A review of Hyphodiscaceae.

In a recently published classification scheme for Leotiomycetes, the new family Hyphodiscaceae was erected; unfortunately, this study was rife with phylogenetic misinterpretations and hampered by a poor understanding of this group of fungi. This manifested in the form of an undiagnostic familial description, an erroneous familial circumscription, and the redescription of the type species of an included genus as a new species in a different genus. The present work corrects these errors by incorporating new molecular data from this group into phylogenetic analyses and examining the morphological features of the included taxa. An emended description of Hyphodiscaceae is provided, notes and descriptions of the included genera are supplied, and keys to genera and species in Hyphodiscaceae are supplied. Microscypha cajaniensis is combined in Hyphodiscus, and Scolecolachnum nigricans is a taxonomic synonym of Fuscolachnum pteridis. Future work in this family should focus on increasing phylogenetic sampling outside of Eurasia and better characterising described species to help resolve outstanding issues. Citation: Quijada L, Baral HO, Johnston PR, Pärtel K, Mitchell JK, Hosoya T, Madrid H, Kosonen T, Helleman S, Rubio E, Stöckli E, Huhtinen S, Pfister DH (2022). A review of Hyphodiscaceae. Studies in Mycology 103: 59-85. doi: 10.3114/sim.2022.103.03.

Phylogenetic relationships of eight new Dacrymycetes collected from New Zealand.

Dacrymycetes, sister to Agaricomycetes, is a noteworthy lineage for studying the evolution of wood-decaying basidiomycetes; however, its species diversity and phylogeny are largely unknown. Species of Dacrymycetes previously used in molecular phylogenetic analyses are mainly derived from the Northern Hemisphere, thus insufficient knowledge exists concerning the Southern Hemisphere lineages. In this study, we investigated the species diversity of Dacrymycetes in New Zealand. We found 11 previously described species, and eight new species which were described here: Calocera pedicellata, Dacrymyces longistipitatus, D. pachysporus, D. stenosporus, D. parastenosporus, D. cylindricus, D. citrinus, and D. cyrtosporus. These eight newly described species and seven of the known ones, namely, Calocera fusca, C. cf. guepinioides, C. lutea, Dacrymyces flabelliformis, D. intermedius, D. subantarcticensis, and Heterotextus miltinus, have rarely or never been recorded from the Northern Hemisphere. In a molecular-based phylogeny, these New Zealand strains were scattered throughout the Dacrymycetaceae clade. Sequences obtained from specimens morphologically matching C. guepinioides were separated into three distant clades. Because no obvious morphological differences could be discerned between the specimens in each clade and no sequence exists from the type specimen, a C. guepinioides s.str. clade could not be determined. This survey of dacrymycetous species in the Southern Hemisphere has increased taxon sampling for phylogenetic analyses that can serve as a basis for the construction of a stable classification of Dacrymycetes.

Clinical efficacy and safety of topiroxostat in Japanese male hyperuricemic patients with or without gout: an exploratory, phase 2a, multicentre, randomized, double-blind, placebo-controlled study.

WHAT IS KNOWN AND OBJECTIVE: In Japan, although topiroxostat, a selective xanthine oxidoreductase inhibitor, has been used for the treatment of patients with hyperuricemia including gout, no published randomized controlled studies evaluating the dose-dependent relationship with respect to the serum urate-lowering efficacy have been reported. The aim of this study was to evaluate the dose-dependent relationship with serum urate-lowering efficacy and safety of topiroxostat in Japanese hyperuricemic patients including gout. METHODS: We conducted an exploratory, phase 2a, multicentre, randomized, double-blind, 8-week, placebo-controlled study in Japanese hyperuricemic patients with or without gout. The study arms were placebo and topiroxostat 40, 60, 80 or 120 mg/day. The primary efficacy endpoint was the per cent change in serum urate level from baseline to the final visit. RESULTS AND DISCUSSION: One hundred and eighty-seven eligible patients were randomized and 186 received at least one dose of the study drug. The study results demonstrated a dose-dependent serum urate reduction effect ranging from 40 to 120 mg/day (P < 0·001, Jonckheere-Terpstra test). The mean per cent change in serum urate level from baseline at the final visit was -30·8% in the 120-mg group and 1·6% with placebo, with a between-group difference of -32·4% ([95% confidence interval, -38·9% to -25·9%]; P < 0·001). Incidences of overall adverse events (AEs) in the topiroxostat groups were comparable to those in the placebo group; however, the incidence of AEs in the 120-mg group was statistically lower than that in the placebo group. The incidences of gouty arthritis were not statistically but numerically higher in the topiroxostat 80- and 120-mg groups. WHAT IS NEW AND CONCLUSIONS: A dose-dependent serum urate-lowering efficacy of topiroxostat was observed in Japanese hyperuricemic male patients with or without gout. Further clinical studies aimed at evaluating the long-term safety and clinical efficacy are warranted.

Comparison of topiroxostat and allopurinol in Japanese hyperuricemic patients with or without gout: a phase 3, multicentre, randomized, double-blind, double-dummy, active-controlled, parallel-group study.

WHAT IS KNOWN AND OBJECTIVE: There are no clinical reports that have compared topiroxostat, a selective xanthine oxidase inhibitor, with allopurinol in serum urate-lowering efficacy. The aim of this study was to compare the efficacy and safety of topiroxostat and allopurinol in Japanese hyperuricemic patients with or without gout. METHODS: A phase 3, multicentre, randomized, double-blind, double-dummy, active-controlled, parallel-group study conducted in Japan. Patients who had inadequate serum urate levels (a gout patient: serum urate level ≥416·4 µmol/L; an asymptomatic hyperuricemic patient with specific complications (urinary lithiasis, hypertension, hyperlipidemia and/or diabetes): serum urate level ≥475·8 µmol/L; and an asymptomatic hyperuricemic patient with no specific complications: serum urate level ≥535·3 µmol/L) were randomized to topiroxostat 120 mg/day or allopurinol 200 mg/day, with an equal allocation ratio, for 16 weeks. To prevent the onset of gouty arthritis by rapid serum urate reduction, these doses were increased in a stepwise manner. The primary efficacy endpoint was the per cent change in serum urate level from baseline to the final visit. RESULTS AND DISCUSSION: Overall, 206 patients were randomly assigned to topiroxostat and allopurinol. Two hundred and three patients (allopurinol: n = 105, topiroxostat: n = 98) received at least one dose of the study drug and had their serum urate level assessed at least once. The baseline characteristics were comparable between groups. The mean age of patients was 53·0 ± 11·4 years and 99% of patients were male. The primary efficacy endpoint was -34·3 ± 11·1% in the allopurinol group (n = 105) and -36·3 ± 12·7% in the topiroxostat group (n = 98). Non-inferiority of the serum urate-lowering efficacy of topiroxostat to allopurinol was proved by the predefined non-inferiority margin (95% confidence interval, -5·3 to 1·3%). The overall incidences of adverse events and adverse drug reactions were similar between both groups. WHAT IS NEW AND CONCLUSION: Topiroxostat 120 mg/day provides non-inferior serum urate reduction compared with allopurinol 200 mg/day and is well tolerated in Japanese hyperuricemic patients with or without gout.

A comprehensive search for mutations in the PKD1 and PKD2 in Japanese subjects with autosomal dominant polycystic kidney disease.

To elucidate the genotypic and phenotypic characteristics of autosomal dominant polycystic kidney disease (ADPKD) in Japanese populations, we performed a comprehensive search for mutations in PKD1 and PKD2 in 180 Japanese ADPKD patients from 161 unrelated families. We identified 112 (89 PKD1 and 23 PKD2) mutations within 135 families. Patients with PKD2 mutations account for 23.6% of all Japanese ADPKD families in this study. Seventy-five out of the 112 mutations have not been reported previously. The estimated glomerular filtration rate (eGFR) decline was significantly faster in patients with PKD1 mutations than in those with PKD2 mutations (-3.25 and -2.08 ml min(-1) year(-1) for PKD1 and PKD2, respectively, p < 0.01). These results indicate that mutations within PKD1 and PKD2 can be linked to most of the cases of Japanese ADPKD, and the renal function decline was faster in patients with PKD1 mutations than in those with PKD2 mutations also in the Japanese ADPKD. We also found that PKD2 mutations were more frequent in Japanese ADPKD than that in European or American ADPKD.

Revision of the Massarineae (Pleosporales, Dothideomycetes).

We here taxonomically revise the suborder Massarineae (Pleosporales, Dothideomycetes, Ascomycota). Sequences of SSU and LSU nrDNA and the translation elongation factor 1-alpha gene (tef1) are newly obtained from 106 Massarineae taxa that are phylogenetically analysed along with published sequences of 131 taxa in this suborder retrieved from GenBank. We recognise 12 families and five unknown lineages in the Massarineae. Among the nine families previously known, the monophyletic status of the Dictyosporiaceae, Didymosphaeriaceae, Latoruaceae, Macrodiplodiopsidaceae, Massarinaceae, Morosphaeriaceae, and Trematosphaeriaceae was strongly supported with bootstrap support values above 96 %, while the clades of the Bambusicolaceae and the Lentitheciaceae are moderately supported. Two new families, Parabambusicolaceae and Sulcatisporaceae, are proposed. The Parabambusicolaceae is erected to accommodate Aquastroma and Parabambusicola genera nova, as well as two unnamed Monodictys species. The Parabambusicolaceae is characterised by depressed globose to hemispherical ascomata with or without surrounding stromatic tissue, and multi-septate, clavate to fusiform, hyaline ascospores. The Sulcatisporaceae is established for Magnicamarosporium and Sulcatispora genera nova and Neobambusicola. The Sulcatisporaceae is characterised by subglobose ascomata with a short ostiolar neck, trabeculate pseudoparaphyses, clavate asci, broadly fusiform ascospores, and ellipsoid to subglobose conidia with or without striate ornamentation. The genus Periconia and its relatives are segregated from the Massarinaceae and placed in a resurrected family, the Periconiaceae. We have summarised the morphological and ecological features, and clarified the accepted members of each family. Ten new genera, 22 new species, and seven new combinations are described and illustrated. The complete ITS sequences of nrDNA are also provided for all new taxa for use as barcode markers.

Lactobacillus helveticus SBT2171, a cheese starter, regulates proliferation and cytokine production of immune cells.

Consumption of a Lactobacillus helveticus SBT2171 (LH2171)-containing cheese has been reported to exhibit immunoregulatory actions, including an increase in regulatory T cell population and reduction in proinflammatory cytokine production in mice. We examined the in vitro effects of LH2171 cells per se on immune cell function, specifically proliferation and cytokine production, which are primary reactions of the immune response. Immune cell fractions were prepared by mechanical disruption of mesenteric lymph nodes (MLN), Peyer's patches (PP), and spleens (SP) of mice. The cell fractions were dispensed into a culture plate and stimulated with anti-CD3/CD28 antibody beads in place of antigen-presenting cells or lipopolysaccharide (LPS) in the presence or absence of heat-treated LH2171 cells and other bacterial strains for comparison. After incubation, proliferation, cytokine production, and cell viability of the immune cells were determined. The LH2171 significantly inhibited the proliferation of MLN immune cells stimulated with anti-CD3/CD28 compared with other bacterial strains. The antiproliferative potency of LH2171 was effective not only on MLN but also on PP and SP stimulated with anti-CD3/CD28 or LPS. The LH2171 also decreased LPS-stimulated IL-6 production from MLN, PP, and SP, and IL-1ß production from SP, but LH2171 did not affect the viability of immune cells. The LH2171 inhibited immune cell proliferation and proinflammatory cytokine (IL-6 and IL-1ß) production. The inhibitory actions were not due to cytotoxicity to immune cells, suggesting that LH2171 is a dairy Lactobacillus strain with beneficial immunoregulatory properties.

Acute neutropenia associated with initiation of febuxostat therapy for hyperuricaemia in patients with chronic kidney disease.

WHAT IS KNOWN AND OBJECTIVE: Febuxostat is a new non-purine selective inhibitor of xanthine oxidase for the treatment of hyperuricaemia in patients with gout. Febuxostat is recommended as the first-line pharmacologic urate-lowering therapy for gout in the American College of Rheumatology guidelines. Febuxostat has not been reported to cause severe complications, especially haematological abnormalities. Our objective is to report two cases of neutropenia associated with initiation of febuxostat therapy for hyperuricaemia in patients with chronic kidney disease (CKD). CASE SUMMARY: A 74-year-old woman with liver cirrhosis and CKD was treated with febuxostat for hyperuricaemia during hospitalization. Eleven days after febuxostat administration, she developed neutropenia. A 68-year-old man with type 2 diabetes mellitus on intermittent haemodialysis was treated with febuxostat for hyperuricaemia during hospitalization. Three days after febuxostat administration, he developed neutropenia. In the two cases, febuxostat treatment was discontinued and granulocyte colony-stimulating factor was administered, with concomitant recovery of the neutrophil count. WHAT IS NEW AND CONCLUSION: We believe this to be the first published case of neutropenia associated with initiation of febuxostat therapy for hyperuricaemia. According to the Naranjo probability scale, febuxostat was the probable cause of neutropenia. In view of the wide clinical usage of this drug, physicians and pharmacists should be alerted to this possible complication.

Effect of κ-opioid receptor agonist on the growth of non-small cell lung cancer (NSCLC) cells.

BACKGROUND: It is becoming increasingly recognised that opioids are responsible for tumour growth. However, the effects of opioids on tumour growth have been controversial. METHODS: The effects of κ-opioid receptor (KOR) agonist on the growth of non-small cell lung cancer (NSCLC) cells were assessed by a cell proliferation assay. Western blotting was performed to ascertain the mechanism by which treatment with KOR agonist suppresses tumour growth. RESULTS: Addition of the selective KOR agonist U50,488H to gefitinib-sensitive (HCC827) and gefitinib-resistant (H1975) NSCLC cells produced a concentration-dependent decrease in their growth. These effects were abolished by co-treatment with the selective KOR antagonist nor-BNI. Furthermore, the growth-inhibitory effect of gefitinib in HCC827 cells was further enhanced by co-treatment with U50,488H. With regard to the inhibition of tumour growth, the addition of U50, 488H to H1975 cells produced a concentration-dependent decrease in phosphorylated-glycogen synthase kinase 3ß (p-GSK3ß). CONCLUSION: The present results showed that stimulation of KOR reduces the growth of gefitinib-resistant NSCLC cells through the activation of GSK3ß.

Submucosal endoscopic tumor resection for subepithelial tumors in the esophagus and cardia.

BACKGROUND AND STUDY AIMS: Resection of submucosal tumors by means of endoscopy has been reported using a variety of techniques, but cannot be performed safely in tumors originating from the muscularis propria. Using the submucosal tunnel created by the technique of peroral endoscopic myotomy (POEM), we report the first series describing the new technique of submucosal endoscopic tumor resection (SET) for tumors of the esophagus and cardia. PATIENTS AND METHODS: SET was attempted in nine consecutive patients with tumors (size >2cm) of either the esophagus or cardia with clinical indications for lesion removal. Following creation of a submucosal tunnel from 5 cm above the tumor, as described previously, the tumor was dissected from the overlying mucosa/submucosa and then carefully removed from the muscular layer using triangle-tip and insulated-tip knives. Following specimen retrieval through the tunnel, the orifice was closed by clips. RESULTS: Of the nine patients, two had tumors that were too large (60 mm and 75 mm, respectively) to allow safe removal due to loss of endoscopic overview. All remaining tumors (maximal tumor extension 12-30 mm) could be resected safely using this method. No complications occurred and follow-up was unremarkable. On histology, all tumors were resected completely (one gastrointestinal stromal tumor, five leiomyomas). The technique had to be modified in one patient with an aberrant pancreas. CONCLUSIONS: SET is a promising new technique for selected submucosal tumors in the esophagus and cardia up to a size of 4 cm and should be studied further.

Successful treatment of monomorphic primary central nervous system post-transplantation lymphoproliferative disorder 5 years after kidney transplantation.

A 31-year-old man underwent living-related kidney transplantation in 2004 as a consequence of primary focal segmental glomerulosclerosis (FSGS). Four years after the transplantation, we confirmed nephrotic syndrome caused by recurrent FSGS. We performed plasmapheresis and low-density lipoprotein adsorption. We also combined steroid therapy with a reduction in the dose of tacrolimus and an increased dose of mycophenolate mofetil. The nephrotic syndrome improved dramatically with this combined therapeutic approach. However, 10 months after these treatments, he revisited our hospital because of altered consciousness. We detected multiple tumor masses in his brain that were ring enhanced on contrast magnetic resonance imaging. Consequently, we suspected primary central nervous system post-transplantation lymphoproliferative disorder (CNS-PTLD). We performed a craniotomy to biopsy the brain tumors. The biopsy specimen showed Epstein-Barr virus-associated diffuse large B-cell lymphoma. There is no definitive treatment for CNS-PTLD. Therefore, we treated the primary CNS-PTLD successfully with whole-brain radiation and discontinuation of immunosuppression therapy.

A cheese-containing diet modulates immune responses and alleviates dextran sodium sulfate-induced colitis in mice.

Diet has a significant effect on immune and inflammatory responses. To date, no studies have described how consumption of a diet containing a relatively high amount of cheese affects immune responses and the inflammatory status of the body. We examined these responses in normal mice and mice with dextran sodium sulfate (DSS)-induced colitis associated with increased inflammatory responses, using a diet containing approximately 44% of a whole cheese powder and a diet containing casein, lard, and corn oil as the control. In normal mice, consumption of the cheese-containing diet induced regulatory T cells (T(reg)), which regulate immune and inflammatory responses, and suppressed the production of IL-17, IL-4, and IL-10 in Peyer's patch cells from the intestine. The T(reg) population and cytokine production were not altered in spleen cells. In mice with DSS-induced colitis, consumption of the cheese-containing diet alleviated the symptoms of colitis, as evidenced by prevention of body weight loss and colon length shortening, and inhibition of an increase in the disease activity index, which includes diarrhea and fecal bleeding. This relief of clinical symptoms was also associated with decreased production of proinflammatory cytokines (IL-17 and IL-6) and increased production of the antiinflammatory cytokine transforming growth factor-ß1 in Peyer's patch cells. The T(reg) population was reduced by consumption of the cheese-containing diet in Peyer's patch cells and spleen cells, which might reflect the alleviated symptoms of colitis. Consumption of the cheese-containing diet compared with the control diet enhanced antiinflammatory and immune regulatory responses in normal mice and in a DSS-colitis mouse model.

Two cases of nephrotic syndrome (NS)-induced acute kidney injury (AKI) associated with renal hypouricemia.

Renal hypouricemia is a clinical disorder attributed to an increased renal urate excretion rate and is well known to involve a high risk of urolithiasis and exercise-induced acute kidney injury (AKI). This report concerns two interesting cases of nephrotic syndrome (NS)-induced AKI associated with renal hypouricemia. A 64-year-old female (Case 1) and a 37-year-old male (Case 2) were hospitalized because of AKI (serum creatinine: 2.07 mg/dl and 3.3 mg/dl, respectively), oliguria and NS. They were treated with prednisolone and temporary hemodialysis. Renal function improved, but hypouricemia persisted during hospitalization. Histological findings in both cases led to a diagnosis of minimal change nephrotic syndrome and identification of the diuretic phase of tubulointerstitial damage because of findings such as acute tubular necrosis. Furthermore, distal tubules of Case 2 showed an amorphous mass, possibly a uric acid crystal. Analysis of the two cases with the URAT1 gene, encoded by SLC22A12, found a homozygous mutation in exon 4 (W258stop) of each one. Our cases show that patients with renal hypouricemia may be susceptible to AKI without involvement of exercise if they possess some facilitators. Renal hypouricemic patients should therefore be carefully examined for all complications from renal hypouricemia because of high risk of AKI.

Difference in coronary artery intima and media calcification in autopsied patients with chronic kidney disease.

BACKGROUND: In patients with chronic kidney disease (CKD), coronary artery calcification occurs at two distinct sites in the vessel wall: the intima and the media. Arterial media calcification (AMC), a nonocclusive condition, affects hemodynamics differently compared to arterial intima calcification (AIC), which occurs in atherosclerotic plaques. Arterial calcification is considered a cell-regulated process resembling intramembranous bone formation. The purpose of this retrospective observational study was to clarify the morphological differences between AIC and AMC and to evaluate the role of vascular smooth muscle cells (VSMCs) and macrophages in AIC and AMC formation. METHODS: We histologically analyzed 14 tissue specimens from 14 autopsies of patients with CKD Stage 5D who underwent hemodialysis and 5 specimens from 5 patients with CKD Stage 2 - 3 (90 ml/min/1.73 m2 > estimated GFR >= 30 ml/min/1.73 m2). We performed immunohistochemical staining of osteopontin (OPN) as a marker for bone matrix protein, alpha-smooth muscle actin (alphaSMA) for VSMCs, Cbfa1/Runx2 as a marker for osteoblastic differentiation of VSMCs, and CD68 for macrophages. RESULTS: In the CKD 2/3 group, we also found AIC and AMC. OPN and CD68 expression in the CKD 2/3 group was similar to that in the CKD 5D group. Although we did not find Cbfa1/Runx2 positive cell expression in the CKD 2/3 group, we did find it in the CKD 5D group. We found CD68-positive cells predominantly in AIC and absent in AMC in both groups. CONCLUSIONS: These findings suggest that the influence of Cbfa1/Runx2 pathway in coronary artery calcification depends on the CKD Stage. Expression of CD68-positive cells depends on the location of the coronary artery calcification.

Clinical impact of a combined therapy of peritoneal dialysis and hemodialysis.

AIMS: Although peritoneal dialysis (PD) is recommended as the first-line treatment for end-stage renal disease, limitations exist to achieving good clinical status when the residual renal function (RRF) has declined. Combined therapy with PD and hemodialysis (HD) is the treatment of choice for patients who cannot control body fluid status and/or cannot obtain adequate solute removal by PD alone. The aim of this study was to evaluate the clinical efficacy of this combined therapy. METHODS: In this retrospective study, 53 patients on PD and diagnosed with underdialysis and/or overhydration with declining RRF were recruited. Parameters of volume control, uremic solute removal, anemia, and predictors for encapsulating peritoneal sclerosis (EPS) were compared before and 1 year after combined therapy. RESULTS: The patients' hydration status improved significantly with reductions in atrial natriuretic peptide and blood pressure. Serum creatinine and beta2 microglobulin also decreased significantly. The hemoglobin level increased remarkably from 8.2 ± 1.6 to 10.7 ± 1.2 g/dl (p < 0.01) and the reticulocyte count also increased significantly, even though at the same time the dose of recombinant human erythropoietin decreased significantly. The dialysate to plasma creatinine ratio obtained from the fast peritoneal equilibration test (PET) decreased significantly from 0.65 ± 0.11 to 0.59 ± 0.13, and the level of interleukin 6 in PET drainage also significantly decreased. Furthermore, serum C-reactive protein and fibrinogen decreased significantly. CONCLUSIONS: Combined therapy with PD and HD is an effective way to control fluid status and to correct inadequate solute removal, leading to improvement in inflammation, peritoneal function and anemia.

Effects of probenecid on the pharmacokinetics of mizoribine and co-administration of the two drugs in patients with nephrotic syndrome.

Probenecid (PRB) is an agent that reduces the systemic level of uric acid, and has the ability to inhibit the renal tubular secretion of agents that are co-administered with it. In this study, we evaluated the effects of PRB co-administered with mizoribine (MZR) on the pharmacokinetics (PK) of MZR in 12 patients with nephrotic syndrome. The elimination rate constant (kel) was used as an indicator of changes in the PK of MZR when the secretion of MZR was inhibited by co-administration of PRB, in order to determine the extent to which MZR was influenced by PRB. In 4 of the 12 patients studied, kel decreased and the biological half-life (t1/2) of MZR was prolonged when co-administered with PRB, in comparison with the values when MZR was used alone, thus revealing that the PK of MZR was influenced by PRB. Co-administration of PRB with MZR appears to be effective in prolonging the biological half-life of MZR and enhancing its effect in patients with nephrotic syndrome, although further studies will be required to determine the optimal dosage of PRB and renoprotective effects.

Therapeutics potentiating microglial p21-Nrf2 axis can rescue neurodegeneration caused by neuroinflammation.

Neurodegenerative disorders are caused by progressive neuronal loss, and there is no complete treatment available yet. Neuroinflammation is a common feature across neurodegenerative disorders and implicated in the progression of neurodegeneration. Dysregulated activation of microglia causes neuroinflammation and has been highlighted as a treatment target in therapeutic strategies. Here, we identified novel therapeutic candidate ALGERNON2 (altered generation of neurons 2) and demonstrate that ALGERNON2 suppressed the production of proinflammatory cytokines and rescued neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease model. ALGERNON2 stabilized cyclinD1/p21 complex, leading to up-regulation of nuclear factor erythroid 2-related factor 2 (Nrf2), which contributes to antioxidative and anti-inflammatory responses. Notably, ALGERNON2 enhanced neuronal survival in other neuroinflammatory conditions such as the transplantation of induced pluripotent stem cell-derived dopaminergic neurons into murine brains. In conclusion, we present that the microglial potentiation of the p21-Nrf2 pathway can contribute to neuronal survival and provide novel therapeutic potential for neuroinflammation-triggered neurodegeneration.

Insulin resistance is a risk factor for the progression of chronic kidney disease.

OBJECTIVE: Insulin resistance may contribute to the pathogenesis of hypertension and progressive chronic kidney disease (CKD), however, few clinical studies have explored the role of insulin resistance in predicting the deterioration of renal function in CKD patients. MATERIALS AND METHODS: Enrolled in the study were non-diabetic hypertensive patients with CKD Stage 3. Insulin resistance was assessed by a homeostasis model assessment of insulin resistance (HOMA-R) measured at the entry to the study. Patients were followed for 3 years and comparisons of renal and metabolic parameters were made in conjunction with HOMA-R between entry and the end of the study period. The insulin-resistant (IR) group was defined as patients with HOMA-R 2.0 and more, and the insulin-sensitive (IS) group as those with HOMA-R < 2.0. RESULTS: Blood pressure in both groups was equally controlled below 130/80 mmHg throughout the observation period. The degree of insulin resistance HOMA-R and immunoreactive insulin (IRI) remained unchanged in the IS group, however, both were ameliorated in the IR group (HOMA-R, from 3.4 +/- 1.5 - 3.0 +/- 1.1, p = 0.022 and IRI, from 14.4 +/- 6.1 microU/ml - 12.6 +/- 6.8 microU/ml, p = 0.012). Creatinine clearance (CCr) and estimated glomerular filtration rate (e-GFR) decreased and serum creatinine (Cr) concentration increased in all patients. The decline in CCr calculated as the slope of the reciprocal of serum Cr concentration (1/Cr) was greater in the IR group (0.007 +/- 0.004 (1/Cr/dl/mg/month) than in the IS group (0.003 +/- 0.002 (1/Cr/dl/mg/month), p < 0.001). Linear regression analysis showed that the slope of 1/Cr was negatively correlated with HOMA-R, IRI, BMI, respectively. Furthermore, stepwise regression analysis showed that the independent variables to explain the decline in renal function were HOMA-R and IRI. CONCLUSION: Insulin resistance is a significant risk factor for the deterioration of renal function in hypertensive non-diabetic patients with CKD.

Sodium-sensitive variability of the antiproteinuric efficacy of RAS inhibitors in outpatients with IgA nephropathy.

AIMS: Inhibition of the renin-angiotensin system (RAS) decreases proteinuria in IgA nephropathy and often retards disease progression. However, its antiproteinuric efficacy varies considerably among patients or different stages in a single patient. We sought for the factor(s) underlying the variation in urinary protein excretion in RAS inhibitor-treated outpatients with IgA nephropathy. PATIENTS: 43 patients with biopsy-proven IgA nephropathy, moderate proteinuria (0.5 - 3.5 g/day), normal to moderately-low estimated GFR (eGFR) (28.6 - 114.2 ml/min/1.73 m2) and normal blood pressure, prehypertension or mild hypertension (systolic/diastolic blood pressures < 160/100 mmHg) were placed on RAS inhibitors following diagnosis. METHOD: Excretion of urinary protein (UprV) and sodium (UNaV), estimated protein intake (EPI) and the mean blood pressure (MBP) were determined on 12 consecutive visits for an average duration of 17.6 months. Analyses were performed to determine which factor(s) influenced the variation in UprV. RESULTS: 14 patients (32.6%) showed a significant correlation between UprV and UNaV, whereas UprV correlated significantly with EPI or MBP in 7 (16.3%) and 3 patients (7.0%), respectively. The 14 patients were characterized by lower eGFR and more extensive glomerulosclerosis and tubulointerstitial damage at baseline than the other 29 patients. The UprV-UNaV correlation was significant in 8 of 12 patients (66.7%) with eGFR < 60 ml/min/1.73 m2 and in 6 of 29 patients (19.4%) with eGFR >= 60 ml/min/1.73 m2 (p < 0.05). The UprV/UNaV regression lines were significantly steeper with more extensive glomerulosclerosis (p < 0.05) and tubulointerstitial damage (p < 0.05) at baseline. The lines also tended to be steeper with lower baseline eGFR (p = 0.062). CONCLUSIONS: These results showed that the antiproteinuric effect of RAS inhibitors becomes susceptible to an increase in urinary sodium excretion as renal function and functioning nephron mass decline with the progression of renal histological damage. Stringent dietary sodium restriction is required to maximize the antiproteinuric effect of RAS inhibitors in outpatients with IgA nephropathy.