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Osteoarthritis (OA) accounts for up to 60% of equine lameness. Agmatine, a decarboxylated arginine, may be a viable option for OA management, based on reports of its analgesic properties. Six adult thoroughbred horses, with lameness attributable to thoracic limb OA, received either daily oral phenylbutazone (6.6 mg/kg), agmatine sulfate (25 mg/kg) or a control for 30 days, with 21-day washout periods between treatments. Subjective lameness, thoracic limb ground reaction forces (GRF), plasma agmatine and agmatine metabolite levels were evaluated using an established rubric, a force platform, and mass spectrometry, respectively, before, during and after each treatment period. Gastric ulceration and plasma chemistries were evaluated before and after treatments. Braking GRFs were greater after 14 and 29 days of agmatine compared to phenylbutazone administration. After 14 days of phenylbutazone administration, vertical GRFs were greater than for agmatine or the control. Glandular mucosal ulcer scores were lower after agmatine than phenylbutazone administration. Agmatine plasma levels peaked between 30 and 60 min and were largely undetectable by 24 h after oral administration. In contrast, plasma citric acid levels increased throughout agmatine administration, representing a shift in the metabolomic profile. Agmatine may be a viable option to improve thoracic limb GRFs while reducing the risk of glandular gastric ulceration in horses with OA. [ABSTRACT FROM AUTHOR]

Adequate management of nocturnal hypertension is crucial to reduce the risk of organ damage and cardiovascular events. The EARLY‐NH study was a prospective, open‐label, multicenter study conducted in Japanese patients with nocturnal hypertension who received esaxerenone treatment for 12 weeks. This post hoc analysis aimed to assess (1) the relationship between changes in morning home systolic blood pressure (SBP), bedtime home SBP, and nighttime home SBP based on changes in SBP and achievement rates of target SBP levels; and (2) the correlation between nighttime home SBP measurements using brachial and wrist home BP monitoring (HBPM) devices. This analysis evaluated 82 patients who completed the 12‐week treatment period. Among those who achieved target morning home SBP (<135 mmHg) and target bedtime home SBP (<135 mmHg), the brachial HBPM device showed achievement rates of 63.6% and 56.4%, respectively, for target nighttime home SBP (<120 mmHg). The wrist device showed achievement rates of 66.7% and 63.4%, respectively, for the same targets. Significant correlations were observed between both devices for nighttime home SBP measurements at baseline (r = 0.790), Week 12 (r = 0.641), and change from baseline to Week 12 (r = 0.533) (all, p < .001). In this patient population, approximately 60% of individuals who reached target morning or bedtime home SBP levels <135 mmHg exhibited well‐controlled nighttime home SBP. Although nighttime home SBP measurements obtained using both brachial and wrist HBPM devices displayed a significant correlation, the wrist device needs to be examined in more detail for clinical use. [ABSTRACT FROM AUTHOR]

Some of the earliest success in de novo tissue generation was in bone tissue, and advances, facilitated by the use of endogenous and exogenous progenitor cells, continue unabated. The concept of one health promotes shared discoveries among medical disciplines to overcome health challenges that afflict numerous species. Carefully selected animal models are vital to development and translation of targeted therapies that improve the health and well‐being of humans and animals alike. While inherent differences among species limit direct translation of scientific knowledge between them, rapid progress in ex vivo and in vivo de novo tissue generation is propelling revolutionary innovation to reality among all musculoskeletal specialties. This review contains a comparison of bone deposition among species and descriptions of animal models of bone restoration designed to replicate a multitude of bone injuries and pathology, including impaired osteogenic capacity. [ABSTRACT FROM AUTHOR]

Osteoarthritis challenges traditional therapies and remains a leading cause of lameness in older dogs. Regenerative medicine offers new strategies, typically involving the injection of autologous adipose-derived mesenchymal stem cells (MSCs). Conversely, allogenic MSCs are appealing candidates to palliate patient morbidity and cell preparation time. Regardless of the source of cells, identifying critical donor characteristics, such as age, is essential to obtain the most competent MSCs. The objectives of this study were to determine the influence of donor's age on proliferation, gene expression, and immunomodulatory properties of MSCs in dogs. Canine adipose tissue-derived MSCs (cAD-MSCs) were isolated from the falciform-ligament adipose tissues of nine pairs of gender-matched young (<2 years) or old (>7 years) client-owned dogs undergoing abdominal surgery. Growth kinetics, transcriptome before and after stimulation by tumor necrosis factor alpha and interferon gamma, MSC-induced lymphocyte suppression assay, and secretion of prostaglandin E2 (PGE2) and indoleamine 2,3-dioxygenase (IDO) were compared between cells obtained from young or old dogs. The doubling times at passages 2 and 3 were shorter when MSCs were isolated from young (34.8 ± 1.8 h and 46.3 ± 2.3 h) rather than old dogs (56.5 ± 8.0 h and 123.8 ± 46.7 h, P < 0.05). The MSC transcriptomes from both populations were similar without stimulation, while stimulation resulted in a 3-fold greater expression of osteogenic gene, fibroblast growth factor 10, in cells from old dogs. cAD-MSCs from young dogs suppressed proliferation of activated T cells more strongly (P < 0.05), although secretion of PGE2 and IDO did not differ between groups. In conclusion, donors' age affected proliferation, immunomodulatory properties of cAD-MSCs, and increased expression of osteogenic gene under proinflammatory conditions in our population of dogs. Collectively, our results provide evidence to support further evaluation of allogenic MSC therapies derived from young donors as alternatives to autologous MSC therapy in older dogs. [ABSTRACT FROM AUTHOR]

Membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in adults. The J-RBR/J-KDR registry developed by the Japanese Society of Nephrology provides nationwide cohort data for epidemiological studies of MN. MN was present in 36.8% of 1,203 primary nephrotic syndrome patients in Japan. In addition, 633 (77.9%) out of 813 MN patients were referred to as 'idiopathic,' whereas 22.1% were classified as 'secondary' and involved conditions such as systemic lupus erythematosus, drug exposure, infections, cancer, and various collagen diseases. The mean age of the MN patients was 62.2 (2-88) years old, their mean eGFR was 76.7 (7.6-154.6) ml/min/1.73 m, and 63.3% had hypertension at the time of renal biopsy. On the basis of these findings, half of Japanese idiopathic MN patients have risk factors (age >60, male, or lower eGFR) for end-stage renal failure, and 10% belong to the high-risk group (daily proteinuria of over 8.0 g). Further studies with high-grade evidence should resolve the natural history and therapeutic problems of idiopathic MN in elderly Japanese. [ABSTRACT FROM AUTHOR]

Environmental and genetic factors influence serum total homocysteine (tHcy), a risk factor for vascular diseases. The gene polymorphism of methylenetetrahydrofolate reductase (MTHFR) is reported to be a genetic factor for influencing tHcy. However, it is not clear whether MTHFR polymorphism influences tHcy in the younger generation. To investigate the influence of MTHFR polymorphism on vascular disease risks in young Japanese females, we determined dietary intakes, serum folate and tHcy, and examined the influence of MTHFR 677C>T polymorphism in healthy junior and high school students (n=192, 12-18y). The relationships between MTHFR polymorphism and folate intake, serum folate or tHcy were investigated by dividing participants into CC, CT and TT types. Among individuals with the TT genotype, folate and tHcy levels were significantly lower (p<0.05) or higher (p<0.0001), respectively, than in those with the other genotypes; although there were no significant differences in the intake of folate among genotypes. In addition, a significant inverse correlation between folate and tHcy (p<0.05) was noted in all genotypes, even in young females, so far not examined in Asian populations. Therefore, MTHFR genotypes were proven to be a significant determinant for folate and tHcy concentrations. However, the association of increased folate intake with lower tHcy concentration, even in cases of the mutation TT type, indicates the importance of folate intake in young Japanese females for early detection of risk, as well as the prevention of vascular diseases. [ABSTRACT FROM AUTHOR]

Environmental and genetic factors influence serum total homocysteine (tHey), a risk factor for vascular diseases. The gene polymorphism of methylenetetrahydrofolate reductase (MTHFR) is reported to be a genetic factor for influencing tHcy. However, it is not clear whether MTHFR polymorphism influences tHey in the younger generation. To investigate the influence of MTHFR polymorphism on vascular disease risks in young Japanese females, we determined dietary intakes, serum folate and tHey, and examined the influence of MTHFR 677C>T polymorphism in healthy junior and high school students (n=192, 12-18y). The relationships between MTHFR polymorphism and folate intake, serum folate or tHcy were investigated by dividing participants into CC, CT and TT types. Among individuals with the TT genotype, folate and tHcy levels were significantly lower (p<0.05) or higher (p<0.0001), respectively, than in those with the other genotypes; although there were no significant differences in the intake of folate among genotypes. In addition, a significant inverse correlation between folate and tHcy (p<0.05) was noted in all genotypes, even in young females, so far not examined in Asian populations. Therefore, MTHFR genotypes were proven to be a significant determinant for folate and tHey concentrations. However, the association of increased folate intake with lower tHcy concentration, even in cases of the mutation TT type, indicates the importance of folate intake in young Japanese females for early detection of risk, as well as the prevention of vascular diseases. [ABSTRACT FROM AUTHOR]

Background. Because of the epidemic of metabolic syndrome (MS) in Australian Aboriginals known for their higher cardiovascular mortality and shorter life expectancy, we analyzed the possible relationship of their MS risks with the current dietary custom. Methods. The subjects were 84 people aged 16-79 years. The health examination was conducted according to the basic protocol of WHO-CARDIAC (Cardiovascular Diseases and Alimentary Comparison) Study. Results. The highest prevalence among MS risks was abdominal obesity (over 60%). After controlling for age and sex, the odds of obesity decreased significantly with high level of urinary magnesium/creatinine ratio (Mg/cre) (OR, 0.11; 95% CI, 0.02-0.57; P < .05). The significant inverse associations of fat intake with Mg/cre and of fast food intake with urinary taurine/creatinine ratio were revealed. Conclusions. The high prevalence of obesity in the Aboriginal people of this area may partly be due to the reduction of beneficial nutrients intake including Mg and taurine. [ABSTRACT FROM AUTHOR]

Taurine (T) was first noted as beneficial for stroke and cardiovascular diseases (CVD) prevention in genetic rat models, stroke-prone spontaneously hypertensive rats (SHRSP). The preventive mechanisms of T were ascribed to sympathetic modulation for reducing blood pressure (BP) and anti-inflammatory action. Recent epidemiological surveys revealed the involvement of inflammatory mediators in the pathogenesis of stroke and also atherosclerosis for which T was proven to be effective experimentally. Arterio-lipidosis prone rats, a substrain of SHRSP selectively bred for higher reactive hypercholesterolemia, quickly develop not only arterial fat deposition but also fatty liver which could be attenuated by dietary T supplementation. CARDIAC (CVD and Alimentary Comparison) Study was a WHO-coordinated multi-center epidemiological survey on diets and CVD risks and mortalities in 61 populations. Twenty-four-hour urinary (24U) T was inversely related significantly with coronary heart disease mortality. Higher 24U-T excreters had significantly lower body mass index, systolic and diastolic BP, total cholesterol (T-Cho), and atherogenic index (AI: T-Cho/high density lipoprotein-cholesterol) than lower T excreters. T effects on CVD risks were intensified in individuals whose 24U-T and -magnesium (M) excretions were higher. Furthermore, higher Na excreters with higher heart rate whose BP were significantly higher than those with lower heart rate were divided into two groups by the mean of 24U-T, high and low T excreters. Since the former showed significantly lower BP than the latter, T may beneficially affect salt-sensitive BP rise. Included among the typical 61 populations, were Guiyang, China or St. John's, Newfoundland, Canada where in which the means of both 24U-T and -M were high or low, respectively. The former and the latter had low and high CVD risks, respectively. Australian Aboriginals living at the coastal area in Victoria were supposed to eat T- and M-rich bush and sea foods and be free from CVD 200 years ago, but they presently have nearly the highest CVD risks indicating that T- and/or M-containing seafood, vegetables, fruits, nuts, milk, etc, similar to prehistoric hunters' and gatherers' food should be good for CVD prevention. The preventive effects of T, good for health and longevity, first noted experimentally, were also proven epidemiologically in humans. [ABSTRACT FROM AUTHOR]

Background: Since taurine (T) administration was proven to decrease blood pressure (BP) and stroke mortality in stroke-prone spontaneously hypertension rates (SHRSP) in the 1980's and our WHO-coordinated CARDIAC (Cardiovascular Diseases and Alimentary Comparison) Study demonstrated that among 5 diet-related factors, namely total cholesterol (T-Cho), body mass index (BMI), sodium (Na), magnesium (M), and T to creatinine (Cr) ratio in 24-hour urine (24U), both T/Cr and M/Cr were inversely related to coronary heart disease mortalities in males and females and T/Cr was inversely related to stroke mortalities in males and females. We further analyzed the associations of individual T/Cr and M/Cr levels to cardiovascular risks in the present study. Method: From WHO-CARDIAC Study populations, 61 populations of 25 countries in the world, Japanese populations with obviously higher 24U T excretion because of their common fish eating custom and the other populations in which both data of T and M were not available were excluded and the data of 3960 individuals from 41 WHO-CARDIAC Study populations were used for the following analyses. Results: The means of 24U T/Cr and M/Cr ratios in total individual data were 639.4 and 82.8, respectively. The average of BMI, systolic and diastolic blood pressure (SBP, DBP), T-Cho and atherogenic index (AI) in the individuals with more than the means of T/Cr or M/Cr were significantly lower than those of individuals with less than the means. The CARDIAC Study participants were divided into the following 4 groups by these means: A (T/Cr and M/ Cr ≧ mean), B (T/Cr ≧ mean, M/Cr < mean), C (T/Cr < mean, M/Cr ≧ mean), D (T/Cr and M/Cr < mean). The group A showed significantly lower values compared with the group D in BMI, SBP, DBP, T-Cho, and AI. Conclusions: Cardiovascular risks were proven to be highly significantly lower in individuals who were excreting both 24U T and M, more than the averages despite differences in ethnicity and genetic background. Since T and M are biomarkers for seafood, vegetables, soy, nuts, milk, etc., dietary custom to eat these food sources could be recommended for cardiovascular disease prevention. [ABSTRACT FROM AUTHOR]

A rare and peculiar glomerulopathy has begun to be recognized in Japan. The Japanese Society of Nephrology has established a research working group and has collected cases from all over Japan in an attempt to understand the complete spectrum of this glomerulopathy. The diagnostic criterion, which was needed to collect the cases, was proposed as a glomerulopathy showing microspheres or microtubular structures or both associated with podocytic infolding into the glomerular basement membrane (GBM) on electron microscopy. The lesion shows a non-argentaffin hole in the GBM with periodic acid methenamine silver staining and is similar to membranous glomerulonephritis. Twenty-five cases were collected from 17 institutions. Patients were 20–69 years old (19 women, 6 men). Seventeen patients also had collagen diseases such as lupus nephritis and Sjögren’s syndrome. All patients had proteinuria. Proteinuria showed a remission in 15 of 23 patients within 12 months, but proteinuria remained higher than 1.0 g/day in five patients despite different types of therapy. Podocytic infolding including microspheres showed either positive or negative staining for immunoglobulins. Cluster formation of microspheres was found in 4 of 17 patients with collagen disease, and in five out eight patients without collagen disease. Electron-dense deposits in the GBM were also found in 6 of 17 patients with collagen disease but were not found in eight patients without collagen disease. Some patients might have a subtype of lupus nephritis, class V, or membranous glomerulonephritis. However, we propose a new disease entity, podocytic infolding glomerulopathy, as a common basis of all 25 patients, because we suspect that microspheres or microtubular structures or both can be derived from podocytic infolding. [ABSTRACT FROM AUTHOR]

Heat shock protein 47 (HSP47) is a collagen-specific molecular chaperone that is required for molecular maturation of various types of collagens. Recent studies have shown a close association between increased expression of HSP47 and excessive accumulation of collagens in scar tissues of various human and experimental fibrotic diseases. It is presumed that the increased levels of HSP47 in fibrotic diseases assist in excessive assembly and intracellular processing of procollagen molecules and, thereby, contribute to the formation of fibrotic lesions. Studies have also shown that suppression of HSP47 expression can reduce accumulation of collagens to delay the progression of fibrotic diseases in experimental animal models. Because HSP47 is a specific chaperone for collagen synthesis, it provides a selective target to manipulate collagen production, a phenomenon that might have enormous clinical impact in controlling a wide range of fibrotic diseases. Here, we outline the fibrogenic role of HSP47 and discuss the potential usefulness of HSP47 as an anti-fibrotic therapeutic target. [Copyright &y& Elsevier]

Abstract: In order to miniaturize large scaled IC (LSI) and/or produce a multi-layered LSI device, copper wire with a smooth surface is required. For reduction of the surface roughness, ion etching with oblique injection was applied for polycrystalline copper. Argon ion irradiation was conducted by changing the incident angle and ion energy. After irradiation, many blisters of various sizes were observed. During normal ion injection, the etched amount of copper increased with ion energy and the average height of blisters also increased. Then, blister formation can be adjusted by ion energy. As the incident angle increased, the blister size became smaller and the surface became smooth compared with normal ion injection. This result suggests that preferential sputtering occurred for the protuberant parts of blisters. In particular, when the incident angle is 67.5°, the average height of blisters became half of the normal value. The present result shows that oblique ion irradiation contributes to the reduction of surface roughness. [Copyright &y& Elsevier]

Vpr, an accessory gene product of HIV-1, is incorporated into cells when added to the culture medium. Via such function Vpr has been shown to transduce a protein into cells that is expressed as a chimeric protein with Vpr. The domain required for protein transduction, however, remained to be clarified. Here we identified a sequence encompassing 52–78 amino acids of Vpr (C45D18) that enables nuclear trafficking of proteins. When chemically synthesized C45D18 was added to the culture medium of human cord blood mononuclear (CBMN) cells, most cells became positive for the incorporated C45D18. Furthermore, recombinant proteins conjugated with the C45D18 were efficiently transduced and transported to regions corresponding to the nucleus. Incorporation of C45D18-conjugated protein was observed within a few hours after addition of the protein, independent of cellular growth. Although it is well known that Tat-derived peptide has a transducing activity, C45D18 was more active than Tat peptide for trafficking proteins into cells. Taking together with results from FACS analysis revealing that more than 90% of CBMN cells were positive for X-gal staining after treatment of C45D18-conjugated β-galactosidase, we propose that C45D18 translocates bioactive macromolecules directly into the nucleus. [Copyright &y& Elsevier]

Focuses on the causes of immunoinflammatory diseases. Level of gene expression; Factors controlling the transcription of the genes; Lack of follicular dendritic cell networks.

Connective tissue remodeling of the interstitium is an important feature of chronic lung diseases encompassing interstitial inflammatory changes and subsequent pulmonary fibrosis. The early inflammatory phase is usually associated with the release of several cytokines and chemokines by activated resident cells and infiltrating cells which, in turn, help further recruit inflammatory mononuclear cells. Cytokines and growth factors secreted by inflammatory cells and by interstitial cells (fibroblasts and myofibroblasts) play an important role in the fibrogenic phase of pulmonary fibrosis by inducing matrix synthesis. In addition, matrix-degrading enzymes and their inhibitors also contribute to extracellular matrix (ECM) remodeling in pulmonary fibrosis. This review addresses the pathophysiology of wound healing and different phases of pulmonary fibrosis. [ABSTRACT FROM AUTHOR]

Examines the role of glomerular epithelial cell-derived heat shock protein 47 in experimental lipid nephropathy. Involvement of collagen-specific stress protein in the synthesis; Induction of dietary-induced hypercholesterolemia; Use of immunohistochemistry for localization of protein products.

Since the two-dimensional electron gas in the modulation-doped AlGaAs/GaAs heterojunctional is an thin as 10 nm and the electron mobility is over 7000 cm²/Vs, this structure is suitable for highly sensitive Hall device. As the room temperature device the following conditions must be satisfied: the carriers should be supplied sufficiently to the two-dimensional gas, but no excess carriers should exist in the highly doped AlGaAs layer. Thus the number of the two-dimensional electron gas should have little dependence on the temperature. The fabrication conditions of the heterojunction and the magnetic property of the devices are discussed. The product sensitivity and the figure of merit of the heterojunction Hall device were 1000 V/AT and 27 (V/A)1/2/T, respectively. These values are comparable to those of InSb Hall devices. The temperature dependence of our device was three times less than that of the InSb Hall device. [ABSTRACT FROM AUTHOR]

We calculated the electronic structures and the thermoelectric properties for type-I and type-VIII Ba8Ga16Sn30 (BGS) clathrates. The band structures show that type-I and type-VIII BGS are indirect semiconductors with band gaps of 0.51 eV and 0.32 eV, respectively. The calculated Seebeck coefficient of n-type type-I BGS is higher than that of n-type type-VIII BGS because of the larger density of states in type-I at the bottom of the conduction band. This is in good agreement with the experimental results. We also calculated the electrical conductivity and thermal conductivity due to charge carriers. Estimated thermoelectric figure of merit, ZT, exceeds 1.0 for both types. [ABSTRACT FROM AUTHOR]

The next‐generation mineralocorticoid receptor blocker (MRB) esaxerenone has favorable antihypertensive effects in patients who do not respond to treatment with first‐line antihypertensive agents and may be beneficial as a second‐line treatment. However, MRBs are currently considered a fourth‐line treatment as there is no clinical evidence comparing the efficacy of esaxerenone with other classes of antihypertensive agents. The multicenter, randomized, open‐label, parallel‐group EXCITE‐HT study will evaluate the efficacy and safety of esaxerenone as a second‐line agent in the treatment of Japanese patients with uncontrolled essential hypertension. After a 4‐week run‐in period, patients will receive either esaxerenone or trichlormethiazide for 12 weeks per the package insert and the Japanese Society of Hypertension Guidelines for the Management of Hypertension. At Weeks 4 and 8, the dose of esaxerenone or trichlormethiazide may be increased. Blood pressure (home [morning and bedtime] and office), serum biomarkers, and urinary biomarkers will be measured. The primary efficacy endpoint is the change from baseline in morning home systolic blood pressure/diastolic blood pressure to the end of treatment. The EXCITE‐HT study is expected to validate the non‐inferiority of esaxerenone to trichlormethiazide and provide the first evidence for the early use of esaxerenone as a second‐line agent in the treatment of Japanese patients with uncontrolled essential hypertension instead of its current use as a fourth‐line agent. [ABSTRACT FROM AUTHOR]

Legumes contain dietary fiber and resistant starch, which are beneficial to the intestinal environment. Here, we investigated the effects of yellow pea noodle consumption on the gut microbiota and fecal metabolome of healthy individuals. This single‐armed pre‐post comparative pilot study evaluated eight healthy female participants who consumed yellow pea noodles for 4 weeks. The gut microbiota composition and fecal metabolomic profile of each participant were evaluated before (2 weeks), during (4 weeks), and after (4 weeks) daily yellow pea noodle consumption. 16S rRNA gene sequencing was performed on stool samples, followed by clustering of operational taxonomic units using the Cluster Database at High Identity with Tolerance and integrated QIIME pipeline to elucidate the gut microbiota composition. The fecal metabolites were analyzed using capillary electrophoresis time‐of‐flight mass spectrometry and liquid chromatography time‐of‐flight mass spectrometry. Compared to day 0, the relative abundances of five bacterial genera (Bacteroides, Bilophila, Hungatella, Parabacteroides, and Streptococcus) in the intestinal microbiota significantly decreased, wherein those of Bifidobacterium longum and Ruminococcus bromii were increased on day 29 and decreased to the basal level (day 0) on day 57. Fecal metabolomic analysis identified 11 compounds showing significant fluctuations in participants on day 29 compared to day 0. Although the average levels of short‐chain fatty acids in participants did not differ significantly on day 29 compared to those on day 0, the levels tended to increase in individual participants with >8% relative abundance of R. bromii in their gut microbiota. In conclusion, incorporating yellow peas as a daily staple may confer human health benefits by favorably altering the intestinal environment. [ABSTRACT FROM AUTHOR]

Examines the effect of the increased expression of synaptic basal lamina protein agrin on the glomerulosclerotic process. Impact of agrin on the acetylcholine receptors in the neuromuscular junction; Speculation on the role of agrin in the sclerotic process; Expression and distribution of agrin in Thy-1, antibody-treated rat kidney.

• New bracing member namely partially-fibered CFRP (PFCFRP) is proposed. • PFCFRP members can provide a compression-free mechanism. • PFCFRP can greatly avoid out-of-plane deformation by buckling. • Structural performance is evaluated by full-scale cyclic loading experiments. Turnbuckle braces have been widely used as the seismic-resistant member of steel structures. Being a very slender member, the compressive resistance capacity is not considered in the structural design, but these braces buckle easily due to compressive forces, and the buckling deformation damages the finishing material and causes local plastic strain concentration and plastic fatigue failure. Based on this, the authors of this study developed a compression-free brace that can be easily installed on existing steel turnbuckle braces. We focused on the use of lightweight, high-strength carbon fiber reinforced polymer (CFRP) as a brace material and joined the CFRP rod to the existing steel turnbuckle braces through a pipe style turnbuckle body. The proposed compression-free brace uses partially fibered CFRP (PFCFRP) rods to absorb compressive deformation so that only tensile forces are applied to the brace, and out-of-plane deformation due to buckling is significantly reduced. In addition, the combined use of steel turnbuckle braces can be expected to absorb seismic energy by the plastic deformation of steel. PFCFRP rods are only fiberized in the middle position and the unfiberized position (CFRP rods positions) at both ends are used for the joints. They are molded by pultrusion because of their excellent cost-effectiveness, superior mechanical performance, and stability. The partially fibered sections are created without resin injection. PFCFRP rods are connected to the braces using a pipe-style turnbuckle body. The method used to fix the PFCFRP rod and the pipe-style turnbuckle body involves widening the end of the PFCFRP rod to drive a wedge and insert it into the turnbuckle body. Then, it is filled with steel balls and epoxy resin to prevent it from pulling out. Furthermore, we use the pipe-style turnbuckle body to connect the steel structure like a sleeve joint to provide easy and useful assembly. Two different tests were carried out to confirm the effectiveness of the compression-free braces. Firstly, testing of materials used in compression-free braces was conducted. The results of the tests were used to compare the strength of steel turnbuckle braces to clarify the scope of the application of compression-free braces. Next, cyclic loading tests were carried out on a full-scale steel structural frame to simulate the actual seismic bracing situation. The results show that the proposed compression-free braces have similar historical behavior to existing steel turnbuckle braces. Because the PFCFRP rod absorbs the compressive axial deformation, the out-of-plane deformation can be significantly reduced. These results demonstrate that the proposed compression-free braces using PFCFRP can provide a safe and applicable seismic bracing system. [ABSTRACT FROM AUTHOR]

Role of glomerular epithelial cell-derived heat shock protein 47 in experimental lipid nephropathy. Background Heat shock protein 47 (hsp47) is a collagen-specific stress protein and is shown to be involved in the synthesis/assembly of various collagens as a molecular chaperone. This study was undertaken to investigate the possible role of hsp47 in dietary-induced hypercholesterolemic rat kidneys, which showed glomerular hypercellularity with expansion of mesangial matrix. Methods Dietary-induced hypercholesterolemia was induced in male Wistar rats by giving 2% cholesterol diet for four months. Immunohistochemistry was used for localization of protein products for collagens (types I, III, and IV), α-smooth muscle actin, vimentin, desmin, and ED-1, a macrophage/monocyte marker, and hsp47 in control and hypercholesterolemic rat kidneys. Results Compared with the control, increased accumulation of collagens was accompanied with increased expression of hsp47 in hypercholesterolemic rat kidneys, with predominant expression in the glomeruli. By double immunostaining, desmin-positive glomerular epithelial cells were found to be the main source of hsp47 in hypercholesterolemic rat kidneys. Conclusion From these results, it is concluded that induced expression of hsp47 by phenotypically altered glomerular epithelial cells might play a role in the excessive assembly/synthesis of collagens and could thereby contribute to the glomerulosclerosis found in dietary-induced hypercholesterolemic rat kidneys. [ABSTRACT FROM AUTHOR]

Abstract: The vascular system secretes many bioactive factors. In a gene chip database, we searched for novel genes with signal sequences that are specifically expressed in murine aorta, and focused on one gene previously named CCDC3 (NCBI nucleotide entry NM_028804), and we designated as Favine (fat/vessel-derived secretory protein). Northern blot analysis revealed that CCDC3 was expressed abundantly in the aorta and adipose tissues. The mRNA levels of CCDC3 were higher in adipose tissues of obese db/db mice than control mice, and induced during differentiation of rat primary adipocytes. In differentiated adipocytes, CCDC3 mRNA expression was enhanced by insulin and pioglitazone, a PPARgamma agonist, and suppressed by TNF-alpha, isoproterenol and norepinephrine. Transient expression experiments followed by N-terminal amino acid sequence analysis revealed secretion of CCDC3 protein into the culture medium, which was dose-dependently reduced by brefeldin A, an inhibitor of Golgi-mediated secretory pathway. When expressed in COS-7 cells, CCDC3 protein was post-transcriptionally modified with N-glycosylation, and formed a dimer complex. These results indicate that CCDC3 is a protein secreted by adipocytes and endothelial cells, and that its level is regulated both hormonally and nutritionally. [Copyright &y& Elsevier]

The role of parathyroid hormone-related peptide (PTHrP) in the regulation of hypercalcemia in patients with malignancies is well studied, but whether its expression in tumor tissue correlates with tumor progression is not clear at present. The majority of tumors that metastasize to the bone produce PTHrP, and PTHrP expression correlates with skeletal localization of tumors. About 95% of colorectal adenocarcinomas overexpress PTHrP mRNA and protein, and the expression level is higher in poorly differentiated than in well-differentiated adenocarcinomas. However, there is some controversy at present about the prognostic significance of PTHrP expression on primary tumor cells, and studies suggest that there might be tissue-specific responses. We will briefly present here existing evidences that suggest that the expression of PTHrP in the primary tumor tissue could have both positive and/or negative impact on tumor progression and clinical outcome of the disease. [ABSTRACT FROM AUTHOR]

Background: We are investigating whether aldosterone breakthrough negatively impacts on the antiproteinuric effects of angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor blockers (ARB). Methods: We examine the role of aldosterone breakthrough in 43 normotensive, proteinuric (0.7 ± 0.3 g/day) outpatients (aged 41.5 ± 10.9 years) with immunoglobulin A nephropathy (IgAN) accompanied by stable renal function (creatinine clearance >50 mL/min). The patients were treated with temocapril (1 mg; n = 14), losartan (12.5 mg; n = 16), or a combination therapy ( n = 13) for 12 months. We prospectively evaluated blood pressure (BP), urinary protein excretion (UPE), biochemical parameters and the renin-angiotensin-aldosterone system before and after 12 months of treatment. Results: Although the overall plasma aldosterone concentrations values did not change after any of the treatments administered for 12 months, they eventually increased in 23 (temocapril, seven patients; losartan, eight patients; combination, seven patients) of the 43 patients (53.4%; aldosterone breakthrough), and fell in the remainder (46.6%). Blood pressure and renal function did not differ among the three groups at 12 months. In contrast, UPE was significantly higher in patients with, than without aldosterone breakthrough during temocapril and losartan administration. However, combination therapy induced a more remarkable reduction in UPE regardless of aldosterone breakthrough. Conclusions: A combination of ACE inhibitors and ARB in normotensive patients with IgAN produces a more profound decrease in proteinuria than either monotherapy. This additive antiproteinuric effect is not dependent on aldosterone breakthrough. Additional larger, prospective, randomized studies will be needed for general acceptance of this strategy. [ABSTRACT FROM AUTHOR]

The article reports on a 12-year-old girl patient with systemic lupus erythematosus which developed into acute pancreatitis. It demonstrates the efficient recovery of the patient through plasmapheresis that is followed by pulse therapy involving methyl prednisolone and cyclophosphamide. It states that systemic lupus erythematosus (SLE) is a fatal multisystemic disease which is capable of affecting the digestive system.

Presents a study which determined the effects of in vivo genetic ablation of fibroblast growth factor 23 on premature aging and survival. Premature aging-like phenotype of the gowth factor mouse; Premature aging features expressed by klotho gene; Genetic rescue of premature aging-like phenotypes of the growth factor mice.

Background: Non-clinical study data suggest that DS-8500a, a G protein-coupled receptor 119 agonist, exhibits antidiabetic activity, inhibition of some transporters and induction of cytochrome P450 (CYP) 3A. Statins are substrates for some transporters and CYP3A that may be coadministered with DS-8500a in clinical practice. Objective: To determine the potential effects of DS-8500a on the pharmacokinetics of statins, we evaluated the effects of repeated oral administration of DS-8500a 75 mg on the pharmacokinetics of rosuvastatin and atorvastatin in healthy adults. Methods: We performed two single-center, open-label, single-sequence studies. In Study I, subjects received single-dose rosuvastatin 10 mg (Period A) and DS-8500a 75 mg once daily + single-dose rosuvastatin 10 mg (Period B). In Study II, subjects received single-dose atorvastatin 10 mg (Period A) and DS-8500a 75 mg once daily + single-dose atorvastatin 10 mg (Period B). Primary pharmacokinetic endpoints were maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) of rosuvastatin and atorvastatin. Safety was evaluated. Results: In Study I, the Cmax and AUC of rosuvastatin increased by 66% and 33%, respectively, when coadministered with DS-8500a, versus rosuvastatin alone. In Study II, the Cmax of atorvastatin increased by 28%, but AUC remained unchanged following coadministration with DS-8500a, versus atorvastatin alone. Treatment-emergent adverse events were mild to moderate and mostly unrelated to the study drugs. Conclusions: Multiple doses of DS-8500a increased exposure to rosuvastatin and atorvastatin. This short-term study suggests that the impact of DS-8500a coadministration on atorvastatin exposure is limited and may not be clinically relevant. Nevertheless, caution may be necessary when patients are coadministered rosuvastatin with DS-8500a. ClinicalTrials.gov identifier: NCT03699774. Japan Pharmaceutical Information Center identifier: JapicCTI-152878. [ABSTRACT FROM AUTHOR]

A limiting mean free path was considered in order to better understand the temperature and wire diameter dependence of the resistivity and Seebeck coefficient of bismuth microwire and nanowire samples. The mean free path limited mobility was numerically calculated from experimentally measured mobility in a bulk bismuth sample, and the electron and hole mobilities were dramatically decreased to a 10 μm mean free path. Therefore, the temperature dependence of resistivity in very thin wire was quite different from that of a bulk sample, which had a positive temperature coefficient. The calculations showed that the temperature coefficient decreased gradually with decreasing mean free path, and the coefficient became negative for a mean free path of less than 1 μm at about 150 K. The Seebeck coefficient was also calculated, but showed only a weak dependence on mean free path compared with the resistivity. Experimental comparisons were made to previous measurements of bismuth microwire or nanowire samples, and the temperature and wire diameter dependencies of the resistivity and Seebeck coefficient were qualitatively and quantitatively in very good agreement. Therefore, the temperature dependencies of nanowire samples over 850 nm in diameter were well described using the mean free path limitation. [ABSTRACT FROM AUTHOR]

Wire-diameter dependencies were investigated using microwire sample arrays with diameters from 2 to 25 ¿m and polycrystalline bulk bismuth. Seebeck coefficient and resistivity were measured from 50 to 300 K. Although the temperature dependence of the Seebeck coefficients of all samples were similar to that of the bulk, the resistivity dependence of the 2-¿m-diameter microwire array sample had a small positive temperature coefficient, and was quite different from the other samples. Mobility was estimated using a simple model to identify the dependences on temperature and wire diameter. The ratio of electron mobility divided by hole mobility gradually decreased with decreasing temperature for samples with wire diameters below 6 ¿m, and electron mobility was suppressed at low temperatures, explaining the promotion of the boundary scattering. Therefore, small positive temperature coefficients of resistivity were obtained for very small diameter microwire array samples. To compare with the temperature dependence of the nanowire array samples that typically have negative temperature coefficient reported, a model for mobility was developed to represent the temperature dependence of resistivity. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Pancreatic β‐cell dysfunction contributes to type 2 diabetes mellitus progression. Drugs that improve insulin secretion might be a valuable treatment approach. The present study aimed to evaluate the effect of the G protein‐coupled receptor 119 agonist DS‐8500a on insulin secretory capacity in Japanese type 2 diabetes mellitus patients. Materials and Methods: This single‐center, 4‐week, randomized, double‐blind, cross‐over study enrolled 21 Japanese drug‐naïve type 2 diabetes mellitus patients aged ≥20 years with glycated hemoglobin ≥7.0 and <9.0% (NCT02669732, JapicCTI 163126). Patients received 75 mg of DS‐8500a or a placebo orally daily for 4 weeks in a random order. A combined euglycemic‐hyperinsulinemic and hyperglycemic clamp test was carried out to assess insulin secretion and insulin sensitivity before and after each 4‐week treatment period. Primary end‐points were first‐phase insulin secretion (insulin area under the curve [AUC]180–190 min and C‐peptide AUC180–190 min during the clamp test) and second‐phase insulin secretion (insulin AUC190–300 min and C‐peptide AUC190–300 min). Insulin sensitivity (M and M/I values), disposition index and changes in lipid profile were also assessed. Results: DS‐8500a significantly increased first‐ and second‐phase insulin AUC (P = 0.0011, P = 0.0112) and C‐peptide AUC (P = 0.0012, P < 0.0001) compared with the placebo. At day 28, M and M/I values were comparable with those of the placebo, whereas the disposition index for insulin and C‐peptide was significantly increased (P = 0.0108, P = 0.0002). Total cholesterol, low‐density lipoprotein cholesterol and triglyceride concentrations were significantly reduced, and high‐density lipoprotein cholesterol concentrations were significantly increased compared with the placebo. No significant treatment‐emergent adverse events occurred. Conclusion: DS‐8500a enhanced insulin secretory capacity, but not insulin sensitivity. This randomized, double‐blind, placebo‐controlled, 2 × 2 crossover study was designed to evaluate the effect of 28‐day oral administration of the G protein‐coupled receptor 119 agonist DS‐8500a on insulin secretory capacity in Japanese T2DM patients. DS‐8500a significantly increased first‐ and second‐phase insulin AUC (P = 0.0011, P = 0.0112) and C‐peptide AUC (P = 0.0012, P < 0.0001) compared with placebo. DS‐8500a enhanced insulin secretory capacity but not insulin sensitivity in Japanese T2DM patients during the study period. [ABSTRACT FROM AUTHOR]

Introduction: We evaluated the efficacy and safety of DS‐8500a as add‐on therapy to sitagliptin in Japanese type 2 diabetes mellitus patients. Materials and Methods: This multicenter, randomized, double‐blind, placebo‐controlled, phase 2 trial randomized patients aged ≥20 years with hemoglobin A1c ≥7.0% and <9.0%, and inadequate glycemic control with sitagliptin 50‐mg monotherapy to receive 25 or 75 mg DS‐8500a, or a placebo, orally. The primary end‐point was change from baseline to day 28 in 24‐h weighted mean glucose. Secondary end‐points included change from baseline in fasting plasma glucose, 2‐h postprandial plasma glucose and lipid profiles. Results: Overall, 29, 28 and 27 patients in the placebo, 25‐ and 75‐mg groups, respectively, were analyzed. A significant dose‐dependent reduction was observed in 24‐h weighted mean glucose (linear: P = 0.0006, saturated at 25 mg: P = 0.0003, responded from 75 mg: P = 0.0176) when compared with the placebo (25 mg: −13.19 mg/dL [−0.73 mmol/L], P = 0.0044 vs placebo and 75 mg: −16.12 mg/dL [−0.89 mmol/L], P = 0.0006 vs placebo). A significant reduction in fasting plasma glucose at 75 mg vs placebo was observed (P < 0.001). At 25 and 75 mg, significant reductions of 2‐h postprandial plasma glucose (after breakfast), total cholesterol, low‐cholesterol and triglycerides were observed (all P < 0.05), with a (non‐significant) trend towards increased high‐density lipoprotein cholesterol. Both doses of DS‐8500a were well tolerated. There were no significant treatment‐emergent adverse events leading to discontinuation during the study. Conclusions: DS‐8500a was well tolerated, and showed significant glycemic benefits and favorable changes in lipid profile in Japanese type 2 diabetes mellitus patients with inadequate glycemic control with sitagliptin therapy. We evaluated the efficacy and safety of the G protein‐coupled receptor 119 agonist DS‐8500a as add‐on therapy for Japanese patients with type 2 diabetes mellitus currently receiving once‐daily sitagliptin 50‐mg monotherapy. In this multicenter, double‐blind, placebo‐controlled, phase 2 trial, patients were randomized to receive 25‐ or 75‐mg DS‐8500a, or placebo. A significant dose‐dependent reduction from baseline to day 28 was observed in 24‐h weighted mean glucose (primary endpoint) compared with placebo; DS‐8500a treatment was well tolerated and elicited significant glycemic benefits and favorable changes in lipid profile. [ABSTRACT FROM AUTHOR]

Background and objectives: G protein-coupled receptor 119 (GPR119) agonists reduce plasma glucose by promoting insulin secretion in a glucose-dependent manner. We evaluated the safety and pharmacokinetics of multiple oral doses of DS-8500a, a GPR119 agonist, under fed conditions in healthy adult Japanese male subjects.Methods: In this Phase 1, randomized, placebo-controlled, double-blind, multiple oral dose study, participants were aged ≥ 20 and ≤ 45 years with a body mass index ≥ 18.5 and < 25.0 kg/m2. DS-8500a 50 and 100 mg or placebo were administered orally, once daily, 30 min after breakfast for 7 days. The primary endpoints were pharmacokinetics and safety.Results: Twenty-four subjects were included (6, 9, and 9 in the placebo, 50-, and 100-mg groups, respectively). On Day 7, the mean maximum plasma concentration (Cmax) was 812 ng/mL in the 50-mg group and 1310 ng/mL in the 100-mg group. The mean area under the plasma concentration-time curve during dosing interval (AUCtau) was 7910 and 13,200 ng·h/mL in the two treatment groups, respectively. The observed accumulation ratio was 1.25 in the 50-mg group and 1.32 in the 100-mg group. All adverse events were mild and judged unrelated to the study drug.Conclusions: DS-8500a plasma concentrations reached steady state from Day 3, and Cmax and AUCtau increased in a less than dose-proportional manner. After repeated doses of DS-8500a at 100 mg, the DS-8500a trough concentration was expected to reach a pharmacologically active dose. DS-8500a was well tolerated up to 100 mg after a 7-day administration.Study registry identification: JAPIC ID: JapicCTI-173550 (registered retrospectively on 30 March 2017). [ABSTRACT FROM AUTHOR]

A new retrofitting method is proposed herein for reinforced concrete (RC) structures through attachment of an external structure. The external structure consists of a fiber concrete encased steel frame, connection slab and transverse beams. The external structure is connected to the existing structure through a connection slab and transverse beams. Pseudostatic experiments were carried out on one unretrofitted specimen and three retrofitted frame specimens. The characteristics, including failure mode, crack pattern, hysteresis loops behavior, relationship of strain and displacement of the concrete slab, are demonstrated. The results show that the load carrying capacity is obviously increased, and the extension length of the slab and the number of columns within the external frame are important influence factors on the working performance of the existing structure. In addition, the displacement difference between the existing structure and the outer structure was caused mainly by three factors: shear deformation of the slab, extraction of transverse beams, and drift of the conjunction part between the slab and the existing frame. Furthermore, the total deformation determined by the first two factors accounted for approximately 80% of the damage, therefore these factors should be carefully considered in engineering practice to enhance the effects of this new retrofitting method. [ABSTRACT FROM AUTHOR]

Critical-sized midfacial bone defects present a unique clinical challenge due to their complex three-dimensional shapes and intimate associations with sensory organs. To address this challenge, a point-of-care treatment strategy for functional, long-term regeneration of 2 cm full-thickness segmental defects in the zygomatic arches of Yucatan minipigs is evaluated. A digital workflow is used to 3D-print anatomically precise, porous, biodegradable scaffolds from clinical-grade poly-ε-caprolactone and decellularized bone composites. The autologous stromal vascular fraction of cells (SVF) is isolated from adipose tissue extracts and infused into the scaffolds that are implanted into the zygomatic ostectomies. Bone regeneration is assessed up to 52 weeks post-operatively in acellular (AC) and SVF groups (BV/DV = 0.64 ± 0.10 and 0.65 ± 0.10 respectively). In both treated groups, bone grows from the adjacent tissues and restores the native anatomy. Significantly higher torque is required to fracture the bone-scaffold interface in the SVF (7.11 ± 2.31 N m) compared to AC groups (2.83 ± 0.23 N m). Three-dimensional microcomputed tomography analysis reveals two distinct regenerative patterns: osteoconduction along the periphery of scaffolds to form dense lamellar bone and small islands of woven bone deposits growing along the struts in the scaffold interior. Overall, this study validates the efficacy of using 3D-printed bioactive scaffolds with autologous SVF to restore geometrically complex midfacial bone defects of clinically relevant sizes while also highlighting remaining challenges to be addressed prior to clinical translation. [ABSTRACT FROM AUTHOR]

Thrombotic microangiopathy (TMA)/thrombotic thrombocytopenic purpura (TTP) is a rare but potentially lethal condition requiring rapid recognition, diagnosis, and initiation of therapy. We experienced a case of a 61-year-old woman with primary Sjögren's syndrome (pSS) complicated with severe renal TMA/TTP following IgM monoclonal gammopathy of undetermined significance (MGUS). She was admitted to our hospital for further evaluation of hypergammaglobulinema, acute renal failure, and severe thrombocytopenia. She had been diagnosed with pSS 13 years prior to admission. Histological examination of her kidney revealed fibrin thrombi in the glomeruli and arterioles, a finding that is consistent with TMA/TTP. The patient was subsequently treated with plasma exchange, which resulted in a successful outcome without any complications. This rare case suggests that it is important to make a therapeutic decision based on appropriate and prompt pathological diagnosis. [ABSTRACT FROM AUTHOR]

Background and objectives: Data regarding renal disease in the elderly (age ≥65 years old) and very elderly (age ≥80 years old) Japanese are extremely limited. The aim of this study was to examine the causes of renal disease and their clinical presentations in elderly patients who underwent renal biopsy. Design, setting, participants, and measurements: From July 2007 to November 2011, all of the elderly native renal biopsy patients who had been registered in the Japan Renal Biopsy Registry (J-RBR; 2802 including 1596 males and 1206 females) were identified. Their data were compared with a control group of 7416 patients who ranged in age from 20 to 64 years old and were registered on the J-RBR over the same period. In addition, the clinical and pathological classifications of 276 very elderly patients were also analyzed. Results: The indications for biopsy were nephrotic syndrome (NS) in 36.2 and 50.7 % of the elderly and the very elderly patients, chronic nephritic syndrome in 31.8 and 17.4 %, and acute kidney injury including rapidly progressive glomerulonephritis in 18.6 and 22.5 %, respectively. Primary glomerular disease was the most frequent diagnosis, followed by MPO-ANCA-positive nephritis, IgA nephropathy (IgAN), and diabetic nephropathy. In primary GN including IgAN, membranous nephropathy (MN) was the most frequent histological type, followed by IgAN and minor glomerular abnormalities. A comparison with the control group showed that MN, MPO-ANCA-positive nephritis, and amyloid nephropathy were more common in the elderly ( P < 0.001), and IgAN was less common ( P < 0.001). As for nephrotic syndrome in the elderly, MN was the most common histological type, followed by minimal change NS, diabetic nephropathy, amyloid nephropathy, and focal segmental glomerulosclerosis. There was a significant discrepancy between the urinary protein/creatinine ratio and daily proteinuria after the 7th decade of life. Conclusions: Renal biopsy is a valuable diagnostic tool, even in elderly and very elderly Japanese patients. In the future, modified clinical guidelines for elderly renal disease should be developed. [ABSTRACT FROM AUTHOR]

We report the clinical and pathological findings of a case of de novo minimal change disease ( MCD) after ABO-incompatible living kidney transplantation. A 62-yr-old man with end-stage renal disease associated with type I diabetes received ABO-incompatible kidney transplantation from his 58-yr-old wife. Although allograft function was excellent immediately after surgery, massive proteinuria (35 g/d) appeared on post-transplantation day 5. After the allograft biopsy taken on post-transplantation day 6, he was treated with 12 cycles of plasma exchange, but the nephrotic-range proteinuria showed no remission. The biopsy specimen showed no significant pathological findings on light microscopy, but electron microscopy showed diffuse effacement of podocyte foot processes. Based on the diagnosis of de novo MCD, the patient received intravenous methylprednisolone pulse therapy, followed by high-dose steroid maintenance therapy. The steroid therapy induced complete remission of nephrotic syndrome and stable allograft function immediately, which was also maintained at one yr after the transplantation. [ABSTRACT FROM AUTHOR]

A 50-year-old woman with a 1-month history of lower extremity edema and a 5 kg weight increase was admitted to our hospital with suspected nephrotic syndrome in October 1999. Urine protein level was 3.5 g per day, 10−15 erythrocytes in urine per high-power field, and serum albumin level 2.5 g/dl. Furthermore, an accumulation of pleural effusion was confirmed by chest X-ray. The results of a renal biopsy indicated slight mesangial proliferation in the glomeruli by light microscopy, and an immunofluorescence study confirmed the deposition of immunoglobulin (Ig) A and C3 in the mesangial area. Diffuse attenuation of foot processes and dense deposits in the mesangial area were observed by electron microscopy. Treatment with 40 mg/day of prednisolone was effective, and proteinuria was negative 1 month later. Because of this course, we diagnosed minimal change nephrotic syndrome complicated by mild-proliferative IgA nephropathy. In November 2000, there was a relapse of nephrotic syndrome, which was believed to be induced by an influenza vaccination, but response to increased steroid treatment was favorable, and proteinuria disappeared on day 13 of steroid increase. A second relapse in May 2001, showed steroid resistance with renal insufficiency, and an increase in the selectivity index to 0.195. Light microscopy revealed focal sclerotic lesions of the glomeruli, and an immunofluorescence study revealed attenuation of mesangial IgA and C3 deposition. These findings led to the diagnosis that minimal change nephrotic syndrome had transitioned to focal segmental glomerulosclerosis, whereby mesangial IgA deposition was reduced by immunosuppressive treatment. Subsequently, her renal function gradually worsened to the point of end-stage renal failure by 27 months after the second relapse of nephrotic syndrome. [ABSTRACT FROM AUTHOR]

Background: IgG4-related disease has attracted wide attention recently. It is characterized by a high level of serum IgG4 and dense infiltration of IgG4-positive plasma cells into multiple organs, with the kidney being one representative target. Although several sets of diagnostic criteria for autoimmune pancreatitis (AIP) are available and renal lesion is recognized as an extra-pancreatic manifestation of AIP, it is difficult to differentiate IgG4-related tubulointerstitial nephritis (TIN) without AIP from other types of TIN. To clarify the entity of IgG4-related kidney disease (IgG4-RKD) and support in-depth studies, the Japanese Society of Nephrology has established a working group to prepare diagnostic criteria for IgG4-RKD. Method: The working group analyzed 41 patients with IgG4-RKD, and collected the following data to devise a diagnostic algorithm and diagnostic criteria for IgG4-RKD: clinical features including extra-renal organ involvement, urinalysis and serological features including serum IgG4 levels, imaging findings demonstrated by computed tomography (CT), renal histology with IgG4 immunostaining, and response to steroid therapy. Results: The conditions for criteria are as follows. (1) Presence of some kidney damage, as manifested by abnormal urinalysis or urine marker(s) and/or decreased kidney function with either elevated serum IgG level, hypocomplementemia, or elevated serum IgE level. (2) Kidney imaging studies showing abnormal renal imaging findings, i.e., multiple low density lesions on enhanced CT, diffuse kidney enlargement, hypovascular solitary mass in the kidney, and hypertrophic lesion of the renal pelvic wall without irregularity of the renal pelvic surface. (3) Serum IgG4 level exceeding 135 mg/dl. (4) Renal histology showing two abnormal findings: (a) dense lymphoplasmacytic infiltration with infiltrating IgG4-positive plasma cells >10/high power field (HPF) and/or ratio of IgG4-positive plasma cells/IgG positive plasma cells >40%. (b) Characteristic 'storiform' fibrosis surrounding nests of lymphocytes and/or plasma cells. (5) Extra-renal histology showing dense lymphoplasmacytic infiltration with infiltrating IgG4-positive plasma cells >10/HPF and/or ratio of IgG4-positive plasma cells/IgG-positive plasma cells >40%. The diagnosis is classified into 3 stages of definite, probable and possible according to the combinations of the above conditions. Thirty-nine cases (95.1%) were diagnosed with IgG4-RKD according to the criteria. Conclusion: The provisional criteria and algorithm appear to be useful for clarifying the entity of IgG4-RKD and seeking underlying IgG4-RKD cases; however, further experience is needed to confirm the validity of these criteria. [ABSTRACT FROM AUTHOR]

Role of obesity in renal pathological and structural changes remains poorly investigated, and this study was designed to examine the pathological effects of obesity on renal structural components in patients with chronic kidney diseases (CKD). The study subjects were obese (body mass index, BMI ≥ 25 kg/m2) patients with nonglomerulonephritis (non-GN, n = 26), IgA nephropathy (IgAN, n = 19), benign nephrosclerosis (BNS, n = 15), and thin basement membrane disease (TMD, n = 6), and 65 nonobese controls ( n = 20, 20, 10, and 15, respectively). Patients were evaluated for glomerular lesions (mesangial proliferation and focal segmental/global glomerulosclerosis), glomerular size, and thickness of glomerular basement membrane (GBM). Urinary protein was higher in obese non-GN, IgAN, and BNS groups than in the respective controls. Focal segmental glomerulosclerosis (FSGS) lesions were noted in all obesity groups. The glomeruli were larger in size in obese than in nonobese patients of the non-GN and IgAN groups. The glomeruli of nonobese TMD and BNS patients were significantly larger in size than those of nonobese non-GN patients. GBM were thicker in obese than in nonobese patients irrespective of types of glomerular diseases, but only significantly so in non-GN and BNS groups. In non-GN, IgAN, and BNS, obesity worsens proteinuria and is associated with structural changes such as glomerulomegaly and GBM thickening, similar to changes observed in obesity-related nephropathy. Obesity seems to worsen the renopathological state in CKD. [ABSTRACT FROM AUTHOR]

A major breakthrough in systemic phosphate homeostasis regulation was achieved by the demonstration of strikingly similar physical, morphological, and biochemical phenotypes of fibroblast growth factor 23 (Fgf23) and klotho ablated mice, which led to identification of klotho as an Fgf23 signaling cofactor. Here, we generated Fgf23 and klotho double-knockout (Fgf23-/-/klotho-/-) mice to test the hypothesis whether Fgf23 has a klotho-independent function. Fgf23-/-/klotho-/- mice are viable and have high serum phosphate levels, similar to Fgf23-/- and klotho-/- single-knockout mice. In addition, the Fgf23-/-/ klotho-/- mice have increased renal expression of the sodium/phosphate cotransporter NaPi2a and of 1- alpha-hydroxylase concomitant with increased serum levels of 1,25-dihydroxyvitamin-D, as also observed in the Fgf23-/- and klotho-/- mice. Moreover, Fgf23-/-/ klotho-/- mice show soft tissue and vascular calcification, severe muscle wasting, hypogonadism, pulmonary emphysema, distention of intestinal wall, and skin atrophy, all of which are also seen in Fgf23-/- and klotho-/- mice. Notably, injection of bioactive FGF23 protein into Fgf23-/-/klotho-/- and klotho-/- mice does not lower serum phosphate, whereas in wild-type and Fgf23-/- mice, it reduces serum phosphate. Together, these results provide compelling evidence that Fgf23 does not have a klotho-independent role in the regulation of systemic phosphate and vitamin D homeostasis. [ABSTRACT FROM AUTHOR]

Objective. In patients with non-alcoholic fatty liver disease (NAFLD), liver biopsy remains the only reliable method to differentiate simple steatosis from non-alcoholic steatohepatitis (NASH). The objective of this study was to evaluate the efficacy of non-invasive 99mTc-phytate scintigraphy in the diagnosis of NASH. Material and methods. Thirty-seven patients with suspected NAFLD at the time of liver biopsy also underwent 99mTc-phytate scintigraphy. Signal intensities of regions of interest (ROI) in the liver, spleen, and heart were measured. We also examined scintigraphic features in a nutritional model of NASH in rats fed a methionine- and choline-deficient (MCD) diet. Results. The liver/spleen uptake ratio determined by scintigraphy was significantly decreased in patients with NASH in comparison with patients with simple steatosis. The liver/spleen ratio was an independent predictor distinguishing NASH from simple steatosis. The decrease was observed for all stages of NASH, including the early stage (stages 1 and 0). In animal studies, the liver/spleen uptake ratio was significantly decreased in rats after 8 weeks of MCD dietary feeding in comparison with control diet-fed rats. Conclusions. The non-invasive 99mTc-phytate scintigraphy test is a reliable tool to differentiate NASH from simple steatosis. [ABSTRACT FROM AUTHOR]

Recent studies describe a novel role of fibroblast growth factor-23 (Fgf23)-klotho activity in the systemic regulation of calcium and phosphate homeostasis. Both Fgf23 and klotho ablated mice develop extensive vascular and soft tissue calcification. Inability to clear the required amount of phosphate by the kidney, due to the absence of Fgf23-klotho activity, leads to increased accumulation of serum phosphate in these genetically modified mice, causing extensive calcification. Serum calcium and 1,25 hydroxyvitamin D levels are also elevated in both Fgf23 and klotho ablated mice. Moreover, increased sodium phosphate co-transporter activity in both Fgf23 and klotho ablated mice increases renal phosphate reabsorption which in turn can facilitate calcification. Collectively, these observations bring new insights into our understanding of the roles of the Fgf23-klotho axis in the development of vascular and soft tissue calcification. [ABSTRACT FROM AUTHOR]

Recent studies describe a novel role of fibroblast growth factor-23 (Fgf23)–klotho activity in the systemic regulation of calcium and phosphate homeostasis. Both Fgf23 and klotho ablated mice develop extensive vascular and soft tissue calcification. Inability to clear the required amount of phosphate by the kidney, due to the absence of Fgf23–klotho activity, leads to increased accumulation of serum phosphate in these genetically modified mice, causing extensive calcification. Serum calcium and 1,25 hydroxyvitamin D levels are also elevated in both Fgf23 and klotho ablated mice. Moreover, increased sodium phosphate co-transporter activity in both Fgf23 and klotho ablated mice increases renal phosphate reabsorption which in turn can facilitate calcification. Collectively, these observations bring new insights into our understanding of the roles of the Fgf23–klotho axis in the development of vascular and soft tissue calcification.Kidney International (2008) 74, 566–570; doi:10.1038/ki.2008.218; published online 4 June 2008 [ABSTRACT FROM AUTHOR]

Background. Patients on long-term peritoneal dialysis develop progressive peritoneal fibrosis and loss of mesothelial layer. Regeneration of the mesothelium has been reported in the normal peritoneum but not the fibrotic peritoneum. Moreover, the origin of the regenerated mesothelial cells remains obscure. The aim of this study was to investigate mesothelial regeneration in fibrotic peritoneum induced by chlorhexidine gluconate. Methods. Peritoneal fibrosis was induced by injection of CG into the peritoneal cavity of Wistar rats. After injection, the abdomen was opened, and the parietal fibrotic peritoneum with mesothelial cells was stripped from the abdominal wall, and then the abdominal incision was closed. Rats were sacrificed, and peritoneal tissues were dissected out at 0, 1, 3, 5, or 7 days after the stripping procedure. Results. Spindle-shaped cells with microvilli appeared on the surface of stripped peritoneum at day 3 after denudation. Immunohistochemistry identified staining for vimentin, a marker of mesoderm cells, in the spindle-shaped cells at days 3, 5, and 7. Expression of α-SMA was observed in the same cells at days 3 and 5, but not 7. Expression of cytokeratin and HBME-1, markers for mesothelial cells, in these cells was delayed until day 7. Conclusions. Mesothelium can regenerate on the fibrotic peritoneum. The regenerated mesothelial cells seem to originate from vimentin-positive mesenchymal cells. [ABSTRACT FROM AUTHOR]

We report two cases of primary non-functioning kidney from the same non-heart beating donor (NHBD). A 42-yr-old man received a renal transplant from a NHBD. The donor was a 38-yr-old male who died of neck spinal injury. The warm ischemic time was 61 min. One h after reperfusion, the graft became edematous and congested in the presence of normal and adequate vascular anastomosis and lack of renal vein thrombosis. The one-h biopsy specimen showed acute tubular necrosis and severe congestion with occasional platelet aggregates in glomerular capillaries. The graft was resected on post-transplantation day 6. Graftectomy specimen revealed renal cortical necrosis. The contralateral kidney of the same donor was transplanted into a 54-yr-old male. The one-h biopsy specimen showed tubular degeneration and neutrophil infiltration in peritubular capillaries, but no glomerular congestion or thrombus. The recipient died on post-transplantation day 4. Although the cause of death was unknown, necropsy of the renal graft showed renal cortical necrosis, similar to case 1. Ischemia/reperfusion injury was considered the cause of non-functioning kidney in both cases, because of long warm ischemic time. The biopsy specimens at zero-h from both grafts showed focal tubular degeneration only without distinct necrosis, indicating it is difficult to predict viability based on the pathological findings at zero-h or one-h biopsies. There is a need for further understanding of clinical and histological patterns in order to define the criteria of viability of kidney transplant. [ABSTRACT FROM AUTHOR]