APC sets the Wnt tone necessary for cerebral cortical progenitor development.

Adenomatous polyposis coli (APC) regulates the activity of ß-catenin, an integral component of Wnt signaling. However, the selective role of the APC-ß-catenin pathway in cerebral cortical development is unknown. Here we genetically dissected the relative contributions of APC-regulated ß-catenin signaling in cortical progenitor development, a necessary early step in cerebral cortical formation. Radial progenitor-specific inactivation of the APC-ß-catenin pathway indicates that the maintenance of appropriate ß-catenin-mediated Wnt tone is necessary for the orderly differentiation of cortical progenitors and the resultant formation of the cerebral cortex. APC deletion deregulates ß-catenin, leads to high Wnt tone, and disrupts Notch1 signaling and primary cilium maintenance necessary for radial progenitor functions. ß-Catenin deregulation directly disrupts cilium maintenance and signaling via Tulp3, essential for intraflagellar transport of ciliary signaling receptors. Surprisingly, deletion of ß-catenin or inhibition of ß-catenin activity in APC-null progenitors rescues the APC-null phenotype. These results reveal that APC-regulated ß-catenin activity in cortical progenitors sets the appropriate Wnt tone necessary for normal cerebral cortical development.

Factors affecting the sodium-glucose cotransporter 2 inhibitors-related initial decline in glomerular filtration rate and its possible effect on kidney outcome in chronic kidney disease with type 2 diabetes: The Japan Chronic Kidney Disease Database.

AIM: Sodium-glucose cotransporter 2 (SGLT2) inhibitors often cause a transient decrease in glomerular filtration rate (GFR) shortly after the initiation, referred to as the 'initial drop'. However, the clinical significance of this initial drop in real-world practice remains unclear. MATERIALS AND METHODS: Using the nationwide Japan Chronic Kidney Disease Database, we examined factors that affected the initial drop, in patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). We also evaluated the effects of the initial drop on a composite kidney outcome (a decline in GFR of ≥50% or progression to end-stage kidney disease). RESULTS: Data from 2053 patients with CKD and T2DM newly prescribed an SGLT2 inhibitor were analysed. The follow-up period after SGLT2 inhibitor administration was 1015 days (interquartile range: 532, 1678). Multivariate linear regression models revealed that the concomitant use of the renin-angiotensin system inhibitors and diuretics, urinary protein levels ≥2+, and changes in GFR before the initiation of the SGLT2 inhibitor were associated with a larger initial GFR decline (ß = -0.609, p = .039; ß = -2.298, p < .001; ß = -0.936, p = .048; ß = -0.079, p < .001, respectively). Patients in the quartile with the largest initial GFR decline experienced a higher incidence of the subsequent composite kidney outcome than those in the other quartiles (p < .001). CONCLUSIONS: The concomitant use of renin-angiotensin system inhibitors and diuretics, higher urine protein levels and pre-treatment GFR changes were associated with a larger initial GFR decline. Of these factors, the use of a diuretic had the largest effect. Furthermore, patients with CKD and T2DM experiencing an excessive initial GFR drop might be at a higher risk of adverse kidney outcomes.

Clinical features and prognostic factors of patients with cancer-associated stroke.

BACKGROUND: Cerebrovascular diseases in cancer patients significantly aggravate their condition and prognosis; therefore, prompt and accurate diagnosis and treatment are important. The purpose of this study was to investigate patient demographics, laboratory data, brain magnetic resonance imaging (MRI) findings, and prognosis among patients with stroke and cancer, especially cancer-associated ischemic stroke (CAIS). METHODS: We performed a retrospective, single-center study. We enrolled consecutive patients who had acute stroke and were admitted to our hospital between January 2011 and December 2021. We collected general demographic characteristics, cancer histopathological type, laboratory data, brain MRI findings, and prognosis data. RESULTS: Among 2040 patients with acute stroke, a total of 160 patients (7.8%) had active cancer. The types of strokes were cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, and transient ischemic attack in 124, 25, 5, and 6 patients, respectively. Among the patients with ischemic stroke, there were 69 cases of CAIS. Pancreas and adenocarcinoma were the most frequent types of primary tumor and histopathology. Patients with adenocarcinoma and those with cerebral infarctions in both bilateral anterior and posterior cerebral circulation areas showed higher D-dimer levels. Pancreatic cancer and high plasma D-dimer levels were associated with poor survival rate. CONCLUSION: CAIS was seen more frequently in patients with pancreatic cancer and adenocarcinoma. Pancreatic cancer and high plasma D-dimer levels were potential factors of poor prognosis in patients with CAIS.

A case series of Fabry diseases with CKD in Japan.

BACKGROUND: It is well known that kidney injury is vital organ damage in Fabry disease (FD). Renin-angiotensin system (RAS) inhibitors are known to reduce proteinuria in patients with chronic kidney disease (CKD) by dilating the glomerular export arteries and reducing intraglomerular pressure. This improvement in intraglomerular pressure, although lowering the glomerular filtration rate, is thought to prevent renal damage and be renoprotective in the long term. RAS inhibitors may be effective in FD patients with proteinuria to prevent the progression of kidney disease, however, the degree to which they are used in clinical practice is unknown. METHODS: The J-CKD-DB-Ex is a comprehensive multicenter database that automatically extracts medical data on CKD patients. J-CKD-DB-Ex contains data on 187,398 patients in five medical centers. FD patients were identified by ICD-10. Clinical data and prescriptions of FD patients between January 1 of 2014, and December 31 of 2020 were used for the analysis. RESULTS: We identified 39 patients with FD from the J-CKD-DB-Ex including those with suspected FD. We confirmed 22 patients as FD. Half of the patients received RAS inhibitors. RAS inhibitors tended to be used in CKD patients with more severe renal impairment. CONCLUSIONS: This case series revealed the actual clinical practice of FD patients with CKD. In particular, we found cases in which patients had proteinuria, but were not treated with RAS inhibitors. The database was shown to be useful in assessing the clinical patterns of patients with rare diseases.

A comparison of the clinical efficacy of tonsillectomy with steroid pulse therapy and tonsillectomy therapy alone for patients with immunoglobulin A nephropathy: a retrospective observational study.

BACKGROUND: Tonsillectomy with steroid pulse therapy (TSP) and tonsillectomy monotherapy (T) have improved the prognosis of patients with immunoglobulin A nephropathy (IgAN). However, a consensus has not been reached on the best treatment for these patients. This study aimed to compare the efficacies of TSP and T. METHODS: Data of patients with IgAN who received TSP or T were retrospectively analyzed. The exclusion criterion was a serum creatinine level > 1.5 mg/dL. The clinical remission and renal survival rates were compared. RESULTS: Patients were divided into groups based on the treatment method: the TSP (n = 82) and T groups (n = 41). No significant differences were observed in patient characteristics, except for the observation period (TSP: 60 months, T: 113 months). The log-rank test revealed that the clinical remission rate was significantly higher in the TSP group than in the T group (p < 0.05). The superiority of TSP was also observed in the urinary protein excretion (> / = or < 1 g/day) of the two subgroups. According to the Cox proportional-hazards model, the treatment method and daily urinary protein extraction were independent factors affecting clinical remission. The 10-year renal survival rates in the TSP and T groups were 100% and 92.5%, respectively. The log-rank test revealed a tendency for a higher renal survival rate in the TSP group than in the T group (p = 0.09). CONCLUSION: The clinical remission rate was significantly higher with TSP than with T, regardless of urinary protein levels. TSP tended to have a better renal survival rate than T.

Kidney outcomes associated with haematuria and proteinuria trajectories among patients with IgA nephropathy in real-world clinical practice: The Japan Chronic Kidney Disease Database.

AIM: Among patients with Immunoglobulin A (IgA) nephropathy, we aimed to identify trajectory patterns stratified by the magnitude of haematuria and proteinuria using repeated urine dipstick tests, and assess whether the trajectories were associated with kidney events. METHODS: Using a nationwide multicentre chronic kidney disease (CKD) registry, we analysed data from 889 patients with IgA nephropathy (mean age 49.3 years). The primary outcome was a sustained reduction in eGFR of 50% or more from the index date and thereafter. During follow-up (median 49.0 months), we identified four trajectories (low-stable, moderate-decreasing, moderate-stable, and high-stable) in both urine dipstick haematuria and proteinuria measurements, respectively. RESULTS: In haematuria trajectory analyses, compared to the low-stable group, the adjusted hazard ratios (HRs) (95% confidence interval [CI]) for kidney events were 2.59 (95% CI, 1.48-4.51) for the high-stable, 2.31 (95% CI, 1.19-4.50) for the moderate-stable, and 1.43 (95% CI, (0.72-2.82) for the moderate-decreasing groups, respectively. When each proteinuria trajectory group was subcategorized according to haematuria trajectories, the proteinuria group with high-stable and with modest-stable haematuria trajectories had approximately 2-times higher risk for eGFR reduction ≥50% compared to that with low-stable haematuria trajectory. CONCLUSION: Assessments of both haematuria and proteinuria trajectories using urine dipstick could identify high-risk IgA nephropathy patients.

Potential Effects of Ischemic Postconditioning and Changes in Heat Shock Protein 72 in Patients with Acute Myocardial Infarction without Prodromal Angina.

The effectiveness of ischemic postconditioning (iPoC) in patients with ST-elevation myocardial infarction (STEMI) without ischemic preconditioning has not been determined. Therefore, we investigated the impact of iPoC and its potential mechanism related to heat shock protein 72 (HSP72) induction on myocardial salvage in patients with STEMI without prodromal angina (PA).We retrospectively analyzed data from 102 patients with STEMI with successful reperfusion among 323 consecutive patients with acute coronary syndrome. Among these, 55 patients with iPoC (iPoC (+) ) underwent 4 cycles of 60-second inflation and 30-second deflation of the angioplasty balloon. Both the iPoC (+) and iPoC (-) groups were divided into 2 further subgroups: patients with PA (PA (+) ) and those without (PA (-) ). We analyzed HSP72 levels in neutrophils, which were measured until 48 hours after reperfusion. I-123 ß-methyl-p-iodophenyl-pentadecanoic acid (BMIPP) scintigraphy was performed within a week of reperfusion therapy. In 64% of patients, thallium-201 (TL) scintigraphy was performed 6-8 months after STEMI onset.Using BMIPP and TL, in the PA (-) subgroups, the iPoC (+) group had a significantly greater myocardial salvage ratio than the iPoC (-) group. iPoC was identified as an independent predictor of the myocardial salvage ratio. The HSP72 increase ratio was significantly elevated in the iPoC (+) PA (-) group. Importantly, the myocardial salvage effect in patients without PA was significantly correlated with the HSP72 increase ratio, which was greater in patients with iPoC.These results suggest the potential impact of iPoC via HSP72 induction on myocardial salvage; however, the effects may be limited to patients with STEMI without PA.

Characteristics of patients presenting with concomitant carpal tunnel syndrome at the initial diagnosis with rheumatoid arthritis.

OBJECTIVE: To investigate the clinical characteristics of patients who presented with concomitant carpal tunnel syndrome (CTS) at the initial diagnosis with rheumatoid arthritis (RA). METHODS: We analyzed patients with newly diagnosed RA at a single institution between 2012 and 2021. Patient demographic and laboratory data, the 2010 ACR/EULAR classification criteria, and the duration from the initial visit to RA diagnosis were compared between RA patients with concomitant CTS (RA with CTS group) and those without CTS (RA without CTS group). RESULTS: The study included 235 patients (157 females), of which 11 patients (4.7%) presented with CTS at the initial diagnosis with RA. In the RA with CTS group, the age was significantly higher (P = .033), all patients were female, and anti-cyclic citrullinated peptide antibody (ACPA) was negative, and the duration to RA diagnosis was longer than in the RA without CTS group. Among all RA with CTS patients, ultrasonography showed power Doppler signal-positive tenosynovitis in the carpal tunnel, which is not usually detected in idiopathic CTS. CONCLUSIONS: Patients with concomitant CTS at the initial diagnosis with RA were characterized by old age, female sex, and negative ACPA. Patients with symptoms of CTS should undergo ultrasonography for early diagnosis of RA.

Prostaglandin E2 mediates the late phase of ischemic preconditioning in the heart via its receptor subtype EP4.

Ischemic preconditioning (IPC) describes a phenomenon wherein brief ischemia of the heart induces a potent cardioprotective mechanism against succeeding ischemic insult. Cyclooxygenase-2 (COX-2), a rate-limiting enzyme in prostanoid biosynthesis, is upregulated in the ischemic heart and contributes to IPC. Prostaglandin E2 (PGE2) protects the heart from ischemia-reperfusion (I/R) injury via its receptor subtype EP4. We sought to clarify the role of the PGE2/EP4 system in the late phase of IPC. Mice were subjected to four IPC treatment cycles, consisting of 5 min of occlusion of the left anterior descending coronary artery (LAD). We found that COX-2 mRNA was significantly upregulated in wild-type hearts at 6 h after IPC treatment. Cardiac PGE2 levels at 24 h after IPC treatment were significantly increased in both wild-type mice and mice lacking EP4 (EP4-/-). At 24 h after IPC treatment, I/R injury was induced by 30 min of LAD occlusion followed by 2 h of reperfusion and the cardiac infarct size was determined. The infarct size was significantly reduced by IPC treatment in wild-type mice; a reduction was not observed in EP4-/- mice. AE1-329, an EP4 agonist, significantly reduced infarct size and significantly ameliorated deterioration of cardiac function in wild-type mice subjected to I/R without IPC treatment. Furthermore, AE1-329 significantly enhanced the I/R-induced activation of Akt, a pro-survival kinase. We demonstrated that the PGE2/EP4 system in the heart plays a critical role in the late phase of IPC, partly by augmenting Akt-mediated signaling. These findings clarify the mechanism of IPC and may contribute to the development of therapeutic strategies for ischemic heart disease.

Demographics and treatment of patients with primary membranoproliferative glomerulonephritis in Japan using a national registry of clinical personal records.

BACKGROUND: Membranoproliferative glomerulonephritis (MPGN) is a rare glomerular injury that causes nephrotic syndrome and end-stage kidney disease. The nationwide demographics and treatment of Japanese patients with primary MPGN have not yet been reported. METHODS: We collected clinical personal records of patients with primary MPGN between 2015 and 2018 from the national registry organized by the Japanese Ministry of Health, Labour, and Welfare and investigated the characteristics of primary MPGN throughout Japan. RESULTS: Of 258 patients with primary MPGN, 199 and 59 showed nephrotic and non-nephrotic syndrome, respectively. The median age at onset was higher in patients with nephrotic syndrome than in those with non-nephrotic syndrome (45 [24-63] vs. 35 [14-53] years, respectively; P = 0.010). The use of oral prednisolone was significantly higher in patients with nephrotic syndrome than in those with non-nephrotic syndrome (73.9% vs. 59.3%, respectively; P = 0.032). When patients were divided into three age groups: adolescent and young adult group (≤ 39 years; n = 80), middle adult group (40-64 years; n = 111), and older adult group (≥ 65 years; n = 67), the use of oral prednisolone, cyclosporine, and mizoribine was significantly higher in the adolescent and young adult group than in the middle adult group. The mean dosage of oral prednisolone and mizoribine showed no differences among the three age groups. CONCLUSION: The national registry of clinical personal records of primary MPGN could provide an informative insight into the characteristics, clinical features, and treatment approaches for patients with primary MPGN in Japan.

A nationwide cross-sectional analysis of biopsy-proven Fabry nephropathy: the Japan Renal Biopsy Registry.

BACKGROUND: Fabry disease (FD) is an X-linked inherited disease where renal complications are associated with a poor prognosis. However, little is known about the prevalence of Fabry nephropathy (FN) in patients with chronic kidney disease (CKD). We extracted FN data from the Japan Renal Biopsy Registry, analyzed the prevalence of FN, and examined the correlation between clinical characteristics and renal involvement according to sex differences and hemi- and heterozygosity in patients with FD. METHODS: A total of 38,351 participants who underwent renal biopsy were retrospectively enrolled, and FN was determined. The clinical characteristics of FD patients were examined based on sex differences. RESULTS: Twenty-nine patients (0.076%) (19 males and 10 females, mean age: 43.7 ± 15.5 years old) were diagnosed with FN. Median estimated urinary protein (UP) and mean eGFR levels were 0.9 [interquartile range (IQR) [0.7-1.6] g/gCr and 67.1 ± 36.8 mL/min/1.73 m2, respectively. Mean systolic blood pressure (SBP) was 126.4 ± 17.1 mmHg and diastolic blood pressure was 76.1 ± 12.6 mmHg. An inverse correlation between eGFR and logarithm UP levels was observed (r2 = 0.23, p = 0.02), SBP was positively associated with logarithm UP (r2 = 0.34, p = 0.004) overall and inversely associated with eGFR (r2 = 0.25, p = 0.007) regardless of sex, and SBP was an independent determinant of proteinuria (p = 0.004) and eGFR (p = 0.007). CONCLUSIONS: The prevalence of biopsy-proven FN was 0.076%. Since SBP is associated with eGFR regardless of zygosity, strict SBP control might be necessary to prevent progression to end-stage kidney disease in both male and female patients with FN.

New-onset and relapse of nephrotic syndrome following COVID-19 vaccination: a questionnaire survey in Japan.

BACKGROUND: Recent clinical reports indicate a correlation between new-onset and relapse of nephrotic syndrome (NS) following coronavirus 2019 (COVID-19) vaccination in patients with glomerular diseases. However, there are no reports of a nationwide survey on NS following COVID-19 vaccination in Japan. METHODS: We conducted a web-based survey of council members of the Japanese Society of Nephrology (581 members, 382 facilities) to elucidate the relationship between COVID-19 vaccination and new-onset and relapse of NS. RESULTS: Following COVID-19 vaccination, 27 patients (male: 15, 55.6%) with new-onset (n = 6) and relapse (n = 21) of NS were reported. Of them, 12 (44.4%) patients were diagnosed with minimal change disease at the occurrence of NS. Five patients developed a slight increase in serum creatinine levels; however, none progressed to severe renal dysfunction. CONCLUSION: Our findings clarify the clinical features of new-onset and relapse of NS following COVID-19 vaccination. Although there was no obvious progression to severe renal dysfunction, clinicians and pathologists should be aware that NS is a potential adverse effect of the vaccines.

A nationwide analysis of renal and patient outcomes for adults with lupus nephritis in Japan.

BACKGROUND: The prognosis of lupus nephritis (LN) has improved following the introduction of effective immunosuppressive therapy and progress in supportive care. This study examined recent renal and patient prognosis for adults with LN in Japan. METHODS: We conducted a nationwide retrospective cohort study of LN patients who received a renal biopsy between 2007 and 2012 that were registered in the Japan Renal Biopsy Registry. Of 623 registered adults with LN from 25 institutions and their affiliated or community hospitals, 489 were eligible for this study. RESULTS: The median age at renal biopsy was 39 years, and 82.2% of patients were female. Renal biopsies were performed in 348 patients with new-onset LN, 106 with relapse LN, and 35 with refractory LN. The distribution of ISN/RPS 2003 Classes was as follows: I 1.6%; II 5.3%; III (± V) 27.0%; IV (± V) 47.0%; V 18.4%; VI 0.6%. During the median observation period of 63.8 months, 36 patients (7.3%) reached a doubling of serum creatinine or end-stage kidney disease (ESKD), and 28 patients (5.7%) died. The 5 year renal and patient survival rates were 93.9% and 94.7%, respectively. Multivariate analysis revealed body mass index (BMI) and estimated glomerular filtration rate (eGFR) were independent risk factors for a doubling of serum creatinine in ESKD. Age and eGFR were independent risk factors for death. CONCLUSION: Recent prognosis for adults with LN are relatively good in Japan. Risk factors for impaired renal function are BMI and eGFR at renal biopsy, while age and eGFR are risk factors for death.

The efficacy and safety of mizoribine for maintenance therapy in patients with myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis: the usefulness of serum mizoribine monitoring.

BACKGROUND: The life prognosis of elderly patients with myeloperoxidase-anti-neutrophil cytoplasmic antibodies-associated vasculitis (MPO-AAV) has been improved by reducing the corticosteroid or cyclophosphamide dose to avoid opportunistic infection. However, many elderly MPO-AAV patients experience recurrence and renal death. An effective and safer maintenance treatment method is necessary to improve the renal prognosis of MPO-AAV. METHODS: Patients with MPO-AAV who reached complete or incomplete remission after induction therapy were prospectively and randomly divided into mizoribine (MZR; n = 25) and control (n = 28) groups. The primary endpoint was relapse of MPO-AAV. The patients' serum MZR concentration was measured before (C0) and 3 h after taking the MZR. The maximum drug concentration (Cmax) and the serum MZR concentration curves were determined using population pharmacokinetics parameters. We also assessed the relationship between the MZR concentrations and adverse events. The observation period was 12 months. RESULTS: Fifty-eight MPO-AAV patients from 16 hospitals in Japan were enrolled. Ten patients relapsed (MZR group, n = 6; control group, n = 4; a nonsignificant between-group difference). Changes in the serum MZR concentration could be estimated for 22 of the 25 MZR-treated patients: 2 of the 11 patients who reached a Cmax of 3 µg/mL relapsed, whereas 4 of the 11 patients who did not reach this Cmax relapsed. The treatment of one patient with C0 > 1 µg/mL was discontinued due to adverse events. No serious adverse events occurred. CONCLUSION: There was no significant difference in the recurrence rate of MPO-AAV between treatment with versus without MZR.

Apposition compound-eye image scanner by glass plate optics.

We propose a design approach for a thin image scanner using the concept of an apposition compound eye comprising many imaging units that take only one pixel image. Although light shielding between adjacent imaging units is always one of the main issues for an artificial compound eye, a simple plane structure using three aperture array layers on two glued glass plates prevents such stray light. Our prototyped scanner, with only 6.8-mm thickness as a packaged module, has 632 microlenses with 200-dpi resolution, resulting in a field of view of 80 mm. The evaluated images show no ghost images.

Pericyte-specific deletion of ninjurin-1 induces fragile vasa vasorum formation and enhances intimal hyperplasia of injured vasculature.

Adventitial abnormalities including enhanced vasa vasorum malformation are associated with development and vulnerability of atherosclerotic plaque. However, the mechanisms of vasa vasorum malformation and its role in vascular remodeling have not been fully clarified. We recently reported that ninjurin-1 (Ninj1) is a crucial adhesion molecule for pericytes to form matured neovessels. The purpose is to examine if Ninj1 regulates adventitial angiogenesis and affects the vascular remodeling of injured vessels using pericyte-specific Ninj1 deletion mouse model. Mouse femoral arteries were injured by insertion of coiled wire. Four weeks after vascular injury, fixed arteries were decolorized. Vascular remodeling, including intimal hyperplasia and adventitial microvessel formation were estimated in a three-dimensional view. Vascular fragility, including blood leakiness was estimated by extravasation of fluorescein isothiocyanate (FITC)-lectin or FITC-dextran from microvessels. Ninj1 expression was increased in pericytes in response to vascular injury. NG2-CreER/Ninj1loxp mice were treated with tamoxifen (Tam) to induce deletion of Ninj1 in pericyte (Ninj1 KO). Tam-treated NG2-CreER or Tam-nontreated NG2-CreER/Ninj1loxp mice were used as controls. Intimal hyperplasia was significantly enhanced in Ninj1 KO compared with controls. Vascular leakiness was significantly enhanced in Ninj1 KO. In Ninj1 KO, the number of infiltrated macrophages in adventitia was increased, along with the expression of inflammatory cytokines. In conclusion, deletion of Ninj1 in pericytes induces the immature vasa vasorum formation of injured vasculature and exacerbates adventitial inflammation and intimal hyperplasia. Thus, Ninj1 contributes to the vasa vasorum maturation in response to vascular injury and to reduction of vascular remodeling.NEW & NOTEWORTHY Although abnormalities of adventitial vasa vasorum are associated with vascular remodeling such as atherosclerosis, the mechanisms of vasa vasorum malformation and its role in vascular remodeling have not been fully clarified. The present study provides a line of novel evidence that ninjurin-1 contributes to adventitial microvascular maturation during vascular injury and regulates vascular remodeling.

Ninjurin 1 mediates peripheral nerve regeneration through Schwann cell maturation of NG2-positive cells.

Ninjurin 1 (Ninj1) is identified as a peripheral nerve injury-induced protein. However, the role of Ninj1 in nerve regeneration is unclear. Schwann cells (SCs) and microvasculature are critical for peripheral nerve regeneration. SCs precursors and microvascular pericytes (PCs), which are nerve/glial antigen 2 (NG2)-positive cells are observed in peripheral nervous system. In this study, we investigated the role of Ninj1 in peripheral nerve regeneration using NG2+cell-specific inducible deletion of Ninj1 mouse model. The number of NG2+cells, which were associated with and without microvessels was increased after sciatic nerve crush injury. There was a significant increase in the expression of Ninj1 and EphA7 in the injured nerve tissue. This increase was mostly observed in NG2+cells. Genetic tracing of NG2+cells was performed using tamoxifen (Tam) treatment on NG2CreERT:R26R-tdTomato mice. The sciatic nerve was injured following the Tam-treatment, then tdTomato-expressing SCs were mostly observed in regenerated SCs at 21 days after nerve injury. Ninj1 gene knockout (Ninj1 KO) in NG2+cells was induced using NG2CreERT:Ninj1loxp mice. Tam-treated-NG2CreERT or Tam-nontreated NG2CreERT:Ninj1loxp mice were used as controls. Following Tam-treatment, the sciatic nerve in each group was injured. Ninj1KO significantly attenuated the expression of the myelin binding protein (MBP) as well as the number of myelinated axons. The expression of MBP in cultured SCs was significantly reduced by SiRNA-mediated Ninj1 knockdown (KD). Ninj1KD also attenuated the differentiation of SCs by isolated EphA7+multipotent PCs. The current data indicate that Ninj1 plays a vital role in peripheral nerve regeneration. This is observed particularly in the myelination process of NG2+cells including SCs precursors and multipotent PCs.

Novel Detection of CALR-Mutated Cells in Myeloproliferative Neoplasm-Related Glomerulopathy With Interstitial Extramedullary Hematopoiesis: A Case Report.

Myeloproliferative neoplasms (MPNs) are associated with somatic mutations of genes including JAK2, CALR, or MPL in hematopoietic stem cells. Various glomerular lesions are known to be involved in MPN-related glomerulopathy, including mesangial hypercellularity, segmental sclerosis, features of chronic thrombotic microangiopathy, and intracapillary hematopoietic cell infiltration. Renal extramedullary hematopoiesis (EMH) is uncommon, but it is reported to occur in the setting of MPN; however, to our knowledge, there have been no reports of renal EMH with pathologically verified mutations. We report the case of a 65-year-old woman with MPN who had a CALR mutation and developed nephrotic syndrome. Kidney biopsy showed the typical findings of MPN-related glomerulopathy. CALR mutation-specific immunostaining of the kidney revealed immunopositive cells in the EMH lesion of the interstitium, indicating that renal EMH was caused by CALR-mutated cells. Based on these findings, we diagnosed nephrotic syndrome caused by MPN-related glomerulopathy. After initiation of steroid therapy, the patient's proteinuria gradually decreased and she achieved an incomplete remission. Additionally, the patient was prescribed the JAK inhibitor ruxolitinib and maintained incomplete remission. There is no established treatment for MPN-related glomerulopathy; therefore, further studies are needed to elucidate its pathophysiology.

High-risk screening for Anderson-Fabry disease in patients with cardiac, renal, or neurological manifestations.

Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder caused by abnormalities in the α-galactosidase (Gal) A gene (GLA; MIM:300644). The reduced activity of the lysosomal enzyme, α-galactosidase A (α-Gal A) leads to classic early manifestations and vascular disease of the heart, kidneys, and brain. As a high-risk screening for symptomatic AFD using an enzymatic assay on dried blood spot samples, we enrolled 2325 individuals (803 females and 1522 males; median age: 66 years) with cardiac, renal, or neurological manifestations that met at least one of the following criteria: (a) family history of early-onset cardiovascular diseases; (b) typical classic manifestations, such as acroparesthesias, clustered angiokeratoma, cornea verticillata, and hypo-anhidrosis; (c) proteinuria; (d) receiving dialysis; (e) left ventricular hypertrophy on electrocardiography or echocardiography; or (f) history of stroke. Ninety-two patients displayed low α-Gal A activity. Four males and two females had different pathogenic GLA mutations (0.26%) including a novel mutation c.908-928del21. Four males (0.17%) harbored the GLA c.196G>C (p.E66Q) variant. This simple screening protocol using dried blood spot samples is useful for early diagnosis of AFD in high-risk and underdiagnosed patients suffering from various cardiac, renal, or neurological manifestations.

Impact of the 2017 American College of Cardiology/American Heart Association Blood Pressure Guidelines on the Next Blood Pressure Guidelines in Asia.

PURPOSE OF REVIEW: To estimate the impact of the 2017 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for high blood pressure (BP) on the next hypertension guidelines in Asia. RECENT FINDINGS: The 2017 ACC/AHA guidelines for high BP in adults changed the diagnostic threshold and the management goal of BP from 140/90 to 130/80 mmHg. Another characteristic of the new guideline is its focus on a practical approach for the effective management of hypertension by using home and ambulatory BP monitoring; this point is also recommended in the 2014 Japanese Society of Hypertension Guidelines for the Management of Hypertension. In Japan, the guidelines for hypertension management are currently under revision and will be released in the spring of 2019. The core concept of the 2019 Japanese Society of Hypertension Guidelines for the Management of Hypertension, i.e., early and tight BP control over 24 h, will contribute to target-organ protection and cardiovascular disease prevention for Asians.