Hyperuricemia and Acute Renal Failure in Renal Transplant Recipients Treated With High-Dose Mizoribine.

BACKGROUND: Hyperuricemia is a common adverse event frequently found in renal transplant recipients with mizoribine (MZ). Hyperuricemia itself will be a cause of renal dysfunction, and renal dysfunction also will be a cause of hyperuricemia simultaneously. This study investigates frequency of hyperuricemia and renal failure in renal transplant recipients treated with high-dose MZ. PATIENTS AND METHODS: From December 2007 to October 2015, there was a total of 32 living related renal transplant recipients treated with high-dose MZ. Of the 32 patients, 28 were treated with urate-lowering medications. RESULTS: One patient received allopurinol (AP) and 13 patients received benzbromarone (BB). For 6 of them, their urate-lowering medications were converted to febuxostat (FX) form AP or BB. In the remaining 14 patients, FX was administered from the beginning. In 2 cases of ABO-incompatible living related renal transplant recipients who were maintained with high-dose MZ and BB, severe hyperuricemia and acute renal failure occurred. One patient was a 48-year-old man, and his creatinine (Cr) level increased to 8.14 mg/dL and his serum uric acid (UA) was 24.6 mg/dL. Another patient was a 57-year-old man, and his Cr level increased to 3.59 mg/dL and his UA was 13.2 mg/dL. In both cases Cr and UA were improved, and no finding of acute rejection and drug toxicity was observed in graft biopsy specimens. BB was switched to FX and discontinuance or reduction of MZ was done. CONCLUSION: Combination of MZ and BB has the risk of acute renal dysfunction after renal transplantation. Latent renal dysfunction should be watched for in renal transplant recipients receiving high-dose MZ.

14-3-3ζ-Mediated Stimulation of Oxidative Phosphorylation Exacerbates Oxidative Damage Under Hypothermic Oxygenated Conditions in Human Renal Tubular Cells (HK-2).

Cellular survival and death are at least partially regulated by the phosphorylation of proteins. A chaperon protein, 14-3-3ζ, regulates the activity of many proteins by covering the phosphorylation site within a 14-3-3 binding motif. Therefore, regulation of 14-3-3ζ activity may affect the fate of cells subjected to cold preservation and/or hypothermic oxygenated conditions. The present study assessed whether 14-3-3ζ protects cells from hypothermic oxygenation-induced injury and clarified its role in mitochondrial functions. Human renal tubular cell line HK-2 or 14-3-3ζ-overexpressed HK-2 (ζHK-2) cells were subjected to 72 hours of normoxic cold preservation in UW solution with or without antioxidants and hydroperoxides. Cellular death, adenosine triphosphate (ATP) content, and MTT catabolism were evaluated. Deferoxamine treatment reduced cellular death and augmented ATP content in both cell types. These indices were higher in ζHK-2, regardless of deferoxamine treatment. Exposure to hydroperoxides did not affect cellular death in either cell type, whereas hydroperoxide supplementation significantly reduced ATP content, except for low-dose hydrogen peroxide in HK-2 cells. MTT assay at normal state showed higher values in ζHK-2 cells, whereas it was impaired by hydroperoxides in both cell types. These results suggest that accumulation of hydroperoxides as a byproduct of the augmented oxidative phosphorylation by 14-3-3ζ overexpression causes mitochondrial dysfunction. In conclusion, despite possessing many potentially protective functions, 14-3-3ζ exacerbates cellular injury under hypothermic oxygenated conditions. 14-3-3ζ accelerates mitochondrial functions together with iron-dependent oxidative damage. Although further investigations are necessary, upregulation of 14-3-3ζ could be a method to maintain mitochondrial function under hypothermic oxygenated conditions, as shown in hypothermic machine preservation of renal grafts, when appropriate antioxidant treatment is administered.

Outcomes of immediate perforator flap reconstruction after skin-sparing mastectomy following neoadjuvant chemotherapy.

BACKGROUND: The impact of neoadjuvant chemotherapy (NACT) on immediate free flap breast reconstruction remains controversial. Furthermore, the oncological outcomes of immediate free flap breast reconstruction after skin-sparing mastectomy (SSM) following NACT remain unclear. This study aimed to investigate the surgical complications and oncological outcomes of immediate perforator flap reconstruction after SSM following NACT. METHODS: A total of 201 consecutive patients with indications for immediate perforator flap reconstruction after SSM were included between 2004 and 2012. Surgical and oncological outcomes were compared between patients with and without NACT. RESULTS: There were 38 patients in the NACT group and 163 in the non-NACT control group. The median age of the NACT group was 39.5 years, which was significantly younger than the control group (43.0 years; P < 0.05). Patients in the NACT group also had more advanced and aggressive disease (P < 0.05). There was no significant difference in the frequency of surgical complications between the groups, no difference in the type of complications, and no significant difference in the frequencies of major and minor complications. No patients in the NACT group had delayed adjuvant therapy. Eight patients (4%) developed recurrences, with a median follow-up time of 3.0 years. Local recurrences occurred in three control patients but no patients in the NACT group. CONCLUSION: NACT does not affect short-term or interim outcomes after immediate perforator flap reconstruction and may thus represent a safe and practical treatment option for the multidisciplinary treatment of breast cancer.

Bystander effect between zebrafish embryos in vivo induced by high-dose X-rays.

We employed embryos of the zebrafish, Danio rerio, for our studies on the in vivo bystander effect between embryos irradiated with high-dose X-rays and naive unirradiated embryos. The effects on the naive whole embryos were studied through quantification of apoptotic signals at 25 h post fertilization (hpf) through the terminal dUTP transferase-mediated nick end-labeling (TUNEL) assay followed by counting the stained cells under a microscope. We report data showing that embryos at 5 hpf subjected to a 4-Gy X-ray irradiation could release a stress signal into the medium, which could induce a bystander effect in partnered naive embryos sharing the same medium. We further demonstrated that this bystander effect (induced through partnering) could be successfully suppressed through the addition of the nitric oxide (NO) scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO) into the medium but not through the addition of the CO liberator tricarbonylchloro(glycinato)ruthenium(II) (CORM-3). This shows that NO was involved in the bystander response between zebrafish embryos induced through X-ray irradiation. We also report data showing that the bystander effect could be successfully induced in naive embryos by introducing them into the irradiated embryo conditioned medium (IECM) alone, i.e., without partnering with the irradiated embryos. The IECM was harvested from the medium that had conditioned the zebrafish embryos irradiated at 5 hpf with 4-Gy X-ray until the irradiated embryos developed into 29 hpf. NO released from the irradiated embryos was unlikely to be involved in the bystander effect induced through the IECM because of the short life of NO. We further revealed that this bystander effect (induced through IECM) was rapidly abolished through diluting the IECM by a factor of 2× or greater, which agreed with the proposal that the bystander effect was an on/off response with a threshold.

Sorption-desorption characteristics of uranium, cesium and strontium in typical podzol soils from Ukraine.

Sorption-desorption behaviour of uranium (U), cesium (Cs) and strontium (Sr) was examined by quantification of the solid-liquid distribution coefficients (K(d)) using batch method in typical podzol soils from Ukraine. The effect of different physico-chemical parameters of soil on K(d) values has been discussed. Sorption reversibility has been tested by single extraction test. U shows reversible sorption and there was no isotopic fractionation observed with a known isotopic U composition using as tracer. Cs sorption mostly occurred in an irreversible manner. The clay content and exchangeable potassium in soil play an important role in Cs fixation. Sr adsorption is observed to be reversible and mainly controlled by cation exchange and shows highest mobility in the soil-water system. The K(d) values are found in the decreasing order U (log K(d) ≈ 2-3) > Cs (log K(d) ≈ 2) > Sr (log K(d) ≈ 1).

Omalizumab is more effective than suplatast tosilate in the treatment of Japanese cedar pollen-induced seasonal allergic rhinitis.

BACKGROUND: Seasonal allergic rhinitis (SAR) induced by Japanese cedar pollens is a major problem in Japan. Omalizumab, a humanized monoclonal anti-IgE antibody, improves symptoms associated with SAR, but a comparative study with an anti-allergy drug has not yet been conducted. OBJECTIVE: To compare the efficacy and safety of omalizumab with suplatast tosilate, a selective T-helper type 2 (Th2) cytokine inhibitor, in patients with Japanese cedar pollen-induced SAR. METHODS: A randomized, double-blind, double-dummy study was conducted in 308 Japanese patients with a history of moderate-to-severe SAR who showed a CAP-RAST value (> or =2+) specifically to Japanese cedar pollens. Patients were treated for 12 weeks with omalizumab plus placebo of suplatast tosilate or suplatast tosilate plus placebo of omalizumab. RESULTS: The mean daily nasal symptom medication scores (sum of the daily nasal symptom severity score and daily nasal rescue medication score) were significantly lower in the omalizumab group than in the suplatast tosilate group during three evaluation periods (P<0.001). The omalizumab group also had significantly lower mean daily nasal severity scores, each of the mean daily nasal and ocular symptom severity scores (sneezing, runny nose, stuffy nose, itchy nose, itchy eyes, watery eyes, and red eyes). Omalizumab reduced rescue medication requirements, and the proportion of days with any rescue medication use in the omalizumab group was significantly lower. Serum-free IgE levels markedly decreased in the omalizumab group and it was associated with clinical efficacy. The adverse reaction profiles were similar between the two groups. The overall incidence of injection site reactions was higher in the omalizumab group than in the suplatast tosilate group, but all these events were of mild degree. No anti-omalizumab antibodies were detected. CONCLUSION: Omalizumab showed significantly greater improvements than suplatast tosilate in the treatment of SAR induced by Japanese cedar pollens.

Heme oxygenase-1 (Hsp32) is involved in the protection of small intestine by whole body mild hyperthermia from ischemia/reperfusion injury in rat.

AIM: The aim of the present study was to explore whether heme oxygenase-1 (HO-1) is involved in the hyperthermia-provided protection of the small intestine from ischemia/reperfusion injury in rats. METHODS: Intestinal damage was induced in male Sprague-Dawley rats by clamping both the superior mesenteric artery and the celiac trunk for 30 min, followed by reperfusion. Whole-body hyperthermia was induced in anesthetized rats by placement in a temperature-controlled water bath. Whole-body hyperthermia to a core temperature of 42-43 degrees C for 15 min was followed by passive cooling. We started the hyperthermic treatment 6 h before the vascular clamping. The severity of the mucosal injury was evaluated by several biochemical markers and histological findings. Hyperthermia-induced heat-shock proteins were detected by Western blotting. We also investigated the effect of zinc protoporphyrin IX (an HO-1 inhibitor) on the protective effect of hyperthermia. RESULTS: The rats, which were killed after ischemia/reperfusion, had severe intestinal inflammation. Hyperthermia significantly induced the production of Hsp70 and HO-1 in intestinal mucosa and significantly reduced ischemia/reperfusion-induced mucosal injury. The combination of zinc protoporphyrin IX with hyperthermia extinguished the protective effects of hyperthermia on ischemia/reperfusion injury. CONCLUSION: Hyperthermia protects against ischemia/reperfusion injury in rat small intestine through the expression of heat-shock proteins, especially HO-1.

Study on adsorption mechanism of proteins onto synthetic calcium hydroxyapatites through ionic concentration measurements.

To clarify the adsorption mechanism of proteins onto calcium hydroxyapatite (Hap), the kinetic studies of dissolution and ion-exchange properties of synthetic Hap particles in the absence and presence of proteins were examined at 15 degrees C. In the absence of proteins, Hap particles slightly dissolved to give low amounts of calcium ([Ca(2+)] = 0.09-0.14 micromol m(-2)) and phosphate [PO(4) (3-)] = 0.01-0.08 micromol m(-2)) ions in KCl, CaCl(2), BaCl(2) and AlCl(3) solutions. The [Ca(2+)] increased with increase in the Ca/P ratio of Hap, while the [PO(4) (3-)] decreased. The[ Ca(2+)] and [ PO(4) (3-)] were independent of the ionic strength. Ba(2+) and AI(3+) ions were completely ion-exchanged with calcium ions in Hap lattice within 2 hr. The solution pH was increased by 1.1-1.8 after the dissolution of OH(-) ions on the Hap surface. In the presence of bovine serum albumin (BSA), the Hap particles dissolved slightly faster than the systems without protein. This fact was explained by a complexation of dissolved ions to functional groups of BSA. The adsorption of BSA induced a reduction of [Ca(2+)] and [ PO(4) (3-)] in the aqueous medium and minima appeared on [Ca(2+)] and [PO(4) (3-)] profiles before the BSA adsorption reached a saturation. This result suggests that the adsorption of BSA onto Hap is governed by [Ca(2+)] ions complexing to BSA molecules (binding effect) together with the operation of [Ca(2+)] ions exposing on the Hap surfaces by dissolution of OH(-) ions, so-called "C-sites". The addition of BaCl(2) and AlCl(3 )steeply increased the amounts of adsorbed BSA (n(BSA)) at the initial adsorption step by the strong binding effect of these di- and tri-valent cations between BSA and Hap. However, after eliminating these cations from the Hap surface by the ion-exchange reaction, the binding effects disappeared and n(BSA) decreased. Since the number of functional groups is small, the binding effect of the counter ions was only slightly detected for the systems with di- and trivalent ions on the adsorption systems of lysozyme (LSZ).

Early invasive colorectal carcinomas with submucosal invasion: radiographic characteristics with barium double contrast images.

BACKGROUND: We assessed the radiographic characteristics of early colorectal carcinomas with submucosal invasion (CCSI) with the use of double-contrast images. METHODS: From 1989 to 1997, 193 patients with 196 CCSI lesions underwent double-contrast barium enema examinations. Three gastrointestinal radiologists retrospectively reviewed the radiographic characteristics of the lesions and classified them as protruding and depressed types by consensus. Further, subclassifying the protruding into lobular and smooth types was accomplished on the basis of surface structure. Each type was compared with pathologic findings of resected specimens. RESULTS: The incidence of the protruding type was 98.0%, and that of the depressed type was only 2.0%. The proportion of smooth lesions was 49.0% for the protruding type; these had a mean diameter of 17.9 mm, which was significantly smaller than the 23.1 mm mean observed for lobular lesions (p < 0.01). Of the smooth lesions, 44.7% demonstrated massive invasion, whereas 91.8% of lobular lesions exhibited only slight or moderate invasion into the submucosa (p < 0.01). The extent of invasion of the smooth lesions was greater than that for their lobular counterparts in terms of venous and lymph node involvement. CONCLUSION: Almost all CCSIs could be identified radiologically as protruding lesions; these had a smooth rather than a lobulated surface and demonstrated greater malignancy, despite the smaller size. It is clinically important to discriminate these from other polypoid lesions in establishing patient treatment. Double-contrast imaging is useful for evaluation of the surface characteristics of CCSIs in barium enema studies.

Ubiquitin-proteasome inhibitor enhances tumour necrosis factor-alpha-induced apoptosis in rat gastric epithelial cells.

BACKGROUND: Tumour necrosis factor (TNF-alpha) is a candidate factor for involvement in inflammation-mediated gastric mucosal injury. However, the effect of this cytokine on gastric epithelial cells has been poorly investigated. In the present study, we examined whether gastric epithelial cells are resistant to TNF-alpha-induced apoptosis, and whether this resistance is related to ubiquitin-proteasome-associated nuclear factor-kappaB (NF-kappaB) activation. METHODS: The rat gastric mucosal cell line RGM-1 was grown in DMEM/F12 medium supplemented with 10% FCS. Confluent monolayers of cells were pretreated or not for 60 min with PSI, a peptide aldehyde known to specifically inhibit the chymotrypsin-like activity of 26S proteasome. Cells were subsequently stimulated with recombinant rat TNF-alpha and their viability was determined by WST-1 assay. Apoptosis was confirmed by fluorescence microscopy after staining with Hoechst 33342 and propidium iodide, and DNA fragmentation was determined by flow cytometry using an APO-BRDU kit. IkappaB-alpha and the p65 binding subunit of NF-kappaB were detected by Western blots. RESULTS: Twenty-four-hour incubation with TNF-alpha alone or PSI alone did not affect the cell viability of RGM-1 cells. Pretreatment with PSI significantly enhanced the level of apoptosis induced by TNF-alpha. In RGM-1 cells treated with TNF-alpha, cytoplasmic IkappaB-alpha decreased and p65 in nuclear extracts increased markedly 30 min after cytokine stimulation. Pretreatment with PSI at 12.5 micromol/L blocked these TNF-alpha-induced changes. CONCLUSION: PSI enhances TNF-alpha-induced apoptosis through inhibition of NF-kappaB activation in RGM-1 cells.

Beta(3)-adrenoceptor agonists for the treatment of frequent urination and urinary incontinence: 2-[4-(2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl)phenoxy]-2-methylpropionic acid.

In a search for novel analogues of beta(3)-adrenoceptor (AR) agonists relaxing the bladder for treatment of urinary dysfunction, 2-[4-(2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl)phenoxy]-2-methylpropionic acids (1a-e), into which a fibrate-like structure had been incorporated, were synthesised. Compound 1a was found to be a selective beta(3)-AR agonist in functional assays using the ferret detrusor (beta(3)-AR), rat uterus (beta(2)-AR), and rat atrium (beta(1)-AR); beta(3): EC(50)=7.8 nM, beta(2): IC(50)=7,300 nM, beta(1): EC(20)=23,000 nM. The introduction of a chlorine atom or methyl substituent at the ortho-position on the phenyl ring of 1a further improved beta(3)-AR selectivity. In an in vivo study, 1a lowered intrabladder pressure (ED(50)=31 microg/kg) in rats, without increasing heart rate, in keeping with the in vitro results. Consequently, it is proposed that 1a and its analogues (1b-e), possess beta(3)-AR agonistic activity in the absence of undesirable beta(1)- or beta(2)-AR mediated actions, and may be useful for clinical treatment and pharmacological studies.

The relationship between a leaf-rolling moth (Dactylioglypha tonica) and fungi covering the cocoon.

To discover the relationship between a leaf-rolling moth and the fungi densely covering its cocoons, the rolled nest leaves were collected in two districts in Japan and antibacterial properties of the fungi were examined. Cocoons and fungi isolated from the nest were classified into 5 categories by the growth stages of the insects, and 7 categories based on taxonomic properties and pigment productivity, respectively. The dominant genus was Penicillium in each location. However, the composition of the fungal categories was different and seemed to depend on their circumstances. From all cocoons with larvae, the strains that belonged to the same fungal category and produced the same antibiotic (deoxyherqueinone) were isolated. From these results, the species-specific relationship between the insect and fungi or fungal products was considered to be not extremely tight, and it was suggested the period of the larval spinning of the cocoon is a key stage of this unique relationship.

Effects of tomato juice consumption on plasma and lipoprotein carotenoid concentrations and the susceptibility of low density lipoprotein to oxidative modification.

Effects of tomato juice supplementation on the carotenoid concentration in lipoprotein fractions and the oxidative susceptibility of LDL were investigated in 31 healthy Japanese female students. These subjects were randomized to one of three treatment groups; Control, Low and High. The Control, Low and High groups consumed 480 g of a control drink, 160 g of tomato juice plus 320 g of the control drink, and 480 g of tomato juice, providing 0, 15 and 45 mg of lycopene, respectively, for one menstrual cycle. The ingestion of tomato juice, rich in lycopene but having little beta-carotene, increased both lycopene and beta-carotene. Sixty-nine percent of lycopene in plasma was distributed in the LDL fraction and 24% in the HDL fraction. In the Low group, the lycopene concentration increased 160% each in the VLDL+IDL, LDL and HDL fractions (p<0.01). In the High group, the lycopene concentration increased 270% each in the VLDL+IDL and LDL fractions, and 330% in the HDL fraction (p<0.01). Beta-carotene also increased 120% and 180% in LDL fractions of the Low and the High groups, respectively. Despite these carotenoid increases in LDL, the lag time before oxidation was not prolonged as compared with that of the Control group. The propagation rate decreased significantly after consumption in the High group. Multiple regression analysis showed a positive correlation between lag time changes and changes in the alpha-tocopherol concentration per triglyceride in LDL, and a negative correlation between propagation rate changes and changes in the lycopene concentration per phospholipid in LDL. These data suggest that alpha-tocopherol is a major determinant in protecting LDL from oxidation, while lycopene from tomato juice supplementaion may contribute to protect phospholipid in LDI, from oxidation. Thus, oral intake of lycopene might be beneficial for ameliorating atherosclerosis.

Water-soluble constituents of ajowan.

From the water-soluble portion of the methanol extract of the fruit of Carum ajowan (ajowan), which has been used as a spice and medicine, 25 compounds, including five new monoterpenoid glucosides, a new monoterpenoid, two new aromatic compound glucosides, and two new glucides, were obtained. Their structures were clarified by spectral investigation.

Water-soluble constituents of Glehnia littoralis fruit.

From the water-soluble portion of the methanol extract of the fruit of Glehnia littoralis Fr. SCHMIDT ex MIQ. (Umbelliferae; "hamabofu" in Japanese), thirty compounds, including three new monoterpenoids and a new monoterpenoid glucoside, a new benzofuran glucoside, a new alkyl glucoside, and a new glucide, were obtained. Their structures were clarified by spectral investigation.

[Long-term study of airborne allergic pollen count, C. Japonica and cupressaceae in Japan].

We have investigated the distribution of airborne pollen at the different eleven points in Japan from 1987 to 1998 using gravity sampler. To clarify the characteristics causative pollen for Japanese cedar pollinosis, we examined annual change of pollen counts, dispersing period and geographical difference of C. japonica and Cupressaceae pollen. C. japonica pollen occupied much more in Central Japan and Cupressaceae in the west of Japan than the other area. In Hamamatsu City, both of pollen counts were most of all and we found a tendency that the more pollen counts the longer dispersing period. As they reported that at the starting day of pollen in this method some patients had already suffered from allergic symptoms, we considered pollen grains were dispersing in spite of being continuously captured. In these twelve years we found that patients with Japanese pollinosis are exposured by causative agents during about 100 days every spring. But we could not observe the trend of increasing pollen counts and earlier starting day because of global warming. Further more we found that the pollen counts of C. japonica in autumn was increasing since 1994. As one of the factors of increasing patients with pollinosis, we thought that total exposure period of causative pollen every year were longer than that of 1980s.

Optimization of atrioventricular delay and follow-up in a patient with congestive heart failure with an implanted DDD pacemaker: case report.

It has been reported that cardiac function can be improved by implanting a DDD pacemaker (PM) and setting a short atrioventricular (AV) delay in patients with impaired cardiac function. A previous report found that the critical AV delay that induces diastolic mitral regurgitation (MR) may represent the upper limit of the optimal AV delay. The optimal AV delay can be predicted by a simple method: slightly prolonged AV delay minus the interval between the end of the atrial kick and complete closure of the mitral valve (duration of diastolic MR) at the AV delay setting. The patient was a 84-year-old man with an old myocardial infarction. He had repeated admissions to hospital for congestive heart failure. ECG showed prolongation of the PQ interval (0.28 s) and complete left bundle branch block. Cardiac function was improved by AV sequential pacing when the AV delay was set at 120ms. After DDD-PM implantation, the cardiothoracic ratio decreased from 57 to 45% and cardiac function was improved from New York Heart Association class III to I. The AV delay was optimized during follow-up. Four years after PM implantation, the patient was in good condition without further hospital admission.

Coumarins and antiplatelet constituents from the root bark of Zanthoxylum schinifolium.

Further study on the chloroform-soluble portion of the root bark of Zanthoxylum schinifolium led to the isolation of eight new coumarins: methylschinilenol (1), hydroxyepoxycollinin I (2), 8-methoxyanisocoumarin H (3), hydroxyschininallylol (4), hydroxyepoxycollinin II (5), schinitrienin (6), schininallylone (7), and isoschinilenol (8), along with twenty-six known compounds including fourteen coumarins, and nine alkaloids. The structural elucidation was determined by spectroscopic data. Among the isolates, terpenyl-coumarins and furoquinolines were the active constituents with antiplatelet aggregation in vitro and collinin (10) showed significant anti-HBC DNA replication activity.