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BACKGROUND: The BNT162b mRNA vaccine for coronavirus disease 2019, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), mimics the immune response to natural infection. Few studies have predicted the adverse effects (AEs) after the second-dose vaccination. We present a predictive model for AEs and immune response after the second-dose of the BNT162b mRNA vaccine. METHODS: To predict AEs, 282 healthcare workers (HCWs) were enrolled in this prospective observational study. The classification and regression tree (CART) model was established, and its predictive efficacy was assessed. To predict immune response, 282 HCWs were included in the analysis. Moreover, the factors affected by anti-SARS-CoV-2 spike protein RBD antibody (s-IgG) were evaluated using serum samples collected 2 months after the second-dose vaccination. The s-IgG level was assessed using Lumipulse G1200. Multiple regression analyses were conducted to evaluate variables associated with anti-s-IgG titer levels. RESULTS: The most common AEs after the second-dose vaccination were pain (87.6%), redness (17.0%) at the injection site, fatigue (68.8%), headache (53.5%), and fever (37.5%). Based on the CART model, headache after the first-dose vaccination and age < 30 years were identified as the first and second discriminators for predicting the headache after the second-dose vaccination, respectively. In the multiple linear regression model, anti-s-IgG titer levels were associated with age, female sex, and AEs including headache and induration at the injection site after the second-dose vaccination. CONCLUSION: Headache after the first-dose vaccination can be a predictor of headache after the second-dose vaccination, and AEs are indicators of immune response.

Background Both renal hypouricemia (RHU) and gout are associated with renal dysfunction and urolithiasis. The difference in renal complications associated with RHU and gout, however, has not been studied. We characterized the urate metabolism and complications of patients with RHU and compared them with patients with gout. Methods Eighteen patients with RHU who had a serum uric acid (SUA) level2 mg/dL (10 men and 8 women), 44 patients with gout (44 men) and 16 normouricemic patients (4 men and 12 women) were included. The blood and urinary biochemical data were evaluated. A genetic analysis of uric acid transporter 1 (URAT1) was also conducted in 15 cases with RHU. Results The SUA level of RHU was 0.9±0.5/mg/dl, and the Uur/Ucr and Cur/Ccr were 0.56%±0.14% and 45.7%±18.0%, respectively. A genetic analysis of URAT1 in 15 RHU patients showed that 13 harbored a URAT1 gene mutation, whereas 2 harbored the wild-type gene. The SUA level was significantly lower in RHU patients (n=11) than in either gout patients (n=44) or normouricemic patients (n=16). This reduction was accompanied by the elevation of Cua/Ccr. Urinary beta 2-microglobulin levels were higher in RHU patients than in gout or normouricemia patients. Cua/Ccr correlated with normalized urinary beta 2-microglobulin levels. The prevalence of urolithiasis was 18.2% in RHU cases and 6.8% in gout cases. A homozygous URAT1 mutation was associated with urolithiasis. Conclusion Besides urolithiasis, RHU can be associated with tubular dysfunction, such as elevated urinary beta 2-microglobulin levels.

Background BNT162b2, an mRNA COVID-19 vaccine, was launched in many countries as an intramuscular vaccination for COVID-19 infection. Few studies have assessed the physical indications of pain at the immunization site. This study aimed to characterize pain at the injection site and investigate morphological attributes using ultrasound. Methods Forty-three of 211 healthcare workers who received a second dose of BNT162b2 between February 2021 and March 2021 were enrolled in the study. The mean age of the subjects was 40 years. We evaluated patients' pain at the injection site using the Numerical Rating Pain Scale (NRPS). We also assessed the thickness of the deltoid muscle fascia at the injection site by ultrasound. Bayesian robust correlation was employed to explore the relationship between the pain intensity scores and ultrasound measurements. Results All eligible subjects complained of pain at the injection site. A median pain onset of 8 hours post-vaccination and a median peak intensity score of 4 were reported. Onset of relief occurred after 2 days. Ultrasound images demonstrated a 2.5-fold increase in fascia thickness at the injection site without intramuscular echogenicity change in all subjects. A correlation was established between the NRPS score and the non-injection-to-injection-side ratio of fascia thickness at the injection site (rho = 0.66). Conclusion A sore arm was the most prevalent side effect of BNT162b2 vaccination and could be attributed to temporal fasciitis.

Antibody-mediated rejection (ABMR) is an important cause of both short- and long-term injury to renal allografts. Transplant glomerulopathy (TG) is strongly associated with ABMR and reduced graft survival. Ultrastructural changes in early-stage ABMR include TG as a duplication of the glomerular basement membrane (GBM), which can be observed only by transmission electron microscopy (TEM). Low-vacuum scanning electron microscopy (LVSEM) is a new technique that allows comparatively inexpensive, rapid, and convenient observations with high magnification. We analyzed human renal transplants using LVSEM and evaluated the ultrastructural changes representing TG in ABMR. GBM duplication was more clearly visible in the LVSEM images than in the light microscopy (LM) images. In the ABMR group, the cg score of the Banff classification was higher in 54% (7/13) of specimens for LVSEM images than for LM images. And 4 specimens exhibited duplication of the GBM analyzed by LVSEM, but not by LM. In addition, three-dimensional ultrastructural changes, such as coarse meshwork structures of GBM, were observed in ABMR specimens. The ABMR group also exhibited ultrastructural changes in the peritubular capillary basement membranes. In conclusion, analyses of renal transplant tissues using LVSEM allows the identification of GBM duplication and ultrastructural changes of basement membranes at the electron microscopic level, and is useful for early-stage diagnosis of ABMR.

In Japan, the “8050 problems” have become a social issue, where parents and children are parents in their 80s and children in their 50s and live together. In the case of parents and children with “8050 problems,” the parents are older, but the children are often dependent, withdrawn, and have financial problems. Recently, the number of such cases has increased in care management. The previous studies indicated that it was important to know what information was gathered in the assessment in such cases. The research was conducted from February to March of 2022 by self-administered questionnaires. The survey was mailed to all 1,410 care management centers in Osaka City. The response rate was 11.8%. The statistical analysis was an exploratory factor analysis. Six factors in the significant information in the assessment were extracted by the factor analysis: Physical, mental and living conditions of children; Parents’ physical and mental conditions; Parents’ perspectives on their lives; Parents and children’s financial situations; Living environment; and Relationships between the informal and formal supports and the parents and children. The Cronbach’s alpha for internal consistency was greater than 0.8 for each factor. In addition, the four factors were strongly associated among the six factors. In conclusions, the present study found that information about the physical and mental status, living conditions, community relations, and financial situations of the parents and children with “8050 problems” was important in the assessment of the parents and children, and that the information is closely related to each other.

Human papillomavirus-induced oropharyngeal squamous cell carcinoma (p16+ OPC) is considered a unique disease entity. Despite highly successful clinical management using (chemo-) radiotherapy, late toxicities cause terrible distress to the patients. Reducing these complications and maintaining a good quality of life are crucial. A 64-year-old woman presented with complaints of a mass on the right side of the neck without pharyngeal symptoms. Positron emission tomography-computed tomography showed accumulation in the right tonsil. The oropharyngeal tumor and involved lymph node were biopsied, and p16-positive squamous cell carcinoma was diagnosed on histopathological analysis. Induction chemotherapy (ICT) was administered using intravenous docetaxel, cisplatin, and 5-fluorouracil. Subsequently, primary transoral resection and neck dissection were performed. The patient is alive with no pharyngeal complications 43 months postoperatively. Surgical intervention after ICT is attractive as a therapeutic strategy for reducing late toxicity. p16+ OPC may be potentially curable without the use of radiation.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disease causing renal cysts. Reports on kidney cyst infection in children are rare despite cyst infections being important complications of ADPKD. Here, we report a case of a child without any medical history who had a urinary tract infection with sepsis at 7 months. Leukocyturia persisted despite antibiotic therapy because the infection was treatment-resistant. Initial ultrasound and contrast computed tomography were inconclusive because cysts could not be detected clearly, and a family history of renal cysts was not determined. Subsequently, history of paternal renal cysts, thick walls in infectious cystic lesions on diffusion-weighted magnetic resonance imaging (MRI), and multiple small lesions with high signals on T2-weighted imaging in both kidneys became apparent. Upon diagnosis of ADPKD with cyst infection, antibiotic therapy was switched from cefotaxime to trimethoprim/sulfamethoxazole to achieve better cyst penetration, which successfully resolved the infection. In this patient, MRI was effective for clear visualization and diagnosis of infectious lesions and small cysts in undiagnosed ADPKD with cyst infection. Administering antibiotics with better cyst penetration is important. Trimethoprim/sulfamethoxazole is an option for use in children. This is the first case report that describes ADPKD with cyst infection in an infant in detail.

Alport syndrome (AS) is a progressive hereditary renal disease that is characterized by sensorineural hearing loss and ocular abnormalities. It is divided into three modes of inheritance, namely, X-linked Alport syndrome (XLAS), autosomal recessive AS (ARAS), and autosomal dominant AS (ADAS). XLAS is caused by pathogenic variants in COL4A5, while ADAS and ARAS are caused by those in COL4A3/COL4A4. Diagnosis is conventionally made pathologically, but recent advances in comprehensive genetic analysis have enabled genetic testing to be performed for the diagnosis of AS as first-line diagnosis. Because of these advances, substantial information about the genetics of AS has been obtained and the genetic background of this disease has been revealed, including genotype-phenotype correlations and mechanisms of onset in some male XLAS cases that lead to milder phenotypes of late-onset end-stage renal disease (ESRD). There is currently no radical therapy for AS and treatment is only performed to delay progression to ESRD using nephron-protective drugs. Angiotensin-converting enzyme inhibitors can remarkably delay the development of ESRD. Recently, some new drugs for this disease have entered clinical trials or been developed in laboratories. In this article, we review the diagnostic strategy, genotype-phenotype correlation, mechanisms of onset of milder phenotypes, and treatment of AS, among others.

【Background】 Pediatric chronic renal disease only shows abnormal values in a urinalysis in the initial stage, and subjective signs and symptoms are rare. If adolescents with chronic renal disease face a disease crisis combined with the usual developmental crisis, this may cause psychosocial maladaptation. We analyzed psychosocial adaptation in Japanese children with chronic renal disease in order to identify factors influencing healthy adaptation. 【Methods】 Ten children and adult patients with chronic kidney disease attending Tottori University Hospital, Japan in 2016 participated in a semi-structured interview (a modified version of the grounded theory approach) comprising questions about episodes since disease onset and thoughts/feelings at onset. 【Results】 Twenty-four concepts extracted from the data were sorted into 5 categories. These concepts and categories were expanded on an orthogonal axis with time and self-esteem in order to establish an adaptation model for children with chronic kidney disease. Category names are as follows. (Cat. 1: Emotional impact on being informed of disease, Cat. 2: Social challenges of treatment and resulting identity diffusion, Cat. 3: Emotional conflict on school return, Cat. 4: Resilience and related factors, Cat. 5: Re-establishment of identity). 【Conclusion】 Since pediatric chronic renal disease has few manifestations, it is difficult for patients to accept. Children facing a chronic disease crisis plus adolescent developmental crisis may show identity diffusion. In order for children to re-establish their identity and adapt to society, factors supporting resilience are important. Key factors include school life, interactions with friends, counseling by adult mentors and family acceptance. Healthcare professionals need to provide age-appropriate information on renal disease and support patients.

Inflammatory process is involved in the pathogenesis of diabetic nephropathy. In this article, we show that cholecystokinin (CCK) is expressed in the kidney and exerts renoprotective effects through its anti-inflammatory actions. DNA microarray showed that CCK was upregulated in the kidney of diabetic wild-type (WT) mice but not in diabetic intracellular adhesion molecule-1 knockout mice. We induced diabetes in CCK-1 receptor (CCK-1R) and CCK-2R double-knockout (CCK-1R−/−,-2R−/−) mice, and furthermore, we performed a bone marrow transplantation study using CCK-1R−/− mice to determine the role of CCK-1R on macrophages in the diabetic kidney. Diabetic CCK-1R−/−,-2R−/− mice revealed enhanced albuminuria and inflammation in the kidney compared with diabetic WT mice. In addition, diabetic WT mice with CCK-1R−/− bone marrow–derived cells developed more albuminuria than diabetic CCK-1R−/− mice with WT bone marrow–derived cells. Administration of sulfated cholecystokinin octapeptide (CCK-8S) ameliorated albuminuria, podocyte loss, expression of proinflammatory genes, and infiltration of macrophages in the kidneys of diabetic rats. Furthermore, CCK-8S inhibited both expression of tumor necrosis factor-α and chemotaxis in cultured THP-1 cells. These results suggest that CCK suppresses the activation of macrophage and expression of proinflammatory genes in diabetic kidney. Our findings may provide a novel strategy of therapy for the early stage of diabetic nephropathy.

NADPH oxidase (Nox) isoforms have been implicated in contributing to diabetic microvascular complications, but the functional role of individual isoforms in diabetic kidney are unclear. Nox2, in particular, is highly expressed in phagocytes and may play a key inflammatory role in diabetic kidney disease. To determine the role of Nox2, we evaluated kidney function and pathology in wild-type (WT; C57BL/6) and Nox2 knockout (KO) mice with type 1 diabetes. Diabetes was induced in male Nox2 KO and WT mice with a multiple low-dose streptozotocin protocol. Groups were studied for kidney disease after 8 and 20 wk of diabetes. Hyperglycemia and body weights were similar in WT and Nox2 KO diabetic mice. All functional and structural features of early and later stage diabetic kidney disease (albuminuria, mesangial matrix, tubulointerstitial disease, and gene expression of matrix and transforming growth factor-β) were similar in both diabetic groups compared with their respective nondiabetic groups, except for reduction of macrophage infiltration and monocyte chemoattractant protein-1 in the diabetic Nox2 KO mice. Systolic blood pressure by telemetry was surprisingly increased in Nox2 KO mice; however, the systolic blood pressure was reduced in the diabetic WT and Nox2 KO mice by tail-cuff. Interestingly, diabetic Nox2 KO mice had marked upregulation of renal Nox4 at both the glomerular and cortical levels. The present results demonstrate that lack of Nox2 does not protect against diabetic kidney disease in type 1 diabetes, despite a reduction in macrophage infiltration. The lack of renoprotection may be due to upregulation of renal Nox4.

Inflammatory process is involved in pathogenesis of diabetic nephropathy, although the activation and phenotypic change of macrophages in diabetic kidney has remained unclear. Sialoadhesin is a macrophage adhesion molecule containing 17 extracellular immunoglobulin-like domains, and is an I-type lectin which binds to sialic acid ligands expressed on hematopoietic cells. The aim of this study is to clarify the activation and phenotypic change of macrophages in the progression of diabetic nephropathy. We examined the expression of surface markers for pan-macrophages, resident macrophages, sialoadhesin, major histocompatibility complex class II and alpha-smooth muscle actin in the glomeruli of diabetic rats using immunohistochemistry at 0, 1, 4, 12, and 24 weeks after induction of diabetes by streptozotocin. Expression of type IV collagen and the change of mesangial matrix area were also measured. The mechanism for up-regulated expression of sialoadhesin on macrophages was evaluated in vitro. The number of macrophages was increased in diabetic glomeruli at 1 month after induction of diabetes and the increased number was maintained until 6 months. On the other hand, sialoadhesin-positive macrophages were increased during the late stage of diabetes concomitantly with the increase of alpha-smooth muscle actin-positive mesangial cells, mesangial matrix area and type IV collagen. Gene expression of sialoadhesin was induced by stimulation with interleukin (IL)-1 beta and tumor necrosis factor-alpha but not with IL-4, transforming growth factor-beta and high glucose in cultured human macrophages. The present findings suggest that sialoadhesin-positive macrophages may contribute to the progression of diabetic nephropathy.

The prevalence of diabetic nephropathy continues to rise, highlighting the importance of investigating and discovering novel treatment strategies. TRB3 is a kinase-like molecule that modifies cellular survival and metabolism and interferes with signal transduction pathways. Herein, we report that TRB3 expression is increased in the kidneys of type 1 and type 2 diabetic mice. TRB3 is expressed in conditionally immortalized podocytes; however, it is not stimulated by elevated glucose. The diabetic milieu is associated with increased oxidative stress and circulating free fatty acids (FFA). We show that reactive oxygen species (ROS) such as H2O2 and superoxide anion (via the xanthine/xanthine oxidase reaction) as well as the FFA palmitate augment TRB3 expression in podocytes. C/EBP homologous protein (CHOP) is a transcription factor that is associated with the endoplasmic reticulum stress response. CHOP expression increases in diabetic mouse kidneys and in podocytes treated with ROS and FFA. In podocytes, transfection of CHOP increases TRB3 expression, and ROS augment recruitment of CHOP to the proximal TRB3 promoter. MCP-1/CCL2 is a chemokine that contributes to the inflammatory injury associated with diabetic nephropathy. In these studies, we demonstrate that TRB3 can inhibit basal and stimulated podocyte production of MCP-1. In summary, enhanced ROS and/or FFA associated with the diabetic milieu induce podocyte CHOP and TRB3 expression. Because TRB3 inhibits MCP-1, manipulation of TRB3 expression could provide a novel therapeutic approach in diabetic kidney disease.

We attempted to clarify the effects of cyclohexenonic long-chain fatty alcohol (CHLFA) on the alterations of type 2 diabetes-induced nephropathy. Forty-week-old male Goto-Kakizaki (GK) and Wistar rats were divided into four groups of 6 to 8 animals. Group A consisted of eight Wistar rats and served as an age-matched control group. Group B (7 GK rats) received no treatment and served as a diabetic group. Group C (6 GK rats) was treated daily with low-dose CHLFA (2 mg/ kg/body weight, subcutaneously) for 30 weeks, and Group D (6 GK rats) with high-dose CHLFA (8 mg/kg/body weight) for 30 weeks. At the end of the treatment period, urinary protein excretion, blood chemistry, renal histological, and immunohistological analyses were conducted. Although CHLFA administration did not influence serum glucose or insulin levels, it reversed diabetes-induced increases in urinary protein excretion and serum creatinine. Light microscopically, CHLFA treatment ameliorated the otherwise elevated glomerular sclerotic scores in the diabetic group.Immunohistochemically, increased expression of desmin and decreased expression of rat endothelial cell antigen-1 in the group with untreated diabetes both showed a reversal to control levels in the high-dose CHLFA treatment group. In conclusion, CHLFA may ameliorate type 2 diabetes-induced nephropathy.

As gastrointestinal motility disorders are frequently reported in patients with diabetes, we attempted to clarify the effects of cyclohexenonic long-chain fatty alcohol in type 2 Goto-Kakizaki (GK) diabetic enteropathy. At 40 weeks of age male GK rats divided into three groups (treated with 0, 2 or 8 mg/kg of cyclohexenonic long-chain fatty alcohol; started at the age of 40 weeks). Age-matched male Wistar rats were used in this study. At 70 weeks of age the ileal functions were estimated by organ bath studies using 100 mM KCl and carbachol. The expression levels of muscarinic M(2) and M(3) receptor mRNAs in the ileum were investigated by real-time polymerase chain reaction (PCR). Treatment with cyclohexenonic long-chain fatty alcohol did not alter the diabetic status of the GK rats, i.e., body weight, serum glucose, and serum insulin levels, but significantly ameliorated diabetes-induced hypercontractility of the rat ileum caused by carbachol in a dose-dependent manner. Although there were no significant differences in the expression levels of muscarinic M(3) receptor mRNAs in any of the groups, cyclohexenonic long-chain fatty alcohol reversed the diabetes-induced up-regulation of intestinal muscarinic M(2) receptor mRNAs in treatment groups. These results indicate that cyclohexenonic long-chain fatty alcohol exerts its therapeutic effects on hypercontractility in the ileum of 70-week-old GK type 2 diabetic rats by ameliorating overexpression of muscarinic M(2) receptors.

土壌汚染が社会的に問題となっている中，コストと環境負荷が小さいファイトレメディエーションへの関心が高まっている．しかし，ファイトレメディエーションによる汚染物質の分解メカニズムには解明されていない部分が残されている．本研究では，長期間にわたって自然に原油が存在している油徴地帯から採取した土壌中の微生物群集に対してイタリアンライグラスが与える影響を評価した．原油資化微生物数，微生物活性及びＰＣＲ－ＤＧＧＥ法による微生物相解析を行うとともに，原油の含有量を経時的に評価した．この結果，イタリアンライグラス栽培土壌では，微生物相の改変が生じ，土壌微生物の活性が向上するとともに，原油資化性菌数が増加することが示された．また，このような微生物相の変化と対応して，栽培区の原油濃度が非栽培区に比べて有意に低下した．以上の結果から，植物の栽培によって生じた選択的な微生物相の改変が，土壌の原油濃度の低下に関与する可能性を示した．

We evaluated the effects of N-hexacosanol, a cyclohexenonic long-chain fatty alcohol, on muscarinic receptors in diabetic rat ileal dysfunction. Eight-week-old male SD rats were divided into four groups. After induction of diabetes (streptozotocin 50 mg/kg, i.p.), three groups were maintained for eight weeks with treatment by N-hexacosanol (0, 2 or 8 mg/kg, s.c. every day). Ileum function was investigated by organ bath studies using carbachol and KCl, and the expression levels of muscarinic M(2) and M(3) receptors were investigated by real-time polymerase chain reaction. Various concentrations of subtype-selective muscarinic antagonists, i.e., atropine (non-selective), pirenzepine (M(1) selective), methoctramine (M(2) selective), and 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP, M(1)/M(3) selective), were used in this study. In the presence and absence of these antagonists, contractile response curves to increasing concentrations of carbachol were investigated. Treatment with N-hexacosanol did not alter the diabetic status of the rats, but did significantly prevent the carbachol-induced hypercontractility in diabetic rat ileum. Estimation of the pA(2) values for atropine, pirenzepine, methoctramine, and 4-DAMP indicated that the carbacholinduced contractile response in the ileum is mainly mediated through the muscarinic M(3) receptor subtype in all groups. Furthermore, N-hexacosanol significantly prevented the diabetes-induced up-regulation of intestinal muscarinic M(2) and M(3) receptor mRNAs in streptozotocin-diabetic rats. Our data indicated that N-hexacosanol exerts preventive effects with respect to carbachol-induced hypercontractility in the diabetic rat ileum without qualitative alteration of the muscarinic receptor system.

High nephritogenicity of monoclonal antibodies belonging to IgG2a and IgG2b subclasses in rat anti-GBM nephritis. Background To examine a subclass-effect relationship and a dose-effect relationship of autoantibodies in the rat antiglomerular basement membrane (GBM) antibody-induced glomerulonephritis (anti-GBM nephritis) model, we injected homologous monoclonal antibodies against the NC1 domains of rat type IV collagen into inbred Wistar-Kyoto (WKY) rats. Methods Eight different autoantibodies from each of the IgG1, IgG2a, and IgG2b subclasses were established and administered to groups of four WKY rats at a dose of 300 μg/rat. To examine the dose-effect relationship, we administered 0 to 300 μg/rat of autoantibodies from each subclass to rats. Results All IgG1 antibodies induced mild nephritis, whereas the IgG2a and IgG2b antibodies induced moderate to severe nephritis. Some IgG2a and IgG2b antibodies induced pulmonary hemorrhage as well. These antibodies were reactive with α3(IV)NC1, α4(IV)NC1, or α5(IV)NC1. The minimum dose of antibody required to induce nephritis was 30 μg/rat for IgG1, 3 μg/rat for IgG2a, and 1 μg/rat for IgG2b. At doses of 30 μg/rat or less, antibody deposition was generally restricted to the GBM. At doses of 100 μg/rat or greater, antibody deposition extended to both the GBM and tubular basement membrane (TBM). Pulmonary hemorrhage was observed only when a large amount of pulmonary hemorrhagic antibody was administered. Conclusion The severity of nephritis was dependent on both subclass and dose of autoantibodies. It becomes clear that pulmonary hemorrhage in anti-GBM nephritis is induced by autoantibodies.

Mononuclear cells infiltrating the interstitium are involved in renal tubulointerstitial injury. The unilateral ureteral obstruction (UUO) is an established experimental model of renal interstitial inflammation. In our previous study, we postulated that L-selectin on monocytes is involved in their infiltration into the interstitium by UUO and that a sulfated glycolipid, sulfatide, is the physiological L-selectin ligand in the kidney. Here we tested the above hypothesis using sulfatide- and L-selectin-deficient mice. Sulfatide-deficient mice were generated by gene targeting of the cerebroside sulfotransferase (Cst) gene. Although the L-selectin-IgG chimera protein specifically bound to sulfatide fraction in acidic lipids from wild-type kidney, it did not show such binding in fractions of Cst(-/-) mice kidney, indicating that sulfatide is the major L-selectin-binding glycolipid in the kidney. The distribution of L-selectin ligand in wild-type mice changed after UUO; sulfatide was relocated from the distal tubules to the peritubular capillaries where monocytes infiltrate, suggesting that sulfatide relocated to the endothelium after UUO interacted with L-selectin on monocytes. In contrast, L-selectin ligand was not detected in Cst(-/-) mice irrespective of UUO treatment. Compared with wild-type mice, Cst(-/-) mice showed a considerable reduction in the number of monocytes/macrophages that infiltrated the interstitium after UUO. The number of monocytes/macrophages was also reduced to a similar extent in L-selectin(-/-) mice. Our results suggest that sulfatide is a major L-selectin-binding molecule in the kidney and that the interaction between L-selectin and sulfatide plays a critical role in monocyte infiltration into the kidney interstitium.

Renin–angiotensin system (RAS) blockade is the gold standard for the treatment of diabetic nephropathy. However, patients with diabetes mellitus still have an increased risk of progressive deterioration of renal function associated with albuminuria. de Zeeuw et al.1 published a paper, entitled Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial, in The Lancet in November 2010. This multinational, placebo‐controlled, double‐blind trial enrolled 281 patients with type 2 diabetes and albuminuria who were receiving angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers to elucidate the efficacy of a vitamin D analogue (19‐nor‐1‐α‐dihydroxyvitamin D2; paricalcitol) on albuminuria. Patients were assigned to receive 24 weeks treatment with placebo or 1 or 2 μg paricalcitol daily. The primary measure of efficacy was the percentage change in geometric mean urinary albumin:creatinine ratio (UACR) from baseline to the last measurement during the treatment period in the combined paricalcitol groups vs the placebo group. The change in UACR from baseline to the last measurement in the 1 and 2 μg paricalcitol‐treated groups was −20% (95% confidence interval [CI] −30 to −8) and −14% (95% CI −24 to −1), respectively (Table 1). The reduction in UACR in the 2 μg paricalcitol‐treated group was sustained throughout the 24‐week treatment period and reversed to baseline values after completion of treatment. However, the primary endpoint was negative: the UACR in the combined paricalcitol groups reduced by 15% compared with placebo (P = 0.071; Figure 1). The UACR fell by 18% in the 2 μg paricalcitol‐treated group and by 11% in the 1 μg paricalcitol‐treated group, but these differences failed to reach statistical significance (P = 0.053 and 0.23, respectively). In the secondary efficacy analysis, 24‐h urine albumin was reduced by −28% (P = 0.009) in the 2 μg paricalcitol‐treated group. Figure 1 Change in the urinary albumin : creatinine ratio (UACR) from baseline to the last measurement during the 24‐week treatment period. Data show the geometric mean of UACR, with error bars representing 95% confidence intervals. ... Table 1 Efficacy analysis of 24 weeks treatment with 1 or 2 μg paricalcitol or placebo (Reprinted from de Zeeuw et al.1, Copyright 2010, with permission from Elsevier.) Several smaller randomized trials have indicated that paricalcitol reduces proteinuria in patients with chronic kidney disease. For example, Alborzi et al.2 showed that administration of 1 and 2 μg paricalcitol for 1 month reduced 24‐h urinary albumin excretion by 48% (P

Alport syndrome (AS) and thin basement membrane nephropathy (TBMN) are genetic disorders caused by mutations of the type IV collagen genes COL4A3, COL4A4, and/or COL4A5. We here aimed to investigate the three-dimensional ultrastructure of the glomerular basement membrane (GBM) in order to introduce a novel method of diagnosing AS and TBMN. The subjects were 4 patients with AS and 6 patients with TBMN. Conventional renal biopsy paraffin sections from AS and TBMN patients were stained with periodic acid methenamine silver (PAM) and observed directly under low vacuum scanning electron microscopy (LVSEM). The PAM-positive GBMs were clearly visible under LVSEM through the overlying cellular components. The GBMs showed characteristic coarse meshwork appearances in AS, and thin and sheet-like appearances in TBMN. At the cut side view of the capillary wall, the GBMs in AS appeared as fibrous inclusions between a podocyte and an endothelial cell, while the GBMs in TBMN showed thin linear appearances. These different findings of GBMs between AS and TBMN were easily observed under LVSEM. Thus, we conclude that three-dimensional morphological evaluation by LVSEM using conventional renal biopsy paraffin sections will likely be useful for the diagnosis of AS and TBMN, including for retrospective investigations.

高Ca尿症を合併し尿路結石を反復した偽性低アルドステロン症II型の1例を経験した。症例は14歳女性。5歳，14歳時に尿路結石をきたした。平成7年7月高血圧，高K血症，高Cl性代謝性アシドーシスを指摘され，精査により，本症と診断された。また高Ca尿症を合併しており，尿路結石との関連が疑われた。サイアザイド系利尿剤投与により，代謝性アシドーシス，高K血症は改善した。高Ca尿症と反復した尿路結石を合併した症例は過去に報告がなく貴重な症例と考えられるので報告する。

非IgA型びまん性メサンギウム増殖を伴うネフローゼ症候群の4例を経験し，臨床病理像とステロイド治療に対する反応性を検討した。全例幼児期発症で，全例血尿，変形赤血球，赤血球円柱，硝子円柱を，2例に明らかな肉眼的血尿を認めた。4例中3例はメサンギウム細胞の増殖が中等度以上であったがステロイドに対し良好な反応性を示した。残りの1例は，メサンギウム細胞の増殖の程度が軽度にもかかわらずステロイドに対する反応性は不良であり，プレドニン投与4週の時点で寛解が得られないためエンドキサンを併用した。全例寛解後のプレドニン減量，あるいは中止によって蛋白尿の増悪やネフローゼの再発を認めなかった。非IgA型メサンギウム増殖を伴うネフローゼ症候群に対するステロイドに対する反応性は必ずしも肉眼的血尿やメサンギウム増殖の程度には関係せず，免疫抑制剤の併用を必要とする症例は存在するもののおおむね良好と思われた。

学校健診をきっかけに耳鼻科医または当センターを受診し, 機能性難聴を疑われた (健診難聴例) 6-15歳の学童32例について, 検討した。32例中26例 (81%) が, 純音聴力検査によって正常聴力を確かめることができ, しかもほとんどが1, 2回の受診であった。ただし, 標準的な純音聴力検査の方法では難聴の結果を示すことが多く, 正常値を得るには, 多くの例で測定法に工夫を加えた検査が必要であった。残りの6例は純音聴力検査では, 正常値が得られず, 他検査により聴力正常が確かめられた。純音聴力検査で正常値を得た例と得なかった例とでは, 自記オージオメトリー, 語音聴取域値検査結果で異なる傾向を示した。健診難聴例では, 初期の段階で純音聴力検査実施に努力すべきことを述べ, 当施設の経験から検査実施上の工夫を紹介した。

軽・中等度感音難聴者335例につき, 臨床上適合した補聴器で頻繁に使用する利得を聴力レベル別に調査した。最頻使用利得は平均聴力レベルが増すほど増加した。 しかしながら, 同じ聴力レベルでも最頻使用利得は一定ではなく, 個々の例により差があった。周波数別の最頻使用利得は, 各周波数とも聴力レベルが増すほど増大したが, その程度は周波数により異なった。 その結果, 聴力レベルの程度によって周波数間の関係に差があり, 聴力が良い場合に高周波数で大きく, 聴力が悪い場合に周波数間の差が小さい傾向にあった。最頻使用利得をハーフゲイン法による値と比較すると最頻使用利得が小さかった。 ハーフゲインによる利得は最頻使用利得を考える上での上限に近いものと思われた。

The elevated glycation of macromolecules by the reactive dicarbonyl and α-oxoaldehyde methylglyoxal (MG) has been associated with diabetes and its complications. We have identified a rare flavone, fisetin, which increases the level and activity of glyoxalase 1, the enzyme required for the removal of MG, as well as the synthesis of its essential co-factor, glutathione. It is shown that fisetin reduces two major complications of diabetes in Akita mice, a model of type 1 diabetes. Although fisetin had no effect on the elevation of blood sugar, it reduced kidney hypertrophy and albuminuria and maintained normal levels of locomotion in the open field test. This correlated with a reduction in proteins glycated by MG in the blood, kidney and brain of fisetin-treated animals along with an increase in glyoxalase 1 enzyme activity and an elevation in the expression of the rate-limiting enzyme for the synthesis of glutathione, a co-factor for glyoxalase 1. The expression of the receptor for advanced glycation end products (RAGE), serum amyloid A and serum C-reactive protein, markers of protein oxidation, glycation and inflammation, were also increased in diabetic Akita mice and reduced by fisetin. It is concluded that fisetin lowers the elevation of MG-protein glycation that is associated with diabetes and ameliorates multiple complications of the disease. Therefore, fisetin or a synthetic derivative may have potential therapeutic use for the treatment of diabetic complications.

279例の軽・中等度感音難聴者について, 臨床上適合した補聴器の最大出力音圧レベルを調査し, 装用耳の不快レベルと比較した。大部分の例において, 最大出力音圧レベルは不快レベル以下に設定されていた。 ただし, 両レベルの差は各例により一定でなく, 最大出力音圧レベルが不快レベルを大きく下回る例が少なくなかった。不快レベルを指標として最大出力音圧レベルの設定を考える方法は, 補聴器適合の臨床では効率性が疑問であると考えられた。

Hyperfiltration in the glomeruli have been considered to be an important cause of glomerular injury; however, the role of intercellular adhesion molecule (ICAM)-1 in the pathogenesis of glomerulosclerosis is not known.To elucidate the effects of ICAM-1 depletion on hyperfiltration-induced glomerular disorder, we used subtotally nephrectomized ICAM-1(+/+) and ICAM-1(-/-) mice. We evaluated macrophage infiltration, mesangial matrix expansion, transforming growth factor (TGF)-β and type IV collagen accumulation in glomeruli.Macrophage infiltration into the glomeruli and mesangial matrix expansion coincident with increased expression of both ICAM-1 and TGF-β, and accumulation of type IV collagen were ameliorated in subtotally nephrectomized ICAM-1(-/-) mice compared to ICAM-1(+/+) mice. ICAM-1 depletion significantly reduced hyperfiltration-induced glomerular injury after renal ablation.Our present findings suggest that glomerular hyperfiltration is the leading cause of glomerulosclerosis, and it is mediated, at least in part, by ICAM-1 expression and macrophage infiltration.

Although several interventions slow the progression of diabetic nephropathy, current therapies do not halt progression completely. Recent preclinical studies suggested that pirfenidone (PFD) prevents fibrosis in various diseases, but the mechanisms underlying its antifibrotic action are incompletely understood. Here, we evaluated the role of PFD in regulation of the extracellular matrix. In mouse mesangial cells, PFD decreased TGF-beta promoter activity, reduced TGF-beta protein secretion, and inhibited TGF-beta-induced Smad2-phosphorylation, 3TP-lux promoter activity, and generation of reactive oxygen species. To explore the therapeutic potential of PFD, we administered PFD to 17-wk-old db/db mice for 4 wk. PFD treatment significantly reduced mesangial matrix expansion and expression of renal matrix genes but did not affect albuminuria. Using liquid chromatography with subsequent electrospray ionization tandem mass spectrometry, we identified 21 proteins unique to PFD-treated diabetic kidneys. Analysis of gene ontology and protein-protein interactions of these proteins suggested that PFD may regulate RNA processing. Immunoblotting demonstrated that PFD promotes dosage-dependent dephosphorylation of eukaryotic initiation factor, potentially inhibiting translation of mRNA. In conclusion, PFD is renoprotective in diabetic kidney disease and may exert its antifibrotic effects, in part, via inhibiting RNA processing.

In the present study, we evaluated the effect of neutrophil elastase inhibitor, sivelestat sodium hydrate on ischemia-reperfusion injury in the rat bladder. Rat abdominal aorta was clamping with a small clip to induce ischemia-reperfusion injury in the bladder. Eight-week-old male Sprague Dawley rats were divided into four groups; sham-operated control rats, 30 min ischemia-60 min reperfusion (IR) rats, and IR rats treated with 15 or 60 mg/kg of sivelestat sodium hydrate. Sixty minutes prior to induction of ischemia, sivelestat sodium hydrate was administrated intraperitoneally. Real-time monitoring of blood flow and nitric oxide (NO) release were measured simultaneously with a laser Doppler flowmeter and an NO-selective electrode, respectively. The NO2-NO3 and malonaldehyde (MDA) concentrations were measured in the experimental urinary bladders. Clamping of the abdominal aorta, blood flow was rapidly decreased and NO release was gradually increased. After removing the clip, blood flow was rapidly increased and NO release was gradually returned to the basal level. These movements of blood flow and NO release were inhibited by treatment with sivelestat sodium hydrate in a dose-dependent manner. Both NO2-NO3 and MDA concentrations in the bladder were increased by induction of IR, and NO2-NO3 and MDA concentrations were decreased by treatment with high dose of sivelestat sodium hydrate significantly. Our data indicated that sivelestat sodium hydrate could inhibit increasing NO2-NO3 and MDA concentrations by IR, and it has potentiality protective effects on IR injury in the rat urinary bladder.