An ecotoxicological assessment of a strigolactone mimic used as the active ingredient in a plant biostimulant formulation.

A risk assessment on the aquatic toxicity of the plant biostimulant strigolactone mimic (2-(4-methyl-5-oxo-2,5-dihydro-furan-2-yloxy)-benzo[de]isoquinoline-1,3-dione (SL-6) was performed using a suite of standardised bioassays representing different trophic groups and acute and chronic endpoints. In freshwater, three trophic groups of algae, crustacea and fish were used. Whilst in seawater, algae (unicellular and macroalgae), Crustacea and Mollusca were employed. In addition, the genotoxicity of SL-6 was determined with the comet assessment performed on unicellular marine algae, oysters, and fish embryos. This was the first time ecotoxicity tests have been performed on SL-6. In freshwater, the lowest LOEC was measured in the unicellular algae at 0.31 mg/L SL-6. Although, similar LOEC values were found for embryo malformations and impacts on hatching rate in zebrafish (LOEC 0.31-0.33 mg/L). Consistent malformations of pericardial and yolk sac oedemas were identified in the zebrafish embryos at 0.31 mg/L. In marine species, the lowest LOEC was found for both Tisbe battagliai mortality and microalgae growth at an SL-6 concentration of 1.0 mg/L. Significant genotoxicity was observed above control levels at 0.0031 mg/L SL-6 in the unicellular algae and 0.001 mg/L SL-6 in the oyster and zebrafish larvae. When applying the simple risk assessment, based on the lowest NOECs and appropriate assessment factors, the calculated predicted no effect concentration (PNEC), for the ecotoxicity and the genotoxicity tests were 1.0 µg/L and 0.01 µg/L respectively.

Antioxidant and Anticancer Activity of Vitis vinifera Extracts in Breast Cell Lines.

Vitis vinifera extracts have been shown to possess antioxidant activity because of their polyphenol content. In addition, their therapeutic potential against several diseases, including cancer, has been reported. In this study, we produced twelve extracts from the seeds, fruit, leaves, and wood of the Vitis vinifera Airen variety using different extraction methodologies and measured their total polyphenol content (TPC). We also determined their antioxidant and antiproliferative effects against normal cells and evaluated the most potent extract against a panel of breast cancer cell lines. We found that the extracts produced by the seeds of Vitis vinifera had a higher TPC compared to the other parts of the plant. Most extracts produced from seeds had antioxidant activity and did not show cytotoxicity against normal breast cells. The extract produced from whole organic seeds of white grape showed the best correlation between the dose and the ROS inhibition at all time points compared to the other seed extracts and also had antiproliferative properties in estrogen-receptor-positive MCF-7 breast cancer cells. Its mechanism of action involves inhibition of proteins Bcl-2, Bcl-xL, and survivin, and induction of apoptosis. Further investigation of the constituents and activity of Vitis vinifera extracts may reveal potential pharmacological applications of this plant.

Ergophysiological evaluation of heart failure patients with reduced ejection fraction undergoing exercise-based cardiac rehabilitation: A systematic review and meta-analysis.

BACKGROUND: This systematic review and meta-analysis aims to explore in heart failure (HF) patients with reduced ejection fraction (EF) undergoing exercise-based cardiac rehabilitation the following: 1) the comparison of temporal changes between peak oxygen uptake (VO2peak) and first ventilatory threshold (VO2VT1), 2) the association of VO2peak and VO2VT1 changes with physiological factors, and 3) the differential effects of continuous aerobic exercise (CAE) and interval training (IT) on VO2peak and VO2VT1. METHODS: A systematic literature search was conducted in PubMed, CENTRAL, and Scopus. Inclusion criteria were 1) original research articles using exercise-based cardiac rehabilitation, 2) stable HF patients with reduced EF, 3) available values of VO2peak and VO2VT1 (in mL/kg/min) both at baseline and after exercise training with comparison between these time points. RESULTS: Among the 30 eligible trials, 24 used CAE, 5 IT, and one CAE and IT. Multivariable meta-regression with duration of exercise training and percentage of males as independent variables and the change in VO2peak as a dependent variable showed that the change in VO2peak was negatively associated with duration of exercise training (coefficient=-0.061, p=0.027), implying the possible existence of a waning effect of exercise training on VO2peak in the long term. Multivariable meta-regression demonstrated that both age (coefficient=-0.140, p<0.001) and EF (coefficient=-0.149, p<0.001) could predict the change in VO2VT1, whereas only age (coefficient=-0.095, p=0.022), but not EF (coefficient = 0.082, p = 0.100), could predict the change in VO2peak. The posttraining peak respiratory exchange ratio, as an index of maximum effort during exercise testing, correlated positively with the change in VO2peak (coefficient=-0.021, p=0.044). The exercise-induced changes of VO2peak (p = 0.438) and VO2VT1 (p = 0.474) did not differ between CAE and IT groups. CONCLUSIONS: Improvement of endurance capacity during cardiac rehabilitation may be detected more accurately with the assessment of VO2VT1 rather than VO2peak.

Investigation of the Critical Biomass of Acclimated Microbial Communities to High Ammonia Concentrations for a Successful Bioaugmentation of Biogas Anaerobic Reactors with Ammonia Inhibition.

This study aimed to investigate the role of the bioaugmented critical biomass that should be injected for successful bioaugmentation for addressing ammonia inhibition in anaerobic reactors used for biogas production. Cattle manure was used as a feedstock for anaerobic digestion (AD). A mixed microbial culture was acclimated to high concentrations of ammonia and used as a bioaugmented culture. Different volumes of bioaugmented culture were injected in batch anaerobic reactors under ammonia toxicity levels i.e., 4 g of NH4+-N L-1. The results showed that injecting a volume equal to 65.62% of the total working reactor volume yielded the best methane production. Specifically, this volume of bioaugmented culture resulted in methane production rates of 196.18 mL g-1 Volatile Solids (VS) and 245.88 mL g-1 VS after 30 and 60 days of AD, respectively. These rates were not significantly different from the control reactors (30d: 205.94 mL CH4 g-1 VS and 60d: 230.26 mL CH4 g-1 VS) operating without ammonia toxicity. Analysis of the microbial community using 16S rRNA gene sequencing revealed the dominance of acetoclastic methanogen members from the genus Methanosaeta in all reactors.

Effects of Hypoglycemia on Cardiovascular Function in Patients with Diabetes.

Hypoglycemia is common in patients with type 1 and type 2 diabetes (T1D, T2D), treated with insulin or sulfonylureas, and has multiple short- and long-term clinical implications. Whether acute or recurrent, hypoglycemia significantly affects the cardiovascular system with the potential to cause cardiovascular dysfunction. Several pathophysiological mechanisms have been proposed linking hypoglycemia to increased cardiovascular risk, including hemodynamic changes, myocardial ischemia, abnormal cardiac repolarization, cardiac arrhythmias, prothrombotic and proinflammatory effects, and induction of oxidative stress. Hypoglycemia-induced changes can promote the development of endothelial dysfunction, which is an early marker of atherosclerosis. Although data from clinical trials and real-world studies suggest an association between hypoglycemia and cardiovascular events in patients with diabetes, it remains uncertain whether this association is causal. New therapeutic agents for patients with T2D do not cause hypoglycemia and have cardioprotective benefits, whereas increasing the use of new technologies, such as continuous glucose monitoring devices and insulin pumps, has the potential to reduce hypoglycemia and its adverse cardiovascular outcomes in patients with T1D.

Structural and Physiological Traits of Compound Leaves of Ceratonia siliqua Trees Grown in Urban and Suburban Ambient Conditions.

Ceratonia siliqua L. (carob tree) is an endemic plant to the eastern Mediterranean region. In the present study, anatomical and physiological traits of successively grown compound leaves (i.e., the first, third, fifth and seventh leaves) of C. siliqua were investigated in an attempt to evaluate their growth under urban and suburban environmental conditions. Chlorophyll and phenolic content, as well as the specific leaf area of the compound leaves were determined. Structural traits of leaflets (i.e., thickness of palisade and spongy parenchyma, abaxial and adaxial epidermis, as well as abaxial and adaxial periclinal wall) were also investigated in expanding and fully expanded leaflets. Fully expanded leaflets from urban sites exhibited increased thickness of the lamina and the palisade parenchyma, while the thickness of the spongy parenchyma was thicker in suburban specimens. The palisade tissue was less extended than the spongy tissue in expanding leaflets, while the opposite held true for the expanded leaflets. Moreover, the thickness of the adaxial and the abaxial epidermises, as well as the adaxial and abaxial periclinal wall were higher in suburban leaflets. The chlorophyll content increased concomitantly with the specific leaf area (SLA) of both expanding and expanded leaflets, and strong positive correlations were detected, while the phenolic content declined with the increased SLA of expanding and expanded leaflets. It is noteworthy that the SLA of expanding leaflets in the suburban site was comparable to the SLA of expanded leaflets experiencing air pollution in urban sites; the size and the mass of leaf blades of C. siliqua possess adaptive features to air pollution. These results, linked to the functional structure of expanding and expanded successive foliar tissues, provide valuable assessment information coordinated with an adaptive process and yield of carob trees exposed to the considered ambient conditions, which have not hitherto been published.

Entomological surveillance and spatiotemporal risk assessment of sand fly-borne diseases in Cyprus.

Visceral and cutaneous leishmaniases are important public health concerns in Cyprus. Although the diseases, historically prevalent on the island, were nearly eradicated by 1996, an increase in frequency and geographical spread has recently been recorded. Upward trends in leishmaniasis prevalence have largely been attributed to environmental changes that amplify the abundance and activity of its vector, the phlebotomine sand flies. Here, we performed an extensive field study across the island to map the sand fly fauna and compared the presence and distribution of the species found with historical records. We mapped the habitat preferences of Phlebotomus papatasi and P. tobbi, two medically important species, and predicted the seasonal abundance of P. papatasi at unprecedented spatiotemporal resolution using a climate-sensitive population dynamics model driven by high-resolution meteorological forecasting. Our compendium holds a record of 18 species and the locations of a subset, including those of potential public and veterinary health concern. We confirmed that P. papatasi is widespread, especially in densely urbanized areas, and predicted that its abundance uniformly peaks across the island at the end of summer. We identified potential hotspots of P. papatasi activity even after this peak. Our results form a foundation to inform public health planning and contribute to the development of effective, efficient, and environmentally sensitive strategies to control sand fly populations and prevent sand fly-borne diseases.

Pre- and peri-operative characteristics, complications and outcomes of patients with biochemically silent pheochromocytomas; a case series.

PURPOSE: Pheochromocytomas are rare tumors and biochemically silent ones with normal catecholamine levels are even rarer. Up to date, biochemically inactive pheochromocytomas are poorly investigated. We aimed to systematically assess the pre- and peri-operative characteristics and the outcomes of patients with these tumors who had been treated and followed-up in 2 tertiary centers. METHODS: Clinical, laboratory and imaging data, treatment outcomes and follow-up of biochemically silent pheochromocytoma patients were recorded. RESULTS: Ten patients (5 men) [median age at diagnosis 52.5 years (24-72)] were included. Adrenal masses were incidentally discovered in all patients except from one who presented with pheochromocytoma-related manifestations. Twenty-four-hour urine metanephrine and normetanephrine levels were in the low-normal, normal and high-normal range in 4, 4 and 2 patients and in 1, 6 and 3 patients, respectively. Tumors were unilateral [median size 46 mm (17-125)] and high density on pre-contrast CT imaging or high signal intensity on T2-weighted MRI scans were found in all cases. Pre-operatively, 5 patients were treated with phenoxybenzamine [median total daily dose 70 mg (20-100)]. Intra-operatively, 4 patients developed hypertension requiring vasodilator administration and 8 developed hypotension; vasoconstrictors were required in 5 cases. One patient, not pre-operatively treated with phenoxybenzamine, developed Takotsubo cardiomyopathy. During a median 24-month (12-88) follow-up period, one patient had disease progression. CONCLUSIONS: The majority (90%) of patients with biochemically silent pheochromocytomas developed hemodynamic instability during adrenal surgery. In patients with biochemically silent adrenal lesions and a high suspicion index for pheochromocytoma based on tumor imaging characteristics, pre-operative alpha-blockade treatment may be advisable.

Short Term Glucose Prediction in Patients with Type 1 Diabetes Mellitus.

Glucose prediction is used in diabetes self-management as it allows to take suitable actions for proper glycemic regulation of the patient. The aim of this work is the short-term personalized glucose prediction in patients with Type 1 diabetes mellitus (T1DM). In this scope, we compared two different models, an autoregressive moving average (ARMA) model and a long short-term memory (LSTM) model for different prediction horizons. The comparison of two models was performed using the evaluation metrics of root mean square error (RMSE) and mean absolute error (MAE). The models were trained and tested in 29 real patients. The results shown that the LSTM model had better performance than ARMA with RMSE 3.13, 6.41 and 8.81 mg/dL and MAE 1.98, 5.06 and 6.47 mg/dL for 5-, 15- and 30-minutes prediction horizon.

The Influence of the Partitioning of Sugars, Starch, and Free Proline in Various Organs of Cyclamen graecum on the Biology of the Species and Its Resistance to Abiotic Stressors.

The geophyte Cyclamen graecum is native to the eastern Mediterranean. Its beautiful flowers with upswept pink petals appear during early autumn, after the summer drought period and before leaf expansion in late autumn. The floral and leaf development alternates with their cessation in early winter and late spring, respectively. Ecophysiological parameters and processes underlining the life-cycle of C. graecum have not previously been published. Seasonal fluctuations of sugars, starch, and free proline have been investigated in tubers, leaves, pedicels, and petals, as well as petal and leaf water status. At the whole plant level, the seasonal co-existence of leaves and flowers is marked by an elevated soluble sugar content, which was gradually reduced as the above-ground plant parts shed. The sugar content of petals and pedicels was lower than that of leaves and tubers. Leaf starch content increased from late autumn to spring and was comparable to that of tubers. The starch content in petals and pedicels was substantially lower than that of tubers and leaves. In tubers, monthly proline accumulation was sustained at relatively constant values. Although the partitioning of proline in various organs did not show a considerable seasonal variation, resulting in an unchanged profile of the trends between tubers, leaves, and flowers, the seasonal differences in proline accumulation were remarkable at the whole plant level. The pronounced petal proline content during the flowering period seems to be associated with the maintenance of floral turgor. Leaf proline content increased with the advance of the growth season. The values of leaf relative water content were sustained fairly constant before the senescence stage, but lower than the typical values of turgid and transpiring leaves. Relationships of the studied parameters with rainfall indicate the responsiveness of C. graecum to water availability in its habitat in the Mediterranean ecosystem.

Sublethal exposure to Microcystis aeruginosa extracts during embryonic development reduces aerobic swimming capacity in juvenile zebrafish.

In the last decades, cyanobacterial harmful algal blooms (CyanoHABs) pose an intensifying ecological threat. Microcystis aeruginosa is a common CyanoHAB species in freshwater ecosystems, with severe toxic effects in a wide range of organisms. In the present paper we examined whether transient and short (48 h) exposure of fish embryos to sublethal levels of M. aeruginosa crude extract (200 mg biomass dw L-1) affects swimming performance at later life stages (end of metamorphosis, ca 12 mm TL, 22,23 days post-fertilization). Pre-exposed metamorphosing larvae presented a significant decrease in swimming performance (9.7 ± 1.6 vs 11.4 ± 1.7 TL s-1 in the control group, p < 0.01), and a significant decrease in the ventricle length-to-depth ratio (1.23 ± 0.15 vs 1.42 ± 0.15 in control fish, p < 0.05). In addition, extract-exposed fish presented significantly elevated rates of vertebral abnormalities (82 ± 13% vs 7 ± 4% in the control group), mainly consisting of the presence of extra neural and haemal processes. No significant differences between groups were detected in survival and growth rates. Results are discussed in respect to the mechanisms that might mediate the detected cyanobacterial effects. This is the first evidence of a direct link between sublethal exposure to M. aeruginosa during the embryonic period and swimming performance at later life-stages. Decreased swimming performance, altered cardiac shape, and elevated vertebral abnormalities in response to early exposure to M. aeruginosa could have significant effects on fish populations in the wild.

AIMSurv: First pan-European harmonized surveillance of Aedes invasive mosquito species of relevance for human vector-borne diseases.

Human and animal vector-borne diseases, particularly mosquito-borne diseases, are emerging or re-emerging worldwide. Six Aedes invasive mosquito (AIM) species were introduced to Europe since the 1970s: Aedes aegypti, Ae. albopictus, Ae. japonicus, Ae. koreicus, Ae. atropalpus and Ae. triseriatus. Here, we report the results of AIMSurv2020, the first pan-European surveillance effort for AIMs. Implemented by 42 volunteer teams from 24 countries. And presented in the form of a dataset named "AIMSurv Aedes Invasive Mosquito species harmonized surveillance in Europe. AIM-COST Action. Project ID: CA17108". AIMSurv2020 harmonizes field surveillance methodologies for sampling different AIMs life stages, frequency and minimum length of sampling period, and data reporting. Data include minimum requirements for sample types and recommended requirements for those teams with more resources. Data are published as a Darwin Core archive in the Global Biodiversity Information Facility- Spain, comprising a core file with 19,130 records (EventID) and an occurrences file with 19,743 records (OccurrenceID). AIM species recorded in AIMSurv2020 were Ae. albopictus, Ae. japonicus and Ae. koreicus, as well as native mosquito species.

Longitudinal placements for trainee pharmacists: Learning whilst improving patient care.

INTRODUCTION: Longitudinal Integrated Clerkships (LICs) have demonstrated benefits for students' learning and development in medical education globally. The model emphasises importance with respect to continuity and time in the workplace for learners. There is a need to explore how LICs become a viable training model for learners. An amalgamative LIC model was drawn upon to inform the design of a placement for trainee pharmacists on a hospital ward. This study sought to determine the local viability of a longitudinal placement for trainee pharmacists, using communities of practice learning theory to interpret findings. METHODS: A design-based research approach informed study design. A longitudinal placement was implemented on two hospital wards for 13 weeks. Trainees (n = 3) were interviewed four times over a 14-week period. Ward staff (n = 14) were interviewed at week 14. Interviews were transcribed verbatim. Qualitative longitudinal analysis, using the trajectory approach, was conducted using abductive analysis. The coded data were organised into a framework and subthemes were created. RESULTS: Trainees acquired membership within the multi-disciplinary ward team over time. This led to an enriched learning experience and the trainee's professional development improved as they attained more responsibilities. This enabled them to make a greater contribution to patient care; more medication consultations occurred, and discharge times improved. DISCUSSION: The local viability of the longitudinal placement appears to be linked to the trainee's ability to acquire membership within the ward community of practice. Membership gave trainee's access to learning opportunities, supporting their development, and they earnt the trust of staff, leading to more responsibilities for providing patient care. Further research into developing longitudinal placements that support trainee healthcare professionals to acquire membership within communities of practice is warranted.

Bone Phenotyping Approaches in Human, Mice and Zebrafish - Expert Overview of the EU Cost Action GEMSTONE ("GEnomics of MusculoSkeletal traits TranslatiOnal NEtwork").

A synoptic overview of scientific methods applied in bone and associated research fields across species has yet to be published. Experts from the EU Cost Action GEMSTONE ("GEnomics of MusculoSkeletal Traits translational Network") Working Group 2 present an overview of the routine techniques as well as clinical and research approaches employed to characterize bone phenotypes in humans and selected animal models (mice and zebrafish) of health and disease. The goal is consolidation of knowledge and a map for future research. This expert paper provides a comprehensive overview of state-of-the-art technologies to investigate bone properties in humans and animals - including their strengths and weaknesses. New research methodologies are outlined and future strategies are discussed to combine phenotypic with rapidly developing -omics data in order to advance musculoskeletal research and move towards "personalised medicine".

Developmental exposure to a POPs mixture or PFOS increased body weight and reduced swimming ability but had no effect on reproduction or behavior in zebrafish adults.

Complex mixtures of persistent organic pollutants (POPs) are regularly detected in the environment and animal tissues. Often these chemicals are associated with latent effects following early-life exposures, following the developmental origin of health and disease paradigm. We investigated the long-term effects of a human relevant mixture of 29 POPs on adult zebrafish following a developmental exposure, in addition to a single PFOS exposure for comparison, as it was the compound with the highest concentration within the mixture. Zebrafish embryos were exposed from 6 to 96 h post fertilization to x10 and x70 the level of POP mixture or PFOS (0.55 and 3.83 µM) found in human blood before being transferred to clean water. We measured growth, swimming performance, and reproductive output at different life stages. In addition, we assessed anxiety behavior of the adults and their offspring, as well as performing a transcriptomic analysis on the adult zebrafish brain, as the POP mixture and PFOS concentrations used are known to affect larval behavior. Exposure to POP mixture and PFOS reduced swimming performance and increased length and weight, compared to controls. No effect of developmental exposure was observed on reproductive output or anxiety behavior. Additionally, RNA-seq did not reveal pathways related to anxiety although pathways related to synapse biology were affected at the x10 PFOS level. Furthermore, pathway analysis of the brain transcriptome of adults exposed as larvae to the low concentration of PFOS revealed enrichment in pathways such as calcium, MAPK, and GABA signaling, all of which are important for learning and memory. Based on our results we can conclude that some effects on the endpoints measured were apparent, but if these effects lead to adversities at population levels remains elusive.

Structured block placements of hospital pre-registration trainee pharmacists in primary care medical practices across the United Kingdom: Lessons from a pilot scheme.

BACKGROUND AND PURPOSE: There is increasing demand for suitably trained pharmacists to undertake clinical roles in primary care general practices across the United Kingdom. This necessitates development of sustainable training opportunities to both better prepare future registrants for such roles and raise awareness of the new career pathway. Educational activity and setting: Hospital pre-registration trainee pharmacists undertook four or eight-week placements in general practice as part of their training year. Trainees attended an introductory session and received educational support tools six weeks prior to their placements. Each trainee had an allocated clinical supervisor in general practice and maintained communication with their hospital tutor. On completion of all placements, trainees and general practice staff were asked to share perceptions and outcomes via online questionnaires. FINDINGS: Most trainees reported that the clinical supervision arrangements were satisfactory and found the placement workbook useful for guiding daily activities. Key benefits from the placements included enhanced understanding of the patient journey across healthcare sectors, increased confidence, and raised awareness of general practice as a career option. Main limitations included restricted opportunities to engage in patient-centred activities and lack of integration with general practice teams. All trainees stated that the presence of a general practice pharmacist was essential for learning support. SUMMARY: This model demonstrated the feasibility of structured block placements of trainee pharmacists in general practice with identified benefits for trainees and pharmacy workforce requirements. Future research:Identified key limitations to this model need further investigation, to improve the design of future placements.

A genome-wide scan for pleiotropy between bone mineral density and nonbone phenotypes.

Osteoporosis is the most common metabolic bone disorder globally and is characterized by skeletal fragility and microarchitectural deterioration. Genetic pleiotropy occurs when a single genetic element is associated with more than one phenotype. We aimed to identify pleiotropic loci associated with bone mineral density (BMD) and nonbone phenotypes in genome-wide association studies. In the discovery stage, the NHGRI-EBI Catalog was searched for genome-wide significant associations (P value < 5 × 10-8), excluding bone-related phenotypes. SNiPA was used to identify proxies of the significantly associated single nucleotide polymorphisms (SNPs) (r 2 = 1). We then assessed putative genetic associations of this set of SNPs with femoral neck (FN) and lumbar spine (LS) BMD data from the GEFOS Consortium. Pleiotropic variants were claimed at a false discovery rate < 1.4 × 10-3 for FN-BMD and < 1.5 × 10-3 for LS-BMD. Replication of these genetic markers was performed among more than 400 000 UK Biobank participants of European ancestry with available genetic and heel bone ultrasound data. In the discovery stage, 72 BMD-related pleiotropic SNPs were identified, and 12 SNPs located in 11 loci on 8 chromosomes were replicated in the UK Biobank. These SNPs were associated, in addition to BMD, with 14 different phenotypes. Most pleiotropic associations were exhibited by rs479844 (AP5B1, OVOL1 genes), which was associated with dermatological and allergic diseases, and rs4072037 (MUC1 gene), which was associated with magnesium levels and gastroenterological cancer. In conclusion, 12 BMD-related genome-wide significant SNPs showed pleiotropy with nonbone phenotypes. Pleiotropic associations can deepen the genetic understanding of bone-related diseases by identifying shared biological mechanisms with other diseases or traits.

Calcium signaling as a possible mechanism behind increased locomotor response in zebrafish larvae exposed to a human relevant persistent organic pollutant mixture or PFOS.

Persistent organic pollutants (POPs) are widespread in the environment and their bioaccumulation can lead to adverse health effects in many organisms. Previously, using zebrafish as a model vertebrate, we found larvae exposed to a mixture of 29 POPs based on average blood levels from the Scandinavian population showed hyperactivity, and identified perfluorooctanesulfonic acid (PFOS) as the driving agent for the behavioral changes. In order to identify possible mechanisms, we exposed zebrafish larvae from 6 to 96 h post fertilization to the same mixture of POPs in two concentrations or a single PFOS exposure (0.55 and 3.83 µM) and performed behavioral tests and transcriptomics analysis. Behavioral alterations of exposed zebrafish larvae included hyperactivity and confirmed previously reported results. Transcriptomics analysis showed upregulation of transcripts related to muscle contraction that is highly regulated by the availability of calcium in the sarcoplasmic reticulum. Ingenuity pathway analysis showed that one of the affected pathways in larvae exposed to the POP mixture and PFOS was calcium signaling via the activation of the ryanodine receptors (RyR). Functional analyses with RyR inhibitors and behavioral outcomes substantiate these findings. Additional pathways affected were related to lipid metabolism in larvae exposed to the lower concentration of PFOS. By using omics technology, we observed that the altered behavioral pattern in exposed zebrafish larvae may be controlled directly by mechanisms affecting muscle function rather than via mechanisms connected to neurotoxicity.

High Tolerability of Pitavastatin Therapy: A Case Report of Comparison with other Statins.

INTRODUCTION: Myopathy is possibly the most clinically relevant statin-induced side effect. CASE PRESENTATION: We report a case of a 63-year-old healthy male with mixed dyslipidemia. He developed bilateral myalgia of the forearms with fluvastatin 40 mg/day, pravastatin 20 mg/day, and combination of atorvastatin 10 mg and ezetimibe 10 mg/day. The only hypolipidemic treatment that was tolerable was the combination of pitavastatin 1 mg and ezetimibe 10 mg/day. DISCUSSION: Pitavastatin demonstrated less potential for the development of myalgia compared to the so far considered most tolerable statins (i.e., fluvastatin and pravastatin). All the tested statins were used at the lowest approved dose for clinical use. CONCLUSION: The combination of pitavastatin 1 mg and ezetimibe appears to be a promising treatment choice for individuals who are intolerant to statin therapy due to muscle complaints.