Oral administration of PEGylated TLR7 ligand ameliorates alcohol-associated liver disease via the induction of IL-22.

Effective therapies for alcohol-associated liver disease (ALD) are limited; therefore, the discovery of new therapeutic agents is greatly warranted. Toll-like receptor 7 (TLR7) is a pattern recognition receptor for single-stranded RNA, and its activation prevents liver fibrosis. We examined liver and intestinal damage in Tlr7-/- mice to determine the role of TLR7 in ALD pathogenesis. In an alcoholic hepatitis (AH) mouse model, hepatic steatosis, injury, and inflammation were induced by chronic binge ethanol feeding in mice, and Tlr7 deficiency exacerbated these effects. Because these results demonstrated that endogenous TLR7 signaling activation is protective in the AH mouse model, we hypothesized that TLR7 activation may be an effective therapeutic strategy for ALD. Therefore, we investigated the therapeutic effect of TLR7 agonistic agent, 1Z1, in the AH mouse model. Oral administration of 1Z1 was well tolerated and prevented intestinal barrier disruption and bacterial translocation, which thus suppressed ethanol-induced hepatic injury, steatosis, and inflammation. Furthermore, 1Z1 treatment up-regulated the expression of antimicrobial peptides, Reg3b and Reg3g, in the intestinal epithelium, which modulated the microbiome by decreasing and increasing the amount of Bacteroides and Lactobacillus, respectively. Additionally, 1Z1 up-regulated intestinal interleukin (IL)-22 expression. IL-22 deficiency abolished the protective effects of 1Z1 in ethanol-induced liver and intestinal damage, suggesting intestinal IL-22 as a crucial mediator for 1Z1-mediated protection in the AH mouse model. Collectively, our results indicate that TLR7 signaling exerts protective effects in the AH mouse model and that a TLR7 ligand, 1Z1, holds therapeutic potential for the treatment of AH.

[A Case of Breast Cancer in the Elderly Localized in the Nipple].

An 89-year-old woman presented to our clinic with a complaint of a wound in the left nipple. The pathological diagnosis via skin biopsy revealed adenocarcinoma. A physical examination, mammography, ultrasonography, and CT scan revealed a mass in the left nipple. However, a definite diagnosis could not be established by skin biopsy. Left breast-conserving surgery and sentinel lymph node biopsy were performed for diagnosis and treatment. Histological examination revealed a scirrhous type invasive ductal carcinoma in the left nipple and areola with skin invasion and lymph node metastasis. Radiation and hormone therapy were used as adjuvant therapy. She is alive with no local recurrence for 5 months post surgery. Since ductal carcinoma of the nipple is uncommon, we present this case report along with a review of the relevant literature.

Hyaluronan synthase 2-mediated hyaluronan production mediates Notch1 activation and liver fibrosis.

Hyaluronan (HA), a major extracellular matrix glycosaminoglycan, is a biomarker for cirrhosis. However, little is known about the regulatory and downstream mechanisms of HA overproduction in liver fibrosis. Hepatic HA and HA synthase 2 (HAS2) expression was elevated in both human and murine liver fibrosis. HA production and liver fibrosis were reduced in mice lacking HAS2 in hepatic stellate cells (HSCs), whereas mice overexpressing HAS2 had exacerbated liver fibrosis. HAS2 was transcriptionally up-regulated by transforming growth factor-ß through Wilms tumor 1 to promote fibrogenic, proliferative, and invasive properties of HSCs via CD44, Toll-like receptor 4 (TLR4), and newly identified downstream effector Notch1. Inhibition of HA synthesis by 4-methylumbelliferone reduced HSC activation and liver fibrosis in mice. Our study provides evidence that HAS2 actively synthesizes HA in HSCs and that it promotes HSC activation and liver fibrosis through Notch1. Targeted HA inhibition may have potential to be an effective therapy for liver fibrosis.

NOD-like receptor C4 Inflammasome Regulates the Growth of Colon Cancer Liver Metastasis in NAFLD.

Nonalcoholic fatty liver disease (NAFLD) enhances the growth and recurrence of colorectal cancer (CRC) liver metastasis. With the rising prevalence of NAFLD, a better understanding of the molecular mechanism underlying NAFLD-associated liver metastasis is crucial. Tumor-associated macrophages (TAMs) constitute a large portion of the tumor microenvironment that promotes tumor growth. NOD-like receptor C4 (NLRC4), a component of an inflammasome complex, plays a role in macrophage activation and interleukin (IL)-1ß processing. We aimed to investigate whether NLRC4-mediated TAM polarization contributes to metastatic liver tumor growth in NAFLD. Wild-type and NLRC4-/- mice were fed low-fat or high-fat diet for 6 weeks followed by splenic injection of mouse CRC MC38 cells. The tumors were analyzed 2 weeks after CRC cell injection. High-fat diet-induced NAFLD significantly increased the number and size of CRC liver metastasis. TAMs and CD206-expressing M2 macrophages accumulated markedly in tumors in the presence of NAFLD. NAFLD up-regulated the expression of IL-1ß, NLRC4, and M2 markers in tumors. In NAFLD, but not normal livers, deletion of NLRC4 decreased liver tumor growth accompanied by decreased M2 TAMs and IL-1ß expression in tumors. Wild-type mice showed increased vascularity and vascular endothelial growth factor (VEGF) expression in tumors with NAFLD, but these were reduced in NLRC4-/- mice. When IL-1 signaling was blocked by recombinant IL-1 receptor antagonist, liver tumor formation and M2-type macrophages were reduced, suggesting that IL-1 signaling contributes to M2 polarization and tumor growth in NAFLD. Finally, we found that TAMs, but not liver macrophages, produced more IL-1ß and VEGF following palmitate challenge. Conclusion: In NAFLD, NLRC4 contributes to M2 polarization, IL-1ß, and VEGF production in TAMs, which promote metastatic liver tumor growth.

Alcoholic liver disease: A current molecular and clinical perspective.

Heavy alcohol use is the cause of alcoholic liver disease (ALD). The ALD spectrum ranges from alcoholic steatosis to steatohepatitis, fibrosis, and cirrhosis. In Western countries, approximately 50% of cirrhosis-related deaths are due to alcohol use. While alcoholic cirrhosis is no longer considered a completely irreversible condition, no effective anti-fibrotic therapies are currently available. Another significant clinical aspect of ALD is alcoholic hepatitis (AH). AH is an acute inflammatory condition that is often comorbid with cirrhosis, and severe AH has a high mortality rate. Therapeutic options for ALD are limited. The established treatment for AH is corticosteroids, which improve short-term survival but do not affect long-term survival. Liver transplantation is a curative treatment option for alcoholic cirrhosis and AH, but patients must abstain from alcohol use for 6 months to qualify. Additional effective therapies are needed. The molecular mechanisms underlying ALD are complex and have not been fully elucidated. Various molecules, signaling pathways, and crosstalk between multiple hepatic and extrahepatic cells contribute to ALD progression. This review highlights established and emerging concepts in ALD clinicopathology, their underlying molecular mechanisms, and current and future ALD treatment options.

Parenchyma-preserving hepatectomy based on portal ramification and perfusion of the right anterior section: preserving the ventral or dorsal area.

BACKGROUND: Anatomical hepatectomy aims to eliminate the spread of malignant tumor cells via portal vein systemically. An anatomical concept of the right anterior section (RAS) and preservation of the liver parenchyma within the RAS has been proposed. METHODS: We focused on the anatomical concept of the RAS based on portal perfusion and described surgical procedures to preserve the ventral or dorsal RAS using preoperative simulation. RESULTS: In 370 patients undergoing a preoperative simulation, the ramification of the tertiary portal branches of the RAS could be divided into three types including the cranio-caudal type; Couinaud's classification in 50% of patients, ventro-dorsal type in 26% of patients, and multiple type in 24% of patients. Then in 32 patients of the ventro-dorsal type, curative parenchyma-sparing hepatectomy of the RAS was performed, preserving the ventral and dorsal RAS in 14 and 18 patients, respectively. There were no differences in the postoperative complications and long-term survival compared with the results obtained after segment 5 or 8 resection (n = 33). CONCLUSION: Three-dimensional simulation revealed three types of portal vein ramification of the RAS. Parenchyma-preserving hepatectomy based on the precise portal ramification may contribute to safe and curative hepatectomy in selected cases with liver neoplasm involving the RAS.

Development of hepatocellular carcinoma in cardiac congestive liver fibrosis: report of a case.

We report an extremely rare case of the development of hepatocellular carcinoma (HCC) in cardiac congestive liver fibrosis. A 62-year-old female presented to our hospital with a complaint of right upper quadrant pain. The patient had undergone cardiac surgery for pulmonary valve insufficiency, pulmonary stenosis and atrial septal defect when she was fifteen years of age. During the subsequent 47 years, she had occasionally suffered from various symptoms associated with right-sided heart failure due to pulmonary stenosis. Computed tomography revealed a liver tumor measuring 63 mm in diameter in segment 5 and other liver tumors in segments 5 (18 mm), 8 (17 mm) and 4 (12 mm), which were diagnosed as HCCs. There was no evidence of stenosis in any hepatic veins or inferior vena cava, and no infectious hepatitis or alcoholic liver damage. Anterior sectionectomy and partial resection of segment 4 was performed, and histological examination showed that these tumors were HCC accompanied by congestive liver fibrosis. Nine months later, multiple recurrent HCCs were detected in segment 6, and transcatheter arterial chemoembolization was employed thereafter. The patient died 40 months after surgery due to advanced recurrence.

Hemodynamic analysis and treatment of an enlarging extrahepatic portal aneurysm: report of a case.

Aneurysms in the portal venous system are relatively rare. We report the case of an extrahepatic portal venous aneurysm, detected incidentally by ultrasonography. The patient, a 75-year-old woman, was initially observed over 18 months, during which time, the aneurysm grew from 36 mm × 32 mm to 51 mm × 37 mm in size, without symptoms. Hemodynamic analysis employing computational flow dynamics technique showed obvious turbulence in the aneurysm, and the wall shear stress (WSS) against that part of the aneurysmal wall was greater than in other sites. To prevent complications such as spontaneous rupture and portal vein thrombosis, the aneurysm was resected, with reconstruction of the portal trunk. While careful follow-up is sufficient for most portal venous aneurysms, its enlargement could indicate possible spontaneous rupture. The increased WSS against part of the aneurysmal wall most likely accounts for the aneurysm enlargement in this case.

Salvage treatment of laparoscopic cholecystectomy-associated bile duct stenosis combining laparoscopic and endoscopic procedures: a case report.

The incidence of laparoscopic cholecystectomy (LC)-associated bile duct injury has reached a steady state despite learning curve effect. Herein we report the case of a 74-year-old Japanese man who suffered from bile duct stenosis and stones after LC. The stenosis was due to stricture caused by surgical clips used inappropriately during LC. We planned a salvage treatment combining laparoscopic and endoscopic approaches. At laparoscopic observation, the clips had already invaded the right side of the bile duct; minimal absorbable suture was performed after all the clips were removed. The bile duct stenosis was then endoscopically dilated and the biliary stones were successfully removed. For the recurrent biliary stenosis after discharge, endoscopic balloon dilation was performed and multiple plastic stent tubes were placed. The stent tubes were removed 4 months later, and the patient has had no symptoms for 1 year. A combined laparoscopic and endoscopic approach was useful for the salvage treatment of LC-associated bile duct stenosis.

Rare form of extraovarian primary peritoneal papillary serous carcinoma with solitary cystic lesion mimicking a liver tumor; report of a case.

Extraovarian primary peritoneal serous papillary carcinoma (EOPPC) has a similar clinical presentation to that of ovarian cancer in advanced stages, such as peritoneal dissemination and a large amount of ascites, while EOPPC with a solitary tumor is very rare. We report here a 47-year-old Japanese woman with solitary form of EOPPC mimicking a liver tumor. Ovaries of both sides had no malignant lesion, which was histologically confirmed. Histological examination revealed that the tumor was located at the right diaphragm and partially invaded into the liver, and papillary or ductal proliferation of the tumor cells with an occasional appearance of psammoma bodies was detected. Immunohistologically, the tumor cells were positive for CA 125 and Ber-EP4 and negative for D2-40 or calretinin, ruling out the possibility of mesothelioma, and the diagnosis of the tumor was EOPPC. After the operation, the patient received chemotherapy with carboplatin and paclitaxel, but died 10 months later due the progression of recurrence. The present case is very rare form of EOPPC without any ascites or peritoneal dissemination.

Impact of low-and high-density lipoprotein cholesterol levels on carotid intima-media thickness differs by smoking status in middle-aged men.

AIM: Cigarette smoking is a strong risk factor for atherosclerotic disease; however, it remains unclear whether the impact of other risk factors differs by smoking status. The aim of this study was to investigate this issue, especially with regard to low-density and high-density lipoprotein (LDL/HDL) levels. METHODS: In total, 448 healthy, middle-aged men (aged 37 to 61) participated in this study. Smoking habits were recorded, carotid intima-media thickness (IMT) was measured by B-mode ultrasound, and serum lipids and other biochemical parameters were determined from fasted blood samples. RESULTS: Among the overall subjects, multivariate regression analyses showed that IMT was significantly associated with age (p < 0.0001 for mean IMT, p= 0.002 for max IMT), body mass index (BMI, mean IMT, p= 0.028), LDL-C levels (mean/max IMT, p= 0.001), HDL-C levels (max IMT, p= 0.022) and current smoking habit (mean IMT, p=0.012). Subgroup analyses according to smoking status revealed that LDL-C levels were significantly associated with mean/max IMT in current smokers (p=0.001) but not in ex- or nonsmokers (never smoked subjects). After adjusting for age, BMI, systolic blood pressure, hemoglobin A1c and serum lipids, mean IMT respectively increased and decreased progressively across LDL-C and HDL-C quartiles (p= 0.004 and 0.045) in the overall subjects. These associations were observed in current smokers (p= 0.01) but not in ex- or nonsmokers for LDL-C, and were observed in ex- and nonsmokers (p= 0.025, 0.017, respectively) but not in current smokers for HDL-C. CONCLUSION: The impact of LDL-C/HDL-C levels on carotid IMT differs by smoking status. These observations imply that distinct mechanisms are involved in the (anti) atherogenesis of LDL/HDL according to smoking status.

Allergic rhinitis and ear pain in flight.

BACKGROUND: Ear pain is the most common physiologic incident in hypobaric chamber training in the Japan Air Self-Defense Force, and the incidence of ear pain has been gradually increasing. There has been a concomitant increase in the incidence of allergic rhinitis in Japan. We hypothesized that the increased incidence of ear pain may be due to the increased incidence of eustachian tube dysfunction associated with allergic rhinitis. OBJECTIVE: To explore whether there is an association between allergic rhinitis and ear pain experienced in hypobaric chamber training. METHODS: We examined 9 years of training records and noted whether there was a seasonal influence on the occurrence of ear pain in 7047 trainees. In addition, we studied the prevalence of allergic rhinitis among trainees during a representative training year using a questionnaire method, noting association between allergic rhinitis and the occurrence of ear pain. RESULTS: Comprehensive review of training records showed 429 (6.1%) of 7047 trainees complained of ear pain. Ear pain occurred more often in spring than the other 3 seasons. The questionnaire data showed 202 (23.0%) of 878 trainees had allergic rhinitis. Trainees with allergic rhinitis complained of ear pain more often in the spring than trainees without allergic rhinitis. CONCLUSIONS: Active allergic rhinitis is closely associated with the occurrence of ear pain in hypobaric chamber training. A similar phenomenon might occur in an actual flight. Special attention should be paid to not only common cold but also allergic rhinitis in both hypobaric chamber training and actual flights.

Arrhythmias observed during high-G training: proposed training safety criterion.

INTRODUCTION: Most arrhythmias during centrifuge training are physiological responses to high +Gz stress. However, potentially dangerous arrhythmias occasionally occur during centrifuge training. We reviewed all arrhythmias recorded during the Japan Air Self-Defense Force (JASDF) centrifuge training from April 2001 to March 2003, and developed a criterion for suspending G-training based on observed arrhythmias. METHOD: There were 195 male fighter pilots who received high-G centrifuge training monitored with electrocardiographs (ECGs). We evaluated types and occurrences of all arrhythmias during high-G training over a 24-mo period. RESULTS: Sinus arrhythmia (48.7%), single premature atrial contraction (32.3%), and single (58.5%) or paired (9.7%) premature ventricular contraction were commonly occurring arrhythmias during high-G training. We considered these arrhythmias as variant physiological responses to high-G training (category 1). In addition, we observed ventricular tachycardia (2.6%), paroxysmal supraventricular tachycardia (1.5%), and paroxysmal atrial fibrillation (0.5%). Further investigation of these trainees revealed a significant proportion with cardiac anomalies. As a result, the JASDF currently categorizes these arrhythmias as indicators to suspend G-training and initiate cardiac workup (category 3). Other arrhythmias, such as non-sustained ventricular tachycardia (VT) or Morbitz type I atrioventricular (AV) block, were considered borderline anomalies; whether training was allowed to continue depended on the decision of the physicians monitoring the training (category 2). CONCLUSION: Routine ECG monitoring during centrifuge training is recommended to catch the pathology underlying dangerous arrhythmias for flight safety. Our proposed criterion for stopping the centrifuge is intended to differentiate between serious arrhythmias and arrhythmias of physiologic response.

Peptic ulcer data from 4 years of endoscopy in 955 pilots of the Japan Air Self Defense Force.

BACKGROUND: The treatment of peptic ulcer disease has undergone profound changes due to the recognition of Helicobacter pylori as a causative factor. A survey of medical records was made to determine the prevalence of peptic ulcer among pilots of the Japan Air Self Defense Force (JASDF) and to decide on a possible change in JASDF medical policy toward an ulcer-treatment regime involving therapy to eradicate Helicobacter pylori. METHODS: The subjects were 955 male pilots, age 40 or older. Between 1996 and 1999, they underwent gastrointestinal endoscopy 2.47 times on average. Annual ulcer rates and recurrence rates were obtained from the endoscopic file data. Smoking habits and use of NSAIDs were also assessed as important risk factors for peptic ulcer. RESULTS: The detection rate of open ulcer for each year was 2.3-3.1% in the stomach and 1.9-4.4% in the duodenum. For ulcers including scarring, the corresponding figures were 7.3-9.5% and 12.7-19.9%. The recurrence rate from S1 scars in the duodenum was 34%, significantly higher than that from S2 scars (7%) (p < 0.0005). There was no significant difference in recurrence rate between S1 scars and S2 scars in the stomach. There was a significant association between gastric ulcer and smoking (p < 0.0005). None of the pilots took long-term NSAID medications. CONCLUSIONS: Peptic ulcer occurs more frequently in the JASDF pilots than in the general population. S1 scarring in the duodenum, as well as open ulcers in either stomach or duodenum, are candidates for Helicobacter pylori eradication therapy if the bacterium is detected. Other types of scars are also candidates for this therapy when pilots have symptoms related to infection with Helicobacter pylori.

Cerebral infarction in a 24-year-old pilot.

Ischemic stroke is a rare event in young adults. We report on a 24-yr-old pilot with cerebral infarction of undetermined etiology, temporally associated with chain smoking. The patient exhibited dysphasia, stupor (confused consciousness), and right facial-nerve palsy. Computed-tomography revealed a low-density area in the left insular cortex. Cerebroangiography showed severe stenosis in a branch of the left middle cerebral artery. After admission, the patient made a rapid and uneventful recovery within 72 h. MRI showed an area of hyperintensity on T2-weighted images 2 mo after the attack. Based on the hyperintense area on FLAIR (fluid attenuated inversion recovery sequence) images obtained in MRI performed 10 mo after the attack, we diagnosed a cerebral infarction. In the Japan Air Self-Defense Force, cerebral infarction is an aeromedically disqualifying condition. However, in the evaluation 2 mo after the attack, differentiation from reversible ischemic neurological deficit was difficult. We discuss the criteria used for diagnosis and the risk factors for cerebral infarction in young adults, as well as the aeromedical disposition of young pilots.

Long-term disability among aviators in Japan Air Self-Defense Force: analysis of 260 cases.

BACKGROUND: As part of a study of the risks associated with aviator incapacitation, we identified the diseases that caused long-term disability (LTD) among aviators in the Japan Air Self-Defense Force (JASDF), and then assessed the magnitude of the problem that each group of diseases represented with regard to the safety of flight. METHODS: Case-notes for JASDF aviators who stopped work for more than 3 mo during 1980-2002 were identified from all files kept at the Medical Evaluation Section of the Aeromedical Laboratory. The case-notes were divided into four age groups and analyzed by diagnostic category or injury. RESULTS: We identified 260 aviators with LTD, including 217 active-duty pilots and 43 navigators with flying status. Of those, 59 cases (22.7%) had permanent disability for flight. About 75% of LTD cases could be attributed to five diagnostic categories: neoplasms, nervous system and sense organs, circulatory system, digestive system, and musculoskeletal system. Peaks in LTD were found in the 20-29 and 40-49 age-groups. In the younger group, 78.2% of the patients were students, of whom 23 were found to have a disability associated with a preexisting medical condition which was not detected in the initial screening process for pilots. In the 20-29 yr age-group, the most common reason for LTD was the nervous system and sense organs, while in the 40-49 yr age-group it was the circulatory system. CONCLUSION: Reduction in the frequency of LTD might be accomplished by improving the medical screening process for applicants and emphasizing the prevention of circulatory diseases during a pilot's career.