Neurotrophic Factors as Regenerative Therapy for Neurodegenerative Diseases: Current Status, Challenges and Future Perspectives.

Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), spinal cord injury (SCI), and amyotrophic lateral sclerosis (ALS), are characterized by acute or chronic progressive loss of one or several neuronal subtypes. However, despite their increasing prevalence, little progress has been made in successfully treating these diseases. Research has recently focused on neurotrophic factors (NTFs) as potential regenerative therapy for neurodegenerative diseases. Here, we discuss the current state of knowledge, challenges, and future perspectives of NTFs with a direct regenerative effect in chronic inflammatory and degenerative disorders. Various systems for delivery of NTFs, such as stem and immune cells, viral vectors, and biomaterials, have been applied to deliver exogenous NTFs to the central nervous system, with promising results. The challenges that currently need to be overcome include the amount of NTFs delivered, the invasiveness of the delivery route, the blood-brain barrier permeability, and the occurrence of side effects. Nevertheless, it is important to continue research and develop standards for clinical applications. In addition to the use of single NTFs, the complexity of chronic inflammatory and degenerative diseases may require combination therapies targeting multiple pathways or other possibilities using smaller molecules, such as NTF mimetics, for effective treatment.

Engineering of regulatory T cells by means of mRNA electroporation in a GMP-compliant manner.

Regulatory T cells (Tregs) are crucial in inducing and maintaining tolerance. This unique capacity of Tregs, in combination with proof-of-principle in preclinical studies, highlights the potential clinical use of Tregs for the treatment of autoimmunity and transplant rejection. Although proven to be safe and well tolerated in the first clinical trials, only modest clinical results were observed. In this regard, it has been hypothesized that current challenges lie in the development of antigen-specific Tregs. Here, we present an innovative, good manufacturing practices (GMP)-compliant manufacturing protocol for Tregs applicable in a clinical-grade setting, allowing efficient and safe redirection of Treg specificity. First, a soluble polymer conjugated with antibodies to CD3 and CD28 and high amounts of exogenous IL-2 for in vitro Treg expansion resulted in a >70-fold and 185-fold increase of a pure population of CD4+CD127-CD25hi Tregs and CD4+CD127-CD25+CD45RA+ Tregs, respectively. Next, as a proof-of-principle, expanded Tregs were engineered by means of TCR-encoding mRNA electroporation to generate antigen-specific Tregs. This resulted in an expression of the newly introduced TCR in up to 85% of Tregs. Moreover, we did not observe a negative effect on the phenotype of Tregs, as demonstrated by the expression of FOXP3, Helios, CTLA-4 and CCR4, nor on the TSDR methylation status. Importantly, mRNA-engineered Tregs were still able to induce in vitro suppression of effector T cells and produced anti-inflammatory, but not pro-inflammatory, cytokines when activated. In conclusion, our findings demonstrate that high numbers of stable and functional Tregs can be obtained with high purity and successfully engineered for gain of function, in a GMP-compliant manner. We envisage that this clinical-grade protocol will provide solid basis for future clinical application of mRNA-engineered Tregs.

Made to Measure: Patient-Tailored Treatment of Multiple Sclerosis Using Cell-Based Therapies.

Currently, there is still no cure for multiple sclerosis (MS), which is an autoimmune and neurodegenerative disease of the central nervous system. Treatment options predominantly consist of drugs that affect adaptive immunity and lead to a reduction of the inflammatory disease activity. A broad range of possible cell-based therapeutic options are being explored in the treatment of autoimmune diseases, including MS. This review aims to provide an overview of recent and future advances in the development of cell-based treatment options for the induction of tolerance in MS. Here, we will focus on haematopoietic stem cells, mesenchymal stromal cells, regulatory T cells and dendritic cells. We will also focus on less familiar cell types that are used in cell therapy, including B cells, natural killer cells and peripheral blood mononuclear cells. We will address key issues regarding the depicted therapies and highlight the major challenges that lie ahead to successfully reverse autoimmune diseases, such as MS, while minimising the side effects. Although cell-based therapies are well known and used in the treatment of several cancers, cell-based treatment options hold promise for the future treatment of autoimmune diseases in general, and MS in particular.

Cells to the Rescue: Emerging Cell-Based Treatment Approaches for NMOSD and MOGAD.

Cell-based therapies are gaining momentum as promising treatments for rare neurological autoimmune diseases, including neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein antibody-associated disease. The development of targeted cell therapies is hampered by the lack of adequate animal models that mirror the human disease. Most cell-based treatments, including HSCT, CAR-T cell, tolerogenic dendritic cell and mesenchymal stem cell treatment have entered early stage clinical trials or have been used as rescue treatment in treatment-refractory cases. The development of antigen-specific cell-based immunotherapies for autoimmune diseases is slowed down by the rarity of the diseases, the lack of surrogate outcomes and biomarkers that are able to predict long-term outcomes and/or therapy effectiveness as well as challenges in the manufacturing of cellular products. These challenges are likely to be overcome by future research.

Clinical and immunological control of experimental autoimmune encephalomyelitis by tolerogenic dendritic cells loaded with MOG-encoding mRNA.

BACKGROUND: Although effective in reducing relapse rate and delaying progression, current therapies for multiple sclerosis (MS) do not completely halt disease progression. T cell autoimmunity to myelin antigens is considered one of the main mechanisms driving MS. It is characterized by autoreactivity to disease-initiating myelin antigen epitope(s), followed by a cascade of epitope spreading, which are both strongly patient-dependent. Targeting a variety of MS-associated antigens by myelin antigen-presenting tolerogenic dendritic cells (tolDC) is a promising treatment strategy to re-establish tolerance in MS. Electroporation with mRNA encoding myelin proteins is an innovative technique to load tolDC with the full spectrum of naturally processed myelin-derived epitopes. METHODS: In this study, we generated murine tolDC presenting myelin oligodendrocyte glycoprotein (MOG) using mRNA electroporation and we assessed the efficacy of MOG mRNA-electroporated tolDC to dampen pathogenic T cell responses in experimental autoimmune encephalomyelitis (EAE). For this, MOG35-55-immunized C57BL/6 mice were injected intravenously at days 13, 17, and 21 post-disease induction with 1α,25-dihydroxyvitamin D3-treated tolDC electroporated with MOG-encoding mRNA. Mice were scored daily for signs of paralysis. At day 25, myelin reactivity was evaluated following restimulation of splenocytes with myelin-derived epitopes. Ex vivo magnetic resonance imaging (MRI) was performed to assess spinal cord inflammatory lesion load. RESULTS: Treatment of MOG35-55-immunized C57BL/6 mice with MOG mRNA-electroporated or MOG35-55-pulsed tolDC led to a stabilization of the EAE clinical score from the first administration onwards, whereas it worsened in mice treated with non-antigen-loaded tolDC or with vehicle only. In addition, MOG35-55-specific pro-inflammatory pathogenic T cell responses and myelin antigen epitope spreading were inhibited in the peripheral immune system of tolDC-treated mice. Finally, magnetic resonance imaging analysis of hyperintense spots along the spinal cord was in line with the clinical score. CONCLUSIONS: Electroporation with mRNA is an efficient and versatile tool to generate myelin-presenting tolDC that are capable to stabilize the clinical score in EAE. These results pave the way for further research into mRNA-electroporated tolDC treatment as a patient-tailored therapy for MS.

Effects of an individual 12-week community-located "start-to-run" program on physical capacity, walking, fatigue, cognitive function, brain volumes, and structures in persons with multiple sclerosis.

BACKGROUND: Exercise therapy studies in persons with multiple sclerosis (pwMS) primarily focused on motor outcomes in mid disease stage, while cognitive function and neural correlates were only limitedly addressed. OBJECTIVES: This pragmatic randomized controlled study investigated the effects of a remotely supervised community-located "start-to-run" program on physical and cognitive function, fatigue, quality of life, brain volume, and connectivity. METHOD: In all, 42 pwMS were randomized to either experimental (EXP) or waiting list control (WLC) group. The EXP group received individualized training instructions during 12 weeks (3×/week), to be performed in their community aiming to participate in a running event. Measures were physical (VO2max, sit-to-stand test, Six-Minute Walk Test (6MWT), Multiple Sclerosis Walking Scale-12 (MSWS-12)) and cognitive function (Rao's Brief Repeatable Battery (BRB), Paced Auditory Serial Attention Test (PASAT)), fatigue (Fatigue Scale for Motor and Cognitive Function (FSMC)), quality of life (Multiple Sclerosis Impact Scale-29 (MSIS-29)), and imaging. Brain volumes and diffusion tensor imaging (DTI) were quantified using FSL-SIENA/FIRST and FSL-TBSS. RESULTS: In all, 35 pwMS completed the trial. Interaction effects in favor of the EXP group were found for VO2max, sit-to-stand test, MSWS-12, Spatial Recall Test, FSMC, MSIS-29, and pallidum volume. VO2max improved by 1.5 mL/kg/min, MSWS-12 by 4, FSMC by 11, and MSIS-29 by 14 points. The Spatial Recall Test improved by more than 10%. CONCLUSION: Community-located run training improved aerobic capacity, functional mobility, visuospatial memory, fatigue, and quality of life and pallidum volume in pwMS.

Adrenergically and non-adrenergically mediated human adipose tissue lipolysis during acute exercise and exercise training.

Obesity-related adipose tissue (AT) dysfunction, in particular subcutaneous AT (SCAT) lipolysis, is characterized by catecholamine resistance and impaired atrial natriuretic peptide (ANP) responsiveness. It remains unknown whether exercise training improves (non-)adrenergically mediated lipolysis in metabolically compromised conditions. We investigated the effects of local combined α-/ß-adrenoceptor blockade on abdominal SCAT lipolysis in lean insulin sensitive (IS) (n=10), obese IS (n=10), and obese insulin resistant (IR) (n=10) men. Obese men participated in a 12-week exercise training intervention to determine the effects on SCAT lipolysis. Abdominal SCAT extracellular glycerol concentration and blood flow (ATBF) were investigated using microdialysis, with/without locally combined α-/ß-adrenoceptor blockade at rest, during low-intensity endurance-type exercise and post-exercise recovery. In obese IR men, microdialysis was repeated after exercise intervention. The exercise-induced increase in SCAT extracellular glycerol was more pronounced in obese IS compared with lean IS men, possibly resulting from lower ATBF in obese IS men. The exercise-induced increase in extracellular glycerol was blunted in obese IR compared with obese IS men, despite comparable local ATBF. Abdominal SCAT extracellular glycerol was markedly reduced (remaining ~60% of exercise-induced SCAT extracellular glycerol) following the local α-/ß-adrenoceptor blockade in obese IS but not in IR men, suggesting reduced catecholamine-mediated lipolysis during exercise in obese IR men. Exercise training did not affect (non-)adrenergically mediated lipolysis in obese IR men. Our findings showed a major contribution of non-adrenergically-mediated lipolysis during exercise in male abdominal SCAT. Furthermore, catecholamine-mediated lipolysis may be blunted during exercise in obese IR men but could not be improved by exercise intervention, despite an improved metabolic profile and body composition.

Twelve Weeks of Medium-Intensity Exercise Therapy Affects the Lipoprotein Profile of Multiple Sclerosis Patients.

Multiple sclerosis (MS) is an inflammatory auto-immune disease of the central nervous system (CNS). Serum glucose alterations and impaired glucose tolerance (IGT) are reported in MS patients, and are commonly associated with the development of cardio-metabolic co-morbidities. We previously found that a subgroup of MS patients shows alterations in their lipoprotein profile that are similar to a pre-cardiovascular risk profile. In addition, we showed that a high-intensity exercise training has a positive effect on IGT in MS patients. In this study, we hypothesize that exercise training positively influences the lipoprotein profile of MS patients. To this end, we performed a pilot study and determined the lipoprotein profile before (controls, n = 40; MS patients, n = 41) and after (n = 41 MS only) 12 weeks of medium-intensity continuous training (MIT, n = 21, ~60% of VO2max) or high-intensity interval training (HIT, n = 20, ~100-200% of VO2max) using nuclear magnetic resonance spectroscopy (NMR). Twelve weeks of MIT reduced intermediate-density lipoprotein particle count ((nmol/L); -43.4%; p < 0.01), low-density lipoprotein cholesterol (LDL-c (mg/dL); -7.6%; p < 0.05) and VLDL size ((nm); -6.6%; p < 0.05), whereas HIT did not influence the lipoprotein profile. These results show that MIT partially normalizes lipoprotein alterations in MS patients. Future studies including larger patient and control groups should determine whether MIT can reverse other lipoprotein levels and function and if these alterations are related to MS disease progression and the development of co-morbidities.

Cardiopulmonary fitness is related to disease severity in multiple sclerosis.

BACKGROUND: In persons with MS (pwMS), a lower cardiopulmonary fitness has been associated with a higher risk for secondary disorders, decreased functional capacity, symptom worsening and reduced health-related quality of life. OBJECTIVE: To investigate the association between disease severity and cardiopulmonary fitness. METHODS: Data from cardiopulmonary exercise tests, previously conducted in three different countries, were pooled. The association between disease severity (Expanded Disability Status Scale (EDSS)) and cardiopulmonary fitness (peak oxygen uptake (VO2peak)) was adjusted for age, sex and the country of origin. RESULTS: The combined sample comprised 116 ambulant pwMS having a mean (± SD) EDSS score of 2.7 ± 1.3. There was a significant correlation (r = -0.418, p < .01) between VO2peak and EDSS. A multiple regression model (R(2) = 0.520, p < .01) was constructed to describe VO2peak (mL∙kg(-1)∙min(-1)); VO2peak = 36.622 - 5.433 (Sex (1=men)) - 0.124 (Age) - 2.082 (EDSS) + 2.737 (Belgium) + 8.674 (Denmark). CONCLUSION: There was a significant association between disease severity and cardiopulmonary fitness. The close relation between cardiopulmonary fitness and chronic conditions associated with physical inactivity, suggest a progressive increase in risk of secondary health conditions in pwMS.

12 Weeks of Combined Endurance and Resistance Training Reduces Innate Markers of Inflammation in a Randomized Controlled Clinical Trial in Patients with Multiple Sclerosis.

Previously, we reported that patients with multiple sclerosis (MS) demonstrate improved muscle strength, exercise tolerance, and lean tissue mass following a combined endurance and resistance exercise program. However, the effect of exercise on the underlying disease pathogenesis remains elusive. Since recent evidence supports a crucial role of dendritic cells (DC) in the pathogenesis of MS, we investigated the effect of a 12-week combined exercise program in MS patients on the number and function of DC. We demonstrate an increased number of plasmacytoid DC (pDC) following the exercise program. These pDC display an activated phenotype, as evidenced by increased numbers of circulating CD62L(+) and CD80(+) pDC. Interestingly, the number of CD80(+) pDC positively correlates with the presence of IL-10-producing regulatory type 1 cells (Tr1), an important cell type for maintaining peripheral tolerance to self-antigens. In addition, decreased production of the inflammatory mediators, TNF-α and MMP-9, upon Toll-like receptor (TLR) stimulation was found at the end of the exercise program. Overall, our findings suggest that the 12-week exercise program reduces the secretion of inflammatory mediators upon TLR stimulation and promotes the immunoregulatory function of circulating pDC, suggestive for a favorable impact of exercise on the underlying immunopathogenesis of MS.

Rapid Exercise-Induced Mobilization of Dendritic Cells Is Potentially Mediated by a Flt3L- and MMP-9-Dependent Process in Multiple Sclerosis.

In healthy individuals, one exercise bout induces a substantial increase in the number of circulating leukocytes, while their function is transiently suppressed. The effect of one exercise bout in multiple sclerosis (MS) is less studied. Since recent evidence suggests a role of dendritic cells (DC) in the pathogenesis of MS, we investigated the effect of one combined endurance/resistance exercise bout on the number and function of DC in MS patients and healthy controls. Our results show a rapid increase in the number of DC in response to physical exercise in both MS patients and controls. Further investigation revealed that in particular DC expressing the migratory molecules CCR5 and CD62L were increased upon acute physical activity. This may be mediated by Flt3L- and MMP-9-dependent mobilization of DC, as demonstrated by increased circulating levels of Flt3L and MMP-9 following one exercise bout. Circulating DC display reduced TLR responsiveness after acute exercise, as evidenced by a less pronounced upregulation of activation markers, HLA-DR and CD86, on plasmacytoid DC and conventional DC, respectively. Our results indicate mobilization of DC, which may be less prone to drive inflammatory processes, following exercise. This may present a negative feedback mechanism for exercise-induced tissue damage and inflammation.

Early Inhibition of Phosphodiesterase 4B (PDE4B) Instills Cognitive Resilience in APPswe/PS1dE9 Mice.

Microglia activity can drive excessive synaptic loss during the prodromal phase of Alzheimer's disease (AD) and is associated with lowered cyclic adenosine monophosphate (cAMP) due to cAMP phosphodiesterase 4B (PDE4B). This study aimed to investigate whether long-term inhibition of PDE4B by A33 (3 mg/kg/day) can prevent synapse loss and its associated cognitive decline in APPswe/PS1dE9 mice. This model is characterized by a chimeric mouse/human APP with the Swedish mutation and human PSEN1 lacking exon 9 (dE9), both under the control of the mouse prion protein promoter. The effects on cognitive function of prolonged A33 treatment from 20 days to 4 months of age, was assessed at 7-8 months. PDE4B inhibition significantly improved both the working and spatial memory of APPswe/PSdE9 mice after treatment ended. At the cellular level, in vitro inhibition of PDE4B induced microglial filopodia formation, suggesting that regulation of PDE4B activity can counteract microglia activation. Further research is needed to investigate if this could prevent microglia from adopting their 'disease-associated microglia (DAM)' phenotype in vivo. These findings support the possibility that PDE4B is a potential target in combating AD pathology and that early intervention using A33 may be a promising treatment strategy for AD.

Risk factors related to cardiovascular diseases and the metabolic syndrome in multiple sclerosis - a systematic review.

Despite many epidemiological studies examining comorbidity in people with multiple sclerosis (pMS), there are conflicting opinions on whether pMS are at more or less risk of cardiovascular disease (CVD) and the metabolic syndrome compared with the general population. As pMS can now expect longer survival, this as an important question both at an individual and public health level. This study aimed to systematically review the literature linking MS to CVD risks and to the risk factors constituting the metabolic syndrome. This systematic review is based on a comprehensive literature search of six databases (Swemed+, Pubmed, Embase, Cochrane, PEDro and CINAHL). In total 34 studies were identified. Despite the high number of identified papers, only limited and inconsistent data exist on the risk factors of the metabolic syndrome and MS. Overall, the data suggest an increased CVD risk in pMS. From the existing studies it is not clear whether the increased risk of CVD is related to an increased risk of obesity or changes in body composition, hypertension, dyslipidemia or type II diabetes in pMS, indicating the need for future research in the field, if we are to advise pMS adequately in avoiding preventable comorbidity.

Are Cell-Based Therapies Safe and Effective in the Treatment of Neurodegenerative Diseases? A Systematic Review with Meta-Analysis.

Over the past two decades, significant advances have been made in the field of regenerative medicine. However, despite being of the utmost clinical urgency, there remains a paucity of therapeutic strategies for conditions with substantial neurodegeneration such as (progressive) multiple sclerosis (MS), spinal cord injury (SCI), Parkinson's disease (PD) and Alzheimer's disease (AD). Different cell types, such as mesenchymal stromal cells (MSC), neuronal stem cells (NSC), olfactory ensheathing cells (OEC), neurons and a variety of others, already demonstrated safety and regenerative or neuroprotective properties in the central nervous system during the preclinical phase. As a result of these promising findings, in recent years, these necessary types of cell therapies have been intensively tested in clinical trials to establish whether these results could be confirmed in patients. However, extensive research is still needed regarding elucidating the exact mechanism of action, possible immune rejection, functionality and survival of the administered cells, dose, frequency and administration route. To summarize the current state of knowledge, we conducted a systematic review with meta-analysis. A total of 27,043 records were reviewed by two independent assessors and 71 records were included in the final quantitative analysis. These results show that the overall frequency of serious adverse events was low: 0.03 (95% CI: 0.01-0.08). In addition, several trials in MS and SCI reported efficacy data, demonstrating some promising results on clinical outcomes. All randomized controlled studies were at a low risk of bias due to appropriate blinding of the treatment, including assessors and patients. In conclusion, cell-based therapies in neurodegenerative disease are safe and feasible while showing promising clinical improvements. Nevertheless, given their high heterogeneity, the results require a cautious approach. We advocate for the harmonization of study protocols of trials investigating cell-based therapies in neurodegenerative diseases, adverse event reporting and investigation of clinical outcomes.

Safety and immunological proof-of-concept following treatment with tolerance-inducing cell products in patients with autoimmune diseases or receiving organ transplantation: A systematic review and meta-analysis of clinical trials.

In the past years, translational approaches have led to early-stage clinical trials assessing safety and efficacy of tolerance-inducing cell-based treatments in patients. This review aims to determine if tolerance-inducing cell-based therapies, including dendritic cells, regulatory T cells and mesenchymal stem cells, are safe in adult patients who underwent organ transplantation or in those with autoimmune diseases, including multiple sclerosis, diabetes mellitus type 1, Crohn's disease and rheumatoid arthritis. Immunological and clinical outcomes were reviewed, to provide evidence for proof-of-concept and efficacy. To summarize the current knowledge, a systematic review and meta-analysis were conducted. A total of 8906 records were reviewed by 2 independent assessors and 48 records were included in the final quantitative analysis. The overall frequency of serious adverse events was low: 0.018 (95% CI: 0.006-0.051). Immunological outcomes could not be assessed quantitatively because of heterogeneity in outcome assessments and description as well as lack of individual data. Most randomized controlled studies were at a medium risk of bias due to open-label treatment without masking of assessors and/or patients to the intervention. In conclusion, tolerance-inducing cell-based therapies are safe. We advocate for harmonization of study protocols of trials investigating cell-based therapies, adverse event reporting and systematic inclusion of immunological outcome measures in clinical trials evaluating tolerance-inducingcell-basedtreatment. Registration: PROSPERO, registration number CRD42020170557.

Impact of Exercise-Nutritional State Interactions in Patients with Type 2 Diabetes.

INTRODUCTION: This study examines the role of nutritional status during exercise training in patients with type 2 diabetes mellitus by investigating the effect of endurance-type exercise training in the fasted versus the fed state on clinical outcome measures, glycemic control, and skeletal muscle characteristics in male type 2 diabetes patients. METHODS: Twenty-five male patients (glycated hemoglobin (HbA1c), 57 ± 3 mmol·mol (7.4% ± 0.3%)) participated in a randomized 12-wk supervised endurance-type exercise intervention, with exercise being performed in an overnight-fasted state (n = 13) or after consuming breakfast (n = 12). Patients were evaluated for glycemic control, blood lipid profiles, body composition and physical fitness, and skeletal muscle gene expression. RESULTS: Exercise training was well tolerated without any incident of hypoglycemia. Exercise training significantly decreased whole-body fat mass (-1.6 kg) and increased high-density lipoprotein concentrations (+2 mg·dL), physical fitness (+1.7 mL·min·kg), and fat oxidation during exercise in both groups (PTIME < 0.05), with no between-group differences (PTIME × GROUP > 0.05). HbA1c concentrations significantly decreased after exercise training (PTIME < 0.001), with a significant greater reduction after consuming breakfast (-0.30% ± 0.06%) compared with fasted state (-0.08% ± 0.06%; mean difference, 0.21%; PTIME × GROUP = 0.016). No interaction effects were observed for skeletal muscle genes related to lipid metabolism or oxidative capacity. CONCLUSIONS: Endurance-type exercise training in the fasted or fed state do not differ in their efficacy to reduce fat mass, increase fat oxidation capacity, and increase cardiorespiratory fitness and high-density lipoprotein concentrations or their risk of hypoglycemia in male patients with type 2 diabetes. HbA1c seems to be improved more with exercise performed in the postprandial compared with the postabsorptive state.

Endurance Exercise Intervention Is Beneficial to Kidney Function in a Rat Model of Isolated Abdominal Venous Congestion: a Pilot Study.

In this study, the effects of moderate intense endurance exercise on heart and kidney function and morphology were studied in a thoracic inferior vena cava constricted (IVCc) rat model of abdominal venous congestion. After IVC surgical constriction, eight sedentary male Sprague-Dawley IVCc rats (IVCc-SED) were compared to eight IVCc rats subjected to moderate intense endurance exercise (IVCc-MOD). Heart and kidney function was examined and renal functional reserve (RFR) was investigated by administering a high protein diet (HPD). After 12 weeks of exercise training, abdominal venous pressure, indices of body fat content, plasma cystatin C levels, and post-HPD urinary KIM-1 levels were all significantly lower in IVCc-MOD versus IVCc-SED rats (P < 0.05). RFR did not differ between both groups. The implementation of moderate intense endurance exercise in the IVCc model reduces abdominal venous pressure and is beneficial to kidney function.

Impact of high-intensity concurrent training on cardiovascular risk factors in persons with multiple sclerosis - pilot study.

PURPOSE: High-intensity concurrent training positively affects cardiovascular risk factors. Because this was never investigated in multiple sclerosis, the present pilot study explored the impact of this training on cardiovascular risk factors in this population. METHODS: Before and after 12 weeks of high-intense concurrent training (interval and strength training, 5 sessions per 2 weeks, n = 16) body composition, resting blood pressure and heart rate, 2-h oral glucose tolerance (insulin sensitivity, glycosylated hemoglobin, blood glucose and insulin concentrations), blood lipids (high- and low-density lipoprotein, total cholesterol, triglyceride levels) and C-reactive protein were analyzed. RESULTS: Twelve weeks of high-intense concurrent training significantly improved resting heart rate (-6%), 2-h blood glucose concentrations (-13%) and insulin sensitivity (-24%). Blood pressure, body composition, blood lipids and C-reactive protein did not seem to be affected. CONCLUSIONS: Under the conditions of this pilot study, 12 weeks of concurrent high-intense interval and strength training improved resting heart rate, 2-h glucose and insulin sensitivity in multiple sclerosis but did not affect blood C-reactive protein levels, blood pressure, body composition and blood lipid profiles. Further, larger and controlled research investigating the effects of high-intense concurrent training on cardiovascular risk factors in multiple sclerosis is warranted. Implications for rehabilitation High-intensity concurrent training improves cardiovascular fitness. This pilot study explores the impact of this training on cardiovascular risk factors in multiple sclerosis. Despite the lack of a control group, high-intense concurrent training does not seem to improve cardiovascular risk factors in multiple sclerosis.

Exercise-induced lactate responses in Multiple Sclerosis: A retrospective analysis.

BACKGROUND: Persons with Multiple Sclerosis have elevated resting serum lactate concentrations compared to healthy controls (HC). OBJECTIVE: To evaluate lactate concentrations during acute exercise and/or following training in MS compared to HC. METHODS: In this retrospective study, blood lactate concentrations (mmol/l) originating from two previous studies were analyzed. Lactate concentrations originated from acute submaximal (MSsubmax; HC, n = 11; MS, n = 32) or maximal (MSmax; HC, n = 20; MS, n = 24) exercise tests and following a 24-week mild to moderate intensity (MSsubmax, n = 12) or 12-week high intensity interval (MSmax, n = 13) exercise intervention. RESULTS: Under submaximal conditions in MS and compared to HC, lactaterest (MS: 2.7±0.6 vs HC: 2.3±0.7 was significantly (p < 0.05) elevated. After 24 weeks of mild-to-moderate-intensity exercise training and compared to PRE-values, lactatebout2 (2.5±0.7 vs 3.4±1.1) significantly (p < 0.05) decreased during submaximal testing in MSsubmax. Under maximal conditions, lactatestart (2.3±1.0 vs 1.7±0.9) was significantly (p > 0.05) elevated in MS. Twelve weeks of high intensity interval training did not improve this (p > 0.05). CONCLUSIONS: Under the conditions of this retrospective analysis we conclude that lactate concentrations during acute submaximal and maximal exercise in persons with MS are similar compared to healthy controls. Moderate intensity exercise therapy appeared to improve lactate accumulation but high intensity exercise therapy did not.

Tolerogenic dendritic cell-based treatment for multiple sclerosis (MS): a harmonised study protocol for two phase I clinical trials comparing intradermal and intranodal cell administration.

INTRODUCTION: Based on the advances in the treatment of multiple sclerosis (MS), currently available disease-modifying treatments (DMT) have positively influenced the disease course of MS. However, the efficacy of DMT is highly variable and increasing treatment efficacy comes with a more severe risk profile. Hence, the unmet need for safer and more selective treatments remains. Specifically restoring immune tolerance towards myelin antigens may provide an attractive alternative. In this respect, antigen-specific tolerisation with autologous tolerogenic dendritic cells (tolDC) is a promising approach. METHODS AND ANALYSIS: Here, we will evaluate the clinical use of tolDC in a well-defined population of MS patients in two phase I clinical trials. In doing so, we aim to compare two ways of tolDC administration, namely intradermal and intranodal. The cells will be injected at consecutive intervals in three cohorts receiving incremental doses of tolDC, according to a best-of-five design. The primary objective is to assess the safety and feasibility of tolDC administration. For safety, the number of adverse events including MRI and clinical outcomes will be assessed. For feasibility, successful production of tolDC will be determined. Secondary endpoints include clinical and MRI outcome measures. The patients' immune profile will be assessed to find presumptive evidence for a tolerogenic effect in vivo. ETHICS AND DISSEMINATION: Ethics approval was obtained for the two phase I clinical trials. The results of the trials will be disseminated in a peer-reviewed journal, at scientific conferences and to patient associations. TRIAL REGISTRATION NUMBERS: NCT02618902 and NCT02903537; EudraCT numbers: 2015-002975-16 and 2015-003541-26.