Involvement of interaction of Cav3.2 and nociceptive TRPA1 in pathological pain transmission.

T-type Ca2+ channels and TRPA1 expressed in sensory neurons are involved in pain. We previously demonstrated a functional interaction of these channels under physiological conditions. Here we investigated the possible involvement of these channels in inflammatory pain condition. We also evaluated the relationship of these channels endogenously expressed in RIN-14B, a rat pancreatic islet tumor cell line. In dorsal root ganglion (DRG) neurons innervated inflammatory side, [Ca2+]i increases induced by 15 mM KCl (15K) were enhanced in neurons responded to AITC. This enhancement was not observed in genetically TRPA1-deficient neurons. The T-type and AITC-induced currents were larger in neurons of the inflammatory side than in those of the control one. In DRGs of the inflammatory side, the protein expression of Cav3.2, but not TRPA1, was increased. In RIN-14B, 15K-induced [Ca2+]i increases were decreased by blockers of T-type Ca2+ channel and TRPA1, and by TRPA1-silencing. Immunoprecipitation suggested the coexistent of these channels in sensory neurons and RIN-14B. In mice with inflammation, mechanical hypersensitivity was suppressed by blockers of both channels. These data suggest that the interaction of Cav3.2 with TRPA1 in sensory neurons is enhanced via the augmentation of the activities of both channels under inflammatory conditions, indicating that both channels are therapeutic targets for inflammatory pain.

A suspected case of drug-induced tubulointerstitial nephritis by pilocarpine hydrochloride.

A 63-year-old man with pharyngeal cancer had been prescribed pilocarpine hydrochloride for xerostomia after concomitant chemoradiotherapy. After 6 months of taking pilocarpine hydrochloride, he was referred to our hospital due to gradually developing renal insufficiency. The patient underwent detailed urinalysis, blood chemistry analysis, immune-serology testing. A renal biopsy was also performed. He was diagnosed with chronic tubulointerstitial nephritis (TIN) caused by lymphocytic infiltration of the interstitium, tubular atrophy, and interstitial fibrotic changes. Infections, autoimmune diseases, and genetic factors were ruled out as causes of TIN; a drug-induced lymphocyte stimulation test confirmed that he had high stimulation index scores for pilocarpine hydrochloride and a normal range stimulation score for other supplements. These results indicated that the TIN could have been induced by pilocarpine hydrochloride. Drug discontinuation partly improved his renal function and tubule marker levels. To our knowledge, this is the first report of TIN following administration of pilocarpine hydrochloride. This finding could contribute to future treatment decisions for patients with TIN and those using pilocarpine hydrochloride.

Suppression of cell cycle progression by poly(ADP-ribose) polymerase inhibitor PJ34 in neural stem/progenitor cells.

Neural stem/progenitor cells (NSPCs) express higher levels of poly(ADP-ribose) polymerase 1 (PARP1) than mouse embryonic fibroblasts (MEFs). Inhibition of PARP induces the expression of several genes in the p53 signaling pathway, including p21, which is critical for cell cycle control at the G1/S phase, triggers apoptosis, and suppresses cell cycle progression in NSPCs. However, upon the up-regulation of p21, the cell cycle does not arrest at any specific phase. In the present study, the expression of genes specific to the G1/S and G2/M phases of the cell cycle were analyzed following treatment with PJ34 (N-[6-oxo-5,6-dihydro-phenanthridin-2-yl]-N,N-dimethylacetamide), an inhibitor of PARP. PJ34 treatment dramatically down-regulated cyclin B1 expression in NSPCs, but not in MEFs, which was confirmed by a promoter assay. Down-regulation of FoxM1 and B-MYB revealed that the down-regulation of cyclin B occurs at the transcriptional level. GADD45 was also specifically up-regulated in NSPCs. Taken together, the activation of p53 by PJ34 treatment in NSPCs induced changes in the expression of genes involved in the cell cycle. Fluorescence-activated cell sorting analysis revealed that PJ34 treatment suppressed G2/M to G1 progression in NSPCs, but not in MEFs. These data indicate that PJ34 treatment inhibits cyclin expression at the mRNA level and suppresses cell cycle progression in NSPCs.

Anticentromere Antibody-positive Scleroderma Renal Crisis Requiring Dialysis.

A 70-year-old man with prior Raynaud's phenomena developed hypertension and renal insufficiency. Raynaud's phenomena, finger skin thickening, interstitial lung disease, and positive anticentromere antibody findings indicated systemic sclerosis (SSc). Based on the presence of SSc, severe hypertension with rapidly progressive renal failure, and proliferative and obliterative arteriolar vasculopathy, scleroderma renal crisis (SRC) was diagnosed. Despite good blood pressure control with antihypertensive drugs, hemodialysis was initiated and could not be withdrawn owing to unimproved renal dysfunction. Although SRC in anticentromere antibody-positive limited cutaneous SSc is extremely rare, some patients may develop SRC, and their renal prognosis may be poor.

Prevalence and mortality of chronic kidney disease in lymphoma patients: A large retrospective cohort study.

In patients with lymphoma, an important issue that has been recognized is renal involvement, including glomerulonephritis, acute kidney injury, and lymphoma infiltrating the kidney. However, the prevalence and mortality of chronic kidney disease (CKD) have not been fully understood in lymphoma patients. This study aimed to evaluate the prevalence of CKD and its impact on mortality in those patients.This was a retrospective cohort study of 429 consecutive lymphoma patients who were admitted or regularly visited our hospital from January 2013 to October 2016. CKD was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m and/or proteinuria ≥ 1+ that was sustained for at least 3 months. The prevalence of CKD at enrollment was evaluated according to the modified CKD classification by Kidney Disease: Improving Global Outcomes (KDIGO) (eGFR and proteinuria category). Dipstick proteinuria was classified into 3 grades: A1 for - and ±; A2 for 1+ or 2+; and A3 for ≥3+. The eGFR (mL/min/1.73 m) was classified into 6 stages: G1 for ≥90, G2 for 60 to 89, G3a for 45 to 59, G3b for 30 to 44, G4 for 15 to 29, and G5 for <15. The cumulative mortality rate was estimated using the Kaplan-Meier method, with stratification into 2 groups based on the presence or absence of CKD. Furthermore, a multivariate Cox proportional hazards regression model was used to calculate the hazard ratio (HR) and its 95% confidence interval (CI) for all-cause mortality, after adjustments for age, sex, pathologic type, clinical stage of lymphoma, presence or absence of diabetes mellitus, hypertension, and cardiovascular disease.The mean follow-up period was 3.06 ±â€Š0.96 years, and the prevalence of CKD at study enrollment was 34.5%. The cumulative mortality rate was 20.7%, and was significantly higher in the CKD group than in the group without CKD (36.4% vs 18.0%, P = .02). Multivariate analysis found mortality to be significantly associated with CKD (HR 1.58; 95% CI, 1.01-2.46), and this association was the most robust with very high-risk CKD (HR 6.94; 95% CI, 2.50-17.33).The prevalence of CKD in lymphoma patients was high. CKD should be considered an independent risk factor for mortality among patients with lymphoma.

Possible involvement of transient receptor potential ankyrin 1 in Ca2+ signaling via T-type Ca2+ channel in mouse sensory neurons.

T-type Ca2+ channels and TRPA1 are expressed in sensory neurons and both are associated with pain transmission, but their functional interaction is unclear. Here we demonstrate that pharmacological evidence of the functional relation between T-type Ca2+ channels and TRPA1 in mouse sensory neurons. Low concentration of KCl at 15 mM (15K) evoked increases of intracellular Ca2+ concentration ([Ca2+ ]i ), which were suppressed by selective T-type Ca2+ channel blockers. RT-PCR showed that mouse sensory neurons expressed all subtypes of T-type Ca2+ channel. The magnitude of 15K-induced [Ca2+ ]i increase was significantly larger in neurons sensitive to allylisothiocyanate (AITC, a TRPA1 agonist) than in those insensitive to it, and in TRPA1-/- mouse sensory neurons. TRPA1 blockers diminished the [Ca2+ ]i responses to 15K in neurons sensitive to AITC, but failed to inhibit 40 mM KCl-induced [Ca2+ ]i increases even in AITC-sensitive neurons. TRPV1 blockers did not inhibit the 15K-induced [Ca2+ ]i increase regardless of the sensitivity to capsaicin. [Ca2+ ]i responses to TRPA1 agonist were enhanced by co-application with 15K. These pharmacological data suggest the possibility of functional interaction between T-type Ca2+ channels and TRPA1 in sensory neurons. Since TRPA1 channel is activated by intracellular Ca2+ , we hypothesize that Ca2+ entered via T-type Ca2+ channel activation may further stimulate TRPA1, resulting in an enhancement of nociceptive signaling. Thus, T-type Ca2+ channel may be a potential target for TRPA1-related pain.

Microwave-assisted synthesis of metallic nanostructures in solution.

Microwave (MW) rapid heating has received considerable attention as a new promising method for the one-pot synthesis of metallic nanostructures in solutions. In this concept, advantageous application of this method has been demonstrated by using some typical examples for the preparation of Ag, Au, Pt, and AuPd nanostructures. Not only spherical nanoparticles, but also single crystalline polygonal plates, sheets, rods, wires, tubes, and dendrites were prepared within a few minutes under MW heating. Morphologies and sizes of nanostructures could be controlled by changing various experimental parameters, such as the concentration of metallic salt and surfactant polymer, the chain length of the surfactant polymer, the solvent, and the reaction temperature. In general, nanostructures with smaller sizes, narrower size distributions, and a higher degree of crystallization were obtained under MW heating than those in conventional oil-bath heating. The origin of these characteristic features under MW irradiation is discussed in terms of thermal and non-thermal effects under MW irradiation.