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The aim of the study was to compare the analgesic efficacy of butorphanol and lidocaine, alone or in combination, in calves undergoing surgical repair of umbilical hernia. The study was conducted in 60 calves of different breeds. Xylazine 0.3 mg/kg was administered intramuscularly to all animals in the study. The animals were then divided into three groups (n = 20) that received different treatments with lidocaine at 4.5 mg/kg and butorphanol at 0.02 mg/kg. The L group received lidocaine both by infiltration of the surgical planes and intraperitoneally, the B group received butorphanol both by infiltration of the surgical planes and intraperitoneally, and finally the LB group received lidocaine by infiltration of the surgical planes and butorphanol intraperitoneally. Heart and respiratory rates, haemoglobin oxygen saturation, non-invasive blood pressure and temperature were recorded during surgery. Response to the surgical stimulus was scored on a cumulative numerical scale that included percentage changes in HR, RR and SAP. Postoperative pain was assessed by three independent observers, blinded to treatment, using the UNESP-Botucatu Unidimensional Composite Pain Scale (UNESP-Botucatu UCPS-IV) for the assessment of postoperative pain in cattle. The course of physiological variables was appropriate for patients under anaesthesia. No subject required rescue intraoperative analgesia. In group L, 4 subjects at 40 m and 5 subjects at 50 m required postoperative rescue analgesia. Both butorphanol alone and the combination of butorphanol and lidocaine showed excellent intraoperative and postoperative scores. Furthermore, this combination did not cause any cardiopulmonary or other adverse effects. Based on the results of this study, both butorphanol alone and the co-administration of butorphanol and lidocaine administered locally proved to be safe and effective in providing adequate and long-lasting analgesia in calves, helping to reduce postoperative discomfort and maintaining adequate animal welfare.

Cancer cell dormancy is a reversible process whereby cancer cells enter a quiescent state characterized by cell cycle arrest, inhibition of cell migration and invasion, and increased chemoresistance. Because of its reversibility and resistance to treatment, dormancy is a key process to study, monitor, and interfere with, in order to prevent tumor recurrence and metastasis and improve the prognosis of cancer patients. However, to achieve this goal, further studies are needed to elucidate the mechanisms underlying this complex and dynamic dual process. Here, we review the contribution of extracellular vesicles (EVs) to the regulation of cancer cell dormancy/awakening, focusing on the cross-talk between tumor and non-tumor cells in both the primary tumor and the (pre-)metastatic niche. Although EVs are recognized as key players in tumor progression and metastasis, as well as in tumor diagnostics and therapeutics, their role specifically in dormancy induction/escape is still largely elusive. We report on the most recent and promising results on this topic, focusing on the EV-associated nucleic acids involved. We highlight how EV studies could greatly contribute to the identification of dormancy signaling pathways and a dormancy/early awakening signature for the development of successful diagnostic/prognostic and therapeutic approaches.

Background Due to the copious disposal of plastics, marine ecosystems receive a large part of this waste. Microplastics (MPs) are solid particles smaller than 5 millimeters in size. Among the plastic polymers, polystyrene (PS) is one of the most commonly used and discarded. Due to its density being greater than that of water, it accumulates in marine sediments, potentially affecting benthic communities. This study investigated the ingestion of MP and their effect on the meiofauna community of a sandy beach. Meiofauna are an important trophic link between the basal and higher trophic levels of sedimentary food webs and may therefore be substantially involved in trophic transfer of MP and their associated compounds. Methods We incubated microcosms without addition of MP (controls) and treatments contaminated with PS MP (1-µm) in marine sediments at three nominal concentrations (103, 105, 107particles/mL), for nine days, and sampled for meiofauna with collections every three days. At each sampling time, meiofauna were collected, quantified and identified to higher-taxon level, and ingestion of MP was quantified under an epifluorescence microscope. Results Except for Tardigrada, all meiofauna taxa (Nematoda, turbellarians, Copepoda, Nauplii, Acari and Gastrotricha) ingested MP. Absorption was strongly dose dependent, being highest at 107 particles/mL, very low at 105 particles/mL and non-demonstrable at 103 particles/mL. Nematodes accumulated MP mainly in the intestine; MP abundance in the intestine increased with increasing incubation time. The total meiofauna density and species richness were significantly lower at the lowest MP concentration, while at the highest concentration these parameters were very similar to the control. In contrast, Shannon-Wiener diversity and evenness were greater in treatments with low MP concentration. However, these results should be interpreted with caution because of the low meiofauna abundances at the lower two MP concentrations. Conclusion At the highest MP concentration, abundance, taxonomic diversity and community structure of a beach meiofauna community were not significantly affected, suggesting that MP effects on meiofauna are at most subtle. However, lower MP concentrations did cause substantial declines in abundance and diversity, in line with previous studies at the population and community level. While we can only speculate on the underlying mechanism(s) of this counterintuitive response, results suggest that further research is needed to better understand MP effects on marine benthic communities.

The aim of this study was to evaluate the effect of oral cannabidiol (CBD) administration in addition to a conventional analgesic protocol on the clinical signs of 20 horses with mild joint osteoarthritis. The horses were randomly assigned to either the control group (C group) or the cannabidiol group (CBD group). Both groups were treated with phenylbutazone for 5 days. The CBD group received 0.03 mg/kg cannabidiol in hemp oil orally once daily for 14 days in addition to phenylbutazone treatment. All subjects were monitored for clinical parameters, oxidative status and blood counts. Pain and quality of life were also assessed using the Horse Chronic Pain Scale (HCPS). The CBD group showed a significant reduction in heart rate, respiratory rate, white blood cell count and oxidative stress (malondialdehyde lipid peroxidation). A significant reduction in HCPS scores was seen in both groups. Lower scores were recorded in the CBD group (3 med; range: 2/4) than in the C group (7 med; range: 4/10). The addition of a cannabidiol-based product to an analgesic protocol was well tolerated and showed positive effects on the treated subjects, improving their quality of life and pain relief.

Type 2 diabetes (T2D) is a progressive metabolic disorder of glucose metabolism. One of the therapeutic approaches for the treatment of T2D is reducing postprandial hyperglycaemia through inhibition of the digestive enzymes α-glucosidase and α-amylase. In this context, aimed at identifying natural products endowed with anti-T2D potential, we focused on Ptilostemon casabonae (L.) Greuter, a species belonging to Asteraceae family. Enzymatic inhibition, antioxidant activity, phenolic composition and cellular assays were performed. This study revealed that the P. casabonae hydroalcoholic extract exerts a potent inhibitory activity against α-glucosidase. This activity is supported by an antioxidant effect, preventing ROS formation in a stressed cellular system. HPLC-PDA-MS/MS analysis, revealed a complex polyphenolic fraction. Among the tested pure compounds, 1,5-dicaffeoylquinic acid, apigenin and rutin displayed good α-glucosidase inhibitory activity. Our study suggested new potential of P. casabonae encouraging us to further testing the possible therapeutic potential of this extract.

Glioblastoma (GB) is a rare but extremely aggressive brain tumor that significantly impacts patient outcomes, affecting both duration and quality of life. The protocol established by Stupp and colleagues in 2005, based on radiotherapy and chemotherapy with Temozolomide, following maximum safe surgical resection remains the gold standard for GB treatment; however, it is evident nowadays that the extreme intratumoral and intertumoral heterogeneity, as well as the invasiveness and tendency to recur, of GB are not compatible with a routine and unfortunately ineffective treatment. This review article summarizes the main challenges in the search for new valuable therapies for GB and focuses on the impact that extracellular vesicle (EV) research and exploitation may have in the field. EVs are natural particles delimited by a lipidic bilayer and filled with functional cellular content that are released and uptaken by cells as key means of cell communication. Furthermore, EVs are stable in body fluids and well tolerated by the immune system, and are able to cross physiological, interspecies, and interkingdom barriers and to target specific cells, releasing inherent or externally loaded functionally active molecules. Therefore, EVs have the potential to be ideal allies in the fight against GB and to improve the prognosis for GB patients. The present work describes the main preclinical results obtained so far on the use of EVs for GB treatment, focusing on both the EV sources and molecular cargo used in the various functional studies, primarily in vivo. Finally, a SWOT analysis is performed, highlighting the main advantages and pitfalls of developing EV-based GB therapeutic strategies. The analysis also suggests the main directions to explore to realize the possibility of exploiting EVs for the treatment of GB.

Background Tramadol produces a significant reduction in both sevoflurane and isoflurane minimum alveolar concentrations in dogs under experimental conditions. This study aims to compare the effects of tramadol administered as a constant rate infusion (CRI) with those of tramadol administered as a single intravenous bolus on physiological parameters and isoflurane requirements in dogs undergoing ovariohysterectomy. Methods In this study, forty female dogs undergoing ovariohysterectomy were enrolled. The bitches were anesthetized with 5 mg/kg of tiletamine/zolazepam combined with 0.05 mg/kg of acepromazine intravenously. Anesthesia was maintained with isoflurane delivered in 100% oxygen. The group A (n = 20) received tramadol 4 mg/kg in a single intravenous bolus, whereas the group B (n = 20) received tramadol 1.5 mg/kg in an intravenous bolus followed by tramadol 2.6 mg/kg/h as a CRI. The following parameters were recorded: heart rate, respiratory rate, non-invasive blood pressure, body temperature, EtCO2, SpO2 and inspired and expired concentrations of isoflurane. Parameter measurements were performed from pre-preedication (baseline) to skin suturing. Results The dogs were healthy subjects that demonstrated no abnormalities on laboratory investigations. Significant tachycardia was recorded after administration of tiletamine/zolazepam combined with acepromazine in both groups. Heart rate decreased after intubation but remained significantly higher compared to baseline values in both groups. Systolic blood pressure significantly decreased in both groups but the recorded values were within the physiological range. Mild reduction in body temperature was recorded in both groups. SpO2 and EtCO2 remained within the physiological range. Isoflurane requirement was significantly lower in the group B compared to the group A. Transient twitching was recorded in two dogs belonging to the group A after tramadol administration. Conclusions Compared to tramadol given as a single intravenous bolus injection during ovariohysterectomy in dogs, tramadol administered as a CRI reduces isoflurane requirements in dogs anesthetized with tiletamine/zolazepam combined with acepromazine. Both tramadol given as a CRI and a single intravenous bolus injection, induce decrease in heart rate, respiratory rate and in body temperature but the values of these parameters remain within physiological range in dogs undergoing ovariohysterectomy.

Objective: Our investigation was conducted to evaluate the incidence of umbilical pathologies and the result of related surgical interventions in Sicilian cattle. Study design: 320 (214 females, 106 males) cattle with umbilical lesions were collected, anesthetized, operated on and follow-up recorded. We evaluated the injury incidence rate. Population: The animals considered were: high productivity dairy cattle (Holstein Friesian and Brown Swiss); meat breeds (Charolaise and Limousine) and some crosses. Results: The highest injury rate was simple omphalocele, followed by purulent omphalitis. A high percentage was found in young cattle. Friesians are the most prone to navel diseases. The dairy breeds, compared to the meat breeds, and double aptitude and crosses, were the most affected. The most common was simple omphalocele, with a small hernial port (1 to 3 cm), while the rest was greater than 3 cm, with severe organs or complications. Methods: the most commonly used surgery was herniorraphy with autologous reinforcement, while classic sutures and mesh sutures were used in the remaining cases. Follow-up demonstrated healing in most of the treated subjects. Conclusions: The study aimed to estimate some surgical clinical cases in Sicilian cattle. Most injuries are lower abdomen injuries, mostly simple or complicated umbilical hernias. Young dairy females were the most affected. Meaning/Impact: Radical surgery is the treatment of choice in the vast majority of symptomatic or asymptomatic umbilical diseases; moreover, the correct management and the choice of an appropriate surgical approach allow to obtain an effective treatment of the lesions. Simple summary: In cattle farm, the correct management of births is a fundamental step for the future of the breeding. In fact, there are numerous critical factors in this phase: calving area management, umbilical disinfection, correct administration of colostrum, management of individual pens. Generally, after a few hours from birth, the calf is transferred in individual pens, the walls of this box allow visual and tactile contact but avoid the possibility of mutual sucking of the umbilical region, a risk factor, in that area, of infections and hernias. In the study have been collected umbilical interventions carried out over twenty years by a team operating in south-eastern Sicily: Ragusa. Out of a total of 320 cases, have been reported: the prevalence of types of umbilical tumefactions, anesthetic techniques and surgical techniques performed. The purpose of the work was to highlight any predispositions of race, sex, age regarding the lesion considered and above all, the effectiveness of the surgical therapy.

The mammarenavirus Junín (JUNV) is the causative agent of Argentine hemorrhagic fever, a severe disease of public health concern. The most abundant viral protein is the nucleoprotein (NP), a multifunctional, two-domain protein with the primary role as structural component of the viral nucleocapsids, used as template for viral polymerase RNA synthesis activities. Here, we report that the C-terminal domain (CTD) of the attenuated Candid#1 strain of the JUNV NP can be purified as a stable soluble form with a secondary structure in line with known NP structures from other mammarenaviruses. We show that the JUNV NP CTD interacts with the viral matrix protein Z in vitro, and that the full-length NP and Z interact with each other in cellulo, suggesting that the NP CTD is responsible for this interaction. This domain comprises an arrangement of four acidic residues and a histidine residue conserved in the active site of exoribonucleases belonging to the DEDDh family. We show that the JUNV NP CTD displays metal-ion-dependent nuclease activity against DNA and single- and double-stranded RNA, and that this activity is impaired by the mutation of a catalytic residue within the DEDDh motif. These results further support this activity, not previously observed in the JUNV NP, which could impact the mechanism of the cellular immune response modulation of this important pathogen.

Umbilical hernias in calves occur with relative frequency. Most abdominal surgeries can be performed in cattle using standing sedation and local blocks. Romifidine is widely used in calves, alone or in combination with opioids. Tramadol administered as an intravenous slow injection provided better analgesia than an IV bolus in cows. The aim of the present study was to compare the response to surgical stimulus, and sedative effects of tramadol administered intravenously either as a bolus or a slow injection in romifidinesedated calves. Twenty Frisian calves undergoing umbilical hernia repair received romifidine (0.08 mg/kg IM; time 0) followed by tramadol (1 mg/kg IV) 5 min later either as a bolus (n = 10, B group) or a slow injection over 10 min (n = 10, SI group). Surgical area was infiltrated with lidocaine (4 mg/kg). Heart rate (HR), respiratory rate (RR), systolic, dyastolic and mean arterial pressure (SAP, DAP, MAP), sedation scores and response to surgical stimulus were recorded for up to 55 min. After the calves recovered a standing position, postoperative pain scores were assessed for up to 50 min. Sedation scores were significantly higher in the SI group than in the B group at 55 min (p < 0.05). HR, RR, SAP and response to surgical stimulus were significantly higher in the B group than in the SI group (p < 0.05). No significant differences were recorded in postoperative pain scores between groups (p > 0.05). Romifidine IM followed by intravenous tramadol, as a bolus or slow injection and local infiltration with lidocaine provided adequate sedation and analgesia in calves undergoing umbilical hernia repair.

Abstract The trend in laparoscopy is to develop easy and rapid techniques associated with reduced intraoperative complications and decreased postoperative pain. The aim of this study was to compare combined laparoscopic ovariectomy (OIE) and laparoscopic‐assisted incisional gastropexy (LAG) with combined laparoscopic OIE and total laparoscopic gastropexy (TLG) for surgical time, incidence of complications and postoperative pain. Twenty‐eight female dogs were randomly assigned to the LAG group (n = 14) or the TLG group (n = 14). All laparoscopic procedures were performed using a three‐port technique. The gastropexy was located 3 cm caudal to the 13th rib and 4 cm lateral to the rectus abdominis muscle. Surgical time (minutes [min]), intraoperative complications and postoperative complications were recorded. The Glasgow pain score (GPS) (short form) was calculated before surgery and at 1, 6, 12, 18 and 24 hr after extubation. Surgical time was significantly longer in the TLG group (48 ± 2 min) compared with the LAG group (39 ± 2 min). Minor postoperative complications occurred in both groups and included swelling (n = 2) and subcutaneous emphysema (n = 1). No significant differences regarding the GPS were recorded between groups. The GPS was significantly higher in both groups at 1 hr and 6 hr than before surgery. Two dogs in each group required rescue analgesia. Combined laparoscopic OIE and TLG require more time to perform than combined laparoscopic OIE and LAG. Neither procedure results in significant surgical complications. Postoperative pain for 24 hr was mild and comparable in both groups.

The aims of the study included evaluating the effects of levobupivacaine combined with cisatracurium on akinesia and mydriasis when administered by peribulbar injection, and evaluating if the chosen dose of cisatracurium is enough to avoid the use of systemic neuromuscular blockade in cats. The animals were divided into four groups as follows: group L received 1.25 mg kg−1 levobupivacaine administered by peribulbar injection; group LC received the same dose of levobupivacaine combined with 0.01 mg kg−1 of cisatracurium administered by peribulbar injection; group C received 0.01 mg kg−1 of cisatracurium administered by peribulbar injection; group GC received 0.01 mg kg−1 of cisatracurium intravenously. Physiological variables, intraocular pressure, akinesia, and mydriasis were measured before and up to 30 min after peribulbar injection. The onset of akinesia, duration of akinesia, and train of four (TOF) were evaluated. Physiological variables remained in the physiological range in all groups. Effective akinesia and mydriasis were observed in all groups. The (TOF) was 0.9 in all groups. Throughout the study was observed in group LC a shortened onset of akinesia and a prolonging its duration. The peribulbar injection of cisatracurium and levobupivacaine provided effective akinesia and mydriasis, and shortened the onset of akinesia while prolonging its duration.

The purpose of the present study was to test whether the addition of cisatracurium in combination with propofol and sevoflurane would result in a change in doses of used anesthetic drugs. Ten dogs (Group A) undergoing elective unilateral mastectomy surgery were included in the study. To induce and maintain anesthesia, subjects received propofol and sevoflurane at varying doses; analgesia was performed with remifentanil. After three months, the same subjects (Group B) underwent contralateral mastectomy and received the same anesthetic protocol with the addition of cisatracurium at a dosage of 0.2 mg/kg−1. The following parameters were monitored during anesthesia: heart rate, systolic blood pressure, end-tidal CO2, oxygen saturation, halogenate requirement, and rectal temperature at baseline (T0), induction (T1), 5 (T5), 10 (T10), 15 (T15), 20 (T20), 25 (T25), 30 (T30), and 35 (T35) time points. In Group A, halogenate requirement was reduced at all the time points other than T1 (p < 0.001); in Group B, the percentage of halogenate requirement was already reduced at T1 and remained constant during the experimental period, showing no significant intragroup differences. The dose requirements of sevoflurane and propofol varied significantly between the two groups, with significantly lower dosages in the Group B (the cisatracurium-treated group). Moreover, patients treated with cisatracurium showed a stable anesthetic plan. The nondepolarizing-muscle-relaxant cisatracurium besylate could be considered a useful adjunct to anesthetic protocols.

The health benefits of switching from tobacco to electronic cigarettes (ECs) are neither confirmed nor well characterized. To address this problem, we used RNA-seq analysis to compare the nasal epithelium transcriptome from the following groups (n = 3 for each group): (1) former smokers who completely switched to second generation ECs for at least 6 months, (2) current tobacco cigarette smokers (CS), and (3) non-smokers (NS). Group three included one former cigarette smoker. The nasal epithelial biopsies from the EC users vs. NS had a higher number of differentially expressed genes (DEGs) than biopsies from the CS vs. NS and CS vs. EC sets (1817 DEGs total for the EC vs. NS, 407 DEGs for the CS vs. NS, and 116 DEGs for the CS vs. EC comparison). In the EC vs. NS comparison, enriched gene ontology terms for the downregulated DEGs included cilium assembly and organization, whereas gene ontologies for upregulated DEGs included immune response, keratinization, and NADPH oxidase. Similarly, ontologies for cilium movement were enriched in the downregulated DEGs for the CS vs. NS group. Reactome pathway analysis gave similar results and also identified keratinization and cornified envelope in the upregulated DEGs in the EC vs. NS comparison. In the CS vs. NS comparison, the enriched Reactome pathways for upregulated DEGs included biological oxidations and several metabolic processes. Regulator effects identified for the EC vs. NS comparison were inflammatory response, cell movement of phagocytes and degranulation of phagocytes. Disease Ontology Sematic Enrichment analysis identified lung disease, mouth disease, periodontal disease and pulmonary fibrosis in the EC vs. NS comparison. Squamous metaplasia associated markers, keratin 10, keratin 13 and involucrin, were increased in the EC vs. NS comparison. Our transcriptomic analysis showed that gene expression profiles associated with EC use are not equivalent to those from non-smokers. EC use may interfere with airway epithelium recovery by promoting increased oxidative stress, inhibition of ciliogenesis, and maintaining an inflammatory response. These transcriptomic alterations may contribute to the progression of diseases with chronic EC use.

Abstract Cellular, inter‐organismal and cross kingdom communication via extracellular vesicles (EVs) is intensively studied in basic science with high expectation for a large variety of bio‐technological applications. EVs intrinsically possess many attributes of a drug delivery vehicle. Beyond the implications for basic cell biology, academic and industrial interests in EVs have increased in the last few years. Microalgae constitute sustainable and renewable sources of bioactive compounds with a range of sectoral applications, including the formulation of health supplements, cosmetic products and food ingredients. Here we describe a newly discovered subtype of EVs derived from microalgae, which we named nanoalgosomes. We isolated these extracellular nano‐objects from cultures of microalgal strains, including the marine photosynthetic chlorophyte Tetraselmis chuii, using differential ultracentrifugation or tangential flow fractionation and focusing on the nanosized small EVs (sEVs). We explore different biochemical and physical properties and we show that nanoalgosomes are efficiently taken up by mammalian cell lines, confirming the cross kingdom communication potential of EVs. This is the first detailed description of such membranous nanovesicles from microalgae. With respect to EVs isolated from other organisms, nanoalgosomes present several advantages in that microalgae are a renewable and sustainable natural source, which could easily be scalable in terms of nanoalgosome production.

Dermal exposure to nicotine is common due to the widespread use of tobacco products. Here, we assessed the effects of nicotine at concentrations found in thirdhand smoke (THS) contaminated environments and electronic cigarette (EC) spills or leaks on a 3D human skin model (EpiDermTM) and on submerged keratinocyte cultures. Air liquid interface treatment of EpiDermTM with 10 or 400 μg/mL of nicotine for 24 h followed by proteomics analysis showed altered pathways related to inflammation, protein synthesis, cell–cell adhesion, apoptosis, and mitochondrial function. Submerged cultured keratinocytes were used to validate the proteomics data and further characterize the response of skin cells to nicotine. Mitochondrial phenotype changed from networked to punctate in keratinocytes treated with 10 or 400 μg/mL of nicotine for 48 h and 24 h, respectively. After 72 h, all concentrations of nicotine caused a significant decrease in the networked phenotype. In Western blots, keratinocytes exposed to 400 μg/mL of nicotine had a significant decrease in mitofusin 2, while mitofusin 1 decreased after 72 h. The shift from networked to punctate mitochondria correlated with a decrease in mitofusin 1/2, a protein needed to establish and maintain the networked phenotype. Mitochondrial changes were reversible after a 24 h recovery period. Peroxisomes exposed to 400 μg/mL of nicotine for 24 h became enlarged and were fewer in number. Nicotine concentrations in THS and EC spills altered the proteome profile in EpiDermTM and damaged organelles including mitochondria and peroxisomes, which are involved in ROS homeostasis. These changes may exacerbate skin infections, inhibit wound healing, and cause oxidative damage to cells in the skin.

In the present work, we use a merger of computational and biochemical techniques as a rational guideline for structural modification of benzofuran derivatives to find pertinent structural features for the butyrylcholinesterase inhibitory activity and selectivity. Previously, we revealed a series of 2-phenylbenzofuran compounds that displayed a selective inhibitory activity for BChE. Here, in an effort to discover novel selective BChE inhibitors with favorable physicochemical and pharmacokinetic profiles, 2-benzylbenzofurans were designed, synthesized, and evaluated as BChE inhibitors. The 2-phenylbenzofuran scaffold structure is modified by introducing one methylene spacer between the benzofuran core and the 2-phenyl ring with a hydroxyl substituent in the para or meta position. Either position 5 or 7 of the benzofuran scaffold was substituted with a bromine or chlorine atom. Further assessment of the selected list of compounds indicated that the substituent’s nature and position determined their activity and selectivity. 5-bromo-2-(4-hydroxybenzyl)benzofuran 9B proved to be the most potent butyrylcholinesterase inhibitor (IC50 = 2.93 µM) of the studied series. Computational studies were carried out to correlate the theoretical and experimental binding affinity of the compounds to the BChE protein.

Recent cardiovascular outcome trials found that sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce cardiovascular disease and mortality in type 2 diabetic patients; however, the underlying mechanisms are not fully known. Since the proliferation and migration of vascular smooth muscle cells (SMCs) contributes to the development of arterial lesions, we hypothesized that SGLT2 inhibitors may exert their beneficial cardiovascular effects by inhibiting the growth and movement of vascular SMCs. Treatment of rat or human aortic SMCs with clinically relevant concentrations of canagliflozin, but not empagliflozin or dapagliflozin, inhibited cell proliferation and migration. The inhibition of SMC growth by canagliflozin occurred in the absence of cell death, and was associated with the arrest of SMCs in the G0/G1 phase of the cell cycle and diminished DNA synthesis. Canagliflozin also resulted in the induction of heme oxygenase-1 (HO-1) expression, and a rise in HO activity in vascular SMCs, whereas, empagliflozin or dapagliflozin had no effect on HO activity. Canagliflozin also activated the HO-1 promoter and this was abrogated by mutating the antioxidant responsive element or by overexpressing dominant-negative NF-E2-related factor-2 (Nrf2). The induction of HO-1 by canagliflozin relied on reactive oxygen species (ROS) formation and was negated by antioxidants. Finally, silencing HO-1 expression partially rescued the proliferative and migratory response of canagliflozin-treated SMCs, and this was reversed by carbon monoxide and bilirubin. In conclusion, the present study identifies canagliflozin as a novel inhibitor of vascular SMC proliferation and migration. Moreover, it demonstrates that canagliflozin stimulates the expression of HO-1 in vascular SMCs via the ROS-Nrf2 pathway, and that the induction of HO-1 contributes to the cellular actions of canagliflozin. The ability of canagliflozin to exert these pleiotropic effects may contribute to the favorable clinical actions of the drug and suggest an extra potential benefit of canagliflozin relative to other SGLT2 inhibitors.

This work has developed and evaluated a microemulsion-based drilling fluid formulation with characteristics to be applied in oil wells. The microemulsion was formulated with a solution of water/glycerol, pine oil, and Tween 80, a nonionic and biodegradable surfactant. The physical and chemical properties of the drilling fluid obtained in this work were investigated through rheology and filtration analysis, solids content, aging, lubricity, toxicity, and thermal degradation. A non-toxic microemulsion-based drilling fluid oil-in-water (O/W) with high lubricity (0.07638) and thermal stability was obtained with suitable viscosity, gel strength and low fluid loss (4.0 mL), low solids content (6%), stability in a wide range of salinity conditions, and the possibility of high water content (above 85% in mass fraction). The fluid presented a pseudoplastic behavior, and statistically significant Herschel–Bulkley parameters were obtained.

In this work, nonionic surfactant NP100 and pine oil influences on the filtrate volume (FV) and the filter-cake thickness (thkns) of microemulsified drilling fluids were studied. A ternary phase diagram was obtained to define the microemulsion region, where a 2k factorial design was used with the addition of four center points and axial points. Twelve microemulsion points were defined and used later in the formulation of the investigated drilling fluids. The results showed that the increase in the surfactant and pine oil’s concentration increased FV and thkns, withthe oil phase being the most influential component in the filtrate volume and the surfactant being the most influential in the filter-cake thickness. Statistically significant models were obtained. The optimal concentrations were determined for the lowest FV and thkns; 45% of surfactant and 5% of pine oil for the filtrate volume (1.3 mL), and 45% of surfactant and 15% of pine oil for the filter-cake thickness (0.64 mm).

Over the past few years, our knowledge of how ecological interactions shape the structure and dynamics of natural communities has rapidly advanced. Plant chemical traits play key roles in these processes because they mediate a diverse range of direct and indirect interactions in a community-wide context. Many chemically mediated interactions have been extensively studied in industrial cropping systems, and thus have focused on simplified, pairwise and linear interactions that rarely incorporate a community perspective. A contrasting approach considers the agroecosystem as a functioning whole, in which food production occurs. It offers an opportunity to better understand how plant chemical traits mediate complex interactions which can enhance or hinder ecosystem functions. In this paper, we argue that studying chemically mediated interactions in agroecosystems is essential to comprehend how agroecosystem services emerge and how they can be guaranteed through ecosystem management. First, we discuss how plant chemical traits affect and are affected by ecological interactions. We then explore research questions and future directions on how studying chemical mediation in complex agroecosystems can help us understand the emergence and management of ecosystem services, specifically biological control and pollination.

The authors report a male patient, a seller with no detected immunosuppression, with an extensive ulcerated skin lesion localized on the left forearm, caused by Cryptococcus neoformans var. gattii serotype B. Oral treatment with fluconazole was successful. A review of the literature showed the rarity of this localization in HIV-negative patients. In contrast, skin lesions frequently occurs in HIV-positive patients, with Cryptococcus neoformans var. neoformans serotype A predominating as the etiological agent. In this paper, the pathogenicity of C. neoformans to skin lesions in patients immunocompromised or not, is discussed, showing the efficacy of fluconazole for the treatment of these processes.

Naturalistic Developmental Behavioral Interventions (NDBIs) have a strong and growing evidence base. Yet, NDBIs are not implemented on a wide scale within early intervention programs for children on the autism spectrum. Potential reasons for the slow adoption of NDBIs likely stem from the differing theoretical orientations of behavioral and developmental sciences from which NDBI are derived, and a lack of training, knowledge, and support for implementing NDBIs within the behavior analytic community. In support of efforts to promote wide-scale implementation of NDBIs, we clarify their common features, discuss possible misconceptions, offer reasons why NDBIs should be widely implemented, and provide recommendations to the autism service community, intervention developers, and researchers to improve their dissemination and implementation.

The effects of land abandonment on biodiversity have received considerable attention by scholars, but results are far from conclusive. Different cultural traditions of scientists seem to underlie the contrasting ways in which land abandonment is understood. Although the forest transition (FT) framework considers land abandonment as an opportunity for biodiversity conservation, European landscape ecologists characterize it as a threat. We use insights from both traditions to analyze the effects of land abandonment on landscape and biodiversity in a mountain area of metropolitan Barcelona. We do so through an in-depth historical case study covering a period of 160 years. A set of landscape metrics was applied to land-cover maps derived from cadastral cartography to characterize the landscape ecological changes brought about by land abandonment. Cadastral data on land uses were used to understand how landscape ecological changes could be explained by changing socioeconomic activities. Information on past land-management practices from semistructured interviews was used to shed light on how peasants shaped the capacity of landscape to host biodiversity. Our results point to a remarkable landscape deterioration along with the disappearance of the peasant land-use mosaics and the ensuing forest expansion. By using insights from landscape ecology in a historically informed manner, we (1) question the alleged relationship between land abandonment and ecosystem recovery; (2) show that the assumed restorative character of the FT is based on the underestimation of the ecological importance of nonforest habitats; and (3) point at a remarkable trade-off between FT and biodiversity in the Mediterranean. Finally, the case study also serves to illustrate some of the strengths and challenges of using historical approaches to land abandonment.

Hospitals, with many features that can evoke severe behavior in patients with autism spectrum disorder (ASD), often use restraint as a behavior management strategy. Prior research on restraint in patients with ASD has primarily focused on children or specific departments. Twenty-five physicians and medical trainees from an urban teaching hospital participated in discussions about experiences managing severe behavior in patients with ASD across the lifespan. Twenty themes emerged from thematic analysis of participant transcripts. The five most salient themes included: lack of procedural knowledge with restraint implemented by other hospital professionals; alternative strategies to manage severe behavior; negative perceptions of restraint; helpful role of caregivers; and limited experience treating patients with ASD, and critical need for training in function-based management.

Dermal exposure to nicotine is common due to the widespread use of tobacco products. Here, we assessed the effects of nicotine at concentrations found in thirdhand smoke (THS) contaminated environments and electronic cigarette (EC) spills or leaks on a 3D human skin model (EpiDermTM) and on submerged keratinocyte cultures. Air liquid interface treatment of EpiDermTM with 10 or 400 μg/mL of nicotine for 24 h followed by proteomics analysis showed altered pathways related to inflammation, protein synthesis, cell–cell adhesion, apoptosis, and mitochondrial function. Submerged cultured keratinocytes were used to validate the proteomics data and further characterize the response of skin cells to nicotine. Mitochondrial phenotype changed from networked to punctate in keratinocytes treated with 10 or 400 μg/mL of nicotine for 48 h and 24 h, respectively. After 72 h, all concentrations of nicotine caused a significant decrease in the networked phenotype. In Western blots, keratinocytes exposed to 400 μg/mL of nicotine had a significant decrease in mitofusin 2, while mitofusin 1 decreased after 72 h. The shift from networked to punctate mitochondria correlated with a decrease in mitofusin 1/2, a protein needed to establish and maintain the networked phenotype. Mitochondrial changes were reversible after a 24 h recovery period. Peroxisomes exposed to 400 μg/mL of nicotine for 24 h became enlarged and were fewer in number. Nicotine concentrations in THS and EC spills altered the proteome profile in EpiDermTM and damaged organelles including mitochondria and peroxisomes, which are involved in ROS homeostasis. These changes may exacerbate skin infections, inhibit wound healing, and cause oxidative damage to cells in the skin.

The health benefits of switching from tobacco to electronic cigarettes (ECs) are neither confirmed nor well characterized. To address this problem, we used RNA-seq analysis to compare the nasal epithelium transcriptome from the following groups (n = 3 for each group): (1) former smokers who completely switched to second generation ECs for at least 6 months, (2) current tobacco cigarette smokers (CS), and (3) non-smokers (NS). Group three included one former cigarette smoker. The nasal epithelial biopsies from the EC users vs. NS had a higher number of differentially expressed genes (DEGs) than biopsies from the CS vs. NS and CS vs. EC sets (1817 DEGs total for the EC vs. NS, 407 DEGs for the CS vs. NS, and 116 DEGs for the CS vs. EC comparison). In the EC vs. NS comparison, enriched gene ontology terms for the downregulated DEGs included cilium assembly and organization, whereas gene ontologies for upregulated DEGs included immune response, keratinization, and NADPH oxidase. Similarly, ontologies for cilium movement were enriched in the downregulated DEGs for the CS vs. NS group. Reactome pathway analysis gave similar results and also identified keratinization and cornified envelope in the upregulated DEGs in the EC vs. NS comparison. In the CS vs. NS comparison, the enriched Reactome pathways for upregulated DEGs included biological oxidations and several metabolic processes. Regulator effects identified for the EC vs. NS comparison were inflammatory response, cell movement of phagocytes and degranulation of phagocytes. Disease Ontology Sematic Enrichment analysis identified lung disease, mouth disease, periodontal disease and pulmonary fibrosis in the EC vs. NS comparison. Squamous metaplasia associated markers, keratin 10, keratin 13 and involucrin, were increased in the EC vs. NS comparison. Our transcriptomic analysis showed that gene expression profiles associated with EC use are not equivalent to those from non-smokers. EC use may interfere with airway epithelium recovery by promoting increased oxidative stress, inhibition of ciliogenesis, and maintaining an inflammatory response. These transcriptomic alterations may contribute to the progression of diseases with chronic EC use.

Thirdhand smoke (THS) is an environmental contaminant that may cause adverse health effects in smokers and nonsmokers. Currently, time-consuming analytical methods are necessary to assess chemicals in THS repositories, like upholstered furniture and clothing. Our goal was to develop a rapid, accessible method that can be used to measure THS contamination in common household fabrics and to evaluate remediation. Cotton, terry cloth, polyester, and wool were exposed to THS for various times in a controlled laboratory environment and then extracted in various media at room temperature or 60 °C to develop an autofluorescent method to quantify THS. Concentrations of nicotine and related alkaloids in the extracts were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and high-performance liquid chromatography (HPLC). The autofluorescence of extracts was proportional to the time and amount of THS exposure received by cotton and terry cloth. Extracts of polyester and wool did not show autofluorescence unless heat was applied during extraction. Nicotine, nicotine alkaloids, and TSNA concentrations were higher in THS extracts from cotton and terry cloth than extracts of polyester and wool carpet, in agreement with the autofluorescence data. For fabrics spiked with 10 mg of nicotine, extraction efficiency was much higher from terry cloth (7 mg) than polyester (0.11 mg). In high relative humidity, nicotine recovery from both cotton and polyester was 80% (~8 mg). Our results provide a simple, rapid method to assess THS contaminants in household fabrics and further show that THS extraction is influenced by fabric type, heat, and humidity. Thus, remediation of THS environments may need to vary depending on the fabric reservoirs being treated. Understanding the dynamics of THS in fabrics can help set up appropriate remediation policies to protect humans from exposure.

ImportanceNo previous studies have shown that acute inhalation of thirdhand smoke (THS) activates stress and survival pathways in the human nasal epithelium.ObjectiveTo evaluate gene expression in the nasal epithelium of nonsmoking women following acute inhalation of clean air and THS.Design, setting, and participantsNasal epithelium samples were obtained from participants in a randomized clinical trial (2011-2015) on the health effects of inhaled THS. In a crossover design, participants were exposed, head only, to THS and to conditioned, filtered air in a laboratory setting. The order of exposures was randomized and exposures were separated by at least 21 days. Ribonucleic acid was obtained from a subset of 4 healthy, nonsmoking women.ExposuresBy chance, women in the subset were randomized to receive clean air exposure first and THS exposure second. Exposures lasted 3 hours.Main outcomes and measuresDifferentially expressed genes were identified using RNA sequencing with a false-discovery rate less than 0.1.ResultsParticipants were 4 healthy, nonsmoking women aged 27 to 49 years (mean [SD] age, 42 [10.2] years) with no chronic diseases. A total of 389 differentially expressed genes were identified in nasal epithelium exposed to THS, while only 2 genes, which were not studied further, were affected by clean air. Enriched gene ontology terms associated with stress-induced mitochondrial hyperfusion were identified, such as respiratory electron transport chain (q = 2.84 × 10-3) and mitochondrial inner membrane (q = 7.21 × 10-6). Reactome pathway analysis identified terms associated with upregulation of DNA repair mechanisms, such as nucleotide excision repair (q = 1.05 × 10-2). Enrichment analyses using ingenuity pathway analysis identified canonical pathways related to stress-induced mitochondrial hyperfusion (eg, increased oxidative phosphorylation) (P = .001), oxidative stress (eg, glutathione depletion phase II reactions) (P = .04), and cell survival (z score = 5.026).Conclusions and relevanceThis study found that acute inhalation of THS caused cell stress that led to the activation of survival pathways. Some responses were consistent with stress-induced mitochondrial hyperfusion and similar to those demonstrated previously in vitro. These data may be valuable to physicians treating patients exposed to THS and may aid in formulating regulations for the remediation of THS-contaminated environments.

The aim of the study was to compare the analgesic efficacy of butorphanol and lidocaine, alone or in combination, in calves undergoing surgical repair of umbilical hernia. The study was conducted in 60 calves of different breeds. Xylazine 0.3mg/kg was administered intramuscularly to all animals in the study. The animals were then divided into three groups (n = 20) that received different treatments with lidocaine at 4.5mg/kg and butorphanol at 0.02mg/kg. The L group received lidocaine both by infiltration of the surgical planes and intraperitoneally, the B group received butorphanol both by infiltration of the surgical planes and intraperitoneally, and finally the LB group received lidocaine by infiltration of the surgical planes and butorphanol intraperitoneally. Heart and respiratory rates, haemoglobin oxygen saturation, non-invasive blood pressure and temperature were recorded during surgery. Response to the surgical stimulus was scored on a cumulative numerical scale that included percentage changes in HR, RR and SAP. Postoperative pain was assessed by three independent observers, blinded to treatment, using the UNESP-Botucatu Unidimensional Composite Pain Scale (UNESP-Botucatu UCPSIV) for the assessment of postoperative pain in cattle. The course of physiological variables was appropriate for patients under anaesthesia. No subject required rescue intraoperative analgesia. In group L, 4 subjects at 40m and 5 subjects at 50m required postoperative rescue analgesia. Both butorphanol alone and the combination of butorphanol and lidocaine showed excellent intraoperative and postoperative scores. Furthermore, this combination did not cause any cardiopulmonary or other adverse effects. Based on the results of this study, both butorphanol alone and the coadministration of butorphanol and lidocaine administered locally proved to be safe and effective in providing adequate and long-lasting analgesia in calves, helping to reduce postoperative discomfort and maintaining adequate animal welfare. [ABSTRACT FROM AUTHOR]

Cancer cell dormancy is a reversible process whereby cancer cells enter a quiescent state characterized by cell cycle arrest, inhibition of cell migration and invasion, and increased chemoresistance. Because of its reversibility and resistance to treatment, dormancy is a key process to study, monitor, and interfere with, in order to prevent tumor recurrence and metastasis and improve the prognosis of cancer patients. However, to achieve this goal, further studies are needed to elucidate the mechanisms underlying this complex and dynamic dual process. Here, we review the contribution of extracellular vesicles (EVs) to the regulation of cancer cell dormancy/awakening, focusing on the cross-talk between tumor and non-tumor cells in both the primary tumor and the (pre-)metastatic niche. Although EVs are recognized as key players in tumor progression and metastasis, as well as in tumor diagnostics and therapeutics, their role specifically in dormancy induction/escape is still largely elusive. We report on the most recent and promising results on this topic, focusing on the EV-associated nucleic acids involved. We highlight how EV studies could greatly contribute to the identification of dormancy signaling pathways and a dormancy/early awakening signature for the development of successful diagnostic/prognostic and therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background: Due to the copious disposal of plastics, marine ecosystems receive a large part of this waste. Microplastics (MPs) are solid particles smaller than 5 millimeters in size. Among the plastic polymers, polystyrene (PS) is one of the most commonly used and discarded. Due to its density being greater than that of water, it accumulates in marine sediments, potentially affecting benthic communities. This study investigated the ingestion of MP and their effect on the meiofauna community of a sandy beach. Meiofauna are an important trophic link between the basal and higher trophic levels of sedimentary food webs and may therefore be substantially involved in trophic transfer of MP and their associated compounds. Methods: We incubated microcosms without addition of MP (controls) and treatments contaminated with PS MP (1-µm) in marine sediments at three nominal concentrations (103, 105, 107particles/mL), for nine days, and sampled for meiofauna with collections every three days. At each sampling time, meiofauna were collected, quantified and identified to higher-taxon level, and ingestion of MP was quantified under an epifluorescence microscope. Results: Except for Tardigrada, all meiofauna taxa (Nematoda, turbellarians, Copepoda, Nauplii, Acari and Gastrotricha) ingested MP. Absorption was strongly dose dependent, being highest at 107 particles/mL, very low at 105 particles/mL and non-demonstrable at 103 particles/mL. Nematodes accumulated MP mainly in the intestine; MP abundance in the intestine increased with increasing incubation time. The total meiofauna density and species richness were significantly lower at the lowest MP concentration, while at the highest concentration these parameters were very similar to the control. In contrast, Shannon-Wiener diversity and evenness were greater in treatments with low MP concentration. However, these results should be interpreted with caution because of the low meiofauna abundances at the lower two MP concentrations. Conclusion: At the highest MP concentration, abundance, taxonomic diversity and community structure of a beach meiofauna community were not significantly affected, suggesting that MP effects on meiofauna are at most subtle. However, lower MP concentrations did cause substantial declines in abundance and diversity, in line with previous studies at the population and community level. While we can only speculate on the underlying mechanism(s) of this counterintuitive response, results suggest that further research is needed to better understand MP effects on marine benthic communities. [ABSTRACT FROM AUTHOR]