with euthyroid Hashimoto thyroiditis (eHT). The study included 32 patients with eHT (27 girls and 5 boys; mean age 11 ± 4.1 years, range 8-16; body mass index 0.47 ± 0.69 kg/m2), as judged by normal or minimally elevated serum TSH levels (normal range: 0.34-5.6 mIU/l) and normal levels of free thyroid hormones (FT4 and FT3) and 38 euthyroid age-matched controls. Patients with eHT and control subjects underwent physical examination and 24-hour ambulatory ECG monitoring. Time-domain parameters of HRV were evaluated for cardiac autonomic functions. Children with eHT displayed significantly lower values of time-domain parameters of SDANN (standard deviation of the averages of NN intervals), RMSSD (square root of the mean of the sum of the squares of differences between adjacent NN intervals), NN50 counts (number of pairs of adjacent NN intervals differing by more than 50 ms) and PNN50 (NN50 count divided by the total number of all NN intervals) for each 5-min interval, compared to healthy controls (p < 0.05 for each), indicating the decreased beat-to-beat variation of heart rate. In conclusion, eHT is associated with disturbed autonomic regulation of heart rate. Hence, the children with eHT are at higher risk for developing cardiovascular diseases.
Hypoxia-inducible factor (HIF) is a transcription factor that regulates cellular hypoxic responses. Despite the therapeutic benefits of cyclosporine A (CsA) in organ transplantation, its clinical use is limited due to chronic nephropathy. We investigated whether HIF activation by cobalt could improve CsA-induced nephropathy, and investigated the related mechanism. In animal experiments, rats were kept on a 0.05% low-salt diet and administered CsA subcutaneously for 28 days (15 mg/kg/day). They also received cobalt (10 mg/kg/day) during the entire experimental period. The administration of cobalt significantly increased HIF-1α expression in the kidney. The increased expression of HIF-1α ameliorated CsA-induced afferent arteriolopathy and tubulointerstitial injury in the kidney. Cobalt significantly reduced the infiltration of macrophages/monocytes into the renal tubulointerstitium. In addition, HIF activation by cobalt reduced the number of CsA-induced apoptotic cells in the kidney. Subsequently, HK-2 human renal tubular epithelial cells were used for in vitro experiments. They were pre-treated with 150 μM of cobalt to activate HIF, and then exposed to 10 μM CsA. HIF activation by cobalt decreased the CsA-induced apoptosis in HK-2 cells, as judged by the decreases in the number of apoptotic cells, pro-apoptotic caspase-3 activity, and the expression level of cleaved caspase-3, together with the increase in the expression of anti-apoptotic bcl-2. Cobalt pretreatment also reduced the CsA-induced phosphorylation of NF-κB and the CsA-induced expression of vimentin and α-smooth muscle actin, suggesting the attenuation of inflammation and fibrosis. In conclusion, the activation of HIF by cobalt may ameliorate the CsA-induced nephropathy by inhibiting apoptosis, inflammation, and fibrosis.
The insula, one of the five cerebral lobes of the brain, is located deep within the brain and lies mainly beneath the temporal lobe. Insular epilepsy can be easily confused and misdiagnosed as temporal lobe epilepsy (TLE) because of the similar clinical symptoms and scalp electroencephalography (EEG) findings due to the insula location and neuronal connections with the temporal lobe. Magnetoencephalography (MEG) has higher sensitivity and spatial resolution than scalp EEG, and thus can often identify epileptic discharges not revealed by scalp EEG. Simultaneous scalp EEG and MEG were performed to detect and localize epileptic discharges in two patients known to have insular epilepsy associated with cavernous angioma in the insula. Epileptic discharges were detected as abnormal spikes in the EEG and MEG findings. In Patient 1, the sources of all MEG spikes detected simultaneously by EEG and MEG (E/M-spikes) were localized in the anterior temporal lobe, similar to TLE. In contrast, the sources of all MEG spikes detected only by MEG (M-spikes) were adjacent to the insular lesion. In Patient 2, the sources of all MEG spikes detected simultaneously by EEG and MEG (E/M-spikes) were localized in the anterior temporal lobe. These findings indicate that MEG allows us to detect insular activity that is undetectable by scalp EEG. In conclusion, simultaneous EEG and MEG are helpful for detecting spikes and obtaining additional information about the epileptic origin and propagation in patients with insular epilepsy.
A common finding in patients admitted to an Intensive Care Unit (ICU) is hyperglycemia without prior history of diabetes. This increase in blood glucose is considered a negative prognostic factor for patients in the ICU. Hence, we performed a retrospective cohort study in patients admitted at the ICU of the National Institute of Respiratory Diseases (INER) in a 7-month period; we collected data about their blood glucose concentration during their stay at the ICU. We gathered the available medical records of 30 patients out of 58 admitted to the ICU. Among the 30 patients, 21 patients survived (70%) and 9 patients with community-acquired pneumonia (CAP) died (30%). The 21 surviving patients included 17 patients with acute respiratory distress secondary to CAP and 4 patients with asthmatic crisis upon admission to the ICU. After admission, all patients progressed to sepsis and showed an increase in blood glucose. We detected higher glucose concentrations in deceased patients (147 mg/dl ± 4.23), as compared to surviving patients (129 mg/dl ± 2.17) (P < 0.001). In addition, the percentage of lymphocytes was lower in deceased patients than that in surviving patients (5.7 vs. 11.8%, P < 0.001), whereas percentage of neutrophils was elevated in the deceased patients (90.7 vs. 80.9%, P < 0.001). It is therefore important to measure continuously glucose concentrations, as well as the numbers of neutrophils and lymphocytes in critically ill patients with hyperglycemia. Such a simple monitoring plan may prevent fatal complications in patients admitted to ICU.
Fibroblast growth factor receptor 2 (FGFR2) plays an important role in tumor cell growth, invasiveness, motility, and angiogenesis. Several single-nucleotide polymorphisms (SNPs) in the second intron of the FGFR2 gene are associated with the risk of breast cancer. In this study, we determined whether these SNPs of the FGFR2 gene are associated with early onset of non-familial breast cancer in a Chinese Han population. Recruited were 118 female breast cancer patients who were less than or equal to 35 years of age and without a family history of breast cancer, and 104 age-matched healthy controls. Six SNPs of the second intron of the FGFR2 gene, including rs2981428C/A (i.e., a change at this particular site from nucleotide C to A), rs11200014G/A, rs2981579C/T, rs1219648A/G, rs2420946C/T, and rs2981582C/T, were detected using matrix-assisted laser desorption/ionization mass spectrometry. The data showed that the homozygotes at each minor allele, rs11200014 (AA), rs1219648 (GG), rs2420946 (TT), and rs2981582 (TT), were significantly associated with an increased risk of early-onset non-familial breast cancer. The haplotype containing rs11200014A, rs1219648G, rs2420946T and rs2981582T also exhibited a significantly higher distribution in patients compared to controls (OR = 1.784, 95% CI = 1.161-2.744). In stratified analyses, each of the above four SNPs conferred a signicantly greater risk of estrogen receptor-positive breast cancer, compared to estrogen receptor-negative breast cancer that is more resistant to treatment. Our data demonstrate that these four SNPs of the FGFR2 gene are associated with the risk of breast cancer at a young age in Chinese Han women.
Adipose tissue-derived stem cells (ADSCs) are a promising source of autologous stem cells that are used for regeneration and repair of infracted heart. However, the efficiency of their transplantation is under debate. One of the possible reasons for marginal improvement in ADSCs transplantation is the significant cell death rate of implanted cells after being grafted into injured heart. Therefore, overcoming the poor survival rate of implanted cells may improve stem cell therapy. Due to limited improvement concerning direct stem cell therapy, gene-transfer methods are used to enhance cellular cardiomyoplasty efficacy. Heme oxygenase-1 (HO-1) can provide various types of cells with protection against oxidative injury and apoptosis. However, exact effects of autologous ADSCs combined with HO-1 on cardiac performance remains unknown. In this study, rabbits were treated with ADSCs transduced with HO-1 (HO-1-ADSCs), treated with non-transduced ADSCs, or injected with phosphate buffered saline 14 days after experimental myocardial infarction was induced, when autologous ADSCs were obtained simultaneously. Four weeks after injection, echocardiography showed significant improvements for cardiac functions and left ventricular dimensions in HO-1-ADSCs-treated animals. Structural consequences of transplantation were determined by detailed histological analysis, which showed differentiation of HO-1-ADSCs to cardiomyocyte-like tissues and lumen-like structure organizations. Apart from improvement in angiogenesis and scar areas, more connexin 43-positive gap junction and greater tyrosine hydroxylase-positive cardiac sympathetic nerves sprouting were observed in the HO-1-ADSCs-treated group compared with ADSCs group. These data suggest that the transplantation of autologous ADSCs combined with HO-1 transduction is a feasible and efficacious method for improving infarcted myocardium.