Exceptionally preserved shark fossils from Mexico elucidate the long-standing enigma of the Cretaceous elasmobranch Ptychodus.

The fossil fish Ptychodus Agassiz, 1834, characterized by a highly distinctive grinding dentition and an estimated gigantic body size (up to around 10 m), has remained one of the most enigmatic extinct elasmobranchs (i.e. sharks, skates and rays) for nearly two centuries. This widespread Cretaceous taxon is common in Albian to Campanian deposits from almost all continents. However, specimens mostly consist of isolated teeth or more or less complete dentitions, whereas cranial and post-cranial skeletal elements are very rare. Here we describe newly discovered material from the early Late Cretaceous of Mexico, including complete articulated specimens with preserved body outline, which reveals crucial information on the anatomy and systematic position of Ptychodus. Our phylogenetic and ecomorphological analyses indicate that ptychodontids were high-speed (tachypelagic) durophagous lamniforms (mackerel sharks), which occupied a specialized predatory niche previously unknown in fossil and extant elasmobranchs. Our results support the view that lamniforms were ecomorphologically highly diverse and represented the dominant group of sharks in Cretaceous marine ecosystems. Ptychodus may have fed predominantly on nektonic hard-shelled prey items such as ammonites and sea turtles rather than on benthic invertebrates, and its extinction during the Campanian, well before the end-Cretaceous crisis, might have been related to competition with emerging blunt-toothed globidensine and prognathodontine mosasaurs.

Sigma-1 receptor agonism exacerbates immune-driven nociception: Role of TRPV1 + nociceptors.

The analgesic effects of sigma-1 antagonists are undisputed, but the effects of sigma-1 agonists on pain are not well studied. Here, we used a mouse model to show that the administration of the sigma-1 agonists dextromethorphan (a widely used antitussive drug), PRE-084 (a standard sigma-1 ligand), and pridopidine (a selective drug being investigated in clinical trials for the treatment of neurodegenerative diseases) enhances PGE2-induced mechanical hyperalgesia. Superficial plantar incision induced transient weight-bearing asymmetry at early time points, but the mice appeared to recover at 24 h, despite noticeable edema and infiltration of neutrophils (a well-known cellular source of PGE2) at the injured site. Sigma-1 agonists induced a relapse of weight bearing asymmetry in a manner dependent on the presence of neutrophils. The effects of sigma-1 agonists were all reversed by administration of the sigma-1 antagonist BD-1063 in wild-type mice, and were absent in sigma-1 knockout mice, supporting the selectivity of the effects observed. The proalgesic effects of sigma-1 agonism were also abolished by the TRP antagonist ruthenium red and by in vivo resiniferatoxin ablation of TRPV1 + peripheral sensory neurons. Therefore, sigma-1 agonism exacerbates pain-like responses in mice with a mild inflammatory state through the action of TRPV1 + nociceptors. We also show that sigma-1 receptors are present in most (if not all) mouse and human DRG neurons. If our findings translate to humans, further studies will be needed to investigate potential proalgesic effects induced by sigma-1 agonism in patients treated with sigma-1 agonists.

The evolutionary origin of the durophagous pelagic stingray ecomorph.

Studies of the origin of evolutionary novelties (novel traits, feeding modes, behaviours, ecological niches, etc.) have considered a number of taxa experimenting with new body plans, allowing them to occupy new habitats and exploit new trophic resources. In the marine realm, colonization of pelagic environments by marine fishes occurred recurrently through time. Stingrays (Myliobatiformes) are a diverse clade of batoid fishes commonly known to possess venomous tail stings. Current hypotheses suggest that stingrays experimented with a transition from a benthic to a pelagic/benthopelagic habitat coupled with a transition from a non-durophagous diet to extreme durophagy. However, there is no study detailing macroevolutionary patterns to understand how and when habitat shift and feeding specialization arose along their evolutionary history. A new exquisitely preserved fossil stingray from the Eocene Konservat-Lagerstätte of Bolca (Italy) exhibits a unique mosaic of plesiomorphic features of the rajobenthic ecomorph, and derived traits of aquilopelagic taxa, that helps to clarify the evolutionary origin of durophagy and pelagic lifestyle in stingrays. A scenario of early evolution of the aquilopelagic ecomorph is proposed based on new data, and the possible adaptive meaning of the observed evolutionary changes is discussed. The body plan of †Dasyomyliobatis thomyorkei gen. et sp. nov. is intermediate between the rajobenthic and more derived aquilopelagic stingrays, supporting its stem phylogenetic position and the hypothesis that the aquilopelagic body plan arose in association with the evolution of durophagy and pelagic lifestyle from a benthic, soft-prey feeder ancestor.

Systematics and Phylogenetic Interrelationships of the Enigmatic Late Jurassic Shark Protospinax annectans Woodward, 1918 with Comments on the Shark-Ray Sister Group Relationship.

The Late Jurassic elasmobranch Protospinax annectans is often regarded as a key species to our understanding of crown group elasmobranch interrelationships and the evolutionary history of this group. However, since its first description more than 100 years ago, its phylogenetic position within the Elasmobranchii (sharks and rays) has proven controversial, and a closer relationship between Protospinax and each of the posited superorders (Batomorphii, Squalomorphii, and Galeomorphii) has been proposed over the time. Here we revise this controversial taxon based on new holomorphic specimens from the Late Jurassic Konservat-Lagerstätte of the Solnhofen Archipelago in Bavaria (Germany) and review its skeletal morphology, systematics, and phylogenetic interrelationships. A data matrix with 224 morphological characters was compiled and analyzed under a molecular backbone constraint. Our results indicate a close relationship between Protospinax, angel sharks (Squatiniformes), and saw sharks (Pristiophoriformes). However, the revision of our morphological data matrix within a molecular framework highlights the lack of morphological characters defining certain groups, especially sharks of the order Squaliformes, hampering the phylogenetic resolution of Protospinax annectans with certainty. Furthermore, the monophyly of modern sharks retrieved by molecular studies is only weakly supported by morphological data, stressing the need for more characters to align morphological and molecular studies in the future.

A Synoptic Review of the Cartilaginous Fishes (Chondrichthyes: Holocephali, Elasmobranchii) from the Upper Jurassic Konservat-Lagerstätten of Southern Germany: Taxonomy, Diversity, and Faunal Relationships.

The Late Jurassic-Early Cretaceous (164-100 Ma) represents one of the main transitional periods in life history. Recent studies unveiled a complex scenario in which abiotic and biotic factors and drivers on regional and global scales due to the fragmentation of Pangaea resulted in dramatic faunal and ecological turnovers in terrestrial and marine environments. However, chondrichthyan faunas from this interval have received surprisingly little recognition. The presence of numerous entire skeletons of chondrichthyans preserved in several localities in southern Germany, often referred to as Konservat-Lagerstätten (e.g., Nusplingen and the Solnhofen Archipelago), provides a unique opportunity of to study the taxonomic composition of these assemblages, their ecological distributions and adaptations, and evolutionary histories in detail. However, even after 160 years of study, the current knowledge of southern Germany's Late Jurassic chondrichthyan diversity remains incomplete. Over the last 20 years, the systematic study and bulk sampling of southern Germany's Late Jurassic deposits significantly increased the number of known fossil chondrichthyan genera from the region (32 in the present study). In the present work, the fossil record, and the taxonomic composition of Late Jurassic chondrichthyans from southern Germany are reviewed and compared with several contemporaneous assemblages from other sites in Europe. Our results suggest, inter alia, that the Late Jurassic chondrichthyans displayed extended distributions within Europe. However, it nevertheless also is evident that the taxonomy of Late Jurassic chondrichthyans is in urgent need of revision.

The Phylogeny of Rays and Skates (Chondrichthyes: Elasmobranchii) Based on Morphological Characters Revisited.

Elasmobranchii are relatively well-studied. However, numerous phylogenetic uncertainties about their relationships remain. Here, we revisit the phylogenetic evidence based on a detailed morphological re-evaluation of all the major extant batomorph clades (skates and rays), including several holomorphic fossil taxa from the Palaeozoic, Mesozoic and Cenozoic, and an extensive outgroup sampling, which includes sharks, chimaeras and several other fossil chondrichthyans. The parsimony and maximum-likelihood analyses found more resolved but contrasting topologies, with the Bayesian inference tree neither supporting nor disfavouring any of them. Overall, the analyses result in similar clade compositions and topologies, with the Jurassic batomorphs forming the sister clade to all the other batomorphs, whilst all the Cretaceous batomorphs are nested within the remaining main clades. The disparate arrangements recovered under the different criteria suggest that a detailed study of Jurassic taxa is of utmost importance to present a more consistent topology in the deeper nodes, as issues continue to be present when analysing those clades previously recognized only by molecular analyses (e.g., Rhinopristiformes and Torpediniformes). The consistent placement of fossil taxa within specific groups by the different phylogenetic criteria is promising and indicates that the inclusion of more fossil taxa in the present matrix will likely not cause loss of resolution, therefore suggesting that a strong phylogenetic signal can be recovered from fossil taxa.

Abordaje perioperatorio en cirugía neurológica con el paciente despierto / Perioperative approach in neurological surgery with the patient awake

Resumen: La craneotomía con el paciente despierto se refiere a aquellos procedimientos en los que el paciente conserva su estado de consciencia durante toda la cirugía o en parte de ésta con el objetivo de explorar la integridad de sus funciones cerebrales superiores en tiempo real. Estas técnicas neuroanestésicas son útiles para ayudar al neurocirujano a preservar la integridad del tejido cerebral, o bien, no causar mayor daño del que la propia enfermedad ha causado.

Abstract: Awake craniotomy refers to those procedures in which the patient remains conscious for all or part the time, with the aim of explore in real time the integrity of their higher brain functions. This kind of neuroanesthetic techniques are useful in assisting the neurosurgeon to preserve the integrity of the brain or not to damage more than what the disease has caused.

Heterozygous Arrhythmogenic Cardiomyopathy-desmoplakin Mutation Carriers Exhibit a Subclinical Cutaneous Phenotype with Cell Membrane Disruption and Lack of Intercellular Adhesion.

Genetic variants that result in truncation in desmoplakin (DSP) are a known cause of arrhythmogenic cardiomyopathy (AC). In homozygous carriers, the combined involvement of skin and heart muscle is well defined, however, this is not the case in heterozygous carriers. The aim of this work is to describe cutaneous findings and analyze the molecular and ultrastructural cutaneous changes in this group of patients. Four women and eight men with a mean age of 48 ± 14 years were included. Eight met definitive criteria for AC, one was borderline and three were silent carriers. No relevant macroscopic changes in skin and hair were detected. However, significantly lower skin temperature (29.56 vs. 30.97 °C, p = 0.036) and higher transepidermal water loss (TEWL) (37.62 vs. 23.95 g m 2 h 1, p = 0.028) were observed compared to sex- and age-matched controls. Histopathology of the skin biopsy showed widening of intercellular spaces and acantholysis of keratinocytes in the spinous layer. Immunohistochemistry showed a strongly reduced expression of DSP in all samples. Trichogram showed regular nodules (thickening) compatible with pseudomonilethrix. Therefore, regardless of cardiac involvement, heterozygous patients with truncation-type variants in DSP have lower skin temperature and higher TEWL, constant microscopic skin involvement with specific patterns and pseudomonilethrix in the trichogram.

High Efficacy of Therapeutic Equine Hyperimmune Antibodies Against SARS-CoV-2 Variants of Concern.

SARS-CoV-2 variants of concern show reduced neutralization by vaccine-induced and therapeutic monoclonal antibodies; therefore, treatment alternatives are needed. We tested therapeutic equine polyclonal antibodies (pAbs) that are being assessed in clinical trials in Costa Rica against five globally circulating variants of concern: alpha, beta, epsilon, gamma and delta, using plaque reduction neutralization assays. We show that equine pAbs efficiently neutralize the variants of concern, with inhibitory concentrations in the range of 0.146-1.078 µg/mL, which correspond to extremely low concentrations when compared to pAbs doses used in clinical trials. Equine pAbs are an effective, broad coverage, low-cost and a scalable COVID-19 treatment.

Development and characterization of two equine formulations towards SARS-CoV-2 proteins for the potential treatment of COVID-19.

In the current global emergency due to SARS-CoV-2 outbreak, passive immunotherapy emerges as a promising treatment for COVID-19. Among animal-derived products, equine formulations are still the cornerstone therapy for treating envenomations due to animal bites and stings. Therefore, drawing upon decades of experience in manufacturing snake antivenom, we developed and preclinically evaluated two anti-SARS-CoV-2 polyclonal equine formulations as potential alternative therapy for COVID-19. We immunized two groups of horses with either S1 (anti-S1) or a mixture of S1, N, and SEM mosaic (anti-Mix) viral recombinant proteins. Horses reached a maximum anti-viral antibody level at 7 weeks following priming, and showed no major adverse acute or chronic clinical alterations. Two whole-IgG formulations were prepared via hyperimmune plasma precipitation with caprylic acid and then formulated for parenteral use. Both preparations had similar physicochemical and microbiological quality and showed ELISA immunoreactivity towards S1 protein and the receptor binding domain (RBD). The anti-Mix formulation also presented immunoreactivity against N protein. Due to high anti-S1 and anti-RBD antibody content, final products exhibited high in vitro neutralizing capacity of SARS-CoV-2 infection, 80 times higher than a pool of human convalescent plasma. Pre-clinical quality profiles were similar among both products, but clinical efficacy and safety must be tested in clinical trials. The technological strategy we describe here can be adapted by other producers, particularly in low- and middle-income countries.

Paclitaxel antitumor effect improvement in lung cancer and prevention of the painful neuropathy using large pegylated cationic liposomes.

Paclitaxel (PTX), a drug widely used in lung cancer, has serious limitations including the development of peripheral neurotoxicity, which may lead to treatment discontinuation and therapy failure. The transport of PTX in large cationic liposomes could avoid this undesirable effect, improving the patient's prognosis. PTX was encapsulated in cationic liposomes with two different sizes, MLV (180-200 nm) and SUV (80-100 nm). In both cases, excellent biocompatibility and improved internalization and antitumor effect of PTX were observed in human and mice lung cancer cells in culture, multicellular spheroids and cancer stem cells (CSCs). In addition, both MLV and SUV with a polyethylene glycol (PEG) shell, induced a greater tumor volume reduction than PTX (56.4 % and 57.1 % vs. 36.7 %, respectively) in mice. Interestingly, MLV-PEG-PTX did not induce either mechanical or heat hypersensitivity whereas SUV-PEG-PTX produced a similar response to free PTX. Analysis of PTX distribution showed a very low concentration of the drug in the dorsal root ganglia (DRG) with MLV-PEG-PTX, but not with SUV-PEG-PTX or free PTX. These results support the hypothesis that PTX induces peripheral neuropathy by penetrating the endothelial fenestrations of the DRG (80-100 nm, measured in mice). In conclusion, our larger liposomes (MLV-PEG-PTX) not only showed biocompatibility, antitumor activity against CSCs, and in vitro and in vivo antitumor effect that improved PTX free activity, but also protected from PTX-induced painful peripheral neuropathy. These advantages could be used as a new strategy of lung cancer chemotherapy to increase the PTX activity and reduce its side effects.

Cómo enfrentar una epidemia respiratoria masiva, desde el punto de vista organizacional y un plan de contingencia / How to face a massive respiratory epidemic, from the organizational point of view and a contingency plan?

Resumen: Las epidemias no son producto de la «globalización¼, han azotado a la humanidad desde sus orígenes, no hay que cerrar fronteras ni al turismo ni al comercio; en la antigüedad no había autopistas, trenes, trasatlánticos ni aviones y existían las epidemias, la historia demuestra que la protección real viene del intercambio de información científica confiable y de la solidaridad real; no obstante, en este mundo globalizado y comunicado, «era del punto com¼, se genera un sinnúmero de información día a día, incluso en minutos se publican cientos de artículos relacionados a la pandemia que hoy nos ocupa, el COVID-19, información que debemos saber seleccionar y discriminar adecuadamente para no perdernos en ella. Una vez entendido que el verdadero antídoto para una epidemia es la cooperación y no la segregación, se debe establecer un diagnóstico situacional, debemos trabajar al unísono, como un equipo con un mismo propósito, en este artículo pretendemos compartir el cómo organizarse desde el punto de vista logístico y cómo proteger y optimizar el valiosísimo recurso humano, el personal sanitario.

Abstract: The epidemics are not a «globalization¼ product, this exists since the humanity begun, it´s not necessary to close borders neither trade between countries, in the past did not exist highways, railway, tall ships or aircraft and the epidemics already existed, the history show and demonstrate us that the real protection is the interchange of confident information and the teamwork, we should work like global unity. In the global universe the information grow up exponentially daily, so we have to be careful with all the data that come to us. If we understand that an epidemic's antidote is the cooperation and unity, we should have the capacity to organize a solid teamwork based on a situational diagnose. Our purpose in this paper is to share our experience in organizational logistics and give its true value to health personnel.

Urinary bladder sigma-1 receptors: A new target for cystitis treatment.

No adequate treatment is available for painful urinary bladder disorders such as interstitial cystitis/bladder pain syndrome, and the identification of new urological therapeutic targets is an unmet need. The sigma-1 receptor (σ1-R) modulates somatic pain, but its role in painful urological disorders is unexplored. The urothelium expresses many receptors typical of primary sensory neurons (e.g. TRPV1, TRPA1 and P2X3) and high levels of σ1-R have been found in these neurons; we therefore hypothesized that σ1-R may also be expressed in the urothelium and may have functional relevance in this tissue. With western blotting and immunohistochemical methods, we detected σ1-R in the urinary bladder in wild-type (WT) but not in σ1-R-knockout (σ1-KO) mice. Interestingly, σ1-R was located in the bladder urothelium not only in mouse, but also in human bladder sections. The severity of histopathological (edema, hemorrhage and urothelial desquamation) and biochemical alterations (enhanced myeloperoxidase activity and phosphorylation of extracellular regulated kinases 1/2 [pERK1/2]) that characterize cyclophosphamide-induced cystitis was lower in σ1-KO than in WT mice. Moreover, cyclophosphamide-induced pain behaviors and referred mechanical hyperalgesia were dose-dependently reduced by σ1-R antagonists (BD-1063, NE-100 and S1RA) in WT but not in σ1-KO mice. In contrast, the analgesic effect of morphine was greater in σ1-KO than in WT mice. Together these findings suggest that σ1-R plays a functional role in the mechanisms underlying cyclophosphamide-induced cystitis, and modulates morphine analgesia against urological pain. Therefore, σ1-R may represent a new drug target for urinary bladder disorders.

Intracolonic Mustard Oil Induces Visceral Pain in Mice by TRPA1-Dependent and -Independent Mechanisms: Role of Tissue Injury and P2X Receptors.

Both TRPA1 and purinergic P2X receptors have been proposed as potential targets for the treatment of visceral pain. We found that the intracolonic administration of a low dose mustard oil (0.5%), a well-known TRPA1 agonist, produced nociceptive responses and abdominal wall referred mechanical hyperalgesia, without inducing apparent tissue damage. Both nociceptive responses and referred hyperalgesia were abolished by the ablation of TRPV1-expressing neurons (and the consequent ablation of TRPA1+ nociceptors) by resiniferatoxin (RTX) treatment, and by the TRPA1 antagonist AP18. However, a higher dose of mustard oil (2.5%) damaged the colonic epithelium and induced pERK activation in the spinal cord, and these processes were clearly independent of TRPV1-expressing neurons ablated by RTX. This higher dose of mustard oil induced nociceptive responses and referred mechanical hyperalgesia which were insensitive or only slightly sensitive to resiniferatoxin or AP18, but were markedly reduced by the P2X antagonist TNP-ATP, which is known to inhibit nociceptive actions induced by ATP released from injured tissues. In conclusion, whereas a low dose of intracolonic mustard oil induces visceral pain in a manner fully dependent on TRPA1 actions, when a high dose of this chemical irritant is used, visceral pain becomes mostly independent of TRPA1 activation but clearly enhanced by ATP purportedly released by the damaged colonic epithelium. Therefore, TRPA1 inhibition is not sufficient to substantially decrease visceral pain during tissue injury, whereas purinergic antagonism appears to be a more effective strategy.

NUTRI-HABI: Estado nutricional y hábitos alimentarios de estudiantes ingresantes a la Universidad Nacional Agraria La Molina. Perú / NUTRI-HABI: Nutritional status and eating habits of incoming students at the National Agrarian University La Molina. Peru

FUNDAMENTOS: La población universitaria es un grupo vulnerable siendo necesario conocer su estado nutricional y hábitos alimentarios, para permitan intervenciones alimentarias. El objetivo fue evaluar el estado nutricional y hábitos alimentarios de estudiantes de la Universidad Nacional Agraria La Molina. MÉTODOS: Estudio observacional (n=102). Las Variables estudiadas fueron: edad, sexo, carrera profesional, índice de masa corporal, perímetro abdominal, hemoglobina, consumo de alimentos fuentes de grasa, fruta, vegetales y fibra. Se calculó número, porcentaje y medidas de tendencia central y dispersión, y la asociación entre variables. RESULTADOS:31,4% de estudiantes tenían exceso de peso, siendo mayor en hombres. El 27,5% de los estudiantes presentaban riesgo metabólico aumentado, siendo este mayor en mujeres. Se encontró una prevalencia de 21,7% de anemia en mujeres, mientras que en hombres no se observó(p < 0,01). El 58,8% de los estudiantes tenían una dieta baja en grasa, el 69,6% mantenía una dieta baja en frutas, vegetales y fibra; las mujeres presentaban un menor consumo de alimentos ricos en grasa, mientras que los hombres presentan menor consumo de frutas, vegetales y fibra. CONCLUSIONES: Se encontró una alta prevalencia de exceso de peso, riesgo metabólico aumentado y anemia, no se encontró anemia en hombres por lo que se concluye que la anemia se relaciona con el sexo. Los estudiantes tienen una dieta baja en grasa, frutas, vegetales y fibra

BACKGROUND: university population is a vulnerable group and exist need to know their nutritional status and dietary habits, whose results allow food interventions. The aim was to evaluate the nutritional status and eating habits of students of the National Agrarian University La Molina. METHODS: Observational study (n = 102). The variables studied were: age, sex, professional career, body mass index, abdominal perimeter, hemoglobin, food consumption sources of fat, fruit, vegetables and fiber. For variables number, percentage, measures of central tendency and dispersionwere calculated, as well asthe association between variables. RESULTS: 31.4% of students are overweight and it is higher in men. 27.5% of students have increased metabolic risk and it is higher in women. A prevalence of 21.7% of anemia was found in women; no anemia was found in men (p <0.01).58.8% of students have a low-fat diet, 69.6% have a low diet of fruits, vegetables and fiber; women present lower consumption of fat sources of food than men, while men have lower consumption of fruits, vegetables and fiber than women. CONCLUSIONS: We found a high prevalence of excess weight, increased metabolic risk and anemia, no anemia was found in men, so it is concluded that anemia is related to sex. Students have a diet low in fat, fruits, vegetables and fiber

[Implementation of intraoperative neurophysiologic monitoring in children and adults in secondary and tertiary health care facilities]. / Implementación del monitoreo neurofisiológico intraoperatorio en niños y adultos en el segundo y tercer nivel de atención.

INTRODUCTION: Intraoperative neurophysiological monitoring (IONM) is a procedure that uses neurophysiological techniques in order to evaluate the motor and sensitive systems during surgeries that endanger the nervous system. METHOD: The approach, scope, target population, and clinical questions to be answered were defined. A systematic search of the evidence was conducted step by step; during the first stage, clinical practice guidelines were collected, during the second stage systematic reviews were obtained, and during the third stage, clinical trials and observational studies were procured. The MeSH nomenclature and free related terminology were used, with no language restrictions and a 5-10 years frame. The quality of the evidence was graded using the CEPD and SIGN scales. RESULTS: Obtained using the search algorrhythms of 892 documents. Fifty-eight were chosen to be included in the qualitative synthesis. A meta-analysis was not possible due to the heterogeneity of the studies. CONCLUSIONS: Eighteen recommendations were issued and will support the adequate use of the IONM.

INTRODUCCIÓN: El monitoreo neurofisiológico intraoperatorio (MNIO) es un procedimiento que emplea técnicas neurofisiológicas con la finalidad de evaluar los sistemas motor y sensitivo durante cirugías que ponen en riesgo al sistema nervioso. MÉTODO: Se definieron el enfoque, los alcances, la población diana y las preguntas clínicas por resolver. Se realizó una búsqueda sistematizada de la evidencia por etapas. En la primera, se buscaron guías de práctica clínica; en la segunda, revisiones sistemáticas; y en la tercera, ensayos clínicos y estudios observacionales. Se utilizaron los términos MeSH y libres correspondientes, sin restricciones de lenguaje y con una temporalidad de 5 a 10 años. Se graduó la calidad de la evidencia utilizando las escalas CEPD y SIGN. RESULTADOS: Mediante los algoritmos de búsqueda se obtuvieron 892 documentos, y se seleccionaron 58 para la inclusión de la síntesis cualitativa. Debido a la heterogeneidad entre los estudios, no fue posible realizar metaanálisis. CONCLUSIONES: Se emitieron 18 recomendaciones, las cuales servirán como apoyo para la adecuada utilización del MNIO.

Grip strength in mice with joint inflammation: A rheumatology function test sensitive to pain and analgesia.

Grip strength deficit is a measure of pain-induced functional disability in rheumatic disease. We tested whether this parameter and tactile allodynia, the standard pain measure in preclinical studies, show parallels in their response to analgesics and basic mechanisms. Mice with periarticular injections of complete Freund's adjuvant (CFA) in the ankles showed periarticular immune infiltration and synovial membrane alterations, together with pronounced grip strength deficits and tactile allodynia measured with von Frey hairs. However, inflammation-induced tactile allodynia lasted longer than grip strength alterations, and therefore did not drive the functional deficits. Oral administration of the opioid drugs oxycodone (1-8 mg/kg) and tramadol (10-80 mg/kg) induced a better recovery of grip strength than acetaminophen (40-320 mg/kg) or the nonsteroidal antiinflammatory drugs ibuprofen (10-80 mg/kg) or celecoxib (40-160 mg/kg); these results are consistent with their analgesic efficacy in humans. Functional impairment was generally a more sensitive indicator of drug-induced analgesia than tactile allodynia, as drug doses that attenuated grip strength deficits showed little or no effect on von Frey thresholds. Finally, ruthenium red (a nonselective TRP antagonist) or the in vivo ablation of TRPV1-expressing neurons with resiniferatoxin abolished tactile allodynia without altering grip strength deficits, indicating that the neurobiology of tactile allodynia and grip strength deficits differ. In conclusion, grip strength deficits are due to a distinct type of pain that reflects an important aspect of the human pain experience, and therefore merits further exploration in preclinical studies to improve the translation of new analgesics from bench to bedside.

Effect of coenzyme A on outer hair cells in cisplatin ototoxicity: functional and ultrastructural study.

The aim of this study was to use functional and morphological analyses to evaluate the protective effect of coenzyme A (CoA) in cisplatin-induced toxicity in outer hair cells (OHC). Three groups of 8 guinea pigs were used: control (group I), cisplatin-treated (group II) and cisplatin + CoA-treated (group III). In groups II and III, a single ototoxic dose of cisplatin (10 mg/kg) was injected intraperitoneally. Group III was co-treated with CoA (900 µg/kg per day for 7 consecutive days). Electrocochleography (ECoG) recordings were made before and after the 7-day treatment period in all groups. After ECoG on day 7, all animals were anesthetized and the cochleae were removed and fixed for ultrastructural analysis. Cell damage in OHC was observed with transmission electron microscopy. Cisplatin induced a significant increase in auditory thresholds (p<0.001) compared to group I (control). In contrast, group III (cisplatin + CoA) had significantly reduced thresholds (p<0.001) compared to the group treated with cisplatin alone (group II).We found no significant differences between the control group and animals co-treated with cisplatin and CoA. The electron microscopy findings in OHC were consistent with these results. Ultrastructural analysis of OHC in group II showed morphological indications of necrosis, i.e. cytoplasmic swelling and vacuolation, and mitochondrial swelling. In group III the cell morphology of OHC was preserved, with ultrastructural characteristics similar to the control group. In conclusion, co-treatment with cisplatin with CoA inhibited antineoplastic-induced cytotoxicity in OHC in a guinea pig model.

Aerobic interval exercise improves parameters of nonalcoholic fatty liver disease (NAFLD) and other alterations of metabolic syndrome in obese Zucker rats.

Metabolic syndrome (MS) is a group of metabolic alterations that increase the susceptibility to cardiovascular disease and type 2 diabetes. Nonalcoholic fatty liver disease has been described as the liver manifestation of MS. We aimed to test the beneficial effects of an aerobic interval training (AIT) protocol on different biochemical, microscopic, and functional liver alterations related to the MS in the experimental model of obese Zucker rat. Two groups of lean and obese animals (6 weeks old) followed a protocol of AIT (4 min at 65%-80% of maximal oxygen uptake, followed by 3 min at 50%-65% of maximal oxygen uptake for 45-60 min, 5 days/week, 8 weeks of experimental period), whereas 2 control groups remained sedentary. Obese rats had higher food intake and body weight (P < 0.0001) and suffered significant alterations in plasma lipid profile, area under the curve after oral glucose overload (P < 0.0001), liver histology and functionality, and antioxidant status. The AIT protocol reduced the severity of alterations related to glucose and lipid metabolism and increased the liver protein expression of PPARγ, as well as the gene expression of glutathione peroxidase 4 (P < 0.001). The training protocol also showed significant effects on the activity of hepatic antioxidant enzymes, although this action was greatly influenced by rat phenotype. The present data suggest that AIT protocol is a feasible strategy to improve some of the plasma and liver alterations featured by the MS.