Examining the association between autism spectrum disorder and atopic eczema: meta-analysis of current evidence.

OBJECTIVES: This study aims to investigate the association between autism spectrum disorder (ASD) and atopic eczema (AE), shedding light on potential associations and underlying mechanisms. METHODS: A comprehensive review of literature was conducted to identify relevant studies published up to August 2023. Various electronic databases, including PubMed, Embase, Scopus, Web of Science, and Cochrane, were searched using specific keywords related to ASD and AE. RESULTS: The meta-analysis covered a total of 30 studies. The first analysis included 23 studies with a combined total of 147430 eczema patients in the ASD group and 8895446 eczema patients in non-ASD group. We calculated the risk ratio of eczema in ASD and non-ASD groups, which revealed a significantly higher risk of eczema in patients with ASD (RR 1.34; 95% CI 1.03, 1.76). The second analysis included seven studies with a combined total of 3570449 ASD patients in the AE group and 3253973 in the non-Eczema group. The risk ratio of ASD in the Eczema and Non-Eczema groups showed a significantly increased risk of ASD in patients with eczema (RR 1.67; 95% CI 0.91, 3.06). CONCLUSION: This study underscores the possible link between ASD and atopic eczema, shedding light on their potential association. IMPACT: Our study conducted a meta-analysis on the association between autism spectrum disorder (ASD) and atopic eczema (AE), shedding light on potential associations and underlying mechanisms. The review we conducted covered a total of 30 studies. This study underscores the possible link between ASD and atopic eczema, shedding light on their potential association.

Endothelial dysfunction in children with newly diagnosed Graves' disease.

The most frequent cause of hyperthyroidism in children is Graves' disease (GD). Vascular endothelium is a specific target of thyroid hormone. The purpose of this study is to assess flow-mediated dilatation (FMD)% and serum von Willebrand factor (vWF) levels in children with newly diagnosed GD to reflect the extent of endothelial dysfunction in those children. In this study, 40 children with newly discovered GD and 40 children who were healthy served as the control group. Both patients and controls had anthropometric assessment, as well as measurements of fasting lipids, glucose, insulin, high-sensitivity C-reactive protein (hs-CRP), TSH, and free thyroxine (FT4 and FT3), thyrotropin receptor antibodies TRAbs and vWF. Noninvasive ultrasound was utilized to quantify the carotid arteries' intima-media thickness and the brachial artery's FMD. Patients reported significantly reduced FMD response and greater vWF and hs-CRP levels compared to controls (P = 0.001 for each). In multivariate analysis, we reported that vWF was significantly correlated with TSH (OR 2.5, 95% CI 1.32-5.32, P = 0.001), FT3 (OR 3.4, 95% CI 1.45-3.55, P = 0.001), TRAb (OR 2.1, 95% CI 1.16-2.23, P = 0.01), and FMD% (OR 4.2, 95% CI 1.18-8.23, P = 0.001).  Conclusions: Children with newly diagnosed GD have endothelial dysfunction, which is shown by impaired FMD and increased vWF. These findings support the idea that GD may need to be treated as soon as possible. What is Known: • Graves' disease is the most common cause of hyperthyroidism in children. • vWF is a reliable marker for detection of vascular endothelial dysfunction. What is New: • Children with newly diagnosed Graves' disease may have endothelial dysfunction as reflected by impairment of FMD and raised vWF level. • Measurement of vWF level in children with newly diagnosed Graves' disease can be used for early detection of endothelial dysfunction.

Effect of mutation and vaccination on spread, severity, and mortality of COVID-19 disease.

Coronavirus disease 2019 (COVID-19) has had different waves within the same country. The spread rate and severity showed different properties within the COVID-19 different waves. The present work aims to compare the spread and the severity of the different waves using the available data of confirmed COVID-19 cases and death cases. Real-data sets collected from the Johns Hopkins University Center for Systems Science were used to perform a comparative study between COVID-19 different waves in 12 countries with the highest total performed tests for severe acute respiratory syndrome coronavirus 2 detection in the world (Italy, Brazil, Japan, Germany, Spain, India, USA, UAE, Poland, Colombia, Turkey, and Switzerland). The total number of confirmed cases and death cases in different waves of COVID-19 were compared to that of the previous one for equivalent periods. The total number of death cases in each wave was presented as a percentage of the total number of confirmed cases for the same periods. In all the selected 12 countries, Wave 2 had a much higher number of confirmed cases than that in Wave 1. However, the death cases increase was not comparable with that of the confirmed cases to the extent that some countries had lower death cases than in Wave 1, UAE, and Spain. The death cases as a percentage of the total number of confirmed cases in Wave 1 were much higher than that in Wave 2. Some countries have had Waves 3 and 4. Waves 3 and 4 have had lower confirmed cases than Wave 2, however, the death cases were variable in different countries. The death cases in Waves 3 and 4 were similar to or higher than Wave 2 in most countries. Wave 2 of COVID-19 had a much higher spread rate but much lower severity resulting in a lower death rate in Wave 2 compared with that of the first wave. Waves 3 and 4 have had lower confirmed cases than Wave 2; that could be due to the presence of appropriate treatment and vaccination. However, that was not reflected in the death cases, which were similar to or higher than Wave 2 in most countries. Further studies are needed to explain these findings.

New cell cycle checkpoint pathways regulators with 2-Oxo-indoline scaffold as potential anticancer agents: Design, synthesis, biological activities and in silico studies.

3-Arylidene-2-oxo-indoline derivatives are at the heart of a wide range of clinically, medicinally and biologically important compounds among the 2-oxo-indolines. A number of 3-arylidene-2-oxo-indolines have been approved for clinical application. Accordingly, the current work describes the structural based design of 3-arylidene-2-oxindole derivatives through docking of their structures in the active site of CDK2 as one of the dominant enzyme checkpoints. Based on the docking studies a range of 3-arylidene-2-oxindole derivatives, 5(a-n) and 6(a-x), with variable substituents at positions 1 and 5 of the 2-oxindole as well as 3 and 4 of the aryl moieties were synthesized. These molecules exist in either E or Z diastereomer about the exocyclic double bond at position 3 of oxindole nucleus. Their structures were confirmed by spectral and elemental methods of analyses and the E/Z-configuration of the diastereomers was confirmed by 2D NOE analysis. In vitro cytotoxicity of these molecules was tested against four cancerous cell lines, namely, breast cancer cell line (MCF7), liver carcinoma cell line (HepG2), cervix carcinoma cell line (HeLa), colon cancer cell line (HCT116) in addition to the diploid human normal non-cancerous cell line (F180) using SRB and MTT assays. The tested molecules showed variable cytotoxic effects on the four cancer cell lines with pronounced selectivity compared to the normal one (F180) with no significant difference between E and Z diastereomers. Compounds 5a, 5b, 5e1, 5m, 6f and 6j were tested for the effect on the expression on CDK2, p53, caspase-3 and caspase-9 proteins, and revealed variable activities compared to the positive controls Sunitinib and Staurosporine. These molecules seem to have multiple cellular targets as they induced expression of p53 and caspases while inhibited that of CDK2. Apoptotic effect of compound 6j was further investigated using annexin V-FITC/PI dual staining assay and showed that cells treated with 6j have nearly 15 folds greater apoptotic effect than that of the control cells. Furthermore, inhibitory activity of compounds 5a, 5b, 5e1, 5m, 6f and 6j on CDK2 enzyme were tested and revealed that compound 6f, with the N-4-flourobenzyl- 2-oxindole and 3-p-chlorobenzylidene moieties, has a comparable inhibitory activity to the reference drug sunitinib.

Architectural distortion outcome: digital breast tomosynthesis-detected versus digital mammography-detected.

OBJECTIVES: To compare the outcome for DBT-detected and DM-detected suspicious AD, to evaluate the risk of malignancy and if is affected by the US or MRI imaging correlation. METHODS: All cases with suspicious AD (ultimately assigned BI-RADS 4 or 5 categories) were retrospectively included. Two radiologists independently reviewed DM and DBT images in two sessions for detection (DM vs. DBT). US and MRI imaging correlation findings were recorded. Pathologic results were compared between DBT-detected and DM-detected AD. RESULTS: Among 137 detected ADs, 103 (75.2%) were DM-detected, and 34 (24.8%) were only DBT-detected (p = 0.01). The malignancy rate was lower for DBT-detected than DM-detected AD (14.7% vs. 45.6%) (p = 0.01). Malignancy rate was higher with US-positive than US-negative correlation at DM-detected AD (49.4% vs. 27.8%) (p = 0.01). Malignancy rate was not different for DBT-detected AD with (16.7%) or without (12.5%) sonographic correlation. NPV based on radiologists' level of suspicion was high (86.2%-97.2%) but not sufficient enough to forgo biopsy. Of 34 sonographically occult ADs, a positive-MRI correlation was identified in 19 (55.9%) ADs (7 were malignant, 12 were benign). A negative-MRI correlation was identified in 15 (44.1%) ADs; all had a benign outcome (p = 0.01). CONCLUSIONS: DBT-detected AD is less likely to represent malignancy than does DM-detected; however, the risk of malignancy is not low enough to forgo biopsy. MRI-negative correlation in sonographically occult AD was significantly associated with benign outcomes and can avoid unnecessary interventions.

Robotic minimally invasive esophagectomy provides superior surgical resection.

INTRODUCTION: Robotic minimally invasive esophagectomy (RMIE) and "traditional" minimally invasive esophagectomy techniques (tMIE) have reported superior outcomes relative to open techniques. Differences in the outcomes of these two approaches have not been examined. We hypothesized that short-term outcomes of RMIE would be superior to tMIE. METHODS AND PROCEDURES: The National Cancer Database was used to analyze outcomes of patients undergoing RMIE and tMIE from 2010 to 2016. Patients with clinical metastatic disease were excluded. Trends in the number of procedures performed with each approach were described using linear regression testing. Primary outcome of interest was 90-day mortality rate. Secondary outcomes of interest were positive surgical margin rate, number of lymph nodes (LN) removed, adequate lymphadenectomy (> 15 LNs), length of hospitalization (LOS), readmission rate, and conversion to open rate. Outcomes of RMIE and tMIE were compared using Wilcoxon rank sum test and chi square test as appropriate. Multivariable regression was also performed to reduce the impact of differences in the cohorts of patients receiving RMIE and tMIE. RESULTS: 6661 minimally invasive esophagectomies were performed from 2010 to 2016 (1543/6661 (23.2%) RMIE and 5118/6661 (76.8%) tMIE). Over the study period, the proportion of RMIE increased from 10.4% (64/618) in 2010 to 27.2% (331/1216) in 2016 (p < 0.001) (Fig. 1). The primary outcome of 90-day mortality was similar between RMIE and tMIE (92/1170 (7.4%) vs 305/4148 (7.9%), p = 0.558) (Table 2). RMIE and tMIE also had similar readmission rate (6.3 vs 7%, p = 0.380). There was no difference between the cohorts based on sex, age, race, insurance, and tumor size. The cohorts of patients receiving RMIE and tMIE differed in that RMIE patients had lower rates of elevated Charlson scores, were more likely to be treated at an academic institution, had a higher rate of advanced clinical T-stage and clinical nodal involvement, and had received neoadjuvant therapy. In a univariate analysis, RMIE had a lower rate of positive margin (3.9 vs 6.1%, p = 0.001), more mean lymph nodes evaluated (16.6 ± 9.74 vs 16.1 ± 10.08 p = 0.018), lower conversion to open rate (5.4 vs 11.4%, p < 0.001), and a shorter mean length of stay (12.1 ± 10.39 vs 12.8 ± 11.18 days, p < 0.001). In multivariable analysis, RMIE was associated with lower risk of conversion to open (OR 0.51, 95% CI: 0.37-0.70, p < 0.001) and lower rate of positive margin (OR 0.62, 95% CI: 0.41-0.93, p = 0.021).). Additionally, in a multivariable logistic regression, RMIE demonstrated superior adequate lymphadenectomy (> 15 LNs) (OR 1.18, 95% CI 1.02-1.37, p < 0.032). CONCLUSION: In the National Cancer Database, robotic esophagectomy is associated with superior rate of conversion to open and positive surgical margin status. We speculate enhanced dexterity and visualization of RMIE facilitates intraoperative performance leading to improvement in these outcomes.

A study of the possible factors affecting COVID-19 spread, severity and mortality and the effect of social distancing on these factors: Machine learning forecasting model.

BACKGROUNDS: SARS-CoV-2 is affecting different countries all over the world, with significant variation in infection-rate and death-ratio. We have previously shown a presence of a possible relationship between different variables including the Bacillus Calmette-Guérin (BCG) vaccine, average age, gender, and malaria treatment, and the rate of spread, severity and mortality of COVID-19 disease. This paper focuses on developing machine learning models for this relationship. METHODS: We have used real-datasets collected from the Johns Hopkins University Center for Systems Science and Engineering and the European Centre for Disease Prevention and Control to develop a model from China data as the baseline country. From this model, we predicted and forecasted different countries' daily confirmed-cases and daily death-cases and examined if there was any possible effect of the variables mentioned above. RESULTS: The model was trained based on China data as a baseline model for daily confirmed-cases and daily death-cases. This machine learning application succeeded in modelling and forecasting daily confirmed-cases and daily death-cases. The modelling and forecasting of viral spread resulted in four different regions; these regions were dependent on the malarial treatments, BCG vaccination, weather conditions, and average age. However, the lack of social distancing resulted in variation in the effect of these factors, for example, double-humped spread and mortality cases curves and sudden increases in the spread and mortality cases in different countries. The process of machine learning for time-series prediction and forecasting, especially in the pandemic COVID-19 domain, proved usefulness in modelling and forecasting the end status of the virus spreading based on specific regional and health support variables. CONCLUSION: From the experimental results, we confirm that COVID-19 has a very low spread in the African countries with all the four variables (average young age, hot weather, BCG vaccine and malaria treatment); a very high spread in European countries and the USA with no variable (old people, cold weather, no BCG vaccine and no malaria). The effect of the variables could be on the spread or the severity to the extent that the infected subject might not have symptoms or the case is mild and can be missed as a confirmed-case. Social distancing decreases the effect of these factors.

In vitro and in vivo performance modelling and optimisation of different dry powder inhalers: A complementary study of neural networks, genetic algorithms and decision trees.

INTRODUCTION: Aerosol delivery from DPIs could be affected by different factors. This study aimed to evaluate and predict the effects of different factors on drug delivery from DPIs. METHODS: Modelling and optimisation for both in vitro and in vivo data of different DPIs (Diskus, Turbohaler and Aerolizer) were carried out using neural networks associated with genetic algorithms and the results are confirmed using a decision tree (DT) and random forest regressor (RFR). All variables (the type of DPI, inhalation flow, inhalation volume, number of inhalations and type of subject) were coded as numbers before using them in the modelling study. RESULTS: The analysis of the in vitro model showed that Turbohaler had the highest emitted dose compared with the Diskus and the Aerolizer. Increasing flow resulted in a gradual increase in the emitted dose. Little differences between the inhalation volumes 2 and 4 litres were shown at fast inhalation flow, and interestingly two inhalations showed somewhat higher emitted doses than one-inhalation mode with Turbohaler and Diskus at slow inhalation flow. Regarding the in vivo model, the percent of drug delivered to the lung was highly increased with Turbohaler and Diskus in healthy subjects where continuous contour lines were observed. The Turbohaler showed increased lung bioavailability with the two-inhalation modes, the Diskus showed a nearly constant level at both one and two inhalations at slow inhalation. The Turbohaler and Aerolizer showed little increasing effect moving from one to two inhalations at slow inhalation. CONCLUSIONS: Modelling of the input data showed a good differentiating and prediction power for both in vitro and in vivo models. The results of the modelling refer to the high efficacy of Diskus followed by Turbohaler for delivering aerosol. With two inhalations, the three DPIs showed an increase in the percent of drug excreted at slow inhalations.

Hexosomal Dispersion: A Nano-Based Approach to Boost the Antifungal Potential of Citrus Essential Oils against Plant Fungal Pathogens.

The demand for natural fungicides to replace synthetic ones has surged since toxic residues persist in soils, causing environmental contamination and posing a serious threat to worldwide public health. In the context of crop protection and enhancing the efficiency and safety of fungicides, nanotechnology is an eco-friendly strategy in managing fungal pathogens. In the present study, essential oils were isolated from the peels of four citrus fruits (Citrus lemon, Citrus aurantifolia, Citrus maxima, and Citrus sinensis) and were investigated using gas chromatography-mass spectrometric analysis. Monoterpene hydrocarbon was the most predominant group and limonene was the most abundant in the four oils. The antifungal potential of the oils was investigated, and the most active oil (Citrus lemon) was loaded into hexosomal dispersion, and its antifungal potential was retested against the same fungi. The structurally unique nano-based formulation showed great potency for fungal control. To the best of our knowledge, it is the first time the oil of Citrus lemon in nano-hexosomes has been formulated and its fungicidal activity examined. The data collected suggest that citrus essential oils (CEOs), especially when nano-formulated, could be successfully used in integrated fungus management programs.

Computational Design and Synthesis of a Deeply Red-Shifted and Bistable Azobenzene.

We computationally dissected the electronic and geometrical influences of ortho-chlorinated azobenzenes on their photophysical properties. X-ray analysis provided the insight that trans-tetra-ortho-chloro azobenzene is conformationally flexible and thus subject to molecular motions. This allows the photoswitch to adopt a range of red-shifted geometries, which account for the extended n → π* band tails. On the basis of our results, we designed the di-ortho-fluoro di-ortho-chloro (dfdc) azobenzene and provided computational evidence for the superiority of this substitution pattern to tetra-ortho-chloro azobenzene. Thereafter, we synthesized dfdc azobenzene by ortho-chlorination via 2-fold C-H activation and experimentally confirmed its structural and photophysical properties through UV-vis, NMR, and X-ray analyses. The advantages include near-bistable isomers and an increased separation of the n → π* bands between the trans- and cis-conformations, which allows for the generation of unusually high levels of the cis-isomer by irradiation with green/yellow light as well as red light within the biooptical window.

Design and synthesis of novel isatin-based derivatives targeting cell cycle checkpoint pathways as potential anticancer agents.

In recent years, cell cycle and checkpoint pathways regulation are offering new therapeutic approaches against cancer. Isatin, is a well exploited scaffold in the anticancer domain. Accordingly, the current work describes the design and synthesis of two series of (Z)-3-substituted-2-(((E/Z)-5-substituted-2-oxo-1-substituted-indolin-3-ylidene)hydrazinylidene)-thiazolidin-4-ones, 4(a-s) and (E/Z)-1-substituted-3-(((Z)-3-substituted-4-methylthiazol-2(3H)-ylidene)hydrazineylidene)-5-substituted-indolin-2-ones, 5(a-s). The structures of the synthesized molecules were confirmed by spectral and elemental methods of analyses. Pure diastereomers were further identified with 1H-1H-NOESY and confirmed with X-ray crystallography. The target compounds were tested in vitro for their cytotoxicity against three human epithelial cell lines, liver (HepG2), breast (MCF-7), and colon (HT-29) in addition to the diploid human normal cells (WI-38) compared to doxorubicin as a reference drug. Variable cytotoxic effects (IC50 3.29-100 µmol) were reported on the three cancer cell lines with pronounced selectivity compared to the normal one WI-38. The potency of the most active compounds, 4o, 4s, 5e, 5f, 5l, 5m and 5o (IC50 3.29-9.92 µmol), in both series associated with the (Z) configurations of N = thiazolidin/ene or one, however, the configuration of the N = isatin moiety seemed to be of no importance to the activity. The tested compounds were grouped for their possible mechanism of action into 4 categories. Compound 4o with no apparent effect on all genes examined. Compounds 4s and 5o affected all genes investigated and seem to have multiple cellular targets; induced the expression of p53 and caspases, and downregulated that of CDK1. Compounds 5l and 5m directly elevated the expression of initiator and effector caspases without going through p53 pathway. Finally, compounds 5e and 5f elevated the expression of p53 and inhibited CDK1. Compounds 4s, 5e, 5f, 5l, 5m, and 5o caused a significant elevation in the activity of cleaved caspase 3 as well. Docking studies on CDK1 revealed that the active molecules bind to the tested enzyme by the same manner of the co-crystallized ligands and the isatin-thiazoldinone/ene scaffold is essential for binding of these molecules.

Spontaneous spondylodiscitis: review, incidence, management, and clinical outcome in 44 patients.

OBJECTIVESpontaneous spondylodiscitis remains uncommon but is a serious complication of the vertebral column. Risk factors include diabetes, hemodialysis, intravenous drug abuse, and chronic steroid use, and pain is the most common presenting symptom. This study aims to review the literature and report on the incidence, management, and clinical outcome of spontaneous spondylodiscitis in 44 patients.METHODSThis is a prospective study including 44 patients with spontaneous spondylodiscitis managed in the neurosurgery department of Cairo University Hospitals during the period between January 2012 and October 2017. All patients had a full clinical assessment, laboratory tests, radiological studies in the form of MRI with and without contrast, and a postoperative follow-up of up to 12 months.RESULTSTwelve cases underwent conservative treatment in the form of complete bed rest, intravenous antibiotics, and a spinal brace. Ten cases underwent surgical intervention in the form of laminectomy, debridement, and open biopsy. Twenty-two cases underwent laminectomy and surgical stabilization with fusion. There were 15 cases of tuberculous spondylodiscitis, 6 cases of brucellosis, 6 cases of pyogenic infection, and 17 cases in which no organism could be detected.CONCLUSIONSOnce the primary diagnosis is confirmed, early and adequately prolonged antibiotic therapy is recommended for spontaneous spondylodiscitis. Some cases can be successfully treated with conservative treatment alone, whereas surgery may be needed in other cases such as severe destruction of endplates, spinal abscess formation, mechanical instability, neurological deficits, and severe pain that have failed to respond to conservative treatment.

Modeling and optimization of nebulizers' performance in non-invasive ventilation using different fill volumes: Comparative study between vibrating mesh and jet nebulizers.

BACKGROUNDS: Substituting nebulisers by another, especially in non-invasive ventilation (NIV), involves many process-variables, e.g. nebulizer-type and fill-volume of respirable-dose, which might affect patient optimum-therapy. The aim of the present work was to use neural-networks and genetic-algorithms to develop performance-models for two different nebulizers. METHODS: In-vitro, ex-vivo and in-vivo models were developed using input-variables including nebulizer-type [jet nebulizer (JN) and vibrating mesh nebulizer (VMN)] fill-volumes of respirable dose placed in the nebulization chamber with an output-variable e.g. average amount reaching NIV patient. Produced models were tested and validated to ensure effective predictivity and validity in further optimization of nebulization process. RESULTS: Data-mining produced models showed excellent training, testing and validation correlation-coefficients. VMN showed high nebulization efficacy than JN. JN was affected more by increasing the fill-volume. The optimization process and contour-lines obtained for in-vivo model showed increase in pulmonary-bioavailability and systemic-absorption with VMN and 2 mL fill-volumes. CONCLUSIONS: Modeling of aerosol-delivery by JN and VMN using different fill-volumes in NIV circuit was successful in demonstrating the effect of different variable on dose-delivery to NIV patient. Artificial neural networks model showed that VMN increased pulmonary-bioavailability and systemic-absorption compared to JN. VMN was less affected by fill-volume change compared to JN which should be diluted to increase delivery.

Molecular characterization of fowl aviadenoviruses species D and E associated with inclusion body hepatitis in chickens and falcons indicates possible cross-species transmission.

During the period from 2015 to 2017, frequent outbreaks of inclusion body hepatitis (IBH) were observed in broiler chickens and falcons in Saudi Arabia. Fifty samples were collected from both species. The histopathological examination and polymerase chain reaction confirmed the IBH infection in eight samples (five samples from chickens and three samples from falcons). The genomic sequence and phylogenetic analysis based on nucleotide and amino acid sequences of Saudi strains, reference fowl aviadenoviruses (FAdVs) and field viruses available in Genbank revealed that all investigated FAdVs clustered into FAdV-2 (species D) and FAdV-6 (species E). The host-dependent characterization revealed that falcon origin strains showed low identity (∼35%) with falcon adenoviruses isolated from USA, which clustered into a separate group. The identification of FAdV-D and FAdV-E in diseased falcons and chickens indicates cross-species transmission although falcons and chickens are phylogenetically different. The control of IBH infection in falcons and chickens should be based on the separation of carriers and susceptible chickens as well as falcons to prevent cross-species contact. Vaccination is an important method for prevention of IBH. The characterization of newly emerging FAdV strains provides valuable information for the development of an efficacious control strategy based on the molecular structure of current circulating FAdV strains in different species of birds.

Development of a nanogel formulation for transdermal delivery of tenoxicam: a pharmacokinetic-pharmacodynamic modeling approach for quantitative prediction of skin absorption.

This study investigates potentials of solid lipid nanoparticles (SLN)-based gel for transdermal delivery of tenoxicam (TNX) and describes a pharmacokinetic-pharmacodynamic (PK-PD) modeling approach for predicting concentration-time profile in skin. A 23 factorial design was adopted to study the effect of formulation factors on SLN properties and determine the optimal formulation. SLN-gel tolerability was investigated using rabbit skin irritation test. Its anti-inflammatory activity was assessed by carrageenan-induced rat paw edema test. A published Hill model for in vitro inhibition of COX-2 enzyme was fitted to edema inhibition data. Concentration in skin was represented as a linear spline function and coefficients were estimated using non-linear regression. Uncertainty in predicted concentrations was assessed using Monte Carlo simulations. The optimized SLN was spherical vesicles (58.1 ± 3.1 nm) with adequate entrapment efficiency (69.6 ± 2.6%). The SLN-gel formulation was well-tolerated. It increased TNX activity and skin level by 40 ± 13.5, and 227 ± 116%, respectively. Average Cmax and AUC0-24 predicted by the model were 2- and 3.6-folds higher than the corresponding values computed using in vitro permeability data. SLN-gel is a safe and efficient carrier for TNX across skin in the treatment of inflammatory disorders. PK-PD modeling is a promising approach for indirect quantitation of skin deposition from PD activity data.

Mucoadhesive niosomal in situ gel for ocular tissue targeting: in vitro and in vivo evaluation of lomefloxacin hydrochloride.

Eradication of ophthalmic infections depends on increasing transcorneal permeation and localizing antibiotics at ocular surface. This study aimed at formulating lomefloxacin HCl (LF) in the form of niosomes and evaluating the in vivo performance of best formula in rabbits' eyes. Vesicles were developed by mixing three surfactants at three molar ratios of 1:1, 1:2 and 1:3 of surfactant to cholesterol. Size, zeta potential, release percentage, transcorneal permeation parameters, stability studies, cytotoxicity and antibacterial activity of niosomes were determined. Niosomes showed encapsulation efficiency of more than 78%, particle size below 500 nm and zeta potential below -43.6. The produced vesicles showed significantly higher amounts of drug permeated across cornea (166%) compared to LF solution. The in vivo study showed 2-5 folds increase in drug concentration in ocular fluids and tissues following administration of niosomes compared to marketed formula (from 3.75 to 10.31 mcg/mL in the cornea). Microbiological studies showed 35 folds increase in the antibacterial activity of LF niosomes compared to free drug; where MBC decreased from 31.25 mcg/mL in case of LF solution to 0.97 mcg/mL for niosomal gel. The formulated niosomes enhanced the ocular bioavailability of LF through increasing transcorneal permeation and localizing drug at site of action.

Regulatory B cells (CD19(+)CD38(hi)CD24(hi)) in alloimmunized and non-alloimmunized children with ß-thalassemia major.

BACKGROUND: ß-Thalassemia major (BTM) is considered the most common hemoglobinopathy in Egypt and is one of the major health problems in our locality. MATERIALS & METHODS: We investigated the frequency of B-regulatory cells (CD19(+)CD38(hi)CD24(hi)); (Bregs) among polytransfused alloimmunized and non-alloimmunized children with BTM. The study included 110 polytransfused pediatric patients with ß-thalassemia major. Clinical and transfusion records of all studied patients were reviewed. Indirect antiglobulin test was performed to detect the presence of alloantibodies. We used flow cytometry for detection of CD19(+)CD38(hi)CD24(hi) regulatory B cells. RESULTS: Alloimmunization was detected in 35.5% of thalassemic patients (39/110). The analysis of our data showed a significantly higher frequency of Bregs (CD19(+)CD38(hi)CD24(hi)) in the peripheral blood of both alloimmunized and non-alloimmunized patients as compared to healthy controls. CONCLUSIONS: Our data showed that the frequencies of CD19(+)CD24(hi)CD38(hi) Bregs cells were significantly increased in children with BTM. Our data suggested that Bregs cells could play a role in the clinical course of BTM. The relationship of Bregs to immune disorders in BTM children remains to be determined. Further longitudinal study with a larger sample size is warranted to explore the mechanisms of Breg cells in the disease process in BTM patients.

Vitamin D status in autism spectrum disorders and the efficacy of vitamin D supplementation in autistic children.

OBJECTIVES: Autism spectrum disorder (ASD) is a developmental disorder characterized by pervasive deficits in social interaction, impairment in verbal and non-verbal communication, and stereotyped patterns of interests and activities. Vitamin-D deficiency was previously reported in autistic children. However, the data on the relationship between vitamin D deficiency and the severity of autism are limited. METHODS: We performed a case-controlled cross-sectional analysis conducted on 122 ASD children, to assess their vitamin D status compared to controls and the relationship between vitamin D deficiency and the severity of autism. We also conducted an open trial of vitamin D supplementation in ASD children. RESULTS: Fifty-seven percent of the patients in the present study had vitamin D deficiency, and 30% had vitamin D insufficiency. The mean 25-OHD levels in patients with severe autism were significantly lower than those in patients with mild/moderate autism. Serum 25-OHD levels had significant negative correlations with Childhood Autism Rating Scale (CARS) scores. Of the ASD group, 106 patients with low-serum 25-OHD levels (<30 ng/ml) participated in the open label trial. They received vitamin D3 (300 IU/kg/day not to exceed 5000 IU/day) for 3 months. Eighty-three subjects completed 3 months of daily vitamin D treatment. Collectively, 80.72% (67/83) of subjects who received vitamin D3 treatment had significantly improved outcome, which was mainly in the sections of the CARS and aberrant behavior checklist subscales that measure behavior, stereotypy, eye contact, and attention span. CONCLUSION: Vitamin D is inexpensive, readily available and safe. It may have beneficial effects in ASD subjects, especially when the final serum level is more than 40 ng/ml. TRIAL REGISTRATION NUMBER: UMIN-CTR Study Design: trial Number: R000016846.

Optimizing the Photocontrol of bZIP Coiled Coils with Azobenzene Crosslinkers: Role of the Crosslinking Site.

DNA binding by bZIP-type coiled-coil proteins can be inhibited by dominant negative versions of the proteins in which the N-terminal basic region is replaced by an acidic extension. Photocontrol of bZIP function can be achieved by introducing intramolecular azobenzene-based crosslinkers into dominant negatives. We show that the largest degree of photocontrol is achieved when the crosslinker is introduced into the zipper region of the dominant negative between Cys residues placed at f sites in the heptad segment showing the highest intrinsic helical propensity. The overall affinity of the dominant negative can then be tuned by varying the length of the acidic extension.