Overall survival from tebentafusp versus nivolumab plus ipilimumab in first-line metastatic uveal melanoma: a propensity score-weighted analysis.

BACKGROUND: Tebentafusp demonstrated a superior overall survival (OS) benefit [hazard ratio (HR) 0.51] compared to investigator's choice (82% pembrolizumab) in a randomized, phase III trial (IMCgp100-202; N = 378) in untreated metastatic uveal melanoma (mUM). The 1-year OS rates for tebentafusp and pembrolizumab were 73% and 59%, respectively. In the single-arm GEM1402 (N = 52), the 1-year OS rate for nivolumab plus ipilimumab (N+I) in mUM was 52%. Due to limitations in conducting randomized trials in mUM, we compared OS on tebentafusp or pembrolizumab (IMCgp100-202) to N+I (GEM1402) in untreated mUM using propensity scoring methods. PATIENTS AND METHODS: Analyses were adjusted using propensity score-based inverse probability of treatment weighting (IPTW), balancing age, sex, baseline lactate dehydrogenase (LDH), baseline alkaline phosphatase, disease location, Eastern Cooperative Oncology Group status, and time from primary diagnosis to metastasis. OS was assessed using IPT-weighted Kaplan-Meier and Cox proportional hazard models. Sensitivity analyses using alternative missing data and weights methods were conducted. RESULTS: The primary IPTW analysis included 240 of 252 patients randomized to tebentafusp from IMCgp100-202 and 45 of 52 N+I-treated patients from GEM-1402. Key baseline covariates, including LDH, were generally well balanced before weighting. The IPTW-adjusted OS favored tebentafusp, HR 0.52 [95% confidence interval (CI) 0.35-0.78]; 1-year OS was 73% for tebentafusp versus 50% for N+I. Sensitivity analyses showed consistent superior OS for tebentafusp with all IPTW HRs ≤0.61. IPTW analysis of pembrolizumab versus N+I showed no significant difference in OS (HR 0.72; 95% CI 0.50-1.06). CONCLUSIONS: Tebentafusp was previously shown to provide an OS benefit compared to checkpoint inhibitors or chemotherapy in untreated mUM. Propensity score analysis demonstrated a similar OS benefit for tebentafusp compared with N+I. These data further support tebentafusp as the standard of care in previously untreated human leukocyte antigen (HLA)-A∗02:01+ adult patients with mUM.

Gas Chromatography-Mass Spectrometry Chemical Profiling of Commiphora myrrha Resin Extracts and Evaluation of Larvicidal, Antioxidant, and Cytotoxic Activities.

Plant extracts and essential oils can be alternative environmentally friendly agents to combat pathogenic microbes and malaria vectors. Myrrh is an aromatic oligum resin that is extracted from the stem of Commiphora spp. It is used in medicine as an insecticide, cytotoxic, and aromatic. The current study assessed the effect of Commiphora myrrha resin extracts on the biological potency of the third larval stage of Aedes aegypti, as well as its antioxidant and cytotoxic properties against two types of tumor cells (HepG-2 and Hela cell lines). It also used GC-MS to determine the chemical composition of the C. myrrha resin extracts. Fifty components from the extracted plant were tentatively identified using the GC-MS method, with curzerene (33.57%) typically listed as the primary ingredient, but other compounds also make up a significant portion of the mixture, including 1-Methoxy-3,4,5,7-tetramethylnaphthalene (15.50%), ß-Elemene (5.80%), 2-Methoxyfuranodiene (5.42%), 2-Isopropyl-4,7-Dimethyl-1-Naphthol (4.71%), and germacrene B (4.35%). The resin extracts obtained from C. myrrha exhibited significant efficacy in DPPH antioxidant activity, as evidenced by an IC50 value of 26.86 mg/L and a radical scavenging activity percentage of 75.06%. The 50% methanol extract derived from C. myrrha resins exhibited heightened potential for anticancer activity. It demonstrated substantial cytotoxicity against HepG-2 and Hela cells, with IC50 values of 39.73 and 29.41 µg mL-1, respectively. Notably, the extract showed non-cytotoxic activity against WI-38 normal cells, with an IC50 value exceeding 100 µg mL-1. Moreover, the selectivity index for HepG-2 cancer cells (2.52) was lower compared to Hela cancer cells (3.40). Additionally, MeOH resin extracts were more efficient against the different growth stages of the mosquito A. aegypti, with lower LC50, LC90, and LC95 values of 251.83, 923.76, and 1293.35 mg/L, respectively. In comparison to untreated groups (1454 eggs/10 females), the average daily number of eggs deposited (424 eggs/L) decreases at higher doses (1000 mg/L). Finally, we advise continued study into the possible use of C. myrrha resins against additional pests that have medical and veterinary value, and novel chemicals from this extract should be isolated and purified for use in medicines.

Exclusive Solvent-Controlled Regioselective Catalytic Synthesis of Potentially Bioactive Imidazolidineiminodithiones: NMR Analysis, Computational Studies and X-ray Crystal Structures.

Herein, we describe the first consistent regiospecific reaction of isothiocyanates with a variety of substituted N-arylcyanothioformamides in a 1:1 molar ratio to generate a series of imidazolidineiminodithiones decorated with a multitude of functional groups on both aromatic rings. The reaction is carried out at room temperature using a 20 mol% catalytic amount of triethylamine with DMF as the solvent to selectively form the mentioned products with exclusive regioselectivity. The methodology features wide substrate scope, no requirement for chromatography, and good to high reaction yields. The products were isolated by simple ether/brine extraction and the structures were verified by multinuclear NMR spectroscopy and high accuracy mass measurements. The first conclusive molecular structure elucidation of the observed regioisomer was established by single-crystal X-ray diffraction analysis. Likewise, the tautomer of the N-arylcyanothioformamide reactant was proven by X-ray diffraction analysis. Density functional theory computations at the B3LYP-D4/def2-TZVP level in implicit DMF solvent were conducted to support the noted regiochemical outcome and proposed mechanism.

Estrogen Attenuates Diethylnitrosamine-Induced Hepatocellular Carcinoma in Female Rats via Modulation of Estrogen Receptor/FASN/CD36/IL-6 Axis.

This study was designed to evaluate the potential protective impact of estrogen and estrogen receptor against diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) in rats. The levels of liver injury serum biomarkers, liver content of interleukin-6 (IL-6), relative liver weight and distortion of liver histological pictures were significantly increased in ovariectomized (OVX) rats and SHAM rats that received DEN alone and were further exaggerated when DEN was combined with fulvestrant (F) compared to non-DEN treated rats. The OVX rats showed higher insults than SHAM rats. The tapering impact on these parameters was clear in OVX rats that received estradiol benzoate (EB), silymarin (S) or orlistat (ORS). The immunohistochemistry and/or Western blot analysis of liver tissues showed a prominent increase in fatty acid synthase (FASN) and cluster of differentiation 36 (CD36) expressions in OVX and SHAM rats who received DEN and/ or F compared to SHAM rats. In contrast to S, treatment of OVX rats with EB mitigated DEN-induced expression of FASN and CD36 in liver tissue, while ORS improved DEN-induced expression of FASN. In conclusion, the protective effect against HCC was mediated via estrogen receptor alpha (ER-α) which abrogates its downstream genes involved in lipid metabolism namely FASN and CD36 depriving the tumor from survival vital energy source. In addition, ORS induced similar mitigating effect against DEN-induced HCC which could be attributed to FASN inhibition and anti-inflammatory effect. Furthermore, S alleviated DEN-induced HCC, independent of its estrogenic effect.

Exploring DSSC Efficiency Enhancement: SQI-F and SQI-Cl Dyes with Iodolyte Electrolytes and CDCA Optimization.

This investigation delves into the potential use of halogen bonding to enhance both the short-circuit current (JSC) and overall efficiency of dye-sensitized solar cells (DSSCs). Specifically, we synthesized two distinct dyes, SQI-F and SQI-Cl, and characterized them using FT-IR, 1HNMR, 13C NMR, and mass spectroscopy. These dyes are based on the concept of incorporating halogen atoms within unsymmetrical squaraine structures with a donor-acceptor-donor (D-A-D) configuration. This strategic design aims to achieve optimal performance within DSSCs. We conducted comprehensive assessments using DSSC devices and integrated these synthesized dyes with iodolyte electrolytes, denoted as Z-50 and Z-100. Further enhancements were achieved through the addition of CDCA. Remarkably, in the absence of CDCA, both SQI-F and SQI-Cl dyes displayed distinct photovoltaic characteristics. However, through sensitization with three equivalents of CDCA, a significant improvement in performance became evident. The peak of performance was reached with the SQI-F dye, sensitized with three equivalents of CDCA, and paired with iodolyte Z-100. This combination yielded an impressive DSSC device efficiency of 6.74%, an open-circuit voltage (VOC) of 0.694 V, and a current density (JSC) of 13.67 mA/cm2. This substantial improvement in performance can primarily be attributed to the presence of a σ-hole, which facilitates a robust interaction between the electrolyte and the dyes anchored on the TiO2 substrate. This interaction optimizes the critical dye regeneration process within the DSSCs, ultimately leading to the observed enhancement in efficiency.

Seasonal variations of physiological responses, milk production, and fatty acid profile of local crossbred cows in Tunisia.

The study investigates the seasonal variations of physiological responses, milk yield, milk composition, and milk fatty acid profile of local crossbred cows (Friesian × Brown Atlas) in northwestern Tunisia. A total of 80 multiparous cows from smallholder farmers were sampled between 2018 and 2019. The cows were feed the same diet ad libitum and exposed to the same Mediterranean climatic conditions. Weekly rectal temperature (RT; °C), respiratory rate (RR; rpm), and heart rate (HR; bpm) were measured per cow in each season. Individual milk yield and samples were recorded bi-weekly and collected in duplicate for chemical analyses. Milk fatty acids (FAs) were analyzed using gas chromatography-mass spectrometry (GC-MS). Results showed an increase (P < 0.05) in RT (+ 1.3%), RR (+ 12.1%), and HR (+ 9.9%) when the temperature-humidity index (THI) increased from winter (53.6) to summer (74.4) in response to heat stress. Milk yield did not vary significantly between seasons (8.3 L/day on average). Summer milk contained more fat (+ 7.8%) and log SCC (+ 13.7%). The proportion of the monounsaturated (31.2 vs. 27.2%) and polyunsaturated (4.29 vs. 3.86%) FAs decreased (P < 0.05) between winter and summer. Saturated FAs (64.5 vs. 67.7%) were higher (P < 0.05) in summer than in winter. Winter milk fat contained higher levels of C18:2cis-9 trans-11 (CLA) (0.73 vs. 0.56%) and ω-3 FA (0.83 vs. 0.63%), but a lower ω-6/ω-3 ratio (4.07 vs. 6.17%) compared to summer. As the cows were fed the same diet throughout the two seasons, the performances obtained were mainly due to the resistance of the local crossbred cow to the hot conditions. It is concluded that the local crossbred cow maintains its productivity and tolerate the hot Mediterranean climate.

Remote ischaemic conditioning: defining critical criteria for success-report from the 11th Hatter Cardiovascular Workshop.

The Hatter Cardiovascular Institute biennial workshop, originally scheduled for April 2020 but postponed for 2 years due to the Covid pandemic, was organised to debate and discuss the future of Remote Ischaemic Conditioning (RIC). This evolved from the large multicentre CONDI-2-ERIC-PPCI outcome study which demonstrated no additional benefit when using RIC in the setting of ST-elevation myocardial infarction (STEMI). The workshop discussed how conditioning has led to a significant and fundamental understanding of the mechanisms preventing cell death following ischaemia and reperfusion, and the key target cyto-protective pathways recruited by protective interventions, such as RIC. However, the obvious need to translate this protection to the clinical setting has not materialised largely due to the disconnect between preclinical and clinical studies. Discussion points included how to adapt preclinical animal studies to mirror the patient presenting with an acute myocardial infarction, as well as how to refine patient selection in clinical studies to account for co-morbidities and ongoing therapy. These latter scenarios can modify cytoprotective signalling and need to be taken into account to allow for a more robust outcome when powered appropriately. The workshop also discussed the potential for RIC in other disease settings including ischaemic stroke, cardio-oncology and COVID-19. The workshop, therefore, put forward specific classifications which could help identify so-called responders vs. non-responders in both the preclinical and clinical settings.

Non-lethal rodent malarial infection prevents collagen-induced arthritis in mice via anti-arthritic immunomodulation.

AIMS: Immunomodulatory effects of parasitic infections on the outcomes of allergic or autoimmune disorders have been addressed in many experimental studies. We examined the effects of Plasmodium yoelii 17X NL (Py) infection on collagen-induced arthritis (CIA). METHODS AND RESULTS: Male DBA/1J mice were immunized with bovine type II collagen (IIC). Py inoculation was induced at three different time points (1, 4 weeks after or 4 weeks before the immunization). Only the inoculation at 4 weeks after IIC immunization significantly inhibited arthritis development. Non-malarial anaemia induced by phenylhydrazine hydrochloride (PHZ) did not affect arthritis development. In the infected mice, anti-IIC IgG levels were transiently reduced. In addition, splenic production of pro-arthritic cytokines (IL-17 and TNF-α) and IFN-γ decreased, whereas IL-10 production increased. Flow cytometric analysis clarified that the main IL-10 producers in Py-infected mice had the CD4+ CD25- Foxp3- phenotype, presumably Tr1 cells. CONCLUSION: We demonstrated that experimental malarial infection alleviated autoimmune arthritis via immunomodulation, suggesting the importance of malaria in the hygiene hypothesis and the significance of searching for therapeutic immunomodulatory molecules from malarial parasites.

Comparison of outcomes using the rituximab originator MabThera with the biosimilar Truxima in patients with ANCA-associated vasculitis.

OBJECTIVES: The use of rituximab (MabThera®), an anti-CD20 monoclonal antibody, is the most significant development in the management of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) since the introduction of cytotoxic therapy in 1950. Truxima® is the first anti-CD20 biosimilar approved for the same indications, and has been available in the UK since 2017. Significant cost savings have been reported when switching to biosimilars, which could lead to greater patient access to such treatment. Therefore, it is important to know whether patients' clinical and laboratory parameters respond equally well to biosimilars as to reference medicines, tested in clinical trials. METHOD: We retrospectively reviewed the clinical outcomes and laboratory parameters in 257 consecutive patients treated with anti-CD20 depletion therapy using MabThera or Truxima, for induction and maintenance of remission, in two tertiary renal centres between 2010 and 2019. RESULTS: We demonstrated no difference between patients treated with MabThera or Truxima in rates of remission, relapse, and hospitalization with infection when used for either induction or maintenance of remission of AAV. In one hospital subgroup analysis, we showed comparable levels of hypogammaglobulinaemia, B-cell depletion, and frequency of infusion reactions, with no significant differences. CONCLUSION: The efficacy and safety of the rituximab biosimilar Truxima are not inferior to the originator MabThera in patients with AAV. Truxima represents a cheaper and safe therapeutic alternative that could increase patient access to rituximab.

Responses to melatonin of 2 breeds of dairy ewes in early lactation under autumn photoperiod conditions.

A total of 72 dairy ewes of 2 breeds (MN, Manchega, 72.4 ± 1.9 kg of body weight, n = 36; LC, Lacaune, 77.7 ± 2.3 kg of body weight; n = 36) were used to evaluate the lactational effects of melatonin implants in early lactation and under the short-day photoperiod conditions of autumn (experiment was centered on the winter solstice). Ewes lambed in autumn and were penned indoors in 12 balanced groups of 6 ewes by breed, body weight, age, and number of lambs, and randomly assigned to a 2 × 2 × 3 factorial design (treatment × breed × replicate). Ewes suckled their lambs for 28 d. Treatments were (1) melatonin (MEL), which received 1 subcutaneous implant of melatonin (18 mg/ewe) in the ear base at 35 ± 1 d (1 wk after lamb weaning), and (2) control, which did not receive any treatment. Ewes were fed ad libitum a total mixed ration (forage:concentrate, 60:40) and machine milked twice daily. Daily milk yield was automatically recorded from d 29 to 105 of lactation and sampled every 2 wk for composition. Jugular blood was sampled for plasma hormone analyses at 30, 50, 80, 110, and 124 d of lactation. Body reserves were assessed every 2 wk. Feed intake was measured by pen during 3 separated periods after the start of the treatments (wk 2 to 3, wk 6 to 7, and wk 10 to 11). Feed intake, and milk yield and composition varied by breed, but no MEL effects were detected on dry matter intake, milk yield, milk composition, or fat and protein standardized milk in either breed. As a result of the unique composition of the implants and the variable body weights of the ewes, the MEL treatment dose (on average, 0.24 mg/kg of body weight) was 6.8% greater in the MN (lighter) than in the LC (heavier) ewes. Plasmatic melatonin markedly increased in the MEL-treated ewes (on average, 111%), but despite the amount of MEL used, the MN responded greatly compared with the LC ewes (150 vs. 63%, respectively). No differences in basal plasmatic melatonin were detected between breeds (6.4 ± 1.1 pg/mL, on average), indicating the greater responsiveness to the implants of the lighter MN ewes. Plasmatic prolactin tended to decrease in the MEL-treated ewes (-35%, on average), but the effect was significant only in the MN ewes (-54%), in agreement with their greater response to MEL. No effects of MEL treatment were detected on plasmatic IGF-I in either breed. Moreover, body reserves did not vary by effect of MEL treatment or breed throughout the experiment. In conclusion, the use of exogenous melatonin as MEL implants, together with the endogenous melatonin naturally produced under short-day photoperiod conditions, had no effects on the early-lactation performances of dairy sheep, despite their breed and level of production.

Investigation and Biological Assessment of Rumex vesicarius L. Extract: Characterization of the Chemical Components and Antioxidant, Antimicrobial, Cytotoxic, and Anti-Dengue Vector Activity.

The objective of this study was to assess the biological potency and chemical composition of Rumex vesicarius aboveground parts using GC-MS. In this approach, 44 components were investigated, comprising 99.99% of the total volatile compounds. The major components were classified as fatty acids and lipids (51.36%), oxygenated hydrocarbons (33.59%), amines (7.35%), carbohydrates (6.06%), steroids (1.21%), and alkaloids (0.42%). The major components were interpreted as 1,3-dihydroxypropan-2-yl oleate (oxygenated hydrocarbons, 18.96%), ethyl 2-hydroxycyclohexane-1-carboxylate (ester of fatty acid, 17.56%), and 2-propyltetrahydro-2H-pyran-3-ol (oxygenated hydrocarbons, 11.18%). The DPPH antioxidant activity of the extracted components of R. vesicarius verified that the shoot extract was the most potent with IC50 = 28.89 mg/L, with the percentages of radical scavenging activity at 74.28% ± 3.51%. The extracted plant, on the other hand, showed substantial antibacterial activity against the diverse bacterial species, namely, Salmonella typhi (23.46 ± 1.69), Bacillus cereus (22.91 ± 0.96), E. coli (21.07 ± 0.80), and Staphylococcus aureus (17.83 ± 0.67). In addition, the extracted plant was in vitro assessed as a considerable anticancer agent on HepG2 cells, in which MTT, cell proliferation cycle, and DNA fragmentation assessments were applied on culture and treated cells. The larvicidal efficacy of the extracted plant was also evaluated against Aedes aegypti, the dengue disease vector. As a result, we may infer that R. vesicarius extract increased cytocompatibility and cell migratory capabilities, and that it may be effective in mosquito control without causing harm.

Sirolimus use in patients with subglottic stenosis in the context of granulomatosis with polyangiitis (GPA), suspected GPA, and immunoglobulin G4-related disease.

Objective: Subglottic stenosis (SGS) is a severe, life-threatening disease found in immune-mediated diseases such as granulomatosis with polyangiitis (GPA) and in rare cases of immunoglobulin G4 (IgG4)-related disease. It can result in persistent airway compromise due to the fibrotic response following inflammation. Standard management involves repeated endoscopic interventions to dilate the airway, and tracheostomy is occasionally required. In addition, immunosuppression remains a cornerstone of therapy aimed at controlling the underlying inflammatory disease; however, cumulative dosing leads to significant adverse effects. We present five cases of predominantly anti-neutrophil cytoplasmic antibody-negative GPA and a case of IgG4-related disease with SGS, in whom we evaluated the long-term utility of sirolimus, which has beneficial anti-proliferative and fibrotic effects, in the management of their disease. Method: We conducted a retrospective review of a cohort of patients with SGS at a tertiary vasculitis unit. These patients were treated with sirolimus, in addition to conventional medical and endoscopic treatment. Clinical symptoms, frequency and time to endoscopic intervention pre- and post-treatment, additional rescue therapy, and any adverse effects were recorded and analysed. Results: Six patients were treated with sirolimus and followed for up to 9 years; two discontinued the drug owing to adverse effects, early on. In the remaining four patients, glucocorticoids were withdrawn, and the frequency of endoscopic intervention was reduced. One patient on sirolimus required rituximab therapy for disease flare. Conclusion: Sirolimus may be a therapeutic option for some patients with severe SGS, allowing steroid withdrawal and resulting in a positive adverse effect profile.

Prediction of the treatment outcome using machine learning with FDG-PET image-based multiparametric approach in patients with oral cavity squamous cell carcinoma.

AIM: To investigate the value of machine learning-based multiparametric analysis using 2-[18F]-fluoro-2-deoxy-d-glucose positron-emission tomography (FDG-PET) images to predict treatment outcome in patients with oral cavity squamous cell carcinoma (OCSCC). MATERIALS AND METHODS: Ninety-nine patients with OCSCC who received pretreatment integrated FDG-PET/computed tomography (CT) were included. They were divided into the training (66 patients) and validation (33 patients) cohorts. The diagnosis of local control or local failure was obtained from patient's medical records. Conventional FDG-PET parameters, including the maximum and mean standardised uptake values (SUVmax and SUVmean), metabolic tumour volume (MTV), and total lesion glycolysis (TLG), quantitative tumour morphological parameters, intratumoural histogram, and texture parameters, as well as T-stage and clinical stage, were evaluated by a machine learning analysis. The diagnostic ability of T-stage, clinical stage, and conventional FDG-PET parameters (SUVmax, SUVmean, MTV, and TLG) was also assessed separately. RESULTS: In support-vector machine analysis of the training dataset, the final selected parameters were T-stage, SUVmax, TLG, morphological irregularity, entropy, and run-length non-uniformity. In the validation dataset, the diagnostic performance of the created algorithm was as follows: sensitivity 0.82, specificity 0.7, positive predictive value 0.86, negative predictive value 0.64, and accuracy 0.79. In a univariate analysis using conventional FDG-PET parameters, T-stage and clinical stage, diagnostic accuracy of each variable was revealed as follows: 0.61 in T-stage, 0.61 in clinical stage, 0.64 in SUVmax, 0.61 in SUVmean, 0.64 in MTV, and 0.7 in TLG. CONCLUSION: A machine-learning-based approach to analysing FDG-PET images by multiparametric analysis might help predict local control or failure in patients with OCSCC.

PRKAR1B-AS2 Long Noncoding RNA Promotes Tumorigenesis, Survival, and Chemoresistance via the PI3K/AKT/mTOR Pathway.

Many long noncoding RNAs have been implicated in tumorigenesis and chemoresistance; however, the underlying mechanisms are not well understood. We investigated the role of PRKAR1B-AS2 long noncoding RNA in ovarian cancer (OC) and chemoresistance and identified potential downstream molecular circuitry underlying its action. Analysis of The Cancer Genome Atlas OC dataset, in vitro experiments, proteomic analysis, and a xenograft OC mouse model were implemented. Our findings indicated that overexpression of PRKAR1B-AS2 is negatively correlated with overall survival in OC patients. Furthermore, PRKAR1B-AS2 knockdown-attenuated proliferation, migration, and invasion of OC cells and ameliorated cisplatin and alpelisib resistance in vitro. In proteomic analysis, silencing PRKAR1B-AS2 markedly inhibited protein expression of PI3K-110α and abrogated the phosphorylation of PDK1, AKT, and mTOR, with no significant effect on PTEN. The RNA immunoprecipitation detected a physical interaction between PRKAR1B-AS2 and PI3K-110α. Moreover, PRKAR1B-AS2 knockdown by systemic administration of 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine nanoparticles loaded with PRKAR1B-AS2-specific small interfering RNA enhanced cisplatin sensitivity in a xenograft OC mouse model. In conclusion, PRKAR1B-AS2 promotes tumor growth and confers chemoresistance by modulating the PI3K/AKT/mTOR pathway. Thus, targeting PRKAR1B-AS2 may represent a novel therapeutic approach for the treatment of OC patients.

Antifungal Activity of New Diterpenoid Alkaloids Isolated by Different Chromatographic Methods from Delphinium peregrinum L. var. eriocarpum Boiss.

This paper aimed to investigate the potential antifungal influences of new alkaloids from Delphinium peregrinum L. var. eriocarpum Boiss. New Diterpenoid alkaloids Delcarpum (1), Hydrodavisine (4) and known alkaloids Peregrine (2), Delphitisine (3) were isolated by different chromatographic methods from the aerial parts of D. Peregrinum eriocarpum Boiss, which grows in Syria. The structures of alkaloids were proposed based on 1D NMR spectroscopy 1H-NMR, 13C-NMR, DEPT-135, DEPT-90, 2D NMR spectroscopy DQF-COSY, HMQC, EI-Ms mass spectrum, and IR spectroscopic measurements. The antifungal activity of the isolated alkaloids was evaluated against different dermatophyte fungal isolates compared with fluconazole. In the case of Peregrine (2) the minimum inhibitory concentrations(MICs) recorded 128-256, 32-64, and 32 for Epidermophyton floccosum, Microsporum canis, and Trichophyton rubrum, respectively, compared to 32-64, 16, and 32 µg/mL in the case of fluconazole, respectively. The MICs recorded on application of the four alkaloids mixture were 64, 32, and 16 in the case of E. floccosum, M. canis, and T. rubrum, respectively, which were significantly lower than that measured for each of the individual alkaloid and were compatible for fluconazole. In conclusion, MICs of the tested alkaloids showed a variable potential effect on the investigated fungal isolates. Peregrine (2) was the most effective alkaloid, however, the application of the mixture of alkaloids induced significant synergistic activity that was more pronounced than the application of individual ones.

Phytochemical and antimicrobial investigation of the leaves of five Egyptian mango cultivars and evaluation of their essential oils as preservatives materials.

The sterols, hydrocarbons and fatty acids constituents of the leaves of five mango cultivars locally implanted in Egypt were identified. The effect of their essential oils (EOs) against food borne microorganisms was studied as preservative materials. The chemical constituents of the EOs isolated from mango leaves were identified by Gas Chromatography-Mass spectrometry (GC-MS) technique. Trans-caryophyllene, α-humulene and α-elemene were identified as terpene hydrocarbons, while 4-hydroxy-4-methyl-2-pentanone as oxygenated compounds were recorded in all tested cultivars with variable amounts. Results showed that Staphylococcus aureus and Escherichia coli were the most sensitive microorganisms tested for Alphonso EOs. On the other hand, Salmonella typhimrium was found to be less susceptible to the EOs of the studied cultivars. The EOs of different mango cultivars induced a steady decrease in the activity of amylase, protease and lipase at the minimum inhibitory concentration (MIC). The treatment of the tested bacteria with the EOs of mango cultivars caused a steady loss in enterotoxins even when applied at the sub-MIC. Bacteria-inoculated apple juice treated with minimum bactericidal concentration of Alphonso oil was free from the bacteria after 5 days of incubation at 25 °C. Eighteeen volatile compounds were found to reduce the activity of the amylase enzyme and the most active was cedrelanol (-7.6 kcal mol-1) followed by alpha-eudesmol (-7.3 kcal mol-1) and humulene oxide (-7 kcal mol-1). The binding mode of both of cedrelanol and alpha-eudesmol with amylase enzyme was illustrated.

Fungal infections in primary immunodeficiency diseases.

Primary immunodeficiency diseases (PID), encompass a heterogeneous group of diseases, with increased susceptibility to recurrent, severe infections. Invasive fungal infections raise a serious concern related to their morbidity and mortality. Herein, we describe various fungal infections among different PID patients. Twenty-eight PID patients diagnosed with fungal infections were included; fourteen patients with chronic granulomatous disease, two with Hyper Immunoglobulin E syndrome, one with LRBA deficiency and one with MHC class II defect, one with unclassified immune dysregulation, one with CD4 lymphopenia and one patient with Immune dysregulation Polyendocrinopathy Enteropathy X-linked syndrome. Aspergillus species were the most common isolated causative organisms in 78% of patients, Candida species were the causative organisms in 32%, Pneumocystis jirovecii caused infections in 7% followed by Malassezia furfur, Fusarium spp., Mucormycosis, and Penicillium chrysogenium 3.5% for each. The mortality rate among our patients was 10/28 (35.7%). PID patients are at high risk of developing fungal infections.

Suppression of prolactin and reduction of milk secretion by effect of cabergoline in lactating dairy ewes.

The effects of cabergoline, an ergot derivative and dopamine receptor agonist, were investigated in 30 ewes of 2 dairy breeds (Manchega; MN, n = 15; Lacaune; LC, n = 15). Ewes were in a similar late-lactation stage, but differed in milk yield according to breed (MN vs. LC, 1.02 ± 0.03 vs. 2.27 ± 0.05 kg/d). Treatments consisted of a single intramuscular injection of cabergoline at different doses per ewe. Cabergoline doses (per ewe) were: low (0.56 mg), high (1.12 mg), and control (CON; 0 mg; 1 mL of saline). Milk yield was recorded daily (d -14 to 25), milk and blood were sampled, and udder traits were measured from d -2 to 14 after injection. No local reaction at the injection site, nor behavior and metabolic indicators of the ewes were detected after the cabergoline injection, but milk yield fell rapidly in both breeds (MN vs. LC, -54% vs. -27%) when compared with CON ewes. Cabergoline effects progressively disappeared after d 5, and no milk yield differences between treatments were detected from d 8 to 25 after injection. Milk fat and protein contents increased similarly (22% and 23%; respectively) in both breeds and at both cabergoline doses until d 5, and the effects disappeared thereafter. Plasma prolactin (PRL) decreased dramatically in the low- and high-treated ewes the day after injection when compared with the CON ewes, and reached values below the detection limit of the assay between d 1 and 5, increasing similarly thereafter. On d 14, PRL values were 58% greater in the low- and high-treated than in the CON ewes, showing that PRL concentrations rebounded when the cabergoline effects ceased. Total udder volume correlated with milk accumulated in the udder (r = 0.77) of all groups of ewes throughout the experiment, suggesting its use as a noninvasive method for the estimation of milk stored in the udder. Udder volume was similar for the low and high ewes, but both values were lower than those of the CON ewes from d 1 to 14 after injection. No other effects on udder size were detected. Cabergoline dramatically inhibited PRL secretion and decreased milk yield and udder volume of lactating dairy ewes. The low dose of cabergoline was as effective as the high dose in the 2 breeds of dairy ewes. These results suggest the use of cabergoline to facilitate the decrease of milk production in dairy ewes (e.g., dry-off, illness care), although further research in pregnant dairy ewes and during the following lactation is still needed.

Correction to: Oral inoculation of ultraviolet-irradiated Eimeria species oocysts protects chickens against coccidiosis.

The author name Salama Abohamra in the original published version of this article should have been Salama Abohamra Sayed Shany.

MAFC: Multi-Agent Fog Computing Model for Healthcare Critical Tasks Management.

In healthcare applications, numerous sensors and devices produce massive amounts of data which are the focus of critical tasks. Their management at the edge of the network can be done by Fog computing implementation. However, Fog Nodes suffer from lake of resources That could limit the time needed for final outcome/analytics. Fog Nodes could perform just a small number of tasks. A difficult decision concerns which tasks will perform locally by Fog Nodes. Each node should select such tasks carefully based on the current contextual information, for example, tasks' priority, resource load, and resource availability. We suggest in this paper a Multi-Agent Fog Computing model for healthcare critical tasks management. The main role of the multi-agent system is mapping between three decision tables to optimize scheduling the critical tasks by assigning tasks with their priority, load in the network, and network resource availability. The first step is to decide whether a critical task can be processed locally; otherwise, the second step involves the sophisticated selection of the most suitable neighbor Fog Node to allocate it. If no Fog Node is capable of processing the task throughout the network, it is then sent to the Cloud facing the highest latency. We test the proposed scheme thoroughly, demonstrating its applicability and optimality at the edge of the network using iFogSim simulator and UTeM clinic data.