Zinc Supplementation and an Improved Quality of Life in Patients with Autoimmune Hepatitis.

Objecive Patients with autoimmune hepatitis (AIH) reportedly have an impaired quality of life (QOL), mainly due to depression, even during remission. In addition, hypozincaemia has been demonstrated in patients with chronic liver disease, including AIH, and is known to be related to depression. Corticosteroids are known to cause mental instability. We therefore investigated the longitudinal association between zinc supplementation and changes in the mental status among AIH patients treated with corticosteroids. Materials This study enrolled 26 patients with serological remission of AIH routinely treated at our facility after excluding 15 patients who either discontinued polaprezinc (150 mg/day) within 24 months or interrupted treatment. Two questionnaires, the Chronic Liver Disease Questionnaire (CLDQ) and SF-36, were adopted to evaluate the QOL before and after zinc supplementation. Results Serum zinc levels were significantly elevated after zinc supplementation (p<0.0001). The CLDQ worry subscale significantly improved after zinc supplementation (p=0.017), but none of the SF-36 subscales was affected. Multivariate analyses demonstrated that daily prednisolone dosing was inversely related to both the CLDQ worry domain score (p=0.036) and the SF-36 mental health component (p=0.031). There was a significant negative correlation between the changes in the daily steroid dose and the CLDQ worry domain scores before and after zinc supplementation (p=0.006). No serious adverse events occurred during the observation period. Conclusion Zinc supplementation safely and efficiently improved mental impairment, possibly caused by continuous treatment with corticosteroids, in patients with AIH.

Differential diagnosis of uterine adenosarcoma: identification of JAZF1-BCORL1 rearrangement by comprehensive cancer genomic profiling.

BACKGROUND: Uterine adenosarcoma is a rare malignant tumor that accounts for 8% of all uterine sarcomas, and less than 0.2% of all uterine malignancies. However, it is frequently misdiagnosed in clinical examinations, including pathological diagnosis, and imaging studies owing to its rare and non-specific nature, which is further compounded by the lack of specific diagnostic markers. CASE PRESENTATION: We report a case of uterine adenosarcoma for which a comprehensive genomic profiling (CGP) test provided a chance to reach the proper diagnosis. The patient, a woman in her 60s with a history of uterine leiomyoma was diagnosed with an intra-abdominal mass post presentation with abdominal distention and loss of appetite. She was suspected to have gastrointestinal stromal tumor (GIST); the laparotomically excised mass was found to comprise uniform spindle-shaped cells that grew in bundles with a herringbone architecture, and occasional myxomatous stroma. Immunostaining revealed no specific findings, and the tumor was diagnosed as a spindle cell tumor/suspicious adult fibrosarcoma. The tumor relapsed during postoperative follow-up, and showed size reduction with chemotherapy, prior to regrowth. CGP was performed to identify a possible treatment, which resulted in detection of a JAZF1-BCORL1 rearrangement. Since the rearrangement has been reported in uterine sarcomas, we reevaluated specimens of the preceding uterine leiomyoma, which revealed the presence of adenosarcoma components in the corpus uteri. Furthermore, both the uterine adenosarcoma and intra-abdominal mass were partially positive for CD10 and BCOR staining. CONCLUSION: These results led to the conclusive identification of the abdominal tumor as a metastasis of the uterine adenosarcoma. The JAZF1-BCORL1 rearrangement is predominantly associated with uterine stromal sarcomas; thus far, ours is the second report of the same in an adenosarcoma. Adenosarcomas are rare and difficult to diagnose, especially in atypical cases with scarce glandular epithelial components. Identification of rearrangements involving BCOR or BCORL1, will encourage BCOR staining analysis, thereby potentially resulting in better diagnostic outcomes. Given that platinum-based chemotherapy was proposed as the treatment choice for this patient post diagnosis with adenosarcoma, CGP also indirectly contributed to the designing of the best-suited treatment protocol.

Effects of reduced glutathione supplementation in semen freezing extender on frozen-thawed bull semen and in vitro fertilization.

During cryopreservation, spermatozoa may suffer cold and cryo-induced injuries -associated with alterations in cell defense systems- that are detrimental to their function and subsequent fertility. This study aimed to determine the efficacy of supplementing the semen freezing extender with the antioxidant reduced glutathione (GSH) in cattle. Semen was collected from four bulls and diluted in a freezing extender supplemented with or without GSH (0, 1, 5, and 10 mM) before the cooling step of the cryopreservation process. After thawing, the quality of the frozen-thawed semen was investigated for motility, viability, acrosomal and DNA integrity, and subsequent embryo development after in vitro fertilization of bovine oocytes. Additionally, semen from one of the bulls was used to analyze semen antioxidative potential, sperm penetration into oocytes, male pronucleus formation rate, and embryo DNA integrity. The sperm quality varied among bulls after GSH supplementation. One bull had decreased sperm total motility, and two bulls had decreased sperm DNA integrity. GSH supplementation had positive effects on embryo development for three bulls. Two of them showed both improved cleavage and blastocyst formation rates, while the other one only showed an improved cleavage rate. We observed positive effects on early male pronucleus formation and no negative effects on DNA integrity and cell number in blastocyst stage embryos. Although the effect varies depending on individual bulls and GSH concentration, GSH supplementation in semen may improve in vitro embryo production from frozen semen.

Zinc Administration and Improved Serum Markers of Hepatic Fibrosis in Patients with Autoimmune Hepatitis.

AIM: The aim of the present study is to investigate the effect of long-term zinc supplementation, which is important for the activation of various enzymes that contribute to antioxidant and antifibrotic activities, on the improvement of serum fibrotic markers in patients with autoimmune hepatitis (AIH). METHODS: A total of 38 patients with AIH under regular treatment at our hospital who provided their consent for being treated with polaprezinc (75 mg twice daily) were included and classified into 2 groups: the patients with zinc elevation (n = 27) and the patients without zinc elevation (n = 11). Serum biomarker of fibrosis, protein expression levels of matrix metalloproteinases (MMPs), and their inhibitors (TIMPs) were evaluated. RESULTS: A significant difference was found between the variability of serum procollagen type Ⅲ and collagen type Ⅳ-7S between the 2 groups before and after zinc administration for more than 24 months (p = 0.043 and p = 0.049). In the patients with zinc elevation, no significant changes were found in collagenase (MMP-1 and MMP-13) before and after zinc administration, whereas a significant increase in the expression of gelatinase (MMP-2 and MMP-9) was found after administration (p = 0.021 and p = 0.005). As for the relative ratio of MMPs to TIMPs, only MMP-9 to TIMP-1 showed a significant increase (p = 0.004). CONCLUSIONS: Long-term treatment with polaprezinc has been demonstrated to safely improve serum fibrosis indices through increases in MMP-2/-9 and MMP-9/TIMP-1 and is expected to be well combined with direct antifibrotic therapies such as molecularly targeted agents.

Effect of L-carnitine on health-related quality of life in patients with liver cirrhosis.

L-carnitine (4-N-trimethylammonium-3-hydroxybutyric acid) is the physiologically active form of carnitine and is a natural compound that has been shown to exhibit antioxidant activity. L-carnitine is used as a supplementary treatment in patients with cirrhosis with hepatic encephalopathy, hyperammonemia or muscle cramps. In the present study, the effect of L-carnitine supplementation on health-related quality of life in 30 patients with cirrhosis was prospectively examined. L-carnitine (1,800 mg/day) was administered orally for 6 months. To assess the effects of L-carnitine on chronic fatigue, patients filled out a self-report questionnaire regarding their physical and mental health. The levels of total and free carnitine, and acylcarnitine were found to be significantly higher 1, 3 and 6 months after therapy initiation compared with before treatment. Serum albumin levels were significantly increased 3 and 6 months after initiation of therapy. L-carnitine supplementation significantly increased the BAP/d-ROM ratio, a marker of antioxidant status in patients with cirrhosis. Changes in serum carnitine concentrations were positively correlated with changes in serum albumin levels (R2=0.369; P=0.012), but not with changes in serum ammonia levels (R2= 0.005; P=0.78). Total and mental health scores improved significantly, and physical scores improved marginally 3 and 6 months after initiation of L-carnitine. These findings may be attributed to the enhanced serum albumin levels and oxidative stress rather than the reduced serum ammonia levels. Based on these results, it is suggested that L-carnitine can potentially alleviate chronic fatigue, along with the increased BAP/d-ROM ratio, which were involved in increased oxidative stress in patients with cirrhosis. The specific mechanisms by which L-carnitine ameliorates chronic fatigue is not fully understood and requires further investigation.

Efficacy of L-carnitine on ribavirin-induced hemolytic anemia in patients with hepatitis C virus infection.

BACKGROUND/AIMS: L-carnitine not only alleviates hyperammonemia and reduces muscle cramps in patients with liver cirrhosis, but also improves anemia in patients with chronic hepatitis and renal dysfunction. This study prospectively evaluated the preventative efficacy of L-carnitine supplementation against hemolytic anemia during antiviral treatment using ribavirin in patients with hepatitis C virus (HCV)-related chronic liver disease. METHODS: A total of 41 patients with chronic hepatitis were consecutively enrolled in this study. Group A (n=22) received sofosbuvir plus ribavirin for 3 months, whereas group B (n=19) was treated with sofosbuvir, ribavirin, and L-carnitine. Hemoglobin concentration changes, the effects of antiviral treatment, and the health status of patients were analyzed using short form-8 questionnaires. RESULTS: A significantly smaller decrease in hemoglobin concentration was observed in group B compared to group A at every time point. Moreover, the prescribed dose intensity of ribavirin in group B was higher than that of group A, resulting in a higher ratio of sustained virological response (SVR) 24 in group B compared with group A. The physical function of patients in group B was also significantly improved compared to group A at the end of antiviral treatment. CONCLUSION: L-carnitine supplementation alleviates ribavirin-induced hemolytic anemia in patients with HCV and helps relieve the physical burden of treatment with ribavirin-containing regimens. These advantages significantly increase the likelihood of achieving SVR.

Management of afatinib-induced stomatitis.

Severe stomatitis may lead to the need to interrupt or discontinue cancer therapy and, thus, may affect control of the primary disease. Stomatitis may also increase the risk of local and systemic infection and significantly affects the quality of life and the cost of care. The present study was conducted to evaluate the efficacy of two traditional herbal medicines in controlling treatment-induced stomatitis in a small cohort of lung cancer patients treated with afatinib. All patients who were treated with afatinib for epidermal growth factor receptor (EGFR) mutated nonsmallcell lung cancer (NSCLC) between January, 2015 and March, 2016, were included in this study. During the study period, a total of 14 NSCLC patients were treated with afatinib, an EGFR-tyrosine kinase inhibitor (TKI). Two patients already had stomatitis at the time of initiation of afatinib therapy; among the remaining 12 NSCLC patients, 2 (16.7%) developed stomatitis. All the lesions in the 4 patients who developed stomatitis were completely alleviated after 2 weeks of therapy with Aznol mouthwash, a chamomile extract with anti-inflammatory effects, and Hangeshashinto, a traditional herbal (Kampo) medicine. Afatinib therapy was re-initiated, but none of the patients developed stomatitis thereafter. To the best of our knowledge, this is the first report evaluating oral care and management of stomatitis. This type of care and treatment may reduce the incidence of complications associated with EGFR-TKI therapy.

Targeting the Notch-regulated non-coding RNA TUG1 for glioma treatment.

Targeting self-renewal is an important goal in cancer therapy and recent studies have focused on Notch signalling in the maintenance of stemness of glioma stem cells (GSCs). Understanding cancer-specific Notch regulation would improve specificity of targeting this pathway. In this study, we find that Notch1 activation in GSCs specifically induces expression of the lncRNA, TUG1. TUG1 coordinately promotes self-renewal by sponging miR-145 in the cytoplasm and recruiting polycomb to repress differentiation genes by locus-specific methylation of histone H3K27 via YY1-binding activity in the nucleus. Furthermore, intravenous treatment with antisense oligonucleotides targeting TUG1 coupled with a drug delivery system induces GSC differentiation and efficiently represses GSC growth in vivo. Our results highlight the importance of the Notch-lncRNA axis in regulating self-renewal of glioma cells and provide a strong rationale for targeting TUG1 as a specific and potent therapeutic approach to eliminate the GSC population.

Improving the Quality of Postgraduate Education in Traditional Japanese Kampo Medicine for Junior Residents: An Exploratory Survey Conducted in Five Institutions in the Tohoku Area.

Traditional Japanese (Kampo) medicine has been widely applied in general medicine in Japan. In 2001, the model core curriculum for Japanese medical education was revised to include Kampo medicine. Since 2007, all 80 Japanese medical schools have incorporated it within their programs. However, postgraduate training or instruction of Kampo medicine has not been recognized as a goal for the clinical training of junior residents by Japan's Ministry of Health, Labour and Welfare; little is known about postgraduate Kampo medicine education. This exploratory study investigated attitudes about Kampo medicine among junior residents in Japanese postgraduate training programs. A questionnaire survey was administered to junior residents at five institutions in the Tohoku area of Japan. Questions evaluated residents' experiences of prescribing Kampo medicines and their expectations for postgraduate Kampo education and training. As a result, 121 residents responded (response rate = 74%). About 96% of participants had previously received Kampo medicine education at their pre-graduate medical schools and 64% had prescribed Kampo medications. Specifically, daikenchuto was prescribed to prevent ileus and constipation after abdominal surgery and yokukansan was prescribed to treat delirium in the elderly. Residents received on-the-job instruction by attending doctors. Over 70% of participants indicated that there was a need for postgraduate Kampo medicine education opportunities and expected lectures and instruction on how to use it to treat common diseases. In conclusion, we have revealed that junior residents require Kampo medicine education in Japanese postgraduate training programs. The programs for comprehensive pre-graduate and postgraduate Kampo education are expected.

RDH13L, an enzyme responsible for the aldehyde-alcohol redox coupling reaction (AL-OL coupling reaction) to supply 11-cis retinal in the carp cone retinoid cycle.

Cone photoreceptors require effective pigment regeneration mechanisms to maintain their sensitivity in the light. Our previous studies in carp cones suggested the presence of an unconventional and very effective mechanism to produce 11-cis retinal, the necessary component in pigment regeneration. In this reaction (aldehyde-alcohol redox coupling reaction, AL-OL coupling reaction), formation of 11-cis retinal, i.e. oxidation of 11-cis retinol is coupled to reduction of an aldehyde at a 1:1 molar ratio without exogenous NADP(H) which is usually required in this kind of reaction. Here, we identified carp retinol dehydrogenase 13-like (RDH13L) as an enzyme catalyzing the AL-OL coupling reaction. RDH13L was partially purified from purified carp cones, identified as a candidate protein, and its AL-OL coupling activity was confirmed using recombinant RDH13L. We further examined the substrate specificity, subcellular localization, and expression level of RDH13L. Based on these results, we concluded that RDH13L contributes to a significant part, but not all, of the AL-OL coupling activity in carp cones. RDH13L contained tightly bound NADP(+) which presumably functions as a cofactor in the reaction. Mouse RDH14, a mouse homolog of carp RDH13L, also showed the AL-OL coupling activity. Interestingly, although carp cone membranes, carp RDH13L and mouse RDH14 all showed the coupling activity at 15-37 °C, they also showed a conventional NADP(+)-dependent 11-cis retinol oxidation activity above 25 °C without addition of aldehydes. This dual mechanism of 11-cis retinal synthesis attained by carp RDH13L and mouse RDH14 probably contribute to effective pigment regeneration in cones that function in the light.

Thermotherapy using magnetic cationic liposomes powerfully suppresses prostate cancer bone metastasis in a novel rat model.

BACKGROUND: Bone metastasis is a serious problem for individuals with prostate cancer, and the effects of the anticancer drug docetaxel (DTX) are insufficient. We therefore examined the therapeutic potential of magnetic cationic liposomes (MCL) in a novel rat model that allows the evaluation of tumor immunity. The effects of MCL thermotherapy were compared with those of DTX as a conventional therapy for the treatment of bone metastatic prostate cancer. METHODS: Prostate tumor tissues were transplanted into the femurs of model rats divided into four groups: control, MCL, DTX, and MCL + DTX. Tumors were injected with MCL, and alternating magnetic field (AMF) irradiation was performed three times a week. Tumor proliferation and bone destruction were evaluated by proliferating cell nuclear antigen positivity, computed tomography, and CD68-positive cell number, while tumor immunity was evaluated by heat shock protein (HSP) 70 expression and CD8-positive lymphocyte number. RESULTS: We successfully established a novel femur metastasis model of prostate cancer, and demonstrated that tumor proliferation and bone destruction in the MCL and MCL + DTX groups were significantly suppressed compared with control and DTX groups. MCL thermotherapy concurrently induced necrosis and apoptosis. The expression of HSP70 in the MCL and MCL + DTX groups was also significantly increased, and tumor immunity was enhanced through the induction of CD8-positive lymphocytes. CONCLUSION: MCL thermotherapy was clearly more effective than DTX in treating bone metastatic prostate cancer. A combination of MCL thermotherapy and DTX therefore deserves consideration as a novel treatment for this disease.

Objective evaluation of the alleviating effects of Goshajinkigan on peripheral neuropathy induced by paclitaxel/carboplatin therapy: A multicenter collaborative study.

Paclitaxel/carboplatin chemotherapy for cancer (TC therapy) exhibits neurotoxicity and causes peripheral neuropathy at a high frequency, which is difficult to cope with. In this study, we investigated the efficacy of Goshajinkigan, a traditional Japanese herbal medicine, for TC therapy-induced peripheral neuropathy. The subjects included in our study were patients with ovarian or endometrial cancer who underwent TC therapy and developed peripheral neuropathy. The patients were randomly divided into Group A, comprising of 14 patients (vitamin B12 treatment), and Group B, comprising of 15 patients (vitamin B12 + Goshajinkigan treatment). The observation period was 6 weeks following treatment initiation, and the evaluation items were as follows: i) the current perception threshold (CPT value) of the peripheral nerve, ii) visual analogue scale for numbness, iii) National Cancer Institute Common Terminology Criteria for Adverse Events v3.0 grade of neurotoxicity, and iv) a questionnaire on the subjective symptoms of peripheral neuropathy (functional assessment of cancer therapy-taxane). These were compared between the groups and no significant differences were noted in any item. However, CTCAE grade 3 neurotoxicity developed in 2 patients (14.3%) after 6 weeks of administration in Group A, whereas no neurotoxicity was observed in Group B. When the change in the frequency of abnormal CPT ratio at 6 weeks of administration from that before treatment was compared between the groups, the frequency of abnormal value was significantly lower in Group B than in Group A (p<0.05). This suggests that Goshajinkigan inhibits the progression of peripheral neuropathy.

Confirmation of the efficacy of vitamin B6 supplementation for McArdle disease by follow-up muscle biopsy.

No effective treatment for McArdle disease exists.We report a Japanese patient with McArdle disease who was treated with vitamin B(6) supplementation (60-90 mg/day). After treatment, increased muscle phosphorylase activity was confirmed by follow-up muscle biopsy (3.8 times higher than pretreatment levels). Increased lactate levels were seen on the forearm exercise test, and regular work activities could be resumed. Vitamin B(6) supplementation can enhance residual phosphorylase activity and improve insufficient anaerobic glycolysis of skeletal muscle.

Anaerobic degradation of p-xylene in sediment-free sulfate-reducing enrichment culture.

Anaerobic degradation of p-xylene was studied with sulfate-reducing enrichment culture. The enrichment culture was established with sediment-free sulfate-reducing consortium on crude oil. The crude oil-degrading consortium prepared with marine sediment revealed that toluene, and xylenes among the fraction of alkylbenzene in the crude oil were consumed during the incubation. The PCR-denaturing gradient gel electrophoresis (DGGE) analysis of 16S rRNA gene for the p-xylene degrading sulfate-reducing enrichment culture showed the presence of the single dominant DGGE band pXy-K-13 coupled with p-xylene consumption and sulfide production. Sequence analysis of the DGGE band revealed a close relationship between DGGE band pXy-K-13 and the previously described marine sulfate-reducing strain oXyS1 (similarity value, 99%), which grow anaerobically with o-xylene. These results suggest that microorganism corresponding to pXy-K-13 is an important sulfate-reducing bacterium to degrade p-xylene in the enrichment culture.

Effect of heat therapy using magnetic nanoparticles conjugated with cationic liposomes on prostate tumor in bone.

BACKGROUND: We have developed magnetite nanoparticles conjugated with cationic liposomes (MCLs) to induce intracellular hyperthermia with exposure to an alternating magnetic field (AMF). We have previously demonstrated the hyperthermic effect of MCLs against certain types of malignant tumor cells in vivo. Here, we examine the effects of MCL + AMF heat therapy on prostate cancer tissue in a bone microenvironment and on bone destruction in a rat model. MATERIALS AND METHODS: Rat prostate cancer nodules were transplanted onto the calvaria of 6-week-old F344 male rats. MCLs were injected into the tumor which reached 7 mm in diameter, and then the animals were exposed to repeated AMF irradiation. The distribution of MCL, tumor necrosis, cell proliferation, and bone destruction in the bone microenvironment were evaluated. RESULTS: MCL + AMF heat therapy suppressed tumor growth on the calvaria, and histologically, the induction of a necrotic mass was observed around magnetic particles in the tumor. The bone destruction index, which indicates the degree of osteolysis associated with prostate tumor growth in the bone microenvironment, was 34.8% in the MCL group and 67.2% in the control group with significant difference. However, almost half of rats were dead in this experiment. CONCLUSION: MCL + AMF heat therapy suppressed tumor proliferation in the bone microenvironment, in addition to bone destruction. However, this method may exhibit side effects for central nerve system. If MCL are specifically taken into the prostate cancer cells in the bone microenvironment, this method may be useful for the treatment of bone metastatic lesions of prostate cancer.