Effects of Resistance Training Volume on Physical Function, Lean Body Mass and Lower-Body Muscle Hypertrophy and Strength in Older Adults: A Systematic Review and Network Meta-analysis of 151 Randomised Trials.

BACKGROUND: The optimal prescription and precise recommendations of resistance training volume for older adults is unclear in the current literature. In addition, the interactions between resistance training volume and program duration as well as physical health status remain to be determined when assessing physical function, muscle size and hypertrophy and muscle strength adaptations in older adults. OBJECTIVES: This study aimed to determine which resistance training volume is the most effective in improving physical function, lean body mass, lower-limb muscle hypertrophy and strength in older adults. Additionally, we examined whether effects were moderated by intervention duration (i.e. short term, < 20 weeks; medium-to-long term, ≥ 20 weeks) and physical health status (i.e. physically healthy, physically impaired, mixed physically healthy and physically impaired; PROSPERO identifier: CRD42023413209). METHODS: CINAHL, Embase, LILACS, PubMed, Scielo, SPORTDiscus and Web of Science databases were searched up to April 2023. Eligible randomised trials examined the effects of supervised resistance training in older adults (i.e. ≥ 60 years). Resistance training programs were categorised as low (LVRT), moderate (MVRT) and high volume (HVRT) on the basis of terciles of prescribed weekly resistance training volume (i.e. product of frequency, number of exercises and number of sets) for full- and lower-body training. The primary outcomes for this review were physical function measured by fast walking speed, timed up and go and 6-min walking tests; lean body mass and lower-body muscle hypertrophy; and lower-body muscle strength measured by knee extension and leg press one-repetition maximum (1-RM), isometric muscle strength and isokinetic torque. A random-effects network meta-analysis was undertaken to examine the effects of different resistance training volumes on the outcomes of interest. RESULTS: We included a total of 161 articles describing 151 trials (n = 6306). LVRT was the most effective for improving timed up and go [- 1.20 standardised mean difference (SMD), 95% confidence interval (95% CI): - 1.57 to - 0.82], 6-min walk test (1.03 SMD, 95% CI: 0.33-1.73), lean body mass (0.25 SMD, 95% CI: 0.10-0.40) and muscle hypertrophy (0.40 SMD, 95% CI: 0.25-0.54). Both MVRT and HVRT were the most effective for improving lower-limb strength, while only HVRT was effective in increasing fast walking speed (0.40 SMD, 95% CI: - 0.57 to 0.14). Regarding the moderators, our results were independent of program duration and mainly observed for healthy older adults, while evidence was limited for those who were physically impaired. CONCLUSIONS: A low resistance training volume can substantially improve healthy older adults' physical function and benefits lean mass and muscle size independently of program duration, while a higher volume seems to be necessary for achieving greater improvements in muscle strength. A low volume of resistance training should be recommended in future exercise guidelines, particularly for physically healthy older adults targeting healthy ageing.

Effects of direction specific exercise training on athletic performance: a systematic review and meta-analysis.

Background: The similarity between movement patterns and force-vector specificity of training exercises and the target movement will likely result in the greatest transfer of the practiced skills and physical abilities to the intended sports skill performance. Therefore, this review aimed to investigate whether specific adaptations in athletic performance would be observed following direction specific exercise training. Methodology: The literature search was performed in PubMed, Web of Science, and MEDLINE. Studies comparing acute (post-activation potentiation enhancement) and short-term (>2 weeks) effects of horizontally vs. vertically oriented resistance and plyometric training on athletic performance of recreationally active participants of either sex were included. The effect sizes were determined using a robust variance estimation random-effects model and were reported as Hedge's g. Results: Twenty-two studies were included. For acute studies (n = 4), a small non-significant effect favoring horizontal training (HT) for sprint performance improvements (g = -0.19, p = 0.17) was evident. For short-term studies (n = 18), the results showed non-significant, small to large differences between HT and vertical training (VT) in pooled vertical and horizontal jump improvements (g = 0.06, p = 0.67), vertical (g = 0.21, p = 0.17) and horizontal jump (g = -0.15, p = 0.40), pooled vertical and horizontal maximal strength (g = 0.27, p = 0.42), horizontal (g = -0.83, p = 0.16) and vertical maximal strength (g = 0.78, p = 0.28), pooled short and medium distance sprint (g = -0.23, p = 0.16), short (g = -0.33 [-0.85, 0.19], p = 0.19) and medium (g = -0.12 [-0.37, 0.13], p = 0.28) distance sprint, and COD speed and maneuverability (g = -0.45, p = 0.26). Conclusions: HT and VT were both equally effective in improving vertically and horizontally athletic performance, potentially refuting the theory of directional specificity of training on athletic performance outcomes.

Anti-HMGCR myopathy mimicking facioscapulohumeral muscular dystrophy.

Introduction: Statin use can lead to various muscle-related issues, including benign creatine kinase (CK) elevations, myalgias, toxic myopathies, rhabdomyolysis, and immune-mediated necrotizing myositis (IMNM), which primarily affects older males. IMNM presents with proximal muscle weakness, elevated CK levels, and specific antibodies. Case presentation: We describe a 72-year-old patient with muscle weakness persisting for over 3 years after statin therapy. Initially suspected to have a genetic disorder, further testing revealed elevated anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) antibodies, indicating immune-mediated myopathy. Despite the absence of inflammatory changes on biopsy, the patient responded positively to immune therapy. Conclusion: This case highlights challenges in diagnosing immune-mediated myopathy, especially in older patients with atypical presentations. Testing for HMGCR antibodies can aid in diagnosis, particularly when inflammatory markers are absent. Awareness of red flags, such as delayed symptom onset and response to prednisone, is crucial for accurate diagnosis and management.

Physiological characterization of a simulated kettlebell routine in experienced kettlebell athletes.

Kettlebell as a sport has gained recognition worldwide. We characterized the physiological responses induced by a simulated kettlebell competition routine in experienced kettlebell athletes (n = 26) in a two-group, pre-post plus short-term follow-up, non-randomized experiment. The experimental group (EXP) included 13 kettlebell athletes, while the control group (CON) consisted of 13 individuals with prior recreational exposure to kettlebell activities. EXP performed a 10-minute-long, long-cycle kettlebell routine, whereas CON engaged in seated rest. Cardiovascular and neuromuscular outcomes were measured at rest, after warm-up, during exercise, at 0 (immediately post), 5 and 15 min into recovery. Group-by-time interactions revealed that the 10-minute-long, long-cycle kettlebell routine increased (P < 0.05) the levels of all outcomes (e.g. heart rate, blood pressure, blood lactate) (range of effect sizes: -0.9-8.9) with many outcomes remaining well above baseline at 5 and 15 min into recovery. A notable exception was a lack of change in maximal squat strength. Kettlebell experience and mass correlated with changes in oxygen uptake (ΔVO2) and in ventilation (ΔVT) (r = -0.70, 0.64, -0.87, and 0.73, respectively, P < 0.05) in EXP. Kettlebell routine evoked significant changes in all physiological variables (respiratory and cardiovascular), out of which the heart rate (HR), diastolic blood pressure (DBP), rate pressure product (RPP), and blood lactate (BL) outlasted the routine for at least 15 min. Future studies should longitudinally examine physiological responses to kettlebell training throughout a season. Long-cycle kettlebell routine adds to the repertoire of evidence-based exercise options for high-intensity exercise.

Effect of forefoot transverse arch stiffness on foot biomechanical response--based on finite element method.

Background: The plantar vault, comprising the transverse and longitudinal arches of the human foot, is essential for impact absorption, elastic energy storage, and propulsion. Recent research underscores the importance of the transverse arch, contributing over 40% to midfoot stiffness. This study aimed to quantify biomechanical responses in the ankle-foot complex by varying the stiffness of the deep metatarsal transverse ligament (DTML). Methods: Using CT image reconstruction, we constructed a complex three-dimensional finite element model of the foot and ankle joint complex, accounting for geometric complexity and nonlinear characteristics. The focus of our study was to evaluate the effect of different forefoot transverse arch stiffness, that is, different Young's modulus values of DTML (from 135 MPa to 405 MPa), on different biomechanical aspects of the foot and ankle complex. Notably, we analyzed their effects on plantar pressure distribution, metatarsal stress patterns, navicular subsidence, and plantar fascial strain. Results: Increasing the stiffness of the DTML has significant effects on foot biomechanics. Specifically, higher DTML stiffness leads to elevate von Mises stress in the 1st, 2nd, and 3rd metatarsals, while concurrently reducing plantar pressure by 14.2% when the Young's modulus is doubled. This stiffening also impedes navicular bone subsidence and foot lengthening. Notably, a 100% increase in the Young's modulus of DTML results in a 54.1% decrease in scaphoid subsidence and a 2.5% decrease in foot lengthening, which collectively contribute to a 33.1% enhancement in foot longitudinal stiffness. Additionally, doubling the Young's modulus of DTML can reduce the strain stretch of the plantar fascia by 38.5%. Conclusion: Preserving DTML integrity sustains the transverse arch, enhancing foot longitudinal stiffness and elastic responsiveness. These findings have implications for treating arch dysfunction and provide insights for shoe developers seeking to enhance propulsion.

Heart rate-related physiological changes induced by classical music-elicited emotions do not underlie alterations in healthy adults' ankle joint target-matching strategy.

Emotions have the potential to modulate human voluntary movement by modifying muscle afferent discharge which in turn may affect kinesthetic acuity. We examined if heart rate (HR)-related physiological changes induced by music-elicited emotions would underlie alterations in healthy young adults' ankle joint target-matching strategy quantified by joint position sense (JPS). Participants (n = 40, 19 females, age = 25.9 ± 2.9 years) performed ipsilateral-, and contralateral ankle target-matching tasks with their dominant and non-dominant foot using a custom-made foot platform while listening to classical music pieces deemed to evoke happy, sad, or neutral emotions (each n = 10). Participants in the 4th group received no music during the task. Absolute (ABS), constant (CONST), and variable (VAR) target-matching errors and HR-related data were analyzed. Participants performed the contralateral target-matching task with smaller JPS errors when listening to sad vs. happy music (ABS: p < 0.001, d = 1.6; VAR: p = 0.010, d = 1.2) or neutral (ABS: p < 0.001, d = 1.6; VAR: p < 0.001, d = 1.4) music. The ABS (d = 0.8) and VAR (d = 0.3) JPS errors were lower when participants performed the task with their dominant vs. non-dominant foot. JPS errors were also smaller during the ipsilateral target-matching task when participants (1) listened to sad vs. neutral (ABS: p = 0.007, d = 1.2) music, and (2) performed the target-matching with their dominant vs. non-dominant foot (p < 0.001, d = 0.4). Although emotions also induced changes in some HR-related data during the matching conditions, i.e., participants who listened to happy music had lower HR-related values when matching with their non-dominant vs. dominant foot, these changes did not correlate with JPS errors (all p > 0.05). Overall, our results suggest that music-induced emotions have the potential to affect target-matching strategy and HR-related metrics but the changes in HR-metrics do not underlie the alteration of ankle joint target-matching strategy in response to classical music-elicited emotions.

Corticomuscular and intermuscular coherence as a function of age and walking balance difficulty.

We determined beta-band intermuscular (IMC) and corticomuscular coherence (CMC) as a function of age and walking balance difficulty. Younger (n=14, 23y) and older individuals (n=19, 71y) walked 13 m overground, on a 6-cm-wide ribbon overground, and on a 6-cm-wide (5-cm-high) beam. Walking distance as a proxy for walking balance and speed were computed. CMC was estimated between electroencephalographic signal at Cz electrode and surface electromyographic signals of seven leg muscles, while IMC was calculated in four pairs of leg muscles, during stance and swing gait phases. With increasing difficulty, walking balance decreased in old individuals and speed decreased gradually independent of age. Beam walking increased IMC, while age increased IMC in proximal muscle pairs, and decreased IMC in distal muscle pairs. Age and difficulty increased CMC independent of gait phases. Concluding, CMC and IMC increased with walking balance difficulty and age, except for distal muscle pairs, which had lower IMC with age. These findings suggest an age-related increase in corticospinal involvement in the neural control of walking balance. DATA AVAILABILITY: The datasets used in this study are available from the corresponding author upon reasonable request.

Early and selective localization of tau filaments to glutamatergic subcellular domains within the human anterodorsal thalamus.

Widespread cortical accumulation of misfolded pathological tau proteins (ptau) in the form of paired helical filaments is a major hallmark of Alzheimer's disease. Subcellular localization of ptau at various stages of disease progression is likely to be informative of the cellular mechanisms involving its spread. Here, we found that the density of ptau within several distinct rostral thalamic nuclei in post-mortem human tissue (n = 25 cases) increased with the disease stage, with the anterodorsal nucleus (ADn) consistently being the most affected. In the ADn, ptau-positive elements were present already in the pre-cortical (Braak 0) stage. Tau pathology preferentially affected the calretinin-expressing subpopulation of glutamatergic neurons in the ADn. At the subcellular level, we detected ptau immunoreactivity in ADn cell bodies, dendrites, and in a specialized type of presynaptic terminal that expresses vesicular glutamate transporter 2 (vGLUT2) and likely originates from the mammillary body. The ptau-containing terminals displayed signs of degeneration, including endosomal/lysosomal organelles. In contrast, corticothalamic axon terminals lacked ptau. The data demonstrate the involvement of a specific cell population in ADn at the onset of the disease. The presence of ptau in subcortical glutamatergic presynaptic terminals supports hypotheses about the transsynaptic spread of tau selectively affecting specialized axonal pathways.

Antidepressant-induced membrane trafficking regulates blood-brain barrier permeability.

As the most prescribed psychotropic drugs in current medical practice, antidepressant drugs (ADs) of the selective serotonin reuptake inhibitor (SSRI) class represent prime candidates for drug repurposing. The mechanisms underlying their mode of action, however, remain unclear. Here, we show that common SSRIs and selected representatives of other AD classes bidirectionally regulate fluid-phase uptake at therapeutic concentrations and below. We further characterize membrane trafficking induced by a canonical SSRI fluvoxamine to show that it involves enhancement of clathrin-mediated endocytosis, endosomal system, and exocytosis. RNA sequencing analysis showed few fluvoxamine-associated differences, consistent with the effect being independent of gene expression. Fluvoxamine-induced increase in membrane trafficking boosted transcytosis in cell-based blood-brain barrier models, while a single injection of fluvoxamine was sufficient to enable brain accumulation of a fluid-phase fluorescent tracer in vivo. These findings reveal modulation of membrane trafficking by ADs as a possible cellular mechanism of action and indicate their clinical repositioning potential for regulating drug delivery to the brain.

Sequencing Effects of Concurrent Strength and Endurance Training on Selected Measures of Physical Fitness in Young Male Soccer Players: A Randomized Matched-Pairs Trial.

BACKGROUND: Various physical fitness qualities such as muscle strength, speed and endurance are related to soccer performance. Accordingly, the combination of strength and endurance training (i.e., concurrent training [CT]) is an often-encountered training regimen in soccer. Less is known about the effects of CT sequencing on performance in young soccer players. The aim of this study was to assess the sequencing effects of strength and intermittent endurance training applied within the same training session (intrasession) on measures of physical fitness and soccer performance in young soccer players. METHODS: Fifty male adolescent soccer players volunteered to participate in this study which was conducted in the Netherlands in 2019. Players were randomly assigned to a strength-endurance (SE) or an endurance-strength (ES) group in matched pairs based on their countermovement jump (CMJ) performance at baseline. Both groups completed a 12-weeks in-season training program with two weekly CT sessions. Training sessions consisted of 15 min plyometric exercises and 15 min soccer-specific intermittent endurance training. Both groups performed the same training volumes and the only difference between the groups was the CT intrasession sequencing scheme (SE vs. ES). Pre and post intervention, proxies of muscle power (CMJ, squat jump [SJ]), linear sprint speed (30-m sprint test), agility (Illinois test with / without ball), and soccer performance (ball kicking velocity) were tested. RESULTS: Data from 38 players aged 14.8 ± 1.0 years (body height 172.9 ± 8.1 cm, body mass: 57.0 ± 7.2 kg, soccer experience: 8.8 ± 2.8 years, age from peak-height-velocity [PHV]: +1.2 ± 1.0 years) were included. Significant main time effects were found for CMJ (p = 0.002, d = 0.55), SJ (p = 0.004, d = 0.51), the Illinois agility test with ball (p = 0.016, d = 0.51), and ball kicking velocity (p = 0.016, d = 0.51). Significant group-by-time interactions were observed for 30-m linear sprint speed (p < 0.001, d = 0.76) with ES showing greater improvements (p = 0.006, d = 0.85, Δ-5%). CONCLUSIONS: Both CT-sequencing types improved performance in the tests administered. The intrasession CT sequencing (SE vs. ES) appears not to have a major impact on physical fitness adaptations, except for linear sprint speed which was in favor of ES.

Walking on a Balance Beam as a New Measure of Dynamic Balance to Predict Falls in Older Adults and Patients with Neurological Conditions.

BACKGROUND: Beam walking is a new test to estimate dynamic balance. We characterized dynamic balance measured by the distance walked on beams of different widths in five age groups of healthy adults (20, 30, 40, 50, 60 years) and individuals with neurological conditions (i.e., Parkinson, multiple sclerosis, stroke, age: 66.9 years) and determined if beam walking distance predicted prospective falls over 12 months. METHODS: Individuals with (n = 97) and without neurological conditions (n = 99, healthy adults, age 20-60) participated in this prospective longitudinal study. Falls analyses over 12 months were conducted. The summed distance walked under single (walking only) and dual-task conditions (walking and serial subtraction by 7 between 300 to 900) on three beams (4, 8, and 12-cm wide) was used in the analyses. Additional functional tests comprised grip strength and the Short Physical Performance Battery. RESULTS: Beam walking distance was unaffected on the 12-cm-wide beam in the healthy adult groups. The distance walked on the 8-cm-wide beam decreased by 0.34 m in the 20-year-old group. This reduction was ~ 3 × greater, 1.1 m, in the 60-year-old group. In patients, beam walking distances decreased sharply by 0.8 m on the 8 versus 12 cm beam and by additional 1.6 m on the 4 versus 8 cm beam. Beam walking distance under single and dual-task conditions was linearly but weakly associated with age (R2 = 0.21 for single task, R2 = 0.27 for dual-task). Age, disease, and beam width affected distance walked on the beam. Beam walking distance predicted future falls in the combined population of healthy adults and patients with neurological conditions. Based on receiver operating characteristic curve analyses using data from the entire study population, walking ~ 8.0 of the 12 m maximum on low-lying beams predicted future fallers with reasonable accuracy. CONCLUSION: Balance beam walking is a new but worthwhile measure of dynamic balance to predict falls in the combined population of healthy adults and patients with neurological conditions. Future studies are needed to evaluate the predictive capability of beam walking separately in more homogenous populations. Clinical Trial Registration Number NCT03532984.

Neural Correlates of Balance Skill Learning in Young and Older Individuals: A Systematic Review and Meta-analysis.

BACKGROUND: Despite the increasing number of research studies examining the effects of age on the control of posture, the number of annual fall-related injuries and deaths continues to increase. A better understanding of how old age affects the neural mechanisms of postural control and how countermeasures such as balance training could improve the neural control of posture to reduce falls in older individuals is therefore necessary. The aim of this review is to determine the effects of age on the neural correlates of balance skill learning measured during static (standing) and dynamic (walking) balance tasks in healthy individuals. METHODS: We determined the effects of acute (1-3 sessions) and chronic (> 3 sessions) balance skill training on balance in the trained and in untrained, transfer balance tasks through a systematic review and quantified these effects by robust variance estimation meta-analysis in combination with meta-regression. We systematically searched PubMed, Web of Science, and Cochrane databases. Balance performance and neural plasticity outcomes were extracted and included in the systematic synthesis and meta-analysis. RESULTS: Forty-two studies (n = 622 young, n = 699 older individuals) were included in the systematic synthesis. Seventeen studies with 508 in-analysis participants were eligible for a meta-analysis. The overall analysis revealed that acute and chronic balance training had a large effect on the neural correlates of balance skill learning in the two age groups combined (g = 0.79, p < 0.01). Both age groups similarly improved balance skill performance in 1-3 training sessions and showed little further improvements with additional sessions. Improvements in balance performance mainly occurred in the trained and less so in the non-trained (i.e., transfer) balance tasks. The systematic synthesis and meta-analysis suggested little correspondence between improved balance skills and changes in spinal, cortical, and corticospinal excitability measures in the two age groups and between the time courses of changes in balance skills and neural correlates. CONCLUSIONS: Balance skill learning and the accompanying neural adaptations occur rapidly and independently of age with little to no training dose-dependence or correspondence between behavioral and neural adaptations. Of the five types of neural correlates examined, changes in only spinal excitability seemed to differ between age groups. However, age or training dose in terms of duration did not moderate the effects of balance training on the changes in any of the neural correlates. The behavioral and neural mechanisms of strong task-specificity and the time course of skill retention remain unclear and require further studies in young and older individuals. REGISTRATION: PROSPERO registration number: CRD42022349573.

A phase Ib/II randomized, open-label drug repurposing trial of glutamate signaling inhibitors in combination with chemoradiotherapy in patients with newly diagnosed glioblastoma: the GLUGLIO trial protocol.

BACKGROUND: Glioblastoma is the most common and most aggressive malignant primary brain tumor in adults. Glioblastoma cells synthesize and secrete large quantities of the excitatory neurotransmitter glutamate, driving epilepsy, neuronal death, tumor growth and invasion. Moreover, neuronal networks interconnect with glioblastoma cell networks through glutamatergic neuroglial synapses, activation of which induces oncogenic calcium oscillations that are propagated via gap junctions between tumor cells. The primary objective of this study is to explore the efficacy of brain-penetrating anti-glutamatergic drugs to standard chemoradiotherapy in patients with glioblastoma. METHODS/DESIGN: GLUGLIO is a 1:1 randomized phase Ib/II, parallel-group, open-label, multicenter trial of gabapentin, sulfasalazine, memantine and chemoradiotherapy (Arm A) versus chemoradiotherapy alone (Arm B) in patients with newly diagnosed glioblastoma. Planned accrual is 120 patients. The primary endpoint is progression-free survival at 6 months. Secondary endpoints include overall and seizure-free survival, quality of life of patients and caregivers, symptom burden and cognitive functioning. Glutamate levels will be assessed longitudinally by magnetic resonance spectroscopy. Other outcomes of interest include imaging response rate, neuronal hyperexcitability determined by longitudinal electroencephalography, Karnofsky performance status as a global measure of overall performance, anticonvulsant drug use and steroid use. Tumor tissue and blood will be collected for translational research. Subgroup survival analyses by baseline parameters include segregation by age, extent of resection, Karnofsky performance status, O6-methylguanine DNA methyltransferase (MGMT) promotor methylation status, steroid intake, presence or absence of seizures, tumor volume and glutamate levels determined by MR spectroscopy. The trial is currently recruiting in seven centers in Switzerland. TRIAL REGISTRATION: NCT05664464. Registered 23 December 2022.

Aerobic exercise training effects on hippocampal volume in healthy older individuals: a meta-analysis of randomized controlled trials.

We conducted a meta-analysis of randomized controlled trials investigating the effects of aerobic exercise training (AET) lasting ≥ 4 weeks on hippocampal volume and cardiorespiratory fitness (CRF) in cognitively unimpaired, healthy older individuals. Random-effects robust variance estimation models were used to test differences between AET and controls, while meta-regressions tested associations between CRF and hippocampal volume changes. We included eight studies (N = 554) delivering fully supervised AET for 3 to 12 months (M = 7.8, SD = 4.5) with an average AET volume of 129.85 min/week (SD = 45.5) at moderate-to-vigorous intensity. There were no significant effects of AET on hippocampal volume (SMD = 0.10, 95% CI - 0.01 to 0.21, p = 0.073), but AET moderately improved CRF (SMD = 0.30, 95% CI 0.12 to 0.48, p = 0.005). Improvement in CRF was not associated with changes in hippocampal volume (bSE = 0.05, SE = 0.51, p = 0.923). From the limited number of studies, AET does not seem to impact hippocampal volume in cognitively unimpaired, healthy older individuals. Notable methodological limitations across investigations might mask the lack of effects.

Neurologic involvement in cystinosis: Focus on brain lesions and new evidence of four-repeat (4R-) Tau immunoreactivity.

Nephropathic cystinosis is a rare autosomal recessive storage disorder caused by CTNS gene mutations, leading to autophagy-lysosomal pathway impairment and cystine crystals accumulation. Neurologic involvement is highly variable and includes both neurodevelopmental and neurodegenerative disturbances, as well as focal neurologic deficits. By presenting longitudinal data of a 28-year-old patient with a large infratentorial lesion, we summarized the pathology, clinical and imaging features of neurological involvement in cystinosis patients. Brain damage in form of cystinosis-related cerebral lesions occurs in advanced disease phases and is characterized by the accumulation of cystine crystals, subsequent inflammation with vasculitis-like features, necrosis, and calcification. Epilepsy is a frequent comorbidity in affected individuals. Steroids might play a role in the symptomatic treatment of "stroke-like" episodes due to edematous-inflammatory lesions, but probably do not change the overall prognosis. Lifelong compliance to depleting therapy with cysteamine still represents the main therapeutic option. However, consequences of CTNS gene defects are not restricted to cystine accumulation. New evidence of four-repeat (4R-) Tau immunoreactivity suggests concurrent progressive neurodegeneration in cystinosis patients, highlighting the need of innovative therapeutic strategies, and shedding light on the crosstalk between proteinopathies and autophagy-lysosomal system defects. Eventually, emerging easily accessible biomarkers such as serum neurofilament light chains (NfL) might detect subclinical neurologic involvement in cystinosis patients.

Blood flow restriction reduces the increases in cardiorespiratory responses and subjective burden without inhibiting muscular activity during cycling at ventilatory threshold in healthy males.

Low-intensity endurance exercise with blood flow restriction (KAATSU) is under consideration for use in cardiac rehabilitation. However, the physiological responses to such exercise have not yet been fully characterized. In an initial effort in healthy males (n = 11, age: 26.3±4.6 y), we compared the physiological responses to low-intensity endurance exercise with and without a thigh KAATSU. Participants performed maximal graded exercise testing using a cycle ergometer with or without KAATSU. We examined responses to cycling exercise at ventilatory threshold (VT) in heart rate (HR), oxygen consumption (VO2), dyspnea, ratings of perceived exertion (RPE), blood pressure (BP), and rectus femoris activation. Participants reached VT at a lower mechanical load, HR, VO2, dyspnea, and double product (HR×systolic BP) with KAATSU vs. no-KAATSU. At VT, RPE, and rectus femoris activity did not differ between the two conditions. These results suggest that KAATSU reduced exercise intensity to reach VT and the physiological responses to exercise at VT without changes in knee extensor muscle activation. Results from this pilot study in healthy males suggest that KAATSU aerobic exercise at VT intensity has the potential to be an effective and low-burden adjuvant to cycling in cardiac rehabilitation.

Early histopathological changes of secondary degeneration in the spinal cord after total MCA territory stroke.

Previous research has not demonstrated secondary degeneration of the spinal cord (SpC) motoneurons after cerebral infarct. The aim of the present study is to investigate the involvement of the anterior horn cells (AHC) in the early post-stroke period using histomorphological and immunohistochemical methods. Post-mortem analysis of the 6th cervical segment was performed in 7 patients who had total MCA stroke within 1 month before death. Nissl-stained sections were used for morphometry, while CD68 and synaptophysin (SYP) immunohistochemistry to monitor microglial activation and synaptic changes in the anterior horn (AH), respectively. Contralateral to the cerebral lesion (contralesional side), cells were smaller after 3 days and larger after 1 week of stroke, especially regarding the large alpha motoneurons. CD68 density increased mainly on the contralesional Rexed's IX lamina of the SpC. SYP coverage of the large motoneurons was reduced on the contralesional side. Early microglial activation in the AH and electrophysiological signs has suggested the possibility of impairment of anterior horn cells (AHC-s). Our study supported that early microglial activation in the contralesional side of the SpC may primarily affect the area corresponding to the location of large motoneurons, and is accompanied by a transient shrinkage followed by increase in size of the large AHC-s with a reduction of their synaptic coverage. After MCA stroke, early involvement of the SpC motoneurons may be suspected by their morphological and synaptic changes and by the pattern of microglial activation.

The Brainbox-a tool to facilitate correlation of brain magnetic resonance imaging features to histopathology.

Magnetic resonance imaging (MRI) has limitations in identifying underlying tissue pathology, which is relevant for neurological diseases such as multiple sclerosis, stroke or brain tumours. However, there are no standardized methods for correlating MRI features with histopathology. Thus, here we aimed to develop and validate a tool that can facilitate the correlation of brain MRI features to corresponding histopathology. For this, we designed the Brainbox, a waterproof and MRI-compatible 3D printed container with an integrated 3D coordinate system. We used the Brainbox to acquire post-mortem ex vivo MRI of eight human brains, fresh and formalin-fixed, and correlated focal imaging features to histopathology using the built-in 3D coordinate system. With its built-in 3D coordinate system, the Brainbox allowed correlation of MRI features to corresponding tissue substrates. The Brainbox was used to correlate different MR image features of interest to the respective tissue substrate, including normal anatomical structures such as the hippocampus or perivascular spaces, as well as a lacunar stroke. Brain volume decreased upon fixation by 7% (P = 0.01). The Brainbox enabled degassing of specimens before scanning, reducing susceptibility artefacts and minimizing bulk motion during scanning. In conclusion, our proof-of-principle experiments demonstrate the usability of the Brainbox, which can contribute to improving the specificity of MRI and the standardization of the correlation between post-mortem ex vivo human brain MRI and histopathology. Brainboxes are available upon request from our institution.