Neuro and hepatic toxicological profile of (S)-2,4-diaminobutanoic acid in embryonic, adolescent and adult zebrafish

(S)-2,4-Diaminobutanoic acid (DABA) is a noncanonical amino acid often co-produced by cyanobacteria along with β-N-methylamino-l-alanine (BMAA) in algal blooms. Although BMAA is a well-established neurotoxin, the toxicity of DABA remains unclear. As part of our development of biocompatible materials, we wish to make use of DABA as both a building block and as the end-product of enzymatically-induced depolymerization; however, if it is toxic at very low concentrations, this would not be possible. We examined the toxicity of DABA using both in vivo embryonic and adult zebrafish models. At higher sub-lethal concentrations (700 µM), the fish demonstrated early signs of cardiotoxicity. Adolescent zebrafish were able to tolerate a higher concentration. Post-mortem histological analysis of juvenile zebrafish showed no liver or brain abnormalities associated with hepato- or neurotoxicity. Combined, these results show that DABA exhibits no overt toxicity at concentrations (100-300 µM) within an order of magnitude of those envisioned for its application. This study further highlights the low-cost and ease of using zebrafish as an early-stage toxicological screening tool

Proteoglycan Breakdown of Meniscal Explants Following Dynamic Compression Using a Novel Bioreactor

Motivated by our interest in examining meniscal mechanotransduction processes, we report on the validation of a new tissue engineering bioreactor. This paper describes the design and performance capabilities of a tissue engineering bioreactor for cyclic compression of meniscal explants. We showed that the system maintains a tissue culture environment equivalent to that provided by conventional incubators and that its strain output was uniform and reproducible. The system incorporates a linear actuator and load cell aligned together in a frame that is contained within an incubator and allows for large loads and small displacements. A plunger with six Teflon-filled Delrin compression rods is attached to the actuator compressing up to six tissue explants simultaneously and with even pressure. The bioreactor system was used to study proteoglycan (PG) breakdown in porcine meniscal explants following various input loading tests (0–20% strain, 0–0.1 MPa). The greatest PG breakdown was measured following 20% compressive strain. These strain and stress levels have been shown to correspond to partial meniscectomy. Thus, these data suggest that removing 30–60% of meniscal tissue will result in the breakdown of meniscal tissue proteoglycans

5-HT1A receptor blockade reverses GABAA receptor α3 subunit-mediated anxiolytic effects on stress-induced hyperthermia

Stress-related disorders are associated with dysfunction of both serotonergic and GABAergic pathways, and clinically effective anxiolytics act via both neurotransmitter systems. As there is evidence that the GABA(A) and the serotonin receptor system interact, a serotonergic component in the anxiolytic actions of benzodiazepines could be present. The main aim of the present study was to investigate whether the anxiolytic effects of (non-)selective alpha subunit GABA(A) receptor agonists could be reversed with 5-HT1A receptor blockade using the stress-induced hyperthermia (SIH) paradigm. The 5-HT1A receptor antagonist WAY-100635 (0.1-1 mg/kg) reversed the SIH-reducing effects of the non-alpha-subunit selective GABA(A) receptor agonist diazepam (1-4 mg/kg) and the GABA(A) receptor alpha(3)-subunit selective agonist TP003 (1 mg/kg), whereas WAY-100635 alone was without effect on the SIH response or basal body temperature. At the same time, co-administration of WAY-100635 with diazepam or TP003 reduced basal body temperature. WAY-100635 did not affect the SIH response when combined with the preferential alpha(1)-subunit GABA(A) receptor agonist zolpidem (10 mg/kg), although zolpidem markedly reduced basal body temperature. The present study suggests an interaction between GABA(A) receptor alpha-subunits and 5-HT1A receptor activation in the SIH response. Specifically, our data indicate that benzodiazepines affect serotonergic signaling via GABA(A) receptor alpha(3)-subunits. Further understanding of the interactions between the GABA(A) and serotonin system in reaction to stress may be valuable in the search for novel anxiolytic drugs

Transient Receptor Potential Ion Channels Control Thermoregulatory Behaviour in Reptiles

Biological functions are governed by thermodynamics, and animals regulate their body temperature to optimise cellular performance and to avoid harmful extremes. The capacity to sense environmental and internal temperatures is a prerequisite for the evolution of thermoregulation. However, the mechanisms that enable ectothermic vertebrates to sense heat remain unknown. The recently discovered thermal characteristics of transient receptor potential ion channels (TRP) render these proteins suitable to act as temperature sensors. Here we test the hypothesis that TRPs are present in reptiles and function to control thermoregulatory behaviour. We show that the hot-sensing TRPV1 is expressed in a crocodile (Crocodylus porosus), an agamid (Amphibolurus muricatus) and a scincid (Pseudemoia entrecasteauxii) lizard, as well as in the quail and zebrafinch (Coturnix chinensis and Poephila guttata). The TRPV1 genes from all reptiles form a unique clade that is delineated from the mammalian and the ancestral Xenopus sequences by an insertion of two amino acids. TRPV1 and the cool-sensing TRPM8 are expressed in liver, muscle (transversospinalis complex), and heart tissues of the crocodile, and have the potential to act as internal thermometer and as external temperatures sensors. Inhibition of TRPV1 and TRPM8 in C. porosus abolishes the typically reptilian shuttling behaviour between cooling and heating environments, and leads to significantly altered body temperature patterns. Our results provide the proximate mechanism of thermal selection in terrestrial ectotherms, which heralds a fundamental change in interpretation, because TRPs provide the mechanism for a tissue-specific input into the animals' thermoregulatory response

What is known about the patient's experience of medical tourism? A scoping review

<p>Abstract</p> <p>Background</p> <p>Medical tourism is understood as travel abroad with the intention of obtaining non-emergency medical services. This practice is the subject of increasing interest, but little is known about its scope.</p> <p>Methods</p> <p>A comprehensive scoping review of published academic articles, media sources, and grey literature reports was performed to answer the question: what is known about the patient's experience of medical tourism? The review was accomplished in three steps: (1) identifying the question and relevant literature; (2) selecting the literature; (3) charting, collating, and summarizing the information. Overall themes were identified from this process.</p> <p>Results</p> <p>291 sources were identified for review from the databases searched, the majority of which were media pieces (<it>n </it>= 176). A further 57 sources were included for review after hand searching reference lists. Of the 348 sources that were gathered, 216 were ultimately included in this scoping review. Only a small minority of sources reported on empirical studies that involved the collection of primary data (<it>n </it>= 5). The four themes identified via the review were: (1) decision-making (e.g., push and pull factors that operate to shape patients' decisions); (2) motivations (e.g., procedure-, cost-, and travel-based factors motivating patients to seek care abroad); (3) risks (e.g., health and travel risks); and (4) first-hand accounts (e.g., patients' experiential accounts of having gone abroad for medical care). These themes represent the most discussed issues about the patient's experience of medical tourism in the English-language academic, media, and grey literatures.</p> <p>Conclusions</p> <p>This review demonstrates the need for additional research on numerous issues, including: (1) understanding how multiple information sources are consulted and evaluated by patients before deciding upon medical tourism; (2) examining how patients understand the risks of care abroad; (3) gathering patients' prospective and retrospective accounts; and (4) the push and pull factors, as well as the motives of patients to participate in medical tourism. The findings from this scoping review and the knowledge gaps it uncovered also demonstrate that there is great potential for new contributions to our understanding of the patient's experience of medical tourism.</p

New developments in osteoarthritis. Posttraumatic osteoarthritis: pathogenesis and pharmacological treatment options

Joint trauma can lead to a spectrum of acute lesions, including osteochondral fractures, ligament or meniscus tears and damage to the articular cartilage. This is often associated with intraarticular bleeding and causes posttraumatic joint inflammation. Although the acute symptoms resolve and some of the lesions can be surgically repaired, joint injury triggers a chronic remodeling process in cartilage and other joint tissues that ultimately manifests as osteoarthritis in a majority of cases. The objective of the present review is to summarize information on pathogenetic mechanisms involved in the acute and chronic consequences of joint trauma and discuss potential pharmacological interventions. The focus of the review is on the early events that follow joint trauma since therapies for posttraumatic joint inflammation are not available and this represents a unique window of opportunity to limit chronic consequences