GDF8 inhibition enhances musculoskeletal recovery and mitigates posttraumatic osteoarthritis following joint injury.

Musculoskeletal disorders contribute substantially to worldwide disability. Anterior cruciate ligament (ACL) tears result in unresolved muscle weakness and posttraumatic osteoarthritis (PTOA). Growth differentiation factor 8 (GDF8) has been implicated in the pathogenesis of musculoskeletal degeneration following ACL injury. We investigated GDF8 levels in ACL-injured human skeletal muscle and serum and tested a humanized monoclonal GDF8 antibody against a placebo in a mouse model of PTOA (surgically induced ACL tear). In patients, muscle GDF8 was predictive of atrophy, weakness, and periarticular bone loss 6 months following surgical ACL reconstruction. In mice, GDF8 antibody administration substantially mitigated muscle atrophy, weakness, and fibrosis. GDF8 antibody treatment rescued the skeletal muscle and articular cartilage transcriptomic response to ACL injury and attenuated PTOA severity and deficits in periarticular bone microarchitecture. Furthermore, GDF8 genetic deletion neutralized musculoskeletal deficits in response to ACL injury. Our findings support an opportunity for rapid targeting of GDF8 to enhance functional musculoskeletal recovery and mitigate the severity of PTOA after injury.

Alteraciones neuropsiquiátricas en menores de 18 años expuestos a opioides en el periodo prenatal: Revisión Narrativa

El consumo de opioides ha venido incrementando en los últimos años, generando una crisis de salud pública que afecta a todo tipo de población. El uso de sustancias opiáceas ilegales en embarazadas también está en incremento, por lo que, en la práctica clínica se evidencian con mayor frecuencia resultados neonatales adversos como el síndrome de abstinencia neonatal (NAS). Adicionalmente, los niños expuestos prenatalmente a estas sustancias pueden sufrir alteraciones cognitivas, motoras o psiquiátricas durante el transcurso de su vida. Este artículo tiene como objetivo proporcionar una revisión de la literatura actualizada acerca del uso de opioides durante el embarazo y las consecuencias para los niños expuestos a estas sustancias.

Opioid consumption has increased greatly in recent years, creating a public health crisis that affects all types of population. The use of illegal opiates amongst pregnant women has also risen, causing a surge in the frequency in which adverse neonatal outcomes, such as Neonatal Abstinence Syndrome (NAS), are seen in clinical practice. Furthermore, children exposed prenatally to these substances have cognitive, motor and psychiatric adverse outcomes throughout their lifetime. This article's objective is to provide an updated literature review about opioid use during pregnancy and its consequences on children exposed in-utero.

Venoms of Centruroides and Tityus species from Panama and their main toxic fractions.

The scorpionism in Panama is notorious for the confluence and coexistence of buthid scorpions from the genera Centruroides and Tityus. This communication describes an overview of the larger representative toxic venom fractions from eight dangerous buthid scorpion species of Panama: Centruroides (C. granosus, C. bicolor, C. limbatus and C. panamensis) and Tityus (T. (A.) asthenes, T. (A.) festae, T. (T.) cerroazul and T. (A.) pachyurus). Their venoms were separated by HPLC and the corresponding sub-fractions were tested for lethality effects on mice and insects. Many fractions toxic to either mice or insects, or both, were found and have had their molecular masses determined by mass spectrometry analysis. The great majority of the lethal components had a molecular mass close to 7000 Da, assumed to be peptides that recognize Na+-channels, responsible for the toxicity symptoms observed in other buthids scorpion venoms. A toxic peptide isolated from the venom of T. pachyurus was sequenced by Edman degradation, allowing the synthesis of nucleotide probe for cloning the correspondent gene. The mature toxin based on the cDNA sequencing has the C-terminal residue amidated, contains 62 amino acid packed by 4 disulfide linkages, with molecular mass of 7099.1 Da. This same toxic peptide seems to be present in scorpions of the species T. pachyurus collected in 5 different regions of Panama, although the overall HPLC profile is quite different. The most diverse neurotoxic venom components from the genus Centruroides were found in the species C. panamensis, whereas T. cerroazul was the one from the genus Tityus. The most common neurotoxins were observed in the venoms of T. festae, T. asthenes and T. pachyurus with closely related molecular masses of 7099.1 and 7332 Da. The information reported here is considered very important for future generation of a neutralizing antivenom against scorpions from Panama. Furthermore, it will contribute to the growing interest in using bioactive toxins from scorpions for drug discovery purposes.

Encefalopatía hipóxicoisquémica en el periodo perinatal, evaluación por resonancia magnética / Hypoxic Ischemic Encephalopathy in the Neonatal Period, Evaluation with Magnetic Resonance

La hipoxia perinatal es una condición médica que tiene una incidencia de dos a cuatro casos por cada mil nacidos vivos. Las principales causas están relacionadas con condiciones que se dan en el anteparto. La evaluación por resonancia magnética (RM) es un método fundamental para determinar el tipo y extensión del compromiso. Se realizó una revisión de la literatura radiológica disponible y posteriormente una evaluación retrospectiva de los pacientes de nuestra institución con el fin de ilustrar, con ejemplos de la práctica diaria, las diferentes presentaciones de dicha entidad, según la edad del paciente al momento de la lesión y el grado de la misma. Se confirmó la utilidad de la RM para caracterizar las diferentes lesiones secundarias a la hipoxia en el periodo perinatal.

Hypoxic ischemic encephalopathy has an incidence between two and four in a thousand newborns. The main causes are related to prenatal factors. Evaluation by MRI has a fundamental role to determine the type and degree of injury. In the following study we reviewed the most concise available radiologic literature and then we made a retrospective evaluation of different cases in our institution to illustrate with examples of our daily practice the different presentations of this entity according to the age of the patient, the timing of the injury and its severity. The value of MRI to characterize the different presentation of these lesions in the perinatal period was confirmed.

Enfermedad de Chagas: Presentación de un caso / Chagas Disease: A Case Report

La enfermedad de Chagas es una infección parasitaria, principalmente transmitida por un insecto y ocurre en el continente americano. La infección tiene fases aguda, indeterminada y crónica; esta última definida por síntomas de compromiso sistémico, principalmente cardiaco o gastrointestinal. La cardiopatía tiene múltiples mecanismos que llevan a fibrosis, remodelación miocárdica y disfunción sistólica; se manifiesta con falla, arritmias y cardioembolismo. Los estudios diagnósticos han demostrado alteraciones autonómicas inicialmente, subsecuentemente electrocardiográficas y finalmente ecocardiográficas y radiográficas. La resonancia magnética (RM) cardiaca permite ver alteraciones de la contractilidad, remodelación y disfunción sistólica con la resolución espacial y temporal de las secuencias de cine y la fibrosis mediante el realce tardío, en algunos incluso desde estadios tempranos. Se presenta el caso de un paciente con síndrome de falla cardiaca, alteración radiográfica y ecocardiográfica, en quien la RM refleja cambios característicos estructurales, funcionales y tisulares de la cardiopatía chagásica.

Chagas Disease is a parasitic infection, mainly transmitted by a vector insect, that occurs in the American continent. The infection has acute, indeterminate and chronic phases; the latter is defined by the presence of symptoms from system involvement, most often cardiac or gastrointestinal. Chagas cardiomyopathy has multiple mechanisms leading to fibrosis, myocardial remodelation and systolic dysfunction; it features heart failure, arrhythmias and embolism. Diagnostic studies have demonstrated alterations that are initially autonomic, subsequently electrocardiographic and finally echocardiographic and radiographic. Cardiac magnetic resonance imaging allows for the detection of alterations in contractility, remodelation and systolic dysfunction with the temporal and spatial resolution of video sequences, and also of fibrosis using late gadolinium enhancement; in some, from early stages of disease. We present the case of a patient with heart failure syndrome, showing radiographic and echocardiographic alterations, in whom cardiac MRI reflects structural, functional and tissue changes due to Chagas cardiomyopathy.

Geographical variability of the venoms of four populations of Bothrops asper from Panama: Toxicological analysis and neutralization by a polyvalent antivenom.

Bothrops asper is the medically most important venomous snake in Central America. In Panama, the country having the highest incidence of snakebites in Latin America, B. asper is widely distributed throughout the country and is responsible for the vast majority of snakebites. This study was performed to analyze whether there are variations in the toxicological profile and in some biochemical parameters between the venoms of B. asper from four different regions in Panama. The venoms showed a similar profile of lethal, hemorrhagic, in vitro coagulant, defibrinogenating, edema-forming, myotoxic and indirect hemolytic activities, with subtle quantitative variations between samples of some regions. The venoms also had similar SDS-PAGE patterns and reverse phase HPLC profiles. A polyvalent antivenom manufactured in Costa Rica, and regularly used in Panama, was effective in the neutralization of lethal activity of the venoms of the four populations, with Mean Effective Doses (ED50) ranging from 5.98 to 9.72 mg venom/mL antivenom. In agreement, a widespread pattern of cross-reactivity between this antivenom and the four venoms was observed by immunoblotting. Overall, results highlight the lack of marked differences between the venoms of the various populations of B. asper in Panama, and that the antivenom from Costa Rica is effective in neutralizing lethality.

Advances in mixed-integer programming methods for chemical production scheduling.

The goal of this paper is to critically review advances in the area of chemical production scheduling over the past three decades and then present two recently proposed solution methods that have led to dramatic computational enhancements. First, we present a general framework and problem classification and discuss modeling and solution methods with an emphasis on mixed-integer programming (MIP) techniques. Second, we present two solution methods: (a) a constraint propagation algorithm that allows us to compute parameters that are then used to tighten MIP scheduling models and (b) a reformulation that introduces new variables, thus leading to effective branching. We also present computational results and an example illustrating how these methods are implemented, as well as the resulting enhancements. We close with a discussion of open research challenges and future research directions.

El símbolo, la fantasía, lo imaginario y su interpretación en “el delirio y los sueños en la Gradiva de W. Jensen” / Symbol, fantasy, imaginary and its interpreta-tion in “the delirium and the dreams in gradi-va of W. Jensen” / Le symbole, la fantaisie, l’imaginaire et leur interpretation en ® le delire et les reves dans la gradiva de W. Jensen ¼

El intento por comprender la formación tanto del símbolo como de la fantasía y el delirio, encuen-tra una vía en el abordaje de estos como forma esencial, natural y primigenia, empleada por el inconsciente para tramitar contenidos de la con-ciencia, de otro modo inaccesibles. Así, podemos contemplar la fantasía y el delirio como corres-pondientes al campo de lo imaginario; mecanis-mos que cumplen una función unificadora, alter-nativos a los mecanismos de defensa más habi-tuales que encuentran en el símbolo la posibili-dad para su expresión y nos facilitan a través de él su comprensión...

The attempt to understand the formation of the symbol, as fantasy and delusion, find a way in addressing these as an essential, natural and primitive form, used by the unconscious to pro-cess contents of consciousness, otherwise inac-cessible. Thus, we can see the fantasy and delu-sion as corresponding to the imaginary order, mechanisms that play a unifying function, alterna-tive to the most frequent defense mechanisms, which are find possibility in the symbol for expres-sion and provide us through it understanding...

La tentative de comprendre la formation de la fois le symbole, comme de la fantaisie et le délire, c'est un chemin dans l'approche de ces comme forme essentielle, naturelle et primitive, utilisé par l'inconscient pour traiter l'contenu de la cons-cience, autrement inaccessibles. Ainsi, nous pou-vons voir la fantaisie et le délire comme corres-pondant sur le terrain de l'imaginaire, méca-nismes qui répondre aux une fonction unificateur, alternative aux mécanismes de défense plus fréquent, qui trouvent le symbole la possibilité d'expression et de nous facilite par le biais il ses compréhension...