Acute pancreatitis as a rare complication of leptospirosis: A case report and literature review.

Leptospirosis is a zoonotic disease. We present a case of acute pancreatitis associated with leptospirosis. An 88-year-old woman was admitted to the hospital with high fever and severe myalgia of the lower extremities. Based on the clinical presentation, hepatic dysfunction with a mild increase in bilirubin, renal dysfunction, and life history, the possibility of leptospirosis was considered. Plain computed tomography of the trunk on admission revealed no special findings. Appropriate antimicrobial therapy was administered at an early stage. After treatment initiation, the clinical symptoms and blood test abnormalities began to improve, and the patient appeared to be doing well. Although no abdominal or back pain was consistently noted during hospitalization, the serum amylase level increased over time; therefore, the patient underwent another computed tomography scan on the ninth day. Acute pancreatitis, which was absent upon admission, was noted. Appropriate treatment for pancreatitis was administered, and the patient was discharged. A subsequent serum antibody test confirmed the diagnosis of leptospirosis. Herein, we also summarized previous cases of acute pancreatitis associated with leptospirosis. The time of onset for pancreatitis was inconsistent, and there were a few cases of pancreatitis without abdominal or back pain. In contrast, serum amylase or lipase levels were elevated in all patients, which could be an important trigger for suspected complications of pancreatitis. When leptospirosis is suspected, complications of pancreatitis should always be considered, even in the absence of apparent abdominal pain. Regular monitoring of pancreatic enzymes such as amylase and lipase is recommended.

Disseminated nontuberculous mycobacterial infection in a patient with idiopathic CD4 lymphocytopenia and IFN-γ neutralizing antibodies: a case report.

BACKGROUND: Disseminated nontuberculous mycobacterial (NTM) infection usually occurs in immunodeficient patients, such as those with human immunodeficiency virus infection and idiopathic CD4 lymphopenia. However, disseminated NTM diseases have also been reported in immunocompetent patients. Autoantibodies to interferon-gamma (IFN-γ) are known to be involved in disseminated NTM disease, although anti-IFN-γ antibodies are mainly seen in immunocompetent patients rather than those with immunodeficiency. Here, we report a rare case of disseminated NTM patient with idiopathic CD4 lymphopenia and anti-IFN-γ antibodies. CASE PRESENTATION: A 64-year-old Asian male presented with fever, back pain, anorexia and weight loss. Physical examination revealed subcutaneous masses in the forehead, sternoclavicular joint, and right inguinal region. Computed tomography showed multiple osteosclerotic changes with soft structures and osteolytic changes. Both blood and sputum cultures were positive for Mycobacterium intracellulare, confirming the presence of disseminated NTM infection. Histopathological evaluation of the subcutaneous mass in the right inguinal region showed numerous granulomas consisting of epithelioid cells with Langhans-type giant cells. He was diagnosed with idiopathic CD4 lymphocytopenia. Interestingly, he also had anti-IFN-γ autoantibodies with suppression of IFN-γ-dependent signal transducer and activator of transcription 1 (STAT1) phosphorylation. Two-drug combination therapy with clarithromycin and ethambutol was started for the NTM infection, which resulted in a favorable disease course. CONCLUSIONS: In patients with disseminated NTM infection, idiopathic CD4 lymphocytopenia and anti-IFN-γ autoantibody-positive immunodeficiency can be coexisted. It is necessary to clarify the pathogenesis and clinical course of CD4 lymphocytopenic conditions and IFN-γ neutralizing antibody-positive in the disseminated NTM disease.

Differences in major limb outcomes by indication for lower extremity endovascular revascularization in patients receiving hemodialysis.

The incidence of lower extremity artery disease (LEAD) in patient receiving hemodialysis is remarkably higher than the general population. The treatment strategy and prognosis for LEAD patients differs depending on whether a patient has intermittent claudication (IC) or critical limb-threatening ischemia (CLTI). However, the distinction between the prognosis in HD-dependent patients with IC and CLTI has not been fully elucidated. This study is to determine whether indication of PAD has a distinct impact on major adverse cardiovascular and cerebrovascular events (MACCE) and limb events in patients receiving hemodialysis. The current study included 2321 prospectively enrolled patients from the Tokyo taMA peripheral vascular intervention research ComraDE registry (UMIN-CTR no. UMIN000015100) between September 2014 and December 2016. Out of the enrolled patients, 1644 were not receiving hemodialysis (non-HD patients) and 603 were receiving hemodialysis (HD patients). A composite of all-cause death, myocardial infarction, and stroke events defined as MACCE; while limb events were defined as a composite of unscheduled major amputation, unscheduled major lower limb surgery, acute limb ischemia, unscheduled endovascular treatment, and target lesion revascularization. Propensity score matching was applied among the non-HD and HD patients, in whole group, IC subgroup, and CLTI subgroup. Kaplan-Meier analysis was used for the analysis of outcomes for the whole group, IC subgroup, and the CLTI subgroup. CLTI accounted for 75.5% of the HD patients, whereas IC was 63.4% in the non-HD patients. The HD patients exhibited more frequent below-the-knee lesions than those in the non-HD patients in both IC (p = 0.01) and CLTI (p < 0.001) subgroups. Overall, HD patients exhibited a significantly higher rate of MACCE at 24 months. This trend was similar for limb events in whole group and CLTI subgroup. In contrast, no significant differences in outcomes for limb events were found in IC subgroup. Although, prognosis after EVT in HD patients were significantly worse than non-HD patients, comparable outcome with non-HD patients was observed in the patients treated for IC. Clinical trial registration: This study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR No. UMIN000015100).

Effects of a novel selective PPARα modulator, statin, sodium-glucose cotransporter 2 inhibitor, and combinatorial therapy on the liver and vasculature of medaka nonalcoholic steatohepatitis model.

OBJECTIVE: Nonalcoholic steatohepatitis (NASH) is a disease entity with an increasing incidence, with involvement of several metabolic pathways. Various organs, including the liver, kidneys, and the vasculature, are damaged in NASH, indicating the urgent need to develop a standard therapy. Therefore, this study was conducted to investigate the effects of drugs targeting various metabolic pathways and their combinations on a high-fat diet (HFD)-induced NASH medaka model. METHODS: To investigate the effects of drugs on vascular structures, the NASH animal model was developed using the fli::GFP transgenic medaka fed with HFD at 20 mg/fish daily. The physiological changes, histological changes in the liver, vascular structures in the fin, and serum biochemical markers were evaluated in a time-dependent manner after treatment with selective peroxisome proliferator-activated receptor α modulator (pemafibrate), statin (pitavastatin), sodium-glucose cotransporter 2 inhibitor (tofogliflozin), and their combinations. Furthermore, to determine the mechanisms underlying the effects, whole transcriptome sequencing was conducted using medaka liver samples. RESULTS: Histological analyses revealed significant suppression of fat accumulation and fibrotic changes in the liver after treatment with drugs and their combinations. The expression levels of steatosis- and fibrosis-related genes were modified by the treatments. Moreover, the HFD-induced vascular damages in the fin exhibited milder changes after treatment with the drugs. CONCLUSION: The effects of treating various metabolic pathways on the medaka body, liver, and vascular structures of the NASH medaka model were evidenced. Moreover, to our knowledge, this study is the first to report whole genome sequence and gene expression evaluation of medaka livers, which could be helpful in clarifying the molecular mechanisms of drugs.

Efficacy and safety of ribavirin therapy for chronic hepatitis E after kidney transplantation.

Hepatitis E virus (HEV) infection has been recognized as an acute condition. However, recent reports have shown that immunocompromised patients, such as those receiving solid-organ transplantation, can develop chronic hepatitis with HEV infection. We report two cases of chronic hepatitis E after kidney transplantation (KT) who were successfully treated with ribavirin monotherapy. Several years after KT, both patients had sustained elevations in the levels of liver enzymes for a period of more than 6 months. Both patients had HEV infection, genotype 3a. Histological studies showed infiltration of inflammatory cells without fibrosis. Treatment included ribavirin monotherapy at a dosage of 600 mg daily for 3 months. One month after therapy initiation, HEV-RNA turned to negative, and remained negative at 24 weeks after ribavirin therapy without severe complications. Although the treatment of chronic hepatitis E is not fully established, ribavirin therapy can be a safe and effective treatment for chronic hepatitis E.

Effect of histidine on sorafenib-induced vascular damage: Analysis using novel medaka fish model.

BACKGROUND: Sorafenib (SFN) is an anti-angiogenic chemotherapeutic that prolongs survival of patients with hepatocellular carcinoma (HCC); its side effects, including vascular damages such as hand-foot syndrome (HFS), are a major cause of therapy discontinuation. We previously reported that maintenance of peripheral blood flow by intake of dried bonito broth (DBB) significantly prevented HFS and prolonged the administration period. The amino acids contained in DBB probably contribute to its effects, but the mechanism has not been clarified. We hypothesized that histidine, the largest component among the amino acids contained in DBB, has effects on SFN-induced vascular damage, and evaluated this possibility using a novel medaka fish model. METHODS: The fli::GFP transgenic medaka fish model has a fluorescently visible systemic vasculature. We fed the fish with SFN with and without histidine to compare blood flow and vascular structure among the differently fed models. The vascular cross-sectional area of each fish was measured to determine vascular diameter changes. RESULTS: Our results demonstrated that SFN-fed medaka developed a narrower vascular diameter. In addition, this narrowing was counteracted by addition of histidine to the medaka diet. We observed no positive effect of histidine on regeneration of cut vessels or on cell growth of endothelial cells and HCC cell lines. CONCLUSION: We proved the efficacy of the medaka model to assess vascular changes after administration of specific chemicals. And our results suggest that SFN causes vascular damage by narrowing peripheral vessel diameter, and that histidine effectively counteracts these changes to maintain blood flow.

Relationship between Perceived Physical Competence and Outdoor Play among Children Aged 9-12 Years-Focused Sex-Specific Differences.

BACKGROUND: Outdoor play (OP), which is considered important for children's development, is declining every year. Perceived physical competence (PPC) is a vital factor that promotes physical activity such as OP, sports clubs, etc., but the relationship between PPC and OP was unknown. The purpose of this research was to investigate the relationship between PPC and OP in children and consider whether there were any sex-specific changes. METHODS: A cross-sectional study was conducted in Japan with 288 children (134 girls, age: 10.6 ± 1.01 years). OP was assessed using an original self-report questionnaire. Each weekday, the children reported the time of OP and were classified as "high" if they played outside for at least an hour three times. PPC was evaluated with a self-report questionnaire developed by Okazawa et al. (1996). It has 12 questions and was assessed on a 5-point Likert scale. After adjusting for age, sex, BMI, screen time, sports club participation, and the number of friends, logistic regression analyses were carried out. RESULTS: Children with better PPC were significantly more likely to be classified as "high" [crude odds ratio (OR): 1.04; 95% confidence interval (CI): 1.00-1.08; adjusted OR: 1.04; 95% CI: 1.00-1.08]. Only girls with better PPC were significantly more likely to be classified as "high" in a sex-based stratified analysis [crude OR: 1.08; 95% CI: 1.01-1.15, adjusted OR 1.09; 95% CI: 1.02-1.17]. CONCLUSIONS: Particularly among girls, OP could be promoted as a voluntary physical activity with improved PPC.

Duodenal Diverticular Bleeding Treated with Endoscopy or Transcatheter Arterial Embolization: A Report of Two Cases and a Literature Review.

Duodenal diverticular bleeding (DDB) is extremely rare. We herein report 2 life-threatening cases of DDB successfully treated with endoscopy or transcatheter arterial embolization (TAE) and review 13 cases of DDB reported from Japan. When upper gastrointestinal bleeding of unknown origin is encountered in middle-aged or older adults, DDB should be included in the differential diagnosis. DDB often causes massive bleeding. It is therefore important to judge which is safer and more effective, endoscopy or TAE, based on the general condition of the patient. In addition, it is critical to attempt hemostasis via various strategies, including different gastroscopes and hemostatic devices.

Association Between Workplace Social Capital and Neck Pain: A Cross-Sectional Study Among Workers.

OBJECTIVE: We examined the association between workplace social capital (WSC) and presence of neck pain (NP) among workers. METHODS: This cross-sectional study included 595 workers. Presence of NP was assessed using Numerical Rating scale. WSC (overall, bonding, bridging, and linking) was divided into three categories (low, middle, and high) based on tertile distributions. We used logistic regression analysis to investigate the association between WSC and presence of NP. RESULTS: Low overall, bonding, and linking social capital were significantly associated with presence of NP in comparison with each high social capital (overall: adjusted odds ratio [aOR] = 1.76, 95% confidence interval [CI] = 1.14 to 2.73; bonding: aOR = 1.78, 95% CI = 1.19 to 2.67, linking: aOR = 2.18, 95% CI = 1.32 to 3.63). CONCLUSION: Lower WSC had an association with higher prevalence of NP among workers.

Effect of Excessive Screen Time on Cardiorespiratory Fitness in Children: A Longitudinal Study.

BACKGROUND: This study investigated the effect of different components of screen time (mobile phone use, TV/video viewing, and video gaming) on cardiorespiratory fitness (CRF) development in children aged 9-12 years. METHODS: This was a two-year longitudinal study conducted with 175 children (49.7% girls, mean age = 9.5) in Japan. CRF was assessed using a 20 m shuttle run test conducted at baseline and again at follow-up. Children were categorized as "Good" or "Poor" based on the change in CRF scores for each gender. Screen time was assessed using a self-reported questionnaire at baseline and termed as "high" if children reported ≥ 2 h/day. Univariate and multivariate logistic regression analyses were performed after adjusting for gender, physical activity, and time of data collection. RESULTS: Children scoring "high" on mobile phone use had lower odds of being categorized as "Good" in CRF change (crude odds ratio (OR): 0.34; 95% confidence interval (CI): 0.15-0.90 (adjusted OR: 0.33; 95% CI: 0.12-0.91)). There were no significant effects of TV/video viewing (crude OR: 1.54; 95% CI: 0.84-2.81) and video gaming (crude OR: 0.98; 95% CI: 0.48-1.97) on changes in CRF. CONCLUSIONS: Limiting excessive mobile phone usage might be important for ensuring healthy development of CRF in children.

Highly photo-stable dye doped solid-state distributed-feedback (DFB) channeled waveguide lasers by a pen-drawing technique.

Pyrromethene dyes doped polymeric channeled waveguide lasers with permanent DFB structures were fabricated via a novel pen-drawing technique with the patterned polydimethylsiloxane (PDMS) chips fabricated through a casting process as the substrates. With the high resolution dispensers, dye doped high viscosity pre-polymers were written into the PDMS grooves and the cross-section of the channeled waveguides could be controlled by both the polymer composition and the pen-drawing parameters. Highly stable laser output with 4.8 × 10(6) pulses of laser lifetime at 500 Hz of pump repetition rate has been obtained, which is suggested to be among one of the best results of pyrromethene 567 (PM567) up to date.

Inhibition of sodium glucose cotransporter 2 (SGLT2) delays liver fibrosis in a medaka model of nonalcoholic steatohepatitis (NASH).

The rise in the incidence of nonalcoholic steatohepatitis (NASH) has necessitated the development of an effective prevention methodology. An antidiabetic drug, belonging to the group of sodium glucose cotransporter 2 (SGLT2) inhibitors, has been tested for its therapeutic effect on NASH; however, no studies to date have demonstrated the preventive effect of an SGLT2 inhibitor on the histological progression of steatosis and fibrosis in a sequential manner in animal models. In the present study, we examined the effect of the SGLT2 inhibitor, tofogliflozin (Tofo), on NASH liver tissue using medaka as an animal model, maintaining a feeding amount and drug concentration in all animal bodies. We generated a medaka NASH model by feeding d-rR/Tokyo medaka a high-fat diet and administered Tofo by dissolving the drug directly in the water of the feeding tank. Thereafter, the effects of Tofo on body weight (BW), liver weight, hepatotoxicity, fatty infiltration, and fibrotic changes in the liver were examined. We report here that SGLT2 is expressed in medaka fish and that Tofo inhibits the accumulation of fatty tissue and delays the progression of liver fibrosis in the medaka NASH model by inhibiting increases in blood sugar, serum lipids, and transaminase, irrespective of changes in BW. These results suggest that Tofo is effective for treating NASH and that the medaka model may be useful for developing new therapeutic drugs for this disease.

Inhibition of sodium-glucose cotransporter 2 ameliorates renal injury in a novel medaka model of nonalcoholic steatohepatitis-related kidney disease.

The effect of sodium-glucose cotransporter 2 inhibitor (SGLT2I) on nonalcoholic steatohepatitis (NASH) has been reported, but there are few studies on its effect on NASH-related renal injury. In this study, we examined the effect of SGLT2I using a novel medaka fish model of NASH-related kidney disease, which was developed by feeding the d-rR/Tokyo strain a high-fat diet. SGLT2I was administered by dissolving it in water of the feeding tank. SGLT2I ameliorates macrophage accumulation and oxidative stress and maintained mitochondrial function in the kidney. The results demonstrate the effect of SGLT2I on NASH-related renal injury and the usefulness of this novel animal model for research into NASH-related complications.

Autonomic nervous system network and liver regeneration.

To date, various signal transducers, cytokines, growth factors, and hormones have been reported to play an important role in homeostasis of various organs. Various cells and organs are involved in the hepatic regeneration process, which proceeds as a result of the coordination of many factors. While these factors are well known to be involved in the liver regeneration after the liver injury, however, as the details of such mechanisms have not been sufficiently elucidated, the practical applicability of hepatic regeneration based on the action of these and cytokines growth factors is still unclear. In terms of the involvement of the autonomic nervous system in hepatic regeneration, cell proliferation resulting from direct signal transduction to the liver has also been reported and recent studies focusing on the inter-organ communication via neural network opened a novel aspect of this field for therapeutic applicability. Therefore, the appropriate understanding of the relationship between autonomic neural network and liver regeneration through various organs including brain, afferent nerve, efferent nerve, etc. is essential. This mini-review explains the principle of neural system involved in the inter-organ communication and its contribution on the liver regeneration upon the liver injury reviewing recent progress in this field.

Effect of a neural relay on liver regeneration in mice: activation of serotonin release from the gastrointestinal tract.

The development of therapeutic options to promote hepatic regeneration following severe liver injury is essential. While humoral factors have been reported as mechanisms of liver regeneration, the contributions of interorgan communication to liver regeneration have not been reported. In this study, we examined the effect of a neural relay on liver regeneration via activation of serotonin release from the gastrointestinal (GI) tract. Our results demonstrated that the afferent visceral nerve from the liver activates the efferent vagus nerve from the brain, leading to activation of serotonin release from the GI tract and contributing to liver regeneration. While it is difficult to apply these results directly to human health, we believe that this study may represent a step toward developing essential therapeutics to promote liver regeneration.

Effective prevention of sorafenib-induced hand-foot syndrome by dried-bonito broth.

BACKGROUND: Sorafenib (SOR) is a molecular medicine that prolongs the survival of patients with hepatocellular carcinoma (HCC). Therefore, the management of side effects is essential for the longer period of continuous medication. Among the various side effects, hand-foot syndrome (HFS) is the most common, occurring in 30%-50% of patients, and often results in discontinuation of the SOR medication. However, its mechanism has not been clarified, and no effective prevention method has been reported for the symptoms. Therefore, this study aimed to analyze its mechanism and to develop an effective prevention regimen for the symptoms. MATERIALS AND METHODS: To assess the mechanism of SOR-induced HFS, the peripheral blood flow in the hand and foot was carefully monitored by Doppler ultrasound, thermography, and laser speckle flowgraphy in the cases treated with SOR and its contribution was assessed. Then, the effect of dried-bonito broth (DBB), which was reported to improve peripheral blood flow, on the prevention of the symptom was examined by monitoring its occurrence and the peripheral blood flow. RESULTS: A total of 25 patients were enrolled in this study. In all, eight patients developed HFS, and all cases showed a significant decrease in the peripheral blood flow. DBB contributed to an increase in the flow (p = 0.009) and significantly decreased occurrence of HFS (p = 0.005) than control. Multivariable analysis showed that the ingestion of DBB is a significant independent contributor to HFS-free survival period (p = 0.035). CONCLUSION: The mechanism of SOR-induced HFS involves a decrease in the peripheral blood flow, and the ingestion of DBB effectively prevents the development of the syndrome by maintaining the flow.

Liver-targeted hydrodynamic gene therapy: Recent advances in the technique.

One of the major research focuses in the field of gene therapy is the development of clinically applicable, safe, and effective gene-delivery methods. Since the first case of human gene therapy was performed in 1990, a number of gene-delivery methods have been developed, evaluated for efficacy and safety, and modified for human application. To date, viral-vector-mediated deliveries have shown effective therapeutic results. However, the risk of lethal immune response and carcinogenesis have been reported, and it is still controversial to be applied as a standard therapeutic option. On the other hand, delivery methods for nonviral vector systems have been developed, extensively studied, and utilized in in vivo gene-transfer studies. Compared to viral-vector mediated gene transfer, nonviral systems have less risk of biological reactions. However, the lower gene-transfer efficiency was a critical hurdle for applying them to human gene therapy. Among a number of nonviral vector systems, our studies focus on hydrodynamic gene delivery to utilize physical force to deliver naked DNA into the cells in the living animals. This method achieves a high gene-transfer level by DNA solution injections into the tail vein of rodents, especially in the liver. With the development of genome editing methods, in vivo gene-transfer therapy using this method is currently the focus in this research field. This review explains the method principle, efficiency, safety, and procedural modifications to achieve a high level of reproducibility in large-animal models.

Effects of Fibrotic Tissue on Liver-targeted Hydrodynamic Gene Delivery.

Hydrodynamic gene delivery is a common method for gene transfer to the liver of small animals, and its clinical applicability in large animals has been demonstrated. Previous studies focused on functional analyses of therapeutic genes in animals with normal livers and little, however, is known regarding its effectiveness and safety in animals with liver fibrosis. Therefore, this study aimed to examine the effects of liver fibrosis on hydrodynamic gene delivery efficiency using a rat liver fibrosis model. We demonstrated for the first time, using pCMV-Luc plasmid, that this procedure is safe and that the amount of fibrotic tissue in the liver decreases gene delivery efficiency, resulting in decrease in luciferase activity depending on the volume of fibrotic tissue in the liver and the number of hepatocytes that are immunohistochemically stained positive for transgene product. We further demonstrate that antifibrotic gene therapy with matrix metalloproteinase-13 gene reduces liver fibrosis and improves efficiency of hydrodynamic gene delivery. These results demonstrate the negative effects of fibrotic tissue on hydrodynamic gene delivery and its recovery by appropriate antifibrotic therapy.