Disease-specific variant interpretation highlighted the genetic findings in 2325 Japanese patients with retinitis pigmentosa and allied diseases.

BACKGROUND: As gene-specific therapy for inherited retinal dystrophy (IRD) advances, unified variant interpretation across institutes is becoming increasingly important. This study aims to update the genetic findings of 86 retinitis pigmentosa (RP)-related genes in a large number of Japanese patients with RP by applying the standardised variant interpretation guidelines for Japanese patients with IRD (J-IRD-VI guidelines) built upon the American College of Medical Genetics and Genomics and the Association for Molecular Pathology rules, and assess the contribution of these genes in RP-allied diseases. METHODS: We assessed 2325 probands with RP (n=2155, including n=1204 sequenced previously with the same sequencing panel) and allied diseases (n=170, newly analysed), including Usher syndrome, Leber congenital amaurosis and cone-rod dystrophy (CRD). Target sequencing using a panel of 86 genes was performed. The variants were interpreted according to the J-IRD-VI guidelines. RESULTS: A total of 3564 variants were detected, of which 524 variants were interpreted as pathogenic or likely pathogenic. Among these 524 variants, 280 (53.4%) had been either undetected or interpreted as variants of unknown significance or benign variants in our earlier study of 1204 patients with RP. This led to a genetic diagnostic rate in 38.6% of patients with RP, with EYS accounting for 46.7% of the genetically solved patients, showing a 9% increase in diagnostic rate from our earlier study. The genetic diagnostic rate for patients with CRD was 28.2%, with RP-related genes significantly contributing over other allied diseases. CONCLUSION: A large-scale genetic analysis using the J-IRD-VI guidelines highlighted the population-specific genetic findings for Japanese patients with IRD; these findings serve as a foundation for the clinical application of gene-specific therapies.

Cross-sectional association of continuous glucose monitoring-derived metrics with cerebral small vessel disease in older adults with type 2 diabetes.

AIM: To examine cross-sectional associations between continuous glucose monitoring (CGM)-derived metrics and cerebral small vessel disease (SVD) in older adults with type 2 diabetes. MATERIALS AND METHODS: In total, 80 patients with type 2 diabetes aged ≥70 years were analysed. Participants underwent CGM for 14 days. From the CGM data, we derived mean sensor glucose, percentage glucose coefficient of variation, mean amplitude of glucose excursion, time in range (TIR, 70-180 mg/dl), time above range (TAR) and time below range metrics, glycaemia risk index and high/low blood glucose index. The presence of cerebral SVD, including lacunes, microbleeds, enlarged perivascular spaces and white matter hyperintensities, was assessed, and the total number of these findings comprised the total cerebral SVD score (0-4). Ordinal logistic regression analyses were performed to examine the association of CGM-derived metrics with the total SVD score. RESULTS: The median SVD score was 1 (interquartile range 0-2). Higher hyperglycaemic metrics, including mean sensor glucose, TAR >180 mg/dl, TAR >250 mg/dl, and high blood glucose index and glycaemia risk index, were associated with a higher total SVD score. In contrast, a higher TIR (per 10% increase) was associated with a lower total SVD score (odds ratio 0.73, 95% confidence interval 0.56-0.95). Glycated haemoglobin, percentage glucose coefficient of variation, mean amplitude of glucose excursions, time below range and low blood glucose index were not associated with total cerebral SVD scores. CONCLUSIONS: The hyperglycaemia metrics and TIR, derived from CGM, were associated with cerebral SVD in older adults with type 2 diabetes.

Prognostic Significance of Asymptomatic Cerebral Infarction in Patients After Cardiac Catheterization.

Recent studies have showed that asymptomatic cerebral infarction (ACI) developed in a reasonable number of patients after cardiac catheterization. However, no study has investigated the long-term prognostic impact of ACI after cardiac catheterization. We investigated whether ACI after cardiac catheterization affects long-term mortality and subsequent cardiovascular events.We retrospectively enrolled patients who underwent cardiac catheterization before cardiac surgery and cerebral diffusion-weighted magnetic resonance imaging (DWI). The incidence and clinical features of ACI were investigated. The long-term prognosis, including all-cause mortality and subsequent major cardiovascular events (MACE; all-cause mortality, stroke, acute myocardial infarction, fatal arrhythmia, and hospitalized heart failure), was also assessed.A total of 203 patients were enrolled. Of these, 10.3% had ACI diagnosed by DWI. There were no differences in baseline characteristics between patients with and without ACI, except more frequent history of symptomatic stroke in patients with ACI. In the Kaplan-Meier analysis during a median follow-up of 1009 days, the patients with ACI showed worse mortality and a slightly higher occurrence of MACE compared with those without ACI (P = 0.01 and P = 0.08, respectively). In addition, ACI was a prognostic marker independent of age, surgery type, and history of stroke.ACI after cardiac catheterization frequently developed and was also associated with long-term prognosis. It may be an independent prognostic marker in high-risk patients who underwent subsequent cardiac surgery.

Cross-sectional association of metrics derived from continuous glucose monitoring with cognitive performance in older adults with type 2 diabetes.

AIM: To examine the association between continuous glucose monitoring (CGM)-derived metrics and cognitive performance in older adults with type 2 diabetes (T2D). MATERIALS AND METHODS: A total of 100 outpatients with T2D aged 70 years or older were analysed. Participants underwent CGM for 14 days. As CGM-derived metrics, mean sensor glucose (SG), glucose coefficient of variation (CV), time in range (TIR; 70-180 mg/dl), time above range (TAR; > 180 mg/dl) and time below range (TBR; < 70 mg/dl), were calculated. Participants underwent cognitive tests, including the Japanese version of the Montreal Cognitive Assessment (MoCA-J), a delayed word-recall test from the Alzheimer's Disease Assessment Scale-cognitive subscale, a digit symbol substitution test, a letter word fluency test, a trail-making test (TMT) and digit span test (DSP). RESULTS: In multiple regression analyses adjusted for confounders, a higher mean SG was associated with a lower performance in MoCA-J and TMT part B (TMT-B) (P < .05). A higher TAR was associated with a lower performance in TMT-B and DSP-backward (P < .05). By contrast, a higher TIR was associated with better function in TMT-B and DSP-backward (P < .05). Furthermore, CV and TBR were not associated with any cognitive function. CONCLUSION: Hyperglycaemia metrics and TIR derived from CGM are associated with cognitive functions, especially with executive function and working memory, in older adults with T2D.

Developing a predictive model for mortality in patients with cognitive impairment.

OBJECTIVES: We developed a predictive model for all-cause mortality and examined the risk factors for cause-specific mortality among people with cognitive impairment in a Japanese memory clinic-based cohort (2010-2018). METHODS: This retrospective cohort study included people aged ≥65 years with mild cognitive impairment or dementia. The survival status was assessed based on the response of participants or their close relatives via a postal survey. Potential predictors including demographic and lifestyle-related factors, functional status, and behavioral and psychological status were assessed at the first visit at the memory clinic. A backward stepwise Cox regression model was used to select predictors, and a predictive model was developed using a regression coefficient-based scoring approach. The discrimination and calibration were assessed via Harrell's C-statistic and a calibration plot, respectively. RESULTS: A total of 2610 patients aged ≥65 years (men, 38.3%) were analyzed. Over a mean follow-up of 4.1 years, 544 patients (20.8%) died. Nine predictors were selected from the sociodemographic and clinical variables: age, sex, body mass index, gait performance, physical activity, and ability for instrumental activities of daily living, cognitive function, and self-reported comorbidities (pulmonary disease and diabetes). The model showed good discrimination and calibration for 1-5-year mortality (Harrell's C-statistic, 0.739-0.779). Some predictors were specifically associated with cause-specific mortality. CONCLUSIONS: This predictive model has good discriminative ability for 1- to 5-year mortality and can be easily implemented for people with mild cognitive impairment and all stages of dementia referred to a memory clinic.

Participatory approaches for developing a practical handbook integrating health information for supporting individuals with mild cognitive impairment and their families.

AIM: This study aimed to develop a patient-centred handbook that integrates information on lifestyle modifications and psychological support strategies for individuals with mild cognitive impairment (MCI). This article provides a comprehensive record of the development process. METHODS: We adopted a participatory research model for the methodology, which comprised five phases and involved an interdisciplinary team specializing in dementia and health literacy. Data were initially collected via interviews conducted among patients with MCI (n = 5) and their families (n = 5). Given the study's preliminary nature, depth and richness of the qualitative data were the key concerns for determining the sample size, rather than broad generalizability. We ensured the inclusion of diverse experiences and perspectives by facilitating the creation of patient questions (PQs) that merged scientific evidence with patient perspectives. To enhance the handbook's accessibility and utility, we continuously evaluated the same using patient interviews, health literacy tool assessments and team discussions. This comprehensive approach harmonized scientific knowledge and patient experience, leading to the development of a personalized MCI management guide. RESULTS: The handbook comprises nine domains, encompassing 38 selected PQs: MCI, lifestyle, lifestyle-related diseases, exercise, nutrition, social participation, cognitive training, psychological care and family support. The health literacy handbook was evaluated based on Clear Communication Index scores. The results revealed that 73.7% of the PQs were deemed difficult prerevision, whereas only 5.3% remained challenging postrevision. The formative evaluation underscored the need for more detailed explanations prerevision, whereas postrevision comments focused primarily on editorial suggestions. CONCLUSION: The inclusion of patients' perspectives right from the outset ensured that the handbook met their specific needs. The final version, which reflects all stakeholders' inputs, is now slated for imminent publication. PATIENT OR PUBLIC CONTRIBUTION: Patients and the public participated extensively throughout the project, from initial interviews to material evaluation and refinement.

CHOP deletion and anti-neuroinflammation treatment with hesperidin synergistically attenuate NMDA retinal injury in mice.

Glaucoma is a leading cause of blindness worldwide and is characterized by degeneration associated with the death of retinal ganglion cells (RGCs). It is believed that glaucoma is a group of heterogeneous diseases with multifactorial pathomechanisms. Here, we investigate whether anti-inflammation treatment with an ER stress blockade can selectively promote neuroprotection against NMDA injury in the RGCs. Retinal excitotoxicity was induced with an intravitreal NMDA injection. Microglial activation and neuroinflammation were evaluated with Iba1 immunostaining and cytokine gene expression. A stable HT22 cell line transfected with an NF-kB reporter was used to assess NF-kB activity after hesperidin treatment. CHOP-deficient mice were used as a model of ER stress blockade. Retinal cell death was evaluated with a TUNEL assay. As results, in the NMDA injury group, Iba1-positive microglia increased 6 h after NMDA injection. Also at 6 h, pro-inflammatory cytokines and chemokine increased, including TNFα, IL-1b, IL-6 and MCP-1. In addition, the MCP-1 promoter-driven EGFP signal, which we previously identified as a stress signal in injured RGCs, also increased; hesperidin treatment suppressed this inflammatory response and reduced stressed RGCs. In CHOP-deficient mice that received an NMDA injection, the gene expression of pro-inflammatory cytokines, chemokines, markers of active microglia, and inflammatory regulators was greater than in WT mice. In WT mice, hesperidin treatment partially prevented retinal cell death after NMDA injury; this neuroprotective effect was enhanced in CHOP-deficient mice. These findings demonstrate that ER stress blockade is not enough by itself to prevent RGC loss due to neuroinflammation in the retina, but it has a synergistic neuroprotective effect after NMDA injury when combined with an anti-inflammatory treatment based on hesperidin.

Chronic Effects of a Static Stretching Program on Hamstring Strength.

ABSTRACT: Nakao, S, Ikezoe, T, Nakamura, M, Umegaki, H, Fujita, K, Umehara, J, Kobayashi, T, Ibuki, S, and Ichihashi, N. Chronic effects of a static stretching program on hamstring strength. J Strength Cond Res 35(7): 1924-1929, 2021-This study investigated the effects of a 4-week static stretching (SS) program on isokinetic and isometric knee flexor peak torque and angle of peak torque. Thirty healthy men (age, 22.7 ± 2.2 years) were randomized to receive either of the following: (a) a 4-week stretch intervention for the hamstrings (SS intervention group; n = 15) or (b) no intervention (control group; n = 15). The maximum pain-free knee angle, passive stiffness, which was determined by a slope of torque-angle curve, isometric and isokinetic (at 60°·s-1 and 180°·s-1) peak torque, and angle of peak torque for knee flexors were measured before and after 4 weeks. After 4 weeks, passive stiffness decreased significantly in the intervention group. There were no significant changes in isometric and isokinetic (neither at 60°·s-1 nor at 180°·s-1) peak torque, or angle of peak torque at 180°·s-1. A significantly increased peak extension angle at 60°·s-1 was observed in the intervention group. These results suggest that SS intervention is effective for decreasing musculotendinous unit stiffness of the hamstrings and that an SS program influences the angle of peak torque, whereas no significant changes occur in peak torque. Because a previous study suggests that angle of peak torque is associated with hamstring strain injuries, the results of this study would be helpful when considering the training program for preventing or treating hamstring strain injuries.

Acute and Prolonged Effects of Stretching on Shear Modulus of the Pectoralis Minor Muscle.

Increased muscle stiffness of the pectoralis minor (PMi) could deteriorate shoulder function. Stretching is useful for maintaining and improving muscle stiffness in rehabilitation and sport practice. However, the acute and prolonged effect of stretching on the PMi muscle stiffness is unclear due to limited methodology for assessing individual muscle stiffness. Using shear wave elastography, we explored the responses of shear modulus to stretching in the PMi over time. The first experiment (n = 20) aimed to clarify the acute change in the shear modulus during stretching. The shear modulus was measured at intervals of 30 s × 10 sets. The second experiment (n = 16) aimed to observe and compare the prolonged effect of different durations of stretching on the shear modulus. Short and long stretching duration groups underwent 30s × 1 set and 30s × 10 sets, respectively. The assessments of shear modulus were conducted before, immediately after, and at 5, 10, and 15 min post-stretching. In experiment I, the shear modulus decreased immediately after a bout (30 s) of stretching (p < 0.001, change: -2.3 kPa, effect size: r = 0.72) and further decreased after 3 repetitions (i.e., 90 s) of stretching (p = 0.03, change: -1.0 kPa, effect size: r = 0.53). In experiment II, the change in the shear modulus after stretching was greater in the long duration group than in the short duration group (p = 0.013, group mean difference: -2.5 kPa, partial η2 = 0.36). The shear modulus of PMi decreased immediately after stretching, and stretching for a long duration was promising to maintain the decreased shear modulus. The acute and prolonged effects on the PMi shear modulus provide information relevant to minimum and persistent stretching time in rehabilitation and sport practice.

In vivo imaging of the light response in mouse retinal ganglion cells based on a neuronal activity-dependent promoter.

Diseases of the retinal ganglion cells (RGCs) are an important cause of blindness, yet the light response of individual RGCs is difficult to assess in vivo, particularly in mammals, due to a lack of effective methods. We report a simple in vivo platform for imaging the light response of mouse RGCs based on a fluorescent reporter-tagged enhanced synaptic activity-responsive element (E-SARE) that mediates neuronal activity-dependent gene transcription. When E-SARE-driven d2Venus, packaged into an AAV vector, was injected intravitreally, light-responsive retinal neurons expressing d2Venus were visible at single-cell resolution using confocal ophthalmoscopy. Immunohistological assessment identified the majority of these cells as RGCs. In a murine model of RGC injury, the number of d2Venus-positive cells was correlated with the amplitude of light-induced responses and with visual acuity, measured electrophysiologically at the visual cortex, indicating that the vector can be used as a tool to assess visual function in RGCs. The platform described herein allows a simple in vivo assessment of RGC function, which should help basic research into the mechanisms of RGC death and the development of treatments for diseases involving the RGCs.

Companion Diagnosis for Retinal Neuroprotective Treatment by Real-Time Imaging of Calpain Activation Using a Novel Fluorescent Probe.

Calpain activation induces retinal ganglion cell (RGC) death, while calpain inhibition suppresses RGC death, in animal studies. However, the role of calpain in human retinal disease is unclear. This study investigated a new strategy to study the role of calpain based on real-time imaging. We synthesized a novel fluorescent probe for calpain, acetyl-l-leucyl-l-methionine-hydroxymethyl rhodamine green (Ac-LM-HMRG) and used it for real-time imaging of calpain activation. The toxicity of Ac-LM-HMRG was evaluated with a lactate dehydrogenase cytotoxicity assay, retinal sections, and electroretinograms. Here, we performed real-time imaging of calpain activation in a rat model. First, we administered N-methyl-d-aspartate (NMDA) to induce retinal injury. Twenty minutes later, we administered an intravitreal injection of Ac-LM-HMRG. Real-time imaging was then completed with a noninvasive confocal scanning laser ophthalmoscope. The inhibitory effect of SNJ-1945 against calpain activation was also examined with the same real-time imaging method. Ac-LM-HMRG had no toxic effects. The number of Ac-LM-HMRG-positive cells in real-time imaging significantly increased after NMDA injury, and SNJ-1945 significantly lowered the number of Ac-LM-HMRG-positive cells. Real-time imaging with Ac-LM-HMRG was able to quickly quantify the NMDA-induced activation of calpain and the inhibitory effect of SNJ-1945. This technique, used as a companion diagnostic system, may aid research into the development of new neuroprotective therapies.

Association of CRX genotypes and retinal phenotypes confounded by variable expressivity and electronegative electroretinogram.

IMPORTANCE: A framework for understanding the phenotypic features of CRX retinopathy was established. BACKGROUND: To perform a phenotype-genotype correlation analysis in two groups of patients with heterozygous mutations in distinct locations of the CRX gene, encoding the cone-rod homeobox. DESIGN: Multicentre retrospective study. PARTICIPANTS: Twenty-one Japanese patients from 14 families with a heterozygous CRX mutation. METHODS: Retrospective data analysis. MAIN OUTCOME MEASURES: Clinical records on CRX mutation, symptoms, best-corrected visual acuity (BCVA), visual field, fundus photography, fundus auto-fluorescence, optical coherence tomography and electroretinograms (ERGs). RESULTS: Six different CRX heterozygous mutations were identified in the subjects. Twelve patients from 9 families shared the p.R41W mutation and 1 patient had the p.R43C mutation, both of which affect the homeobox domain of CRX. These patients often displayed adult-onset retinal dystrophy with macular degeneration. In contrast, five patients with downstream mutations (p.S204fs, p.S213fs, p.G243X and p.L299F) displayed retinal degeneration or macular degeneration with bone-spicule pigmentation. Three asymptomatic carriers with different mutations (p.R41W, p.S213fs and p.G243X) were present in both groups. Nearly all patients and carriers had an electronegative ERG in response to a bright flash under dark adaptation. There was no cross-sectional association between patients' age and BCVA, despite progressive decline in BCVA. CONCLUSIONS AND RELEVANCE: Heterozygous mutations within or downstream of the homeobox domain in CRX relate to the difference associated retinal phenotypes, which was confounded by variable expressivity and electronegative ERGs. CRX mutations should be considered in patients with an electronegative ERG with minimal or no macular changes.

Phenotypic Features of Oguchi Disease and Retinitis Pigmentosa in Patients with S-Antigen Mutations: A Long-Term Follow-up Study.

PURPOSE: To present phenotypic features of 22 patients with S-antigen (SAG) mutations. DESIGN: Retrospective cohort study. PARTICIPANTS: Twenty-one Japanese patients from 16 families with a homozygous c.924delA mutation and 1 patient with a homozygous c.636delT mutation in the SAG gene. METHODS: Clinical records on symptoms; best-corrected visual acuity; and Goldmann perimetry, fundus photography, fundus autofluorescence (FAF), OCT, and electroretinography results were reviewed. MAIN OUTCOME MEASURES: Best-corrected visual acuity, Goldmann perimetry results, imaging findings, and electroretinography results. RESULTS: Ten patients had Oguchi disease and 12 had retinitis pigmentosa (RP) with mean follow-up periods of 13.8 and 10.2 years, respectively. Retinitis pigmentosa patients were older (mean age, 56.0 years) than those with Oguchi disease (mean age, 22.1 years; P < 0.001) at the initial visit. Night blindness noted in childhood was the most common initial symptom for both Oguchi disease (80.0%) and RP (91.7%) patients. Best-corrected visual acuity in the logarithm of the minimum angle of resolution (logMAR) was well preserved in Oguchi disease patients (mean, 0.02 logMAR in both eyes) but reduced in most RP patients (mean, 1.32 logMAR [right eye] and 1.35 logMAR [left eye]). Similarly, the visual field in the retinal area was preserved in Oguchi disease patients (mean, 677 mm2 right eye and 667 mm2 left eye) and reduced in RP patients (mean, 369 mm2 right eye and 294 mm2 left eye). Fundus images revealed a characteristic golden sheen with no retinal degeneration in Oguchi disease patients, excluding 2 with macular degeneration detected by FAF, OCT, or both and 1 with mild retinal degeneration confirmed by OCT and fluorescein angiography. Pigmentary retinal degeneration most evident posteriorly was observed in RP patients, accompanied by a characteristic golden sheen in 12 of 14 patients undergoing ultra-widefield fundus imaging. OCT showed disrupted macular structure, and FAF revealed variable hypofluorescence. Electroretinography identified absent rod responses in both diseases, along with relative preservation of cone responses in Oguchi disease patients. Three patients showed progressive loss of the golden sheen based on fundus images, including 1 who demonstrated RP 26 years after the initial diagnosis of Oguchi disease. CONCLUSIONS: Retinitis pigmentosa with SAG mutations often shows a characteristic golden sheen surrounding posterior pigmentary retinal degeneration. Oguchi disease can show progressive degeneration in adulthood, rarely resulting in RP.

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.

Improvement in muscle strength with low-load isotonic training depends on fascicle length but not joint angle.

INTRODUCTION: In this study we investigate whether low-load isotonic training will elicit greater improvement in muscle strength at the same fascicle length, rather than at the same joint angle. METHODS: Sixteen healthy men (24.1 ± 2.5 years of age) were randomly divided into intervention and control groups. Pre- and posttraining maximum isometric and isokinetic strengths and fascicle lengths of the medial gastrocnemius muscle were measured. Isotonic resistance training at 15 ° to 30 ° ankle plantarflexion at low intensity was conducted for 4 weeks. RESULTS: The maximum isometric and isokinetic strength of the intervention group increased significantly only at 15 ° dorsiflexion and 8 ° to 12 ° dorsiflexion. Fascicle length during maximum voluntary contraction at 15 ° dorsiflexion to 0 ° was similar to fascicle length under training conditions. DISCUSSION: It is possible that the improvement in muscle strength with low-load training depends on fascicle length rather than joint angle. Muscle Nerve 57: 83-89, 2018.

Electrical Stimulation to the Infraspinatus on Hypertrophy and Strength of the Shoulder.

The purpose of this study was to determine the effects of six weeks of electrical muscle stimulation (EMS) on the strength and muscle mass of the infraspinatus muscle. Twenty non-athletes (age: 24±3.4 years, height: 171.5±5.6 cm, mass: 65.2±8.1 kg) were randomly classified into two groups, an electrical muscle stimulation group (EMS group) and a control group (CON group). The EMS group completed a total of 18 20- min EMS sessions, three times per week over a period of six weeks, while the CON group received no intervention. The muscle thicknesses of both the infraspinatus and the deltoid muscles, the cross-sectional area (CSA) of the whole infraspinatus muscle, and the isometric and isokinetic peak torques of shoulder external rotations were measured before and after intervention. It was found that the muscle thickness of the superior infraspinatus (Pre 0.92±0.19 cm2, Post 0.99±0.16 cm2, p=0.02) and the CSA (Pre 10.99±1.32 cm2, Post 11.99±1.02 cm2, p=0.03) significantly increased in the EMS group. This study demonstrated that EMS of the infraspinatus muscle over a period of six weeks resulted in hypertrophy of the infraspinatus muscle.

Effects of a Thermal Agent and Physical Activity on Muscle Tendon Stiffness, as Well as the Effects Combined With Static Stretching.

CONTEXT: A recent review or article reported that thermal agents (TA) or physical activity (PA) can increase range of motion (ROM) and that the combination of TA with stretching is superior to performing stretching only. However, since ROM is affected by the psychological factors, it is questionable whether these studies measured the effect of these interventions on muscle flexibility. By measuring muscle stiffness, the authors attempted to evaluate the effect these interventions on muscle flexibility. OBJECTIVE: To compare the individual effects of TA and PA on muscle flexibility, as well as their effectiveness when combined with static stretching (SS). DESIGN: Crossover trial. SETTING: University research laboratory. PARTICIPANTS: 15 healthy men without a history of orthopedic disease in their lower limbs. INTERVENTIONS: 15 minutes of 3 different conditions: hot pack as TA, pedaling exercise as PA, and the control group with no TA or PA intervention, followed by 3 min of SS for the hamstrings. MAIN OUTCOME MEASURES: Joint angle and passive torque of the knee during passive elongation were obtained prior to interventions, after 3 kinds of intervention, and after SS. From these data, muscle-tendon-unit (MTU) stiffness of the hamstrings was calculated. RESULTS: Although knee-joint ROM increased with both TA and PA (P < .05), there were no significant differences in MTU stiffness between pre- and postintervention measurements for either of the interventions (TA, P = .477; PA, P = .377; control, P = .388). However, there were similar significant decreases in MTU stiffness between postintervention and post-SS for all conditions (P < .01). CONCLUSIONS: TA and PA did not decrease MTU stiffness, and combining these interventions with SS did not provide additional decreases in MTU stiffness compared with performing SS alone.

The neuroprotective effect of latanoprost acts via klotho-mediated suppression of calpain activation after optic nerve transection.

Latanoprost was first developed for use in glaucoma therapy as an ocular hypotensive agent targeting the prostaglandin F2α (FP) receptor. Subsequently, latanoprost showed a neuroprotective effect, an additional pharmacological action. However, although it is well-known that latanoprost exerts an ocular hypotensive effect via the FP receptor, it is not known whether this is also true of its neuroprotective effect. Klotho was firstly identified as the gene linked to the suppression of aging phenotype: the defect of klotho gene in mice results aging phenotype such as hypokinesis, arteriosclerosis, and short lifespan. After that, the function of klotho was also reported to maintain calcium homeostasis and to exert a neuroprotective effect in various models of neurodegenerative disease. However, the function of klotho in eyes including retina is still poorly understood. Here, we show that klotho is a key factor underlying the neuroprotective effect of latanoprost during post-axotomy retinal ganglion cell (RGC) degeneration. Importantly, a quantitative RT-PCR gene expression analysis of klotho in sorted rat retinal cells revealed that the highest expression level of klotho in the retina was in the RGCs. Latanoprost acid, the biologically active form of latanoprost, inhibits post-traumatic calpain activation and concomitantly facilitates the expression and shedding of klotho in axotomized RGCs. This expression profile is a good match with the localization, not of the FP receptor, but of organic anion transporting polypeptide 2B1, known as a prostaglandin transporter, in the ocular tissue. Furthermore, an organic anion transporting polypeptide 2B1 inhibitor suppressed latanoprost acid-mediated klotho shedding ex vivo, whereas an FP receptor antagonist did not. The klotho fragments shed from the RGCs reduced the intracellular level of reactive oxygen species, and a specific klotho inhibitor accelerated and increased RGC death after axotomy. We conclude that the shed klotho fragments might contribute to the attenuation of axonal injury-induced calpain activation and oxidative stress, thereby protecting RGCs from post-traumatic neuronal degeneration.