Transforming Growth Factorß1 Overexpression Is Associated with Insulin Resistance and Rapidly Progressive Kidney Fibrosis under Diabetic Conditions.

Diabetes mellitus is a global health problem. Diabetic nephropathy is a common complication of diabetes mellitus and the leading cause of end-stage renal disease. The clinical course, response to therapy, and prognosis of nephropathy are worse in diabetic than in non-diabetic patients. The role of transforming growth factorß1 in kidney fibrosis is undebatable. This study assessed whether the overexpression of transforming growth factorß1 is associated with insulin resistance and the rapid progression of transforming growth factorß1-mediated nephropathy under diabetic conditions. Diabetes mellitus was induced with streptozotocin in wild-type mice and transgenic mice with the kidney-specific overexpression of human transforming growth factorß1. Mice treated with saline were the controls. Glucose tolerance and kidney fibrosis were evaluated. The blood glucose levels, the values of the homeostasis model assessment for insulin resistance, and the area of kidney fibrosis were significantly increased, and the renal function was significantly impaired in the diabetic transforming growth factorß1 transgenic mice compared to the non-diabetic transgenic mice, diabetic wild-type mice, and non-diabetic mice. Transforming growth factorß1 impaired the regulatory effect of insulin on glucose in the hepatocyte and skeletal muscle cell lines. This study shows that transforming growth factorß1 overexpression is associated with insulin resistance and rapidly progressive kidney fibrosis under diabetic conditions in mice.

Thrombomodulin ameliorates transforming growth factor-ß1-mediated chronic kidney disease via the G-protein coupled receptor 15/Akt signal pathway.

Kidney fibrosis is the common consequence of chronic kidney diseases that inexorably progresses to end-stage kidney disease with organ failure treatable only with replacement therapy. Since transforming growth factor-ß1 is the main player in the pathogenesis of kidney fibrosis, we posed the hypothesis that recombinant thrombomodulin can ameliorate transforming growth factor-ß1-mediated progressive kidney fibrosis and failure. To interrogate our hypothesis, we generated a novel glomerulus-specific human transforming growth factor-ß1 transgenic mouse to evaluate the therapeutic effect of recombinant thrombomodulin. This transgenic mouse developed progressive glomerular sclerosis and tubulointerstitial fibrosis with kidney failure. Therapy with recombinant thrombomodulin for four weeks significantly inhibited kidney fibrosis and improved organ function compared to untreated transgenic mice. Treatment with recombinant thrombomodulin significantly inhibited apoptosis and mesenchymal differentiation of podocytes by interacting with the G-protein coupled receptor 15 to activate the Akt signaling pathway and to upregulate the expression of anti-apoptotic proteins including survivin. Thus, our study strongly suggests the potential therapeutic efficacy of recombinant thrombomodulin for the treatment of chronic kidney disease and subsequent organ failure.

Long-term course of Crohn's disease in Japan: Incidence of complications, cumulative rate of initial surgery, and risk factors at diagnosis for initial surgery.

BACKGROUND AND AIMS: Intestinal complications of stenosis or fistula may occur during the course of Crohn's disease (CD), and surgery is performed in a fair number of patients. The risk factors for initial surgery in a Japanese hospital-based cohort of CD patients were evaluated. METHODS: This study was a single-center, retrospective, cohort study. The subjects were 520 patients who underwent inpatient and outpatient treatment at our hospital, had a definitive diagnosis of CD, and no previous surgery. Three parameters were investigated: (i) cumulative incidence of stenosis and fistula; (ii) cumulative rate of initial surgery for each disease type; and (iii) risk factors at diagnosis for initial surgery. RESULTS: (i) Stenosis and fistula increased with time, with stenosis or fistula appearing in about half of the patients after 5 years. (ii) The cumulative rate of initial surgery was about 50% after 10 years. (iii) The patient factors at diagnosis of current smoker, upper gastrointestinal disease, stricturing, penetrating, moderate to severe stenosis of the jejunum, moderate to severe stenosis of the ileum, and moderate to severe stenosis of the terminal ileum were risk factors for initial surgery. CONCLUSIONS: Stenosis or fistula appeared in about half of the patients after 5 years from diagnosis. When upper gastrointestinal disease or complicated small intestinal lesions are seen at the time of diagnosis, the cumulative rate of initial surgery is significantly higher.

Occurrence, molecular characterization, and antimicrobial susceptibility of Aeromonas spp. in marine species of shrimps cultured at inland low salinity ponds.

We aimed to document the risk of Aeromonas spp. in marine shrimp species cultured in inland low salinity ponds in Thailand. In 14 of 18 shrimp samples retrieved from inland grow-up ponds, Aeromonas spp. were detected at ranges from 4667 to 1,500,000 CFU/g body weight. The phylogenetic tree constructed with the gyrB and cpn60 concatenated sequences indicated that the 87 isolates consisted of Aeromonas veronii (70%), Aeromonas aquariorum (18%), Aeromonas caviae (7%), Aeromonas jandaei (2%), and Aeromonas schubertii (2%). The potential virulence of the isolates was examined by phenotypic and PCR assays. Hemolytic activity and the extracellular activity of lipase, DNase, and gelatinase were observed in most isolates (94-99%). PCR revealed the presence of 9 genes related to virulence in the 87 isolates: act (75%), aer (74%), alt (30%), ast (1%), ascV (34%), aexT (24%), fla (92%), ela (34%), and lip (24%). The susceptibility profiles to 14 antimicrobial agents of isolates were typical for the genus, but resistance to cefotaxime, a third-generation cephalosporin, and imipenem were found in two A. aquariorum and in three A. veronii isolates, respectively. These resistances were confirmed by determining minimum inhibitory concentrations. Our results indicate that the microbiological risk posed by Aeromonas should be considered for marine shrimp species that are cultured in low-salinity ponds. These shrimps may also be a vehicle for the transfer of different genotypes of Aeromonas and antibiotic-resistant determinants to regions worldwide through trade.

Mucosal healing of ileal lesions is associated with long-term clinical remission after infliximab maintenance treatment in patients with Crohn's disease.

BACKGROUND AND AIM: The aim of the present study was to endoscopically evaluate ileal mucosal healing during maintenance therapy with infliximab in order to investigate the clinical significance of endoscopic examination of ileal lesions in Crohn's disease patients. METHODS: This study retrospectively analyzed 54 patients who mainly had active ulcers of the ileum on endoscopy at baseline who were responsive to infliximab induction and who received infliximab maintenance therapy. Mucosal healing was defined as no ulcer or only ulcer scar. At the time of follow-up endoscopy after starting infliximab, endoscopic score, mucosal healing, and clinical remission were evaluated. On long-term follow up, correlations between mucosal healing and long-term clinical remission, and between mucosal healing and the need for major abdominal surgery, were also evaluated. RESULTS: Ileal mucosal healing and complete mucosal healing were significantly correlated with clinical remission (P = 0.046, P = 0.0001, respectively). The rate of long-term clinical remission was significantly higher in patients with complete mucosal healing (P = 0.025). The rate of major abdominal surgery for strictures was significantly lower in patients with complete mucosal healing (P = 0.044). CONCLUSIONS: Complete mucosal healing after 1-2 years was a predictive factor for long-term clinical remission up to 4 years after starting infliximab. A lack of complete mucosal healing was a predictive factor for major abdominal surgery for strictures. The present study suggests that endoscopic evaluation of ileal lesions is useful for long-term prognosis of Crohn's disease patients.

Sulfitobacter porphyrae sp. nov., isolated from the red alga Porphyra yezoensis.

Gram-stain-negative, aerobic, halophilic bacteria, designated SCM-1(T), LCM10-1 and CTBL-B-147, were isolated from modified half-strength SWM-III medium, PES medium and thalli after laboratory cultivation of a red alga, Porphyra yezoensis. Phylogenetic analysis of 16S rRNA gene sequences indicated that the new isolates were affiliated to the genus Sulfitobacter of the class Alphaproteobacteria, and the 16S rRNA gene sequence similarity of the new isolates with the closest related species, Sulfitobacter mediterraneus CH-B427(T), was 98.8%. The DNA G+C contents of the new isolates were in the range of 61.4-62.3 mol%. DNA-DNA relatedness values of strain SCM-1(T) with other type strains of the genus Sulfitobacter were less than 15.9%. The new isolates contained Q-10 as the predominant ubiquinone, phosphatidylcholine, phosphatidylglycerol, an unidentified amino lipid and an unidentified lipid as the main polar lipids, and C(18 : 1)ω7c, C(19 : 1)ω7c and C(16 : 0) as the major fatty acids (>10% of the total). Strain SCM-1(T) could be differentiated from Sulfitobacter mediterraneus JCM 21792(T) by 35 morphological and phenotypic characteristics. On the basis of the phylogenetic, genetic and phenotypic properties of the new isolates, the name Sulfitobacter porphyrae sp. nov. is proposed, with strain SCM-1(T) ( = LMG 27110(T) = NBRC 109054(T)) as the type strain.

Isolation of hyphomonas strains that induce normal morphogenesis in protoplasts of the marine red alga Pyropia yezoensis.

Marine macroalgae cannot develop normal morphology under axenic conditions although normal morphogenesis can be sustained when certain bacteria are present. In this study, bacteria that induced normal morphogenesis in the red alga Pyropia yezoensis (Nori) were identified. The bacteria were isolated from algal media, thalli, tissue debris, and purified protoplasts during protoplast isolation from P. yezoensis laboratory cultures. 16S rRNA gene sequence analysis showed these bacterial isolates belonged to α-Proteobacteria (12 groups), γ-Proteobacteria (3 groups), and Flavobacteria (2 groups). Axenic protoplasts of P. yezoensis generated by removing epiphytic bacteria were co-cultured along with the bacterial isolates. Most axenic protoplasts showed irregular morphogenetic and anaplastic cells; cells with normal morphology were scarce. However, inoculation with 11 strains of Hyphomonas (α-Proteobacteria) led to significantly higher normal morphogenetic rates (4.5-7.3 %, P < 0.01 or 0.05) compared to axenic protoplasts (0.06 %). These Hyphomonas strains were recovered from all experiments; thus, certain Hyphomonas strains can induce normal morphogenesis in P. yezoensis protoplasts. Direct inoculation of the Hyphomonas strain exhibited higher morphogenetic activity than inoculation of its extracellular and intracellular products. This is the first study demonstrating the influence of specific bacteria on protoplast morphology in marine macroalgae.

Impact of CYP3A5 genetic polymorphisms on the pharmacokinetics and short-term remission in patients with ulcerative colitis treated with tacrolimus.

BACKGROUND AND AIM: The pharmacokinetics of tacrolimus (Tac) differ among individuals, and genetic polymorphisms of cytochrome P-450 (CYP) 3A4, CYP3A5, and ABCB1 are thought to be involved. The aim of this study was to clarify whether these genetic polymorphisms affect the pharmacokinetics of Tac in patients with ulcerative colitis. METHODS: The subjects in this study were 45 patients with moderate-to-severe ulcerative colitis who were resistant to other therapies and were treated with Tac. The subjects were tested for genetic polymorphisms of CYP3A4, CYP3A5, and ABCB1, and the relationship between Tac pharmacokinetics and the remission rate was investigated. RESULTS: Of the 45 subjects, 24 (53.3%) were CYP3A5 expressers (Exp), and 21 (46.7%) were non-expressers (Non-Exp). The trough level and the dose-adjusted trough level on days 2-5 were significantly higher in the Non-Exp group than in the Exp group (10.16 ± 5.84 vs 4.47 ± 2.50 ng/mL, P < 0.0001, 139.36 ± 77.43 vs 61.37 ± 41.55 ng/mL per mg/kg/day, P < 0.0001). The percentage of patients achieving the optimal trough level on days 2-5 was significantly higher in the Non-Exp group than in the Exp group (40.0% vs 4.3%, P = 0.01). This trend was also observed on days 7-10. On multivariate analysis, factors associated with achievement of the optimal trough level were food non-intake and Non-Exp of CYP3A5. The remission rate was significantly higher in the Non-Exp group than in the Exp group (47.6% vs 16.7%, P = 0.046). CONCLUSIONS: CYP3A5 genetic polymorphisms affected the pharmacokinetics of Tac, so that the short-term clinical remission rate was different between Exp and Non-Exp of CYP3A5.

Second peak in the distribution of age at onset of ulcerative colitis in relation to smoking cessation.

BACKGROUND AND AIM: The prevalence of ulcerative colitis (UC) is increasing steadily in Japan. In Western countries, a bimodal distribution, with UC onset peaks in youth and middle age, is observed, and smoking cessation is reported as a risk factor for UC. However, there are few reports on a bimodal distribution of onset age among Japanese patients. Therefore, the distribution of onset age and factors related to late onset (i.e. onset at 50 years old or later) were investigated in UC patients in Japan. METHODS: A questionnaire survey of UC patients was conducted to investigate the distribution of the age of onset and factors that may be related to UC onset in a Japanese university hospital. RESULTS: Among 465 UC patients, 343 patients responded. In the distribution of onset age, a large peak was seen in patients aged 10-20s, and small peaks were seen at age 40-44 years and then in 50-60s. In addition, the onset age was older in the UC patients diagnosed in 2001 or later than in those diagnosed in 2000 or earlier. Late onset was more common among the UC patients diagnosed in 2001 or later (vs 2000 or earlier: interaction odds ratio = 4.98, 95% CI: 2.21-11.25, P < 0.01) and among former smokers (vs never-smokers: interaction odds ratio = 2.93, 95% CI: 1.40-6.14, P < 0.01) on multivariate analysis. CONCLUSIONS: Similar to UC patients in Western countries, a bimodal distribution of onset age was also observed in Japanese UC patients, and smoking cessation may partly contribute to the increase in late-onset UC patients in recent years in Japan.

Patients' assessment of adalimumab self-injection for Crohn's disease: a multicenter questionnaire survey (The PEARL Survey).

BACKGROUND/AIMS: Adalimumab (ADA) is a self-injectable anti-tumor necrosis factor-α antibody used for treating Crohn's disease (CD). Although self-injecting ADA may be convenient for patients, few reports have assessed patients receiving ADA self-injection therapy. METHODOLOGY: We conducted a questionnaire survey involving outpatients on ADA self-injection therapy at four university hospitals. We analyzed the degree of satisfaction with and adherence to the self-injection therapy and performed sub-analyses. RESULTS: Responses were obtained from 124 patients. Before treatment initiation, 38% patients replied that they were unwilling to accept the self-injection therapy. However, after treatment initiation, 75% patients were satisfied with the treatment. 66 patients previously treated with infliximab (IFX), the degree of treatment satisfaction was significantly higher in patients who felt burdened to the time required for IFX infusion than in those who had not felt burdened (P < 0.05). Patient adherence to ADA was high (85%). Multivariate analysis regarding adherence revealed that duration of disease (OR, 0.99), degree of treatment efficacy satisfaction (OR, 13.42), and schedule registration (OR, 7.95) were significant. Safety assessment results were within the range of those already reported. CONCLUSIONS: ADA self-injection was thought to have good adherence and a safe administration method according to patients' assessments.

Long-term outcome of endoscopic balloon dilation for small bowel strictures in patients with Crohn's disease.

BACKGROUND AND AIM: Endoscopic balloon dilation (EBD) is an alternative to surgery for small bowel strictures of patients with Crohn's disease (CD). However, little is known about the long-term efficacy of EBD. The aim of the present study was to clarify the long-term outcome of EBD for small bowel strictures in patients with CD. METHODS: Subjects comprised 65 patients with CD who underwent EBD for small intestinal strictures and were followed up for at least 6 months. All subjects had obstructive symptoms as a result of small bowel strictures. Short-term success was defined as technical success and the disappearance of obstructive symptoms. The short-term success rate of EBD, its safety profile, the cumulative surgery-free rate and the cumulative redilation-free rate were investigated. RESULTS: Short-term success rate was 80.0% (52/65). Complications were encountered in six of the 65 patients (9.2%). Seventeen patients (26.2%) underwent surgery during the observation period of this study. Cumulative surgery-free rate after initial EBD was 79% at 2 years and 73% at 3 years, respectively. EBD successful cases showed significantly higher surgery-free rates than unsuccessful cases (P < 0.0001). In 52 of the successful cases, the cumulative redilation-free rate after initial EBD was 64% at 2 years and 47% at 3 years, respectively. CONCLUSION: EBD for small bowel strictures secondary to CD provides not only short-term success but also long-term efficacy. However, the high redilation rate is one of the clinical problems of this procedure.

Algimonas ampicilliniresistens sp. nov., isolated from the red alga Porphyra yezoensis, and emended description of the genus Algimonas.

Three strains (14A-2-7(T), 14A-3-1 and 14A-3) of Gram-stain-negative, prosthecate, motile bacteria were isolated from an algal medium supplemented with 10 mg ampicillin l(-1) (w/v), in which the red alga Porphyra yezoensis had been cultured. Based on the 16S rRNA gene sequence analysis, the three isolates formed a cluster with the genus Algimonas of the family Hyphomonadaceae. The sequences of the three isolates had high similarity with those of Algimonas porphyrae 0C-2-2(T) (97.6 % similarity) and Litorimonas taeanensis G5(T) (95.6 % similarity). The DNA G+C contents of the three isolates ranged from 54.3 to 55.0 mol%, which were more similar to that of A. porphyrae 0C-2-2(T) (58.5 mol%) than to that of L. taeanensis G5(T) (47.1 mol%). The DNA-DNA relatedness showed that the three isolates were representatives of the same species (88.1-94.0 % relatedness) and that strain 14A-2-7(T) was a representative of a different species from A. porphyrae 0C-2-2(T) and L. taeanensis G5(T) (1.2-8.6 % relatedness). The phenotypic characteristics of strain 14A-2-7(T) differed by 20 results and 30 results from A. porphyrae 0C-2-2(T) and L. taeanensis G5(T), respectively. The three isolates contained ubiquinone-10 as the predominant quinone and C18 : 1ω7c as the major fatty acid. Based on the polyphasic taxonomic analysis, the three isolates represent a novel species of the genus Algimonas, for which the name Algimonas ampicilliniresistens sp. nov. is proposed. The type strain is 14A-2-7(T) ( = LMG 26421(T) = NBRC 108219(T)). An emended description of the genus Algimonas is also proposed.

Polaribacter porphyrae sp. nov., isolated from the red alga Porphyra yezoensis, and emended descriptions of the genus Polaribacter and two Polaribacter species.

Three Gram-negative, non-motile, strictly aerobic strains, designated LNM-20(T), LCM-1 and LAM-13, were isolated from thalli of the marine red alga Porphyra yezoensis. Phylogenetic analysis based on 16S rRNA gene sequences revealed that the isolates were associated with the genus Polaribacter in the family Flavobacteriaceae and were most closely related to Polaribacter dokdonensis DSW-5(T) (96.2 % 16S rRNA gene sequence similarity) and Polaribacter gangjinensis K17-16(T) (95.0 %). The DNA G+C content of the isolates was 28.6-29.2 mol%. DNA-DNA hybridization analysis showed that the isolates belonged to a single species distinct from both of their closest relatives. The only isoprenoid quinone detected was menaquinone-6. The main polar lipids were phosphatidylethanolamine, two unidentified aminolipids and two unidentified lipids. The major fatty acids were iso-C15 : 0, iso-C15 : 1ω10c and iso-C15 : 0 3-OH. The phenotypic features of strain LNM-20(T) differed from those of their closest relatives in several regards (colony colour, growth with 1 % NaCl and on TSA plus 2.5 % NaCl, hydrolysis of Tweens 40 and 80, and oxidization of five carbon compounds). On the basis of phylogenetic, chemotaxonomic and phenotypic analysis, the isolates represent a novel species in the genus Polaribacter, for which the name Polaribacter porphyrae sp. nov. is proposed. The type strain is LNM-20(T) ( = LMG 26671(T)  = NBRC 108759(T)). Emended descriptions of the genus Polaribacter and P. dokdonensis and P. gangjinensis are also proposed.

Algimonas porphyrae gen. nov., sp. nov., a member of the family Hyphomonadaceae, isolated from the red alga Porphyra yezoensis.

Three Gram-negative, stalked, motile bacteria, designated 0C-2-2(T), 0C-17 and LNM-3, were isolated from the red alga Porphyra yezoensis. 16S rRNA gene sequence analysis revealed that the three novel strains belonged to the family Hyphomonadaceae, and were closely related to Litorimonas taeanensis G5(T) (96.5 % 16S rRNA gene sequence similarity) and Hellea balneolensis 26III/A02/215(T) (94.3 %). The DNA G+C contents of the novel isolates (58.5-60.2 mol%) were clearly distinguished from those of L. taeanensis G5(T) (47.1 mol%) and H. balneolensis DSM 19091(T) (47.9 mol%). The G+C content of L. taeanensis G5(T) obtained in this study was quite different from a previous report (63.6 mol%). DNA-DNA hybridization experiments showed that the novel strains constituted a single species. Eleven phenotypic features of the three isolates differed from those of both related genera. The predominant respiratory quinone was ubiquinone-10 and the major fatty acid was C(18 : 1)ω7c. On the basis of this polyphasic taxonomic analysis, the novel strains represent a novel genus and species, for which the name Algimonas porphyrae gen. nov., sp. nov. is proposed. The type strain of Algimonas porphyrae is 0C-2-2(T) (= LMG 26424(T) = NBRC 108216(T)).

Cancer risk in Japanese Crohn's disease patients: investigation of the standardized incidence ratio.

BACKGROUND AND AIM: There have been very few reported investigations on the standardized incidence ratio (SIR) of intestinal cancer and all cancers other than intestinal cancer with Crohn's disease (CD) by organ in Japan. This study examined the risk of developing cancer (i.e. SIR) that occurs in association with CD. METHODS: The subjects were 770 CD patients managed at our hospital department, which specializes in inflammatory bowel disease, during the approximately 25 years from July 1985 to August 2010. The number of expected cancer patients in a healthy population matched for sex and age with the CD patients in our hospital was then calculated. The relative risk, or SIR, was also calculated. RESULTS: The total observation period was 10,552 person-years, during which 19 cases (2.5%) of cancer were discovered in 770 subjects. The cancer cases included nine cases of colorectal cancer (CRC), one case of small bowel cancer, one case of stomach cancer, three cases of acute myeloid leukemia, two cases of endometrial cancer, one case of lung cancer, one case of skin cancer, and one case of thyroid cancer. The SIR for cancers in Japan in 2003 was 0.87 (95% confidence interval [CI] 0.52-1.35) for all cancers, 2.79 (95% CI 1.28-5.29) for CRC, and 6.94 (95% CI 1.43-20.3) for leukemia. CONCLUSIONS: Among the cancers in CD patients in our hospital, no significant difference was seen in the risk for all cancers in comparison with the standard population. However, the risks for CRC and leukemia were significantly higher than in the standard population.

Incidence, clinical characteristics, long-term course, and comparison of progressive and nonprogressive cases of aphthous-type Crohn's disease: a single-center cohort study.

BACKGROUND/AIMS: In Japan, aphthous-type Crohn's disease (type A CD) is thought to represent an early phase of Crohn's disease (CD), and diagnosis of type A CD is possible in the diagnostic criteria for CD in Japan. However, the details of type A CD are not well understood. METHODS: Subjects comprised 649 CD patients diagnosed between 1985 and 2011. The incidence of type A CD over time was clarified in two periods (1985-2004 and 2005-2011). The course of type A CD was also investigated, and cases that did and did not progress to typical CD were compared. RESULTS: No significant difference was seen in the incidence of type A CD between the two periods (5.2 vs. 8.5%, p = 0.125). Type A CD patients followed at our hospital progressed to typical CD at a rate of 59.3%. In comparing progressive and nonprogressive cases, the frequency of large, densely distributed aphthous lesions in the small intestine was higher among progressive cases (p = 0.018). CONCLUSION: Type A CD is an early phase of CD, and CD diagnostic criteria including early cases are valid in Japan.

DHA and EPA levels in a piscivorous fish changed by preying upon stocked salmon fry.

Increases in prey population size can affect the physiology and ecology of upper-trophic level organisms. This phenomenon is known as a bottom-up effect. For example, the increased abundance of prey resources can trigger physiological (internal) changes in predators, such as improvements in nutritional status. However, these physiological aspects of bottom-up effects have not been considered. In this study, we tested the hypothesis that white-spotted charr Salvelinus leucomaenis, a salmonid fish, increases body stores of omega-3 fatty acids, especially docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), by preying upon stocked hatchery-reared masu salmon Oncorhynchus masou fry in streams. The dynamics of fatty acid contents in charr inhabiting salmon-stocked and unstocked streams clearly support this hypothesis: fatty acid contents (DHA, EPA, and total fatty acid) increased after stocking in stocked streams, but not in unstocked streams. In addition, DHA increased with increasing body size of white-spotted charr and vice versa for EPA. The impacts of human activities, such as fish stocking, on freshwater ecosystems are a matter of serious concern for conservation. Future attempts to gain a comprehensive understanding of the impacts of fish stocking should consider not only community ecology but also physiology.

Reduced blood glucose levels by the combination of vadadustat in an elderly patient with chronic kidney disease who was receiving mitiglinide and sitagliptin: a case report.

BACKGROUND: Our case is the first report showing the development of hypoglycemia following the administration of vadadustat in a patient with chronic kidney disease being treated with mitiglinide and sitagliptin, possibly due to drug-drug interaction between vadadustat and sitagliptin under the administration of mitiglinide. CASE PRESENTATION: A 72-year-old man with type 2 diabetes mellitus had received sitagliptin 50 mg once daily and mitiglinide 10 mg three times daily over the last 3 years. He initiated vadadustat 300 mg once daily orally on day X owing to renal anemia (hemoglobin A1c: 7.4% and estimated glomerular filtration rate: 28.0 mL/min/1.73 m2). On day 23, he developed hypoglycemia with a blood glucose level of 67 mg/dL. The mean blood glucose level ± standard deviation was lower in the first 24 days of co-administration of vadadustat (before breakfast: 94 ± 14 mg/dL, before lunch: 109 ± 24 mg/dL, and before dinner: 126 ± 39 mg/dL) than in the last 2 weeks (before breakfast: 108 ± 14 mg/dL, before lunch: 122 ± 24 mg/dL, and before dinner: 158 ± 39 mg/dL). Considering the timing of the concomitant administration of vadadustat, hypoglycemia may have been caused by the drug-drug interaction between sitagliptin and vadadustat, and he discontinued treatment with vadadustat. The mean blood glucose levels improved two weeks after the discontinuation of vadadustat (before breakfast: 121 ± 25 mg/dL, before lunch: 147 ± 38 mg/dL, and before dinner: 161 ± 36 mg/dL). The drug interaction probability scale was classified as "Probable" (5 points). CONCLUSIONS: Hypoglycemia was observed when sitagliptin, mitiglinide, and vadadustat were concomitantly administered, which may have resulted in a drug-drug interaction between vadadustat and sitagliptin via OAT3 inhibition in the renal tubules.

Associated factors and effects of comorbid atrial fibrillation in hypertensive patients due to primary aldosteronism.

The incidence of atrial fibrillation (AF) and risk of cardiovascular events are reportedly higher in patients with primary aldosteronism (PA) than essential hypertension. However, associated factors of comorbid AF and cardiovascular events in PA patients after PA treatment remain unclear. This nationwide registration study included PA patients ≥20 years old. Incident cardiovascular events were observed with a mean follow-up of approximately 3 years. A total of 3654 patients with PA were included at the time of analysis. Prevalence of AF was 2.4%. PA patients with AF were older, more frequently male and had longer duration of hypertension than those without AF. No significant difference in basal plasma and adrenal venous aldosterone concentration, renin activity, potassium concentration, confirmatory tests of PA, laterality or surgery rate were seen between groups. Logistic regression analysis showed age, male sex, cardiothoracic ratio, past history of coronary artery disease and heart failure were independent factors associated with AF. PA patients with AF showed a higher frequency of cardiovascular events than those without AF (P < 0.001). Multivariate Cox analyses demonstrated AF in addition to older age, duration of hypertension, body mass index and chronic kidney disease as independent prognostic factors for cardiovascular events after PA treatment. Incidence of cardiovascular events were significantly lower in PA patients with AF than AF patients from the Fushimi registry during follow-up after adjusting age, sex and systolic blood pressure. Early diagnosis of PA may prevent AF and other cardiovascular events in PA patients by shortening the duration of hypertension and appropriate PA treatment.