"Weariness" and "unpleasantness" reduce adherence to branched-chain amino acid granules among Japanese patients with liver cirrhosis: results of a single-center cross-sectional survey.

AIM: Branched-chain amino acids (BCAA) are valuable in the treatment of liver cirrhosis because they increase serum albumin levels. Poor adherence to BCAA may adversely affect prognosis, but little is known about factors predicting adherence. We undertook a survey of patients prescribed BCAA for the treatment of cirrhosis. METHODS: Pharmacists carried out face-to-face interviews with patients (or their representatives) prescribed any of nine BCAA formulations. Question categories included patient characteristics, prescription of BCAA granules, and perceptions of BCAA administration, including adherence and possible factors that might impact adherence. "Poor adherence" was defined as "not taking the medication appropriately" or "forgetting to take the medication". RESULTS: Overall, 253 patients (or representatives) completed the survey, of whom 135 were men, 114 were women, and 148 were ≥70 years old. Most patients (163) were prescribed BCAA for ≥2 years and were using three packs per day. Thirty-two patients did not take their medication appropriately and 69 sometimes forgot to administer it. Weariness of taking the medication (P < 0.001) and the perceived unpleasantness (P = 0.023) of the medication in terms of its taste and volume were significantly associated with poor adherence. The patients reported that the most influential educators were general practitioners, followed by certified hepatologists, then pharmacists. CONCLUSION: Most patients had good adherence to BCAA in clinical practice. Poor adherence was associated with weariness with taking medication, and the unpleasantness of the medication itself. Patient education from general practitioners and hepatologists combined with adherence counseling from pharmacists may help improve adherence.

Effectiveness of Endoscopic Hemostasis with Soft Coagulation for Non-Variceal Upper Gastrointestinal Bleeding over a 12-Year Period.

BACKGROUND/AIMS: In this study, investigations were carried out to ascertain whether soft coagulation hemostasis for non-variceal upper gastrointestinal bleeding (UGIB) has ever been performed in a time-dependent manner. METHODS: Medical records of 502 patients who had undergone emergency endoscopic hemostasis for non-variceal UGIB from 2003 to 2014 were checked and the modalities were used to achieve hemostasis compared between the first period from 2003 to 2008 (197 patients) and the second period from 2009 to 2014 (305 patients). RESULTS: Endoscopic hemostasis was successfully achieved in 96.0% of study patients. Peptic ulcers were the main cause of bleeding (89.4%). Endoscopic hemostasis was performed by soft coagulation significantly more frequently during the second (71.1%) than the first period (11.7%; p < 0.001). Endoscopic hemostasis was mainly achieved by trainees during the second period (76.1%); these trainees comprised a significantly greater proportion of endoscopists than during the first period (56.3%; p < 0.001). Endoscopic-related complications did not differ between the 2 periods. The only risk factor for rebleeding after hemostasis was Helicobacter pylori infection; the use of soft coagulation and the fact that endoscopists were just trainees were not risk factors. CONCLUSION: Our findings suggest that using soft coagulation to achieve endoscopic hemostasis for non-variceal UGIB is safe and effective, even when it is performed by trainees.

Clinical course of hepatitis B surface antigen positive subjects following screening: A retrospective observational study from April 2008 to January 2013.

AIM: Determination of the percentage of hepatitis B surface antigen (HBsAg) positive participants who undergo screening and treatment may reduce the development of hepatocellular carcinoma. This study assessed the percentages of HBsAg positive participants detected by free screening at medical institutions in Saga Prefecture who underwent detailed examinations and antiviral treatment. METHODS: Participants were screened for HBsAg positivity at medical institutions in Saga Prefecture from April 2008 to January 2013, with some visiting physicians for detailed examinations and applying for reimbursement. Participants in the database of the Health Promotion Division of Saga Prefecture and results of detailed examinations were analyzed retrospectively. RESULTS: Screening revealed 193 eligible participants, 105 men (54%) and 88 women (46%), of a mean age of 55.5 ± 14.9 years. Of these 193 participants, 147 (76%) visited physicians for detailed examinations, 24 (16%) were regarded as needing treatment and seven (3.6%) were reimbursed for antiviral treatments. The 46 participants who did not undergo detailed examinations were significantly younger than the 147 examined participants (50.9 ± 13.2 vs 56.9 ± 15.2 years, P = 0.018). Of the 110 participants thought to require observation, 68 (62%) were assigned to this group without determination of alanine aminotransferase or hepatitis B virus DNA concentration, and 15 (14%) had indications for antiviral treatment according to the 2014 guidelines of the Japanese Society of Hepatology. CONCLUSION: The proportion of HBsAg positive participants receiving antiviral treatment was lower than that of participants undergoing detailed examinations.

Therapeutic drug monitoring of ganciclovir for postnatal cytomegalovirus infection in an extremely low birth weight infant: a case report.

BACKGROUND: Ganciclovir is a therapeutic choice for extremely premature infants with severe postnatal cytomegalovirus disease, but little is known about its optimal dose size and dosing interval for them. CASE PRESENTATION: We treated an extremely premature female infant with postnatal cytomegalovirus infection with intravenous administration of ganciclovir since 49 days of life (postmenstrual age of 31 weeks). After ganciclovir treatment was initiated at a dose of 5 mg/kg every 12 h, cytomegalovirus loads in the peripheral blood were markedly decreased. However, since plasma ganciclovir trough level was too high, the interval was extended to every 24 h. Subsequently, the trough level and the estimated 12-h area under the concentration-time curve (AUC0-12) were decreased from 3.5 mg/L to 0.3 mg/L and 53.9 mg · h/L to 19.2 mg · h/L, respectively, resulting in an exacerbation of viremia and clinical condition. Adjustment of dosing interval from 24 h to 12 h led to a peak level of 4.2 mg/L, trough level of 1.1 mg/L, and AUC0-12 of 31.8 mg · h/L, resulting in a marked suppression of viral load. CONCLUSIONS: Monitoring the therapeutic drug levels and cytomegalovirus loads is useful in obtaining a proper treatment effect and preventing overdosage during ganciclovir therapy in premature infants with postnatal cytomegalovirus infection.

Neudesin, an extracellular heme-binding protein, suppresses adipogenesis in 3T3-L1 cells via the MAPK cascade.

Adult mice abundantly express neudesin, an extracellular heme-binding protein with neurotrophic activity, in white adipose tissues. At the early stage of adipocyte differentiation during adipogenesis, however, the expression of neudesin decreased transiently. Neudesin-hemin significantly suppressed adipogenesis in 3T3-L1 cells. The knockdown of neudesin by RNA interference markedly promoted adipogenesis in 3T3-L1 cells and decreased MAPK activation during adipocyte differentiation. The addition or knockdown of neudesin affected the expression of C/EBPalpha and PPARgamma but not of C/EBPbeta. These findings suggest that neudesin plays a critical role in the early stage of adipocyte differentiation in which C/EBPbeta induces PPARgamma and C/EBPalpha expressions, by controlling the MAPK pathway.

Transcriptomic analysis of nephrotoxicity induced by cephaloridine, a representative cephalosporin antibiotic.

Cephaloridine (CER) is a classical beta-lactam antibiotic that has long served as a model drug for the study of cephalosporin antibiotic-induced acute tubular necrosis. In the present study, we analyzed gene expression profiles in the kidney of rats given subtoxic and toxic doses of CER to identify gene expression alterations closely associated with CER-induced nephrotoxicity. Male Fischer 344 rats were intravenously injected with CER at three different dose levels (150, 300, and 600 mg/kg) and sacrificed after 24 h. Only the high dose (600 mg/kg) caused mild proximal tubular necrosis and slight renal dysfunction. Microarray analysis identified hundreds of genes differentially expressed in the renal cortex following CER exposure, which could be classified into two main groups that were deregulated in dose-dependent and high dose-specific manners. The genes upregulated dose dependently mainly included those involved in detoxification and antioxidant defense, which was considered to be associated with CER-induced oxidative stress. In contrast, the genes showing high dose-specific (lesion-specific) induction included a number of genes related to cell proliferation, which appeared to reflect a compensatory response to CER injury. Of the genes modulated in both manners, we found many genes reported to be associated with renal toxicity by other nephrotoxicants. We could also predict potential transcription regulators responsible for the observed gene expression alterations, such as Nrf2 and the E2F family. Among the candidate gene biomarkers, kidney injury molecule 1 was markedly upregulated at the mildly toxic dose, suggesting that this gene can be used as an early and sensitive indicator for cephalosporin nephrotoxicity. In conclusion, our transcriptomic data revealed several characteristic expression patterns of genes associated with specific cellular processes, including oxidative stress response and proliferative response, upon exposure to CER, which may enhance our understanding of the molecular mechanisms behind cephalosporin antibiotic-induced nephrotoxicity.

Toxicogenomics of drug-induced hemolytic anemia by analyzing gene expression profiles in the spleen.

Hemolytic anemia is a serious adverse effect of therapeutic drugs that is caused by increased destruction of drug-damaged erythrocytes by macrophages in the spleen and liver. We previously applied a toxicogenomic approach to the toxicity by analyzing microarray data of the liver of rats dosed with two hemolytic agents: phenylhydrazine and phenacetin. In the present study, we analyzed gene expression profiles in the spleen, the primary organ for destruction of damaged erythrocytes, of the same models in order to identify splenic gene expression alterations that could be used to predict the hematotoxicity. Microarray analyses revealed hundreds of genes commonly deregulated under all severe hemolytic conditions, which included genes related to splenic events characteristic of the hematotoxicity, such as proteolysis and iron metabolism. Eleven upregulated genes were selected as biomarker candidates, and their expression changes were validated by quantitative real-time PCR. The transcript levels of most of these genes showed strong correlation with the results of classical toxicological assays (e.g., histopathology and hematology). Furthermore, hierarchical clustering analysis suggested that altered expression patterns of the 11 genes sensitively reflected the erythrocyte damage even under a condition that caused no decrease in erythrocyte counts. Among the selected genes, heme oxygenase 1 was one of the most promising biomarker candidates, the upregulation of which on the protein level was confirmed by immunohistochemistry. These results indicate that altered splenic expression of a subset of genes may allow detection of drug-induced hemolytic anemia, with better sensitivity than that of erythrocyte counts in the blood.

A toxicogenomic approach revealed hepatic gene expression changes mechanistically linked to drug-induced hemolytic anemia.

A variety of pharmaceutical compounds causes hemolytic anemia as a significant adverse effect and this toxicity restricts the clinical utility of these drugs. In this study, we applied microarray technology to investigate hepatic gene expression changes associated with drug-induced hemolytic anemia and to identify potential biomarker genes for this hematotoxicity. We treated female Sprague-Dawley rats with two hemolytic anemia-inducing compounds: phenylhydrazine and phenacetin. Hepatic gene expression profiles were obtained using a whole-genome oligonucleotide microarray with pooled RNA samples from individual rats within each dose group and analyzed in comparison with hepatic histopathology, hematology, and blood chemistry data. We identified a small subset of genes that were commonly deregulated in all the severe hemolytic conditions, some of which were considered to be involved in hepatic events characteristic of hemolytic anemia, such as hemoglobin biosynthesis, heme metabolism, and phagocytosis. Among them, we selected six upregulated genes as putative biomarkers, and their expression changes from microarray measurements were confirmed by quantitative real-time PCR using RNAs from individual animals. They were Alas2, beta-glo, Eraf, Hmox1, Lgals3, and Rhced. Expression patterns of all these genes showed high negative and positive correlation against erythrocyte counts and total bilirubin levels in circulation, respectively, suggesting that these genes may be the potential biomarkers for hemolytic anemia. These findings indicate that drug-induced hemolytic anemia may be detected based on hepatic changes in the expression of a subset of genes that are mechanistically linked to the hematotoxicity.

Spontaneous dissection limited to left gastric artery.

Spontaneous dissection without an aneurysm limited to left gastric artery is fairly rare. Physicians should be alert to the possibility of this condition in patients with sudden-onset abdominal pain.

Left Mandibular Pain: A Rare Initial Symptom of Acute Aortic Dissection Without Coronary Obstruction.

An 88-year-old woman experienced sharp pain in the left mandible for a few minutes 3 days prior to hospital presentation. On the day of hospital presentation, the patient experienced similar pain and cold sweating for more than an hour early in the morning. On arrival, there was only mild discomfort ranging from the left mandible to the neck, without definite pain. Computed tomography revealed Stanford type A acute aortic dissection. Blood vessel prosthesis implantation was performed. Intraoperatively, the coronary arteries were confirmed to be intact. Mandibular pain is a rare but potential symptom of aortic dissection without coronary artery obstruction.

Extremely High Serum Ferritin: An Instrumental Marker of Masquerading Adult-Onset Still's Disease with Hemophagocytic Syndrome.

BACKGROUND Adult-onset Still's disease (AOSD) is a rare multi-systemic inflammatory disorder of unknown etiology characterized by spiking fever, characteristic rash, and arthritis. It often associates with high serum ferritin levels. CASE REPORT An 88-year-old woman had fever of over 39°C without response to extended-spectrum antibiotics for 6 days. She had non-specific erythema with infiltration on her trunk. She had leukocytosis with neutrophilia of 80%, mild hepatic dysfunction, normal level of rheumatoid factor and antinuclear antibody, thrombocytopenia, elevated d-dimer and soluble interleukin2 receptor, extremely high serum ferritin (78 662 ng/mL), and splenomegaly. Although she had no arthritis or specific erythema, we made the diagnosis of AOSD according to Yamaguchi's criteria with disseminated intravascular coagulation (DIC) and hemophagocytic syndrome (HPS) after ruling out infections, malignancies, or other connective tissue diseases. Twelve percent of AOSD patients have HPS. The mean serum ferritin of AOSD with HPS was reported at 18 179 ng/mL, which supported the diagnosis of AOSD because only a few other diseases could show such extremely high serum ferritin. Although she was treated with prednisolone (30 mg/day), her condition deteriorated and her left pleural effusion increased. Therefore, methylprednisolone 500 mg/day for 3 days was started followed by prednisolone 30 mg/day and immunosuppressive agent (Cyclosporine 50 mg/day), which improved her general condition, elevated C-reactive protein levels, and extremely high serum ferritin levels. CONCLUSIONS We report the case of an elderly patient with severe AOSD, who developed HPS and DIC, whose extremely high serum ferritin level was useful in diagnosis.

Temporary unilateral abdominal muscle paralysis due to herpes zoster without typical vesicles or pain.

A 45-year-old man was evaluated for right abdominal bulging. Computed tomography showed segmental flaccidity of the right abdominal muscle without an abdominal hernia. Although typical vesicles and pain were absent, we diagnosed herpes zoster (HZ) because of the presence of a few eschars on the affected area without a history of diabetes mellitus. Although transient unilateral abdominal muscle paralysis due to HZ without typical skin vesicles or pain is rare, it is imperative to consider the possibility of HZ and seek skin changes such as eschars in such cases.

Recurrent Stenosis of the Ileum Caused by Rheumatoid Vasculitis.

A 65-year-old man with a 20-year history of rheumatoid arthritis was transferred to our hospital due to a second episode of intestinal obstruction, a fever, and joint pain within the previous 6 months. He had an extremely high rheumatoid factor level and decreased complement levels. Abdominal computed tomography, a small bowel series, and small intestinal endoscopy revealed severe ileal stenosis. Resection of the stenotic lesion was performed, and a histopathological examination revealed vasculitis. Rheumatoid vasculitis was diagnosed, and the patient began treatment with prednisolone and methotrexate, which improved his condition. Rheumatoid vasculitis is a rare, but possible cause of recurrent bowel obstruction.

Optimal Follow-up of Patients with Viral Hepatitis Improves the Detection of Early-stage Hepatocellular Carcinoma and the Prognosis of Survival.

Objective To manage patients with viral hepatitis, it is important to screen for hepatitis, conduct a comprehensive examination if such screening is positive, administer antiviral treatment, and conduct surveillance for hepatocellular carcinoma (HCC). The proper execution of this strategy is expected to effectively reduce the number of deaths from viral hepatitis. Such an "optimal" follow-up for HCC surveillance is therefore important. This study aimed to determine the benefits of performing an optimal follow-up of patients with viral hepatitis. Methods The subjects were infected with the hepatitis virus and were initially diagnosed with or treated for HCC from 2004-2012. We retrospectively analyzed the history of a patient's current illness using the hospital discharge summary. To minimize any lead-time bias, we calculated the corrected survival for patients who received an optimal follow-up. Results Of 333 patients, 107 (32.1%) did not receive an optimal follow-up and thus had low cumulative survival rates in comparison to those who did. The median corrected survival was 51.5 months for patients with an optimal follow-up compared with 31.4 months for those without (p=0.011). A multivariate analysis revealed that AFP <35 [odds ratio (OR), 2.054], Child-Pugh A (OR, 2.488), and an optimal follow-up (OR, 4.539) were independent factors associated with the detection of early-stage HCC. Age (OR, 0.939), tumor stage I/II (OR, 6.918), and an optimal follow-up (OR, 3.213) were found to be independent factors associated with receiving curative treatment. Conclusion An optimal follow-up of patients with viral hepatitis independently increased the detection of early-stage HCC and the administration of curative treatment. Patients with an optimal follow-up survived longer than those without.