Retinal Dysfunction in a Mouse Model of HCN1 Genetic Epilepsy.

Pathogenic variants in HCN1 are associated with a range of epilepsy syndromes including a developmental and epileptic encephalopathy. The recurrent de novo HCN1 pathogenic variant (M305L) results in a cation leak, allowing the flux of excitatory ions at potentials where the wild-type channels are closed. The Hcn1M294L mouse recapitulates patient seizure and behavioral phenotypes. As HCN1 channels are highly expressed in rod and cone photoreceptor inner segments, where they shape the light response, mutated channels are likely to impact visual function. Electroretinogram (ERG) recordings from male and female mice Hcn1M294L mice revealed a significant decrease in the photoreceptor sensitivity to light, as well as attenuated bipolar cell (P2) and retinal ganglion cell responses. Hcn1M294L mice also showed attenuated ERG responses to flickering lights. ERG abnormalities are consistent with the response recorded from a single female human subject. There was no impact of the variant on the structure or expression of the Hcn1 protein in the retina. In silico modeling of photoreceptors revealed that the mutated HCN1 channel dramatically reduced light-induced hyperpolarization, resulting in more Ca2+ flux during the response when compared with the wild-type situation. We propose that the light-induced change in glutamate release from photoreceptors during a stimulus will be diminished, significantly blunting the dynamic range of this response. Our data highlight the importance of HCN1 channels to retinal function and suggest that patients with HCN1 pathogenic variants are likely to have a dramatically reduced sensitivity to light and a limited ability to process temporal information.SIGNIFICANCE STATEMENT Pathogenic variants in HCN1 are emerging as an important cause of catastrophic epilepsy. HCN1 channels are ubiquitously expressed throughout the body, including the retina. Electroretinogram recordings from a mouse model of HCN1 genetic epilepsy showed a marked decrease in the photoreceptor sensitivity to light and a reduced ability to respond to high rates of light flicker. No morphologic deficits were noted. Simulation data suggest that the mutated HCN1 channel blunts light-induced hyperpolarization and consequently limits the dynamic range of this response. Our results provide insights into the role HCN1 channels play in retinal function as well as highlighting the need to consider retinal dysfunction in disease caused by HCN1 variants. The characteristic changes in the electroretinogram open the possibility of using this tool as a biomarker for this HCN1 epilepsy variant and to facilitate development of treatments.

Is there evidence for the asymmetrical transfer of strength to an untrained limb?

PURPOSE: The literature predominantly addresses cross-education of strength in the dominant limb rather than the non-dominant limb, guided by the hypothesis of an asymmetrical transfer of strength from unilateral training protocols. The purpose of the study was to review the literature and determine how much evidence was available to support this claim. A meta-analysis was performed to estimate the magnitude of this hypothesized asymmetrical transfer of strength. METHODS: A literature search of all possible records was implemented using Cochrane Library, PubMed, and Scopus from February 2022 to May 2022. Comparison of randomized controlled trials was computed. The change scores and standard deviations of those change scores were extracted for each group. Only three studies met the criteria, from which a total of five effect sizes were extracted and further analyzed. RESULTS: The overall effect of resistance training of the dominant limb on strength transfer to the non-dominant limb relative to the effects of resistance training the non-dominant limb on strength transfer to the dominant (non-training) limb was 0.46 (SE 0.42). The analysis from this study resulted in minimal support for the asymmetry hypothesis. Given the small number of studies available, we provide the effect but note that the estimate is unlikely to be stable. CONCLUSION: Although it is repeatedly stated that there is an asymmetrical transfer of strength, our results find little support for that claim. This is not to say that it does not exist, but additional research implementing a control group and a direct comparison between limbs is needed to better understand this question.

Blood flow restriction augments the cross-education effect of isometric handgrip training.

INTRODUCTION: The application of blood flow restriction (BFR) to low-intensity exercise may be able to increase strength not only in the trained limb but also in the homologous untrained limb. Whether this effect is repeatable and how that change compares to that observed with higher intensity exercise is unknown. PURPOSE: Examine whether low-intensity training with BFR enhances the cross-education of strength compared to exercise without BFR and maximal efforts. METHODS: A total of 179 participants completed the 6-week study, with 135 individuals performing isometric handgrip training over 18 sessions. Participants were randomly assigned to one of four groups: 1) low-intensity (4 × 2 min of 30% MVC; LI, n = 47), 2) low-intensity with blood flow restriction (LI + 50% arterial occlusion pressure; LI-BFR, n = 41), 3) maximal effort (4 × 5 s of 100% MVC; MAX, n = 47), and 4) non-exercise control (CON, n = 44). RESULTS: LI-BFR was the only group that observed a cross-education in strength (CON: 0.64 SD 2.9 kg, LI: 0.95 SD 3.6 kg, BFR-LI: 2.7 SD 3.3 kg, MAX: 0.80 SD 3.1 kg). In the trained hand, MAX observed the greatest change in strength (4.8 SD 3.3 kg) followed by LI-BFR (2.8 SD 4.0 kg). LI was not different from CON. Muscle thickness did not change in the untrained arm, but ulna muscle thickness was increased within the trained arm of the LI-BFR group (0.06 SD 0.11 cm). CONCLUSION: Incorporating BFR into low-intensity isometric training led to a cross-education effect on strength that was greater than all other groups (including high-intensity training).

Fractalkine-induced microglial vasoregulation occurs within the retina and is altered early in diabetic retinopathy.

Local blood flow control within the central nervous system (CNS) is critical to proper function and is dependent on coordination between neurons, glia, and blood vessels. Macroglia, such as astrocytes and Müller cells, contribute to this neurovascular unit within the brain and retina, respectively. This study explored the role of microglia, the innate immune cell of the CNS, in retinal vasoregulation, and highlights changes during early diabetes. Structurally, microglia were found to contact retinal capillaries and neuronal synapses. In the brain and retinal explants, the addition of fractalkine, the sole ligand for monocyte receptor Cx3cr1, resulted in capillary constriction at regions of microglial contact. This vascular regulation was dependent on microglial Cx3cr1 involvement, since genetic and pharmacological inhibition of Cx3cr1 abolished fractalkine-induced constriction. Analysis of the microglial transcriptome identified several vasoactive genes, including angiotensinogen, a constituent of the renin-angiotensin system (RAS). Subsequent functional analysis showed that RAS blockade via candesartan abolished microglial-induced capillary constriction. Microglial regulation was explored in a rat streptozotocin (STZ) model of diabetic retinopathy. Retinal blood flow was reduced after 4 wk due to reduced capillary diameter and this was coincident with increased microglial association. Functional assessment showed loss of microglial-capillary response in STZ-treated animals and transcriptome analysis showed evidence of RAS pathway dysregulation in microglia. While candesartan treatment reversed capillary constriction in STZ-treated animals, blood flow remained decreased likely due to dilation of larger vessels. This work shows microglia actively participate in the neurovascular unit, with aberrant microglial-vascular function possibly contributing to the early vascular compromise during diabetic retinopathy.

Blood flow restriction augments exercise-induced pressure pain thresholds over repetition and effort matched conditions.

We sought to determine the effects of blood flow restriction (BFR) on exercise-induced hypoalgesia, specifically using low-load (LL) resistance exercise (30% 1RM) protocols that accounted for each individual's local muscular endurance capabilities. Forty-four participants completed four conditions: (1) 70% of maximal BFR repetitions with blood flow restriction (LL+BFR exercise); (2) 70% maximal BFR repetitions without LL+BFR (LL exercise); (3) 70% maximal free flow repetitions (LL+EFFORT exercise); (4) time-matched, non-exercise control (CON). Pressure pain threshold (PPT) was measured before and after exercise. Ischaemic pain threshold and tolerance was assessed only at post. The change in upper body PPT was greater for LL+BFR exercise compared to LL exercise [difference of 0.15 (0.35) kg/cm2], LL+EFFORT exercise [difference of 0.23 (0.45) kg/cm2], and the CON condition. The change in lower body PPT was greater for LL+BFR exercise compared to LL exercise [difference of 0.40 (0.55) kg/cm2], LL+EFFORT exercise [difference of 0.36 (0.62) kg/cm2], and the CON condition. Ischaemic pain thresholds and tolerances did not change. Submaximal exercise with BFR resulted in systemic increases in PPT but had no influence on ischaemic pain sensitivity. This effect is likely unique to BFR as we did not see changes in the effort matched free flow condition.

The Impact of Different Ischemic Preconditioning Pressures on Pain Sensitivity and Resistance Exercise Performance.

ABSTRACT: Kataoka, R, Song, JS, Yamada, Y, Hammert, WB, Seffrin, A, Spitz, RW, Wong, V, Kang, A, and Loenneke, JP. The impact of different ischemic preconditioning pressures on pain sensitivity and resistance exercise performance. J Strength Cond Res 38(5): 864-872, 2024-To determine (a) the impact of ischemic preconditioning pressures (applied as a % of arterial occlusion pressure [AOP]) on pressure pain threshold (PPT) and resistance exercise performance and (b) whether changes in performance could be explained by changes in PPT. Subjects ( n = 39) completed 4 protocols in a randomized order: (a) ischemic preconditioning (IPC) at 110% AOP (IPC 110%), (b) IPC at 150% AOP (IPC 150%), (c) IPC at 10% AOP (Sham), and (d) time-matched control (CON). Each protocol included 4 cycles of 5 minutes of occlusion followed by 5 minutes of reperfusion. Pressure pain threshold was taken before and after. Discomfort ratings were given at the end of each cycle. Every visit finished with 2 sets of 75-second maximal isokinetic unilateral elbow flexion or extension. Overall, IPC 110% and IPC 150% resulted in similar increases in PPT relative to CON [110%: difference of 0.36 (0.18, 0.54) kg·m -2 ; 150%: difference of 0.377 (0.15, 0.59) kg·m -2 ] and Sham. Both resulted in greater discomfort than Sham and CON, with IPC 150% inducing greater discomfort than IPC 110% (BF 10 : 14.74). There were no differences between the conditions for total work (BF 10 : 0.23), peak torque (BF 10 : 0.035), or average power (BF 10 : 0.159). We did not find evidence that PPT mediated performance. We did not detect changes in performance with 2 different relative pressures greater than AOP. Our mean applied pressures were lower than those used previously. There might be a minimal level of pressure (e.g., >150% of AOP) that is required to induce ergogenic effects of ischemic preconditioning.

Sex segregation in strength sports: Do equal-sized muscles express the same levels of strength between sexes?

OBJECTIVES: Concerns have been raised against the current two-sex binary category in sports competitions. The thesis states that if males and females were separated based on muscle size, it would negate the strength advantage between the sexes. We tested the possible sex differences in various strength outcomes when pair-matched for muscle thickness. METHODS: A total of 16 different data sets (n = 963) were assessed to pair-match females with males who had a muscle thickness value within 2%. We further compared the competition performances of the smallest male weight class within the International Powerlifting Federation (IPF) to different weight classes in females. RESULTS: Overall, 76%-88% of the strength assessments were greater in males than females with pair-matched muscle thickness, regardless of contraction types (i.e., isotonic, isometric, isokinetic). Additionally, males in the lightest weight division in the IPF largely outperformed females in heavier weight divisions. CONCLUSIONS: Our results would suggest that segregation based on muscle mass or surrogates of muscle mass (e.g., lean body mass) might not be an appropriate classification to create fair competition within strength sports. This is not to refute the concept of the desegregation of the two-sex binary category but to present data that raises important concerns about the potential sex-based differences in strength performance.

Potential considerations with estimating blood flow restriction pressure in the lower body using a narrower cuff.

Blood flow restriction pressures are typically set as a percentage of the arterial occlusion pressure. For those who do not have the ability to measure the arterial occlusion pressure, estimation equations are available. However, notable considerations are needed when estimating pressure with a narrow cuff (5 cm) in the lower body. A previously published equation in this journal was developed but was created only using 55% of the sample because the arterial occlusion of the others could not be obtained within the manufacturer's pressure limit. The purpose of this article was twofold: (1) to investigate how previous studies have implemented the equation and (2) to highlight potential concerns of using this equation. Two databases were used to locate articles that used the equation from Loenneke et al. (2015). We found that this equation had been cited 10 times to estimate arterial occlusion pressure with some notable concerns. Some did not use a 5 cm wide cuff, while others used it for participants who had arterial occlusion pressures exceeding 300 mmHg. To highlight the latter, we also applied the Loenneke et al. (2015) lower body equation to participants with arterial occlusion pressures known to exceed 300 mmHg to demonstrate potential concerns. This retrospective analysis found that 52% of the sample with known pressures over 300 mmHg (40 out of 77) would be estimated below 300 mmHg. This paper highlighted important considerations for those trying to estimate arterial occlusion pressure in the lower body with a narrow cuff (5 cm).

Effect of Increased Pressure Pain Threshold on Resistance Exercise Performance With Blood Flow Restriction.

ABSTRACT: Kataoka, R, Song, JS, Bell, ZW, Wong, V, Spitz, RW, Yamada, Y, and Loenneke, JP. Effect of increased pressure pain threshold on resistance exercise performance with blood flow restriction. J Strength Cond Res 37(6): 1204-1210, 2023-This study aimed to examine whether increasing pressure pain threshold (PPT) through isometric handgrip exercise (HG) affects the number of repetitions completed and discomfort with knee extension exercise (KE) with blood flow restriction (BFR), and examine whether performing additional exercise leads to a further increase in PPT. Forty-one participants completed 2 trials: rest followed by low-load KE with BFR at 80% of resting arterial occlusion pressure (Rest + KE BFR) and low-intensity (30% of maximal strength) HG exercise followed by KE with BFR (HG + KE BFR). Pressure pain threshold was measured before and after exercise at the forearm and tibialis anterior. Results are presented as median difference (95% credible interval). Pressure pain threshold increased at the forearm (Bayes factor [BF 10 ]: 5.2 × 10 7 ) and tibialis anterior (BF 10 : 1.5 × 10 6 ) after HG exercise. However, this did not lead to greater repetitions being completed with BFR exercise (0.2 [-0.1, 0.6] repetitions, BF 10 : 0.07). Pressure pain threshold after BFR exercise was not augmented over that observed with HG exercise (0.02 [-0.15, 0.2] kg·cm -2 , BF 10 : 0.175) at the forearm. More data are needed in the lower body to determine which model best fits the data (BF 10 : 0.84). Discomfort with BFR exercise was not different between conditions (1.0 [-2.3, 4.4] arbitrary units, BF 10 : 0.10). The pain-reducing effect of prior exercise did not change the repetitions completed with BFR exercise, suggesting that the change in PPT may not have been great enough to alter performance. Performing additional exercise did not elicit further increases in PPT nor was perceived discomfort to BFR exercise altered by changes in PPT.

Hypoalgesia following isometric handgrip exercise with and without blood flow restriction is not mediated by discomfort nor changes in systolic blood pressure.

The purpose was to examine the effect of isometric handgrip exercise with and without blood flow restriction on exercise-induced hypoalgesia at a local and non-local site, and its underlying mechanisms. Sixty participants (21 males & 39 females, 18-35 years old) completed 3 trials: four sets of 2-minute isometric handgrip exercise at 30% of maximum handgrip strength; isometric handgrip exercise with blood flow restriction at 50% of arterial occlusion pressure; and a non-exercise time-matched control. Pain thresholds increased similarly in both exercise conditions at a local (exercise conditions: ~0.45 kg/cm2, control: ~-0.04 kg/cm2) and non-local site (exercise conditions: ~0.37 kg/cm2, control: ~-0.16 kg/cm2). Blood flow restriction induced greater feelings of discomfort compared to exercise alone [median difference (95% credible interval) of 4.5 (0.5, 8.6) arbitrary units]. Blood pressure increased immediately after exercise (systolic: 10.3 mmHg, diastolic: 7.7 mmHg) and decreased in recovery. There was no within participant correlation between changes in discomfort and pressure pain threshold. A bout of isometric handgrip exercise with or without blood flow restriction can provide exercise-induced hypoalgesia at a local and non-local site. However, discomfort and changes in systolic blood pressure do not explain this response.

Can Individuals Be Taught to Sense the Degree of Vascular Occlusion? A Comparison of Methods and Implications for Practical Blood Flow Restriction.

ABSTRACT: Bell, ZW, Spitz, RW, Wong, V, Yamada, Y, Song, JS, Abe, T, and Loenneke, JP. Can individuals be taught to sense the degree of vascular occlusion? A comparison of methods and implications for practical blood flow restriction. J Strength Cond Res 36(12): 3359-3365, 2022-The study objective was to determine whether subjects could be conditioned to a relative blood flow restriction pressure in the lower body and compare 2 separate conditioning methods (unconstrained vs. constrained). Thirty-five subjects completed 4 visits, involving measurements for arterial occlusion and pressure estimations at 5 minutes and 24 hours after conditioning. The constrained method involved applying 40% of measured arterial occlusion 11 times, along with 10% above and below this pressure. The unconstrained method was time-matched, involving a series of inflations to 40% arterial occlusion for 12 seconds and then deflated for 22 seconds. Data are presented as mean differences (95% credible interval) unless otherwise noted. The absolute error between conditioning methods was found to be similar at 5 minutes (-1.1 [-5.9, 3.7] mm Hg) and 24 hours (-2.4 [-7, 2.2] mm Hg) after conditioning. The constant error differed between methods at 5 minutes [-8.2 (-14.4, -1.9) mm Hg] but was similar at 24 hours (-2.5 [-8.5, 3.6] mm Hg; H0: 0.680; H1: 0.068; and H2: 0.252) after conditioning. The bias and 95% limits of agreement for the unconstrained method were -3.9 (-33.8, 25.9) mm Hg at 5 minutes and -2.9 (-32, 26.1) mm Hg at 24 hours. The agreement for the constrained method was 4.2 (-28, 36.5) mm Hg at 5 minutes and -0.54 (-37.3, 36.2) mm Hg at 24 hours. Conditioning methods produced similar levels of absolute error, indicating that either method may offer a viable means of pressure application. Most estimates were between 20 and 60% of arterial occlusion pressure. Additional conditioning sessions may be needed to narrow this range at the individual level.

The Effect of Blood Flow Restriction Therapy on Recovery After Experimentally Induced Muscle Weakness and Pain.

ABSTRACT: Wong, V, Dankel, SJ, Spitz, RW, Bell, ZW, Viana, RB, Chatakondi, RN, Abe, T, and Loenneke, JP. The effect of blood flow restriction therapy on recovery after experimentally induced muscle weakness and pain. J Strength Cond Res 36(4): 1147-1152, 2022-The purpose was to determine if blood flow restriction with no external load could be used as a means of active therapy after experimentally induced fatigue and soreness. Twelve women and 7 men (aged 18-35 years) participated in a randomized controlled trial using a within-subject design. The study intervention was 3 consecutive visits. Visit 1 included the fatiguing/soreness-inducing protocol for the elbow flexors, which was performed only once during the study. Torque was measured before/after to confirm individuals began in a weakened state. Subjects then completed blood flow restriction therapy on one arm and the sham therapy on the other. Subjects performed elbow flexion/contraction with no external load on both arms. Torque was measured once more 10 minutes after the fatiguing/soreness-inducing protocol. Twenty-four hours later, soreness and torque were assessed in each arm, followed by another bout of therapy. Forty-eight hours after the initial visit, soreness and torque were measured again. There were no differences (median difference [95% credible interval]) in the recovery of torque between the blood flow restriction and sham therapy conditions at 10 minutes (0.5 [-2.7, 3.8] N·m), 24 hours (-2.34 [-6, 1.14] N·m), or 48 hours (-1.94 [-5.45, 1.33] N·m). There were also no differences in ratings of soreness at 24 hours (-2.48 [-10.05, 5.05]) or 48 hours (2.58 [-4.96, 10.09]). Our results indicate that this specific model of blood flow restriction therapy did not enhance the recovery of the muscle compared with a sham condition without the application of pressure.

Blood Flow Restricted Exercise and Discomfort: A Review.

ABSTRACT: Spitz, RW, Wong, V, Bell, ZW, Viana, RB, Chatakondi, RN, Abe, T, and Loenneke, JP. Blood flow restricted exercise and discomfort: A review. J Strength Cond Res 36(3): 871-879, 2022-Blood flow restriction exercise involves using a pneumatic cuff or elastic band to restrict arterial inflow into the muscle and block venous return out of the muscle during the exercise bout. The resultant ischemia in conjunction with low-load exercise has shown to be beneficial with increasing muscle size and strength. However, a limitation of using blood flow restriction (BFR) is the accompanying discomfort associated with this type of exercise. Factors that may influence discomfort are applied pressure, width of the cuff, cuff material, sex, and training to failure. The goal of this review was to evaluate the existing literature and elucidate how these factors can be manipulated to reduce discomfort during exercise as well as provide possible directions for future research. Thirty-eight different studies were located investigating BFR and discomfort. It was found that BFR training causes more discomfort than exercise without BFR. However, chronic use of BFR may increase tolerability, but discomfort may still be elevated over traditional non-blood flow restricted exercise. Discomfort can be attenuated by the application of lower applied pressures and stopping short of task failure. Finally, in the upper body, wider cuffs seem to increase ratings of discomfort compared with more narrow cuffs. In conclusion, applying the proper-sized cuff and making the applied pressure relative to both the individual and the cuff applied may attenuate discomfort. Reducing discomfort during exercise may help increase adherence to exercise and rehabilitation programs.

A drug-tunable Flt23k gene therapy for controlled intervention in retinal neovascularization.

Gene therapies that chronically suppress vascular endothelial growth factor (VEGF) represent a new approach for managing retinal vascular leakage and neovascularization. However, constitutive suppression of VEGF in the eye may have deleterious side effects. Here, we developed a novel strategy to introduce Flt23k, a decoy receptor that binds intracellular VEGF, fused to the destabilizing domain (DD) of Escherichia coli dihydrofolate reductase (DHFR) into the retina. The expressed DHFR(DD)-Flt23k fusion protein is degraded unless "switched on" by administering a stabilizer; in this case, the antibiotic trimethoprim (TMP). Cells transfected with the DHFR(DD)-Flt23k construct expressed the fusion protein at levels correlated with the TMP dose. Stabilization of the DHFR(DD)-Flt23k fusion protein by TMP was able to inhibit intracellular VEGF in hypoxic cells. Intravitreal injection of self-complementary adeno-associated viral vector (scAAV)-DHFR(DD)-Flt23k and subsequent administration of TMP resulted in tunable suppression of ischemia-induced retinal neovascularization in a rat model of oxygen-induced retinopathy (OIR). Hence, our study suggests a promising novel approach for the treatment of retinal neovascularization. Schematic diagram of the tunable system utilizing the DHFR(DD)-Flt23k approach to reduce VEGF secretion. a The schematic shows normal VEGF secretion. b Without the ligand TMP, the DHFR(DD)-Flt23k protein is destabilized and degraded by the proteasome. c In the presence of the ligand TMP, DHFR(DD)-Flt23k is stabilized and sequestered in the ER, thereby conditionally inhibiting VEGF. Green lines indicate the intracellular and extracellular distributions of VEGF. Blue lines indicate proteasomal degradation of the DHFR(DD)-Flt23k protein. Orange lines indicate the uptake of cell-permeable TMP. TMP, trimethoprim; VEGF, vascular endothelial growth factor; ER, endoplasmic reticulum.

Increased episcleral venous pressure in a mouse model of circumlimbal suture induced ocular hypertension.

PURPOSE: To investigate changes in aqueous humor dynamics during intraocular pressure (IOP) elevation induced by circumlimbal suture in mice. METHODS: Ocular hypertension (OHT) was induced by applying a circumlimbal suture behind the limbus in male adult C57BL6/J mice. In the OHT group, the suture was left in place for an average of 8 weeks (n = 10, OHT group). In the sham control group the suture was cut at 2 days (n = 9, sham group) and in the naïve control group (n = 5) no suture was implanted. IOP was measured at baseline across 3 days, 1 h post-suture implantation, and at the chronic endpoint. Anterior segments were assessed using optical coherence tomography (OCT). Episcleral venous pressure (EVP), total outflow facility (C), uveoscleral outflow (Fu) and aqueous humor flow rate (Fin) were determined using a constant-flow infusion model. RESULTS: All aqueous dynamic and chronic IOP outcome measures showed no difference between sham and naïve controls (p > 0.05) and thus these groups were combined into a single control group. IOP was elevated in OHT group compared with controls (p < 0.01). Chronic suture implantation did not change pupil size, anterior chamber depth or iridocorneal angles (p > 0.05). EVP was significantly higher in OHT eyes compared to control eyes (p < 0.01). There was no statistical difference in C, Fu and Fin between groups (p > 0.05). A significant linear correlation was found between IOP and EVP (R2 = 0.35, p = 0.001). CONCLUSIONS: Circumlimbal suture implantation in mouse eyes results in chronic IOP elevation without angle closure. Chronic IOP elevation is likely to reflect higher EVP.

Gene Therapy Intervention in Neovascular Eye Disease: A Recent Update.

Aberrant growth of blood vessels (neovascularization) is a key feature of severe eye diseases that can cause legal blindness, including neovascular age-related macular degeneration (nAMD) and diabetic retinopathy (DR). The development of anti-vascular endothelial growth factor (VEGF) agents has revolutionized the treatment of ocular neovascularization. Novel proangiogenic targets, such as angiopoietin and platelet-derived growth factor (PDGF), are under development for patients who respond poorly to anti-VEGF therapy and to reduce adverse effects from long-term VEGF inhibition. A rapidly advancing area is gene therapy, which may provide significant therapeutic benefits. Viral vector-mediated transgene delivery provides the potential for continuous production of antiangiogenic proteins, which would avoid the need for repeated anti-VEGF injections. Gene silencing with RNA interference to target ocular angiogenesis has been investigated in clinical trials. Proof-of-concept gene therapy studies using gene-editing tools such as CRISPR-Cas have already been shown to be effective in suppressing neovascularization in animal models, highlighting the therapeutic potential of the system for treatment of aberrant ocular angiogenesis. This review provides updates on the development of anti-VEGF agents and novel antiangiogenic targets. We also summarize current gene therapy strategies already in clinical trials and those with the latest approaches utilizing CRISPR-Cas gene editing against aberrant ocular neovascularization.

The Relationship Between Muscle Size and Strength Does not Depend on Echo Intensity in Healthy Young Adults.

Muscle quality is typically defined as muscle strength relative to muscle size. Echo intensity has gained popularity as an index of skeletal muscle quality. There is common agreement that muscle size is related to strength at baseline and echo intensity is purported to impact this relationship. Thus, the purpose of this study was to examine whether echo intensity can be used as a physiological marker for muscle quality by investigating the moderating effect of echo intensity on the relationship between muscle size and strength. A sample of 96 participants was used for the upper body analysis and a separate sample of 96 participants was used for the lower body analysis. Echo intensity, muscle thickness, and strength measurements were measured on each limb. For strength, participants performed unilateral elbow flexion (upper body analysis) and knee extension (lower body analysis) to quantify 1-repetition maximum. Muscle thickness and echo intensity were determined from images captured using B-mode ultrasound. Muscle size correlated with muscle strength for all limbs. However, the relationship between muscle size and strength was not significantly moderated by echo intensity for Arm 1 (b = 0.042, p = 0.54) or Arm 2 (b = -0.002, p = 0.97). At the proximal site, no significant moderating effect of echo intensity was found in Leg 1 (b = 0.037, p = 0.67) or Leg 2 (b = -0.085, p = 0.29). Similarly, no significant moderating effect was observed at the distal site for Leg 1 (b = 0.03, p = 0.69) or Leg 2 (b = -0.026, p = 0.75). The results would indicate that the relationship between muscle size and strength does not depend on echo intensity. Therefore, the use of echo intensity as an index of muscle quality in healthy young adults may need to be reconsidered.

Skeletal muscle size distribution in large-sized male and female athletes.

OBJECTIVE: In healthy adults, it is generally accepted that women have less upper body muscle mass compared to men. However, it is unknown whether there are sex differences in skeletal muscle distribution in highly trained large-sized athletes. Our aim was to compare the skeletal muscle size distribution between large-sized male and female athletes. METHODS: Ten female athletes (>80 kg body mass) and twenty-one male athletes (>100 kg body mass) had muscle thickness (MT) and subcutaneous adipose tissue thickness measured by ultrasound at nine sites on the anterior and posterior aspects of the body. Total muscle mass (SM) was estimated from an ultrasound-derived prediction equation. Body fat percentage and fat-free mass were calculated from ultrasound measured subcutaneous fat thickness. RESULTS: The average SM in female athletes (30.0 kg) was approximately 70% of the mean value of the male athletes (45.3 kg).With respect to MT, the relative values of femaleto male athletes were 68% to 78% in the upper body and 85% to 92% in the lower body. Similar results were observed when analyzing data for male and female athletes (n = 5 each) who were pair matched for height. CONCLUSION: The relative values of MT for female/male athletes were higher in the lower body compared to the upper body. This is similar to that observed in healthy non-athletes indicating that this difference is not due to resistance training. The lower muscle mass in the arms and trunk of females appears to be a true sex difference but the cause of this difference is unknown.

The Water-Fat Separation Method for Determining the Fat-free Component of Subcutaneous Adipose Tissue in Humans: A Brief Review.

Fat-free mass as well as lean soft tissue mass is a surrogate for skeletal muscle mass and is often used for the normalization of several physiological variables or for the diagnosing of low muscle mass in older adults. However, both fat-free mass and lean tissue mass include nonskeletal muscle components such as the fat-free component of adipose tissue fat cells. A technique known as water-fat MRI provides a noninvasive and radiation-free assessment of the fat-free component of adipose tissue in humans. However, if this method is impractical or unavailable, some authors suggest that a constant value for the fat-free component of adipose tissue can be used as an indirect estimate. The purpose of this review is to examine the fat fraction percentage of white (subcutaneous) adipose tissue in adolescents and young/middle-aged/older adults measured by water-fat MRI and provide discussion on how the fat-free adipose tissue values from the water-fat separation method compare with the constant value used in previous studies. Calculated mean values for the percentage of fat fraction in subcutaneous adipose tissue were 86.9% in the overall sample, 86.4% in adolescents (3 studies), and 87.1% in young, middle-aged and older adults (7 studies). This is similar to the 85% value proposed in the classical studies but in the majority of studies the 85% estimate was outside of the 95% confidence interval (CI) of the water-fat MRI estimate. There may be several factors to consider that may affect the fat fraction percentage (e.g. reliability of the MRI estimate, age, sex, obesity, etc.), however, at this time there is insufficient evidence to determine the effect of each of these variables. If the measurement is reliable, then this might suggest that the 85% constant may need to be altered to better reflect the water-fat MRI estimate.

Why is low body fat rarely seen in large-sized male athletes?

OBJECTIVES: It is unknown why low body fat is rarely seen in large-sized athletes (>100 kg body mass). The aim of this review was to examine the relationship between body mass and body composition (fat mass and fat-free mass) in elite male athletes, and to discuss the possible reasons why low body fat is rarely seen in large-sized male athletes. METHODS: A search using two electronic databases was conducted. Eighteen studies estimated body composition in elite athletes by dual-energy X-ray absorptiometry, totaling 2249 elite male athletes and 72 data points. RESULTS: Our results indicated that low body fat (eg, less than 10% body fat) was rarely seen in large-sized male athletes over 100 kg body mass. The larger the body mass, the higher the fat-free mass, with fat-free mass leveling off when body mass exceeds approximately 120 kg. CONCLUSION: Possible reasons for this are unknown but we provide some ideas for why this might occur. The two different stages to consider with respect to skeletal muscle growth: the amount of growth during development and the amount of growth as a result of long-term resistance training. In certain sporting events, a large body mass may be favored. However, the large-sized athletes have to balance any potential positive influence of body mass on sports performance with the potential negative factors associated with body fat accumulation. Further research is warranted, as there is currently limited evidence on this topic.