International treatment outcomes of neonates on extracorporeal membrane oxygenation (ECMO) with persistent pulmonary hypertension of the newborn (PPHN): a systematic review.

BACKGROUND: PPHN is a common cause of neonatal respiratory failure and is still a serious condition and associated with high mortality. OBJECTIVES: To compare the demographic variables, clinical characteristics, and treatment outcomes in neonates with PHHN who underwent ECMO and survived compared to neonates with PHHN who underwent ECMO and died. METHODS: We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline and searched ProQuest, Medline, Embase, PubMed, CINAHL, Wiley online library, Scopus and Nature for studies on the development of PPHN in neonates who underwent ECMO, published from January 1, 2010 to May 31, 2023, with English language restriction. RESULTS: Of the 5689 papers that were identified, 134 articles were included in the systematic review. Studies involving 1814 neonates with PPHN who were placed on ECMO were analyzed (1218 survived and 594 died). Neonates in the PPHN group who died had lower proportion of normal spontaneous vaginal delivery (6.4% vs 1.8%; p value > 0.05) and lower Apgar scores at 1 min and 5 min [i.e., low Apgar score: 1.5% vs 0.5%, moderately abnormal Apgar score: 10.3% vs 1.2% and reassuring Apgar score: 4% vs 2.3%; p value = 0.039] compared to those who survived. Neonates who had PPHN and died had higher proportion of medical comorbidities such as omphalocele (0.7% vs 4.7%), systemic hypotension (1% vs 2.5%), infection with Herpes simplex virus (0.4% vs 2.2%) or Bordetella pertussis (0.7% vs 2%); p = 0.042. Neonates with PPHN in the death group were more likely to present due to congenital diaphragmatic hernia (25.5% vs 47.3%), neonatal respiratory distress syndrome (4.2% vs 13.5%), meconium aspiration syndrome (8% vs 12.1%), pneumonia (1.6% vs 8.4%), sepsis (1.5% vs 8.2%) and alveolar capillary dysplasia with misalignment of pulmonary veins (0.1% vs 4.4%); p = 0.019. Neonates with PPHN who died needed a longer median time of mechanical ventilation (15 days, IQR 10 to 27 vs. 10 days, IQR 7 to 28; p = 0.024) and ECMO use (9.2 days, IQR 3.9 to 13.5 vs. 6 days, IQR 3 to 12.5; p = 0.033), and a shorter median duration of hospital stay (23 days, IQR 12.5 to 46 vs. 58.5 days, IQR 28.2 to 60.7; p = 0.000) compared to the neonates with PPHN who survived. ECMO-related complications such as chylothorax (1% vs 2.7%), intracranial bleeding (1.2% vs 1.7%) and catheter-related infections (0% vs 0.3%) were more frequent in the group of neonates with PPHN who died (p = 0.031). CONCLUSION: ECMO in the neonates with PPHN who failed supportive cardiorespiratory care and conventional therapies has been successfully utilized with a neonatal survival rate of 67.1%. Mortality in neonates with PPHN who underwent ECMO was highest in cases born via the caesarean delivery mode or neonates who had lower Apgar scores at birth. Fatality rate in neonates with PPHN who underwent ECMO was the highest in patients with higher rate of specific medical comorbidities (omphalocele, systemic hypotension and infection with Herpes simplex virus or Bordetella pertussis) or cases who had PPHN due to higher rate of specific etiologies (congenital diaphragmatic hernia, neonatal respiratory distress syndrome and meconium aspiration syndrome). Neonates with PPHN who died may need a longer time of mechanical ventilation and ECMO use and a shorter duration of hospital stay; and may experience higher frequency of ECMO-related complications (chylothorax, intracranial bleeding and catheter-related infections) in comparison with the neonates with PPHN who survived.

Early time course of oxidative stress in hippocampal synaptosomes and cognitive loss following impaired insulin signaling in rats: Development of sporadic Alzheimer's disease.

Oxidative stress, caused by impaired insulin signaling, plays a pivotal role in the pathogenesis of sporadic Alzheimer's disease (sAD). We investigated the oxidative stress parameters in the synaptosomes prepared from the hippocampus tissue in order to identify their potential role in sAD development in intraperitoneal (IP) and intracerebroventricular (ICV) streptozotocin (STZ) injections models of insulin signaling impairment. Rats were harvested 1, 3, or 6 weeks post treatment. Spatial learning and memory, several antioxidants and oxidative stress markers were analyzed. Results showed a significant deficit in learning and memory in rats injected with STZ through IP and ICV routes. Glutathione, glutathione/oxidized glutathione, glutathione S-transferase, glutathione peroxidase, glutathione reductase, catalase, superoxide dismutase(SOD)-total, Zn/Cu(SOD), Mn/Fe(SOD) are significantly decreased in IP-STZ and ICV-STZ groups at 1, 3, and 6 weeks after STZ injection. Oxidized glutathione, thiobarbituric acid reactive species, glucose 6-Phosphate dehydrogenase, protein carbonyls, 4-Hydroxynonenal, and 3-Nitrotyrosine are significantly increased in IP-STZ and ICV-STZ groups at 1,3, and 6 weeks after STZ injection. Changes in oxidative stress parameters in ICV-STZ groups are greater than IP-STZ groups. STZ treatment induced cognitive impairments by 3-W and 6-W, and it was significantly correlated with the extent of oxidative damage. In conclusion, STZ administration through ICV route is deleterious in causing early synaptosomal oxidative damage that exacerbated with time and correlated with cognitive impairments. Our data implicate the involvement of oxidative stress as an early feature of sAD and provide insights into the behavioral and biochemical changes over the course of disease development.

Early pathogenesis in rabbit hemorrhagic disease virus 2.

To detail early tissue distribution and innate immune response to rabbit hemorrhagic disease virus 2 (RHDV2), 13 rabbits were orally (Oryctolagus cuniculus) inoculated with liver homogenate made from a feral rabbit that succumbed to RHDV2 during the 2020 outbreak in Oregon, USA. Rabbits were monitored regularly, with euthanasia and collection of tissues and swabs, at 12, 24, 36, 48, 96, and 144 h post inoculation. Livers from these rabbits were positive by RT-rtPCR for presence of the virus. Using RNAscope for viral and replicative intermediates, rabbits had detectable viral genomic RNA at each time point, initially within the gastrointestinal tract, then in the liver by 36 h post inoculation. Also using RNAscope, there were increasing amounts of mRNA coding for TNF-α, IL-6, and IL-1ß within the liver and spleen through 48 h post inoculation. The results of this study aided our understanding of the local innate immune response to RHDV2, as well as aspects of pathogenesis.

1,2,3-Triazolyl-tetrahydropyrimidine Conjugates as Potential Sterol Carrier Protein-2 Inhibitors: Larvicidal Activity against the Malaria Vector Anopheles arabiensis and In Silico Molecular Docking Study.

Alteration of insect growth regulators by the action of inhibitors is becoming an attractive strategy to combat disease-transmitting insects. In the present study, we investigated the larvicidal effect of 1,2,3-triazolyl-pyrimidinone derivatives against the larvae of the mosquito Anopheles arabiensis, a vector of malaria. All compounds demonstrated insecticidal activity against mosquito larvae in a dose-dependent fashion. A preliminary study of the structure-activity relationship indicated that the electron-withdrawing substituent in the para position of the 4-phenyl-pyrimidinone moiety enhanced the molecules' potency. A docking study of these derivatives revealed favorable binding affinity for the sterol carrier protein-2 receptor, a protein present in the intestine of the mosquito larvae. Being effective insecticides against the malaria-transmitting Anopheles arabiensis, 1,2,3-triazole-based pyrimidinones represent a starting point to develop novel inhibitors of insect growth regulators.

Diabetic ketoacidosis in patients with SARS-CoV-2: a systematic review and meta-analysis.

BACKGROUND: One possible reason for increased mortality due to SARS-CoV-2 in patients with diabetes is from the complication of diabetic ketoacidosis (DKA). OBJECTIVES: To re-evaluate the association of SARS-CoV-2 and development of DKA and analyse the demographic and biochemical parameters and the clinical outcomes in COVID-19 patients with DKA. DESIGN: A systematic review and meta-analysis. Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement was followed. METHODS: Electronic databases (Proquest, Medline, Embase, Pubmed, CINAHL, Wiley online library, Scopus and Nature) were searched from 1 December 2019 to 30 June 2021 in the English language using the following keywords alone or in combination: COVID-19 OR SARS-CoV-2 AND diabetic ketoacidosis OR DKA OR ketosis OR ketonemia OR hyperglycaemic emergency OR hyperglycaemic crisis. We included studies in adults and children of all ages in all healthcare settings. Binary logistic regression model was used to explore the effect of various demographic and biochemical parameters variables on patient's final treatment outcome (survival or death). RESULTS: Of the 484 papers that were identified, 68 articles were included in the systematic review and meta-analysis (54 case report, 10 case series, and 4 cohort studies). Studies involving 639 DKA patients with confirmed SARS-CoV-2 [46 (7.2%) were children and 334 (52.3%) were adults] were analyzed. The median or mean patient age ranged from < 1 years to 66 years across studies. Most of the patients (n = 309, 48.3%) had pre-existing type 2 diabetes mellitus. The majority of the patients were male (n = 373, 58.4%) and belonged to Hispanic (n = 156, 24.4%) and black (n = 98, 15.3%) ethnicity. The median random blood glucose level, HbA1c, pH, bicarbonate, and anion gap in all included patients at presentation were 507 mg/dl [IQR 399-638 mg/dl], 11.4% [IQR 9.9-13.5%], 7.16 [IQR 7.00-7.22], 10 mmol/l [IQR 6.9-13 mmol/l], and 24.5 mEq/l [18-29.2 mEq/l]; respectively. Mortality rate was [63/243, 25.9%], with a majority of death in patients of Hispanic ethnicity (n = 17, 27%; p = 0.001). The odd ratios of death were significantly high in patients with pre-existing diabetes mellitus type 2 [OR 5.24, 95% CI 2.07-15.19; p = 0.001], old age (≥ 60 years) [OR 3.29, 95% CI 1.38-7.91; p = 0.007], and male gender [OR 2.61, 95% CI 1.37-5.17; p = 0.004] compared to those who survived. CONCLUSION: DKA is not uncommon in SARS-CoV-2 patients with diabetes mellitus and results in a mortality rate of 25.9%. Mortality key determinants in DKA patients with SARS-CoV-2 infection are individuals with pre-existing diabetes mellitus type 2, older age [≥ 60 years old], male gender, BMI ≥ 30, blood glucose level > 1000 mg/dl, and anion gap ≥ 30 mEq/l.

Objective treatment outcome assessment of a completely customized lingual appliance: A retrospective study.

OBJECTIVE: To assess the outcome quality of subjects treated with a completely customized lingual appliance (CCLA) in a postgraduate university program, using the ABO Objective Grading System (OGS), by testing the null-hypothesis of a significant proportion of post-treatment cases exceeding an adjusted 'exam failure' threshold value of OGS=24. MATERIALS AND METHODS: This retrospective single-arm study included 66 consecutively debonded CCLA cases (m/f 19/47; mean age: 25.1±9 years) treated at Hannover Medical School (MHH, Hannover, Germany). The discrepancy index (DI) was assessed on initial plaster casts. The OGS of the cast-radiograph evaluation was scored for both set-up and post-treatment casts, including the seven components of alignment/rotation, marginal ridges, buccolingual inclination, overjet, occlusal contacts, occlusal relationships and interproximal contacts, to parameterize differences between those. RESULTS: DI score distribution (≥20, <20) was 25 (37.9%)/41 (62.1%) subjects. Mean initial DI was 17.3±8.5. Mean set-up OGS was 10.4±4.4 (min-max: 3-21), mean final OGS was 17.7±5.9 (min-max: 7-33), and the difference 7.3 (post-treatment - set-up) was statistically significant (p<0.0001; 95% CI [5.8, 8.7]). The null-hypothesis was rejected: A statistically significant proportion of the final casts (n=58; 87.8%) scored below OGS=24 by exact binomial test (P<0.0001; 95% CI [77.5%, 94.6%]). The rate of a final OGS score<24 was not significantly different (P=0.98) between both DI (≥20, <20) groups. CONCLUSIONS: The outcome quality of the CCLA treatment in this postgraduate university setting was high and therefore sufficient for a vast majority of treated cases to pass the ABO-OGS clinical examination.

Crystallography, Molecular Modeling, and COX-2 Inhibition Studies on Indolizine Derivatives.

The cyclooxygenase-2 (COX-2) enzyme is an important target for drug discovery and development of novel anti-inflammatory agents. Selective COX-2 inhibitors have the advantage of reduced side-effects, which result from COX-1 inhibition that is usually observed with nonselective COX inhibitors. In this study, the design and synthesis of a new series of 7-methoxy indolizines as bioisostere indomethacin analogues (5a-e) were carried out and evaluated for COX-2 enzyme inhibition. All the compounds showed activity in micromolar ranges, and the compound diethyl 3-(4-cyanobenzoyl)-7-methoxyindolizine-1,2-dicarboxylate (5a) emerged as a promising COX-2 inhibitor with an IC50 of 5.84 µM, as compared to indomethacin (IC50 = 6.84 µM). The molecular modeling study of indolizines indicated that hydrophobic interactions were the major contribution to COX-2 inhibition. The title compound diethyl 3-(4-bromobenzoyl)-7-methoxyindolizine-1,2-dicarboxylate (5c) was subjected for single-crystal X-ray studies, Hirshfeld surface analysis, and energy framework calculations. The X-ray diffraction analysis showed that the molecule (5c) crystallizes in the monoclinic crystal system with space group P 21/n with a = 12.0497(6)Å, b = 17.8324(10)Å, c = 19.6052(11)Å, α = 90.000°, ß = 100.372(1)°, γ = 90.000°, and V = 4143.8(4)Å3. In addition, with the help of Crystal Explorer software program using the B3LYP/6-31G(d, p) basis set, the theoretical calculation of the interaction and graphical representation of energy value was measured in the form of the energy framework in terms of coulombic, dispersion, and total energy.

A comprehensive phytochemical, biological, toxicological and molecular docking evaluation of Suaeda fruticosa (L.) Forssk.: An edible halophyte medicinal plant.

Suaeda fruticosa is an edible medicinal halophyte known for its traditional uses. In this study, methanol and dichloromethane extracts of S. fruticosa were explored for phytochemical, biological and toxicological parameters. Total phenolic and flavonoid constituents were determined by using standard aluminum chloride and Folin-Ciocalteu methods, and UHPLC-MS analysis of methanol extract was performed for tentative identification of secondary metabolites. Different standard methods like DPPH, ABTS, FRAP, CUPRAC, total antioxidant capacity (TAC), and metal chelation assays were utilized to find out the antioxidant potential of extracts. Enzyme inhibition studies of extracts against acetylcholinesterase, butyrylcholinesterase, tyrosinase, α-amylase and, α-glucosidase enzymes were also studied. Likewise, the cytotoxicity was also assessed against MCF-7, MDA-MB-231, and DU-145 cell lines. The higher phenolic and flavonoids contents were observed in methanol extracts which can be correlated to its higher radical scavenging potential. Similarly, 11 different secondary metabolites were tentatively identified by UHPLC profiling. Both the extract showed significant inhibition against all the enzymes except for α-glucosidase. Moreover, docking studies were also performed against the tested enzymes. In the case of cytotoxicity, both the samples were found moderately toxic against the tested cell lines. This plant can be explored further for its potential therapeutic and edible uses.

Essential Oils as Natural Sources of Fragrance Compounds for Cosmetics and Cosmeceuticals.

Fragrance is an integral part of cosmetic products and is often regarded as an overriding factor in the selection of cosmetics among consumers. Fragrances also play a considerable role in masking undesirable smells arising from fatty acids, oils and surfactants that are commonly used in cosmetic formulations. Essential oils are vital assets in the cosmetic industry, as along with imparting pleasant aromas in different products, they are able to act as preservatives and active agents and, simultaneously, offer various benefits to the skin. Moreover, the stimulating demand for natural ingredients has contributed massively to a renewed interest in cosmetic and wellness industries in plant derivatives, especially essential oils. This has led popular cosmetic companies to endorse natural fragrances and opt for minimally processed natural ingredients, given the potentially adverse health risks associated with artificial fragrance chemicals, which are major elements of cosmetics. Among the high-valued essential oils used as fragrances are citrus, lavender, eucalyptus, tea tree and other floral oils, among others, while linalool, geraniol, limonene, citronellol, and citral are much-appreciated fragrance components used in different cosmetics. Thus, this review aimed to highlight the enormous versatility of essential oils as significant sources of natural fragrances in cosmetics and cosmeceuticals. Moreover, a special focus will be laid on the different aspects related to essential oils such as their sources, market demand, chemistry, fragrance classification, aroma profile, authenticity and safety.

New insights into the phytochemical composition, enzyme inhibition and antioxidant properties of desert cotton (Aerva javanica (Bum.f) Shult. -Amaranthaceae).

This study sets out to probe into total bioactive contents, UHPLC-MS secondary metabolites profiling, antioxidant (DPPH, ABTS, FRAP, CUPRAC, phosphomolybdenum and metal chelating) and enzyme inhibitory (acetylcholinesterase- AChE, butyrylcholinesterase- BChE, α-amylase, α glucosidase, and tyrosinase) activities of methanol extract of Aerva javanica, also known as desert cotton or Kapok bush. Aerva javanica contains considerable phenolic (44.79 ± 3.12 mg GAE/g) and flavonoid (28.86 ± 0.12 mg QE/g) contents which tends to correlate with its significant antioxidant potential for ABTS, FRAP and CUPRAC assays with values of 101.41 ± 1.18, 124.10 ± 1.71 and 190.22 ± 5.70 mg TE/g, respectively. The UHPLC-MS analysis identified the presence of 45 phytochemicals belonging to six major groups: phenolic, flavonoids, lignin, terpenes, glycoside and alkaloid. Moreover, the plant extract also showed potent inhibitory action against AChE (3.73 ± 0.22 mg GALAE/g), BChE (3.31 ± 0.19 mg GALAE/g) and tyrosinase (126.05 ± 1.77 mg KAE/g). The observed results suggest A. javanica could be further explored as a natural source of bioactive compounds.

Multidirectional insights into the phytochemical, biological, and multivariate analysis of the famine food plant (Calligonum polygonoides L).: A novel source of bioactive phytocompounds.

Calligonum polygonoides L. also known as famine food plant, is normally consumed in times of food scarcity in India and Pakistan and also used traditionally in the management of common diseases. The present design aims to provide an insight into the medicinal potential of four solvent extracts of C. polygonoides via an assessment of its phytochemical profile, antioxidant and enzyme inhibitory potential. Phytochemical composition was estimated by deducing total bioactive constituents, UHPLC-MS secondary metabolites profile, and HPLC phenolic quantification. Antioxidant potential was determined via six methods (radical scavenging (DPPH and ABTS), reducing power (FRAP and CUPRAC), phosphomolybdenum total antioxidant capacity and metal chelation activity). Enzyme inhibitory potential was assessed against clinical enzymes (acetylcholinesterase -AChE, butyrylcholinesterase -BChE, tyrosinase, and α-amylase). The highest amounts of phenolic contents were found in chloroform extract (76.59 mg GAE/g extract) which may be attributed to its higher radical scavenging, reducing power and tyrosinase inhibition potential. The n-butanol extract containing the maximum amount of flavonoids (55.84 mg RE/g extract) exhibited highest metal chelating capacity. Similarly, the n-hexane extract was found to be most active against AChE (4.65 mg GALAE/g extract), BChE (6.59 mg GALAE/g extract), and α-amylase (0.70 mmol ACAE/g extract) enzymes. Secondary metabolite assessment of the crude methanol extract as determined by UHPLC-MS analysis revealed the presence of 24 (negative ionization mode) and 15 (positive ionization mode) secondary metabolites, with most of them belonging to phenolic, flavonoids, terpene, and alkaloid groups. Moreover, gallic acid and naringenin were the main phenolics quantified by HPLC-PDA analysis in all the tested extracts (except n-butanol extract). PCA statistical analysis was also conducted to establish any possible relationship amongst bioactive contents and biological activities. Overall, the C. polygonoides extracts could be further considered to isolate bioactive enzyme inhibitory and antioxidant natural phytocompounds.

Protective effects of lycopene in cancer, cardiovascular, and neurodegenerative diseases: An update on epidemiological and mechanistic perspectives.

Recent mechanistic and epidemiological studies have provided insights into health benefits of dietary lycopene to decrease the risk and complications associated with several chronic diseases such as cardiovascular diseases (CVD), obesity, type 2 diabetes, cancer, and neurodegenerative disorders. These chronic diseases are primarily associated with oxidative stress-induced systemic and low-grade chronic inflammation. Owing to its potent antioxidant properties, lycopene can potentially alleviate enhanced levels of proinflammatory mediators (e.g., proinflammatory cytokines IL-8, -6, and -1, and oxidized phospholipids) and prevent NF-κB activation by modulating oxidative stress. Moreover, lycopene serves as a precursor for various oxidative cleavage products and metabolites including Apo-8'-, apo-10'-, and apo-12'-lycopenals that can interact with multiple transcription factors (e.g., Nrf2, RARs, RXRs, and PPARs) to overexpress antioxidant and cytoprotective Phase II enzymes and other growth-stimulating proteins (e.g., brain-derived neurotrophic factor (BDNF) for enhanced neuroprotection. These events altogether can protect the body from chronic inflammatory disorders. In the present review, the latest mechanistic development from cell and animal models and results of case-control, cohort, and randomized trials are discussed to support the protective part of lycopene in cancer, CVD, and neurodegenerative disorders. This review focuses on cellular and molecular events involved in protective effects of lycopene. Although molecular and cellular mechanisms involved in health-promoting activities of lycopene have been reported, no detailed mechanistic studies have been published. Hence, future studies should be conducted to elucidate the mechanistic role(s) of lycopene-derived oxidation products in modulating cellular signaling.

Independent 6D quality assurance of stereotactic radiotherapy repositioning on linacs.

PURPOSE: A high level of accuracy while positioning the patient is mandatory for frameless stereotactic radiotherapy (SRT), as large doses in multiple fractions can be delivered near organs at risk. The objective of this study is to propose an end-to-end quality assurance method to verify that submillimetre alignment can be achieved with stereotactic conventional linacs. METHODS: We used a TrueBeam® linear accelerator equipped with a 6DOF robotic couch. The "ISO Cube" phantom was used with a homemade stand designed to generate known translational and rotational offsets. A reference CT scan was performed with straight alignment of the phantom. The procedure introduced 1.6° angular offset for the couch pitch and roll, at various gantry angles. The couch base was also moved between 0° and 270°. We compared the results with the daily machine performance check tests (MPC, Varian). RESULTS: The mean isocentre size, MV and kV imager offsets were found to agree to within 0.1mm, 0.1mm and 0.3mm respectively, and were in close agreement between the methods. For a total four months data collection period, the mean deviation between requested and measured 6DOF couch shifts was 0.6mm and 0.2°. Errors on field size were smaller than 1mm for 97.7% of the 324 data points. CONCLUSION: Results demonstrate that the linac equipped with a 6DOF robotic positioner and CBCT imaging satisfies requirements for SRT. Our methodology, based on a modified Winston-Lutz quality control, allowed us to quantitatively assess end-to-end accuracy of a linac in order to safely deliver SRT.

Comparative secondary metabolites profiling and biological activities of aerial, stem and root parts of Salvadora oleoides decne (Salvadoraceae).

In this study, different parts (aerial, stem and root) of Salvadora oleoides Decne were investigated in order to explore their phytochemical composition and biological potential. The bioactive contents were evaluated by conventional spectrophotometric methods. Additionally, the secondary metabolite compounds were identified by UHPLC-MS analysis. Biological potential was evaluated by determining antioxidant (DPPH, FRAP, and Phosphomolybdenum) and enzyme inhibitory (butrylcholinesterase and lipoxygenase) effects. Higher total bioactive contents were found in methanolic extracts which tend to correlate with higher radical scavenging and reducing potential of these extracts. LC/MS spectrum revealed the presence of 16 different secondary metabolites belonging to terpene, glucoside and sesquiterpenoid dervivatives. Glucocleomin and emotin A were the main compounds present in all three parts. The strongest butrylcholinesterase and lipoxygenase inhibitory activity was observed for root and stem DCM extracts. Demonstrated biological potential of S. oleoides plant can trace a new road map for developing newly designed bioactive pharmaceuticals.

The CHRNA5 Polymorphism (rs16969968) and its Association with Waterpipe Smoking Addiction among Jordanians.

Waterpipe smoking is a form of tobacco use that causes nicotine/tobacco dependence and has become a global health problem. In the current study, the association of rs16969968 SNP in the CHRNA5 gene with waterpipe dependence was investigated. A total of 386 men and women who used a waterpipe to smoke tobacco were recruited and divided into less dependent and more dependent smokers based on their score on the Lebanon Waterpipe Dependence Scale (LWDS). Results showed a significant difference in the distribution of GG, GA, and AA genotypes by waterpipe dependence status (P<0.001). The more dependent group showed a higher frequency of the AA genotype than the less dependent smokers' group (38% versus 23% respectively). In addition, the more dependent smokers exhibited more A allele than less dependent smokers (53% versus 37% respectively, P<0.001). In conclusion, there is an association between the rs16969968 SNP and waterpipe dependence as assessed by the LWDS.

Anti-Tubercular Activity of Substituted 7-Methyl and 7-Formylindolizines and In Silico Study for Prospective Molecular Target Identification.

Novel series of diversely substituted indolizines were designed, synthesized, and evaluated for their in vitro anti-mycobacterial activity against H37Rv and multi-drug-resistant (MDR) strains of Mycobacterium tuberculosis (MTB). Many compounds exhibited significant inhibitory activity against MTB H37Rv strains. Indolizines 2d, 2e, and 4 were also found to be active against MTB clinical isolates with multi-resistance to rifampicin and isoniazid. Indolizine 4 was identified as the most promising anti-mycobacterial agent, displaying minimum inhibitory concentration (MIC) values of 4 and 32 µg/mL against H37Rv and MDR strains, respectively. Furthermore, an in silico study was carried out for prospective molecular target identification and revealed favorable interactions with the target enzymes CYP 121, malate synthase, and DNA GyrB ATPase. None of the potent molecules presented toxicity against peripheral blood mononuclear (PBM) cell lines, demonstrating their potentiality to be used for drug-sensitive and drug-resistant tuberculosis therapy.

Computational, crystallographic studies, cytotoxicity and anti-tubercular activity of substituted 7-methoxy-indolizine analogues.

Indolizines are heteroaromatic compounds, and their synthetic analogues have reportedly showed promising pharmacological properties. In this study, a series of synthetic 7-methoxy-indolizine derivatives were synthesised, characterised and evaluated for in vitro whole-cell anti-tuberculosis (TB) screening against susceptible (H37Rv) and multi-drug-resistant (MDR) strains of Mycobacterium tuberculosis (MTB) using the resazurin microplate assay method. The cytotoxicity was evaluated using the MTT assay. In silico molecular-docking study was conducted for compounds 5a-j against enoyl-[acyl-carrier] protein reductase, a key enzyme of the type II fatty acid synthesis that has attracted much interest for the development of novel anti-TB compounds. Thereafter, molecular dynamic (MD) simulation was undertaken for the most active inhibitors. Compounds 5i and 5j with the methoxy functional group at the meta position of the benzoyl group, which was at the third position of the indolizine nucleus, demonstrated encouraging anti-TB activity against MDR strains of MTB at 16 µg/mL. In silico studies showed binding affinity within the range of 7.07-8.57 kcal/mol, with 5i showing the highest binding affinity. Hydrogen bonding, π-π- interactions, and electrostatic interactions were common with the active site. Most of these interactions occurred with the catalytic amino acids (Pro193, Tyr158, Phe149, and Lys165). MD simulation showed that 5j possessed the highest binding affinity toward the enzyme, according to the two calculation methods (MM/PBSA and MM/GBSA). The single-crystal X-ray studies of compounds 5c and 5d revealed that the molecular arrangements in these two structures were mostly guided by C-H···O hydrogen-bonded dimeric motifs and C-H···N hydrogen bonds, while various secondary interactions (such as π···π and C-H···F) also contributed to crystal formation. Compounds 5a, 5c, 5i, and 5j exhibited no toxicity up to 500 µg/mL. In conclusion, 5i and 5j are promising anti-TB compounds that have shown high affinity based on docking and MD simulation results.

Association of ficolin-2 gene polymorphisms and susceptibility to systemic lupus erythematosus in Egyptian children and adolescents: a multicenter study.

BACKGROUND: Pediatric-onset SLE (pSLE) is a multisystem autoimmune disease. Recently, the ficolin-2 (FCN2) gene has emerged as a potential candidate gene for susceptibility to SLE. OBJECTIVES: The objective of this study was to evaluate the association of the FCN2 gene polymorphisms at positions -986 (G/A), -602 (G/A), -4 (A/G) and SNP C/T (rs3124954) located in intron 1, with susceptibility to pSLE in Egyptian children and adolescents. METHODS: This was a multicenter study of 280 patients diagnosed with pSLE, and 280 well-matched healthy controls. The FCN2 promoter polymorphisms at -986 G/A (rs3124952), -602 G/A (rs3124953), -4 A/G (rs17514136) and SNP C/T (rs3124954) located in intron 1 were genotyped by polymerase chain reaction, while serum ficolin-2 levels were assessed using enzyme-linked immunosorbent assay. RESULTS: The frequencies of the FCN2 GG genotype and G allele at -986 and -602 positions were significantly more represented in patients with pSLE than in controls (p < 0.001). Conversely, the FCN2 AA genotype and A allele at position -4 were more common in patients than in controls (p < 0.001). Moreover, patients carrying the FCN2 GG genotype in -986 position were more likely to develop lupus nephritis (odds ratio: 2.6 (95% confidence interval: 1.4-4.78); p = 0.006). The FCN2 AA genotype at position -4 was also identified as a possible risk factor for lupus nephritis (odds ratio: 3.12 (95% confidence interval: 1.25-7.84); p = 0.024). CONCLUSION: The FCN2 promoter polymorphisms may contribute to susceptibility to pSLE in Egyptian children and adolescents. Moreover, the FCN2 GG genotype at position -986 and AA genotype at position -4 were associated with low serum ficolin-2 levels and may constitute risk factors for lupus nephritis in pSLE.

Multidirectional insights into the biochemical and toxicological properties of Bougainvillea glabra (Choisy.) aerial parts: A functional approach for bioactive compounds.

The current research work was conducted in order to probe into the biochemical and toxicological characterisation of methanol and dichloromethane (DCM) extracts of Bougainvillea glabra (Choisy.) aerial parts. Biological fingerprints were assessed for in vitro antioxidant, key enzyme inhibitory and cytotoxicity potential. Total bioactive contents were determined spectrophotometrically and the secondary metabolite components of methanol extract was assessed by UHPLC mass spectrometric analysis. The antioxidant capabilities were evaluated via six different in vitro antioxidant assays namely DPPH, ABTS (free radical scavenging), FRAP, CUPRAC (reducing antioxidant power), phosphomolybdenum (total antioxidant capacity) and ferrous chelating activity. Inhibition potential against key enzymes urease, α-glucosidase and cholinesterases were also determined. Methanol extract exhibited higher phenolic (24.01 mg GAE/g extract) as well as flavonoid (41.51 mg QE/g extract) contents. Phytochemical profiling of methanol extract identified a total of twenty secondary metabolites and the major compounds belonged to flavonoids, phenolics and alkaloid derivatives. The findings of antioxidant assays revealed the methanol extract to exhibit stronger antioxidant (except phosphomolybdenum) activities. Similarly, the methanol extract showed highest butyrylcholinesterase and urease inhibition. The DCM extract was most active for phosphomolybdenum and α-glucosidase inhibition assays. Moreover, both extracts exhibited significant cytotoxic potential against five (MCF-7, MDA-MB-231, CaSki, DU-145, and SW-480) human carcinoma cell lines with half maximal inhibitory concentration values of 22.09 to 257.2 µg/mL. Results from the present study highlighted the potential of B. glabra aerial extracts to be further explored in an endeavour to discover novel phytotherapeutics as well as functional ingredients.

Influence of age, gender, smoking, diabetes, thyroid and cardiac dysfunctions on cystatin C biomarker / Influencia de edad, género, tabaquismo, diabetes, disfunciones tiroidea y cardíacas en el biomarcador cistatina C

BACKGROUND: Creatinine is the most widely used renal failure biomarker; however, it has a lot of drawbacks. One of the major drawbacks is the blind range (does not increase until 50% of the kidney deteriorates). On the other hand, cystatin C has gained more attention as a promising biomarker due to several advantages over creatinine. Cystatin C levels are elevated as soon as any mild defect in the kidney occurs. Furthermore, cystatin C is influenced by several non-renal diseases which provide an additional prognostic value for this promising biomarker. OBJECTIVES: 1. Study the effects of age, gender and smoking on cystatin C levels to. 2. Challenge the adoption of glomerular filtration rate equations for healthy population. 3. Compare the values generated from different glomerular filtration rate equations. 4. Evaluate the prognostic value of cystatin C for selected non-renal diseases. Methods: Using cross sectional analyses, we established the relationship between cystatin C levels and non-renal predictors. The quantification of cystatin C was performed by high performance liquid chromatographic method, while for creatinine by a colorimetric enzymatic method. Results: In the healthy volunteers the levels of cystatin C were slightly higher in men than in women and in individuals older than 50 years old than those under 50 years old and in smokers than non-smokers, however, statistical data confirmed a non-significant relationship with respect to the aforementioned factors. For the recruited patients suffering from (diabetes, hyper- and hypothyroidism and cardiac dysfunctions) a clear increase in cystatin C levels were observed with the exception of hypothyroidism patients in which a decrease in their cystatin C levels were observed. CONCLUSION: Diabetes, thyroid and cardiac dysfunctions have a clear impact on the levels of cystatin C in human blood, whereas age, gender and smoking habit have no effect. Therefore, cystatin C could be considered as a useful biomarker of the aforementioned diseases, in turn, this requires extra precautions including the evaluation of several clinical conditions by physicians should CC is considered as a renal failure biomarker

ANTECEDENTES: La creatinina es el biomarcador de la insuficiencia renal más utilizado; sin embargo, tiene muchos inconvenientes. Una de las principales desventajas es que los niveles no aumentan hasta que el 50% del riñón se deteriora. Por este motivo, la cistatina C ha ganado atención como biomarcador prometedor, los niveles de cistatina C se elevan tan pronto como aparece un defecto leve en el riñón, lo que permite una detección en estadios previos de deterioro. Además, la cistatina C está influenciada por varias enfermedades no renales que proprcionan un valor pronóstico adicional para este prometedor biomarcador. OBJETIVOS: 1. Estudio de los efectos de edad, género y tabaquismo en los niveles de cistatina C. 2. Verificación de la aplicabilidad de la ecuación de eGFR en poblaciones sanas. 3. Comparación de los valores de eGFR obtenidos mediante tres ecuaciones diferentes. 4. Evaluación de la utilidad de CC como biomarcador temprano de enfermedades diferentes a la insuficiencia renal como las disfunciones tiroidea y cardíaca y la diabetes. Métodos: Usando análisis transversales, establecimos la relación entre los niveles de cistatina C y los predictores no renales. La cuantificación de cistatina C se ha realizado mediante HPLC analítico, mientras que la creatinina se ha cuantificado mediante un método enzimático colorimétrico. RESULTADOS: En los voluntarios sanos, los niveles de cistatina C fueron ligeramente más altos en hombres que en mujeres y en individuos mayores de 50 años que en menores de 50 años y en fumadores que en no fumadores; sin embargo, los datos estadísticos confirmaron una relación no significativa con respecto a los factores antes mencionados. Para los pacientes reclutados que padecen (diabetes, hiper e hipotiroidismo y disfunciones cardíacas) se observó un claro aumento en los niveles de cistatina C, con la excepción de los pacientes con hipotiroidismo, en los que se observó una disminución en sus niveles de cistatina C. CONCLUSIÓN: Las disfunciones tiroideas y cardíacas, así como la diabetes, tienen un impacto claro en los niveles de cistatina C en la sangre humana, mientras que la edad, el género y el tabaquismo tienen un efecto leve. Por lo tanto, cistatina C podría considerarse como un biomarcador de las enfermedades anteriormente citadas. A su vez, esto requiere precauciones adicionales, incluida la evaluación de varias condiciones clínicas por parte de los médicos si se considera que CC es un biomarcador renal