Publications by authors named "Takako Saito"

48 Publications

Visualization of cross-resistance between antimicrobial agents by asymmetric multidimensional scaling.

J Clin Pharm Ther 2021 Nov 24. Epub 2021 Nov 24.

Faculty of Management and Information Sciences, Tama University, Tokyo, Japan.

What Is Known And Objective: In our previous studies, we developed a cross-resistance rate (CRR) correlation diagram (CRR diagram) that visually captures the magnitude of CRRs between antimicrobials using scatter plots. We used asymmetric multidimensional scaling (MDS) to transform cross-resistance similarities between antimicrobials into a 2-dimensional map and attempted to visually express them. We also explored the antibiograms of Pseudomonas aeruginosa before and after the transfer to newly built hospitals, and we determined by the CRR diagram that the CRRs among β-lactam antimicrobials other than carbapenems decreased substantially with the facility transfer. The present study tests whether the analysis of CRRs by asymmetric MDS can be used as new visual information that is easy for healthcare professionals to understand.

Method: We tested the impact of changes in the nosocomial environment due to institutional transfers on CRRs among antimicrobials in asymmetric MDS, as well as contrasted the asymmetric MDS map and CRR diagram.

Results And Discussion: In the asymmetric MDS map, antimicrobial groups with the same mechanism of action were displayed close together, and antimicrobial groups with different mechanisms of action were displayed separately. The asymmetric MDS map drawn solely for antimicrobials belonging to the group with the same mechanism of action showed similarities to the CRR diagram. Also, the distance of each antimicrobial to other antimicrobials shown in the asymmetric MDS map was negatively correlated with the CRRs for them against that antimicrobial.

What Is New And Conclusion: The asymmetric MDS map expresses the dissimilarity as distances between agents, and there are no meanings or units on the ordinate and abscissa axes of the output map. In contrast, the CRR diagram expresses the antimicrobials' resistance status as values, such as resistance rate and CRR. By analysing the CRRs in the asymmetric MDS, it is feasible to visually recognize cross-resistance similarities between antimicrobial groups as distances. The use of the asymmetric MDS combined with the CRR diagram allows us to visually understand the resistance and cross-resistance status of each antimicrobial agent as a 2-dimensional map, as well as to understand the trends and characteristics of the data by means of quantitative values.
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http://dx.doi.org/10.1111/jcpt.13564DOI Listing
November 2021

Monitoring antimicrobial cross-resistance with cross-resistance rate correlation diagrams: Changes in antibiotic susceptibility of Pseudomonas aeruginosa due to hospital relocation.

J Clin Pharm Ther 2021 Apr 28;46(2):395-407. Epub 2020 Oct 28.

Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi-shi, Osaka, Japan.

What Is Known And Objective: Though most medical institutions calculate antimicrobial susceptibility and resistance rates of microbes isolated at their own facility as part of their efforts to promote the proper use of antibiotics, very few, if any, regularly monitor cross-resistance rates between antimicrobial agents. The authors have devised a tool in the form of a cross-resistance rate correlation diagram (CRR diagram) that allows easy identification of increases or decreases in, or changes in the pattern of, antimicrobial cross-resistance. The objective was to perform an analysis by CRR diagrams of the effect of relocation to a newly built facility on antimicrobial resistance and cross-resistance rates at a medical facility.

Methods: The Sakai City Medical Center relocated in July 2015 to a newly built facility located in a different primary medical care zone 3.5 km away. Based on the drug susceptibility test data compiled at the Sakai City Medical Center, resistance and cross-resistance rates of Pseudomonas aeruginosa before and after the relocation of the hospital facility were calculated, and the rates were assessed using CRR diagrams.

Results And Discussion: It was possible to confirm the effect of hospital relocation on antibiotic susceptibility of P aeruginosa in terms of changes in resistance and cross-resistance rates. The effect of the facility's relocation on cross-resistance rates was particularly notable with respect to β-lactam antibiotics: cross-resistance rates among β-lactams decreased substantially, represented as a large wedge-shaped change towards the origin on the CRR diagram. Rates of cross-resistance between classes of antibiotics with a different mechanism of antibiotic action changed little.

What Is New And Conclusion: Including cross-resistance rates in the routine monitoring of resistance and susceptibility rates practiced by a medical institution can provide a comprehensive insight into the dynamics of bacterial flora in the facility. CRR diagrams, which allow visualization of the status and changes in cross-resistance, not only provide a new perspective for clinicians, but they also contribute to the proper use of antibiotics and serve as a tool in the education of healthcare professionals and students about antibiotic resistance.
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http://dx.doi.org/10.1111/jcpt.13296DOI Listing
April 2021

Unveiling a novel function of CD9 in surface compartmentalization of oocytes.

Development 2020 08 14;147(15). Epub 2020 Aug 14.

Department of Cell Science, Institute of Biomedical Sciences, School of Medicine, Fukushima Medical University, 1 Hikarigaoka, Fukushima City, Fukushima 960-1295, Japan.

Gamete fusion is an indispensable process for bearing offspring. In mammals, sperm IZUMO1-oocyte JUNO recognition essentially carries out the primary step of this process. In oocytes, CD9 is also known to play a crucial role in gamete fusion. In particular, microvilli biogenesis through CD9 involvement appears to be a key event for successful gamete fusion, because CD9-disrupted oocytes produce short and sparse microvillous structures, resulting in almost no fusion ability with spermatozoa. In order to determine how CD9 and JUNO cooperate in gamete fusion, we analyzed the molecular profiles of each molecule in CD9- and JUNO-disrupted oocytes. Consequently, we found that CD9 is crucial for the exclusion of GPI-anchored proteins, such as JUNO and CD55, from the cortical actin cap region, suggesting strict molecular organization of the unique surface of this region. Through distinct surface compartmentalization due to CD9 governing, GPI-anchored proteins are confined to the appropriate fusion site of the oocyte.
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http://dx.doi.org/10.1242/dev.189985DOI Listing
August 2020

Influence of analysis conditions for antimicrobial susceptibility test data on susceptibility rates.

PLoS One 2020 23;15(6):e0235059. Epub 2020 Jun 23.

Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi-shi, Osaka, Japan.

Background: To support effective antibiotic selection in empirical treatments, infection control interventions, and antimicrobial resistance containment strategies, many medical institutions collect antimicrobial susceptibility test data conducted at their facilities to prepare cumulative antibiograms.

Aim: To evaluate how the setpoints of duplicate isolate removal period and data collection period affect the calculated susceptibility rates in antibiograms.

Methods: The Sakai City Medical Center is a regional core hospital for tertiary emergency medical care with 480 beds for general clinical care. In this study, all the Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae isolates collected at the Sakai City Medical Center Clinical Laboratory between July 2013 and December 2018 were subjected to antimicrobial susceptibility tests and the resulting data was analyzed.

Findings: The longer the duplicate isolate removal period, the fewer the isolates are available for every bacterial species. Differences in the length of the duplicate isolate removal period affected P. aeruginosa susceptibility rates to β-lactam antibiotics by up to 10.8%. The setpoint of the data collection period affected the antimicrobial susceptibility rates by up to 7.3%. We found that a significant change in susceptibility could be missed depending on the setting of the data collection period, in preparing antibiogram of β-lactam antibiotics for P. aeruginosa.

Conclusions: When referring to antibiograms, medical professionals involved in infectious disease treatment should be aware that the parameter values, such as the duplicate isolate removal period and the data collection period, affect P. aeruginosa susceptibility rates especially to β-lactam antibiotics. And antibiogram should be updated within the shortest time period that is practically possible, taking into account restrictions such as numbers of specimen.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235059PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310835PMC
September 2020

Sperm IZUMO1-Dependent Gamete Fusion Influences Male Fertility in Mice.

Int J Mol Sci 2019 Sep 27;20(19). Epub 2019 Sep 27.

Department of Cell Science, Institute of Biomedical Sciences, School of Medicine, Fukushima Medical University, 1 Hikarigaoka, Fukushima City, Fukushima 960-1295, Japan.

Sperm-egg fusion is accomplished through the interaction of a specific set of membrane proteins in each gamete: sperm IZUMO1 and oocyte JUNO. Recently, we found that alternative splicing of the gene generates a novel IZUMO1 isoform (IZUMO1_v2). Here, we obtained four mouse lines, having graded different levels of IZUMO1 protein by combining an original IZUMO1 (IZUMO1_v1) knockout with IZUMO1-null (both IZUMO1_v1 and _v2 disrupted) genetic background, in order to determine how the quantity of IZUMO1 influences male fertility. Subsequently, we clarified that the signal intensity from two quantitative assays, western blot and immunostaining analyses with a monoclonal antibody against mouse IZUMO1, were strongly correlated with average litter size. These results suggest that evaluating IZUMO1 protein levels is useful for predicting fecundity, and is a suitable test for male fertility.
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http://dx.doi.org/10.3390/ijms20194809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801368PMC
September 2019

Alternative splicing of the Izumo1 gene ensures triggering gamete fusion in mice.

Sci Rep 2019 02 28;9(1):3151. Epub 2019 Feb 28.

Department of Cell Science, Institute of Biomedical Sciences, School of Medicine, Fukushima Medical University, 1 Hikarigaoka, Fukushima City, Fukushima, 960-1295, Japan.

IZUMO1 is a sperm acrosomal membrane protein that is essential for mammalian fertilization through recognition of JUNO on the oocyte surface and accompanying IZUMO1-JUNO complex formation. Here, we report a new Izumo1 gene splicing variant (IZUMO1_v2) with a unique 52-amino-acid-long signal sequence transcribed from Exon 1b. Although the mRNA amount of Izumo1_v2 is 76 times lower than that of the original Izumo1 (IZUMO1_v1) in the testis, the cell-oocyte assay indicates that IZUMO1_v2-expressing COS-7 cells have the ability to attach to the oocyte equivalent of IZUMO1_v1. To clarify the physiological function of IZUMO1_v2, we produced an IZUMO1_v1-specific knockout mouse line with a nine-base deletion adjacent to the initial methionine codon of IZUMO1_v1 by the CRISPR/Cas9 system. The IZUMO1_v1 knockout male mice carry 0.19-fold lower level of IZUMO1 protein in the spermatozoon; however, reduction in fertility was only minimally affected compared to the wild-type mice, suggesting that only a small fraction of IZUMO1 is sufficient for triggering sperm-egg fusion. We propose that the alternative splicing generating IZUMO1_v2 might function as a fail-safe in mouse for when splicing is disturbed.
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http://dx.doi.org/10.1038/s41598-019-40130-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395798PMC
February 2019

Structural Basis of the Human Endoglin-BMP9 Interaction: Insights into BMP Signaling and HHT1.

Cell Rep 2017 05;19(9):1917-1928

Department of Biosciences and Nutrition and Center for Innovative Medicine, Karolinska Institutet, Huddinge 14183, Sweden. Electronic address:

Endoglin (ENG)/CD105 is an essential endothelial cell co-receptor of the transforming growth factor β (TGF-β) superfamily, mutated in hereditary hemorrhagic telangiectasia type 1 (HHT1) and involved in tumor angiogenesis and preeclampsia. Here, we present crystal structures of the ectodomain of human ENG and its complex with the ligand bone morphogenetic protein 9 (BMP9). BMP9 interacts with a hydrophobic surface of the N-terminal orphan domain of ENG, which adopts a new duplicated fold generated by circular permutation. The interface involves residues mutated in HHT1 and overlaps with the epitope of tumor-suppressing anti-ENG monoclonal TRC105. The structure of the C-terminal zona pellucida module suggests how two copies of ENG embrace homodimeric BMP9, whose binding is compatible with ligand recognition by type I but not type II receptors. These findings shed light on the molecular basis of the BMP signaling cascade, with implications for future therapeutic interventions in this fundamental pathway.
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http://dx.doi.org/10.1016/j.celrep.2017.05.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464963PMC
May 2017

Dual Impact of Tolvaptan on Intracellular and Extracellular Water in Chronic Kidney Disease Patients with Fluid Retention.

Intern Med 2016;55(19):2759-2764. Epub 2016 Oct 1.

Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Japan.

Objective Tolvaptan, an oral selective V2-receptor antagonist, is a water diuretic that ameliorates fluid retention with a lower risk of a worsening renal function than conventional loop diuretics. Although loop diuretics predominantly decrease extracellular water (ECW) compared with intracellular water (ICW), the effect of tolvaptan on fluid distribution remains unclear. We therefore examined how tolvaptan changes ICW and ECW in accordance with the renal function. Methods Six advanced chronic kidney disease patients (stage 4 or 5) with fluid retention were enrolled in this study. Tolvaptan (7.5 mg/day) added to conventional diuretic treatment was administered to remove fluid retention. The fluid volume was measured using a bioimpedance analysis device before (day 0) and after (day 5 or 6) tolvaptan treatment. Results Body weight decreased by 2.6%±1.3% (64.4±6.5 vs. 62.8±6.3 kg, p=0.06), and urine volume increased by 54.8%±23.9% (1,215±169 vs. 1,709±137 mL/day, p=0.03) between before and after tolvaptan treatment. Tolvaptan significantly decreased ICW (6.5%±1.5%, p=0.01) and ECW (7.5%±1.4%, p=0.02), which had similar reduction rates (p=0.32). The estimated glomerular filtration rate remained unchanged during the treatment (14.6±2.8 vs. 14.9±2.7 mL/min/1.73 m, p=0.35). Conclusion Tolvaptan ameliorates body fluid retention, and induces an equivalent reduction rate of ICW and ECW without a worsening renal function. Tolvaptan is a novel water diuretic that has a different effect on fluid distribution compared with conventional loop diuretics.
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http://dx.doi.org/10.2169/internalmedicine.55.7133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5088534PMC
February 2017

Easy mammalian expression and crystallography of maltose-binding protein-fused human proteins.

J Struct Biol 2016 Apr 3;194(1):1-7. Epub 2016 Feb 3.

Karolinska Institutet, Department of Biosciences and Nutrition & Center for Innovative Medicine, Huddinge, Sweden. Electronic address:

We present a strategy to obtain milligrams of highly post-translationally modified eukaryotic proteins, transiently expressed in mammalian cells as rigid or cleavable fusions with a mammalianized version of bacterial maltose-binding protein (mMBP). This variant was engineered to combine mutations that enhance MBP solubility and affinity purification, as well as provide crystal-packing interactions for increased crystallizability. Using this cell type-independent approach, we could increase the expression of secreted and intracellular human proteins up to 200-fold. By molecular replacement with MBP, we readily determined five novel high-resolution structures of rigid fusions of targets that otherwise defied crystallization.
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http://dx.doi.org/10.1016/j.jsb.2016.01.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4771870PMC
April 2016

Hypothermia and hypokalemia in a patient with diabetic ketoacidosis.

Saudi J Kidney Dis Transpl 2015 May-Jun;26(3):580-3

Division of Nephrology, Department of Medicine, Jichi Medical University, Shimotuke, Japan.

We present the case of a 36-year-old man with type-1 diabetes who was hospitalized with diabetic ketoacidosis (DKA). On admission, he had hypothermia, hypokalemia and combined metabolic and respiratory alkalosis, in addition to hyperglycemia. Hypothermia, hypokalemia and metabolic alkalosis, with a concurrent respiratory alkalosis, are not commonly seen in DKA. After admission, intravenous infusion of 0.45% saline was administered, which resulted in the development of pure metabolic acidosis. After starting insulin infusion, hypokalemia and hypophosphatemia became evident and finally resulted in massive rhabdomyolysis. Hyperkalemia accompanying oliguric acute kidney injury (AKI) warranted initiation of hemodialysis (HD) on Day-five. On the 45th hospital day, his urine output started to increase and a total of 22 HD sessions were required. We believe that in this case severe dehydration, hypothermia and hypokalemia might have contributed to the initial symptoms of DKA as well as the prolongation of AKI.
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http://dx.doi.org/10.4103/1319-2442.157387DOI Listing
May 2015

Changes in glomerular filtration rate after donation in living kidney donors: a single-center cohort study.

Int Urol Nephrol 2015 Feb 1;47(2):397-403. Epub 2014 Nov 1.

Department of Medicine, Kidney Center, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, 162-8666, Japan.

Purpose: A number of studies have reported on decline in glomerular filtration rate (GFR) after donation in Japanese living kidney donors. The purpose of the present study was to examine the clinicopathological factors associated with changes in GFR after donation in living kidney donors.

Methods: We reviewed the charts of living kidney donors (n = 294) and monitored estimated GFR (eGFR) values from the time of 0-h kidney biopsy until 3 years after donation. We assessed donor age, gender, body mass index, blood pressure, urinalysis, and several other clinical parameters including the severity of glomerulosclerosis and arteriosclerosis.

Results: The grade of arteriosclerosis in 0-h biopsy specimens was higher in the older donor group (57-76 years) than in the younger donor group (30-56 years). Mean donor eGFR at the time of the donation was 80.1 ± 13.6 ml/min/1.73 m(2). Most of the living kidney donors in this study developed stage 3 chronic kidney disease (CKD). The mean changes in eGFR at 1-3 years after donation showed a steady state that was distinct from the generally accepted notion that GFR declines with age. Multivariate regression analyses showed that the changes in eGFR were negatively associated with age (r = -0.21, P < 0.001) and preoperative eGFR (r = -0.18, P < 0.001), but not associated with the grade of glomerulosclerosis and arteriosclerosis.

Conclusion: Donor age and pre-GFR at the time of nephrectomy were associated with decline in kidney function in living kidney donors after donation. Most of the donors developed stage 3 CKD within 3 years after donation but without subsequent progression, at least for several years.
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http://dx.doi.org/10.1007/s11255-014-0861-4DOI Listing
February 2015

Mizoribine requires individual dosing due to variation of bioavailability.

Pediatr Int 2012 Dec;54(6):885-91

Department of Hospital Pharmaceutics, School of Pharmacy, Showa University, Tokyo, Japan.

Background: Mizoribine (MZR) is an immunosuppressant used for the treatment of glomerular diseases, but there are few reports on the pharmacokinetics of MZR in children.

Methods: First, we performed a pharmacokinetic study on nine childhood-onset glomerular disease patients. The MZR dosages ranged from 1.8 to 14.5 mg/kg/dose. Pharmacokinetic parameters were analyzed using 38 MZR concentration-time curves. Second, nine patients who were newly treated with MZR were enrolled to validate the findings obtained from prior investigation.

Results: In the prior study, peak serum MZR concentration (C(max) ) was dose-dependent in each patient. Although proportionality between dosage and C(max) was observed in each patient, the regression coefficient was in a wide range from 0.075 to 1.04 and was specific to each patient. This variability was likely caused by individual variation of bioavailability. When the optimal time-point to monitor C(max) was investigated, the time-to-reach peak serum MZR concentration (T(max)) was similar among all the patients, which was from 2.5 to 3.5 h after administration of MZR. T(max) was most frequently observed at 3 h and the serum MZR concentration ratio relative to C(max) at 3 h was also highest (0.93 ± 0.07). In the following study, it was validated that monitoring C(3) is reproducible and reliable after adjusting the dosage of MZR to obtain target serum concentration.

Conclusion: Individual dosing is required to optimize C(max) in childhood-onset glomerular disease patients. The safe dosage of MZR for each patient could be predicted by evaluating the serum MZR concentration 3 h after administration.
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http://dx.doi.org/10.1111/j.1442-200X.2012.03733.xDOI Listing
December 2012

Comparison between serum free triiodothyronine levels and body fluid distribution in hemodialysis patients.

Clin Exp Nephrol 2012 Dec 8;16(6):952-8. Epub 2012 Jun 8.

Division of Nephrology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan.

Aim: Low free triiodothyronine (fT3) has been associated with the presence of malnutrition-inflammation syndrome in patients with end-stage renal disease (ESRD) and decreased overall survival in ESRD. Since thyroid hormone has a particular effect on body fluid status, we hypothesized that hemodialysis patients with low-T3 syndrome might have interstitial edema. In this study, we examined the relationship between levels of thyroid hormone and body composition parameters in Japanese hemodialysis patients.

Methods: The subjects were 52 patients on maintenance hemodialysis. Serum levels of thyroid hormone and atrial natriuretic peptide (hANP) were measured. Body composition parameters were measured using a bioimpedance body composition analyzer.

Results: Serum fT3 had positive correlations with body mass index (BMI), body fat mass (BFM), total body water (TBW) and intracellular water (ICW), and negative correlations with the ratio of extracellular water to total body water (ECW/TBW) and hANP. There were no correlations between serum fT4 and any body composition parameter. The 49 patients with data at baseline and after 1 year were divided into groups with increased (n = 33) and decreased (n = 16) fT3 after 1 year. ΔBMI and ΔBFM were significantly lower and ΔTBW, ΔICW, ΔECW and ΔECW/TBW (changes over 1 year from baseline) were significantly higher in patients with decreased fT3 compared to those with increased fT3. There was no significant difference in ΔhANP or Δcardiothoracic ratio between the two groups.

Conclusion: These results show that a decrease in fT3 might be associated with emaciation and interstitial edema in Japanese hemodialysis patients.
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http://dx.doi.org/10.1007/s10157-012-0648-9DOI Listing
December 2012

Metabolic syndrome and risk of progression of chronic kidney disease: a single-center cohort study in Japan.

Heart Vessels 2013 May 21;28(3):323-9. Epub 2012 Apr 21.

Department of Medicine, Kidney Center, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.

Metabolic syndrome (MetS) is a risk factor for the development of diabetes and cardiovascular disease, and recently was linked to incident chronic kidney disease (CKD). The purpose of this study is to examine whether MetS is associated with CKD progression in Japanese at a single center. Outcome variables were a decrease in estimated glomerular filtration rate (eGFR) of 50 % or 25 ml/min/1.73 m(2), end-stage renal disease (ESRD), death, or a composite outcome of all three. There were 213 subjects in the analysis, 40.4 % of whom met the criteria for MetS. The group of subjects with MetS had higher urinary albumin-to-creatinine (UACR) levels. Survival curves stratified by MetS status showed early separation of the curves and a significantly higher survival rate in the group without MetS (P = 0.0086). Comparisons with normoalbuminuria and microalbuminuria showed that macroalbuminuria was equally associated with predicted composite outcome (GFR, ESRD, or death) both in the presence and absence of MetS. Multivariate analyses for all covariates showed that eGFR (hazard ratio (HR) 8.286, 95 % confidence interval (CI) 2.360-28.044, P = 0.0012) and the UACR (HR 2.338, 95 % CI 1.442-3.861, P = 0.0005) at baseline were independently associated with the composite outcomes. The results show that MetS was associated with albuminuria in a cohort of Japanese CKD patients, and both MetS and albuminuria were independently associated with CKD progression.
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http://dx.doi.org/10.1007/s00380-012-0254-5DOI Listing
May 2013

Effects of raloxifene on bone metabolism in hemodialysis patients with type 2 diabetes.

Int J Endocrinol Metab 2012 20;10(2):464-9. Epub 2012 Apr 20.

Department of Nephrology, Jichi Medical University, Tochigi, Japan.

Background: Osteoporosis and chronic kidney disease are common conditions in older adults, and often occur concurrently. Bone disease is caused by increased bone turnover accompanying secondary hyperparathyroidism, and by factors such as bone metabolic disorder accompanying kidney disease and postmenopausal or age-related osteoporosis, even in hemodialysis patients. Raloxifene is commonly used for the treatment of postmenopausal osteoporosis in the general population, and may be a treatment option for osteoporosis in hemodialysis patients. However, the effects of raloxifene in hemodialysis patients with type 2 diabetes have not been examined in detail.

Objectives: This study was performed to investigate the effects of raloxifene on bone turnover markers and bone density in postmenopausal women with type 2 diabetes mellitus who were undergoing hemodialysis in Japan.

Patients And Methods: The subjects were 60 female patients on maintenance hemodialysis (non-diabetic, n=30; diabetic, n=30). Raloxifene hydrochloride (60 mg) was administered to 14 diabetic patients and 14 non-diabetic patients for one year, and these patients were compared with control groups (no raloxifene) of 16 diabetic patients and 16 non-diabetic patients. Serum levels of N-terminal cross-linking telopeptide of type I collagen (NTx), bone alkaline phosphatase, and intact parathyroid hormone (iPTH) were measured, and bone density was determined by quantitative heel ultrasound at the speed of sound (SOS) in the calcaneus during this period.

Results: There were no significant differences in the levels of bone turnover markers except for iPTH after treatment of diabetic and non-diabetic patients with raloxifene for one year. SOS increased after treatment with raloxifene, but was significantly decreased in the control groups. Treatment with raloxifene resulted in a significant decrease in NTx and a significant increase in SOS in both diabetic and non-diabetic patients. There were no significant differences between the diabetic and non-diabetic patients who received raloxifene.

Conclusions: Treatment with raloxifene can suppress reduction in bone density in postmenopausal women with type 2 diabetes who are undergoing hemodialysis.
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http://dx.doi.org/10.5812/ijem.3794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693610PMC
July 2013

Self-incompatibility response induced by calcium increase in sperm of the ascidian Ciona intestinalis.

Proc Natl Acad Sci U S A 2012 Mar 22;109(11):4158-62. Epub 2012 Feb 22.

Sugashima Marine Biological Laboratory, Graduate School of Science, Nagoya University, Toba, Mie 517-0004, Japan.

Many hermaphroditic organisms possess a self-incompatibility system to avoid self-fertilization. Recently, we identified the genes responsible for self-sterility in a hermaphroditic primitive chordate (ascidian), Ciona intestinalis: sperm-side polycystin 1-like receptors s-Themis-A/B and egg-side fibrinogen-like ligands on the vitelline coat (VC) v-Themis-A/B. Here, we investigated the sperm behavior and intracellular Ca(2+) concentration ([Ca(2+)](i)) in response to self/nonself-recognition. We found that sperm motility markedly decreased within 5 min after attachment to the VC of self-eggs but not after attachment to the VC of nonself-eggs and that the apparent decrease in sperm motility was suppressed in low Ca(2+) seawater. High-speed video analysis revealed that sperm detached from the self-VC or stopped motility within 5 min after binding to the self-VC. Because s-Themis-B contains a cation channel domain in its C terminus, we monitored sperm [Ca(2+)](i) by real-time [Ca(2+)](i) imaging using Fluo-8H-AM (AAT Bioquest, Inc.). Interestingly, we found that sperm [Ca(2+)](i) rapidly and dramatically increased and was maintained at a high level in the head and flagellar regions when sperm interacted with the self-VC but not when the sperm interacted with the nonself-VC. The increase in [Ca(2+)](i) was also suppressed by low-Ca(2+) seawater. These results indicate that the sperm self-recognition signal triggers [Ca(2+)](i) increase and/or Ca(2+) influx, which elicits a self-incompatibility response to reject self-fertilization in C. intestinalis.
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http://dx.doi.org/10.1073/pnas.1115086109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306710PMC
March 2012

Identification and localization of the sperm CRISP family protein CiUrabin involved in gamete interaction in the ascidian Ciona intestinalis.

Mol Reprod Dev 2011 Jul 8;78(7):488-97. Epub 2011 Jun 8.

Sugashima Marine Biological Laboratory, Graduate School of Science, Nagoya University, Sugashima, Toba, Japan.

Ascidians are hermaphrodites, and most release sperm and eggs nearly simultaneously. Many species, including Halocynthia roretzi and Ciona intestinalis, are self-sterile. We previously reported that the interaction between a 12 EGF-like repeat-containing vitelline-coat (VC) protein, HrVC70, and a sperm GPI-anchored CRISP, HrUrabin, in lipid rafts plays a key role in self-/nonself-recognizable gamete interaction in H. roretzi. On the other hand, we recently identified two pairs of polymorphic genes responsible for self-incompatibility in C. intestinalis by positional cloning: The sperm polycystin 1-like receptors s-Themis-A/B and its fibrinogen-like ligand v-Themis-A/B on the VC. However, it is not known if the orthologs of HrVC70 and HrUrabin also participate in gamete interaction in C. intestinalis since they are from different orders. Here, we tested for a C. intestinalis ortholog (CiUrabin) of HrUrabin by searching the genome database and proteomes of sperm lipid rafts. The identified CiUrabin belongs to the CRISP family, with a PR domain and a GPI-anchor-attachment site. CiUrabin appears to be specifically expressed in the testis and localized at the surface of the sperm head, as revealed by Northern blotting and immunocytochemistry, respectively. The specific interaction between CiVC57, a C. intestinalis ortholog of HrVC70, and CiUrabin was confirmed by Far Western analysis, similarly to the interaction between HrVC70 and HrUrabin. The molecular interaction between CiVC57 and CiUrabin may be involved in the primary binding of sperm to the VC prior to the allorecognition process, mediated by v-Themis-A/B and s-Themis-A/B, during fertilization of C. intestinalis.
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http://dx.doi.org/10.1002/mrd.21329DOI Listing
July 2011

The effects of raloxifene on bone turnover markers and bone mineral density in women on maintenance hemodialysis.

Clin Exp Nephrol 2011 Feb 11;15(1):126-31. Epub 2010 Nov 11.

Department of Nephrology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan.

Background: Bone disease is caused not only by increased bone turnover accompanying secondary hyperparathyroidism but also by factors such as bone metabolic disorder accompanying kidney disease and postmenopausal or age-related osteoporosis in hemodialysis patients. In this study, we investigated the effects of raloxifene on bone turnover markers and bone mineral density (BMD) in female hemodialysis patients to determine involvement of estrogen deficiency in bone disease.

Methods: The subjects were 47 female patients on maintenance hemodialysis. Raloxifene hydrochloride (60 mg) was administered to 21 patients for 1 year, and these patients were compared with a control group of 26 patients. Serum levels of N-terminal cross-linking telopeptide of type I collagen (NTx), bone alkaline phosphatase, and intact parathyroid hormone were measured, and BMD was determined by quantitative heel ultrasound as the speed of sound (SOS) in the calcaneus over this period.

Results: NTx decreased after treatment with raloxifene for 1 year, but significantly increased in the control group. SOS increased after treatment with raloxifene for 1 year, but significantly decreased in the control group. Treatment with raloxifene resulted in a significant decrease of NTx and a significant increase of SOS in subgroups of patients aged <60 and ≥ 60 years.

Conclusions: Treatment with raloxifene can suppress a rise in NTx and increase bone mineral density in patients around the time of menopause and in postmenopausal patients of advanced age. A reduction in bone mineral density caused by estrogen deficiency may be involved in the development of bone disease in female hemodialysis patients.
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http://dx.doi.org/10.1007/s10157-010-0366-0DOI Listing
February 2011

[Analysis of metabolic syndrome and pulse wave velocity in hemodialysis patients: diagnosis of obesity by bioelectrical impedance analysis and a novel risk factor for atherosclerosis].

Nihon Jinzo Gakkai Shi 2009 ;51(4):476-83

Kawashima Medical Clinic, Ibaraki, Japan.

Purpose: Metabolic syndrome (Met S) is one of the risk factors of atherosclerotic vascular diseases related to visceral fat accumulation. However, it is well known that morbidity and mortality of hemodialysis (HD) patients are associated with malnutrition and emaciation rather than obesity, representing "reverse epidemiology". The risk of visceral fat accumulation or Met S in HD patients remains unclear. Therefore, we evaluated atherosclerosis and Met S in HD patients using various markers of obesity by means of bioelectrical impedance analysis (BIA) and brachial-ankle PWV(baPWV).

Methods: The subjects comprised 52 patients who were undergoing maintenance dialysis. In addition to a general physical examination and routine blood tests, immunoreactive insulin (IRI), homeostasis model assessment for insulin resistance (HOMA-R), serum adiponectin (ADPN) and C-reactive protein (CRP)were measured before dialysis. Furthermore, we measured various body fluid components, such as the ratio of extracellular water to total body water (ECW/TBW), body fat mass (BFM), percent body fat(PBF) and visceral fat accumulation (BIA-VFA), using a body composition analyzer (InBody S20)and baPWV as a marker of atherosclerosis.

Results: There was no significant difference between HD patients with and without Met S for baPWV. baPWV was positively correlated with age, systolic BP and ECW/TBW, and negatively correlated with serum albumin level, BMI and serum ADPN. However, no significant correlations were observed between baPWV and the durations of HD, Ca x P product, BIA-VFA, PBF, HOMA-R and CRP. The serum ADPN level was significantly lower in Met S than in non-Met S. In addition, the ADPN level was positively correlated with HDL-cholesterol, and negatively correlated with TG, HbA1c, CRP and various markers of obesity (Waist, BIA-VFA, BFM and PBF). In a multiple regression analysis for baPWV, the ECW/TBW ratio and serum ADPN level, as well as age and systolic BP, were independent predictors for the enhancement of baPWV in HD patients.

Conclusion: The present study demonstrated that the ECW/TBW ratio and low serum ADPN level, but not Met S or obesity, could be risk factors for the acceleration of atherosclerosis in HD patients. In addition, the results showed that the relationship between ADPN,as an anti-atherosclerotic factor, and body fat or lipid metabolism were also maintained in HD patients.
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October 2009

Metabolic and hemodynamic advantages of an acetate-free citrate dialysate in a uremic case of congenital methylmalonic acidemia.

Am J Kidney Dis 2009 Oct 4;54(4):764-9. Epub 2009 Jul 4.

Division of Nephrology, Department of Medicine, Jichi Medical University, Shimotuke, Tochigi, Japan.

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http://dx.doi.org/10.1053/j.ajkd.2009.04.033DOI Listing
October 2009

Comprehensive egg coat proteome of the ascidian Ciona intestinalis reveals gamete recognition molecules involved in self-sterility.

J Biol Chem 2009 Apr 3;284(14):9402-10. Epub 2009 Feb 3.

Division of Disease Proteomics, Institute for Enzyme Research, The University of Tokushima, 3-15-18 Kuramoto-cho, Tokushima 770-8503, Japan.

Despite central roles of egg coat proteins in gamete recognition, their functions and composition are poorly understood. Here, we report that the proteome of the egg coat in the solitary ascidian Ciona intestinalis, called vitelline coat (VC) fraction, contains more than 800 proteins identified by mass spectrometry-based analyses. Over 100 proteins were enriched in the VC fraction compared with the VC-free egg proteome. The most abundant component in the VC was an apolipoprotein-like protein. The VC contained multiple homologs of mammalian zona pellucida (ZP) proteins, the number of which was unexpectedly large and most of which possessed epidermal growth factor-like repeats. Furthermore, the present study revealed that two fibrinogen-like proteins, v-Themis-A and -B, both of which are expressed in the VC, are the molecules responsible for the two self-sterility loci that were identified by our previous genetic study in this species.
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http://dx.doi.org/10.1074/jbc.M809672200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2666592PMC
April 2009

Pathophysiological role of aquaporin-2 in impaired water excretion.

Prog Brain Res 2008 ;170:581-8

Department of Medicine, Jichi Medical University Saitama Medical Center, Saitama, Japan.

In a state of chronic arginine vasopressin (AVP)-induced antidiuresis, the antidiuretic efficacy has been attenuated: a phenomenon known as "AVP escape". We compared the experimental SIADH rats with 1-deamino-8-D-AVP (dDAVP)-excess rats. The SIADH rats, but not the dDAVP-excess rats, showed a marked attenuation of urinary concentrating ability. This is closely associated with diminished up-regulation of aquaporin-2 (AQP-2) mRNA and protein expression. The following in vitro study clarified tonicity-response elements in the 5'-flanking region of AQP-2 gene. There are at least more than two hypertonicity-response elements, and a hypotonicity-response element resided at tonicity-response enhancer (TonE) (-570 to -560bp) in the AQP-2 gene. Hypotonicity directly reduced the cAMP-induced AQP-2 promoter activity by mediating JNK kinase. Reduction in transcriptional regulation of AQP-2 under hypotonic state may support the in vivo finding of AVP escape phenomenon in chronic AVP-induced antidiuresis.
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http://dx.doi.org/10.1016/S0079-6123(08)00445-7DOI Listing
February 2009

Hypotonicity reduces the activity of murine aquaporin-2 promoter induced by dibutyryl cAMP.

Exp Physiol 2008 Oct 30;93(10):1147-56. Epub 2008 May 30.

Department of Medicine, Jichi Medical University, Saitama Medical Center, 1-847 Amanuma Omiya-ku, Saitama, Saitama 330-8503, Japan.

The present study was undertaken to determine whether hypotonicity regulates the aquaporin-2 (AQP-2) gene in vitro. The 5'-flanking region of the AQP-2 gene contains the tonicity-response enhancer (TonE) promoter located between -570 and -560 bp, and another distinct hypertonicity-responsive region between -6.1 and -4.3 kb of the AQP-2 gene. The 5'-flanking region of murine AQP-2 gene up to -9.5 kb was cloned into a luciferase (Luc) reporter plasmid. The constructs, which have TonE and/or the hypertonicity-responsive region, together with the murine AQP-2 gene, were co-transfected into murine IMCD(3) cells. When the cells were co-transfected with the construct containing more than 1.1 kb of the 5'-flanking region of murine AQP-2 gene (-9.5AQP2, -6.1AQP2 and -1.1AQP2) and the AQP-2 gene, 24 h exposure to 5 micromol l(-1) dibutyryl cAMP (DBcAMP) significantly increased the Luc activity by 2.3-fold in the isotonic medium (300 mosmol kg(-1)). In the hypotonic medium (225 mosmol kg(-1)), basal activity was not altered, and the response of Luc activity to 24 h exposure to 5 micromol l(-1)DBcAMP was abolished. Similar findings were obtained in isosmotic, urea-supplemented medium (estimated tonicity, 225 mosmol kg(-1)). The response of Luc activity to 5 micromol l(-1) DBcAMP in the hypotonic medium was not affected in cells either transfected with 0.36 kb of the 5'-flanking region of AQP-2 or co-transfected with -1.1AQP2 and a dominant-negative TonE binding protein (pDNTonEBP). Pre-incubation of cells with 1 micromol l(-1) SP600125, an inhibitor of c-Jun N-terminal kinase (JNK), restored the response of Luc activity to 5 micromol l(-1) DBcAMP under hypotonic conditions. These findings may indicate that hypotonicity reduces the cAMP-induced AQP-2 promoter activity mediated via TonE by activating JNK kinase.
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http://dx.doi.org/10.1113/expphysiol.2008.042663DOI Listing
October 2008

Mechanism of self-sterility in a hermaphroditic chordate.

Science 2008 Apr 20;320(5875):548-50. Epub 2008 Mar 20.

Sugashima Marine Biological Laboratory, Graduate School of Science, Nagoya University, Sugashima, Toba 517-0004, Japan.

Hermaphroditic organisms avoid inbreeding by a system of self-incompatibility (SI). A primitive chordate (ascidian) Ciona intestinalis is an example of such an organism, but the molecular mechanism underlying its SI system is not known. Here, we show that the SI system is governed by two gene loci that act cooperatively. Each locus contains a tightly linked pair of polycystin 1-related receptor (s-Themis) and fibrinogen-like ligand (v-Themis) genes, the latter of which is located in the first intron of s-Themis but transcribed in the opposite direction. These genes may encode male- and female-side self-recognition molecules. The SI system of C. intestinalis has a similar framework to that of flowering plants but utilizing different molecules.
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http://dx.doi.org/10.1126/science.1152488DOI Listing
April 2008

Serum adiponectin and markers of endothelial injury in hemodialysis patients with arteriosclerosis obliterans.

Clin Exp Nephrol 2008 Feb 5;12(1):58-64. Epub 2008 Jan 5.

Department of Nephrology, Jichi Medical University, Simotsuke, Tochigi 329-0498, Japan.

Background: Arteriosclerosis obliterans (ASO) in hemodialysis patients is the dominant cause of morbidity evolving from arteriosclerosis. Adiponectin is an adipose-derived cytokine which, because of its modulation of endothelial adhesion molecules, has potential anti-inflammatory and anti-atherogenic properties. However, the implications of adiponectin and endothelial function in ASO of hemodialysis patients has not been fully elucidated.

Methods: In this study we measured serum levels of adiponectin, adhesion molecules (VCAM-1 and ICAM-1), and an endothelial cell injury marker (CD146) in patients with ASO. We sought to determine clinical and laboratory correlates of ASO in ESRD patients. A total of 80 hemodialysis patients and 82 patients with normal serum creatinine levels were enrolled. Serum levels of adiponectin, ICAM-1, VCAM-1, and CD146 were measured by ELISA.

Results: Serum adiponectin levels in 41 hemodialysis patients with ASO were significantly lower than in 39 patients without ASO. Serum CD146 levels in hemodialysis patients with ASO were significantly higher than in patients without ASO. There were no significant differences between levels of ICAM-1 and VCAM-1 in these two groups. Similar results were obtained for patients with normal renal function. Serum adiponectin was related to hemodialysis duration and BMI in hemodialysis patients. In patients with normal renal function, adiponectin was related to HDL-cholesterol, triglyceride, and ICAM-1.

Conclusion: A decrease in serum adiponectin levels and an increase in serum CD146 may be closely associated with the development of ASO, regardless of renal function. However, there are different mechanisms determining serum adiponectin levels in patients with normal kidney function and in hemodialysis patients.
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http://dx.doi.org/10.1007/s10157-007-0012-7DOI Listing
February 2008

Intrathyroidal persistence of human parvovirus B19 DNA in a patient with Hashimoto's thyroiditis.

J Infect 2007 Aug 19;55(2):e29-31. Epub 2007 Jun 19.

Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.

Previous studies suggest a role of viral infection in the development of Hashimoto's thyroiditis (HT). Here we report a patient with HT in whom human parvovirus B19 (B19) DNA has been persistently detected in the thyroid regardless of the presence or absence of B19 DNA in peripheral blood mononuclear cells. In contrast to the DNA persistence, however, VP1 capsid protein was not detected in the thyroid by immunohistochemical studies. Thyroid specimens obtained by fine needle aspiration biopsy from two patients with HT and two with Graves' disease were negative for B19 DNA. Thus, whereas a causal link between B19 infection and HT remains to be determined, B19 DNA may persist in the thyroid and B19 infection may facilitate the intrathyroidal inflammatory process in HT patients.
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http://dx.doi.org/10.1016/j.jinf.2007.05.173DOI Listing
August 2007

SIADH is only an atypical clinical feature in a patient with prolactinoma.

Intern Med 2007 24;46(10):653-6. Epub 2007 May 24.

Department of Medicine, Jichi Medical University Omiya Medical Center, Saitama, Japan.

A 50-year-old man was admitted to determine the pathogenesis of hyponatremia. He had a poor appetite and was easily fatigued. Physical findings showed that he was conscious and alert. He had neither dry skin or tongue, nor pretibial edema. Laboratory data revealed that the serum sodium level was 110 mmol/l; plasma osmolality, 238 mmol/kg; and urinary osmolality, 417 mmol/kg. Plasma arginine vasopressin was 0.5 pg/ml despite plasma osmolality of 242 mmol/kg. An acute water load showed impaired water excretion, as percent excretion of water load was 30% and minimal urinary osmolality was 642 mmol/kg. Serum prolactin was 254 ng/ml, and anterior pituitary hormones of ACTH, TSH and GH were in the normal ranges. Brain magnetic resonance imaging (MRI) showed a pituitary tumor with a size of 20 x 22 x 21 mm and it pushed a pituitary stalk upward. Immunohistochemistry revealed prolactinoma. After the adenomectomy, serum sodium level has been kept normal with free access to water intake. The present study indicates that syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is manifested in association with pituitary macroadenoma of prolactinoma.
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http://dx.doi.org/10.2169/internalmedicine.46.6422DOI Listing
June 2007

Hypoadiponectinemia in patients with cerebral infarction: comparison with other atherosclerotic disorders.

Am J Med Sci 2007 Mar;333(3):140-4

Department of Medicine, Jichi Medical University Omiya Medical Center, Saitama, Japan.

The present study was undertaken to determine serum adiponectin level in patients with cerebral infarction and to further analyze any difference in serum adiponectin levels among atherosclerotic disorders. One hundred fifty-two subjects with atherosclerotic disorders were enrolled, 110 males and 42 females, with the age of 67.0 +/- 9.9 years (mean +/- SD). They were divided into 62 patients with cerebral infarction, 48 patients with ischemic heart disease, and 42 patients with arteriosclerosis obliterans. Thirty-two subjects matched by age, gender, and body mass index served as controls. Serum adiponectin levels were 7.2 +/- 0.6 microg/mL (mean +/- SE) in the patients with cerebral infarction, 7.2 +/- 0.8 microg/mL in those with ischemic heart disease, and 6.9 +/- 0.9 microg/mL in those with arteriosclerosis obliterans. They were significantly less than the level of 12.6 +/- 1.9 microg/mL in the control group (P < 0.01). However, there was no difference in serum adiponectin level among three groups of atherosclerotic disorders. In the patients with acute cerebral infarction, serum adiponectin level was temporarily reduced from 7.3 +/- 0.9 to 6.2 +/- 0.8 microg/mL 14 days after the hospitalization (P < 0.01), followed by recovery to the basal value. The present findings indicate that serum adiponectin levels are equivalently reduced in patients with atherosclerotic disorders, and that serum adiponectin is changeable under acute phase of cerebral infarction.
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http://dx.doi.org/10.1097/MAJ.0b013e318031b7afDOI Listing
March 2007

Elevation of serum adiponectin and CD146 levels in diabetic nephropathy.

Diabetes Res Clin Pract 2007 Oct 9;78(1):85-92. Epub 2007 May 9.

Department of Medicine, Jichi Medical University, Omiya Medical Center, 1-847 Amanuma, Saitama, Japan.

Objective: The present study was undertaken to measure serum levels of adiponectin and CD146, an endothelial cell injury marker, and to clarify the property of adiponectin and CD146 in patients with diabetic nephropathy.

Design: A total of 280 diabetic patients, and 49 control subjects were enrolled. Serum levels of adiponectin and CD146 were measured by ELISA.

Results: Serum adiponectin levels were relatively low in the diabetic patients as compared to the control subjects. Inversely, serum adiponectin levels were significantly greater in those with stages IV and V of diabetic nephropathy than the control subjects. Serum CD146 levels were gradually increased according to the progression of diabetic nephropathy, and that in the stages IIIb-V was significantly greater than that in the control group. Serum adiponectin positively correlated with serum creatinine and negatively correlated with 1/creatinine. Similar results were obtained with serum CD146 levels. However, there was no relationship between serum adiponectin and CD146 levels.

Conclusion: These results indicate that serum adiponectin levels seem to reduce in the diabetic patients, and finally increase in end stage of diabetic nephropathy. In contrast, serum CD146 may closely associate with development of micro- and macrovascular complications in diabetic patients. Further study is required to elucidate the exact role of adiponectin and CD146 in the development of vascular complication in end stage of diabetic nephropathy.
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http://dx.doi.org/10.1016/j.diabres.2007.02.014DOI Listing
October 2007

Possibly simultaneous primary aldosteronism and preclinical Cushing's syndrome in a patient with double adenomas of right adrenal gland.

Endocr J 2007 Apr 20;54(2):287-93. Epub 2007 Mar 20.

Department of Medicine, Jichi Medical University Omiya Medical Center, Japan.

We reported a rare case of simultaneous primary aldosteronism and preclinical Cushing's syndrome due to unilateral double adrenocortical adenomas in a 57 year-old woman who had had hypertension for the last 10 years. Abdominal computed tomography showed double tumors in her right adrenal gland. Physical findings revealed simple obesity and hypertension, but no other abnormal findings were detected. Laboratory findings demonstrated that serum potassium was 3.8 mmol/l; plasma renin activity, 0.3 ng/ml/h; plasma aldosterone, 100 pg/ml, and aldosterone renin ratio (ARR), 33. Serum cortisol was 15.7 microg/dl. There was no circadian rhythm of serum cortisol, and no suppression of serum cortisol in response to exogenous dexamethasone administration. Right adrenalectomy was performed under laparoscopy. Two well-circumscribed tumors, whose sizes were 21 and 19 mm in greatest diameter, were detected. They were macroscopically composed of a golden-yellow portion admixed with a brown portion, which corresponded to clear cells and compact cells, respectively. Immunohistochemical staining for steroidogenic enzymes demonstrated the presence of all the enzymes involved in corticosteroidogenesis in these two adenomas, indicating that the two adenomas produced both cortisol and mineralocorticoid. Specifically, one adenoma mainly caused excessive production of cortisol as compared to the other one. These findings indicate that overproduction of both cortisol and mineralocorticoid was evident in the two adenomas of the right adrenal gland in immunohistochemical study for steroidogenic enzymes, whereas there was less clinical manifestation of primary aldosteronism and Cushing's syndrome in the present patient.
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http://dx.doi.org/10.1507/endocrj.k06-180DOI Listing
April 2007
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