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Abstract Background Renal tubular acidosis is the principal clinical feature associated with tubulointerstitial nephritis in patients with primary Sjögren’s syndrome. Renal tubular dysfunction due to interstitial nephritis has been considered the underlying pathophysiology connecting renal tubular acidosis and primary Sjögren’s syndrome. However, the detailed mechanisms underlying the pathophysiology of renal tubular acidosis in primary Sjögren’s syndrome is not fully understood. Case presentation A 30-year-old woman was admitted with complaints of weakness in the extremities. The patient was hospitalized thirteen years earlier for similar issues and was diagnosed with hypokalemic paralysis due to distal renal tubular acidosis with primary Sjögren’s syndrome. This diagnosis was based on a positive Schirmer's test. Besides, anti-Sjögren’s syndrome-related antigen A was also detected. Laboratory tests indicated distal RTA; however, a renal biopsy showed no obvious interstitial nephritis. Laboratory tests conducted during the second admission indicated distal renal tubular acidosis. Therefore, a renal biopsy was performed again, which revealed interstitial nephritis. Histological analysis of acid–base transporters revealed the absence of vacuolar type H+-ATPases in the collecting duct. The vacuolar type H+-ATPase was also absent in the past renal biopsy, suggesting that the alteration in acid–base transporters is independent of interstitial nephritis. Conclusions This case study demonstrates that vacuolar-type H+-ATPases are associated with distal renal tubular acidosis, and distal renal tubular acidosis precedes interstitial nephritis in patients with primary Sjögren’s syndrome.

Abstract Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders of the gastrointestinal tract that share similar genetic risk factors. However, while fibrotic stricture of the intestine is a major characteristic of CD; it is rarely observed in UC. Deposition of collagen in the extracellular matrix contributes to the formation of fibrotic strictures in CD, but the underlying mechanisms are unknown. In the present study, we found that heat shock protein 47 (HSP47), a stress-response protein that acts as a molecular chaperone during the processing and secretion of collagen, expressed in the intestinal tissue from patients with CD. Serum HSP47 levels and anti-HSP47 antibody titers were significantly higher in patients with CD than in those with UC. Furthermore, anti-HSP47 antibody levels correlated significantly with fibrosis in CD. In addition, HSP47 inhibition significantly suppressed collagen production in fibroblasts in vitro. These findings suggest that HSP47 is a biomarker for differentiating fibrotic from non-fibrotic forms of CD. Additionally, we propose that HSP47 could be a potential target for treating fibrosis in patients with CD.

Abstract Background Gastroesophageal varices (GOV) are a life-threatening complication in chronic liver disease. A method for non-invasively predicting GOV is crucial for management. This study aimed to determine whether a vein-viewing application can detect abdominal wall varices (AWV) and elucidate the relationship between AWV and GOV. Methods One-hundred patients with chronic liver diseases were prospectively enrolled. All the patients underwent esophagogastroduodenoscopy within three months of the enrollment. Unmanipulated images (UI) and vein-weighted images (VWI) were taken for assessing AWV by a vein-viewing application on iPhone. Two doctors independently evaluated both image types. We defined the grading of both UI and AWV as grade 0 (non-detectable), grade 1 (slightly detectable), and grade 2 (distinct). Results The causes of liver diseases among the 71 men and 29 women (median age, 70.5 yr) included Hepatitis B (n = 19), Hepatitis C (n = 21), alcoholism (n = 33), primary biliary cholangitis (n = 3), autoimmune hepatitis (n = 4) and others (n = 20). GOV was indicated in 60 patients, and half of them had not been treated previously (non-treated). VWI could significantly visualize AWV than UI (72% vs. 24%, p = 0.0005). The presence of cirrhosis (chronic hepatitis vs. cirrhosis = 64.6% vs. 91.4%, p = 0.004) and GOV (52.3% vs. 74.3%, p = 0.032) were significantly higher in the VWI-AWV grade 2 group. Multivariate analysis demonstrated that VWI-AWV grade 2 was an independent factor related to the presence of non-treated GOV [OR = 3.05 (1.24–7.53), p = 0.016]. Conclusions The vein-viewing application non-invasively detected AWV related to the presence of cirrhosis and GOV, and VWI-AWV grade 2 was an independent factor related to the presence of non-treated GOV.

COVID-19 is primarily known for its respiratory tract involvement, often leading to severe pneumonia and exacerbation of underlying diseases. However, emerging evidence suggests that COVID-19 can result in multiorgan failure, affecting organs beyond the respiratory system. We present the case of a 62-year-old male with COVID-19 who developed acute liver failure (ALF) and rhabdomyolysis in the absence of respiratory failure. Initially, the patient presented with significantly elevated aspartate transaminase (5398 U/L) and alanine transaminase (2197 U/L) levels. Furthermore, a prolonged prothrombin time international normalized ratio (INR) of 2.33 indicated the diagnosis of ALF without hepatic coma, according to Japanese diagnostic criteria. The patient also exhibited elevated creatine kinase (9498 U/L) and a mild increase in creatinine (1.25 mg/dL) levels, but both values improved with intravenous fluid support and molnupiravir administration. To our knowledge, this is the first reported case presenting with both ALF and rhabdomyolysis associated with COVID-19. In addition, we review the existing literature to summarize previously reported cases of ALF triggered by SARS-CoV-2. This case report underscores the significance of recognizing COVID-19 as a significant contributing factor in the development of multiorgan failure. Furthermore, it suggests that COVID-19 can lead to severe illness, irrespective of the absence of respiratory failure.

Jaundice is caused by excess circulating bilirubin, known as hyperbilirubinemia. This symptom is sometimes caused by a critical hepatobiliary disorder, and is generally identified as yellowish sclera when bilirubin levels increase more than 3 mg/dL. It is difficult to identify jaundice accurately, especially via telemedicine. This study aimed to identify and quantify jaundice by trans-conjunctiva optical imaging. Patients with jaundice (total bilirubin ≥3 mg/dL) and normal control subjects (total bilirubin n = 10), chronic hepatitis or cirrhosis (n = 6), pancreatic cancer (n = 4), acute liver failure (n = 2), cholelithiasis or cholangitis (n = 2), acute pancreatitis (n = 1), and Gilbert’s syndrome (n = 1). The maximum hue degree (MHD) optimal cutoff to identify jaundice was 40.8 (sensitivity 81% and specificity 80%), and the AUROC was 0.842. The MHD was moderately correlated to total serum bilirubin (TSB) levels (rS = 0.528, p < 0.001). TSB level (≥5 mg/dL) can be estimated by the formula 21.1603 − 0.7371 × 56.3−MHD2. In conclusion, the ABHB-based MHD of conjunctiva imaging identified jaundice using an ordinary smartphone without any specific attachments and deep learning. This novel technology could be a helpful diagnostic tool in telemedicine or self-medication.

Chronic kidney disease (CKD) and non-alcoholic steatohepatitis (NASH) are major health issues associated with the metabolic syndrome. Although NASH is a known risk factor of CKD, the mechanisms linking these two diseases remain poorly understood. We aimed to investigate alterations in the kidney complicated with dyslipidemia in an established NASH mouse model. Male C57BL6/J mice were fed with control diet or high-fat diet (HFD), containing 40% fat, 22% fructose, and 2% cholesterol for 16 weeks. Metabolic characteristics, histological changes in the kidney, endoplasmic reticulum (ER) stress, apoptosis, and fibrosis were evaluated by histological analysis, immunoblotting, and quantitative reverse transcription-polymerase chain reaction. Levels of serum aspartate aminotransferase, alanine aminotransferase, alkali-phosphatase, total cholesterol, and urinary albumin were significantly higher in mice fed with HFD. Remarkable steatosis, glomerular hypertrophy, and interstitial fibrosis were also shown in in the kidney by leveraging HFD. Furthermore, HFD increased the mRNA expression levels of Casp3, Tgfb1, and Nfe2l2 and the protein level of BiP. We observed the early changes of CKD and speculate that the underlying mechanisms that link CKD and NASH are the induction of ER stress and apoptosis. Further, we observed the activation of Nfe2l2 in the steatosis-induced CKD mouse model. This NASH model holds implications in investigating the mechanisms linking dyslipidemia and CKD.

Chronic kidney disease (CKD) and non-alcoholic steatohepatitis (NASH) are major health issues associated with the metabolic syndrome. Although NASH is a known risk factor of CKD, the mechanisms linking these two diseases remain poorly understood. We aimed to investigate alterations in the kidney complicated with dyslipidemia in an established NASH mouse model. Male C57BL6/J mice were fed with control diet or high-fat diet (HFD), containing 40% fat, 22% fructose, and 2% cholesterol for 16 weeks. Metabolic characteristics, histological changes in the kidney, endoplasmic reticulum (ER) stress, apoptosis, and fibrosis were evaluated by histological analysis, immunoblotting, and quantitative reverse transcription-polymerase chain reaction. Levels of serum aspartate aminotransferase, alanine aminotransferase, alkali-phosphatase, total cholesterol, and urinary albumin were significantly higher in mice fed with HFD. Remarkable steatosis, glomerular hypertrophy, and interstitial fibrosis were also shown in in the kidney by leveraging HFD. Furthermore, HFD increased the mRNA expression levels of Casp3, Tgfb1, and Nfe2l2 and the protein level of BiP. We observed the early changes of CKD and speculate that the underlying mechanisms that link CKD and NASH are the induction of ER stress and apoptosis. Further, we observed the activation of Nfe2l2 in the steatosis-induced CKD mouse model. This NASH model holds implications in investigating the mechanisms linking dyslipidemia and CKD.

Abstract is missing (Short communication)

BACKGROUND: Patient-derived xenografts (PDX) provide histologically accurate cancer models that recapitulate patient malignant phenotype and allow for highly correlative oncologic in-vivo downstream translational studies. Primary PDX engraftment failure has significant negative consequences on programmatic efficiency and resource utilization and is due to either no tumor growth or development of lymphoproliferative tumors. We aimed to determine if secondary engraftment of previously cryopreserved patient tumor tissues would allow salvage of PDX models that failed previous primary engraftment and increase overall engraftment efficiency. METHODS: Patient hepatobiliary and pancreatic cancers that failed primary engraftment were identified. Previously cryopreserved primary patient cancerous tissues were implanted into immunodeficient mice (NOD/SCID). Mice were monitored, growth metrics calculated, and secondary engraftment outcomes were recorded. Established PDX were verified and compared to original patient tissue through multiple generations by a GI pathologist. RESULTS: We identified 55 patient tumors that previously failed primary engraftment: no tumor growth (n = 46, 84%) or lymphoproliferative tumor (LT) (n = 9, 16%). After secondary implantation using cryopreserved patient tissues, 29 new histologically validated PDX models were generated with an overall secondary engraftment rate of 53% for all tumor types with greatest yield in pancreatic and biliary tract cancers. Of the secondary engraftment failures (n = 26), 21 (38%) were due to no growth and 5 (9%) developed LT. CONCLUSION: Secondary PDX engraftment using cryopreserved primary cancerous is feasible after previous failed engraftment attempts and can result in a 50% increase in overall engraftment efficiency with decreases in LT formation. This technique allows for salvage of critical patient PDX models that would otherwise not exist. SYNOPSIS: Patient-derived xenografts have many important translational applications however can be limited by engraftment failure. We demonstrate optimized methodology utilizing cryopreservation of primary tumor tissue that allows for subsequent successful secondary engraftment and creation of PDX models that failed previous primary engraftment and allowed salvage of patient PDX models that would otherwise not exist.

Helicobacter pylori infection results in gastric cancer (GC) with gastric mucosal atrophy (GMA). Some single-nucleotide polymorphisms (SNPs) in the prostate stem cell antigen gene (PSCA) are associated with GC and duodenal ulcers. However, the relationship of other identified SNPs in PSCA with these diseases remains unclear. Herein, the association between PSCA SNPs and GMA among 195 Japanese individuals with H. pylori infection was evaluated. The definition of GMA or non-GMA was based on serum pepsinogen levels or endoscopic findings. Five tag PSCA SNPs were analyzed using PCR high-resolution melting curve analysis with nonlabelled probes. The frequencies of alleles and the genotypes of each tag SNP were compared between the GMA and non-GMA groups. Subsequently, a genetic test was performed using associated SNPs as biomarkers to detect patients developing GMA. Two tag PSCA SNPs (rs2920280 and rs2294008) were related to GMA susceptibility. Individuals with the rs2920280 G/G genotype or the rs2294008 T/T genotype in PSCA had 3.5- and 2.1-fold susceptibility to GMA, respectively. In conclusion, SNP rs2920280 is a possible biomarker for detecting individuals developing GMA. PSCA polymorphisms may be useful biomarkers for predicting GMA linked to GC risk and a screening endoscopy strategy to detect GC related to early stage H. pylori associated GMA.

INTRODUCTION:Non-alcoholic fatty liver disease (NAFLD) has a wide spectrum, eventually leading to cirrhosis and hepatic carcinogenesis. We previously reported that a series of microRNAs (miRNAs) mapped in the 14q32.2 maternally imprinted gene region (Dlk1-Dio3 mat) are related to NAFLD development and progression in a mouse model. We examined the suitability of miR-379, a circulating Dlk1-Dio3 mat miRNA, as a human NAFLD biomarker. METHODS:Eighty NAFLD patients were recruited for this study. miR-379 was selected from the putative Dlk1-Dio3 mat miRNA cluster because it exhibited the greatest expression difference between NAFLD and non-alcoholic steatohepatitis in our preliminary study. Real-time PCR was used to examine the expression levels of miR-379 and miR-16 as an internal control. One patient was excluded due to low RT-PCR signal. RESULTS:Compared to normal controls, serum miR-379 expression was significantly up-regulated in NAFLD patients. Receiver operating characteristic curve analysis suggested that miR-379 is a suitable marker for discriminating NAFLD patients from controls, with an area under the curve value of 0.72. Serum miR-379 exhibited positive correlations with alkaline phosphatase, total cholesterol, low-density-lipoprotein cholesterol and non-high-density-lipoprotein cholesterol levels in patients with early stage NAFLD (Brunt fibrosis stage 0 to 1). The correlation between serum miR-379 and cholesterol levels was lost in early stage NAFLD patients treated with statins. Software-based predictions indicated that various energy metabolism-related genes, including insulin-like growth factor-1 (IGF-1) and IGF-1 receptor, are potential targets of miR-379. CONCLUSIONS:Serum miR-379 exhibits high potential as a biomarker for NAFLD. miR-379 appears to increase cholesterol lipotoxicity, leading to the development and progression of NAFLD, via interference with the expression of target genes, including those related to the IGF-1 signaling pathway. Our results could facilitate future research into the pathogenesis, diagnosis, and treatment of NAFLD.

Duodenogastric reflux (DGR) causes bile reflux gastritis (BRG) and may develop into gastric cancer. DGR is classified as primary in non-operated stomachs or secondary to surgical intervention. Primary DGR and Helicobacter pylori (H. pylori) infection are reportedly related. However, the mechanism is not fully understood. This study aimed to elucidate the relationship between H. pylori infection and pyloric incompetence in a non-operated stomach. A total of 502 non-operated participants who underwent an upper intestinal endoscopy were prospectively enrolled. Endoscopic findings (EAC, endoscopic atrophy classification; nodular gastritis; xanthoma; fundic gland polyp; and incompetence of pylorus), sex, age, gastrin, pepsinogen (PG) I and PG II levels were evaluated. PG I/PG II ratio, anti-H. pylori-Ab positivity, and atrophic gastritis status were significantly different between the normal and incompetent pylori (p = 0.043, H. pylori-Ab was the only independent factor associated with the incompetence of the pylorus, with an adjusted odds ratio of 2.70 (95% CI: 1.47–4.94, p = 0.001). In conclusion, pyloric incompetence was associated with H. pylori infection and moderately correlated to the severity of atrophic gastritis in non-operated stomachs.

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease related to metabolic syndrome. No standard pharmacological treatment has yet been established. We retrospectively evaluated the efficacy of pemafibrate in 16 NAFLD patients (11 men and 5 women; median age, 59 years; range, 27–81 years) who had taken pemafibrate for at least one year. They were all diagnosed with fatty liver according to imaging and clinical criteria. They were administered pemafibrate from October 2018 to October 2021 (median, 94 weeks; range, 56–157 weeks). Serum triglyceride was significantly decreased by −41.9% (342.3 ± 54.0 to 198.9 ± 20.4 mg/dL, p < 0.001). Aspartate aminotransferase (AST), alanine aminotransferase, and gamma-glutamyl transferase levels significantly decreased by −42.1% (49.6 ± 7.0 to 28.7 ± 3.4 U/L, p < 0.001), −57.1% (65.1 ± 10.8 to 27.9 ± 3.7 U/L, p < 0.001), and −43.2% (68.9 ± 10.9 to 39.1 ± 5.3 U/L, p < 0.05), respectively. The AST to platelet ratio (APRI) (0.8 ± 0.1 to 0.4 ± 0.1, p < 0.001) and fibrosis based on four factors (FIB-4) index (1.8 ± 0.3 to 1.4 ± 0.2, p < 0.05) also significantly decreased. Liver attenuation (39.1 ± 1.2 to 57.8 ± 2.7 HU, p = 0.028) and liver/spleen ratio (0.76 ± 0.04 to 1.18 ± 0.02, p = 0.012) significantly improved in three patients, as assessed by computed tomography. In conclusion, pemafibrate significantly improves serum triglyceride levels, liver function, FIB-4 index, APRI, and fatty liver in NAFLD patients with hypertriglyceridemia.

The early detection of a kidney injury is essential to protect against the progression of kidney damage owing to the progressive nature of chronic kidney disease. A renal biopsy is the gold standard for the assessment of pathological alterations such as interstitial fibrosis and glomerulosclerosis. However, there are concerns regarding potential complications including bleeding and a reduction in renal function. Ultrasound elastography is an ideal modality for assessing the alterations in various organs and diagnosing malignant tumors. This technique has the potential to help detect early changes in renal function and pathological alterations. However, the careful application and interpretation of this technique in the kidney is required because of its complex hemodynamics and architecture. Shear wave elastography is the most widely investigated technique among ultrasound elastography. This review aims to summarize the previous investigations of the kidney using shear wave elastography, particularly for renal malignancy, kidney transplantation, and chronic kidney disease. Additionally, we have highlighted the influencing factors concerning the practical measurement of renal elasticity.