Knockdown of the ecdysone receptor disrupts development and causes mortality in the melon fly, Zeugodacus cucurbitae.

Cucurbits are important economic plants that are attacked by numerous pests, among which the melon fly Zeugodacus cucurbitae is extremely problematic. New sustainable pest control strategies are necessary to replace chemical insecticides that are harmful to the environment, human health and nontarget species. The RNA interference (RNAi) technology is one of the most promising tools due to high efficiency and species specificity. We developed an RNAi strategy targeting the ecdysone receptor (ECR) of Z. cucurbitae, which plays an important role in moulting and reproduction. We identified, described and isolated the ECR gene of Z. cucurbitae and measured its expression pattern across developmental stages and tissues. ZcECR knockdown via dsZcECR ingestion caused a significant larval mortality and abnormal phenotypes in pupae and adults. About 68% of larvae fed with a dsZcECR-treated diet failed to enter the pupal stage and died. In addition, ZcECR knockdown dramatically reduced pupal weight (by 3.24 mg on average) and fecundity (by about 23%). RNAi targeting the ECR gene is therefore a promising method to control Z. cucurbitae, paving the way for the development of novel sustainable and highly specific control strategies.

Three-dimensional (3D) printing in dental practice: Applications, areas of interest, and level of evidence.

OBJECTIVES: The aim of this review to overview three-dimensional (3D) printing technologies available for different dental disciplines, considering the applicability of such technologies and materials development. MATERIALS AND METHODS: Source Arksey and O'Malley's five stages framework using PubMed, EMBASE, and Scopus (Elsevier) databases managed this review. Papers focusing on 3D printing in dentistry and written in English were screened. Scientific productivity by the number of publications, areas of interest, and the focus of the investigations in each dental discipline were extracted. RESULTS: Nine hundred thirty-four studies using 3D printing in dentistry were assessed. Limited clinical trials were observed, especially in Restorative, endodontics, and pediatric dentistry. Laboratory or animal studies are not reliable for clinical success, suggesting that clinical trials are a good approach to validate the new methods' outcomes and ensure that the benefits outweigh the risk. The most common application for 3D printing technologies is to facilitate conventional dental procedures. CONCLUSIONS: The constantly improving quality of 3D printing applications has contributed to increasing the popularity of these technologies in dentistry; however, long-term clinical studies are necessary to assist in defining standards and endorsing the safe application of 3D printing in dental practice. CLINICAL RELEVANCE: The recent progress in 3D materials has improved dental practice capabilities over the last decade. Understanding the current status of 3D printing in dentistry is essential to facilitate translating its applications from laboratory to the clinical setting.

Transdermal Delivery of a Hydrogen Sulphide Donor, ADT-OH Using Aqueous Gel Formulations for the Treatment of Impaired Vascular Function: an Ex Vivo Study.

PURPOSE: Hydrogen sulphide (H2S) is an important signalling molecule involved in the regulation of several physiological and pathophysiological processes. The objective of this study was to investigate the feasibility of transdermal delivery of ADT-OH, a H2S donor, by investigating the transdermal flux of aqueous gels loaded with penetration enhancers or liposomes. Furthermore, we explored the ability of permeated ADT-OH to promote angiogenesis and mitochondrial bioenergetics in HUVEC cells. METHODS: Aqueous hypromellose gels (5% w/v) were prepared with up to 10% v/v propylene glycol (PG) or deformable liposomes with 0.025% w/w ADT-OH. ADT-OH permeation from formulations across excised murine skin into PBS was quantified over 24 h using HPLC-UV detection. Media was collected and applied to HUVEC cells to evidence ADT-OH functionality following permeation. Tube formation assays were performed as indicative of angiogenesis and mitochondrial oxygen consumption was evaluated using a Seahorse XF24. RESULTS: Increasing the loading of PG caused an increase in ADT-OH permeation rate across skin and a decrease in dermal drug retention whereas liposomal gels produced a slow-release profile. Treatment of HUVEC's using conditioned media collected from the ADT-OH loaded permeation studies enhanced tube formation and the basal oxygen consumption rates after 30 min of treatment. CONCLUSIONS: These findings demonstrate that transdermal delivery of ADT-OH may provide a promising approach in the treatment of impaired vascular function. Gels prepared with 10% v/v PG have the potential for use in conditions requiring rapid H2S release whereas liposomal loaded gels for treatment requiring sustained H2S release.

Current state of ethical challenges reported in Saudi Arabia: a systematic review & bibliometric analysis from 2010 to 2021.

BACKGROUND: Over the past few years, five domains of importance about the current state of bioethics in Saudi Arabia have shaped the perspective of most research: doctor-patient relationship, informed consent, do-not-resuscitate, organ donation, and transplantation, medical students' knowledge and attitudes about medical ethics curriculum. This systematic review aimed to systematically identify, compile, describe and discuss ethical arguments and concepts in the best-studied domains of bioethics in Saudi Arabia and to present cultural, social, educational, and humane perspectives. METHODS: Six databases were searched using Boolean operators (PubMed, Embase, Web of Science, Scopus, CINAHL, Google Scholar) from December 2020-June 2021. The search and report process followed the statement and flowchart of preferred reporting items for systematic reviews and meta-analyses (PRISMA). RESUTLS: The search resulted in 1651 articles, of which 82 studies were selected for a final review and assessment. There is a gradual increase in research, whereby a substantial increase was observed from 2017. Most of the published articles focused on 'Organ Donation & Transplantation' with 33 articles, followed by 'Doctor-Patient Relations' with 18 publications. Most of the published articles were from Central Province (33), followed by Western Province (16). The authorship pattern showed a collaborative approach among researchers. The thematic analysis of keywords analysis showed that 'Saudi Arabia,' 'attitude PHC,' 'organ donation,' 'knowledge and education,' and 'donation' have been used the most commonly. CONCLUSION: This systematic quantitative synthesis is expected to guide researchers, stakeholders, and policymakers about the strengths and gaps in knowledge and attitudes regarding medical ethics in Saudi Arabia, both among the general public and health professionals.

Expression and co-localization of RFRP-3 and kisspeptin during breeding and non-breeding season in the hypothalamus of male rhesus monkey (Macaca mulatta).

Propose: The mechanism that underpins how RFRP-3 and kisspeptin interacts are not fully understood in higher primates. This study therefore set out to assess RFRP-3 and kisspeptin expression and their morphological interactions in the breeding, and in the non-breeding period in monkey hypothalamus. Methods: Eight mature male macaques (Macaca mulatta) in the breeding season (February; n = 4) and non-breeding season (June; n = 4) were used. To reveal the expression and co-localization of RFRP-3 and kisspeptin, double-labeled immunohistochemistry was performed. Testicular volume, sperm count, and plasma testosterone level were also measured to validate the breeding and non-breeding paradigms. Results: Testicular volume, plasma testosterone level, and sperm count showed a significant reduction during non-breeding season. The number of kisspeptin-positive cells was significantly increased during the breeding season (p < 0.05), whereas more RFRP-3-positive cell bodies were seen in the non-breeding season (p < 0.01). Close contacts of RFRP-3 fibers with kisspeptin cells showed no significant difference (p > 0.05) across seasons. However, co-localization of RFRP-3-ir cell bodies onto kisspeptin IR cell bodies showed a statistical increase (p < 0.01) in non-breeding season. Conclusion: In higher primates, RFRP-3 decreases kisspeptin drives from the same cells to GnRH neurons in an autocrine manner causing suppression of the reproductive axis during the non-breeding period.

Pharmacy practice research in Saudi Arabia; A bibliometrics analysis from (2000 to 2021).

Background: Pharmacy is a growing profession in the Kingdom of Saudi Arabia which has experienced tremendous changes in the past 20 years. Pharmacy practice or clinical pharmacy have an attention ever since the emerging of PharmD programs throughout the Saudi universities. As a result, the number of affiliated faculty in the pharmacy practice departments has increased dramatically in the past 20 years and thus significant changes in research output were observed. Objectives: The main objective is to conduct a bibliometric analysis and evaluate the research output of pharmacy practice faculty in Saudi Universities from 2000 to 2021. Methods: A systematic search was conducted using Scopus database to explore the research output from pharmacy practice affiliated faculty from 2000 to 2021. The following search terms AFFILORG ("Pharmacy Practice Department" OR "Department of Pharmacy practice" OR "Clinical Pharmacy Department" OR "Department of Clinical Pharmacy" OR "Department of Pharmacy Services") AND AFFILCOUNTRY ("Saudi Arabia" OR "KSA" OR "Kingdom of Saudi Arabia") were used. Only original research papers were retrieved and analyzed using MS Excel (v16.0), MS Access (v16.0), Bibexcel (v2017), VOS viewer, and Biblioshiny. Results: In the past two decades, most publications with pharmacy practice departments affiliation were pharmacy practice research irrelevant (only 1075 out of 2809). King Saud University and King Abdulaziz University were the top performing institutes, and median of 5-year impact factor for journals was more than 3 for most of the top 10 institutes. 19% of the total retrieved articles were review publications were the rest majorly classified as cross-sectional studies. Conclusion: The research contribution of pharmacy practice departments in Saudi Arabia has been improving. Key recommendations are to promote more applied and interventional research, increase publications in top journals, and enhance national collaborations.

Removal of levofloxacin from aqueous solution by green synthesized magnetite (Fe3O4) nanoparticles using Moringa olifera: Kinetics and reaction mechanism analysis.

Levofloxacin antibiotic is frequently being detected in the environment and regarded as an emerging contaminant. The present study was focused on the green synthesis of magnetite (Fe3O4 - gINPs) nanoparticles from Moringa olifera and its efficiency for removal of levofloxacin from aqueous solution. The adsorbent magnetite nanoparticles (Fe3O4) were prepared by green synthesis using Moringa olifera and coprecipitation method. Characterizations analyses of both chemically and green synthesized nanoparticles were performed by SEM, XRD, and FTIR. The average crystallite size of gINPs was 14.34 nm and chemically synthesized was 18.93 nm. The performance of the synthesized product was evaluated by adsorption capacity and removal efficiency. The parameters considered included adsorbent (gINPs) dosage, initial concentration of adsorbate, pH, contact time, and temperature. The obtained data were fitted to kinetic and isotherm models to determine the mechanism. Adsorption batch experiments were conducted to determine the reaction mechanism by studying kinetics while fitting isotherm models for samples analyzed using HPLC at 280 nm. Results showed that 86.15% removal efficiency of 4 mg L-1 levofloxacin was achieved by 100 mg L-1 gINPs in 24 h contact time when all other parameters (pH 7, temperature 25 °C) were kept constant. The maximum adsorption capacity achieved at equilibrium was 22.47 mg/g. Further, it was identified as a pseudo-second-order model with R2 = 0.965 for adsorption kinetics while isotherm data better fitted to the Freundlich model compared to Langmuir isotherm with R2 = 0.994. The potential pathway determined for levofloxacin removal was chemisorption with minor diffusion, multilayer, spontaneous and exothermic processes on the gINPs (Fe3O4). Reusability experiments were conducted in four cycles and removal efficiency varied from 85.35% to 80.47%, indicating very high potential of the adsorbent for re-use.

Five decades of the International Endodontic Journal: Bibliometric overview 1967-2020.

AIM: The International Endodontic Journal (IEJ) has served as a platform for research and clinical practice in Endodontics since 1967. This study provides a bibliographic analysis and overview of the publications that have appeared in the IEJ from 1967 to 2020. METHODOLOGY: A literature search was performed in Elsevier's Scopus database to locate all the publications of the International Endodontic Journal. Various bibliometric software packages including the open-source visualization software Gephi and Biblioshiny (version 2.0) were employed for data visualization and analysis. RESULTS: A total of 3739 records with citation and bibliographic details were selected and retrieved to allow a bibliometric analysis to be performed. The bibliometric analysis indicates that the IEJ has grown both in terms of productivity and influence. Over time, the journal has been associated with an increase in the number of manuscripts published and the citations they have attracted, but with minor downward fluctuations in citations in the last few years. Bibliographic coupling of the IEJ articles revealed that the major research themes published in the journal include 'endodontics', 'root canal treatment', 'calcium hydroxide', 'apical periodontitis', 'mineral trioxide aggregate', 'microbiology', 'cyclic fatigue', 'cone-beam computed tomography' and 'micro-computed tomography'. Authors affiliated to institutions in the UK were the major contributors to the journal and were linked with other countries such as Brazil, USA and Malaysia. The largest number of publications were from the University of São Paulo, Brazil. CONCLUSION: The IEJ is one of the leading journals in Endodontology and has been providing a platform for innovative research and clinical reports for more than 50 years. Publications have been associated with a wide range of authors, institutions and countries around the world.

Multi-element uptake and growth responses of Rice (Oryza sativa L.) to TiO2 nanoparticles applied in different textured soils.

The aim of present work was to evaluate the effects of titanium dioxide nanoparticles (TiO2 NPs) on rice's growth (Oryza sativa L.) and nutrient availability under different soil textures. Greenhouse experiment was carried out with three soil textures (sandy loam, silt loam and silty clay loam) and two concentrations of TiO2 NPs (500, 750 mg kg-1). Control (without TiO2 NPs) was also maintained for the comparison. Growth parameters including chlorophyll content, root/shoot length, fresh/dry biomass and nutrients' uptake including calcium (Ca), copper (Cu), iron (Fe), magnesium (Mg), phosphorous (P), potassium (K) and zinc (Zn) were determined. The results revealed that application of 500 mg kg-1 TiO2 NPs in silty clay loam soil increased the chlorophyll content (3.3-folds), root length (49%), shoot length (31%), root and shoot biomass (41% & 39%, respectively) as compared to other soil textures. The maximum plant growth was observed in silty clay loam > silt loam > sandy loam. Concentration of Cu, Fe, P and Zn in shoot was increased by 8 - , 2.3 - , 0.4 - , 0.05 -folds in silty clay loam upon 500 mg kg-1 TiO2 NPs application as compared to the control. Backward selection method to model the parameters (nutrients in soil) for the response variables (root/shoot length and biomass) showed that Ca, Fe, P are the main nutrients responsible for the increase in plant length and biomass. Overall, the growth of rice was better in silty clay loam at 500 mg kg-1 of TiO2 NPs.

60Co-γ Radiation Alters Developmental Stages of Zeugodacus cucurbitae (Diptera: Tephritidae) Through Apoptosis Pathways Gene Expression.

Radiation is considered as a promising insect pest control strategy for minimizing postharvest yield losses. Among various techniques, irradiation is a method of choice as it induces lethal biochemical or molecular changes that cause a downstream cascade of abrupt physiological abnormalities at the cellular level. In this study, we evaluated the effect of 60Co-γ radiation on various developmental stages of Zeugodacus cucurbitae Coquillett and subsequent carry-over effects on the progeny. For this purpose, we treated eggs with 30- and 50-Gy radiation doses of 60Co-γ. We found that radiation significantly affected cellular antioxidants, insect morphology, and gene expression profiles. Our results indicate that in response to various doses of irradiation reactive oxygen species, catalase, peroxidase, and superoxide dismutase activities were increased along with a significant increase in the malondialdehyde (MDA) content. We observed higher mortality rates during the pupal stage of the insects that hatched from irradiated eggs (50 Gy). Furthermore, the life span of the adults was reduced in response to 50 Gy radiation. The negative effects carried over to the next generation were marked by significantly lower fecundity in the F1 generation of the irradiation groups as compared to control. The radiation induced morphological abnormalities at the pupal, as well as the adult, stages. Furthermore, variations in the gene expression following irradiation are discussed. Taken together, our results signify the utility of 60Co-γ radiation for fruit fly postharvest management.

Analysis of Peganum harmala, Melia azedarach and Morus alba extracts against six lethal human cancer cells and oxidative stress along with chemical characterization through advance Fourier Transform and Nuclear Magnetic Resonance spectroscopic methods towards green chemotherapeutic agents.

Traditional medicines implicate consumption of plant crude extracts, which may consist of extensive phytochemical diversity. Overall, the most biologically active extract of Peganum harmala (seeds) exhibited significant cytotoxic activity on Artemia salina with LC50 value of 61.547 µg/mL, while P. harmala (roots) [LC50 = 124.229 µg/mL] and M. azedarach (fruits) [LC50 = 147.813 µg/mL] showed moderate cytotoxic potential. P. harmala (seeds) extract also showed the maximum antitumor potential with 52.278 µg/mL LC50. Branches of P. harmala and Morus alba were not active in both bioassays. These outcomes were further reinforced by the levels of phenolics and flavonoids checked against gallic acid and quercetin equivalents, respectively, by standard curves. Current study aims to isolate, structurally characterize and analyze the bioactive compound from plant extracts by using chromatographic and spectrophotometric techniques. Bioactivity guided isolation of extracts led to the isolation of PH-HM-16 from ethyl acetate fraction P. harmala seeds. Chemical structure of PH-HM-16 was elucidated by ESI-MS, 1H NMR, 13C NMR, HSQC and IR spectrum. The results demonstrated significant positive anticancer activities against six human cancer cell lines assessed through MTT cancer cell growth inhibition assay. PH-HM-16 was most effective against prostate cancer cell lines [IC50 = 17.63 µg/mL] followed by breast cancer cell line MCF7 [IC50 value of 41.81 µg/mL]. IC50 value of PH-HM-16 against human myeloid leukemia cell line HL-60 and human colorectal tumor cells HCT-116 was observed as 68.77 µg/mL and 71.54 µg/mL respectively. The IC 50 value of PH-HM-16 compound was not significant against human gastric cancer SGC-7901 (111.89 µg/mL) and human lung adenocarcinoma epithelial cell line A549 (176.04 µg/mL). Isolated bioactive metabolite PH-HM-16 possesses significant antitumor potential so this could be the first step to develop an effective anticancer agent. Hence, this compound represents a promising potential to be chemically standardized or developed into pharmaceuticals for the chemoprevention and/or the treatment of certain types of cancer, especially as adjuvant phytotherapeutics in conventional chemotherapy.

Contribution of the neuronal sodium channel NaV1.8 to sodium- and calcium-dependent cellular proarrhythmia.

OBJECTIVE: In myocardial pathology such as heart failure a late sodium current (INaL) augmentation is known to be involved in conditions of arrhythmogenesis. However, the underlying mechanisms of the INaL generation are not entirely understood. By now evidence is growing that non-cardiac sodium channel isoforms could also be involved in the INaL generation. The present study investigates the contribution of the neuronal sodium channel isoform NaV1.8 to arrhythmogenesis in a clearly-defined setting of enhanced INaL by using anemone toxin II (ATX-II) in the absence of structural heart disease. METHODS: Electrophysiological experiments were performed in order to measure INaL, action potential duration (APD), SR-Ca2+-leak and cellular proarrhythmic triggers in ATX-II exposed wild-type (WT) and SCN10A-/- mice cardiomyocytes. In addition, WT cardiomyocytes were stimulated with ATX-II in the presence or absence of NaV1.8 inhibitors. INCX was measured by using the whole cell patch clamp method. RESULTS: In WT cardiomyocytes exposure to ATX-II augmented INaL, prolonged APD, increased SR-Ca2+-leak and induced proarrhythmic triggers such as early afterdepolarizations (EADs) and Ca2+-waves. All of them could be significantly reduced by applying NaV1.8 blockers PF-01247324 and A-803467. Both blockers had no relevant effects on cellular electrophysiology of SCN10A-/- cardiomyocytes. Moreover, in SCN10A-/--cardiomyocytes, the ATX-II-dependent increase in INaL, SR-Ca2+-leak and APD prolongation was less than in WT and comparable to the results which were obtained with WT cardiomyocytes being exposed to ATX-II and NaV1.8 inhibitors in parallel. Moreover, we found a decrease in reverse mode NCX current and reduced CaMKII-dependent RyR2-phosphorylation after application of PF-01247324 as an underlying explanation for the Na+-mediated Ca2+-dependent proarrhythmic triggers. CONCLUSION: The current findings demonstrate that NaV1.8 is a significant contributor for INaL-induced arrhythmic triggers. Therefore, NaV1.8 inhibition under conditions of an enhanced INaL constitutes a promising antiarrhythmic strategy which merits further investigation.

Inhibition of NaV1.8 prevents atrial arrhythmogenesis in human and mice.

Pharmacologic approaches for the treatment of atrial arrhythmias are limited due to side effects and low efficacy. Thus, the identification of new antiarrhythmic targets is of clinical interest. Recent genome studies suggested an involvement of SCN10A sodium channels (NaV1.8) in atrial electrophysiology. This study investigated the role and involvement of NaV1.8 (SCN10A) in arrhythmia generation in the human atria and in mice lacking NaV1.8. NaV1.8 mRNA and protein were detected in human atrial myocardium at a significant higher level compared to ventricular myocardium. Expression of NaV1.8 and NaV1.5 did not differ between myocardium from patients with atrial fibrillation and sinus rhythm. To determine the electrophysiological role of NaV1.8, we investigated isolated human atrial cardiomyocytes from patients with sinus rhythm stimulated with isoproterenol. Inhibition of NaV1.8 by A-803467 or PF-01247324 showed no effects on the human atrial action potential. However, we found that NaV1.8 significantly contributes to late Na+ current and consequently to an increased proarrhythmogenic diastolic sarcoplasmic reticulum Ca2+ leak in human atrial cardiomyocytes. Selective pharmacological inhibition of NaV1.8 potently reduced late Na+ current, proarrhythmic diastolic Ca2+ release, delayed afterdepolarizations as well as spontaneous action potentials. These findings could be confirmed in murine atrial cardiomyocytes from wild-type mice and also compared to SCN10A-/- mice (genetic ablation of NaV1.8). Pharmacological NaV1.8 inhibition showed no effects in SCN10A-/- mice. Importantly, in vivo experiments in SCN10A-/- mice showed that genetic ablation of NaV1.8 protects against atrial fibrillation induction. This study demonstrates that NaV1.8 is expressed in the murine and human atria and contributes to late Na+ current generation and cellular arrhythmogenesis. Blocking NaV1.8 selectively counteracts this pathomechanism and protects against atrial arrhythmias. Thus, our translational study reveals a new selective therapeutic target for treating atrial arrhythmias.

Modulation of Chemokine- and Adhesion-Molecule Gene Expression and Recruitment of Neutrophil Granulocytes in Rat and Mouse Liver after a Single Gadolinium Chloride or Zymosan Treatment.

Kupffer cells are professional phagocytes of the liver clearing bacteria from portal blood. Their clearance capacity, however, can be overwhelmed, transforming them into critical mediators of hepatic-injury. We investigated the consequences of selective Kupffer cell-overload by intraperitoneally administering pyrogen-free gadolinium chloride (GdCl3) or Zymosan into rats and into endotoxin-resistant mice (C3H/HeJ). The number of myeloperoxidase-positive (MPO⁺) cells increased at 3 h mainly around the portal vessel after both GdCl3 and Zymosan treatment. Simultaneously, GdCl3 administration reduced detectability of ED-1⁺ (but not ED-2) cells near the portal vessel. Serum chemokine (C-X-C motif) ligand 1 (CXCL-1), CXCL-2 and chemokine (C-C motif) ligand 2 (CCL-2) showed a peak at 3 h after both treatment regimens although at a higher extent after Zymosan administration. Accordingly, CXCL-1, CXCL-5 and CCL-2 gene expression in the liver was up-regulated after GdCl3 treatment at 3 h. After Zymosan administration a significant up-regulation of CXCL-1, CXCL-2, CXCL-10, CCL-2, CCL-3 and CCL-20 gene expression in liver at 3 h was observed. After Zymosan administration intracellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) gene expression was up-regulated in rat liver tissue. In C3H/HeJ mice both treatment regimens up-regulated CCL-2 and ICAM-1 gene expression after 3 h and down-regulated platelet endothelial cell adhesion molecule 1 (PECAM-1) gene expression. In conclusion, phagocytosis overload of Kupffer cells causes induction of several CXC, CC-chemokines, upregulation of "positive" adhesion molecule gene expression, down-regulation of the "negative" adhesion molecule PECAM-1 and a recruitment of neutrophil granulocytes in the portal area of the liver of treated rats and mice mainly in close contact to the liver macrophages.

Inhibition of Late Sodium Current as an Innovative Antiarrhythmic Strategy.

PURPOSE OF REVIEW: Over the last years, evidence is accumulating that enhanced late sodium current (INaL) in cardiac pathologies has fundamental consequences for cellular electrophysiology. This review discusses the underlying mechanisms of INaL-induced arrhythmias and the significance of INaL-inhibition as a possible therapeutic approach. RECENT FINDINGS: Inhibition of enhanced INaL, e.g., by ranolazine, was shown to reverse these effects in different myocardial diseases including heart failure. The antianginal drug ranolazine has already been examined in larger clinical trials with promising antiarrhythmic actions. Enhanced INaL was found to be present in several cardiac pathologies like ischemia, long QT syndromes, hypertrophic cardiomyopathy, and heart failure. In settings of enhanced INaL, a sodium-dependent calcium overload leads to severe impairment of excitation-contraction coupling and therefore has a high proarrhythmogenic potential. Experimental data showed that inhibition of INaL has a high antiarrhythmic potential which could be confirmed in further clinical trials.

Induction of Lipocalin2 in a Rat Model of Lung Irradiation.

Previously, we showed that lipocalin2 (LCN2) serum levels increased after liver irradiation and during acute-phase conditions. Here, we evaluate LCN2 expression and serum levels after single-dose lung irradiation with 25 Gy, percutaneously administered to the lung of randomly-paired male Wistar rats. Due to the concave anatomy of the lung recesses, the irradiation field included the upper part of the liver. No rat died due to irradiation. In control tissue, lung immunohistochemistry showed a high constitutive expression of LCN2+ granulocytes. LCN2 mRNA levels in lung tissue increased up to 24 h (9 ± 2.3-fold) after irradiation. However, serum LCN2 levels remained undetectable after lung irradiation. LCN2 expression in the upper part of the liver increased up to 4.2-fold after lung irradiation, but the lower liver showed an early decrease. Acute-phase cytokines (IL-1ß and TNF-α) showed a significant increase on transcript level in both lung and upper liver, whilst the lower liver did not show any considerable increase. In conclusion, constitutive expression of LCN2 in local immune cells demonstrates its local role during stress conditions in the lung. The absence of LCN2 in the serum strengthens our previous findings that the liver is the key player in secreting LCN2 during stress conditions with liver involvement.

Dysregulation of hydrogen sulfide producing enzyme cystathionine γ-lyase contributes to maternal hypertension and placental abnormalities in preeclampsia.

BACKGROUND: The exact etiology of preeclampsia is unknown, but there is growing evidence of an imbalance in angiogenic growth factors and abnormal placentation. Hydrogen sulfide (H2S), a gaseous messenger produced mainly by cystathionine γ-lyase (CSE), is a proangiogenic vasodilator. We hypothesized that a reduction in CSE activity may alter the angiogenic balance in pregnancy and induce abnormal placentation and maternal hypertension. METHODS AND RESULTS: Plasma levels of H2S were significantly decreased in women with preeclampsia (P<0.01), which was associated with reduced placental CSE expression as determined by real-time polymerase chain reaction and immunohistochemistry. Inhibition of CSE activity by DL-propargylglycine reduced placental growth factorproduction from first-trimester (8-12 weeks gestation) human placental explants and inhibited trophoblast invasion in vitro. Knockdown of CSE in human umbilical vein endothelial cells by small-interfering RNA increased the release of soluble fms-like tyrosine kinase-1 and soluble endoglin, as assessed by enzyme-linked immunosorbent assay, whereas adenoviral-mediated CSE overexpression in human umbilical vein endothelial cells inhibited their release. Administration of DL-propargylglycine to pregnant mice induced hypertension and liver damage, promoted abnormal labyrinth vascularization in the placenta, and decreased fetal growth. Finally, a slow-releasing H2S-generating compound, GYY4137, inhibited circulating soluble fms-like tyrosine kinase-1 and soluble endoglin levels and restored fetal growth in mice that was compromised by DL-propargylglycine treatment, demonstrating that the effect of CSE inhibitor was attributable to inhibition of H2S production. CONCLUSIONS: These results imply that endogenous H2S is required for healthy placental vasculature and that a decrease in CSE/H2S activity may contribute to the pathogenesis of preeclampsia.

Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia.

Despite intense investigation, mechanisms that facilitate the emergence of the pre-eclampsia phenotype in women are still unknown. Placental hypoxia, hypertension, proteinuria and oedema are the principal clinical features of this disease. It is speculated that hypoxia-driven disruption of the angiogenic balance involving vascular endothelial growth factor (VEGF)/placenta-derived growth factor (PLGF) and soluble Fms-like tyrosine kinase-1 (sFLT-1, the soluble form of VEGF receptor 1) might contribute to some of the maternal symptoms of pre-eclampsia. However, pre-eclampsia does not develop in all women with high sFLT-1 or low PLGF levels, and it also occurs in some women with low sFLT-1 and high PLGF levels. Moreover, recent experiments strongly suggest that several soluble factors affecting the vasculature are probably elevated because of placental hypoxia in the pre-eclamptic women, indicating that upstream molecular defect(s) may contribute to pre-eclampsia. Here we show that pregnant mice deficient in catechol-O-methyltransferase (COMT) show a pre-eclampsia-like phenotype resulting from an absence of 2-methoxyoestradiol (2-ME), a natural metabolite of oestradiol that is elevated during the third trimester of normal human pregnancy. 2-ME ameliorates all pre-eclampsia-like features without toxicity in the Comt(-/-) pregnant mice and suppresses placental hypoxia, hypoxia-inducible factor-1alpha expression and sFLT-1 elevation. The levels of COMT and 2-ME are significantly lower in women with severe pre-eclampsia. Our studies identify a genetic mouse model for pre-eclampsia and suggest that 2-ME may have utility as a plasma and urine diagnostic marker for this disease, and may also serve as a therapeutic supplement to prevent or treat this disorder.

Perception and behavior toward neuropsychiatric disorders in Saudi Arabia: A systematic review and quality assessment.

LAY ABSTRACT: In 2010, Saudi Arabia became the first country from the Gulf Cooperation Council states to join the World Mental Health Survey Initiative, which collaborates with Harvard University and has undertaken over 33 countries. The Saudi National Mental Health Survey revealed that 80% of Saudis with severe mental health disorders do not seek treatment. Considering the strong evidence set out in Saudi national study and the recommendations for future research, this systematic literature review was initiated to examine the most studied neurodevelopmental disorders reported in the Kingdom of Saudi Arabia to explore public knowledge, attitudes, and behaviors. Findings have shown that attention deficit hyperactivity disorder and autism spectrum disorder have been the most studied neurodevelopmental disorders in Saudi Arabia since 2010. However, various groups in Saudi society, including healthcare professionals, medical students, and the general public, lacked knowledge about these health conditions, often leading to stigmatized attitudes and behaviors toward people with attention deficit hyperactivity disorder and autism spectrum disorder. However, demographic data showed that most of the studies were carried out in the Central and Western provinces. More research is needed in all regions of the Kingdom of Saudi Arabia to contribute to the knowledge about mental health conditions of attention deficit hyperactivity disorder and autism spectrum disorder children and their parents to increase knowledge about neurodevelopmental disorders and mental health disorders in the Kingdom of Saudi Arabia, thereby enabling people to rethink their attitudes and behavior.

Serum Lipocalin2 is a potential biomarker of liver irradiation damage.

BACKGROUND/AIM: IL-6 - IL-1- lipocalin2 (LCN2) - liver irradiation - oxidative stress - TNF-a Lipocalin2 (LCN2) is an acute phase protein. The source of its increased serum level in oxidative stress conditions (ROS) remains still unknown. We prospectively evaluate the serum LCN2 increase after single dose liver irradiation along with hepatic LCN2 gene and protein expression. METHODS: A single dose of 25 Gray was administered percutaneously to the liver of randomly paired rats after a planning CT scan. Male Wistar rats were sacrificed 1, 3, 6, 12, 24 and 48 h after irradiation along with sham-irradiated controls. ELISA, RT-PCR, Western blot and immunofluorescence staining was performed. Furthermore, hepatocytes, myofibroblasts and Kupffer cells were isolated from the liver of healthy rats and irradiated ex-vivo. RESULTS: After liver irradiation, LCN2 serum levels increased significantly up to 2.7 µg/ml within 6 h and stayed elevated over 24 h. LCN2 specific transcripts increased significantly up to 552 ± 109-fold at 24 h after liver irradiation, which was further confirmed at protein level. α2-macroglobulin and hemoxygenase-1 also showed an increase, but the magnitude was less as compared to LCN2. LCN2+ granulocytes were detected within 1 h after irradiation around central and portal fields and remained high during the course of study. Ex-vivo irradiated hepatocytes (2.4 ± 0.6-fold) showed a higher LCN2 gene expression as compared to myofibroblasts and Kupffer cells. IL-1ß treatment further increased LCN2 gene expression in cultured hepatocytes. CONCLUSIONS: Single dose liver irradiation induces a significant increase in LCN2 serum levels, comparable to the induction of acute phase proteins. We suggest LCN2 as marker for the early phase of radiation-induced tissue damage.