Retro-mode imaging of fibrovascular membrane in proliferative diabetic retinopathy after intravitreal bevacizumab injection

The F10 is a new commercially available scanning laser confocal ophthalmoscope (SLO) that can perform multiple functions. We determined the usefulness of noninvasive evaluation of proliferative diabetic retinopathy (PDR) pathologies before and after intravitreal injection of bevacizumab (IVB) using the new indirect viewing system of the retro-mode function of the F10 SLO, and compared the images histologically with surgically excised fibrovascular membrane from two cases. In PDR, neovascular vessels in fibrovascular membrane were clearly seen with the retro-mode, even after IVB and without blood flow. The F10 SLO may be useful in evaluating neovascular vessels in fibrovascular membrane in PDR and for determining the precise retinal changes in diabetic retinopathy

アイヌの千島交易と松前藩 ―『蝦夷島奇観』と『蝦夷見聞記』に描かれたニウェンをめぐって―

departmental bulletin pape

Alteration of primary afferent activity following inferior alveolar nerve transection in rats

<p>Abstract</p> <p>Background</p> <p>In order to evaluate the neural mechanisms underlying the abnormal facial pain that may develop following regeneration of the injured inferior alveolar nerve (IAN), the properties of the IAN innervated in the mental region were analyzed.</p> <p>Results</p> <p>Fluorogold (FG) injection into the mental region 14 days after IAN transection showed massive labeling of trigeminal ganglion (TG). The escape threshold to mechanical stimulation of the mental skin was significantly lower (i.e. mechanical allodynia) at 11-14 days after IAN transection than before surgery. The background activity, mechanically evoked responses and afterdischarges of IAN Aδ-fibers were significantly higher in IAN-transected rats than naive. The small/medium diameter TG neurons showed an increase in both tetrodotoxin (TTX)-resistant (TTX-R) and -sensitive (TTX-S) sodium currents (<it>I</it>_Na) and decrease in total potassium current, transient current (<it>I</it>_A) and sustained current (<it>I</it>_K) in IAN-transected rats. The amplitude, overshoot amplitude and number of action potentials evoked by the depolarizing pulses after 1 μM TTX administration in TG neurons were significantly higher, whereas the threshold current to elicit spikes was smaller in IAN-transected rats than naive. Resting membrane potential was significantly smaller in IAN-transected rats than that of naive.</p> <p>Conclusions</p> <p>These data suggest that the increase in both TTX-S <it>I</it>_Naand TTX-R <it>I</it>_Naand the decrease in <it>I</it>_Aand <it>I</it>_kin small/medium TG neurons in IAN-transected rats are involved in the activation of spike generation, resulting in hyperexcitability of Aδ-IAN fibers innervating the mental region after IAN transection.</p

Magma Plumbing System at Izu-Oshima Volcano, Japan: Constraints From Petrological and Geochemical Analyses

The Izu-Oshima volcano is one of the most active volcanoes in Japan, and has generated relatively large-scale eruptions every 30–40 years for the past 200 years. As more than 30 years have passed since the last eruptions in 1986–87, volcanic activity is expected to resume in the near future. To help elucidate the current and future state of the volcano’s magma system, the temporal evolution of the recent magma plumbing system was investigated through a petrological and geochemical analysis of its basaltic lavas and pyroclastics (&lt;∼53 wt.% of SiO2) that were erupted during the last ∼1.5 kyr. The basaltic products have variable phenocryst contents, ranging from ∼0 to ∼20 vol.%, and phenocryst-bearing samples commonly contain plagioclase, orthopyroxene, and clinopyroxene phenocrysts. The whole-rock compositions are significantly scattered in the Harker variation diagrams, suggesting that the compositional diversity was established by at least two independent magmatic processes. The application of principal component analysis on the whole-rock major element data suggests that one magmatic process was crystal fractionation of crystal-poor magmas, and the other process was either plagioclase accumulation or mixing of plagioclase-rich magmas. Based on this observation, and combined with the petrological analysis and previous geophysical studies, we propose that aphyric magmas, stored in an 8–10 km-deep magma chamber, progressively differentiated over time from the 7th to 20th century. Furthermore, the compositional variations in basalts resulted from the mixing of the differentiating aphyric magmas with variable proportions of porphyritic magmas derived from a 13–18 km-deep magma chamber. Because recent eruptions have been triggered by the ascent of porphyritic magma from the 13–18 km-deep magma chamber, and its injection into the 8–10 km-deep magma chamber, it is important to monitor the deeper magma chamber to predict future volcanic activity

Succinate Increases in the Vitreous Fluid of Patients With Active Proliferative Diabetic Retinopathy

Purpose: To examine vitreous succinate levels from proliferative diabetic retinopathy (PDR) patients and ascertain their association with PDR activity. Design: Comparative case series. Methods: A total of 81 eyes of 72 PDR patients were divided into active PDR (22 eyes), quiescent PDR (21 eyes), and active PDR with intravitreal bevacizumab injection (38 eyes). Twenty epiretinal membrane (ERM) patients (21 eyes) served as controls. Results: Mean vitreous succinate levels were 1.27 μM in ERM and 2.20 μM in PDR, with the differences statistically significant (P = .03). When comparing mean vitreous succinate levels (active PDR: 3.32 μM; quiescent PDR: 1.02 μM; active PDR with intravitreal bevacizumab injection: 1.20 μM), significant differences were found between active and quiescent PDR (P < .01) and between active PDR and active PDR with intravitreal bevacizumab injection (P < .01). Even though succinate levels were low, retinopathy activities were very high in patients with active PDR with intravitreal bevacizumab injection. Mean vitreous vascular endothelial growth factor (VEGF) levels (active PDR: 1696 pg/mL; quiescent PDR: 110 pg/mL; active PDR with intravitreal bevacizumab injection: n.d.) were similar to previous reports. Mean vitreous erythropoietin levels (active PDR: 703 mIU/mL; quiescent PDR: 305 mIU/mL; active PDR with intravitreal bevacizumab injection: 1562 mIU/mL) suggested very high retinopathy activities in patients with active PDR with intravitreal bevacizumab injection. Conclusions: Succinate, like VEGF, may be an angiogenic factor that is induced by ischemia in PDR. Although succinate is reported to promote VEGF expression, VEGF inhibition decreases succinate. Thus, VEGF, via a positive feedback mechanism, may regulate succinate

RETINAL BLOOD FLOW LEVELS MEASURED BY LASER SPECKLE FLOWGRAPHY IN PATIENTS WHO RECEIVED INTRAVITREAL BEVACIZUMAB INJECTION FOR MACULAR EDEMA SECONDARY TO CENTRAL RETINAL VEIN OCCLUSION

Purpose: To report retinal blood flow levels measured by Laser speckle flowgraphy in three patients after they received an intravitreal bevacizumab injection (IVB) for macular edema secondary to central retinal vein occlusion (CRVO). Methods: Three patients (3 eyes) being treated with IVB (1.25 mg/0.05 mL) for secondary macular edema of CRVO were examined. Laser speckle flowgraphy analyses of the blood flow were based on the examinations of mean blur rate (MBR) at the major vessels of the optic disk. Central retinal thickness (CRT) was measured by optical coherence tomography using Macular Cube 512 128 scanning protocol. Results: After the first IVB, Case 1 exhibited an increase in MBR and decrease in CRT. After 4months, an additional injectionwas required because of a subsequentMBR decrease and CRT increase, which led to an increase inMBR and decrease in CRT similar to that observed after the first treatment. Subsequently, blood flow has continued to improve without additional IVB. Macular edema recurrence in Case 2 led to 3 further IVBs over a 6-month period. Although increases inMBRanddecreases inCRTwerenoted,MBRvalues tendedtodeclineafter eachIVB. In Case 3, macular edema recurrence led to 5 additional IVBs being carried out within a 1-year period. Continuous MBR increases and CRT decreases were observed in the patient after each IVB. By measuringMBR using laser speckle flowgraphy,wemay predict the prognosis of CRVO. Conclusion: Mean blur rate increases after IVB were confirmed by laser speckle flowgraphy in three patients. Even though CRVO pathology backgrounds can vary, laser speckle flowgraphy may be useful in both determining the CRVO prognosis and in evaluating treatment efficacy

Receptor ligand-triggered resistance to alectinib and its circumvention by Hsp90 inhibition in EML4-ALK lung cancer cells

Alectinib is a new generation ALK inhibitor with activity against the gatekeeper L1196M mutation that showed remarkable activity in a phase I/II study with echinoderm microtubule associated protein-like 4 (EML4) - anaplastic lymphoma kinase (ALK) non-small cell lung cancer (NSCLC) patients. However, alectinib resistance may eventually develop. Here, we found that EGFR ligands and HGF, a ligand of the MET receptor, activate EGFR and MET, respectively, as alternative pathways, and thereby induce resistance to alectinib. Additionally, the heat shock protein 90 (Hsp90) inhibitor suppressed protein expression of ALK, MET, EGFR, and AKT, and thereby induced apoptosis in EML4-ALK NSCLC cells, even in the presence of EGFR ligands or HGF. These results suggest that Hsp90 inhibitors may overcome ligand-triggered resistance to new generation ALK inhibitors and may result in more successful treatment of NSCLC patients with EML4-ALK

Influence of Ovariectomy on Bone Turnover and Trabecular Bone Mass in Mature Cynomolgus Monkeys

Purpose: To examine the influence of ovariectomy (OVX) on bone turnover and trabecular bone mass at the 3 clinically important skeletal sites in mature cynomolgus monkeys. Materials and Methods: Six female cynomolgus monkeys, aged 17-21 years, were randomized into 2 groups by the stratified weight: the OVX and sham-operation groups (n = 3 in each group). The experimental period was 16 months. Lumbar bone mineral density (BMD) in vivo and serum and urinary bone turnover markers were longitudinally measured, and peripheral quantitative computed tomographic and bone histomorphometric analyses were performed on trabecular bone of the lumbar vertebra, femoral neck, and distal radius at the end of the experiment. Results: OVX induced in a reduction in lumbar BMD compared with the sham controls and the baseline, as a result of increased serum levels of bonespecific alkaline phosphatase and urinary levels of cross-lined N- and C-terminal telopeptides of type I collagen. Furthermore, OVX induced reductions in trabecular volumetric BMD and trabecular bone mass compared with the sham controls, with increased bone formation rate at the lumbar vertebra, femoral neck, and distal radius. Conclusion: The results indicated that OVX in mature cynomolgus monkeys (17-21 years of age) increased bone turnover and induced trabecular bone loss at the three skeletal sites compared with the sham controls. Thus, mature cynomolgus monkeys could be utilized for preclinical studies to examine the effects of interventions on bon

Transient IGF-1R inhibition combined with osimertinib eradicates AXL-low expressing EGFR mutated lung cancer

Drug tolerance is the basis for acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) including osimertinib, through mechanisms that still remain unclear. Here, we show that while AXL-low expressing EGFR mutated lung cancer (EGFRmut-LC) cells are more sensitive to osimertinib than AXL-high expressing EGFRmut-LC cells, a small population emerge osimertinib tolerance. The tolerance is mediated by the increased expression and phosphorylation of insulin-like growth factor-1 receptor (IGF-1R), caused by the induction of its transcription factor FOXA1. IGF-1R maintains association with EGFR and adaptor proteins, including Gab1 and IRS1, in the presence of osimertinib and restores the survival signal. In AXL-low-expressing EGFRmut-LC cell-derived xenograft and patient-derived xenograft models, transient IGF-1R inhibition combined with continuous osimertinib treatment could eradicate tumors and prevent regrowth even after the cessation of osimertinib. These results indicate that optimal inhibition of tolerant signals combined with osimertinib may dramatically improve the outcome of EGFRmut-LC