Optogenetic stimulation of vagal nerves for enhanced glucose-stimulated insulin secretion and ß cell proliferation.

The enhancement of insulin secretion and of the proliferation of pancreatic ß cells are promising therapeutic options for diabetes. Signals from the vagal nerve regulate both processes, yet the effectiveness of stimulating the nerve is unclear, owing to a lack of techniques for doing it so selectively and prolongedly. Here we report two optogenetic methods for vagal-nerve stimulation that led to enhanced glucose-stimulated insulin secretion and to ß cell proliferation in mice expressing choline acetyltransferase-channelrhodopsin 2. One method involves subdiaphragmatic implantation of an optical fibre for the photostimulation of cholinergic neurons expressing a blue-light-sensitive opsin. The other method, which suppressed streptozotocin-induced hyperglycaemia in the mice, involves the selective activation of vagal fibres by placing blue-light-emitting lanthanide microparticles in the pancreatic ducts of opsin-expressing mice, followed by near-infrared illumination. The two methods show that signals from the vagal nerve, especially from nerve fibres innervating the pancreas, are sufficient to regulate insulin secretion and ß cell proliferation.

Phagocytosis by macrophages promotes pancreatic ß cell mass reduction after parturition in mice.

Elucidating the mechanism(s) modulating appropriate tissue size is a critical biological issue. Pancreatic ß cells increase during pregnancy via cellular proliferation, but how ß cells promptly decrease to the original amount after parturition remains unclear. Herein, we demonstrate the role and mechanism of macrophage accumulation in this process. In the final stage of pregnancy, HTR1D signaling upregulates murine ß cell CXCL10, thereby promoting macrophage accumulation in pancreatic islets via the CXCL10-CXCR3 axis. Blocking this mechanism by administering an HTR1D antagonist or the CXCR3 antibody and depleting islet macrophages inhibited postpartum ß cell mass reduction. ß cells engulfed by macrophages increased in postpartum islets, but Annexin V administration suppressed this engulfment and the postpartum ß cell mass reduction, indicating the accumulated macrophages to phagocytose ß cells. This mechanism contributes to both maintenance of appropriate ß cell mass and glucose homeostasis promptly adapting to reduced systemic insulin demand after parturition.

A highly sensitive strategy for monitoring real-time proliferation of targeted cell types in vivo.

Cell proliferation processes play pivotal roles in timely adaptation to many biological situations. Herein, we establish a highly sensitive and simple strategy by which time-series showing the proliferation of a targeted cell type can be quantitatively monitored in vivo in the same individuals. We generate mice expressing a secreted type of luciferase only in cells producing Cre under the control of the Ki67 promoter. Crossing these with tissue-specific Cre-expressing mice allows us to monitor the proliferation time course of pancreatic ß-cells, which are few in number and weakly proliferative, by measuring plasma luciferase activity. Physiological time courses, during obesity development, pregnancy and juvenile growth, as well as diurnal variation, of ß-cell proliferation, are clearly detected. Moreover, this strategy can be utilized for highly sensitive ex vivo screening for proliferative factors for targeted cells. Thus, these technologies may contribute to advancements in broad areas of biological and medical research.

Insulin allergy manifesting soon after COVID-19 vaccination (BNT162b2).

We experienced a case with insulin allergy which manifested soon after COVID-19 vaccination.

Roles of FoxM1-driven basal ß-cell proliferation in maintenance of ß-cell mass and glucose tolerance during adulthood.

AIMS/INTRODUCTION: Whether basal ß-cell proliferation during adulthood is involved in maintaining sufficient ß-cell mass, and if so, the molecular mechanism(s) underlying basal ß-cell proliferation remain unclear. FoxM1 is a critical transcription factor which is known to play roles in 'adaptive' ß-cell proliferation, which facilitates rapid increases in ß-cell mass in response to increased insulin demands. Therefore, herein we focused on the roles of ß-cell FoxM1 in 'basal' ß-cell proliferation under normal conditions and in the maintenance of sufficient ß-cell mass as well as glucose homeostasis during adulthood. MATERIALS AND METHODS: FoxM1 deficiency was induced specifically in ß-cells of 8-week-old mice, followed by analyzing its short- (2 weeks) and long- (10 months) term effects on ß-cell proliferation, ß-cell mass, and glucose tolerance. RESULTS: FoxM1 deficiency suppressed ß-cell proliferation at both ages, indicating critical roles of FoxM1 in basal ß-cell proliferation throughout adulthood. While short-term FoxM1 deficiency affected neither ß-cell mass nor glucose tolerance, long-term FoxM1 deficiency suppressed ß-cell mass increases with impaired insulin secretion, thereby worsening glucose tolerance. In contrast, the insulin secretory function was not impaired in islets isolated from mice subjected to long-term ß-cell FoxM1 deficiency. Therefore, ß-cell mass reduction is the primary cause of impaired insulin secretion and deterioration of glucose tolerance due to long-term ß-cell FoxM1 deficiency. CONCLUSIONS: Basal low-level proliferation of ß-cells during adulthood is important for maintaining sufficient ß-cell mass and good glucose tolerance and ß-cell FoxM1 underlies this mechanism. Preserving ß-cell FoxM1 activity may prevent the impairment of glucose tolerance with advancing age.

Early neurosyphilis presenting with multiple cranial nerve palsies: A case report of management by combined penicillin-corticosteroid treatment.

Early neurosyphilis commonly appears in basilar meninges, and its meningeal inflammation can spread to neighboring cranial nerves, resulting in some cranial nerve palsies. Herein, we report a case of a 51-year-old man who presented with right peripheral facial nerve palsy. His symptoms completely disappeared with prednisolone monotherapy without antibiotics use and were not exacerbated during clinical treatment. However, 2 months after remission of seventh cranial neuropathy, fifth and eighth cranial neuropathies appeared on the right side. Serologic tests for syphilis were revealed to be abnormal. Finally, the patient was diagnosed with early neurosyphilis with multiple cranial palsies. His neurological symptoms were markedly improved by combined penicillin-corticosteroid treatment. Systemic corticosteroids could be effective as adjunctive therapy to ameliorate neurological sequelae in early neurosyphilis.

Retained Plasticity and Substantial Recovery of Rod-Mediated Visual Acuity at the Visual Cortex in Blind Adult Mice with Retinal Dystrophy.

In patients born blind with retinal dystrophies, understanding the critical periods of cortical plasticity is important for successful visual restoration. In this study, we sought to model childhood blindness and investigate the plasticity of visual pathways. To this end, we generated double-mutant (Pde6ccpfl1/cpfl1Gnat1IRD2/IRD2) mice with absent rod and cone photoreceptor function, and we evaluated their response for restoring rod (GNAT1) function through gene therapy. Despite the limited effectiveness of gene therapy in restoring visual acuity in patients with retinal dystrophy, visual acuity was, unexpectedly, successfully restored in the mice at the level of the primary visual cortex in this study. This success in visual restoration, defined by changes in the quantified optokinetic response and pattern visually evoked potential, was achieved regardless of the age at treatment (up to 16 months). In the contralateral visual cortex, cortical plasticity, tagged with light-triggered transcription of Arc, was also restored after the treatment in blind mice carrying an Arc promoter-driven reporter gene, dVenus. Our results demonstrate the remarkable plasticity of visual circuits for one of the two photoreceptor mechanisms in older as well as younger mice with congenital blindness due to retinal dystrophies.

A simulated car-driving study on the effects of acute administration of levocetirizine, fexofenadine, and diphenhydramine in healthy Japanese volunteers.

OBJECTIVE: Antihistamines are often used for treating allergic rhinitis. However, many older antihistamines cause sedative side effects. The sedative effects of antihistamines on car-driving have been investigated. This has not been investigated for levocetirizine, a new-generation antihistamine, in Asian populations, and so we evaluated its sedative effects in healthy Japanese subjects. METHODS: In this double-blind, placebo-controlled, four-way crossover study, healthy volunteers received single doses of levocetirizine 5 mg, fexofenadine 60 mg, diphenhydramine 50 mg, and placebo at intervals of at least 6 days. Simple brake reaction time and choice brake reaction time task (CBRT), a lateral tracking (LT) task, and a multiple task, a mixture of CBRT and LT task, were used to compare driving performance between the four drugs. Subjective sedation was also assessed. RESULTS: The simple brake reaction time and CBRT, and the CBRT component of the multiple task, did not show any significant differences between the drugs. In contrast, the LT, both as a single parameter and as a component of the multiple task, showed significant differences between diphenhydramine and the newer-generation antihistamines in a manner that corresponds with subjective sedation. CONCLUSIONS: Levocetirizine and fexofenadine did not impair psychomotor performance in subjects performing simulated car-driving tasks, while diphenhydramine did impair psychomotor performance in the subjects. Copyright © 2016 John Wiley & Sons, Ltd.