Neuroendocrine pathways at risk? Simvastatin induces inter and transgenerational disruption in the keystone amphipod Gammarus locusta.

The primary focus of environmental toxicological studies is to address the direct effects of chemicals on exposed organisms (parental generation - F0), mostly overlooking effects on subsequent non-exposed generations (F1 and F2 - intergenerational and F3 transgenerational, respectively). Here, we addressed the effects of simvastatin (SIM), one of the most widely prescribed human pharmaceuticals for the primary treatment of hypercholesterolemia, using the keystone crustacean Gammarus locusta. We demonstrate that SIM, at environmentally relevant concentrations, has significant inter and transgenerational (F1 and F3) effects in key signaling pathways involved in crustaceans' neuroendocrine regulation (Ecdysteroids, Catecholamines, NO/cGMP/PKG, GABAergic and Cholinergic signaling pathways), concomitantly with changes in apical endpoints, such as depressed reproduction and growth. These findings are an essential step to improve hazard and risk assessment of biological active compounds, such as SIM, and highlight the importance of studying the transgenerational effects of environmental chemicals in animals' neuroendocrine regulation.

The effect of thoracic manipulation on pulmonary function in swimmers / Efecto de la manipulación torácica en la función pulmonar de nadadores / Efeito da manipulação torácica na função pulmonar em nadadores

Objective: Spinal manipulation has been used to improve respiratory function in healthy individuals. However, it has been observed that there are no studies in the context of sports activities. The objective of this study was to analyse the effect of thoracic spinal manipulation on forced vital capacity, forced expiratory volume in one second and maximal voluntary ventilation in swimmers.Method: A randomized controlled crossover study consisting of 21 swimmers, divided into two groups (Intervention vs Control), aged 16 – 24y, where forced vital capacity, forced expiratory volume in one second and maximal voluntary ventilation were measured in five evaluation moments: at baseline and, 1 minute, 10 minutes, 20 minutes and 30 minutes following the thoracic spinal manipulation procedures.Results: ANOVA tests showed no statistically significant differences for forced vital capacity (p = 0.35) and forced expiratory volume in one second (p = 0.25) among the five evaluation moments. With the maximal voluntary ventilation there was a statistically significant (p = 0.02) reduction, observed between baseline (86.00 litres) and at 10 minutes (79.29 litres) and 30 minutes (76.24 litres). No significant differences were observed between the results of intervention and control groups.Conclusions: In the current study no significant differences were observed in pulmonary function after thoracic spinal manipulation. Future research efforts should examine the effects of different manual therapy techniques and treatment protocols. (AU)

Objetivo: La manipulación espinal se ha utilizado para mejorar la función respiratoria en individuos sanos. Sin embargo, se ha observado que no hay estudios en el contexto de las actividades deportivas. El objetivo de este estudio fue analizar el efecto de la manipulación de la columna torácica en la capacidad vital forzada, el volumen espiratorio forzado en el primer segundo y la ventilación voluntaria máxima en nadadores.Método: Un estudio cruzado controlado aleatorio que consta de 21 nadadores, divididos en dos grupos (Intervención vs Control), de 16 a 24 años, donde se midieron la capacidad vital forzada, el volumen espiratorio forzado en el primer segundo y la ventilación voluntaria máxima en cinco momentos de evaluación: al inicio y, 1 minuto, 10 minutos, 20 minutos y 30 minutos después de los procedimientos de la manipulación de la columna torácica.Resultados: Las pruebas ANOVA no mostraron diferencias estadísticamente significativas para la capacidad vital forzada (p = 0.35) y el volumen espiratorio forzado en el primer segundo (p = 0.25) entre los cinco momentos de evaluación. Con la ventilación voluntaria máxima hubo una reducción estadísticamente significativa (p = 0.02), observada entre lo inicio (86.00 litros) y a los 10 minutos (79.29 litros) y 30 minutos (76.24 litros). No se observaron diferencias significativas entre los resultados de los grupos de intervención y control.Conclusiones: En el presente estudio, no se observaron diferencias significativas en la función pulmonar después de la manipulación de la columna torácica. Futuros estudios de investigación deberían examinar los efectos de diferentes técnicas de terapia manual y protocolos de tratamiento. (AU)

Objetivo: A manipulação da coluna vertebral tem sido utilizada para melhorar a função respiratória em indivíduos saudáveis. No entanto, observou-se que não existem estudos no contexto de atividades desportivas. O objetivo deste estudo foi analisar o efeito da manipulação da coluna torácica na capacidade vital forçada, volume expiratório forçado no primeiro segundo e ventilação voluntária máxima em nadadores.Método: Estudo aleatorizado controlado cruzado composto por 21 nadadores, divididos em dois grupos (Intervenção vs Controlo), com idades entre 16 e 24 anos, onde a capacidade vital forçada, volume expiratório forçado no primeiro segundo e ventilação voluntária máxima foram medidos em cinco momentos de avaliação: no início e, 1 minuto, 10 minutos, 20 minutos e 30 minutos após os procedimentos da manipulação da coluna torácica.Resultados: Os testes ANOVA não mostraram diferenças estatisticamente significativas para a capacidade vital forçada (p = 0.35) e volume expiratório forçado no primeiro segundo (p = 0.25) entre os cinco momentos da avaliação. Com a ventilação voluntária máxima houve uma redução estatisticamente significante (p = 0.02), observada entre o início (86.00 litros) e as medições aos 10 minutos (79.29 litros) e 30 minutos (76.24 litros). Não foram observadas diferenças significativas entre os resultados dos grupos intervenção e controlo.Conclusões: No presente estudo, não foram observadas diferenças significativas na função pulmonar após a manipulação da coluna torácica. Futuras pesquisas devem examinar os efeitos de diferentes técnicas de terapia manual e protocolos de tratamento. (AU)

Transgenerational inheritance of chemical-induced signature: A case study with simvastatin.

The hypothesis that exposure to certain environmental chemicals during early life stages may disrupt reproduction across multiple non-exposed generations has significant implications for understanding disease etiology and adverse outcomes. We demonstrate here reproductive multi and transgenerational effects, at environmentally relevant levels, of one of the most prescribed human pharmaceuticals, simvastatin, in a keystone species, the amphipod Gammarus locusta. The transgenerational findings has major implications for hazard and risk assessment of pharmaceuticals and other contaminants of emerging concern given that transgenerational effects of environmental chemicals are not addressed in current hazard and risk assessment schemes. Considering that the mevalonate synthesis, one of the key metabolic pathways targeted by simvastatin, is highly conserved among metazoans, these results may also shed light on the potential transgenerational effects of simvastatin on other animals, including humans.

Persistent radiologic thoracic hypotransparency: A case report and review of the literature.

A thymolipoma is a slow-growing, anterior mediastinal tumor, rare in childhood. The authors present a report of a 4-year-old girl with persistent right thoracic hypotransparency on the chest radiograph. Computed tomography and magnetic resonance imaging revealed an anterior, well-limited, mediastinal mass of heterogeneous density, with lipomatous and soft tissue density areas. The tumor was totally excised and the histopathologic findings revealed a thymolipoma. A year and a half after surgery, the child remains well. This report enhances the relevance of differential diagnosis in the presence of persistent radiologic thoracic hypotransparency.

Identifying the gaps: Resources and perspectives on the use of nuclear receptor based-assays to improve hazard assessment of emerging contaminants.

Biological control of key processes, such as development and reproduction, is largely ascribed to a superfamily of ligand-dependent and independent transcription factors named Nuclear Receptors (NRs). Given their ability to accommodate ligands, NRs are prime targets of man-made compounds that mimic or antagonise the action of endogenous ligands. Accordingly, NRs occupy a prominent role in OECD and EPA guidelines for testing and assessment of Endocrine disrupting chemicals (EDCs). Although NR assays are already a key instrument in the OECD Conceptual Framework for Testing and Assessment of EDCs, the focus is mostly on vertebrate NRs. Here, we address the chief knowledge gaps in the field. More specifically, we (1) verify the growing availability of genomes/transcriptome projects, (2) highlight gaps in the identification and characterization of metazoan NR and in the establishment of (3) life cycle and (4) toxicity testing protocols. An overall bias towards vertebrates and selected invertebrate groups, notably Arthropoda, Annelida and Mollusca, was observed. Hence, if we aim to improve risk assessment of EDCs and emerging pollutants at an ecosystems scale, and understand their mode of action (MOA), we must establish a framework to include a broad phylogenetic sampling of Metazoans.

The cycling gonad: retinoic-acid synthesis and degradation patterns during adult zebrafish Danio rerio oogenesis.

The expression pattern of genes coding for enzymes of the retinoic acid (RA) synthetic and degradation pathways was characterized in adult female zebrafish Danio rerio. Females were conditioned until maturation and post-spawn expression dynamics were determined. A striking upregulation of cyp26b1, but not cyp26a1, was observed following egg deposition, decreasing to initial levels during recovery. A similar, yet lower, fluctuation was observed for aldh1a2 and rdh10a, the enzymes participating in the two-step RA biosynthesis cascade. The present work highlights the dynamics of the adult D. rerio oogenesis and uncovers novel, yet elusive, metabolic contributors. Possible compartmentalized roles for the different gene paralogue isoforms are discussed.

Retinoid level dynamics during gonad recycling in the limpet Patella vulgata.

Germ cell commitment and meiosis initiation are among the multitude of physiological roles of retinoic acid (RA) in vertebrates. Acting via receptor-mediated transcription, RA induces the expression of meiotic factors, triggering meiosis. Contrasting with vertebrates, invertebrate RA metabolism is scarcely understood. Still, some physiological processes appear to be conserved. Here we set to evaluate the role of retinoids in the gonad maturation process of the marine gastropod Patella vulgata. We found that retinoid concentration in gonadal tissue, namely RA, varies between breeding and resting specimens, with maxima attained in the latter. Additionally, we isolated and quantified the expression of both the retinoic acid receptor (RAR) and the retinoid X receptor (RXR) in gonads. In view of the stability of retinoid receptor expression, we suggest that the balance of RA levels operates through the enzymatic control of synthetic and catabolic processes. Overall, the reported data are supportive for a developmental role of RA during gonadal maturation in P. vulgata, which should be addressed in other protostome lineages.

The effects of training and detraining after an 8 month resistance and stretching training program on forward head and protracted shoulder postures in adolescents: Randomised controlled study.

PURPOSE: This study aimed to evaluate the effects of a 32-week resistance and stretching training program applied in Physical Education classes on forward head posture and protracted shoulder posture of Portuguese adolescents (15-17 years old). The detraining effects after a 16-week period were also measured. METHODS: This prospective, randomized and controlled study was conducted in two secondary schools in Portugal. One hundred and thirty adolescents with forward head and protracted shoulder posture were randomly assigned to a control or experimental group. The sagittal head, cervical and shoulder angle were measured before and after a 32-week time intervention period. The control group (n = 46) did only the Physical Education classes whereas the exercise group (n = 42) received a posture corrective exercise programme in addition to Physical Education classes. A 16 week detraining period followed the 32-week. RESULTS: Significant increase were observed in the cervical and shoulder angle in the experimental group following the 32 week-intervention period. After the 16-week detraining period no significant differences were observed in the three postural angles in the intervention group. CONCLUSIONS: The exercise intervention was successful at decreasing forward head and protracted shoulder in adolescents. Detraining period was not sufficient to reduce the overall training effects. This study supports the postural training and rehabilitation performed during Physical Education classes, with the aim of preventing and managing upper quadrant musculoskeletal pain. CLINICALTRIALS. GOV IDENTIFIER: NCT02190331.

Retinoid metabolism in invertebrates: when evolution meets endocrine disruption.

Recent genomic and biochemical evidence in invertebrate species pushes back the origin of the retinoid metabolic and signaling modules to the last common ancestor of all bilaterians. However, the evolution of retinoid pathways are far from fully understood. In the majority of non-chordate invertebrate lineages, the ongoing functional characterization of retinoid-related genes (metabolism and signaling pathways), as well as the characterization of the endogenous retinoid content (precursors and active retinoids), is still incomplete. Despite limited, the available data supports the presence of biologically active retinoid pathways in invertebrates. Yet, the mechanisms controlling the spatial and temporal distribution of retinoids as well as their physiological significance share similarities and differences with vertebrates. For instance, retinol storage in the form of retinyl esters, a key feature for the maintenance of retinoid homeostatic balance in vertebrates, was only recently demonstrated in some mollusk species, suggesting that such ability is older than previously anticipated. In contrast, the enzymatic repertoire involved in this process is probably unlike that of vertebrates. The suggested ancestry of active retinoid pathways implies that many more metazoan species might be potential targets for endocrine disrupting chemicals. Here, we review the current knowledge about the occurrence and functionality of retinoid metabolic and signaling pathways in invertebrate lineages, paying special attention to the evolutionary origin of retinoid storage mechanisms. Additionally, we summarize existing information on the endocrine disruption of invertebrate retinoid modules by environmental chemicals. Research priorities in the field are highlighted.

Complexing Aß prevents the cellular anomalies induced by the Peptide alone.

Retention of intracellular secreted APP (isAPP) can be provoked by the neurotoxic peptide Aß. The latter decreases in the cerebrospinal fluid of Alzheimer's disease (AD) patients, as a consequence of its cerebral accumulation and deposition into senile plaques. Of similar relevance, secreted APP (sAPP) levels can be associated with AD. The studies here presented, reinforce the link between sAPP and Aß and address putative therapeutic strategies. Laminin and gelsolin are potential candidates; both prevent Aß fibril formation by complexing with Aß, thus attenuating its neurotoxicity. We show that preincubation of Aß with laminin and gelsolin has the effect of rendering it less potent to isAPP accumulation in cortical neurons. This appears to be related to a decrease in F-actin polymerization, whereas Aß alone induces the polymerization. Further, Aß decreases gelsolin levels, and the latter is involved in Aß removal. Our data indicates that Aß-laminin and Aß-gelsolin complexes are less neurotoxic and also less potent than fibrillar Aß at inducing isAPP retention. These results validate the potential of these proteins as therapeutic strategies that prevent the Aß-induced effects. In hence, given that Aß decreases the levels of proteins involved in its own clearance, this may contribute to the mechanisms underlying AD pathology.

New concepts in restoring shoulder elevation in a stiff and painful shoulder patient.

The treatment and evaluation of a stiff and painful shoulder, characteristic of adhesive capsulitis and "frozen" shoulders, is a dilemma for orthopedic rehabilitation specialists. A stiff and painful shoulder is all-inclusive of Adhesive capsulitis and Frozen Shoulder diagnoses. Adhesive capsulitis and frozen shoulder will be referred to as a stiff and painful shoulder, throughout this paper. Shoulder motion occurs in multiple planes of movement. Loss of shoulder mobility can result in significant functional impairment. The traditional treatment approach to restore shoulder mobility emphasizes mobilization of the shoulder overhead. Forced elevation in a stiff and painful shoulder can be painful and potentially destructive to the glenohumeral joint. This manuscript will introduce a new biomechanical approach to evaluate and treat patients with stiff and painful shoulders.

Expression and lysosomal targeting of CLN7, a major facilitator superfamily transporter associated with variant late-infantile neuronal ceroid lipofuscinosis.

Neuronal ceroid lipofuscinoses (NCLs) constitute a group of progressive neurodegenerative disorders resulting from mutations in at least eight different genes. Mutations in the most recently identified NCL gene, MFSD8/CLN7, underlie a variant of late-infantile NCL (vLINCL). The MFSD8/CLN7 gene encodes a polytopic protein with unknown function, which shares homology with ion-coupled membrane transporters. In this study, we confirmed the lysosomal localization of the native CLN7 protein. This localization of CLN7 is not impaired by the presence of pathogenic missense mutations or after genetic ablation of the N-glycans. Expression of chimeric and full-length constructs showed that lysosomal targeting of CLN7 is mainly determined by an N-terminal dileucine motif, which specifically binds to the heterotetrameric adaptor AP-1 in vitro. We also show that CLN7 mRNA is more abundant in neurons than astrocytes and microglia, and that it is expressed throughout rat brain, with increased levels in the granular layer of cerebellum and hippocampal pyramidal cells. Interestingly, this cellular and regional distribution is in good agreement with the autofluorescent lysosomal storage and cell loss patterns found in brains from CLN7-defective patients. Overall, these data highlight lysosomes as the primary site of action for CLN7, and suggest that the pathophysiology underpinning CLN7-associated vLINCL is a cell-autonomous process.