Use of Cells, Supplements, and Peptides as Therapeutic Strategies for Modulating Inflammation after Spinal Cord Injury: An Update.

Spinal cord injury is a traumatic lesion that causes a catastrophic condition in patients, resulting in neuronal deficit and loss of motor and sensory function. That loss is caused by secondary injury events following mechanical damage, which results in cell death. One of the most important events is inflammation, which activates molecules like proinflammatory cytokines (IL-1ß, IFN-γ, and TNF-α) that provoke a toxic environment, inhibiting axonal growth and exacerbating CNS damage. As there is no effective treatment, one of the developed therapies is neuroprotection of the tissue to preserve healthy tissue. Among the strategies that have been developed are the use of cell therapy, the use of peptides, and molecules or supplements that have been shown to favor an anti-inflammatory environment that helps to preserve tissue and cells at the site of injury, thus favoring axonal growth and improved locomotor function. In this review, we will explain some of these strategies used in different animal models of spinal cord injury, their activity as modulators of the immune system, and the benefits they have shown.

Copolymer-1 as a potential therapy for mild cognitive impairment.

Mild cognitive impairment (MCI) is a prodromal stage of memory impairment that may precede dementia. MCI is classified by the presence or absence of memory impairment into amnestic or non-amnestic MCI, respectively. More than 90% of patients with amnestic MCI who progress towards dementia meet criteria for Alzheimer's disease (AD). A combination of mechanisms promotes MCI, including intracellular neurofibrillary tangle formation, extracellular amyloid deposition, oxidative stress, neuronal loss, synaptodegeneration, cholinergic dysfunction, cerebrovascular disease, and neuroinflammation. However, emerging evidence indicates that neuroinflammation plays an important role in the pathogenesis of cognitive impairment. Unfortunately, there are currently no Food and Drug Administration (FDA)-approved drugs for MCI. Copolymer-1 (Cop-1), also known as glatiramer acetate, is a synthetic polypeptide of four amino acids approved by the FDA for the treatment of relapsing-remitting multiple sclerosis. Cop-1 therapeutic effect is attributed to immunomodulation, promoting a switch from proinflammatory to anti-inflammatory phenotype. In addition to its anti-inflammatory properties, it stimulates brain-derived neurotrophic factor (BDNF) secretion, a neurotrophin involved in neurogenesis and the generation of hippocampal long-term potentials. Moreover, BDNF levels are significantly decreased in patients with cognitive impairment. Therefore, Cop-1 immunization might promote synaptic plasticity and memory consolidation by increasing BDNF production in patients with MCI.

"Back Rx, a personalized mobile phone application for discogenic chronic low back pain: a prospective pilot study".

BACKGROUND: Intervertebral disc pathology is the most common identifiable cause of chronic lower back pain (CLBP). There are limited conservative alternatives to treat discogenic axial CLBP. Back Rx is a mobile application (app) developed to treat patients with this condition, following the Back Rx exercise program, assisted by a virtual coach. METHODS: Patients 18 to 65 years of age, with axial CLBP (more than 3 months), and evidence of lumbar disc pathology by magnetic resonance imaging (MRI) were enrolled to the study. Patients' symptomatology was prospectively evaluated at baseline and after 3 months of using the Back Rx app. The main outcome of the study was back pain evaluated using the visual analog scale (VAS) for pain. Secondary outcomes were the patient's functionality, the weekly pain medication intake, the patients' adherence to the app, and the patients´ satisfaction rate. RESULTS: Seventy-five patients with CLBP were enrolled in the study. All patients had a statistically significant improvement from baseline to final follow-up in the average VAS scores, and the functionality evaluations. Average VAS scores decreased from 5.17 ± 2.1 at baseline to 3.8 ± 2.6 at final follow-up (P = 0.016). Patients showed a significant decrease in the number of pain medications taken during a week (P = 0.001). Overall compliance with the app was 52%, and 65% of the patients rated the overall experience as good or excellent. CONCLUSION: The Back Rx app decreased pain and increased function in patients with discogenic axial CLBP compared to their baseline status. Further measures are needed to increase patients' compliance with the app and the Back Rx program. TRIAL REGISTRATION: Retrospectively registered in 2/2/2017 NCT03040310 (ClinicalTrials.gov).

Laser-assisted in-situ keratomileusis (LASIK) with a mechanical microkeratome compared to LASIK with a femtosecond laser for LASIK in adults with myopia or myopic astigmatism.

BACKGROUND: Laser-assisted in-situ keratomileusis (LASIK) is a surgical procedure that corrects refractive errors. This technique creates a flap of the outermost parts of the cornea (epithelium, bowman layer, and anterior stroma) to expose the middle part of the cornea (stromal bed) and reshape it with excimer laser using photoablation. The flaps can be created by a mechanical microkeratome or a femtosecond laser. OBJECTIVES: To compare the effectiveness and safety of mechanical microkeratome versus femtosecond laser in LASIK for adults with myopia. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2019, Issue 2); Ovid MEDLINE; Embase; PubMed; LILACS; ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We used no date or language restrictions. We searched the reference lists of included trials. We searched the electronic databases on 22 February 2019. SELECTION CRITERIA: We included randomized controlled trials (RCTs) of LASIK with a mechanical microkeratome compared to a femtosecond laser in people aged 18 years or older with more than 0.5 diopters of myopia or myopic astigmatism. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 16 records from 11 trials enrolling 943 adults (1691 eyes) with spherical or spherocylindrical myopia, who were suitable candidates for LASIK. Five hundred and forty-seven participants (824 eyes) received LASIK with a mechanical microkeratome and 588 participants (867 eyes) with a femtosecond laser. Each trial included between nine and 360 participants. In six trials, the same participants received both interventions. Overall, the trials were at an uncertain risk of bias for most domains. At 12 months, data from one trial (42 eyes) indicates no difference in the mean uncorrected visual acuity (logMAR scale) between LASIK with a mechanical microkeratome and LASIK with a femtosecond laser (mean difference (MD) -0.01, 95% confidence interval (CI) -0.06 to 0.04; low-certainty evidence). Similar findings were observed at 12 months after surgery, regarding participants achieving 0.5 diopters within target refraction (risk ratio (RR) 0.97, 95% CI 0.85 to 1.11; 1 trial, 79 eyes; low-certainty evidence) as well as mean spherical equivalent of the refractive error 12 months after surgery (MD 0.09, 95% CI -0.01 to 0.19; 3 trials, 168 eyes [92 participants]; low-certainty evidence). Based on data from three trials (134 eyes, 66 participants), mechanical microkeratome was associated with lower risk of diffuse lamellar keratitis compared with femtosecond laser (RR 0.27, 95% CI 0.10 to 0.78; low-certainty evidence). Thus, diffuse lamellar keratitis was a more common adverse event with femtosecond laser than with mechanical microkeratome, decreasing from an assumed rate of 209 per 1000 people in the femtosecond laser group to 56 per 1000 people in the mechanical microkeratome group. Data from one trial (183 eyes, 183 participants) indicates that dry eye as an adverse event may be more common with mechanical microkeratome than with femtosecond laser, increasing from an assumed rate of 80 per 1000 people in the femtosecond laser group to 457 per 1000 people in the mechanical microkeratome group (RR 5.74, 95% CI 2.92 to 11.29; low-certainty evidence). There was no evidence of a difference between the two groups for corneal haze (RR 0.33, 95% CI 0.01 to 7.96; 1 trial, 43 eyes) and epithelial ingrowth (RR 1.04, 95% CI 0.11 to 9.42; 2 trials, 102 eyes [50 participants]). The certainty of evidence for both outcomes was very low. AUTHORS' CONCLUSIONS: Regarding the visual acuity outcomes, there may be no difference between LASIK with mechanical microkeratome and LASIK with femtosecond laser. Dry eye and diffuse lamellar keratitis are likely adverse events with mechanical microkeratome and femtosecond laser, respectively. The evidence is uncertain regarding corneal haze and epithelial ingrowth as adverse events of each intervention. The limited number of outcomes reported in the included trials, some with potentially significant risk of bias, makes it difficult to draw a firm conclusion regarding the effectiveness and safety of the interventions investigated in this review.

Immunization with neural derived peptides plus scar removal induces a permissive microenvironment, and improves locomotor recovery after chronic spinal cord injury.

BACKGROUND: Immunization with neural derived peptides (INDP) as well as scar removal-separately-have shown to induce morphological and functional improvement after spinal cord injury (SCI). In the present study, we compared the effect of INDP alone versus INDP with scar removal on motor recovery, regeneration-associated and cytokine gene expression, and axonal regeneration after chronic SCI. Scar removal was conducted through a single incision with a double-bladed scalpel along the stump, and scar renewal was halted by adding α,α'-dipyridyl. RESULTS: During the chronic injury stage, two experiments were undertaken. The first experiment was aimed at testing the therapeutic effect of INDP combined with scar removal. Sixty days after therapeutic intervention, the expression of genes encoding for TNFα, IFNγ, IL4, TGFß, BDNF, IGF1, and GAP43 was evaluated at the site of injury. Tyrosine hydroxylase and 5-hydroxytryptamine positive fibers were also studied. Locomotor evaluations showed a significant recovery in the group treated with scar removal + INDP. Moreover; this group presented a significant increase in IL4, TGFß, BDNF, IGF1, and GAP43 expression, but a decrease of TNFα and IFNγ. Also, the spinal cord of animals receiving both treatments presented a significant increase of serotonergic and catecholaminergic fibers as compared to other the groups. The second experiment compared the results of the combined approach versus INDP alone. Rats receiving INDP likewise showed improved motor recovery, although on a lesser scale than those who received the combined treatment. An increase in inflammation and regeneration-associated gene expression, as well as in the percentage of serotonergic and catecholaminergic fibers was observed in INDP-treated rats to a lesser degree than those in the combined therapy group. CONCLUSIONS: These findings suggest that INDP, both alone and in combination with scar removal, could modify the non-permissive microenvironment prevailing at the chronic phase of SCI, providing the opportunity of improving motor recovery.

Long-term production of BDNF and NT-3 induced by A91-immunization after spinal cord injury.

BACKGROUND: After spinal cord (SC)-injury, a non-modulated immune response contributes to the damage of neural tissue. Protective autoimmunity (PA) is a T cell mediated, neuroprotective response induced after SC-injury. Immunization with neural-derived peptides (INDP), such as A91, has shown to promote-in vitro-the production of neurotrophic factors. However, the production of these molecules has not been studied at the site of injury. RESULTS: In order to evaluate these issues, we performed four experiments in adult female Sprague-Dawley rats. In the first one, brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) concentrations were evaluated at the site of lesion 21 days after SC-injury. BDNF and NT-3 were significantly increased in INDP-treated animals. In the second experiment, proliferation of anti-A91 T cells was assessed at chronic stages of injury. In this case, we found a significant proliferation of these cells in animals subjected to SC-injury + INDP. In the third experiment, we explored the amount of BDNF and NT3 at the site of injury in the chronic phase of rats subjected to either SC-contusion (SCC; moderate or severe) or SC-transection (SCT; complete or incomplete). The animals were treated with INDP immediately after injury. Rats subjected to moderate contusion or incomplete SCT showed significantly higher levels of BDNF and NT-3 as compared to PBS-immunized ones. In rats with severe SCC and complete SCT, BDNF and NT-3 concentrations were barely detected. Finally, in the fourth experiment we assessed motor function recovery in INDP-treated rats with moderate SC-injury. Rats immunized with A91 showed a significantly higher motor recovery from the first week and up to 4 months after SC-injury. CONCLUSIONS: The results of this study suggest that PA boosted by immunization with A91 after moderate SC-injury can exert its benefits even at chronic stages, as shown by long-term production of BDNF and NT-3 and a substantial improvement in motor recovery.

Cytokine and Growth Factor Activation In Vivo and In Vitro after Spinal Cord Injury.

Spinal cord injury results in a life-disrupting series of deleterious interconnected mechanisms encompassed by the primary and secondary injury. These events are mediated by the upregulation of genes with roles in inflammation, transcription, and signaling proteins. In particular, cytokines and growth factors are signaling proteins that have important roles in the pathophysiology of SCI. The balance between the proinflammatory and anti-inflammatory effects of these molecules plays a critical role in the progression and outcome of the lesion. The excessive inflammatory Th1 and Th17 phenotypes observed after SCI tilt the scale towards a proinflammatory environment, which exacerbates the deleterious mechanisms present after the injury. These mechanisms include the disruption of the spinal cord blood barrier, edema and ion imbalance, in particular intracellular calcium and sodium concentrations, glutamate excitotoxicity, free radicals, and the inflammatory response contributing to the neurodegenerative process which is characterized by demyelination and apoptosis of neuronal tissue.

Nutritional Support System (NSS) as a New Therapeutic Strategy for Cerebral Palsy.

Cerebral palsy (CP) is part of a group of nonprogressive motor disorders. The disease affects movement and posture and constitutes the most frequent cause of motor disability in childhood. CP is characterized by spasticity, reflecting lesions in the pyramidal pathway. Treatment is currently focused on physical rehabilitation, and the annual progression of the disease is 2-3%. About 60% of these patients present severe degrees of malnutrition associated with dysphagia, gastrointestinal abnormalities, malabsorption, increased metabolism, and depression. These alterations promote sarcopenia functional dependence and affect the quality of life and delay the evolution of motor skills. Currently, there is evidence that the supplementation of several nutrients, dietary correction, and probiotics can improve neurological response by stimulating neuroplasticity, neuroregeneration, neurogenesis, and myelination. This therapeutic strategy could shorten the response period to treatment and increase both gross and fine motor skills. The interaction of nutrients and functional foods integrating a Nutritional Support System (NSS) has shown greater efficiency in neurological stimulation than when nutrients are supplied separately. The most studied elements in the neurological response are glutamine, arginine, zinc, selenium, cholecalciferol, nicotinic acid, thiamine, pyridoxine, folate, cobalamin, Spirulina, omega-3 fatty acids, ascorbic acid, glycine, tryptophan, and probiotics. The NSS represents a therapeutic alternative that will restore neurological function in patients with spasticity and pyramidal pathway lesions, both characteristics of patients with CP.

Cognitive Impairment Induced by Gestational Diabetes: Implications of Oxidative Stress as an Inducing Mechanism.

BACKGROUND: Cognitive impairment is defined as a neurological condition that alters multiple cerebral functions such as reasoning, memory, concentration, and association, among others. It has found to be widely correlated with several factors such as oxidative stress. The latter could be induced by numerous pathological conditions characterized by increased levels of free radicals and decreased levels of antioxidants. Pregnancy is a period when women undergo a physiological state of oxidative stress due to hormonal changes and increased oxygen requirements to maintain pregnancy. However, when oxidative stress exceeds antioxidant capacity, this leads to cellular damage that promotes a diabetogenic state. Recent studies suggest a possible association between gestational diabetes and cognitive impairment, but the underlying mechanisms remain unclear. AIMS: We aim to explore the pathophysiological relationship between cognitive impairment and oxidative stress, focusing on the possible involvement of oxidative stress as the inducing mechanism. METHODS: We performed a comprehensive literature review through PubMed and Google Scholar. Our keywords were "neuroinflammation", "cognitive impairment", "gestational diabetes", "oxidative stress", "antioxidants", and "free radicals". RESULTS: From the initial 400 records identified, a total of 78 studies were analyzed and included in our study. CONCLUSION: Oxidative stress plays a fundamental role in the development of cognitive impairment. Understanding this correlation is essential to the development of targeted medical interventions and, ultimately, promote research and prevention that will benefit the mother-child binomial in the short and long term.

Supplementation with a Symbiotic Induced Neuroprotection and Improved Memory in Rats with Ischemic Stroke.

After an ischemic stroke, various harmful mechanisms contribute to tissue damage, including the inflammatory response. The increase in pro-inflammatory cytokines has been related to greater damage to the neural tissue and the promotion of neurological alterations, including cognitive impairment. Recent research has shown that the use of prebiotics and/or probiotics counteracts inflammation and improves cognitive function through the production of growth factors, such as brain-derived neurotrophic factor (BDNF), by reducing inflammatory molecules. Therefore, in this study, the effect of the symbiotic inulin and Enterococcus faecium on neuroprotection and memory improvement was evaluated in a rat model of transient middle cerebral artery occlusion (tMCAO). In order to accomplish this, the animals were subjected to ischemia; the experimental group was supplemented with the symbiotic and the control group with the vehicle. The neurological deficit as well as spatial and working memory were evaluated using the Zea Longa scale, Morris water maze, and the eight-arm maze tests, respectively. Infarct size, the levels of BDNF, and tumor necrosis factor-alpha (TNF-α) were also assessed. The results show that supplementation with the symbiotic significantly diminished the neurological deficit and infarct size, improved memory and learning, increased BDNF expression, and reduced TNF-α production. These findings provide new evidence about the therapeutic use of symbiotics for ischemic stroke and open up the possibilities for the design of further studies.

PLEIAData: consumption, HVAC, temperature, weather and motion sensor data for smart buildings applications.

The current cost that energy represents is crucial in a field like climate control which has high energy demands, therefore its reduction must be prioritized. The expansion of ICT and IoT come with an extensive deployment of sensors and computation infrastructure creating an opportunity to analyze and optimize energy management. Data on building internal and external conditions is essential for developing efficient control strategies in order to minimize energy consumption while maintaining users' comfort inside. We here present a dataset that provides key features that could be useful for a wide range of applications in the context of modeling temperature and consumption via Artificial Intelligence algorithms. The data gathering has taken place for almost 1 year in the Pleiades building of the University of Murcia, which is a pilot building of the European project PHOENIX aiming to improve building energy efficiency.

Recent advances in the combination of cellular therapy with stem cells and nanoparticles after a spinal cord injury.

Background: Currently, combined therapies could help to reduce long-term sequelae of spinal cord injury (SCI); stem cell therapy at the site of injury in combination with other therapies has shown very promising results that can be transferred to the clinical field. Nanoparticles (NPs) are versatile technologies with applications to medical research for treatments of SCI since they could deliver therapeutic molecules to the target tissue and may help to reduce the side effects of non-targeted therapies. This article's purpose is to analyze and concisely describe the diverse cellular therapies in combination with NPs and their regenerative effect after SCI. Methods: We reviewed the literature related to combinatory therapy for motor impairment following SCI that has been published by Web of Science, Scopus, EBSCO host, and PubMed databases. The research covers the databases from 2001 to December 2022. Result: Animal models of SCI have shown that the combination of NPs plus stem cells has a positive impact on neuroprotection and neuroregeneration. Further research is required to better understand the effects and benefits of SCI on a clinical level; therefore, it is necessary to find and select the most effective molecules that are capable of exacerbating the neurorestorative effects of the different stem cells and then try them out on patients after SCI. On the other hand, we consider that synthetic polymers such as poly [lactic-co-glycolic acid] (PLGA) could be a candidate for the design of the first therapeutic strategy that combines NPs with stem cells in patients with SCI. The reasons for the selection are that PLGA has shown important advantages over other NPs, such as being biodegradable, having low toxicity levels, and high biocompatibility; In addition, researchers could control the release time and the biodegradation kinetics, and most importantly, it could be used as NMs on other clinical pathologies (12 studies on www.clinicaltrials.gov) and has been approved by the Federal Food, Drug, and Cosmetic Act (FDA). Conclusion: The use of cellular therapy and NPs may be a worthwhile alternative for SCI therapy; however, it is expected that the data obtained from interventions after SCI reflect an important variability of molecules combined with NPs. Therefore, it is necessary to properly define the limits of this research to be able to continue to work on the same line. Consequently, the selection of a specific therapeutic molecule and type of NPs plus stem cells are crucial to evaluate its application in clinical trials.

Immunization with Neural-Derived Peptides in Neurodegenerative Diseases: A Narrative Review.

Neurodegenerative diseases (NDDs) are a major health problem worldwide. Statistics suggest that in America in 2030 there will be more than 12 million people suffering from a neurodegenerative pathology. Furthermore, the increase in life expectancy enhances the importance of finding new and better therapies for these pathologies. NDDs could be classified into chronic or acute, depending on the time required for the development of clinical symptoms and brain degeneration. Nevertheless, both chronic and acute stages share a common immune and inflammatory pathway in their pathophysiology. Immunization with neural-derived peptides (INDP) is a novel therapy that has been studied during the last decade. By inoculating neural-derived peptides obtained from the central nervous system (CNS), this therapy aims to boost protective autoimmunity, an autoreactive response that leads to a protective phenotype that produces a healing environment and neuroregeneration instead of causing damage. INDP has shown promising findings in studies performed either in vitro, in vivo or even in some pre-clinical trials of different NDDs, standing as a potentially beneficial therapy. In this review, we will describe some of the studies in which the effect of INDP strategies have been explored in different (chronic and acute) neurodegenerative diseases.

Symbiotic Supplementation (E. faecium and Agave Inulin) Improves Spatial Memory and Increases Plasticity in the Hippocampus of Obese Rats: A Proof-of-Concept Study.

Obesity has been linked to cognitive impairment through systemic low-grade inflammation. High fat and sugar diets (HFSDs) also induce systemic inflammation, either by induced Toll-like receptor 4 response, or by causing dysbiosis. This study aimed to evaluate the effect of symbiotics supplementation on spatial and working memory, butyrate concentration, neurogenesis, and electrophysiological recovery of HFSD-fed rats. In a first experiment, Sprague-Dawley male rats were given HFSD for 10 weeks, after which they were randomized into 2 groups (n = 10 per group): water (control), or Enterococcus faecium + inulin (symbiotic) administration, for 5 weeks. In the fifth week, spatial and working memory was analyzed through the Morris Water Maze (MWM) and Eight-Arm Radial Maze (RAM) tests, respectively, with 1 week apart between tests. At the end of the study, butyrate levels from feces and neurogenesis at hippocampus were determined. In a second experiment with similar characteristics, the hippocampus was extracted to perform electrophysiological studies. Symbiotic-supplemented rats showed a significantly better memory, butyrate concentrations, and neurogenesis. This group also presented an increased firing frequency in hippocampal neurons [and a larger N-methyl-d-aspartate (NMDA)/α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) current ratio] suggesting an increase in NMDA receptors, which in turn is associated with an enhancement in long-term potentiation and synaptic plasticity. Therefore, our results suggest that symbiotics could restore obesity-related memory impairment and promote synaptic plasticity.

Immunization with A91 peptide or copolymer-1 reduces the production of nitric oxide and inducible nitric oxide synthase gene expression after spinal cord injury.

Immunization with neurally derived peptides (INDP) boosts the action of an autoreactive immune response that has been shown to induce neuroprotection in several neurodegenerative diseases, especially after spinal cord (SC) injury. This strategy provides an environment that promotes neuronal survival and tissue preservation. The mechanisms by which this autoreactive response exerts its protective effects is not totally understood at the moment. A recent study showed that INDP reduces lipid peroxidation. Lipid peroxidation is a neurodegenerative phenomenon caused by the increased production of reactive nitrogen species such as nitric oxide (NO). It is possible that INDP could be interfering with NO production. To test this hypothesis, we examined the effect of INDP on the amount of NO produced by glial cells when cocultured with autoreactive T cells. We also evaluated the amount of NO and the expression of the inducible form of nitric oxide synthase (iNOS) at the injury site of SC-injured animals. The neural-derived peptides A91 and Cop-1 were used to immunize mice and rats with SC injury. In vitro studies showed that INDP significantly reduces the production of NO by glial cells. This observation was substantiated by in vivo experiments demonstrating that INDP decreases the amount of NO and iNOS gene expression at the site of injury. The present study provides substantial evidence on the inhibitory effect of INDP on NO production, helpingour understanding of the mechanisms through which protective autoimmunity promotes neuroprotection.

Spinal cord injury-induced cognitive impairment: a narrative review.

Spinal cord injury is a serious damage to the spinal cord that can lead to life-long disability. Based on its etiology, spinal cord injury can be classified as traumatic or non-traumatic spinal cord injury. Furthermore, the pathology of spinal cord injury can be divided into two phases, a primary injury phase, and a secondary injury phase. The primary spinal cord injury phase involves the initial mechanical injury in which the physical force of impact is directly imparted to the spinal cord, disrupting blood vessels, axons, and neural cell membranes. After the primary injury, a cascade of secondary events begins, expanding the zone of neural tissue damage, and exacerbating neurological deficits. Secondary injury is a progressive condition characterized by pro-inflammatory cytokines, reactive oxygen species, oxidative damage, excitatory amino acids such as glutamate, loss of ionic homeostasis, mitochondrial dysfunction, and cell death. This secondary phase lasts for several weeks or months and can be further subdivided into acute, subacute, and chronic. One of the most frequent and devastating complications developed among the spinal cord injury population is cognitive impairment. The risk of cognitive decline after spinal cord injury has been reported to be 13 times higher than in healthy individuals. The exact etiology of this neurological complication remains unclear, however, many factors have been proposed as potential contributors to the development of this disorder, such as concomitant traumatic brain injury, hypoxia, anoxia, autonomic dysfunction, sleep disorders such as obstructive sleep apnea, body temperature dysregulation, alcohol abuse, and certain drugs. This review focuses on a deep understanding of the pathophysiology of spinal cord injury and its relationship to cognitive impairment. We highlight the main mechanisms that lead to the development of this neurological complication in patients with spinal cord injury.

Supplementation With Vitamin E, Zinc, Selenium, and Copper Re-Establishes T-Cell Function and Improves Motor Recovery in a Rat Model of Spinal Cord Injury.

Spinal cord injury (SCI) causes a dysfunction of sympathetic nervous system innervation that affects the immune system, leading to immunosuppression syndrome (ISS) and contributing to patient degeneration and increased risk of several infections. A possible therapeutic strategy that could avoid further patient deterioration is the supplementation with Vitamin E or trace elements, such as Zinc, Selenium, and Copper, which individually promotes T-cell differentiation and proliferative responses. For this reason, the aim of the present study was to evaluate whether Vitamin E, Zinc, Selenium, and Copper supplementation preserves the number of T-lymphocytes and improves their proliferative function after traumatic SCI. Sprague-Dawley female rats were subjected to moderate SCI and then randomly allocated into three groups: (1) SCI + supplements; (2) SCI + vehicle (olive oil and phosphate-buffered saline); and (3) sham-operated rats. In all rats, the intervention was initiated 15 min after SCI and then administered daily until the end of study. Locomotor recovery was assessed at 7 and 15 days after SCI. At 15 days after supplementation, the quantification of the number of T-cells and its proliferation function were examined. Our results showed that the SCI + supplements group presented a significant improvement in motor recovery at 7 and 15 days after SCI. In addition, this group showed a better T-cell number and proliferation rate than that observed in the group with SCI + vehicle. Our findings suggest that Vitamin E, Zinc, Selenium, and Copper supplementation could be part of a therapy for patients suffering from acute SCI, helping to preserve T-cell function, avoiding complications, and promoting a better motor recovery. All procedures were approved by the Animal Bioethics and Welfare Committee (Approval No. 201870; CSNBTBIBAJ 090812960).

Effect of a Nutritional Support System to Increase Survival and Reduce Mortality in Patients with COVID-19 in Stage III and Comorbidities: A Blinded Randomized Controlled Clinical Trial.

The COVID-19 evolution depends on immunological capacity. The global hospital mortality rate is 15-20%, but in México it is 46%. There are several therapeutic protocols, however, integral nutrition is not considered. In this study, a Nutritional Support System (NSS) was employed to increase survival and reduce mortality in patients with stage III COVID-19. A randomized, blinded, controlled clinical trial was performed. Eighty patients (aged 30 to 75 years, both sexes) were assigned to (1) "Control Group" (CG) hospital diet and medical treatment or (2) "Intervention Group" (IG) hospital diet, medical treatment, and the NSS (vitamins, minerals, fiber, omega-3, amino acids, B-complex, and probiotics). IG significantly increased survival and reduced mortality compared to CG (p = 0.027). IG decreased progression to Mechanical Ventilation Assistance (MVA) by 10%, reduced the intubation period by 15 days, and increased survival in intubated patients by 38% compared to CG. IG showed improvement compared to CG in decrease in supplemental oxygen (p = 0.014), the qSOFA test (p = 0.040), constipation (p = 0.014), the PHQ-9 test (p = 0.003), and in the follow-up, saturation with oxygen (p = 0.030). The NSS increases survival and decreases mortality in patients with stage III COVID-19.

Memory improvement in senile rats after prebiotic and probiotic supplementation is not induced by GLP-1.

INTRODUCTION: The mechanism underlying the memory improvement induced by prebiotic and probiotic supplementation remains unclear. Glucagon-like peptide type 1 (GLP-1) could play an important role since it is induced by prebiotics and enhances memory and learning. AIMS: We correlated the levels of GLP-1 with spatial memory in senile animals to determine its role in memory improvement after prebiotic and probiotic supplementation. METHODS: Senile rats were randomly assigned to four groups: (1) water (control); (2) Enterococcus faecium (probiotic); (3) agave inulin (prebiotic); and (4) E. faecium + agave inulin (symbiotic). Each supplement was administered by an orogastric cannula for 5 weeks. In the fifth week, spatial memory was assessed using the Morris Water Maze test (MWM). We extracted the hippocampus, intestine, and serum. GLP-1 levels were quantified by enzyme-linked immunosorbent assay. RESULTS: A significant decrease in escape latency time in the MWM was observed in all groups treated with supplements. The symbiotic group achieved the highest reduction (15.13 s ± 6.40) (p < 0.01). We did not find a significant increase in GLP-1 levels nor a direct correlation of its levels with spatial memory improvement (p > 0.05). CONCLUSION: Prebiotic and probiotic supplementation improved spatial memory in senile animals. However, this beneficial effect did not correlate with GLP-1 levels.

Carboplasty, a Simple Tibial Marrow Technique for Knee Osteoarthritis: A Placebo-Controlled Randomized Trial.

Background: Carboplasty is a new minimally invasive technique for knee osteoarthritis (OA) that consists of injecting tibial marrow aspirate into the bone-cartilage interface as well as intra-articularly. Purpose: To compare the clinical and imaging outcomes, as well as the safety, of carboplasty for symptomatic knee OA in a placebo-controlled trial. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: The authors conducted a randomized controlled trial to compare carboplasty with placebo for the treatment of symptomatic knee OA. Patients who had failed medical treatment and had bone edema on magnetic resonance imaging (MRI) were randomized in a 1:1 ratio to carboplasty or placebo. The primary outcome of the study was the Numeric Pain Rating Scale (NPRS) for the knee at 1 year (scores range from 0 to 10, with a higher score indicating worse pain). Secondary outcomes were the Knee injury and Osteoarthritis Outcome Score (KOOS), treatment responder rate (based on achieving the minimal clinically important difference of the NPRS), MRI bone edema reduction, and treatment safety. Results: In total, 50 patients (25 carboplasty vs 25 placebo) were enrolled and followed up with for an average of 18 months (range, 14-24 months). The average NPRS at baseline decreased from 7.1 ± 0.9 to 2.9 ± 2.1 (P < .001) at 1 year in the carboplasty group and from 7.7 ± 0.9 to 4.9 ± 2.2 (P < .001) in the placebo group. On average, patients after carboplasty improved 60% from their initial NPRS, and patients after placebo improved 37% (P = .003). Patients had a statistically significantly greater improvement from baseline in all KOOS subscales in the carboplasty group compared with the placebo group (P < .001). The responder rates were 96% for carboplasty and 76% for placebo (P = .098). Bone edema was reduced in 72% of patients in the carboplasty group and 44% of patients in the placebo group (P = .045). Neither group had adverse events related to treatment. Conclusion: Carboplasty resulted in greater pain reduction, a significantly greater improvement in all KOOS subscales, and a similar safety profile compared with placebo in patients with symptomatic knee OA and bone edema. Registration: ISRCTN69838191 (ISRCT Registry).