HIF-1α-dependent upregulation of angiogenic factors by mechanical stimulation in retinal pigment epithelial cells.

Mechanical stimulation as a mimic of drusen formation in the eye increases the expression of angiogenic factors in retinal pigment epithelial (RPE) cells, but the underlying molecular mechanisms remain unclear. We investigated and characterized the effects of mechanical stimulation on the expression of angiogenic factors in RPE cells both in vitro and in a mouse model. Mechanical stimulation increased the expression of vascular endothelial growth factor (VEGF, encoded by VEGFA) and other angiogenesis-related genes in cultured RPE1 cells. The presence of hypoxia-inducible factor 1α (HIF-1α, encoded by HIF1A) was also increased, and both knockdown of HIF-1α and treatment with the HIF-1α inhibitor CAY10585 attenuated the effect of mechanical stimulation on angiogenesis factor gene expression. Signaling by the tyrosine kinase SRC and p38 mitogen-activated protein kinase was involved in HIF-1α activation and consequent angiogenesis-related gene expression induced by mechanical stimulation. Our results suggest that SRC-p38 and HIF-1α signaling are involved in the upregulation of angiogenic factors in RPE cells by mechanical stimulation. Such in vivo suppression of upregulated expression of angiogenesis-related genes by pharmacological inhibitors of HIF-1α suggests a new potential approach to the treatment of age-related macular degeneration.

Mutual oligosynaptic inhibition of group Ia afferents between the anterior and posterior parts of the deltoid in humans.

The anterior (DA) and posterior parts of the deltoid (DP) show alternating contraction during shoulder flexion and extension movements. It is expected that an inhibitory spinal reflex between the DA and DP exists. In this study, spinal reflexes between the DA and DP were examined in healthy human subjects using post-stimulus time histogram (PSTH) and electromyogram averaging (EMG-A). Electrical conditioning stimulation was delivered to the axillary nerve branch that innervates the DA (DA nerve) and DP (DP nerve) with the intensity below the motor threshold. In the PSTH study, the stimulation to the DA and DP nerves inhibited (decrease in the firing probability) 31 of 54 DA motor units and 31 of 51 DP motor units. The inhibition was not provoked by cutaneous stimulation. The central synaptic delay of the inhibition between the DA and DP nerves was 1.5 ± 0.5 ms and 1.4 ± 0.4 ms (mean ± SD) longer than those of the homonymous facilitation of the DA and DP, respectively. In the EMG-A study, conditioning stimulation to the DA and DP nerves inhibited the rectified and averaged EMG of the DP and DA, respectively. The inhibition diminished with tonic vibration stimulation to the DA and DP and recovered 20-30 min after vibration removal. These findings suggest that oligo(di or tri)-synaptic inhibition mediated by group Ia afferents between the DA and DP exists in humans.

The Rax homeoprotein in Müller glial cells is required for homeostasis maintenance of the postnatal mouse retina.

Müller glial cells, which are the most predominant glial subtype in the retina, play multiple important roles, including the maintenance of structural integrity, homeostasis, and physiological functions of the retina. We have previously found that the Rax homeoprotein is expressed in postnatal and mature Müller glial cells in the mouse retina. However, the function of Rax in postnatal and mature Müller glial cells remains to be elucidated. In the current study, we first investigated Rax function in retinal development using retroviral lineage analysis and found that Rax controls the specification of late-born retinal cell types, including Müller glial cells in the postnatal retina. We next generated Rax tamoxifen-induced conditional KO (Rax iCKO) mice, where Rax can be depleted in mTFP-labeled Müller glial cells upon tamoxifen treatment, by crossing Raxflox/flox mice with Rlbp1-CreERT2 mice, which we have produced. Immunohistochemical analysis showed a characteristic of reactive gliosis and enhanced gliosis of Müller glial cells in Rax iCKO retinas under normal and stress conditions, respectively. We performed RNA-seq analysis on mTFP-positive cells purified from the Rax iCKO retina and found significantly reduced expression of suppressor of cytokinesignaling-3 (Socs3). Reporter gene assays showed that Rax directly transactivates the Socs3 promoter. We observed decreased expression of Socs3 in Müller glial cells of Rax iCKO retinas by immunostaining. Taken together, the present results suggest that Rax suppresses inflammation in Müller glial cells by transactivating Socs3. This study sheds light on the transcriptional regulatory mechanisms underlying retinal Müller glial cell homeostasis.

FGFR blockade inhibits targeted therapy-tolerant persister in basal FGFR1- and FGF2-high cancers with driver oncogenes.

Cancer cell resistance arises when tyrosine kinase inhibitor (TKI)-targeted therapies induce a drug-tolerant persister (DTP) state with growth via genetic aberrations, making DTP cells potential therapeutic targets. We screened an anti-cancer compound library and identified fibroblast growth factor receptor 1 (FGFR1) promoting alectinib-induced anaplastic lymphoma kinase (ALK) fusion-positive DTP cell's survival. FGFR1 signaling promoted DTP cell survival generated from basal FGFR1- and fibroblast growth factor 2 (FGF2)-high protein expressing cells, following alectinib treatment, which is blocked by FGFR inhibition. The hazard ratio for progression-free survival of ALK-TKIs increased in patients with ALK fusion-positive non-small cell lung cancer with FGFR1- and FGF2-high mRNA expression at baseline. The combination of FGFR and targeted TKIs enhanced cell growth inhibition and apoptosis induction in basal FGFR1- and FGF2-high protein expressing cells with ALK-rearranged and epidermal growth factor receptor (EGFR)-mutated NSCLC, human epidermal growth factor receptor 2 (HER2)-amplified breast cancer, or v-raf murine sarcoma viral oncogene homolog B1 (BRAF)-mutated melanoma by preventing compensatory extracellular signal-regulated kinase (ERK) reactivation. These results suggest that a targeted TKI-induced DTP state results from an oncogenic switch from activated oncogenic driver signaling to the FGFR1 pathway in basal FGFR1- and FGF2-high expressing cancers and initial dual blockade of FGFR and driver oncogenes based on FGFR1 and FGF2 expression levels at baseline is a potent treatment strategy to prevent acquired drug resistance to targeted TKIs through DTP cells regardless of types of driver oncogenes.

Role of CRP2-MRTF interaction in functions of myofibroblasts.

Inflammatory response induces phenotypic modulation of fibroblasts into myofibroblasts. Although transforming growth factor-ßs (TGF-ßs) evoke such transition, the details of the mechanism are still unknown. Here, we report that a LIM domain protein, cysteine-and glycine-rich protein 2 (CSRP2 [CRP2]) plays a vital role in the functional expression profile in myofibroblasts and cancer-associated fibroblasts (CAFs). Knock-down of CRP2 severely inhibits the expression of smooth muscle cell (SMC) genes, cell motility, and CAF-mediated collective invasion of epidermoid carcinoma. We elucidate the following molecular bases: CRP2 directly binds to myocardin-related transcription factors (MRTF-A/B [MRTFs]) and serum response factor (SRF) and stabilizes the MRTF/SRF/CArG-box complex to activate SMC gene expression. Furthermore, a three-dimensional structural analysis of CRP2 identifies the amino acids required for the CRP2-MRTF-A interaction. Polar amino acids in the C-terminal half (serine-152, glutamate-154, serine-155, threonine-156, threonine-157, and threonine-159 in human CRP2) are responsible for direct binding to MRTF-A. On the other hand, hydrophobic amino acids outside the consensus sequence of the LIM domain (tryptophan-139, phenylalanine-144, leucine-153, and leucine-158 in human CRP2) play a role in stabilizing the unique structure of the LIM domain.Key words: CRP2, 3D structure, myocardin-related transcription factor, myofibroblast, cancer-associated fibroblasts.

Prognostic value of PD-L1 expression in recurrent renal cell carcinoma after nephrectomy: a secondary analysis of the ARCHERY study.

BACKGROUND: Nephrectomy is a curative treatment for localized renal cell carcinoma (RCC), but patients with poor prognostic features may experience relapse. Understanding the prognostic impact of programmed death-ligand 1 (PD-L1) expression in patients who underwent nephrectomy for RCC may aid in future development of adjuvant therapy. METHODS: Of 770 surgical specimens collected from Japanese patients enrolled in the ARCHERY study, only samples obtained from patients with recurrent RCC after nephrectomy were examined for this secondary analysis. Patients were categorized into low- and high-risk groups based on clinical stage and Fuhrman grade. Time to recurrence (TTR) and overall survival (OS) were analyzed. RESULTS: Both TTR and OS were shorter in patients with PD-L1-positive than -negative tumors (median TTR 12.1 vs. 21.9 months [HR 1.46, 95% CI 1.17, 1.81]; median OS, 75.8 vs. 97.7 months [HR 1.32, 95% CI 1.00, 1.75]). TTR and OS were shorter in high-risk patients with PD-L1-positive than -negative tumors (median TTR 7.6 vs. 15.3 months [HR 1.49, 95% CI 1.11, 2.00]; median OS, 55.2 vs. 83.5 months [HR 1.53, 95% CI 1.06, 2.21]) but not in low-risk patients. CONCLUSIONS: This ARCHERY secondary analysis suggests that PD-L1 expression may play a role in predicting OS and risk of recurrence in high-risk patients with localized RCC. CLINICAL TRIAL REGISTRATION: UMIN000034131.

Prognostic value of immune phenotype and PD-L1 status in recurrent or metastatic renal cell carcinoma: an exploratory analysis of the ARCHERY study.

Studies have reported the relevance of immune phenotype, or presence of cluster of differentiation 8 (CD8)-positive tumour-infiltrating lymphocytes, to the anti-tumour efficacy of checkpoint inhibitors and to prognosis. The multicentre, retrospective ARCHERY study (UMIN000034131) collected tissue samples from Japanese patients with recurrent or metastatic renal cell carcinoma (RCC) who received systemic therapy between 2010 and 2015. In this exploratory analysis, the prognostic impact of immune phenotype and PD-L1 expression (separately and combined) was investigated using 770 surgical specimens and outcomes from patients enrolled in ARCHERY. A key objective was to determine overall survival (OS), defined as time from nephrectomy to death from any cause, by immune and PD-L1 subgroups. The median OS by immune phenotype was 28.8, 57.3, and 63.4 months in patients with inflamed, excluded, and desert tumours, respectively [hazard ratio (95% CI): inflamed 1.78 (1.27-2.49); excluded 1.08 (0.89-1.30); desert as reference]. PD-L1 positivity by SP142 showed a strong association with immune phenotype; 88.1%, 61.9%, and 8.7% of PD-L1-positive patients had inflamed, excluded, and desert phenotypes, respectively. PD-L1 positivity was also associated with worse OS in each phenotype, except for the inflamed phenotype (due to limited sample size in the PD-L1-negative immune inflamed subgroup; n=7). Additionally, the difference in OS by PD-L1 status was larger in the desert versus excluded phenotype [median OS in PD-L1 positive vs negative: 27.1 vs 67.2 months (desert), and 48.2 vs 78.1 months (excluded)]. Results show that PD-L1 expression was highly associated with immune phenotype, but both covariates should be evaluated when determining prognosis.

Evaluation of microaneurysms as predictors of therapeutic response to anti-VEGF therapy in patients with DME.

Administration of intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is the first-line therapy for diabetic macular oedema (DME). However, some patients show no or insufficient response to repeated anti-VEGF injections. Therefore, it is necessary to identify factors that can predict this resistance against anti-VEGF treatment. Presence of microaneurysms (MAs) is a predictor of the development and progression of DME, but its relationship with the treatment response to the anti-VEGF agents is not well known. Therefore, we aimed to elucidate the relationship between the distribution of MAs and the response to anti-VEGF therapy in patients with DME. The number of MAs was measured before anti-VEGF therapy in each region using fluorescein angiography, indocyanine green angiography (IA), and optical coherence tomography angiography. Patients with DME were divided into the responder and non-responder groups after three loading phases. Differences in the distribution of MAs between the groups were investigated. Pre-treatment IA revealed more MAs in the nasal area in the non-responder group than in the responder group (10.7 ± 10.7 and 5.7 ± 5.7, respectively, in the nasal macula) (1.4 ± 2.1 and 0.4 ± 0.7, respectively, in the nasal fovea). Whereas, pre-treatment FA and OCTA could not reveal significantly difference between the groups. Detection of MAs in the nasal macula using pre-treatment IA may indicate resistance to anti-VEGF therapy. We recommend the clinicians confirm the presence of MAs in the nasal macula, as shown by IA, as a predictor of therapeutic response to anti-VEGF therapy in patients with treatment naive DME.

Evaluation of corneal hysteresis after pars plana vitrectomy combined phacoemulsification and intraocular lens implantation.

We evaluated the early effects of pars plana vitrectomy (PPV) on corneal biomechanics by comparing corneal hysteresis (CH) after cataract surgery (phacoemulsification and aspiration with intraocular lens implantation; PEA + IOL) alone and PPV combined with cataract surgery. This study included 20 eyes (18 patients), who underwent cataract surgery alone (PEA + IOL group), and 28 eyes (27 patients) who underwent PPV combined with cataract surgery (PPV triple group). The CH was 11.1 ± 1.1, 10.4 ± 1.1, and 11.0 ± 1.0 mmHg in the PEA + IOL group and 11.0 ± 1.4, 9.8 ± 1.4, and 10.6 ± 1.6 mmHg in the PPV triple group, preoperatively, at 2 weeks, and 3 months after surgery, respectively. The CH was not significantly different after surgery in the PEA + IOL group, but decreased significantly in the PPV triple group 2 weeks following surgery (p < 0.01). Intraocular pressure (IOP) and central corneal thickness (CCT) did not change significantly after surgery in either group. Preoperatively, there was a positive correlation between CH and CCT in the PPV triple group, but the correlation disappeared postoperatively. In PPV combined with cataract surgery, CH temporarily decreased postoperatively, independent of IOP and CCT. Removal of the vitreous may reduce the elasticity and rigidity of the entire eye.

Monosynaptic facilitation of motoneurons innervating intrinsic hand muscles mediated by group Ia afferents from the extensor carpi radialis in humans.

The projection pattern of low-threshold afferents from the extensor carpi radialis (ECR) to motoneurons supplying intrinsic hand muscles was investigated using the post-stimulus time-histogram (PSTH) and electromyogram-averaging (EMG-A) methods. Electrical conditioning stimulation was applied to the radial nerve branch innervating the ECR. In the PSTH study, changes in the firing probability of single motor units following the stimulation were examined. An early and significant peak (facilitation) was induced in the motoneurons innervating the muscles, but the facilitation was induced infrequently. The central latency of the facilitation was equivalent to that of homonymous facilitation through monosynaptic path in the spinal cord. In the EMG-A study, changes in the rectified and averaged electromyograms following the conditioning stimulation were examined. An early and significant peak (facilitation) was also induced. The facilitation disappeared after withdrawal of the vibration to the ECR muscle belly. Cutaneous nerve stimulation overlaying ECR never induced such facilitation in the PSTH and EMG-A studies. These findings suggest that monosynaptic facilitation mediated by group Ia afferents of ECR to the motoneurons supplying intrinsic hand muscles exists in humans, but the connection seems to be weak. This weakness might allow manipulatory movements of the hand.

Monosynaptic facilitation of flexor digitorum superficialis motoneurons mediated by Group Ia afferents from the extensor carpi radialis in humans.

Wrist position is known to affect the grip strength. We focused on the spinal reflex arc, which would support the movement, and investigated the effects of low-threshold afferents from the extensor carpi radialis (ECR) on the excitability of the flexor digitorum superficialis (FDS) motoneurons using the post-stimulus time-histogram (PSTH) and electromyogram-averaging (EMG-A) methods. Electrical conditioning stimulation of an intensity below the motor threshold was applied to the radial nerve branch innervating the ECR. In the PSTH study, changes in the firing probability of single motor units after electrical conditioning stimulation were investigated in seven subjects. An early and significant peak (increase in the firing probability: facilitation) was recorded for 36/60 FDS motor units. The remaining 24 motor units did not show any effects. Weak mechanical conditioning stimulation of the ECR muscle belly induced a similar peak. The central latency of the facilitation was equivalent to that of the homonymous monosynaptic facilitation. In the EMG-A study, changes in the rectified and averaged electromyograms of FDS induced by conditioning stimulation were examined in 12 subjects. An early and significant peak (facilitation) was induced by both electrical and mechanical conditioning stimulations. The facilitation decreased after withdrawal of the vibration to the ECR muscle belly. The facilitation was never induced by cutaneous nerve stimulation in the PSTH and EMG-A studies. These findings suggest that Group Ia afferents from the ECR increase the excitability of FDS motoneurons through a monosynaptic path in the spinal cord. These reflex arcs likely facilitate hand grasping movements.

Pertuzumab Plus Trastuzumab for Treatment-Refractory HER2-Amplified Metastatic Colorectal Cancer: Comparison of the MyPathway Trial With a Real-World External Control Arm.

PURPOSE: We compared overall survival (OS) in patients with human epidermal growth factor receptor 2 (HER2)-amplified, treatment-refractory metastatic colorectal cancer (mCRC) receiving pertuzumab plus trastuzumab (PER-HER) in the phase IIa MyPathway multibasket study (ClinicalTrials.gov identifier: NCT02091141) with OS in those receiving routine clinical care in an electronic health record-derived external control arm. METHODS: A noninterventional study was conducted using patient-level data from MyPathway participants receiving PER-HER and real-world patients with HER2-amplified treatment-refractory mCRC receiving routine clinical care. This study used a deidentified US-based clinico-genomic database (CGDB). For patients in the CGDB who met study eligibility criteria at multiple index dates (treatment initiation dates in the treatment-refractory setting), all eligible index dates were used for the analysis. Standardized mortality ratio weighting on the basis of propensity score derived a pseudopopulation (postweighting population) balancing key prognostic variables between arms. Multivariate Cox proportional hazards models were used for estimation of the hazard ratio (HR) in the primary OS analysis. A series of sensitivity analyses were conducted to investigate the robustness and consistency of the primary analysis. RESULTS: The PER-HER arm comprised 57 patients enrolled in the MyPathway study by August 1, 2017 (data cutoff); the external control arm comprised 18 patients (27 index dates) with HER2-amplified mCRC who met the major MyPathway eligibility criteria in CGDB collected between 2011 and 2019. The estimated HR for OS from the multivariate Cox proportional hazards model in the postweighting population was 0.729 (95% CI, 0.184 to 3.900). The results of sensitivity analyses were consistent with the primary analysis in terms of the point estimate of HR. CONCLUSION: Despite a small sample size, these findings suggest that PER-HER could have a potential OS benefit for this population.

Simultaneous Vitreoretinal Surgery and Sclerokeratoplasty for Keratoglobus with Intraocular Hemorrhage and Extensive Corneal Rupture.

We reported a case of simultaneous vitrectomy and sclerokeratoplasty (SKP) performed for keratoglobus with extensive corneal rupture and intraocular hemorrhage caused by trauma. A 73-year-old woman was treated for keratoglobus and glaucoma. She was punched in both eyes, her right eye showed corneal rupture and the left eye showed prolapse of the ocular contents due to eyeball rupture. She immediately underwent corneal sutures in the right eye and resection of the prolapsed ocular contents in the left eye at a nearby ophthalmological clinic. Three days after the injury, the patient was referred to our clinic for vision recovery. The best corrected visual acuity of the right eye was measured by counting fingers. Her right eye presented severe corneal edema with a sutured corneal wound in the upper periphery, which was positive in the Seidel test. B-mode ultrasound revealed choroidal detachment and subchoroidal hemorrhage. Fourteen days after injury, simultaneous corneal suture and posterior sclerotomy were performed in the right eye, but corneal fragility and corneal opacity were prominent, and B-mode examination revealed prolonged vitreous hemorrhage and retinal detachment. Twenty-one days after injury, we performed simultaneous SKP and 25-G pars plana vitrectomy (PPV). In this procedure, we initially performed SKP followed by 25-G PPV without a keratoprosthesis or endoscope. The visibility of the fundus through the corneoscleral graft was good during vitrectomy. Three months after surgery, her corrected visual acuity improved to 10/1,000. Although there was mild corneal stromal edema and khodadoust line, there were no obvious fundus complications. Simultaneous SKP and PPV for keratoglobus with extensive corneal rupture and vitreous diseases may be a good option.

Monosynaptic facilitation mediated by group Ia afferents from deltoid to biceps brachii motoneurons in humans.

Effects of low-threshold afferents from the anterior (DA), middle (DM) and posterior parts of the deltoid (DP) on the excitability of biceps brachii (BB) motoneurons in humans were studied. We evaluated the effects on individual motor units and motoneuron pool using a post-stimulus time-histogram (PSTH) and an electromyogram-averaging (EMG-A) methods, respectively, in 11 healthy human subjects. Electrical conditioning stimulation was delivered to the axillary nerve branch innervating DA (DA nerve), DM (DM nerve) and DP (DP nerve) with the intensity below the motor threshold. In the PSTH study, stimulation to the DA, DM and DP nerves produced a significant peak (facilitation) in 26/40 (65%), 28/47 (59%) and 0/32 (0%) of BB motor units, respectively. Since the central latency of the facilitation from the DA and DM nerves was 0.1 ± 0.3 and 0.1 ± 0.2 ms (mean ± S.D.) longer than that of the homonymous monosynaptic Ia facilitation of BB, respectively, the facilitation thus being compatible with monosynaptic path. In the EMG-A study, stimulation to the DA and DM nerves produced a significant peak (facilitation) for the BB motoneuron pool in all the subjects, whereas stimulation to the DP nerve produced no effect on BB. The facilitation diminished by vibration stimulation, and the suppression lasted for 30-40 min after removal of the vibration. Therefore, group Ia afferents should be responsible for the facilitation. These findings suggest that monosynaptic facilitation mediated by group Ia afferents from the DA and DM nerves to BB motoneurons exists in humans.

Molecular mechanisms of TGFß-mediated EMT of retinal pigment epithelium in subretinal fibrosis of age-related macular degeneration.

Age-related macular degeneration (AMD) is one of the leading causes of blindness in the elderly, affecting the macula of the retina and resulting in vision loss. There are two types of AMD, wet and dry, both of which cause visual impairment. Wet AMD is called neovascular AMD (nAMD) and is characterized by the formation of choroidal neovascular vessels (CNVs) in the macula. nAMD can be treated with intravitreal injections of vascular endothelial growth factor (VEGF) inhibitors, which help improve vision. However, approximately half the patients do not achieve satisfactory results. Subretinal fibrosis often develops late in nAMD, leading to irreversible photoreceptor degeneration and contributing to visual loss. Currently, no treatment exists for subretinal fibrosis, and the molecular mechanisms of fibrous tissue formation following neovascular lesions remain unclear. In this review, we describe the clinical features and molecular mechanisms of macular fibrosis secondary to nAMD. Myofibroblasts play an essential role in the development of fibrosis. This review summarizes the latest findings on the clinical features and cellular and molecular mechanisms of the pathogenesis of subretinal fibrosis in nAMD and discusses the potential therapeutic strategies to control subretinal fibrosis in the future.

Intravitreal Tissue Plasminogen Activator Injection for Treatment-Resistant Diabetic Macular Edema of the Vitrectomized Eye.

Diabetic macular edema (DME) is the main cause of visual loss in patients with diabetic retinopathy. DME has been treated using intravitreal anti-vascular endothelial growth factor (VEGF) drugs, steroids, laser photocoagulation, vitreoretinal surgery, and their combinations. These modalities are generally effective in preserving vision, but they sometimes produce only limited responses in patients with persistent or refractory DME. The levels of various inflammatory factors, including cytokines, chemokines, and extracellular matrices, as well as VEGF in the vitreous fluid, are increased in patients with DME. Excessive fibrinogen/fibrin levels in the vitreous fluid or fibrin deposition in the retina also contribute to DME pathogenesis. Tissue plasminogen activator (t-PA) promotes the degradation of fibrinogen or fibrin. Intravitreal t-PA injection is a commonly used treatment for subretinal hemorrhage secondary to age-related macular degeneration. Intravitreal t-PA injections have previously been used to restore vision by inducing posterior vitreous detachment in patients with DME. Herein, we describe the visual outcomes of intravitreal t-PA injection in a 78-year-old woman with treatment-resistant DME in her vitrectomized eye after several previous treatments. Before the injection, her best-corrected visual acuity (BCVA) was 0.7 logMAR and central foveal retinal thickness (CRT) was 735 µm. At 1 month after the injection, her BCVA was 0.8 logMAR and CRT was 558 µm, and 3 months later, her BCVA was 0.8 logMAR and CRT was 207 µm. Her BCVA was sustained, and CRT showed gradual improvements. These findings suggested the effectiveness of intravitreal t-PA injections for DME in the vitrectomized eye.

Early manifestations and differential gene expression associated with photoreceptor degeneration in Prom1-deficient retina.

Retinitis pigmentosa (RP) and macular dystrophy (MD) are characterized by gradual photoreceptor death in the retina and are often associated with genetic mutations, including those in the prominin-1 (Prom1) gene. Prom1-knockout (KO) mice recapitulate key features of these diseases including light-dependent retinal degeneration and constriction of retinal blood vessels. The mechanisms underlying such degeneration have remained unclear, however. We here analysed early events associated with retinal degeneration in Prom1-KO mice. We found that photoreceptor cell death and glial cell activation occur between 2 and 3 weeks after birth. Whereas gene expression was not affected at 2 weeks, the expression of several genes was altered at 3 weeks in the Prom1-KO retina, with the expression of that for endothelin-2 (Edn2) being markedly upregulated. Expression of Edn2 was also induced by light stimulation in Prom1-KO mice reared in the dark. Treatment with endothelin receptor antagonists attenuated photoreceptor cell death, gliosis and retinal vessel stenosis in Prom1-KO mice. Our findings thus reveal early manifestations of retinal degeneration in a model of RP/MD and suggest potential therapeutic agents for these diseases. This article has an associated First Person interview with the first author of the paper.

Cases of replacing diffractive bifocal intraocular lens with extended depth of focus intraocular lens due to waxy vision.

PURPOSE: To investigate the postoperative course of patients who explanted a diffractive bifocal intraocular lens (IOL) due to waxy vision and implanted with an extended depth of focus IOL. METHODS: This study evaluated 29 eyes of 25 patients who underwent diffractive bifocal IOL explantation followed by TECNIS Symfony® implantation because of dissatisfaction due to waxy vision at the Takabatake West Eye Clinic between January 2018 and November 2019. The indication criteria for this surgery were patients with uncorrected distance visual acuity of 0.05 logMAR or better, without eye diseases that may affect visual function, and no dissatisfactions about photic phenomena. We investigated patient demographics, uncorrected and corrected visual acuity, manifest refraction, contrast sensitivity, subjective symptoms, time to IOL explantation, explanted IOL type, and spectacle independence. RESULTS: The time to the IOL exchange after the initial IOL implantation was 55.3 ± 50.4 days (range: 14-196 days). The logMAR corrected distance visual acuity before and after IOL exchange were -0.13 ± 0.06 and -0.14 ± 0.06, respectively (p = 0.273). After IOL exchange surgery, the area under log contrast sensitivity function increased significantly from 1.07 ± 0.12 to 1.21 ± 0.12 (p < 0.001), and the waxy vision symptoms improved. The spectacle independence rate at the last visit was 88.0%. CONCLUSION: For patients who complain of waxy vision despite good visual acuity after diffractive bifocal IOL implantation, exchange to extended depth of focus IOL was considered one of the useful surgical options.

Vibration decreases the responsiveness of Ia afferents and spinal motoneurons in humans.

After vibration, Hoffmann reflex (H reflex) amplitude is depressed; however, the mechanisms underlying these phenomena remain unknown. This study investigated the influence of frequency and duration of vibration on the H reflex amplitude, heteronymous facilitation of the tendon jerk (T wave) mediated by group Ia afferents, and cervicomedullary motor evoked potential (CMEP) amplitude in 18 healthy human subjects. The H reflex of the flexor carpi radialis (FCR) was induced by median nerve stimulation at the elbow, and the conditioning FCR stimulation enhanced the T wave of the biceps brachii (BB). After vibration was applied to the FCR muscle belly, the amplitudes of the H reflex and heteronymous facilitation of the T wave were depressed; these influences persisted after the removal of vibration in all subjects. For the H reflex, there was no difference in the amount of depression among the frequencies of vibration used (57, 77, and 100 Hz). Higher frequencies of vibration were associated with longer recovery times of postvibration depression, and a longer duration of vibration was associated with a longer recovery time of the depression. Similar results were observed for heteronymous facilitation of the T wave, suggesting that the depression is caused by a decrease in postsynaptic potentials evoked by Ia afferents in spinal motoneurons; it was probably due to reduction in the number of Ia afferents recruited by the median nerve stimulation. Moreover, because the FCR CMEP amplitude was depressed after vibration, vibration should affect the responsiveness of spinal motoneurons. These mechanisms are considered to contribute to the H reflex depression after vibration.NEW & NOTEWORTHY Vibration decreased the responsiveness of Ia afferents from the muscle exposed to vibration, and the duration of depressive effect was modulated by the duration and frequency of the vibration: a longer duration and a higher frequency of vibration led to a longer recovery time of the depression. In addition to this presynaptic effect, it also depressed the responsiveness of spinal motoneurons, indicating postsynaptic inhibition through specific circuits triggered by Ia impulses.