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Osteonecrosis of the femoral head (ONFH) involves necrosis of bone and bone marrow of the femoral head caused by ischemia with unknown etiology. Previous genetic studies on ONFH failed to produce consistent results, presumably because ONFH has various causes with different genetic backgrounds and the underlying diseases confounded the associations. Steroid-associated ONFH (S-ONFH) accounts for one-half of all ONFH, and systemic lupus erythematosus (SLE) is a representative disease underlying S-ONFH. We performed a genome-wide association study (GWAS) to identify genetic risk factors for S-ONFH in patients with SLE. We conducted a two-staged GWAS on 636 SLE patients with S-ONFH and 95 588 non-SLE controls. Among the novel loci identified, we determined S-ONFH-specific loci by comparing allele frequencies between SLE patients without S-ONFH and non-SLE controls. We also used Korean datasets comprising 148 S-ONFH cases and 37 015 controls to assess overall significance. We evaluated the functional annotations of significant variants by in silico analyses. The Japanese GWAS identified 4 significant loci together with 12 known SLE susceptibility loci. The four significant variants showed comparable effect sizes on S-ONFH compared with SLE controls and non-SLE controls. Three of the four loci, MIR4293/MIR1265 [odds ratio (OR) = 1.99, P-value = 1.1 × 10-9)], TRIM49/NAALAD2 (OR = 1.65, P-value = 4.8 × 10-8) and MYO16 (OR = 3.91, P-value = 4.9 × 10-10), showed significant associations in the meta-analysis with Korean datasets. Bioinformatics analyses identified MIR4293, NAALAD2 and MYO16 as candidate causal genes. MIR4293 regulates a PPARG-related adipogenesis pathway relevant to S-ONFH. We identified three novel susceptibility loci for S-ONFH in SLE.
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Necrose da Cabeça do Fêmur , Lúpus Eritematoso Sistêmico , Esteroides , Carboxipeptidases/genética , Proteínas de Transporte/genética , Cabeça do Fêmur , Necrose da Cabeça do Fêmur/induzido quimicamente , Necrose da Cabeça do Fêmur/complicações , Necrose da Cabeça do Fêmur/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Lúpus Eritematoso Sistêmico/genética , MicroRNAs/genética , Cadeias Pesadas de Miosina/genética , Polimorfismo de Nucleotídeo Único , Esteroides/efeitos adversosRESUMO
BACKGROUND: In patients with normophosphatemia with chronic kidney disease (CKD), fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) increase urinary phosphate excretion while maintaining serum phosphate within the normal range. Recent reports have shown that, in this stage, phosphate binders do not decrease serum FGF23 and PTH levels. Iron deficiency promotes transcription of FGF23 and iron-supplementation for iron deficiency decreases serum FGF23 levels. We hypothesized that ferric citrate hydrate, an iron-based phosphate binder, will decrease serum FGF23 levels in patients with non-dialysis-dependent CKD with normophosphatemia and iron deficiency. METHODS: This was a single-center, randomized, open-label interventional study. The inclusion criteria were as follows: (1) eGFR < 45 mL/min/1.73 m2, (2) normophosphatemia, (3) iron deficiency. Patients were assigned to the following groups: ferric citrate hydrate (FCH)-group, sodium ferrous citrate (SFC)-group, and control-group. After 12 weeks of intervention, we evaluated serum FGF23 levels and CKD-mineral bone disorder markers. RESULTS: There were 17 patients in the FCH-group, 14 in the SFC-group, and 9 in the control-group. The serum ferritin levels increased in the FCH-group and SFC-group compared with baseline. Serum FGF23 levels were unchanged; the change in the FCH-group was from 52.91 RU/mL (42.48-72.91) to 40.00 RU/mL (30.30-58.13) (P = 0.1764). However, in the FCH-group, serum PTH levels significantly decreased compared with baseline, from 68.00 pg/mL (49.00-141.00) to 60.00 pg/mL (44.00-144.00) (P = 0.0101). CONCLUSION: Iron-based phosphate binder did not decrease serum FGF23 levels, but decreased serum PTH levels.
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Anemia Ferropriva/complicações , Compostos Férricos/farmacologia , Fatores de Crescimento de Fibroblastos/metabolismo , Hormônio Paratireóideo/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Idoso , Feminino , Fator de Crescimento de Fibroblastos 23 , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/metabolismo , TóquioRESUMO
Podoplanin was identified as a protein associated with the transformation of arborized foot processes of glomerular epithelial cells (podocytes) to flat feet. However, the function of podoplanin in the podocyte is not yet fully clarified. In this study, we analyzed the molecular nature of podoplanin, and its expression in rat nephrotic models and patients with minimal change nephrotic syndrome (MCNS). We demonstrated here that podoplanin has two forms: one contains abundant sialic acid and the other a lesser amount of sialic acid. Podoplanin bound ezrin to interact with the cytoskeleton. The silencing of podoplanin in cultured podocytes caused a change in the cell shape and the distribution of ezrin and actin. The expression of podoplanin was clearly reduced before the onset of proteinuria in puromycin aminonucleoside (PAN) nephropathy, a mimic of MCNS, and the decrease in the expression of podoplanin became more evident at the proteinuric stage. Podoplanin was detected in normal urine samples, and the amount of urinary podoplanin markedly increased on day 1 of PAN nephropathy. Urinary ezrin was also detected. The amount of the phosphorylated ezrin was reduced, while the amount of the podoplanin-interacting ezrin increased. The podoplanin expression was reduced in a patient with active-phase MCNS. It is conceivable that the alteration of the podoplanin-ezrin-cytoskeleton linkage is an important event of the podocyte injury in MCNS.
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Citoesqueleto/metabolismo , Nefropatias/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Nefrose Lipoide/genética , Nefrose Lipoide/metabolismo , Podócitos/metabolismo , Animais , Humanos , Nefropatias/patologia , Puromicina Aminonucleosídeo/metabolismo , Coelhos , RatosRESUMO
We report an intriguing case of Epstein-Barr virus (EBV)-related multiple lymphadenopathy that clinically mimics immunoglobulin G4-related disease (IgG4-RD). A 72-year-old woman presented with a history of asthma attacks, systemic lymphadenopathy, hypergammaglobulinemia, proteinuria, and an elevated level of serum IgG4, leading to a possible diagnosis of IgG4-RD based on current comprehensive diagnostic criteria. However, a percutaneous kidney biopsy specimen showed mild mesangial proliferative glomerulonephritis with focal membranous transformation, and there was no interstitial lesion or lymphocyte infiltration. Cervical lymph node biopsy demonstrated follicular hyperplasia associated with prominent lymphoplasmacytic infiltration in the interfollicular area. However, only a few IgG4-positive plasma cells were present. An in situ hybridization study demonstrated many EBV-infected lymphocytes in the germinal center as well as in the interfollicular area. This case illustrates the diversity of conditions associated with elevated levels of serum IgG4 and the necessity for tissue biopsy when diagnosing IgG4-RD.
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Infecções por Vírus Epstein-Barr/diagnóstico , Hipergamaglobulinemia/diagnóstico , Imunoglobulina G/sangue , Doenças Linfáticas/diagnóstico , Idoso , Diagnóstico Diferencial , Infecções por Vírus Epstein-Barr/sangue , Feminino , Humanos , Hipergamaglobulinemia/sangue , Doenças Linfáticas/sangueRESUMO
We report a case of ruptured low-grade appendiceal mucinous neoplasm with an impressive toy puffer ball-like appearance on magnetic resonance imaging. A 79-year-old woman with lower abdominal pain underwent computed tomography scanning, revealing a 6-cm mass in the right lower abdomen. T2-weighted images showed a radial low-signal structure in the central area of the mass, which was presumed to be fibrotic. Pathology confirmed ruptured low-grade appendiceal mucinous neoplasm. The rupture point was at the tip of the appendix, coinciding with the center of radial fibrosis. The unique morphology of the puffer ball-like appearance in this case may be a characteristic of low-grade appendiceal mucinous neoplasms.
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BACKGROUND AND OBJECTIVE: Renin-angiotensin system (RAS) inhibitors reduce glomerular injury and proteinuria, indicating that angiotensin II (Ang II) is involved in glomerular diseases. Although the local RAS is reported to play an essential role in maintaining local tissue functions, the role of the local RAS in regulating glomerular function is not well evaluated. In this study, we analyzed the glomerular expression of RAS components in nephrotic models and the effect of Ang II receptor blockers (ARB) on the expression of angiotensinogen (AGT). METHODS: The levels of glomerular expression of RAS components were analyzed in two nephrotic models: anti-nephrin antibody-induced nephropathy and PAN nephropathy, a mimic of human minimal change nephrotic syndrome. The effect of the ARB irbesartan on the expression of AGT in the nephrotic model was analyzed. RESULTS: Glomerular expression of AGT and the receptors for Ang II was clearly increased in the nephrotic models, while the expression levels of renin, ACE and ACE2 were decreased. ARB treatment suppressed the increase of glomerular expression of AGT in the nephrotic model. CONCLUSION: It is conceivable that the promoted local RAS action participated in the glomerular dysfunction, and that ARB treatment ameliorated slit diaphragm injury by inhibiting the positive feedback loop of the activated local Ang II action.
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Angiotensinogênio/metabolismo , Glomérulos Renais/metabolismo , Síndrome Nefrótica/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Feminino , Glomérulos Renais/patologia , Proteínas de Membrana/metabolismo , Síndrome Nefrótica/genética , Podócitos/metabolismo , Podócitos/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Wistar , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/genéticaRESUMO
Hereditary hypouricemia is generally caused by renal hypouricemia, an autosomal recessive disorder that is characterized by impaired renal tubular uric acid transport, or by xanthinuria, a rare autosomal recessive disorder caused by a deficiency of xanthine dehydrogenase (XDH; xanthinuria type I) or by a deficiency of both XDH and aldehyde oxidase (xanthinuria type II). In contrast to renal hypouricemia, which sometimes leads to exercise-induced acute kidney injury (EIAKI), xanthinuria has not been associated with this disorder. We report here a case of xanthinuria type I due to a compound heterozygous mutation. A 46-year-old woman was found to have undetectable plasma and urinary levels of uric acid. She had no symptoms and no history of EIAKI. Xanthinuria type I was diagnosed following the allopurinol loading test. Mutation analysis revealed a compound heterozygous mutation [c.305A>G (p.Gln102Arg) and c.2567delC (p.Thr856Lysfs*73)] in the XDH gene. Of these two mutations, the former is novel. The patient did not exhibit EIAKI. However, because xanthinuria is a rare disease, the identification of additional cases is necessary to determine whether this disease is complicated with EIAKI.
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The aim of the present study was to determine predictors of a sustained virological response (SVR) with a regimen of double filtration plasmapheresis (DFPP) combined with interferon-ß plus ribavirin (IFN-ß/RBV) induction therapy prior to pegylated (PEG-IFN/RBV) standard of care (SOC) therapy for patients with chronic hepatitis C who had experienced SOC treatment failure. Predictors of a SVR were analyzed in chronic hepatitis C patients with genotype 1b hepatitis C virus (HCV), who had a high viral load. The patients had been unresponsive to previous IFN therapy and underwent induction therapy with IFN-ß/RBV plus DFPP, which was performed five times during the same period, followed by PEG-IFN/RBV. In total, 10 patients received the combination DFPP plus IFN-ß/RBV induction therapy prior to PEG-IFN/RBV therapy for the treatment of chronic hepatitis C. Two weeks after treatment initiation, a decrease in the HCV RNA levels of ≥2 log IU/ml occurred in 9/10 patients (90%), while a decrease of ≥4 log IU/ml was observed in 4/10 patients (40%). The HCV RNA levels at week 2 after treatment initiation in the SVR and non-SVR patients decreased by 5.0±0.8 and 2.9±1.1 log IU/ml, respectively. Despite no response to previous IFN therapy, three of the 10 patients (30%) experienced a SVR. The results indicated that a rapid virological response ensued following IFN-ß/RBV induction and DFPP supplementary therapy. Although the level of interleukin-28B is an important predictor of a SVR, a decrease in the HCV RNA volume of ≥4 log IU/ml at week 2 after the initial treatment is also an important predictor. Therefore, rapid virological reduction using DFPP, in addition to IFN-ß/RBV induction therapy, is an important predictor of a SVR.
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PURPOSE: To clarify the usefulness of glycerol-induced cerebral blood flow measurement (G-CBF) as a method for prognostic evaluation of an asymptomatic unruptured cerebral aneurysm (AUCA). SUBJECTS AND METHODS: Fifty-three patients (age: 26-72 years; ratio of males to females, 23: 30; 56 AUCAs) who were found to have an AUCA(s) on brain checkup at our hospital and then received treatment (direct or intravascular surgery) were the subject of our study. The patients underwent the N-type psychofunction test (NPT) and G-CBF. As the control group, G-CBF was also performed on 50 subjects (age: 36-73 years; ratio of males to females, 27; 23), who were found, by brain checkup, to have no intracranial disease. We investigated (1) the occurrence of post-treatment complications (symptoms/psychofunctional disorders) in the treated group, and compared (2) G-CBF between the complication-developing group, the non-complication-developing group, and the control group. RESULTS: (1) Complications were observed in 9 patients (17%), including convulsions in 2 patients, hemiparalysis in 1, disorientation in 3. Psychofunctional disorders (less than 80 points on the NPT score) were observed in all of the 9 patients developing complications, but could be determined as higher brain dysfunctions only in the 3 patients with disorientation. (2) The mean cerebral blood flow (mCBF) before glycerol administration was 34.17 +/- 4.82 ml/100 g/min in the complication-developing group, 32.41 +/- 7.29 ml/100 g/min in the non-complication-developing group, and 31.98 +/- 5.04 ml/100 g/min in the control group, showing no significant intergroup differences. The mean increased rate of cerebral blood flow (mIR) after glycerol administration was 7.05 +/- 3.96%, 23.63 +/- 5.5%, and 30.64 +/- 13.08%, respectively, showing a significantly lower increase in the complication-developing group (p < 0.01), particularly low in the frontal lobe. Paradoxical flow reactivity was observed in 2 patients, both of whom were in the complication-developing group. CONCLUSIONS: (1) The complication-developing group showed a significantly lower pre-treatment mIR (less than 10%), particularly low in the frontal lobe, (2) Paradoxical flow reactivity was observed only in the complication-developing group. (3) G-CBF was very useful for prognostic evaluation prior to the treatment of AUCA.
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Circulação Cerebrovascular , Glicerol , Aneurisma Intracraniano/cirurgia , Adulto , Idoso , Feminino , Humanos , Aneurisma Intracraniano/fisiopatologia , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
PURPOSE: To improve the diagnostic precision of the lumbar tap test (LTT). SUBJECTS AND METHODS: Thirty one patients (mean age, 65.4 years; male to female ratio, 12:19) suspected of having idiopathic normal pressure hydrocephalus (INPH) were used in the study. They underwent LTT (20-30 ml of cerebrospinal fluid was drained through a puncture with a 18 G needle; evaluation within 3 days after LTT). Based on changes in symptoms after LTT, including dementia (evaluated according to the duration of time needed to accomplish No. 7 items in the N method psychofunction test) and gait disturbance (evaluated according to the duration and the number of steps needed to walk 4 m in a straight line), mean cerebral blood flow (mCBF) monitored with 133Xe-CT, and electroencephalographic topography (EEG-T). The patients were divided into symptom-improved [LTT (+)] and no change [LTT(-)] groups. Changing patterns of EEG-T and mCBF after LTT and the efficacy of V-P shunt at 1 month after shunt administration (effective: E; non-effective: NE) were analyzed and compared. Changing patterns of EEG-T and mCBF after LTT were categorized as improvement of both parameters (type A), that of mCBF only (type B), that of EEG-T only (type C), and no change in either parameter (type D). RESULTS: (1) Twenty patients were classified as LTT(+) and eleven as LTT(-). (2) The false positive rate was 25% (5/20) for LTT(+); the false negative rate was 27.3% (3/11) for LTT (-). (3) In all the patients, in relation to changing patterns of EEG-T and mCBF, 100% of type A patients (9/9), 75% of type B (6/8), 42.9% of type C (3/7), and 0% of type D (0/7) responded to shunting. (4) Increased rates (IR) of mCBF in 17 patients with improvement of mCBF were 24.2 +/- 10.6% in E patients and 8.9 +/- 5.2% in NE patients, demonstrating a significantly higher percentage in E patients (p < 0.005). The borderline of IR between E and NE was around 15%. CONCLUSION: (1) Although quantitative evaluation of symptoms (dementia and gait disturbance) before and after LTT, 27.3% of false negative and 25% of false positive were recognized. (2) According to changing patterns of EEG-T and mCBF after LTT, all type A patients responded to shunting (E), whereas type D patients were all categorized as NE. (3) When the IR of mCBF was 15% or more after LTT, such patients all responded to shunting. (4) The diagnostic precision of LTT in efficacy evaluation is improved when this test is combined with EEG-T and mCBF, in addition to quantitative evaluation of symptoms.
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Circulação Cerebrovascular , Eletroencefalografia/métodos , Hidrocefalia de Pressão Normal/diagnóstico , Punção Espinal/métodos , Idoso , Feminino , Humanos , Hidrocefalia de Pressão Normal/fisiopatologia , Hidrocefalia de Pressão Normal/cirurgia , Masculino , Derivação VentriculoperitonealRESUMO
BACKGROUND: The precise pathogenic mechanism and role of angiotensin II (Ang II) action in the development of proteinuria in minimal change nephrotic syndrome (MCNS) is uncertain. METHODS: The glomerular expressions of the slit diaphragm (SD) molecules nephrin, podocin and NEPH1 in rat puromycin aminonucleoside (PAN) nephropathy, a mimic of MCNS, were analyzed. The effects of Ang II receptor blockade (ARB) (irbesartan 15 mg/kg body weight/day) on proteinuria and on the expression of the SD molecules were analyzed. RESULTS: mRNA expressions of nephrin, podocin and NEPH1 were decreased to an undetectable level at 1 h. The staining of these SD molecules shifted to a discontinuous pattern, and their intensity was reduced. NEPH1 staining was reduced to an undetectable level on day 10. ARB treatment ameliorated the peak value of proteinuria (237.6 ± 97.0 vs. 359.0 ± 63.3 mg/day, p < 0.05), and prevented the decrease in the mRNA expression of the SD molecules (nephrin 66.96 %, podocin 60.40 %, NEPH1 77.87 % of normal level). The immunofluorescence staining of NEPH1 was restored by ARB. ARB treatment enhanced the expression of NEPH1 of normal rats. CONCLUSIONS: Dysfunction of the SD molecules including NEPH1 is a crucial initiation event of PAN nephropathy. ARB treatment ameliorates proteinuria in PAN nephropathy by inhibiting the reduction of NEPH1 and nephrin. Ang II action regulates the expression of NEPH1 and nephrin in not only the pathological but also physiological state.