An Overview of Degradation Strategies for Amitriptyline.

Antidepressant drugs play a crucial role in the treatment of mental health disorders, but their efficacy and safety can be compromised by drug degradation. Recent reports point to several drugs found in concentrations ranging from the limit of detection (LOD) to hundreds of ng/L in wastewater plants around the globe; hence, antidepressants can be considered emerging pollutants with potential consequences for human health and wellbeing. Understanding and implementing effective degradation strategies are essential not only to ensure the stability and potency of these medications but also for their safe disposal in line with current environment remediation goals. This review provides an overview of degradation pathways for amitriptyline, a typical tricyclic antidepressant drug, by exploring chemical routes such as oxidation, hydrolysis, and photodegradation. Connex issues such as stability-enhancing approaches through formulation and packaging considerations, regulatory guidelines, and quality control measures are also briefly noted. Specific case studies of amitriptyline degradation pathways forecast the future perspectives and challenges in this field, helping researchers and pharmaceutical manufacturers to provide guidelines for the most effective degradation pathways employed for minimal environmental impact.

The effect of oral administration of zeolite on the energy metabolism and reproductive health of Romanian spotted breed in advanced gestation and post partum period.

The dairy cow experiences the most significant impact from negative energy balance during this period, which adversely affects reproductive health. Consequently, most pathologies affect dairy cows during this time frame. Thus, with the primary objective of reducing the incidence of these pathologies on dairy farms, we questioned whether supplemental zeolite administration in cattle feed would affect metabolism and reproductive health. Therefore, we proposed introducing an antepartum and postpartum supplementation of 400 g of zeolite in the basal diet. The control group received only the basal diet without zeolite supplementation. Monitoring the results stemmed from the consideration that reproductive health can only be present based on an unaltered energy metabolism. Hence, we deemed it necessary to analyze several metabolic markers in light of the expected outcomes concerning reproductive health. Cows treated with zeolite exhibited a calving to first service interval 12.78 days earlier than those in the control group. Moreover, the average number of services per conception used for future gestation was 0.44 lower in the zeolite-treated group compared to the control group (p<0.05). Additionally, the treatment group showed a lower presence of pathogens in the uterus and displayed a more favorable average uterine score. Observations following the completion of the research point towards an improvement in the health of transition dairy cows, opening a new path for dairy farms in terms of preventing postpartum pathologies. Indeed, the benefits from this study primarily impact the animals rather than directly influencing milk production. Therefore, further research is necessary in this regard.

Health-related quality of life after burn injury due to bioethanol-fueled fireplaces.

OBJECTIVE: Commercially available bioethanol-fueled fireplaces are a potential source of burns and are commonly used for home use. The present study aimed to evaluate the quality of life following burn injuries that were caused by bioethanol-related accidents. METHODS: Burned patients who were admitted to our burn unit with burn injury due to bio-ethanol fueled fire places between January 2010 and December 2021 were contacted to ask for their willingness to participate in this study. They were asked to answer questions regarding the circumstances of the accident and three questionnaires to capture burn specific and general health related quality of life (Burn Specific Health Scale-Brief (BSHS-B), Short-Form Health Survey 36 (SF-36)) and general information about the accident. Patients were matched and compared to a group of patients suffering comparable burns from other burn mechanisms, which were also admitted to our burn unit at the same time. RESULTS: Of 35 patients that met the inclusion criteria, 19 answered the questionnaire and were compared to 38 patients with other burn mechanisms. There were no statistical differences regarding age (bioethanol: 37.4 ± 14.7 years vs. control: 36.2 ± 14.3 years, p = 0.777), TBSA (9.9 ± 6.8% vs. 8.9 ± 10.4, p = 0.715), and sex (42.1% females vs. 36.8% females, p = 0.882). Most patients in the bioethanol-group reported that they did not follow the manual instructions (68.4%) and that the accident happened during the refilling process (52.6%). There was no significant difference in any subscale of the BSHS-B or the SF-36. DISCUSSION: Burns related to bioethanol-fueled fireplaces are rare compared to other typical burn mechanisms. However, as they are used for personal pleasure and interior design, psychological impairment following burn may be even more critical. Detailed education on the use of these fireplaces needs to take place in order to reduce the risk of accidents.

Development of Visible Spectrophotometric Methods for the Determination of Tricyclic Antidepressants Based on Formation of Molecular Complexes with p-Benzoquinones.

Tricyclic antidepressants are commonly employed in the management of major depressive disorders. The present work describes two visible (VIS) spectrophotometric techniques that utilize the formation of charge transfer complexes between four antidepressant compounds, namely, amitriptyline hydrochloride (AMI), imipramine hydrochloride (IMI), clomipramine hydrochloride (CLO), and trimipramine maleate (TRI) acting as electron donors and two p-benzoquinones, namely, p-chloranilic acid (pCA) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), serving as electron acceptors. The stoichiometry of the compounds produced exhibited a consistent 1:1 ratio in all instances, as established by Job's method. Molar absorptivities, equilibrium association constants, and several other spectroscopic properties were determined for all complexes. The developed spectrophotometric techniques were validated intra-laboratory and successfully applied for quantitative assessment of the four antidepressant active ingredients in several commercial pharmaceutical formulations. The methods are relatively simple, fast, and use readily available laboratory instrumentation, making them easily applicable by most quality control laboratories worldwide.

Functional Enhancement and Characterization of an Electrophysiological Mapping Electrode Probe with Carbonic, Directional Macrocontacts.

Electrophysiological mapping (EM) using acute electrode probes is a common procedure performed during functional neurosurgery. Due to their constructive specificities, the EM probes are lagging in innovative enhancements. This work addressed complementing a clinically employed EM probe with carbonic and circumferentially segmented macrocontacts that are operable both for neurophysiological sensing ("recording") of local field potentials (LFP) and for test stimulation. This paper illustrates in-depth the development that is based on the direct writing of functional materials. The unconventional fabrication processes were optimized on planar geometry and then transferred to the cylindrically thin probe body. We report and discuss the constructive concept and architecture of the probe, characteristics of the electrochemical interface deduced from voltammetry and chronopotentiometry, and the results of in vitro and in vivo recording and pulse stimulation tests. Two- and three-directional macrocontacts were added on probes having shanks of 550 and 770 µm diameters and 10-23 cm lengths. The graphitic material presents a ~2.7 V wide, almost symmetric water electrolysis window, and an ultra-capacitive charge transfer. When tested with clinically relevant 150 µs biphasic current pulses, the interfacial polarization stayed safely away from the water window for pulse amplitudes up to 9 mA (135 µC/cm2). The in vivo experiments on adult rat models confirmed the high-quality sensing of LFPs. Additionally, the in vivo-prevailing increase in the electrode impedance and overpotential are discussed and modeled by an ionic mobility-reducing spongiform structure; this restricted diffusion model gives new applicative insight into the in vivo-uprisen stimulation overpotential.

Microemulsions of Nonionic Surfactant with Water and Various Homologous Esters: Preparation, Phase Transitions, Physical Property Measurements, and Application for Extraction of Tricyclic Antidepressant Drugs from Aqueous Media.

Microemulsions are nanocolloidal systems composed of water, an oil, and a surfactant, sometimes with an additional co-surfactant, which have found a wide range of practical applications, including the extractive removal of contaminants from polluted water. In this study, microemulsion systems, including a nonionic surfactant (Brij 30), water, and esters selected from two homologous series of C1-C6 alkyl acetates and ethyl C1-C4 carboxylates, respectively, were prepared by the surfactant titration method. Phase transitions leading to the formation of Winsor II and Winsor IV microemulsions were observed and phase diagrams were constructed. The dependences of phase transitions on the salinity and pH and the addition of isopropanol as a co-surfactant were also investigated. Some physical properties, namely density, refractive index, electrical conductivity, dynamic viscosity, and particle size, were measured for a selection of Winsor IV microemulsions, providing further insight into some other phase transitions occurring in the monophasic domains of phase diagrams. Finally, Winsor II microemulsions were tested as extraction solvents for the removal of four tricyclic antidepressant drugs from aqueous media. Propyl acetate/Brij 30/H2O microemulsions provided the best extraction yields (>90%), the highest Nernst distribution coefficients (~40-88), and a large volumetric ratio of almost 3 between the recovered purified water and the resulting microemulsion extract. Increasing the ionic strength (salinity) or the pH of the aqueous antidepressant solutions led to an improvement in extraction efficiencies, approaching 100%. These results could be extrapolated to other classes of pharmaceutical contaminants and suggest ester- and nonionic surfactant-based microemulsions are a promising tool for environmental remediation.

Linkage of NAMPT promoter variants to eNAMPT secretion, plasma eNAMPT levels, and ARDS severity.

BACKGROUND AND OBJECTIVES: eNAMPT (extracellular nicotinamide phosphoribosyltransferase), a novel DAMP and TLR4 ligand, is a druggable ARDS therapeutic target with NAMPT promoter SNPs associated with ARDS severity. This study assesses the previously unknown influence of NAMPT promoter SNPs on NAMPT transcription, eNAMPT secretion, and ARDS severity. METHODS AND DESIGN: Human lung endothelial cells (ECs) transfected with NAMPT promoter luciferase reporters harboring SNPs G-1535A, A-1001 C, and C-948A, were exposed to LPS or LPS/18% cyclic stretch (CS) and NAMPT promoter activity, NAMPT protein expression, and secretion assessed. NAMPT genotypes and eNAMPT plasma measurements (Days 0/7) were assessed in two ARDS cohorts (DISCOVERY n = 428; ALVEOLI n = 103). RESULTS: Comparisons of minor allelic frequency (MAF) in both ARDS cohorts with the 1000 Human Genome Project revealed the G-1535A and C-948A SNPs to be significantly associated with ARDS in Blacks compared with controls and trended toward significance in non-Hispanic Whites. LPS-challenged and LPS/18% CS-challenged EC harboring the -1535G wild-type allele exhibited significantly increased NAMPT promoter activity (compared with -1535A) with the -1535G/-948A diplotype exhibiting significantly increased NAMPT promoter activity, NAMPT protein expression, and eNAMPT secretion compared with the -1535A/-948 C diplotype. Highly significant increases in Day 0 eNAMPT plasma values were observed in both DISCOVERY and ALVEOLI ARDS cohorts (compared with healthy controls). Among subjects surviving to Day 7, Day 7 eNAMPT values were significantly increased in Day 28 non-survivors versus survivors. The protective -1535A SNP allele drove -1535A/-1001A and -1535A/-948 C diplotypes that confer significantly reduced ARDS risk (compared with -1535G, -1535G/-1001 C, -1535G/-948A), particularly in Black ARDS subjects. NAMPT SNP comparisons within the two ARDS cohorts did not identify significant association with either APACHE III scores or plasma eNAMPT levels. CONCLUSION: NAMPT SNPs influence promoter activity, eNAMPT protein expression/secretion, plasma eNAMPT levels, and ARDS severity. NAMPT genotypes are a potential tool for stratification in eNAMPT-focused ARDS clinical trials.

The epigenetic hallmark of early-life α-hexabromocyclododecane exposure: From cerebellar 6-mA levels to locomotor performance in adulthood.

There is a growing evidence that methylation at the N6 position of adenine (6-mA), whose modulation occurs primarily during development, would be a reliable epigenetic marker in eukaryotic organisms. The present study raises the question as to whether early-life exposure to α-hexabromocyclododecane (α-HBCDD), a brominated flame retardant, may trigger modifications in 6-mA epigenetic hallmarks in the brain during the development which, in turn could affect the offspring behaviour in adulthood. Pregnant Wistar rats were split into two groups: control and α-HBCDD (66 ng/kg/per os, G0-PND14). At PND1, α-HBCDD levels were assessed in brain and liver by LC-MS/MS. At PND14, DNA was isolated from the offspring's cerebellum. DNA methylation was measured by 6-mA-specific immunoprecipitation and Illumina® sequencing (MEDIP-Seq). Locomotor activity was finally evaluated at PND120. In our early-life exposure model, we confirmed that α-HBCDD can cross the placental barrier and be detected in pups at birth. An obvious post-exposure phenotype with locomotor deficits was observed when the rats reached adulthood. This was accompanied by sex-specific over-methylation of genes involved in the insulin signaling pathway, MAPK signaling pathway as well as serotonergic and GABAergic synapses, potentially altering the normal process of neurodevelopment with consequent motor impairments crystalized at adulthood.

Curcumin: Overview of Extraction Methods, Health Benefits, and Encapsulation and Delivery Using Microemulsions and Nanoemulsions.

Curcumin is the principal curcuminoid found in the rhizomes of turmeric. Due to its therapeutic action against cancer, depression, diabetes, some bacteria, and oxidative stress, it has been used widely in medicine since ancient times. Due to its low solubility, the human organism cannot completely absorb it. Advanced extraction technologies, followed by encapsulation in microemulsion and nanoemulsion systems, are currently being used to improve bioavailability. This review discusses the different methods available for curcumin extraction from plant material, methods for the identification of curcumin in the resulting extracts, its beneficial effects on human health, and the encapsulation techniques into small colloidal systems that have been used over the past decade to deliver this compound.

Biochemical and genomic identification of novel biomarkers in progressive sarcoidosis: HBEGF, eNAMPT, and ANG-2.

Background: Progressive pulmonary fibrosis is a serious complication in subjects with sarcoidosis. The absence of reliable, non-invasive biomarkers that detect early progression exacerbates the difficulty in predicting sarcoidosis severity. To potentially address this unmet need, we evaluated a panel of markers for an association with sarcoidosis progression (HBEGF, NAMPT, IL1-RA, IL-6, IL-8, ANG-2). This panel encompasses proteins related to inflammation, vascular injury, cell proliferation, and fibroblast mitogenesis processes. Methods: Plasma biomarker levels and biomarker protein expression in lung and lymph nodes tissues (immunohistochemical studies) from sarcoidosis subjects with limited disease and progressive (complicated) sarcoidosis were performed. Gene expression of the protein-coding genes included in this panel was analyzed using RNAseq in sarcoidosis granulomatous tissues from lung and lymph nodes. Results: Except for IL-8, plasma levels of each biomarker-eNAMPT, IL-1RA, IL-6, ANG-2, and HBEGF-were significantly elevated in sarcoidosis subjects compared to controls. In addition, plasma levels of HBEGF were elevated in complicated sarcoidosis, while eNAMPT and ANG-2 were observed to serve as markers of lung fibrosis in a subgroup of complicated sarcoidosis. Genomic studies corroborated HBEGF and NAMPT among the top dysregulated genes and identified cytokine-related and fibrotic pathways in lung granulomatous tissues from sarcoidosis. Conclusion: These findings suggest HBEGF, eNAMPT, and ANG-2 may serve as potential novel indicators of the clinical severity of sarcoidosis disease.

Circulating eNAMPT as a biomarker in the critically ill: acute pancreatitis, sepsis, trauma, and acute respiratory distress syndrome.

BACKGROUND: Nicotinamide phosphoribosyltransferase (NAMPT) exhibits dual functionality - as an intracellular enzyme regulating nicotinamide adenine dinucleotide metabolism and as an extracellular secreted protein (eNAMPT) to function as a cytokine regulator of innate immunity via binding to Toll-Like receptor 4 and NF-κB activation. In limited preclinical and clinical studies, eNAMPT was implicated in the pathobiology of acute respiratory distress syndrome (ARDS) suggesting that eNAMPT could potentially serve as a diagnostic and prognostic biomarker. We investigated the feasibility of circulating eNAMPT levels to serve as a biomarker in an expanded cohort of patients with ARDS and ARDS-predisposing conditions that included acute pancreatitis, sepsis, and trauma with comparisons to controls. METHODS: A total of 671 patients and 179 healthy controls were included in two independent cohorts. Plasma and serum eNAMPT levels were quantified using one of two complementary Enzyme-linked Immunosorbent Assays. After log base 2 variance stabilizing transformation of plasma/serum eNAMPT measurements, differences between healthy controls and each disease cohort were compared using linear regression or a generalized estimating equation (GEE) model where applicable. Complementary analyses included sensitivity, specificity, positive predictive values, negative predictive values, and the area under the receiver operating curve. RESULTS: Compared to controls, circulating eNAMPT levels were significantly elevated in subjects with acute pancreatitis, sepsis, trauma, and ARDS (all p < 0.01). In the acute pancreatitis cohort, circulating eNAMPT levels positively correlated with disease severity (p < 0.01). CONCLUSIONS: Circulating eNAMPT levels are novel biomarker in the critically ill with acute pancreatitis, sepsis, trauma, and/or ARDS with the potential to reflect disease severity.

eNAMPT Is a Novel Damage-associated Molecular Pattern Protein That Contributes to the Severity of Radiation-induced Lung Fibrosis.

The paucity of therapeutic strategies to reduce the severity of radiation-induced lung fibrosis (RILF), a life-threatening complication of intended or accidental ionizing radiation exposure, is a serious unmet need. We evaluated the contribution of eNAMPT (extracellular nicotinamide phosphoribosyltransferase), a damage-associated molecular pattern (DAMP) protein and TLR4 (Toll-like receptor 4) ligand, to the severity of whole-thorax lung irradiation (WTLI)-induced RILF. Wild-type (WT) and Nampt+/- heterozygous C57BL6 mice and nonhuman primates (NHPs, Macaca mulatta) were exposed to a single WTLI dose (9.8 or 10.7 Gy for NHPs, 20 Gy for mice). WT mice received IgG1 (control) or an eNAMPT-neutralizing polyclonal or monoclonal antibody (mAb) intraperitoneally 4 hours after WTLI and weekly thereafter. At 8-12 weeks after WTLI, NAMPT expression was assessed by immunohistochemistry, biochemistry, and plasma biomarker studies. RILF severity was determined by BAL protein/cells, hematoxylin and eosin, and trichrome blue staining and soluble collagen assays. RNA sequencing and bioinformatic analyses identified differentially expressed lung tissue genes/pathways. NAMPT lung tissue expression was increased in both WTLI-exposed WT mice and NHPs. Nampt+/- mice and eNAMPT polyclonal antibody/mAb-treated mice exhibited significantly attenuated WTLI-mediated lung fibrosis with reduced: 1) NAMPT and trichrome blue staining; 2) dysregulated lung tissue expression of smooth muscle actin, p-SMAD2/p-SMAD1/5/9, TGF-ß, TSP1 (thrombospondin-1), NOX4, IL-1ß, and NRF2; 3) plasma eNAMPT and IL-1ß concentrations; and 4) soluble collagen. Multiple WTLI-induced dysregulated differentially expressed lung tissue genes/pathways with known tissue fibrosis involvement were each rectified in mice receiving eNAMPT mAbs.The eNAMPT/TLR4 inflammatory network is essentially involved in radiation pathobiology, with eNAMPT neutralization an effective therapeutic strategy to reduce RILF severity.

Involvement of eNAMPT/TLR4 signaling in murine radiation pneumonitis: protection by eNAMPT neutralization.

Therapeutic strategies to prevent or reduce the severity of radiation pneumonitis are a serious unmet need. We evaluated extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a damage-associated molecular pattern protein (DAMP) and Toll-Like Receptor 4 (TLR4) ligand, as a therapeutic target in murine radiation pneumonitis. Radiation-induced murine and human NAMPT expression was assessed in vitro, in tissues (IHC, biochemistry, imaging), and in plasma. Wild type C57Bl6 mice (WT) and Nampt+/- heterozygous mice were exposed to 20Gy whole thoracic lung irradiation (WTLI) with or without weekly IP injection of IgG1 (control) or an eNAMPT-neutralizing polyclonal (pAb) or monoclonal antibody (mAb). BAL protein/cells and H&E staining were used to generate a WTLI severity score. Differentially-expressed genes (DEGs)/pathways were identified by RNA sequencing and bioinformatic analyses. Radiation exposure increases in vitro NAMPT expression in lung epithelium (NAMPT promoter activity) and NAMPT lung tissue expression in WTLI-exposed mice. Nampt+/- mice and eNAMPT pAb/mAb-treated mice exhibited significant histologic attenuation of WTLI-mediated lung injury with reduced levels of BAL protein and cells, and plasma levels of eNAMPT, IL-6,  and IL-1ß. Genomic and biochemical studies from WTLI-exposed lung tissues highlighted dysregulation of NFkB/cytokine and MAP kinase signaling pathways which were rectified by eNAMPT mAb treatment. The eNAMPT/TLR4 pathway is essentially involved in radiation pathobiology with eNAMPT neutralization an effective therapeutic strategy to reduce the severity of radiation pneumonitis.

Reproductive Health Risks Associated with Occupational and Environmental Exposure to Pesticides.

A marked reduction in fertility and an increase in adverse reproductive outcomes during the last few decades have been associated with occupational and environmental chemical exposures. Exposure to different types of pesticides may increase the risks of chronic diseases, such as diabetes, cancer, and neurodegenerative disease, but also of reduced fertility and birth defects. Both occupational and environmental exposures to pesticides are important, as many are endocrine disruptors, which means that even very low-dose exposure levels may have measurable biological effects. The aim of this review was to summarize the knowledge collected between 2000 and 2020, to highlight new findings, and to further interpret the mechanisms that may associate pesticides with infertility, abnormal sexual maturation, and pregnancy complications associated with occupational, environmental and transplacental exposures. A summary of current pesticide production and usage legislation is also included in order to elucidate the potential impact on exposure profile differences between countries, which may inform prevention measures. Recommendations for the medical surveillance of occupationally exposed populations, which should be facilitated by the biomonitoring of reduced fertility, is also discussed.

mTORC1/2 signaling is downregulated by amino acid-free culture of mouse preimplantation embryos and is only partially restored by amino acid readdition.

Development of the mammalian preimplantation embryo is influenced by autocrine/paracrine factors and the availability of nutrients. Deficiencies of these during in vitro culture reduce the success of assisted reproductive technologies. The mechanistic target of rapamycin complex 1 (mTORC1) pathway integrates external and internal signals, including those by amino acids (AAs), to promote normal preimplantation development. For this reason, AAs are often included in embryo culture media. In this study, we examined how withdrawal and addition of AAs to culture media modulate mTORC1 pathway activity compared with its activity in mouse embryos developed in vivo. Phosphorylation of signaling components downstream of mTORC1, namely, p70 ribosomal protein S6 kinase (p70S6K), ribosomal protein S6, and 4E binding protein 1 (4E-BP1), and that of protein kinase B (Akt), which lies upstream of mTORC1, changed significantly across stages of embryos developed in vivo. For freshly isolated blastocysts placed in vitro, the absence of AAs in the culture medium, even for a few hours, decreased mTORC1 signaling, which could only be partially restored by their addition. Long-term culture of early embryos to blastocysts in the absence of AAs decreased mTORC1 signaling to a greater extent and again this could only be partially restored by their inclusion. This failure to fully restore is probably due to decreased phosphatidylinositol 3-kinase (PI3K)/Akt/mTORC2 signaling in culture, as indicated by decreased P-AktS473. mTORC2 lies upstream of mTORC1 and is insensitive to AAs, and its reduced activity probably results from loss of maternal/autocrine factors. These data highlight reduced mTORC1/2 signaling activity correlating with compromised development in vitro and show that the addition of AAs can only partially offset these effects.

Endothelial eNAMPT amplifies pre-clinical acute lung injury: efficacy of an eNAMPT-neutralising monoclonal antibody.

RATIONALE: The severe acute respiratory syndrome coronavirus 2/coronavirus disease 2019 pandemic has highlighted the serious unmet need for effective therapies that reduce acute respiratory distress syndrome (ARDS) mortality. We explored whether extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a ligand for Toll-like receptor (TLR)4 and a master regulator of innate immunity and inflammation, is a potential ARDS therapeutic target. METHODS: Wild-type C57BL/6J or endothelial cell (EC)-cNAMPT -/- knockout mice (targeted EC NAMPT deletion) were exposed to either a lipopolysaccharide (LPS)-induced ("one-hit") or a combined LPS/ventilator ("two-hit")-induced acute inflammatory lung injury model. A NAMPT-specific monoclonal antibody (mAb) imaging probe (99mTc-ProNamptor) was used to detect NAMPT expression in lung tissues. Either an eNAMPT-neutralising goat polyclonal antibody (pAb) or a humanised monoclonal antibody (ALT-100 mAb) were used in vitro and in vivo. RESULTS: Immunohistochemical, biochemical and imaging studies validated time-dependent increases in NAMPT lung tissue expression in both pre-clinical ARDS models. Intravenous delivery of either eNAMPT-neutralising pAb or mAb significantly attenuated inflammatory lung injury (haematoxylin and eosin staining, bronchoalveolar lavage (BAL) protein, BAL polymorphonuclear cells, plasma interleukin-6) in both pre-clinical models. In vitro human lung EC studies demonstrated eNAMPT-neutralising antibodies (pAb, mAb) to strongly abrogate eNAMPT-induced TLR4 pathway activation and EC barrier disruption. In vivo studies in wild-type and EC-cNAMPT -/- mice confirmed a highly significant contribution of EC-derived NAMPT to the severity of inflammatory lung injury in both pre-clinical ARDS models. CONCLUSIONS: These findings highlight both the role of EC-derived eNAMPT and the potential for biologic targeting of the eNAMPT/TLR4 inflammatory pathway. In combination with predictive eNAMPT biomarker and NAMPT genotyping assays, this offers the opportunity to identify high-risk ARDS subjects for delivery of personalised medicine.

Random-pattern versus perforator-based adipocutaneous skin paddles for postoperative monitoring of free muscle flaps-a comparative retrospective cohort study.

INTRODUCTION: Free microvascular muscle flaps represent well-established reconstructive options for complex soft tissue defects. However, due to their lack of cutaneous capillary beds, they are difficult to monitor postoperatively. To this end, random and axial-pattern adipocutaneous skin paddles are often included. The objective of the study was to compare the impact of random-pattern versus perforator-based adipocutaneous skin paddles on operative efficacy and muscle flap safety. METHODS: Between August 2014 and July 2016, a total of 120 free muscle flaps were included in this retrospective monocentric cohort study. Based on their skin-paddle type, they were either grouped into a 'perforator-based' (group Pb) or 'random-pattern' (group Rp) cohort. The electronic medical records and operative reports of all patients were subsequently reviewed and patient, defect, and flap characteristics of both groups were compared. The effect of the competing skin paddle types on the overall operative time, incidences of flap loss or microvascular complications, and total length of hospital stay were then assessed. RESULTS: Group Pb comprised 72 flaps, whereas 48 flaps constituted group Rp. Patient, defect, and flap characteristics were similar between both groups. Groups Pb and Rp were comparable regarding patient age (group Pb: 61 (10-90) vs. Rp: 59 (13-81), p = 0.556), ASA (American Society of Anesthesiologists) class (group Pb: 3 (1-4) vs. Rp 3 (1-3), p = 0.977), and comorbidities, summarized by the Charlson comorbidity index (CCI; group Pb: 1 (0-4 vs. Rp: 1 (0-5), p = 0.295). Both types of monitoring skin paddles were equally reliable. There was no significant difference in the mean operation time between both groups (group Pb: 373 ±â€¯122 min vs. Rp: 342 ±â€¯84 min, p = 0.124). In-patient treatment after flap surgery and total length of hospital stay were significantly shorter in group Pb (group Pb: 24 ±â€¯10 days vs. Rp: 32 ±â€¯17 days, p = 0.002 and group Pb: 39 ±â€¯15 vs. Rp: 48 ±â€¯24, p = 0.022). CONCLUSION: Perforator-based skin paddles are a reliable tool for postoperative perfusion monitoring of free muscle flaps and help avoid additional surgical interventions as opposed to their random-pattern counterparts. Thus, the overall and postoperative length of hospital stay is significantly reduced.

Effects of Smoking Temperature, Smoking Time, and Type of Wood Sawdust on Polycyclic Aromatic Hydrocarbon Accumulation Levels in Directly Smoked Pork Sausages.

Smoking is an excellent food preservation method but also a source of contamination of foodstuffs with carcinogenic polycyclic aromatic hydrocarbons (PAHs). Herein we investigated the influence of smoking temperature, smoking time, and type of wood sawdust used as smoke source on PAH levels attained through controlled smoking of pork sausages. Four PAHs (benz[a]anthracene, chrysene, benzo[b]fluoranthene, benzo[a]pyrene) were monitored, as required by European Commission Regulation 835/2011. PAH concentrations increased continuously both with higher temperatures (55-95 °C) and with longer smoking periods (2-9 h), although the level of benzo[a]pyrene exhibited a tendency to plateau after 6 h. Among seven types of hardwoods tested, plum, alder, and birch yielded PAH concentrations considerably higher than that of commonly used beech, and oak showed similar levels to beech while apple and, to a lesser extent, walnut caused lower levels of sausage contamination. These findings could guide the establishment of good practices in the smoked meat industry.

The acute respiratory distress syndrome biomarker pipeline: crippling gaps between discovery and clinical utility.

Recent innovations in translational research have ushered an exponential increase in the discovery of novel biomarkers, thereby elevating the hope for deeper insights into "personalized" medicine approaches to disease phenotyping and care. However, a critical gap exists between the fast pace of biomarker discovery and the successful translation to clinical use. This gap underscores the fundamental biomarker conundrum across various acute and chronic disorders: how does a biomarker address a specific unmet need? Additionally, the gap highlights the need to shift the paradigm from a focus on biomarker discovery to greater translational impact and the need for a more streamlined drug approval process. The unmet need for biomarkers in acute respiratory distress syndrome (ARDS) is for reliable and validated biomarkers that minimize heterogeneity and allow for stratification of subject selection for enrollment in clinical trials of tailored therapies. This unmet need is particularly highlighted by the ongoing SARS-CoV-2/COVID-19 pandemic. The unprecedented numbers of COVID-19-induced ARDS cases has strained health care systems across the world and exposed the need for biomarkers that would accelerate drug development and the successful phenotyping of COVID-19-infected patients at risk for development of ARDS and ARDS mortality. Accordingly, this review discusses the current state of ARDS biomarkers in the context of the drug development pipeline and highlight gaps between biomarker discovery and clinical implementation while proposing potential paths forward. We discuss potential ARDS biomarkers by category and by context of use, highlighting progress in the development continuum. We conclude by discussing challenges to successful translation of biomarker candidates to clinical impact and proposing possible novel strategies.

Fruits By-Products - A Source of Valuable Active Principles. A Short Review.

The growing demand for more sustainable, alternative processes leading to production of plant-derived preparations imposes the use of plants waste generated mainly by agri-food and pharmaceutical industries. These mostly unexploited but large quantities of plants waste also increase the interest in developing alternative approaches for sustainable production of therapeutic molecules. In order to reduce the amount of plant waste by further processing, different novel extraction techniques can be applied. Fruits and their industrial by-products are rich sources of different classes of compounds with therapeutic properties. The processed fruits waste can be reused and lead to novel pharmaceuticals, food supplements or functional foods. This review intends to briefly summarize recent aspects regarding the production of different active compounds from fruit by-products, and their therapeutic properties. The potential use of fruits by-products in different industries will be also discussed.