Impaired Consciousness in a Coronavirus Disease 2019 Patient Caused by Low Serum Sodium: A Case Report.

A 30 year-old man with a high fever (37.5°C-40°C), vomiting, slurred speech, and mild cognitive impairment was admitted to our Emergency Department. He had traveled from Spain to the UK on business at the end of February 2020. A nasopharyngeal swab was positive by RT-PCR for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but a cerebrospinal fluid (CSF) sample was negative. His neurological abnormalities recovered completely on saline infusion to normalize his low serum sodium level. Although neurological abnormalities in patients with COVID-19 are rare, it is important to distinguish the etiologies including encephalitis, meningitis, or merely electrolyte abnormalities.

Efficient induction of apoptosis by wee1 kinase inhibition in hepatocellular carcinoma cells.

Transforming growth factor-ß1 (TGF-ß1) potently inhibits human hepatocellular carcinoma (HCC) cell growth. Here we demonstrated that TGF-ß1-induced apoptosis is mediated by decreased phosphorylation of cdc2 at Tyr15 accompanied by down-regulation of Wee1 kinase expression. As expected from these results, a Wee1 kinase inhibitor efficiently induced apoptosis in HCC cells in the absence of TGF-ß1 treatment. In surgically resected samples, Wee1 kinase was expressed in moderately to poorly differentiated HCC, whereas no Wee1 kinase expression was observed in non-cancerous tissue, including cirrhotic tissue. Our results suggest that Wee1 kinase inhibitors may be a practical novel therapeutic option against advanced HCC.

Risk factors associated with Barrett's epithelial dysplasia.

AIM: To elucidate risk factors associated with dysplasia of short-segment Barrett's esophagus (BE). METHODS: A total of 151 BE patients who underwent endoscopic examination from 2004 to 2008 in Aoyama Hospital, Tokyo Women's Medical University, Japan and whose diagnosis was confirmed from biopsy specimens were enrolled in the study. BE was diagnosed based on endoscopic findings of gastric-appearing mucosa or apparent columnar-lined esophagus proximal to the esophagogastric junction. Dysplasia was classified into three grades - mild, moderate and severe - according to the guidelines of the Vienna Classification System for gastrointestinal epithelial neoplasia. Anthropometric and biochemical data were analyzed to identify risk factors for BE dysplasia. The prevalence of Helicobacter pylori (H. pylori) infection and the expression of p53 by immunohistological staining were also investigated. RESULTS: Histological examination classified patients into three types: specialized columnar epithelium (SCE) (n = 65); junctional (n = 38); and gastric fundic (n = 48). The incidence of dysplasia or adenocarcinoma from BE of the SCE type was significantly higher than that of the other two types (P < 0.01). The univariate analysis revealed that sex, H. pylori infection, body weight, p53 overexpression, and low diastolic blood pressure (BP) were associated with BE dysplasia. In contrast, body mass index, waist circumference, metabolic syndrome complications, and variables related to glucose or lipid metabolism were not associated with dysplasia. Multivariate logistic analysis showed that overexpression of p53 [odds ratio (OR) = 13.1, P = 0.004], H. pylori infection (OR = 0.19, P = 0.066), and diastolic BP (OR = 0.87, P = 0.021) were independent risk factors for epithelial dysplasia in BE patients with the SCE type. CONCLUSION: Overexpression of p53 is a risk factor for dysplasia of BE, however, H. pylori infection and diastolic BP inversely associated with BE dysplasia might be protective.

Transdifferentiation of human fibroblasts into hepatocyte-like cells by defined transcriptional factors.

PURPOSE: Liver transplantation is currently the only curative therapeutic option for end-stage liver cirrhosis. However, due to the limitations of donor liver availability and occasional rejection, it cannot always be successfully applied. In this study, we determined whether fibroblasts can be transdifferentiated into hepatocyte-like cells by transcription factors that initiate and maintain hepatocyte differentiation. METHODS: Fibroblasts were transduced with retrovirus vectors carrying FOXA2, HNF4α, and C/EBPß. To enhance the efficiency of transdifferentiation, cMyc was also expressed. RESULTS: Transdifferentiation was successful using both neonatal fibroblasts and human forehead fibroblasts. The transdifferentiated cells produced hepatocyte-specific proteins such as albumin and cytochrome, and had important hepatocyte-specific functions, such as glycogen storage and indocyanine green uptake, suggesting that the cells function at least as partial hepatocytes. CONCLUSIONS: These results provide a novel method of generating differentiated hepatocyte-like cells, and may represent an alternative source of cells for future cell-based therapeutics for end-stage liver diseases.

Low-dose aspirin delays gastric healing after Helicobacter pylori eradication.

BACKGROUND AND AIM: Helicobacter pylori (H. pylori) and aspirin are the major causes of gastric injury, and eradication of H. pylori can restore mucosal injury such as gastric ulcer. The aim of the present study was to investigate the effects of low-dose aspirin on the healing process, determined by endoscopic features, after H. pylori eradication. METHODS: From 2001 to 2008, 12,887 patients underwent endoscopic examination at our hospital. From these, 100 patients with and 100 patients without H. pylori infection were analyzed to identify the endoscopic features characteristic of H. pylori-infected stomach. Based on these characteristic features, we observed the healing process of 89 patients not taking low-dose aspirin and 12 patients taking low-dose aspirin for 6 months, 1 year, and 5 years, which was successful in eradicating H. pylori. RESULTS: Diffuse redness (DR) of the fundic mucosa was the characteristic feature of H. pylori-infected stomach, whereas reddish streaks (RS) on the greater curvature of the antrum was the characteristic finding in non-infected stomach. In the no aspirin group, DR faded by 6 months and new expression of RS was observed 1 year after H. pylori eradication. In contrast, in the aspirin group, both fading of DR and the expression of RS were observed 5 years after eradication. CONCLUSION: Low-dose aspirin delayed the early phase of the healing process in the gastric mucosa after H. pylori eradication.

Toxic hepatitis induced by show-wu-pian, a Chinese herbal preparation.

Herbal preparations are widely available and often regarded by the public as harmless remedies for a variety of medical ailments. However, some of these products or their metabolites can cause adverse effects such as liver damage. In this case report a 53-year-old female taking shou-wu-pian for 8 months presented with acute hepatitis. Histopathological assessment of liver tissue obtained by biopsy was consistent with a toxic reaction. Clinical and biochemical resolution was brought about following cessation of the drug. It is important for clinicians to consider Chinese herbal preparations as a potential cause of abnormal liver function test results.

Nonalcoholic fatty liver is a risk factor for postprandial hyperglycemia, but not for impaired fasting glucose.

PURPOSE: The first aim of this study was to elucidate the relationship between impaired glucose tolerance (IGT) and nonalcoholic fatty liver. The second was to make a rule regarding to whom 75-g oral glucose tolerance tests (OGTTs) should be applied to identify subjects with IGT and diabetes mellitus (DM) in the annual check-up at the human dry dock. METHODS: A total of 716 subjects who visited the Department of General Medicine of the International Medical Center of Japan from May 2001 through January 2008 for an annual check-up at the human dry dock were analyzed. We evaluated risk factors related to nonalcoholic fatty liver using multivariate logistic regression analysis and compared the difference of body mass index (BMI) and glucose level at 75-g OGTT at two different time points in subjects whose fatty change had improved or worsened. RESULTS: Nonalcoholic fatty liver was strongly related to 2-h- and 1-h-post-challenge glucose level (P<0.0001 and P=0.018, respectively), but not fasting plasma glucose (FPG) (P=0.706). The risk factors for IGT were nonalcoholic fatty liver (P<0.05), low levels of high-density lipoprotein cholesterol (HDL-C) (P=0.026) and age (P=0.013). A clearly positive relationship was observed between the difference of BMI and 2-h-post-challenge glucose level among the subjects whose fatty change had improved or worsened (R=0.6, P=0.018). CONCLUSIONS: Nonalcoholic fatty liver was clearly related to the 2-h- or 1-h-post-challenge glucose level, but not to FPG, in 75-g OGTT, and this IGT was corrected by body weight reduction in accordance with diminished nonalcoholic fatty liver. Thus, 75-g OGTT should be applied to subjects with nonalcoholic fatty liver to evaluate IGT.

High-sensitivity C-reactive protein as a serum predictor of nonalcoholic fatty liver disease based on the Akaike Information Criterion scoring system in the general Japanese population.

BACKGROUND: High-sensitivity C-reactive protein (hs-CRP) has been developed and used as a marker to predict coronary vascular diseases in metabolic syndrome (MS). We investigated whether serum hs-CRP concentration was associated with nonalcoholic fatty liver disease (NAFLD) based on the Akaike Information Criterion (AIC) scoring system, using patients from the human dry dock program. METHODS: From 2004 to 2005, 1254 subjects visited our human dry dock annual checkup program. We excluded from this study individuals with markers of viral hepatitis and those whose alcohol consumption was more than 20 g/week. Finally, 230 subjects (93 men and 137 women) were investigated. Serum hs-CRP concentrations were measured using a highly sensitive latex agglutination assay system. The AIC scoring system with the CATDAP-20 program was introduced to evaluate the parameters that are present frequently in NAFLD. RESULTS: NAFLD was diagnosed by ultrasound sonography in 35.4% of the men and 18.9% of the women. High serum hs-CRP concentrations were observed in women with NAFLD (normal: NAFLD = 0.45:1.47 mg/l, P < 0.05). Body mass index (BMI), waist circumference, and body weight had the three lowest AIC score (P = 4.5e(-19) to 2.6e(-16)). hs-CRP was the third lowest variable among the serum markers associated with NAFLD (P = 2.3e(-6)) In addition, the hs-CRP concentration was correlated strongly with triglyceride values in females with NAFLD and with fasting blood glucose, HbA1c, and waist/hip ratio in males with NAFLD (P < 0.05). CONCLUSIONS: The serum hs-CRP concentration was a strong predictor for NAFLD with a low AIC score and correlated with serum markers that indicated lipid and glucose metabolism.

An analysis of risk factors for asymptomatic cerebral infarction.

OBJECTIVE: The aim of this study is to identify risk factors for asymptomatic cerebral infarction (ACI) in the general Japanese population. MATERIALS AND METHODS: A total of 634 subjects (272 men aged 55.4+/-8.8 years and 362 women aged 55.2+/-8.5 years) who visited the Health Management Center at Aoyama Hospital (Tokyo, Japan) from January 2004 through January 2005 for an annual brain dry dock examination were analyzed. We evaluated 21 risk factors for ACI by multivariate logistic regression analysis. RESULTS: Abnormal or potentially abnormal conditions were detected in 258 subjects (40.7% of all subjects who had an annual check-up program for brain disease). The most frequent abnormal finding was ACI, which was observed in 208 subjects. The significant risk factors for ACI, as determined by multivariate logistic analysis, were age (P <0.01), hypertension (P <0.01), and hypertensive vascular changes in the fundus (P <0.05). CONCLUSION: The hypertensive vascular abnormalities in the fundus might be a risk factor for ACI independent of age and hypertension.

Clinical significance of fatty liver associated with metabolic syndrome.

AIM: Metabolic syndrome (MS) has been recognized as a high-risk disorder that leads to life-threatening diseases, such as coronary vascular disease. The aim of the present study was to investigate the association of fatty liver (FL) with MS in order to establish an effective treatment for FL. METHODS: One thousand two hundred and fifty-four individuals (694 males, 560 females) who visited the Department of General Medicine, International Medical Center of Japan for a human dry dock annual check-up from 2000 to 2004 were analyzed. RESULTS: FL was diagnosed in 41.5% of the males and 10.7% of the females, with the prevalence rate increasing in postmenopausal females over 55 years old. High body mass index and waist circumference were observed in those with FL, whereas body mass index reduction was strongly correlated with a decrease in alanine aminotransferase level (R = 0.6,P < 0.01). MS complications were more common in subjects with FL and the most common initial events of MS were shown to be obesity, hyperlipidemia and FL, followed by glucose intolerance and hypertension. Subjects with FL showed a higher level of high-sensitivity C-reactive protein (hs-CRP) (normal: FL = 0.38: 0.73 mg/L, P < 0.05), which was strongly correlated with serum markers that indicated lipid and glucose metabolism in females with FL (R = 0.61-0.77, P < 0.05). CONCLUSIONS: FL could be a part of or, at least, a predictor of MS. Further, bodyweight reduction is an effective treatment for FL.

Primary hepatocyte survival on non-integrin-recognizable matrices without the activation of Akt signaling.

The suppression of the detachment-induced cell death (anoikis) by the interaction between the cells and extracellular matrix (ECM) is necessary for the application of liver tissue engineering because the disruption of interaction with ECM leads hepatocytes to anoikis. It has been considered, in general, that integrin signal plays an important role in the hepatocyte survival although hepatocytes survive on some types of non-integrin-recognizable matrices, such as poly(N-p-vinylbenzyl-4-O-beta-D-galactopyranosyl-D-gluconamide) (PVLA) and poly-L-lysine (PLL) for several days without the serum. Anoikis was suppressed in the non-adherent culture of hepatocytes isolated from gld/gld mouse, indicating that Fas signal induces hepatocyte anoikis. Fas production is decreased in the adherent culture of hepatocytes on both integrin- and non-integrin-recognizable matrices. Akt activation was hardly observed in the adherent culture of hepatocytes on non-integrin-recognizable matrices whereas the activation occurred in the adherent culture on integrin-recognizable matrices. In the adherent culture of hepatocytes on non-integrin-recognizable matrices, Akt does not contribute to the hepatocyte survival. To prolong the viability of hepatocytes in the adherent culture on PVLA matrix on which hepatocytes maintain their functions for longer period than those on PLL matrix, it might be a good approach to activate Akt signaling pathway.

A murine model of acute liver injury induced by human monoclonal autoantibody.

We have previously reported an immunoglobulin (Ig) M autoantibody to hepatocyte-related 190-kd molecules in patients with type 1 autoimmune hepatitis (AIH). This molecule was first isolated by hepatocyte-specific human monoclonal antibody (MoAb). To elucidate the role of this IgM autoantibody in hepatocyte injury, we examined the reactivity of this MoAb to murine hepatocytes and then questioned whether acute hepatic injury could be induced in mice via injection of this MoAb. The reactivity of MoAb was examined via both FACS analysis using murine hepatocytes and immunostaining of liver tissues. We then identified the murine hepatocyte membrane molecule recognized by this MoAb. The role of this MoAb in the immunopathogenesis of AIH was assessed by testing whether its injection into mice could increase serum aminotransferase levels as well as cause changes in liver histology. The present results demonstrate that this MoAb cross-reacted with murine hepatocytes and recognized a 190-kd molecule on the murine hepatocyte membrane just as in human hepatocytes. One hour after the injection of MoAb, the deposition of both IgM and complement component 3 was found in liver tissues. At 8 hours after the injection, serum aminotransferase levels were significantly increased in MoAb-injected mice compared with controls. Histological study revealed massive hepatocyte necrosis in MoAb-injected mice. In conclusion, human MoAb recognized a 190-kd molecule of both human and murine hepatocytes, and the injection of this MoAb to mice resulted in acute liver injury, indicating that this type of autoantibody may play an important role in the immunopathogenesis of AIH.

Cell adhesion aside from integrin system can abrogate anoikis in rat liver cells by down-regulation of FasL expression, not by activation of PI-3K/Akt and ERK signaling pathway.

Epithelial cells require contact with extracellular matrix (ECM) to inhibit detachment-induced apoptosis (anoikis). The ERK and PI-3K/Akt signaling pathways have been identified to inhibit anoikis. We present here a different story. An adult rat liver cell line, ARLJ301-3, underwent apoptosis within 4h under suspension conditions even with active forms of Akt and ERK1/2. Once ARLJ301-3 cells are plated on tissue culture plates coated with synthetic polymer, such as poly-(N-p-vinyl benzyl-O-beta-D-galactopyranosyl-D-gluconamide) (PVLA), poly-L-lysine or polystyrene, instead of functional ECM such as fibronectin, they could survive and proliferate without activation of Akt and ERK1/2. The expression of Fas receptor ligand (FasL) is specifically detected in cells under suspension conditions or treated with cytochalasin-D. We present here the first report that FasL expression is up-regulated by the cytoskeletal disruption directed by cytochalasin-D treatment or cell detachment from ECM.