Emerging insights into macrophage extracellular traps in bacterial infections.

Macrophages possess a diverse range of well-defined capabilities and roles as phagocytes, encompassing the regulation of inflammation, facilitation of wound healing, maintenance of tissue homeostasis, and serving as a crucial element in the innate immune response against microbial pathogens. The emergence of extracellular traps is a novel strategy of defense that has been observed in several types of innate immune cells. In response to infection, macrophages are stimulated and produce macrophage extracellular traps (METs), which take the form of net-like structures, filled with strands of DNA and adorned with histones and other cellular proteins. METs not only capture and eliminate microorganisms but also play a role in the development of certain diseases such as inflammation and autoimmune disorders. The primary objective of this study is to examine the latest advancements in METs for tackling bacterial infections. We also delve into the current knowledge and tactics utilized by bacteria to elude or endure the effects of METs. Through this investigation, we hope to shed light on the intricate interactions between bacteria and the host's immune system, particularly in the context of microbicidal effector mechanisms of METs. The continued exploration of METs and their impact on host defense against various pathogens opens up new avenues for understanding and potentially manipulating the immune system's response to infections.

Natural compounds targeting miRNAs: a novel approach in oral cancer therapy.

Oral cancer (OC) is a significant global health issue, with high rates of both mortality and morbidity. Conventional treatments, including surgery, radiation, and chemotherapy, are commonly used, but they often come with serious side effects and may not fully eliminate cancer cells, resulting in recurrence and resistance to treatment. In recent years, natural products derived from plants and other biological sources have gained attention for their potential anticancer properties. These compounds offer advantages such as lower toxicity compared to traditional chemotherapy. Notable natural compounds like quercetin, berberine, curcumin, andrographolide, nimbolide, ovatodiolide, and cucurbitacin B have demonstrated effectiveness in inhibiting OC cell growth by targeting various signaling pathways involved in cancer progression. Recent breakthroughs in molecular biology have highlighted the crucial role of microRNAs (miRNAs) in the development of OC. Targeting dysregulated miRNAs with natural products offers a promising strategy for treating the disease. Natural compounds exert anticancer effects by influencing both altered cellular signaling pathways and miRNA expression profiles. This study aims to explore the role of miRNAs as potential molecular targets in OC and to investigate how natural products may regulate these miRNAs. Additionally, this review will shed light on the therapeutic potential of phytochemicals in modulating miRNA expression and their significance in OC treatment.

Heart failure with reduced ejection fraction and chronic kidney disease: a focus on therapies and interventions.

In heart failure with reduced ejection fraction (HFrEF), the presence of concomitant chronic kidney disease (CKD) predicts poorer cardiovascular outcomes, more aggravated heart failure (HF) status, and higher mortality. Physicians might be reluctant to initiate life-saving anti-HF medications out of fear of worsening renal function and a higher incidence of adverse events. Moreover, international guidelines do not give clear recommendations on managing this subgroup of patients as well as advanced CKD was always an exclusion criterion in most major HF trials. Nevertheless, in this review, we will highlight several recent clinical trials and post-hoc analyses of major trials that showed the safety and efficacy of the different therapies in HFrEF patients with CKD, besides several small-scale cohorts that tested guideline-directed medical therapies in End Stage Kidney Disease (ESKD). Regarding interventions in this subgroup of patients, we will provide up-to-date data on implantable cardioverter defibrillators, cardiac resynchronization therapy, and coronary revascularization, in addition to mitral valve transcatheter edge-to-edge repair and implantable pulmonary artery pressure sensors.

Metabolic profile and gene expression pattern of cytokines and antioxidants markers during different physiological stages in Barki ewes.

BACKGROUND: In livestock, identifying the physiological and reproductive stages is valuable in guiding management decisions related to nutrition, veterinary procedures, and breeding programs. To achieve this goal, a cohort of Barki ewes in this research underwent observation across three pivotal physiological conditions: pre-pregnancy, late pregnancy, and early lactation. Blood samples were collected to investigate the changes in serum metabolic profile as well as gene expression pattern of cytokines and antioxidants markers during these stages. RESULTS: Our results showed that during late pregnancy, there was a significant (P < 0.05) increase in red blood cells (11.9 ± 0.5 1012/L), hemoglobin (10.8 ± 0.4 g/dl) and neutrophils count (7 ± 0.1 109/L) with significant decrease (P < 0.05) of total white blood cell count (9.1 ± 0.05 109/L). The packed cell volume (%) and monocyte count showed a significant (P < 0.05) decrease during both late pregnancy and early lactation stages. The serum concentrations of glucose, cholesterol, GSH, GPx, SOD and catalase displayed significant (P < 0.05) decrease during late pregnancy and early-lactation. Notably, during late pregnancy, there was a significant (P < 0.05) increase in the serum concentrations of albumin, globulin, urea, IGF-1, and malondialdehyde with significant decrease (P < 0.05) of total protein (4.9 ± 0.08 g/dl). Additionally, during early lactation, there was a significant (P < 0.05) increase in the serum levels of non-esterified fatty acids, triiodothyronine (T3), and thyroxin (T4). The gene expression profiles of cytokines (IL-4, IL-6, IL-8, and NFKB) were decreased in the ewes during late pregnancy compared to pre-pregnant and early lactation stages. In addition, the expression profile of antioxidant genes (SOD, CAT, GPX, and Nrf2) was significantly upsurged in the non-pregnant ewes compared to late pregnancy and early lactation ones. CONCLUSIONS: The results concluded that different physiological status significantly affects the blood metabolic profile and gene expression pattern in Barki sheep. Our findings can be helpful in monitoring animal health and applying in breeding programs of Barki sheep under harsh environmental conditions.

Partial (incomplete) removal of granulation tissue using modified minimally invasive surgical technique in treatment of infrabony defects (randomized control clinical trial).

AIM: This study aims to compare the clinical and radiographic outcomes after complete versus incomplete removal of granulation tissue (GT) during modified minimally invasive surgical technique (M-MIST) for management of periodontitis patients with deep pockets associated with infra-bony defects. METHODOLOGY: Ten patients with a total of 14 deep non-resolving pockets (≥ 5 mm) associated with a vertical infra-bony defect were recruited for this study. They were randomized into 2 groups; a test group with incomplete removal of GT and a control group with complete removal of GT. Clinical parameters of clinical attachment level (CAL), residual probing depth (rPD) and buccal recession (Rec.) were recorded every 3 months. Radiographic periapicals were taken at baseline, 6 and 9 months. The significance level was set to 0.05. RESULTS: None of the results showed statistical significance between the 2 groups (p > 0.05). The test group showed less CAL gain (2 ± 0.87 mm, p = 0.062), more reduction in rPD (3.1 ± 0.96 mm, p = 0.017) and more recession (0.857 ± 0.26 mm, p = 0.017) than control group CAL gain (2.4 ± 0.58 mm, p = 0.009), rPD reduction (2.9 ± 0.3 mm, p = 0.001) and recession (0.5 ± 0.34 mm, p = 0.203) respectively. Control group had linear reduction in depth defect (DD) (0.68 ± 0.287, p = 0.064) compared to an increase in DD in test group (-0.59 ± 0.5, p = 0.914). CONCLUSIONS: No statistical significance were observed in healing parameters between complete removal of GT in M-MIST and incomplete (partial) removal of GT of deep pockets with infra-bony defects both clinically and radiographically. Further studies with larger samples are needed to confirm the results.

The Dual Roles of Activating Transcription Factor 3 (ATF3) in Inflammation, Apoptosis, Ferroptosis, and Pathogen Infection Responses.

Transcription factors are pivotal regulators in the cellular life process. Activating transcription factor 3 (ATF3), a member of the ATF/CREB (cAMP response element-binding protein) family, plays a crucial role as cells respond to various stresses and damage. As a transcription factor, ATF3 significantly influences signal transduction regulation, orchestrating a variety of signaling pathways, including apoptosis, ferroptosis, and cellular differentiation. In addition, ATF3 serves as an essential link between inflammation, oxidative stress, and immune responses. This review summarizes the recent advances in research on ATF3 activation and its role in regulating inflammatory responses, cell apoptosis, and ferroptosis while exploring the dual functions of ATF3 in these processes. Additionally, this article discusses the role of ATF3 in diseases related to pathogenic microbial infections. Our review may be helpful to better understand the role of ATF3 in cellular responses and disease progression, thus promoting advancements in clinical treatments for inflammation and oxidative stress-related diseases.

Clinical and biochemical assessment of the soft tissue response to titanium stock versus custom composite resin healing abutments.

STATEMENT OF PROBLEM: Custom healing abutments made of flowable composite resin have gained popularity, although the soft tissue response to composite resin has not been adequately studied. PURPOSE: The purpose of this randomized controlled clinical trial was to evaluate the soft tissue response to titanium stock healing abutments and custom composite resin healing abutments by assessing clinical indices and the level of matrix metalloproteinase-8 (MMP-8) in the peri-implant crevicular fluid (PICF). MATERIAL AND METHODS: A randomized controlled clinical trial was performed on 42 osseointegrated implants. The implants were divided into 2 groups: a test group comprising 21 custom composite resin healing abutments that were attached to the implants at second stage surgery and a control group comprising 21 stock titanium healing abutments. Plaque index (PL), bleeding on probing (BOP), modified gingival index (MGI), and level of MMP8 were measured at the second and fourth week after second stage surgery. Peri-implant crevicular fluid was collected by paper points at each follow-up, and the level of MMP8 was measured by an enzyme-linked immunosorbent assay kit. For statistical analysis, group comparisons used the Mann-Whitney U test, and comparisons within each group at 2 and 4 weeks used the Wilcoxon Sign Rank test. Group differences were analyzed with the Fisher exact test, and the McNemar test was used to compare percentages at 2 and 4 weeks. All tests were two-tailed (α=.05). RESULTS: For the PI, no statistically significant differences were found within groups or between groups (P>.05). Bleeding on probing was positive in 14.3% of titanium abutments versus 20% of composite resin abutments at 4 weeks, with no significant difference between groups (P>.05). Similarly, the mean MGI was 0.38 ±0.5 in the control group while it was 0.4 ±0.5 in the test group, with no significant differences between groups (P>.05). The MMP8 level at 2 weeks was 11.1 ±8.65 and 13.11 ±9.29 for the control and test groups, respectively while it was 16.35 ±8.31 and 19.80 ±8.44 at 4 weeks, showing a statistically significant increase within groups (P<.05). No significant difference between groups was detected at either follow-up time point regarding MMP8 level (P>.05). CONCLUSIONS: The clinical and biochemical soft tissue response to composite resin healing abutments and titanium stock healing abutments were comparable, suggesting the clinical safety of custom composite resin healing abutments.

Natural sesquiterpene zingiberene exerts ameliorative effects on growth of glioblastoma cells by instigating ROS mediated apoptosis.

Glioblastoma multiforme is the most aggressive and invasive primary brain tumor in adults and its prognosis and survival rate remain poor. Despite substantial improvements in therapy, the 5-year survival rate of glioblastoma patients remains low. Sesquiterpenes have previously been found to be effective in inhibiting the proliferation and growth of breast, gastric and lung cancer cells. Owing to their efficacy, sesquiterpenes have been used in various clinical trials. In the present study, we investigated the anticancer efficacy of a well-known sesquiterpene, Zingiberene, isolated from Zingiber officinale in C6 glioblastoma cells. Zingiberene suppresses the growth and proliferation of C6 cells. Upon treatment of C6 cells with zingiberene, nuclear fragmentation and ROS were qualitatively enhanced compared to untreated control cells. The levels of caspase-3 were also significantly reduced (p<0.01), with a concomitant decline in the mRNA expression of Bax and Bcl-2. On the basis of molecular docking studies, Zingiberene demonstrated good binding energy score of -6.8 and -5.5 Kcal/mol towards Bax and Bcl-2 proteins, respectively. Based on these observations, it was inferred that zingiberene has potential as a plausible therapeutic agent against glioblastoma cells. Detailed mechanistic studies are needed to substantiate and establish the anticancer effects of zingiberene against glioblastoma cells.

LppA is a novel plasminogen receptor of Mycoplasma bovis that contributes to adhesion by binding the host extracellular matrix and Annexin A2.

Mycoplasma bovis is responsible for various inflammatory diseases in cattle. The prevention and control of M. bovis are complicated by the absence of effective vaccines and the emergence of multidrug-resistant strains, resulting in substantial economic losses worldwide in the cattle industry. Lipoproteins, vital components of the Mycoplasmas cell membrane, are deemed potent antigens for eliciting immune responses in the host upon infection. However, the functions of lipoproteins in M. bovis remain underexplored due to their low sequence similarity with those of other bacteria and the scarcity of genetic manipulation tools for M. bovis. In this study, the lipoprotein LppA was identified in all examined M. bovis strains. Utilizing immunoelectron microscopy and Western blotting, it was observed that LppA localizes to the surface membrane. Recombinant LppA demonstrated dose-dependent adherence to the membrane of embryonic bovine lung (EBL) cells, and this adhesion was inhibited by anti-LppA serum. In vitro binding assays confirmed LppA's ability to associate with fibronectin, collagen IV, laminin, vitronectin, plasminogen, and tPA, thereby facilitating the conversion of plasminogen to plasmin. Moreover, LppA was found to bind and enhance the accumulation of Annexin A2 (ANXA2) on the cell membrane. Disrupting LppA in M. bovis significantly diminished the bacterium's capacity to adhere to EBL cells, underscoring LppA's function as a bacterial adhesin. In conclusion, LppA emerges as a novel adhesion protein that interacts with multiple host extracellular matrix proteins and ANXA2, playing a crucial role in M. bovis's adherence to host cells and dissemination. These insights substantially deepen our comprehension of the molecular pathogenesis of M. bovis.

Drug complexes: Perspective from Academic Research and Pharmaceutical Market.

Despite numerous research efforts, drug delivery through the oral route remains a major challenge to formulation scientists. The oral delivery of drugs poses a significant challenge because more than 40% of new chemical entities are practically insoluble in water. Low aqueous solubility is the main problem encountered during the formulation development of new actives and for generic development. A complexation approach has been widely investigated to address this issue, which subsequently improves the bioavailability of these drugs. This review discusses the various types of complexes such as metal complex (drug-metal ion), organic molecules (drug-caffeine or drug-hydrophilic polymer), inclusion complex (drug-cyclodextrin), and pharmacosomes (drug-phospholipids) that improves the aqueous solubility, dissolution, and permeability of the drug along with the numerous case studies reported in the literature. Besides improving solubility, drug-complexation provides versatile functions like improving stability, reducing the toxicity of drugs, increasing or decreasing the dissolution rate, and enhancing bioavailability and biodistribution. Apart, various methods to predict the stoichiometric ratio of reactants and the stability of the developed complex are discussed.

Outcomes of bio-esthetic single implant-supported restorations after peri-implant soft tissue conditioning with two prosthetic techniques: A 1-year randomized clinical trial.

STATEMENT OF PROBLEM: Providing a definitive restoration with an emergence profile matching that of the contralateral or extracted tooth should result in an esthetic peri-implant soft tissue contour. Whether a custom healing abutment improves the outcome of a bio-copied definitive restoration compared with a stock abutment is unclear. PURPOSE: The purpose of this 1-year randomized clinical trial was to evaluate the peri-implant soft and hard tissues related to bio-esthetic single implant-supported restorations having a contralateral tooth-matching restorative emergence profile after peri-implant soft tissue conditioning with either custom or stock healing abutment for patients indicated for immediate implant placement. MATERIAL AND METHODS: Twenty-four participants indicated for immediate implant placement in the maxillary esthetic zone received bio-esthetic single implant-supported restorations after peri-implant soft tissue conditioning with either a custom healing abutment (n=12) or a stock healing abutment (n=12). The pink and white esthetic score (PES-WES) was evaluated 6 and 12 months after implant placement. Peri-implant bone changes were measured with cone beam computed tomography (CBCT) scans at the same intervals. RESULTS: The PES-WES showed significant difference between the 2 groups at 6 and 12 months. The CBCT scans did not show significant difference between the 2 groups. CONCLUSIONS: The use of the bio-esthetic concept for immediate single implant placement achieved successful esthetic restorations after conditioning the peri-implant tissues using either custom or stock healing abutments. However, the use of custom healing abutments was associated with higher PES-WES values in comparison with the use of stock healing abutments.

Hard Gelatin Capsules Containing Hot Melt Extruded Solid Crystal Suspension of Carbamazepine for improving dissolution: Preparation and In vitro Evaluation.

Aqueous solubility is one of the key parameters for achieving the desired drug concentration in systemic circulation for better therapeutic outcomes. Carbamazepine (CBZ) is practically insoluble in water, is a BCS class II drug, and exhibits dissolution-dependent oral bioavailability. This study explored a novel application of hot-melt extrusion in the manufacture and development of a thermodynamically stable solid crystal suspension (SCS) to improve the solubility and dissolution rate of CBZ. The SCSs were prepared using sugar alcohols, such as mannitol or xylitol, as crystalline carriers. The drug-sugar blend was processed by hot melt extrusion up to 40 % (w/w) drug loading. The extruded SCS was evaluated for drug content, saturation solubility, differential scanning calorimetry (DSC), Fourier-transform infrared (FTIR) spectroscopy, powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), in vitro release, and stability studies. The physicochemical characterization revealed the highly crystalline existence of pure drug, pure carriers, and extruded SCS. FTIR analysis did not reveal any physical or chemical incompatibilities between the drug and sugar alcohols and showed a homogeneous CBZ distribution within respective crystalline carriers. The SEM micrographs of the solidified SCS revealed the presence of approximately 100 µm crystalline agglomerates. In vitro dissolution and solubility studies showed that the CBZ dissolution rate and solubility were improved significantly from both crystalline carriers for all tested drug loads. The SCSs showed no significant changes in drug content, in vitro release profiles, and thermal characteristics over 3 months of storage at accelerated stability conditions (40±2°C/75±5% RH). As a result, it can be inferred that the SCS strategy can be employed as a contemporary alternative technique to improve the dissolution rate of BCS class II drugs via HME technology.

Curcumin/Fusidic Acid Bitherapy Loaded Mixed Micellar Nanogel for Acne Vulgaris Treatment: In Vitro and In Vivo Studies.

The combination of herbal drugs with a topical antibacterial for managing a chronic disease like acne vulgaris has emerged lately to settle side effects and bacterial multidrug resistance. Mixed micelles (MMs) incorporated into nanogel were explored for hybrid delivery of curcumin (Cur) and fusidic acid (FA) combination presenting a multi-strategic treatment. Curcumin-fusidic acid-loaded mixed micelles (Cur-FA-MMs) were assessed for size, surface charge, compatibility, in vitro release, and encapsulation. The selected formula was further loaded into nanogel and investigated for viscosity, ex vivo permeation, and in vivo potential. Cur-FA-MMs exhibited uniform nanosized spherical morphology, and negative surface charge affording high encapsulation for both drugs with a biphasic in vitro release over a period of 48h and good colloidal stability. The attained Cur-FA-MM-loaded nanogel had optimum viscosity with remarkable permeation coefficient values nearly 2-fold that related to plain nanogel. The pharmacodynamic effect of Cur on FA was pronounced by the significant improvement of the skin's degree of inflammation, epidermal hypertrophy, and congestion in animals treated with Cur-FA-MM-loaded nanogel. In conclusion, micellar nanogel could enable the progressive effect of Cur (an antioxidant with reported antibiotic activity) on FA (antibiotic) and decrease the risk of emerging antibiotic resistance by enhancing the solubility and permeation of Cur.

Comparison between platelet rich fibrin as space filling material versus xenograft and alloplastic bone grafting materials in immediate implant placement: a randomized clinical trial.

BACKGROUND: This study aimed to compare the efficacy of different gap filling materials in immediate implant in anterior and premolar regions of maxilla. MATERIALS AND METHODS: Thirty-six implants were inserted in patients seeking for replacement of non-restorable maxillary anterior and premolar teeth (esthetic zone) by immediate implant. Patients were randomly distributed into three equal groups, twelve implants in each group. Group 1 received Platelet Rich Fibrin (PRF) into the jumping distance, Group 2 received Xenograft into the jumping distance and Group 3 received Alloplastic bone grafting material into the jumping distance. Implant stability by measuring the changes in Resonance Frequency Analysis (RFA), peri-implant pocket depth, marginal bone loss and changes in buccal bone thickness were evaluated during follow up periods. All the clinical and radiographic data were subjected to statistical analysis by One Way ANOVA test and the Post Hoc Tukey test. RESULTS: This study involved 19 female patients and 17 male patients who received 36 dental implants. There was no significant difference between the study groups regarding implant stability, peri-implant pocket depth and palatal bone loss, while there was a significant difference between PRF Group (Group 1) and the other Groups regarding buccal bone loss and changes in buccal bone thickness. CONCLUSION: PRF can be used as a gap filling material in conjunction with immediate implant placement, but other bone grafting materials give superior result regarding buccal bone loss and changes in buccal bone thickness. TRIAL REGISTRATION: The study was listed on www. CLINICALTRIALS: gov with registration number (NCT05878392) on 26/05/2023. The Institutional Review Board (IRB) of the Faculty of Dentistry, Mansoura University, Mansoura, Egypt, approved the current study in compliance with the seventh revision of the Helsinki Declaration in 2013 (A0103023OS).

Comparison between Two Design Concepts of Four Implants Placement Used to Support Telescopic Mandibular Overdenture: A Prospective Study of Implant Marginal Bone Height Changes.

AIM: The aim of this present study was to compare two placement designs of four implants used to support a telescopic mandibular overdenture regarding the marginal bone height changes. MATERIALS AND METHODS: Each patient received four implants. Two anterior implants were installed vertically in the canine area. Patients were randomized into two groups according to the direction of posterior implants installed in the premolar area. Group I: where the implants were installed vertically parallel to the anterior implants and group II: where the implants were installed 30º distally. The implants were delayed loaded with a telescopic mandibular overdenture. The implant's marginal bone changes were evaluated after 6 and 12 months of overdenture insertion. RESULTS: Mean marginal bone loss of anterior implants showed a statistically significant difference between both groups. The vertically parallel posterior implants in group I showed statistically significant higher marginal bone loss than posterior implants in group II after follow-up periods. The 30º distally tilted posterior implants maintained the implant marginal bone after 12 months of overdenture insertion. CONCLUSION: Rehabilitation of the edentulous mandible with telescopic overdenture supported by four parallel implants is a promising successful treatment option. CLINICAL SIGNIFICANCE: Tilting the posterior implants will improve the anteroposterior spread that in turn increases the support and the survival rate of the implants. Also, using this technique gives us an opportunity to use fewer implants.

Global identification of quantitative trait loci and candidate genes for cold stress and chilling acclimation in rice through GWAS and RNA-seq.

MAIN CONCLUSION: Associated analysis of GWAS with RNA-seq had detected candidate genes responsible for cold stress and chilling acclimation in rice. Haplotypes of two candidate genes and geographic distribution were analyzed. To explore new candidate genes and genetic resources for cold tolerance improvement in rice, genome-wide association study (GWAS) mapping experiments with 351 rice core germplasms was performed for three traits (survival rate, shoot length and chlorophyll content) under three temperature conditions (normal temperature, cold stress and chilling acclimation), yielding a total of 134 QTLs, of which 54, 59 and 21 QTLs were responsible for normal temperature, cold stress and chilling acclimation conditions, respectively. Integrated analysis of significant SNPs in 134 QTLs further identified 116 QTLs for three temperature treatments, 53, 43 and 18 QTLs responsible for normal temperature, cold stress and chilling acclimation, respectively, and 2 QTLs were responsible for both cold stress and chilling acclimation. Matching differentially expressed genes from RNA-seq to 43 and 18 QTLs for cold stress and chilling acclimation, we identified 69 and 44 trait-associated candidate genes, respectively, to be classified into six and five groups, particularly involved in metabolisms, reactive oxygen species scavenging and hormone signaling. Interestingly, two candidate genes LOC_Os01g04814, encoding a vacuolar protein sorting-associating protein 4B, and LOC_Os01g48440, encoding glycosyltransferase family 43 protein, showed the highest expression levels under chilling acclimation. Haplotype analysis revealed that both genes had a distinctive differentiation with subpopulation. Haplotypes of both genes with more japonica accessions have higher latitude distribution and higher chilling tolerance than the chilling sensitive indica accessions. These findings reveal the new insight into the molecular mechanism and candidate genes for cold stress and chilling acclimation in rice.

Therapeutic Properties of Highly Selective ß-blockers With or Without Additional Vasodilator Properties: Focus on Bisoprolol and Nebivolol in Patients With Cardiovascular Disease.

Bisoprolol and nebivolol are highly selective ß1-adrenoceptor antagonists, with clinical indications in many countries within the management of heart failure with reduced left ventricular ejection fraction (HFrEF), ischaemic heart disease (IHD), and hypertension. Nebivolol has additional vasodilator actions, related to enhanced release of NO in the vascular wall. In principle, this additional mechanism compared with bisoprolol might lead to more potent vasodilatation, which in turn might influence the effectiveness of nebivolol in the management of HFrEF, IHD and hypertension. In this article, we review the therapeutic properties of bisoprolol and nebivolol, as representatives of "second generation" and "third generation" ß-blockers, respectively. Although head-to-head trials are largely lacking, there is no clear indication from published studies of an additional effect of nebivolol on clinical outcomes in patients with HFrEF or the magnitude of reductions of BP in patients with hypertension.

Nutritional value of commercial broiler feed supplemented with olive mill waste fermented with probiotic Rhizopus oryzae strains.

AIMS: The changes in chemical composition and metabolizable energy (ME) of both olive mill waste (OMW) upon fermentation by three potential probiotic Rhizopus oryzae strains and commercial feed (CF) upon its supplementation by fermented olive mill waste (FOMW) were investigated. The objective was to test whether there will be an enhancement in the nutritional value of OMW after fermentation and/or commercial broiler feed upon supplementation by potentially probiotic filamentous fungi. METHODS AND RESULTS: A three Rhizopus oryzae strains (92/1, 236/2 and 284) isolated from agricultural soil that were proven to have good probiotic properties (non-toxic, antimicrobial activity, antioxidant capacity and gastrointestinal tolerance) were used to ferment OMW, then the chemical composition was analysed after 7 and 14 days of fermentation. The FOMW with the R. oryzae 284 strain, which gave the best results, was added to a commercial broiler feed at 20%, 30% and 40% supplementation ratios. Then proximal analyses were done to compare non-supplemented with supplemented CF. Chemical analyses included dry weight, crude protein, crude fats, crude fibres, crude ash, sugars and starch, and then ME was calculated from the given values. CONCLUSIONS: Compared to non-fermented OMW, the best results were obtained by the R. oryzae 284 strain allowing an increase in crude protein content by 23.4% after 7 days of fermentation, a decrease in crude fibre content by 9.8% after 14 days of fermentation and an increase in ME by 3.6% after 7 days of fermentation. Compared to non-supplemented CF, the ME changes of 20%, 30% and 40% supplementation increased by 8.38%, 2.83% and decreased by 4.27%, respectively. SIGNIFICANCE AND IMPACT OF THE STUDY: FOMW can be incorporated into broiler feed rations until 30% without causing any decrease in metabolizable energy. It can be a cheaper alternative with promising productivity and chicken health improvements.

A comparative study between ciclosporine A eye drop (2%) and tacrolimus eye ointment (0.03%) in management of children with refractory vernal keratoconjunctivitis.

PURPOSE: To compare the effects of ciclosporine A (2%) eye drop and tacrolimus (0.03%) eye ointment on children with vernal keratoconjunctivitis (VKC) who were not responding to corticosteroid eye drops. METHODS: A prospective comparative study was carried out on children who were diagnosed with refractory VKC at the ophthalmology clinic in Benha University, Delta area, Egypt, during the period from October 2019 to February 2020. RESULTS: Fifty-nine patients completed this study. Regarding the individual symptom score, redness, burning, photophobia, and foreign body sensation were significantly reduced in the tacrolimus group compared to those in the ciclosporine A group during the 1st week (p < 0.05). Moreover, the tacrolimus group showed a statistically significant reduction in burning and foreign body sensation at the 4th week (both p = 0.032), and in redness and burning sensation at the 12th week compared to those in the ciclosporine A group (p = 0.005 and 0.048, respectively). The tacrolimus group showed significantly lower mean scores for tarsal conjunctival papillary hypertrophy at the 1st week and 12th week (p = 0.037 and 0.046, respectively), and for punctate erosion and cobblestone papillae at the 1st week (p = 0.029 and 0.037, respectively) than the ciclosporine group. Failure of treatment was observed in 6 patients (19.35%) in the ciclosporine A group and in 5 patients (17.85%) in the tacrolimus group. No serious side effects were detected in any group. CONCLUSION: A higher reduction in inflammatory symptoms and signs as well as compliance with tacrolimus 0.03% eye ointment than with ciclosporine A 2% eye drops was observed. Moreover, long-term medication for refractory cases is needed to control inflammation. Overall, our finding suggested that ciclosporine A eye drops and tacrolimus eye ointment could be considered as corticosteroid-sparing drugs in the management of children with refractory VKC.

Quercetin and naringenin abate diethylnitrosamine/acetylaminofluorene-induced hepatocarcinogenesis in Wistar rats: the roles of oxidative stress, inflammation and cell apoptosis.

This study was designed to assess the preventive effects and to suggest the probable mechanisms of action of quercetin and naringein in diethylnitrosamine (DEN)/2-acetylaminofluorene (2AAF)-induced hepatocarcinogenesis in Wistar male rats. The chemical-induction of hepatocarcinogenesis was performed by injection of DEN intraperitoneally at 150 mg/kg body weight (b.w.) twice/week for two weeks, followed by oral administration of 2AAF at 20 mg/kg body weight (b.w.) 4 times/week for 3 weeks. The DEN/2AAF-administered rats were co-treated with quercetin and naringenin at dose level of 10 mg/kg b. w. by oral gavage for 20 weeks. The treatment of DEN/2AAF-administered rats with quercetin and naringenin significantly prevented the elevations in serum levels of liver function indicators (ALT, AST, ALP, γ-GT, total bilirubin and albumin) and liver tumor biomarkers including AFP, CEA and CA19.9. The cancerous histological lesions and inflammatory cells infiltration in liver of DEN/2AAF-administered rats were remarkably suppressed by treatments with quercetin and naringenin. The hepatic oxidative stress markers including NO level and lipid peroxidation significantly decreased while the SOD, GPx and CAT activities and GSH content significantly increased in DEN/2AAF-administered rats treated with quercetin and naringenin when compared to DEN/2AFF-administered control rats. Furthermore, the lowered mRNA expression of liver IL-4, P53 and Bcl-2 in of DEN/2AAF-administered rats were significantly counteracted by treatment with quercetin and naringenin. Taken together, our results demonstrate that quercetin and naringenin may abate hepatocarcinogenesis via enhancement of anti-inflammatory, anti-oxidant and apoptotic actions.