Establishment of Immunodeficient Retinal Degeneration Model Mice and Functional Maturation of Human ESC-Derived Retinal Sheets after Transplantation

Increasing demand for clinical retinal degeneration therapies featuring human ESC/iPSC-derived retinal tissue and cells warrants proof-of-concept studies. Here, we established two mouse models of end-stage retinal degeneration with immunodeficiency, NOG-rd1-2J and NOG-rd10, and characterized disease progress and immunodeficient status. We also transplanted human ESC-derived retinal sheets into NOG-rd1-2J and confirmed their long-term survival and maturation of the structured graft photoreceptor layer, without rejection or tumorigenesis. We recorded light responses from the host ganglion cells using a multi-electrode array system; this result was consistent with whole-mount immunostaining suggestive of host-graft synapse formation at the responding sites. This study demonstrates an application of our mouse models and provides a proof of concept for the clinical use of human ESC-derived retinal sheets

NAADP-mediated Ca²⺠signalling in the mouse pancreatic acinar cell

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Health-Related Quality of Life in Patients on Home Oxygen Therapy with Telemonitoring

Home oxygen therapy (HOT) is an important treatment for patients with chronic respiratory diseases. Recently, telemonitoring of HOT has been become available. In the present study, we examined whether telemonitoring of HOT could improve health-related quality of life (HRQOL). Twelve patients receiving HOT participated in this study. The oxygen flow rates, use of the oxygen concentrator, and the values of percutaneous arterial oxygen saturation measured by each patient with a pulse oximeter were checked using a telemonitoring system for a period of one month. Interventions based on the results obtained were carried out in order to optimize oxygen use in this patient cohort. We evaluated the results of the SF-36 questionnaire before the initiation of telemonitoring and at 3 months after completion of the study. We identified significant improvements in SF-36 sub-scores after completion of this intervention. We conclude that telemonitoring may be a useful method to improve HRQOL

CD38 antigen, a key player in NAADP production and CCK responses in pancreatic exocrine cells

Meeting Abstrac

The ecto-enzyme CD38 is a nicotinic acid adenine dinucleotide phosphate (NAADP) synthase that couples receptor activation to Ca2+ mobilization from lysosomes in pancreatic acinar cells.

International audienceNicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca(2+)-mobilizing intracellular messenger and is linked to a variety of stimuli and cell surface receptors. However, the enzyme responsible for endogenous NAADP synthesis in vivo is unknown, and it has been proposed that another enzyme differing from ADP-ribosyl cyclase family members may exist. The ecto-enzyme CD38, involved in many functions as diverse as cell proliferation and social behavior, represents an important alternative. In pancreatic acinar cells, the hormone cholecystokinin (CCK) stimulates NAADP production evoking Ca(2+) signals by discharging acidic Ca(2+) stores and leading to digestive enzyme secretion. From cells derived from CD38(-/-) mice, we provide the first physiological evidence that CD38 is required for endogenous NAADP generation in response to CCK stimulation. Furthermore, CD38 expression in CD38-deficient pancreatic AR42J cells remodels Ca(2+)-signaling pathways in these cells by restoring Ca(2+) mobilization from lysosomes during CCK-induced Ca(2+) signaling. In agreement with an intracellular site for messenger synthesis, we found that CD38 is expressed in endosomes. These CD38-containing vesicles, likely of endosomal origin, appear to be proximal to lysosomes but not co-localized with them. We propose that CD38 is an NAADP synthase required for coupling receptor activation to NAADP-mediated Ca(2+) release from lysosomal stores in pancreatic acinar cells

Different renoprotective effects of luseogliflozin depend on the renal function at the baseline in patients with type 2 diabetes: A retrospective study during 12 months before and after initiation.

AimsThe safety and efficacy, particularly, the factors associated with the renal prognosis, were assessed over 12 months after the initiation of luseogliflozin therapy in Japanese patients with type 2 diabetes and renal impairment.MethodsIn total, 238 patients treated with luseogliflozin (2.5 mg, once daily) were studied as the safety analysis set. Two hundred and two subjects whose medication was continued over 12 months were investigated as the full analysis set. The subjects were divided into 3 groups based on the estimated glomerular filtration rate (eGFR): high eGFR (n = 49), normal eGFR (n = 116) and low eGFR (n = 37) groups.ResultsThe body weight, systolic blood pressure, HbA1c and urinary protein excretion gradually decreased from baseline in all eGFR groups. While the eGFR was significantly reduced from baseline in the high and normal eGFR groups, the eGFR did not significantly differ over time in the low eGFR group. There was no marked difference in the frequency of adverse events that were specific for SGLT2 inhibitors among the 3 groups in the safety analysis set.ConclusionsLuseogliflozin can preserve the renal function in the medium term in patients with type 2 diabetes and renal impairment without an increase in specific adverse events

Cytosolic [Ca2+] regulation of InsP3-evoked puffs

Inositol trisphosphate (InsP(3))-mediated puffs are fundamental building blocks of cellular Ca(2+) signalling, and arise through the concerted opening of clustered InsP(3) receptors (InsP(3)Rs) coordinated via Ca(2+)-induced Ca(2+) release. Although the Ca(2+) dependency of InsP(3)Rs has been extensively studied at the single channel level, little is known as to how changes in basal cytosolic [Ca(2+)] would alter dynamics of InsP(3)-evoked Ca(2+) signals in intact cells. To explore this question, we expressed Ca(2+)-permeable channels (nicotinic acetylcholine receptors) in the plasma membrane of voltage-clamped Xenopus oocytes to regulate cytosolic [Ca(2+)] by changing the electrochemical gradient for extracellular Ca(2+) entry, and imaged Ca(2+) liberation evoked by photolysis of caged InsP(3). Elevation of basal cytosolic [Ca(2+)] strongly increased the amplitude and shortened the latency of global Ca(2+) waves. In oocytes loaded with EGTA to localize Ca(2+) signals, the number of sites at which puffs were observed, and the frequency and latency of puffs were strongly dependent on cytosolic [Ca(2+)], whereas puff amplitudes were only weakly affected. Our result indicates that basal cytosolic [Ca(2+)] strongly affects the triggering of puffs, but has less effect on puffs once they have been initiated

The clinical characteristics of the full analysis set at baseline.

The clinical characteristics of the full analysis set at baseline.</p