Inositol 1,4,5-trisphosphate receptor and dSTIM function in Drosophila insulin-producing neurons regulates systemic intracellular calcium homeostasis and flight

Calcium (Ca2+) signaling is known to regulate the development, maintenance and modulation of activity in neuronal circuits that underlie organismal behavior. In Drosophila, intracellular Ca2+ signaling by the inositol 1,4,5-trisphosphate receptor and the store-operated channel (dOrai) regulates the formation and function of neuronal circuits that control flight. Here, we show that restoring InsP3R activity in insulin-producing neurons of flightless InsP3R mutants (itpr) during pupal development can rescue systemic flight ability. Expression of the store operated Ca2+ entry (SOCE) regulator dSTIM in insulin-producing neurons also suppresses compromised flight ability of InsP3R mutants suggesting that SOCE can compensate for impaired InsP3R function. Despite restricted expression of wild-type InsP3R and dSTIM in insulin-producing neurons, a global restoration of SOCE and store Ca2+ is observed in primary neuronal cultures from the itpr mutant. These results suggest that restoring InsP3R-mediated Ca2+ release and SOCE in a limited subset of neuromodulatory cells can influence systemic behaviors such as flight by regulating intracellular Ca2+ homeostasis in a large population of neurons through a non-cell-autonomous mechanism

Compensation of inositol 1,4,5-trisphosphate receptor function by altering sarco-endoplasmic reticulum calcium ATPase activity in the Drosophila flight circuit

Ionic Ca2+ functions as a second messenger to control several intracellular processes. It also influences intercellular communication. The release of Ca2+ from intracellular stores through the inositol 1,4,5-trisphosphate receptor (InsP3R) occurs in both excitable and nonexcitable cells. In Drosophila, InsP3R activity is required in aminergic interneurons during pupal development for normal flight behavior. By altering intracellular Ca2+ and InsP3 levels through genetic means, we now show that signaling through the InsP3R is required at multiple steps for generating the neural circuit required in air puff-stimulated Drosophila flight. Decreased Ca2+ release in aminergic neurons during development of the flight circuit can be compensated by reducing Ca2+ uptake from the cytosol to intracellular stores. However, this mode of increasing intracellular Ca2+ is insufficient for maintenance of flight patterns over time periods necessary for normal flight. Our study suggests that processes such as maintenance of wing posture and formation of the flight circuit require InsP3 receptor function at a slow timescale and can thus be modulated by altering levels of cytosolic Ca2+ and InsP3. In contrast, maintenance of flight patterns probably requires fast modulation of Ca2+ levels, in which the intrinsic properties of the InsP3R play a pivotal role

Interplay of spherical closed shells and N/Z asymmetry in quasifission dynamics

Background: Quasifission (QF) has gained tremendous importance in heavy-ion nuclear physics research because of its strong influence on superheavy-element synthesis. Collisions involving closed-shell nuclei in the entrance channel are found to affect the QF reaction mechanism. Hence, it is important to improve the understanding of their effect on QF. Apart from that, some recent studies show that the difference in N/Z of reaction partners influences the reaction dynamics. Since heavier doubly magic nuclei have different N/Z than lighter doubly magic nuclei, it is important to understand the effect of N/Z mismatch as well as the effect of shell closures.The authors acknowledge the Australian Research Council for support through Discovery Grants No. DP140101337, No. DP160101254, No. FL110100098, No. DE140100784, No. FT120100760, and No. DP170102318

Ossifying renal tumor of infancy-a case report

Introduction: An extremely rare pediatric renal tumor, ossifying renal tumor of infancy (ORTI) usually presents in male infants with intermittent episodes of painless gross hematuria. The tumor is benign and surgically treatable. Imaging typically shows a preserved renal outline with a calcified intrapelvic mass. Microscopically, these lesion shows varying components of osteoid, osteoblastic cells, and spindle cells. However, the etiology is unclear. Surgical excision is curative and recurrence or malignant disease is unheard of.We report a case of ORTI and review the literature to assess the clinicopathological features of this unusual neoplasm. Case presentation: A 5-month-old boy was admitted with isolated gross hematuria. Ultrasound showed a well-defined solid mass in the lower pole of right kidney that was heterogenous on CT (Computed Tomography) but without calcifications. Nephrectomy was done and histopathology showed an ossified core surrounded by a spindle cell component confirming the diagnosis of an ORTI. Conclusion: ORTI is a rare benign pediatric renal tumor with some typical clinical, radiological and pathological features. A male infant with painless intermittent macroscopic hematuria with an endophytic calcified renal mass involving the calyceal system, points towards an ORTI as the possible diagnosis

Treatment Outcomes of Ranibizumab versus Aflibercept for Neovascular Age-Related Macular Degeneration: Data from the Fight Retinal Blindness! Registry

PURPOSE Ranibizumab and aflibercept are both approved for the treatment of neovascular age-related macular degeneration (nAMD). Herein, we compare the 3-year treatment outcomes of the 2 in routine clinical practice. DESIGN Retrospective analysis of data from a prospectively designed observational outcomes registry, the Fight Retinal Blindness! PROJECT PARTICIPANTS Treatment-naïive eyes starting nAMD treatment from December 1, 2013 through December 31, 2015, with either ranibizumab or aflibercept that were tracked in the registry. METHODS Visual acuity (VA) was analyzed annually in completers (those who completed 3 years of treatment) and in all eyes (completers, noncompleters, and those who switched treatment ). MAIN OUTCOME MEASURES The primary outcome was mean change in VA (number of letters read on a logarithm of the minimum angle of resolution chart). RESULTS A total of 965 eyes of 897 patients (ranibizumab, 499 eyes [469 patients]; aflibercept, 466 eyes [432 patients) were identified. The mean VA and the type of the choroidal neovascularization (CNV) at the start of treatment were similar between the 2 groups. The group receiving ranibizumab was older. The crude mean VA change of +1.5 letters (95% confidence interval [CI], 0-3.1 letters) in the ranibizumab group and of +1.6 letters (95% CI, -0.2 to 3.3 letters; P = 0.97) in the aflibercept group at 3 years in all eyes was similar, as was the adjusted mean VA change, +0.3 letters (95% CI, -1.5 to 2.0 letters) versus +1.0 letters (95% CI, -0.7 to 2.8 letters; P = 0.66). Both treatment groups received a median of 18 injections from a median of 21 clinical visits. The adjusted proportion of clinical visits when the CNV was graded active over 3 years was similar between ranibizumab (43%) and aflibercept (51%; P = 0.9). More switches from ranibizumab to aflibercept (P < 0.001) took place than vice versa. The proportion of eyes that did not complete 3 years of treatment in each of the group was similar (P = 0.21). CONCLUSIONS Neither ranibizumab nor aflibercept was superior to the other in terms of VA outcomes and treatment frequency at 3 years for nAMD

Incidence and Outcomes of Infectious and Noninfectious Endophthalmitis after Intravitreal Injections for Age-Related Macular Degeneration

International audiencePURPOSE:To assess the incidence, cumulative rate, and long-term outcomes of infectious and noninfectious endophthalmitis after intravitreal injections (IVTs) of anti-vascular endothelial growth factor (VEGF) agents.DESIGN:Database study, prospectively designed.PARTICIPANTS:Treatment-naïve eyes with neovascular age-related macular degeneration (nAMD) tracked by the Fight Retinal Blindness! (FRB!) registry that commenced anti-VEGF therapy between January 1, 2006, and November 30, 2016.METHODS:Cumulative rate of endophthalmitis and survival curves were measured using Cox-proportional hazards models. Locally weighted scatterplot smoothing curves were used to display visual acuity (VA).MAIN OUTCOME MEASURES:Incidence and cumulative rate of endophthalmitis, and change in VA 12 months after endophthalmitis.RESULTS:Infectious endophthalmitis developed in 18 of 88 150 injections (1/4897 injections [0.020%]; 95% confidence interval [CI], 0.012-0.032) with no difference found between types of anti-VEGF medications (P = 0.896). The cumulative rate of infectious endophthalmitis per patient was 0.055%, 0.183%, 0.360%, 0.360%, 0.555%, and 0.843% after 10, 20, 30, 40, 50, and 60 IVTs, respectively. However, the "risk" of infectious endophthalmitis did not increase with each successive injection (P = 0.202). Noninfectious endophthalmitis developed in 11 of 88 150 injections (1/8013 injections [0.012%]; 95% CI, 0.006-0.022). The cumulative rate of noninfectious endophthalmitis per patient was 0.087% and 0.228% after 10 and 20 IVTs, respectively, and then remained stable up to 60 IVTs. The incidence of noninfectious endophthalmitis was higher for bevacizumab (8/9931, 0.081%) compared with ranibizumab (3/54 776, 0.005%; P = 0.005) and aflibercept (0/23 425; P = 0.016), and no differences were observed between ranibizumab and aflibercept (P = 1.0). The 12-month VA in infectious and noninfectious endophthalmitis was within ±2 lines of before endophthalmitis in 53% and 75% of eyes, respectively; a loss >2 lines was observed in 31% and 25% of eyes, respectively.CONCLUSIONS:The incidences of infectious and noninfectious endophthalmitis after IVT were low, and the risk did not increase with each successive injection. We found higher rates of noninfectious endophthalmitis with bevacizumab compared with ranibizumab or aflibercept. Three quarters of cases with infectious and two thirds of cases with noninfectious endophthalmitis retained vision within 10 letters of the pre-endophthalmitis level

A Multicountry Comparison of Real-World Management and Outcomes of Polypoidal Choroidal Vasculopathy: Fight Retinal Blindness! Cohort

PURPOSE To compare the 12-month real-world visual and disease activity outcomes of eyes with polypoidal choroidal vasculopathy (PCV) treated with a combination of photodynamic therapy (PDT) and anti-vascular endothelial growth factor (VEGF) injections (combination group) versus those eyes treated with anti-VEGF monotherapy alone with rescue PDT being used as required (monotherapy group). DESIGN Database comparative observational study. PARTICIPANTS Eyes with PCV as graded in the Fight Retinal Blindness! database from Australia, New Zealand, Singapore, and Switzerland. METHODS Clinical information from a multisite, international registry of neovascular age-related macular degeneration was analyzed with an intention-to-treat approach. MAIN OUTCOME MEASURES Primary outcome measure was the change in visual acuity in logMAR letters over 12 months between the two groups analyzed with intention-to-treat approach. RESULTS Forty-one and 152 eyes received combination therapy and anti-VEGF monotherapy, respectively. All anti-VEGF agents were pooled, and bevacizumab represented 66.1% of injections administered. The adjusted mean change in visual acuity between the combination group and monotherapy group at 12 months was +16.9 letters (95% confidence interval [CI], 10.6-23.3 letters) and +8.2 letters (95% CI, 5.2-11.3 letters), respectively (P = 0.02). Proportion of inactive lesions and mean time to inactivity was 85.3% and 80.7 days (95% CI, 62.8-98.5 days), respectively, in the combination group compared with 76.8% and 150.4 days (95% CI, 132.8-168.0 days), respectively, in the monotherapy group (P = 0.01). The mean number of injections of anti-VEGF agent between the combination and monotherapy groups was 4.3 injections (95% CI, 3.6-5.2 injections) and 6.4 injections (95% CI, 5.9-6.9 injections), respectively (P = 0.01). CONCLUSIONS The real-world outcomes for treatment of PCV showed larger gains in vision, higher proportion of inactive lesions, quicker time to inactivity, and fewer injections administered in the combination group compared with the monotherapy group. These findings are consistent with current evidence reporting the advantages of combination therapy for PCV