A Novel Morphine Drinking Model of Opioid Dependence in Rats.

An animal model of voluntary oral morphine consumption would allow for a pre-clinical evaluation of new treatments aimed at reducing opioid intake in humans. However, the main limitation of oral morphine consumption in rodents is its bitter taste, which is strongly aversive. Taste aversion is often overcome by the use of adulterants, such as sweeteners, to conceal morphine taste or bitterants in the alternative bottle to equalize aversion. However, the adulterants' presence is the cause for consumption choice and, upon removal, the preference for morphine is not preserved. Thus, current animal models are not suitable to study treatments aimed at reducing consumption elicited by morphine itself. Since taste preference is a learned behavior, just-weaned rats were trained to accept a bitter taste, adding the bitterant quinine to their drinking water for one week. The latter was followed by allowing the choice of quinine or morphine (0.15 mg/mL) solutions for two weeks. Then, quinine was removed, and the preference for morphine against water was evaluated. Using this paradigm, we show that rats highly preferred the consumption of morphine over water, reaching a voluntary morphine intake of 15 mg/kg/day. Morphine consumption led to significant analgesia and hyperlocomotion, and to a marked deprivation syndrome following the administration of the opioid antagonist naloxone. Voluntary morphine consumption was also shown to generate brain oxidative stress and neuroinflammation, signs associated with opioid dependence development. We present a robust two-bottle choice animal model of oral morphine self-administration for the evaluation of therapeutic interventions for the treatment of morphine dependence.

[Percutaneous implantation of an aortic prosthetic valve on a degenerated mitral bioprosthesis. Report of one case]. / Implantación percutánea transeptal de válvula protésica aórtica sobre bioprótesis mitral degenerada.

Reintervention of a mitral degenerated bioprosthesis has a high surgical risk, especially in elderly patients with multiple comorbidities. We report a 74 years old female with two previous cardiac surgical procedures and a new structural mitral bioprosthesis deterioration with severe mitral regurgitation. Considering her high-surgical risk, a fully percutaneous treatment was performed with a balloon-expandable aortic valve in mitral position (valve-in-valve) through a transseptal approach with a favorable outcome. This technique is an attractive and effective option with a relatively low rate of complications that could solve this challenging and complex disease.

Robotic therapy for the hemiplegic shoulder pain: a pilot study.

BACKGROUNDS: Exoskeletons development arises with a leading role in neurorehabilitation technologies; however, very few prototypes for upper limbs have been tested, contrasted and duly certified in terms of their effectiveness in clinical environments in order to incorporate into the health system. The purpose of this pilot study was to determine if robotic therapy of Hemiplegic Shoulder Pain (HSP) could lead to functional improvement in terms of diminishing of pain, spasticity, subluxation, the increasing of tone and muscle strength, and the satisfaction degree. METHODS: An experimental study was conducted in 16 patients with painful shoulder post- ischemic stroke in two experimental groups: conventional and robotic therapy. At different stages of its evolution, the robotic therapy effectiveness applied with anti-gravitational movements was evaluated. Clinical trial was developed at the Physical Medicine and Rehabilitation Department of the Surgical Clinical Hospital "Dr. Juan Bruno Zayas Alfonso" in Santiago de Cuba, from September 2016 - March 2018. Among other variables: the presence of humeral scapular subluxation (HSS), pain, spasticity, mobility, tone and muscle strength, and the satisfaction degree were recorded. Results with 95% reliability were compared between admission and third months of treatment. The Mann-Whitney U-Test, Chi-Square and Fisher's Exact Tests were used as comparison criteria. RESULTS: Robotic therapy positively influenced in the decrease and annulment of pain and the spasticity degree, reaching a range increase of joint movement and the improvement of muscle tone.

Amelioration of morphine withdrawal syndrome by systemic and intranasal administration of mesenchymal stem cell-derived secretome in preclinical models of morphine dependence.

BACKGROUND: Morphine is an opiate commonly used in the treatment of moderate to severe pain. However, prolonged administration can lead to physical dependence and strong withdrawal symptoms upon cessation of morphine use. These symptoms can include anxiety, irritability, increased heart rate, and muscle cramps, which strongly promote morphine use relapse. The morphine-induced increases in neuroinflammation, brain oxidative stress, and alteration of glutamate levels in the hippocampus and nucleus accumbens have been associated with morphine dependence and a higher severity of withdrawal symptoms. Due to its rich content in potent anti-inflammatory and antioxidant factors, secretome derived from human mesenchymal stem cells (hMSCs) is proposed as a preclinical therapeutic tool for the treatment of this complex neurological condition associated with neuroinflammation and brain oxidative stress. METHODS: Two animal models of morphine dependence were used to evaluate the therapeutic efficacy of hMSC-derived secretome in reducing morphine withdrawal signs. In the first model, rats were implanted subcutaneously with mini-pumps which released morphine at a concentration of 10 mg/kg/day for seven days. Three days after pump implantation, animals were treated with a simultaneous intravenous and intranasal administration of hMSC-derived secretome or vehicle, and withdrawal signs were precipitated on day seven by i.p. naloxone administration. In this model, brain alterations associated with withdrawal were also analyzed before withdrawal precipitation. In the second animal model, rats voluntarily consuming morphine for three weeks were intravenously and intranasally treated with hMSC-derived secretome or vehicle, and withdrawal signs were induced by morphine deprivation. RESULTS: In both animal models secretome administration induced a significant reduction of withdrawal signs, as shown by a reduction in a combined withdrawal score. Secretome administration also promoted a reduction in morphine-induced neuroinflammation in the hippocampus and nucleus accumbens, while no changes were observed in extracellular glutamate levels in the nucleus accumbens. CONCLUSION: Data presented from two animal models of morphine dependence suggest that administration of secretome derived from hMSCs reduces the development of opioid withdrawal signs, which correlates with a reduction in neuroinflammation in the hippocampus and nucleus accumbens.

Effect of human mesenchymal stem cell secretome administration on morphine self-administration and relapse in two animal models of opioid dependence.

The present study investigates the possible therapeutic effects of human mesenchymal stem cell-derived secretome on morphine dependence and relapse. This was studied in a new model of chronic voluntary morphine intake in Wistar rats which shows classic signs of morphine intoxication and a severe naloxone-induced withdrawal syndrome. A single intranasal-systemic administration of MSCs secretome fully inhibited (>95%; p < 0.001) voluntary morphine intake and reduced the post-deprivation relapse intake by 50% (p < 0.02). Since several studies suggest a significant genetic contribution to the chronic use of many addictive drugs, the effect of MSCs secretome on morphine self-administration was further studied in rats bred as high alcohol consumers (UChB rats). Sub-chronic intraperitoneal administration of morphine before access to increasing concentrations of morphine solutions and water were available to the animals, led UChB rats to prefer ingesting morphine solutions over water, attaining levels of oral morphine intake in the range of those in the Wistar model. Intranasally administered MSCs secretome to UChB rats dose-dependently inhibited morphine self-administration by 72% (p < 0.001); while a single intranasal dose of MSC-secretome administered during a morphine deprivation period imposed on chronic morphine consumer UChB rats inhibited re-access morphine relapse intake by 80 to 85% (p < 0.0001). Both in the Wistar and the UChB rat models, MSCs-secretome administration reversed the morphine-induced increases in brain oxidative stress and neuroinflammation, considered as key engines perpetuating drug relapse. Overall, present preclinical studies suggest that products secreted by human mesenchymal stem cells may be of value in the treatment of opioid addiction.

Shoulder-specific rehabilitation combined with aerobic exercises versus solely shoulder-specific rehabilitation in patients with type 2 diabetes mellitus: study protocol for a randomized controlled superiority trial.

BACKGROUND: Musculoskeletal disorders are very common in patients with diabetes mellitus (DM). The upper limb is one of the regions that is most frequently affected generally presenting limited joint mobility, pain, and a decreased muscle strength. Most clinical trials with a focus on shoulder musculoskeletal rehabilitation are carried out in patients who do not present DM. Thus, the purpose of the present study is to compare the effects of two distinct treatment protocols (conventional shoulder musculoskeletal rehabilitation combined with aerobic exercises versus solely conventional shoulder musculoskeletal rehabilitation) on shoulder pain, function, strength, kinematics, and supraspinatus tendon thickness in patients with type 2 DM after 12 weeks of intervention and a subsequent follow-up at week 20. METHODS: A randomized controlled superiority trial will be conducted. Participants with a clinical diagnosis of type 2 DM of both sexes, age between 40 and 70 years, presenting shoulder pain will be randomly assigned to one of the following groups: (1) conventional shoulder musculoskeletal rehabilitation combined with aerobic exercises; (2) solely conventional shoulder musculoskeletal rehabilitation. All individuals will be evaluated before starting the treatment protocol (baseline) and at the end of treatment (post 12 weeks) and as a follow-up at 20 weeks. The shoulder function assessed by the SPADI (Shoulder Pain and Disability Index) questionnaire will be considered as primary outcome; the secondary outcome will be shoulder pain, measured with NPRS scales. Other outcomes will include range of motion, measured using a digital inclinometer; isometric shoulder muscle strength, measured using a manual muscle dynamometer; shoulder kinematics, measured using three-dimensional inertial units measurement; supraspinatus tendon thickness, measured using an ultrasound; AGE accumulation, using a skin autofluorescence measurement; and HbA1c (hemoglobin a1c), fasting glucose and lipid profile measured by a simple blood test. DISCUSSION: DM is a highly prevalent disease and a public health problem worldwide, and the upper extremity musculoskeletal disorders in DM are barely recognized and largely underestimated. In this way, it would be interesting to analyze if the combination of aerobic exercises with conventional musculoskeletal rehabilitation protocols could generate better results in the functionality, pain, mobility and an improvement in the biochemical aspects related to the hyperglycemia of these patients compared to solely the conventional musculoskeletal rehabilitation. TRIAL REGISTRATION: ClinicalTrials.gov NCT04817514. Registered on March 26, 2021.

Oxidative Stress and Neuroinflammation as a Pivot in Drug Abuse. A Focus on the Therapeutic Potential of Antioxidant and Anti-Inflammatory Agents and Biomolecules.

Drug abuse is a major global health and economic problem. However, there are no pharmacological treatments to effectively reduce the compulsive use of most drugs of abuse. Despite exerting different mechanisms of action, all drugs of abuse promote the activation of the brain reward system, with lasting neurobiological consequences that potentiate subsequent consumption. Recent evidence shows that the brain displays marked oxidative stress and neuroinflammation following chronic drug consumption. Brain oxidative stress and neuroinflammation disrupt glutamate homeostasis by impairing synaptic and extra-synaptic glutamate transport, reducing GLT-1, and system Xc- activities respectively, which increases glutamatergic neurotransmission. This effect consolidates the relapse-promoting effect of drug-related cues, thus sustaining drug craving and subsequent drug consumption. Recently, promising results as experimental treatments to reduce drug consumption and relapse have been shown by (i) antioxidant and anti-inflammatory synthetic molecules whose effects reach the brain; (ii) natural biomolecules secreted by mesenchymal stem cells that excel in antioxidant and anti-inflammatory properties, delivered via non-invasive intranasal administration to animal models of drug abuse and (iii) potent anti-inflammatory microRNAs and anti-miRNAs which target the microglia and reduce neuroinflammation and drug craving. In this review, we address the neurobiological consequences of brain oxidative stress and neuroinflammation that follow the chronic consumption of most drugs of abuse, and the current and potential therapeutic effects of antioxidants and anti-inflammatory agents and biomolecules to reduce these drug-induced alterations and to prevent relapse.

Differences in Muscle Strength Performance According to the Genotypes of the rs4646994 Polymorphism of the ACE Gene in a Sedentary Population

SUMMARY: The angiotensin converting enzyme gene (ACE) has been associated with endurance and strength performance through its I/D polymorphism. Nevertheless, contradictory results exist between different populations. In this context, the purpose of this research was to determine the influence of the I/D polymorphism of the ACE gene on muscle strength in a sedentary Chilean sample. In this study 102 healthy male students (21.3 ± 2.2 years) completed the assessment. I/D genotyping, cardiovascular, anthropometric, grip strength and knee extensor peak strength were evaluated. The ACE polymorphism frequency was: II, 33.3 %; ID, 46.1 %; DD, 20.6 %. The results showed significant differences and large effect size in maximum (p = 0.004; d = 0.85) and relative handgrip strength (p = 0.004; d = 0.9) between genotype II vs DD. No difference was found for maximal or relative knee extensor strength between groups (p = 0.74), showing a low effect size (d = 0.20). In conclusion, this study provides insights into the role of the ACE gene in muscle strength and highlights the importance of investigating genetic variants in sedentary populations to better understand strength performance.

El gen de la enzima convertidora de angiotensina (ACE) se ha asociado con el rendimiento de resistencia y fuerza a través de su polimorfismo I/D. Sin embargo, existen resultados contradictorios entre diferentes poblaciones. En este contexto, el propósito de esta investigación fue determinar la influencia del polimorfismo I/D del gen ACE sobre la fuerza muscular en una muestra chilena sedentaria. En este estudio, fueron evaluados 102 estudiantes varones sanos (21,3 ± 2,2 años). Se realizaron aplicaron las siguientes evaluaciones: genotipado del polimorfismo I/D, cardiovascular, antropométrica, fuerza de prensión y fuerza máxima de extensión de rodilla. La frecuencia del polimorfismo I/D de ACE fue: II, 33,3 %; DNI, 46,1 %; DD, 20,6 %. Los resultados mostraron diferencias significativas y un gran tamaño del efecto en la fuerza máxima (p = 0,004; d = 0,85) y relativa de prensión manual (p = 0,004; d = 0,9) entre el genotipo II y el DD. No se encontraron diferencias en la fuerza máxima o relativa de los extensores de rodilla entre los grupos (p = 0,74), lo que muestra un tamaño de efecto bajo (d = 0,20). En conclusión, este estudio proporciona información sobre el papel del gen ACE en la fuerza muscular y destaca la importancia de investigar variantes genéticas en poblaciones sedentarias para comprender mejor el rendimiento de la fuerza.

Polyunsaturated fatty acid induces cardioprotection against ischemia-reperfusion through the inhibition of NF-kappaB and induction of Nrf2.

The mechanistic evidence to support the cardioprotective effects of polyunsaturated fatty acids (PUFA) are controversial. The aim was to test cardioprotective mechanisms induced by PUFA supplementation against cardiac ischemia-reperfusion (IR) injury. Ten-week-old male Wistar rats (225 ± 14 g, n = 14) were divided in two groups: rats without supplementation ( n = 7) and a PUFA group, supplemented by PUFA (0.6 g/kg/day; DHA:EPA = 3:1) for eight weeks ( n = 7). Hearts were perfused with Krebs-Henseleit buffer for 20 min (control conditions); others were subjected to control conditions, 30 min of global ischemia and 120 min of reperfusion (IR group). Infarct size (IS) and left ventricular developed pressure (LVDP) were measured at 120 min of reperfusion. Oxidative stress biomarkers (TBARS, total carbonyls), antioxidant status (CAT, catalase; SOD, superoxide dismutase; GSH-Px, glutathione peroxidase activity and GSH/GSSG ratio), myeloperoxidase activity, ATP levels and nuclear transcription factor erythroid 2-related factor 2 (Nrf2) and nuclear factor kappaB (NF-κB) were determined in both experimental conditions. At the end of reperfusion, hearts supplemented with PUFA showed lower IS and a higher LVDP compared with the nonsupplemented rats. Hearts in the group supplemented with PUFA showed lower levels of oxidative stress markers and higher antioxidant activity, decreased MPO activity and NF-κB and Nrf2 activation compared with the nonsupplemented group. Cardioprotective effects of PUFA are exerted through induction of anti-inflammatory and antioxidant mechanism at tissue level.

Prediction and Characterization of High-Activity Events in Social Media Triggered by Real-World News.

On-line social networks publish information on a high volume of real-world events almost instantly, becoming a primary source for breaking news. Some of these real-world events can end up having a very strong impact on on-line social networks. The effect of such events can be analyzed from several perspectives, one of them being the intensity and characteristics of the collective activity that it produces in the social platform. We research 5,234 real-world news events encompassing 43 million messages discussed on the Twitter microblogging service for approximately 1 year. We show empirically that exogenous news events naturally create collective patterns of bursty behavior in combination with long periods of inactivity in the network. This type of behavior agrees with other patterns previously observed in other types of natural collective phenomena, as well as in individual human communications. In addition, we propose a methodology to classify news events according to the different levels of intensity in activity that they produce. In particular, we analyze the most highly active events and observe a consistent and strikingly different collective reaction from users when they are exposed to such events. This reaction is independent of an event's reach and scope. We further observe that extremely high-activity events have characteristics that are quite distinguishable at the beginning stages of their outbreak. This allows us to predict with high precision, the top 8% of events that will have the most impact in the social network by just using the first 5% of the information of an event's lifetime evolution. This strongly implies that high-activity events are naturally prioritized collectively by the social network, engaging users early on, way before they are brought to the mainstream audience.

Implantación percutánea transeptal de válvula protésica aórtica sobre bioprótesis mitral degenerada / Percutaneous implantation of an aortic prosthetic valve on a degenerated mitral bioprosthesis. Report of one case

Reintervention of a mitral degenerated bioprosthesis has a high surgical risk, especially in elderly patients with multiple comorbidities. We report a 74 years old female with two previous cardiac surgical procedures and a new structural mitral bioprosthesis deterioration with severe mitral regurgitation. Considering her high-surgical risk, a fully percutaneous treatment was performed with a balloon-expandable aortic valve in mitral position (valve-in-valve) through a transseptal approach with a favorable outcome. This technique is an attractive and effective option with a relatively low rate of complications that could solve this challenging and complex disease.