Efficient Prediction of In Vitro Piroxicam Release and Diffusion From Topical Films Based on Biopolymers Using Deep Learning Models and Generative Adversarial Networks

The purpose of this study was to simultaneously predict the drug release and skin permeation of Piroxicam (PX) topical films based on Chitosan (CTS), Xanthan gum (XG) and its Carboxymethyl derivatives (CMXs) as matrix systems. These films were prepared by the solvent casting method, using Tween 80 (T80) as a permeation enhancer. All of the prepared films were assessed for their physicochemical parameters, their in vitro drug release and ex vivo skin permeation studies. Moreover, deep learning models and machine learning models were applied to predict the drug release and permeation rates. The results indicated that all of the films exhibited good consistency and physicochemical properties. Furthermore, it was noticed that when T80 was used in the optimal formulation (F8) based on CTS-CMX3, a satisfactory drug release pattern was found where 99.97% of PX was released and an amount of 1.18 mg/cm² was permeated after 48 h. Moreover, Generative Adversarial Network (GAN) efficiently enhanced the performance of deep learning models and DNN was chosen as the best predictive approach with MSE values equal to 0.00098 and 0.00182 for the drug release and permeation kinetics, respectively. DNN precisely predicted PX dissolution profiles with f₂ values equal to 99.99 for all the formulations.     

Structural,Electromagnetic and Microwave Properties of Magnetite Extracted from Mill Scale Waste via Conventional Ball Milling and Mechanical Alloying Techniques

This study presents the utilization of mill scale waste, which has attracted much attention due to its high content of magnetite (Fe₃O₄). This work focuses on the extraction of Fe₃O₄ from mill scale waste via magnetic separation, and ball milling was used to fabricate a microwave absorber. The extracted magnetic powder was ground-milled using two different techniques: (i) a conventional milling technique (CM) and (ii) mechanical alloying (MM) process. The Fe₃O₄/CM samples were prepared by a conventional milling process using steel pot ball milling, while the Fe₃O₄/MM samples were prepared using a high-energy ball milling (HEBM) method. The effect of milling time on the structural, phase composition, and electromagnetic properties were examined using X-ray diffraction (XRD) and a vector network analyzer (VNA). XRD confirmed the formation of magnetite after both the magnetic separation and milling processes. The results revealed that Fe₃O₄ exhibited excellent microwave absorption properties because of the synergistic characteristics of its dielectric and magnetic loss. The results showed that the Fe₃O₄/CM particle powder had a greater absorption power (reflection loss: <−10 dB) with 99.9% absorption, a minimum reflection loss of −30.83 dB, and an effective bandwidth of 2.30 GHz for 2 mm thick samples. The results revealed the Fe₃O₄/MM powders had higher absorption properties, including a higher RL of −20.59 dB and a broader bandwidth of 2.43 GHz at a matching thickness of only 1 mm. The higher microwave absorption performance was attributed to the better impedance matching property caused by the porous microstructure. Furthermore, the magnetite, Fe₃O₄ showed superior microwave absorption characteristics because of the lower value of permittivity, which resulted in better impedance matching. This study presents a low-cost approach method by reutilizing mill scale waste to fabricate a high purity crystalline Fe₃O₄ with the best potential for designing magnetic nano-sized based microwave absorbers.     

The small molecule Zaractin activates ZAR1-mediated immunity in Arabidopsis

Pathogenic effector proteins use a variety of enzymatic activities to manipulate host cellular proteins and favor the infection process. However, these perturbations can be sensed by nucleotide-binding leucine-rich-repeat (NLR) proteins to activate effector-triggered immunity (ETI). Here we have identified a small molecule (Zaractin) that mimics the immune eliciting activity of the Pseudomonas syringae type III secreted effector (T3SE) HopF1r and show that both HopF1r and Zaractin activate the same NLR-mediated immune pathway in Arabidopsis. Our results demonstrate that the ETI-inducing action of pathogenic effectors can be harnessed to identify synthetic activators of the eukaryotic immune system.

Gram-negative bacterial plant pathogens such as Pseudomonas syringae use the type III secretion system (T3SS) to inject type III secreted effectors (T3SEs) into plant cells (1). A major function of T3SEs is to suppress plant immunity by targeting host proteins involved in disease resistance (2). However, plant nucleotide-binding leucine-rich-repeat (NLR) proteins can directly or indirectly recognize T3SEs and activate a response known as effector-triggered immunity (ETI), which can be accompanied by a hypersensitive cell death response (2, 3). The Arabidopsis thaliana NLR ZAR1 recognizes T3SE-induced complexes of ZED1-related kinases (ZRKs; RLCK XII-2 family) and PBS1-like (PBL) kinases (RLCK VII family) to activate ETI (4–7). T3SEs modify either ZRK and/or PBL kinases and promote their interaction, which activates ZAR1-mediated ETI (5, 6). For example, the Xanthomonas campestris AvrAC, uridylates PBL2 kinase, promoting an interaction with ZRK1 (also known as RKS1) that then acts as a nucleotide exchange factor to activate the ZAR1 resistosome (8, 9).In addition to AvrAC, five P. syringae effector families have been shown to trigger ZAR1/ZRK-mediated immunity in Arabidopsis (4, 10–13). ZAR1-mediated immunity triggered by the acetyltransferase HopZ1a requires the ZRK kinase ZED1 and the functionally redundant PBL kinases SZE1 and SZE2 (4, 7). Interestingly, acetylation of ZED1 by HopZ1a can activate immunity, suggesting that modification of either ZRK or PBL kinases can activate the ZAR1 resistosome (4, 6). HopX1i-recognition also requires ZED1 and SZE1, but not SZE2 (13). HopO1c- and HopF1r-mediated immunity requires ZRK3, whereas HopBA1a recognition requires ZRK2, but no PBL kinase requirement has been identified (11, 13). Based on the genetic requirements of ZAR1-mediated ETI against P. syringae effectors and the model of AvrAC recognition, a general mechanism of ZAR1 activation likely involves T3SE perturbations of ZRK and/or PBL kinases that promote their interaction, which in turn activates the ZAR1 resistosome (8, 9).We hypothesized that small molecules that mimic ETI-promoting effector perturbations would represent a powerful, targeted approach to activate plant immunity. Given the model of ZAR1 activation described above, we developed a chemical screen to identify small molecules that enhance ETI-inducing ZRK/PBL interactions. First, we show that the P. syringae T3SE HopF1r can enhance the interaction between ZRK3 and PBL27 and that PBL27 is a required component of ZAR1-mediated recognition of HopF1r. We then used our chemical screen to identify a small molecule (Zaractin) that can enhance the ZRK3/PBL27 interaction and activate ZAR1-dependent immunity. Overall, our results demonstrate that chemical mimicry of type III effector function can activate an NLR-mediated immune response, providing an approach to identify chemical immunomodulators.     

Fungal infections following liver transplantation

With increasing morbidity and mortality from chronic liver disease and acute liver failure, the need for liver transplantation is on the rise. Most of these patients are extremely vulnerable to infections as they are immune-compromised and have other chronic co-morbid conditions. Despite the recent advances in practice and improvement in diagnostic surveillance and treatment modalities, a major portion of these patients continue to be affected by post-transplant infections. Of these, fungal infections are particularly notorious given their vague and insidious onset and are very challenging to diagnose. This mini-review aims to discuss the incidence of fungal infections following liver transplantation, the different fungi involved, the risk factors, which predispose these patients to such infections, associated diagnostic challenges, and the role of prophylaxis. The population at risk is increasingly old and frail, suffering from various other co-morbid conditions, and needs special attention. To improve care and to decrease the burden of such infections, we need to identify the at-risk population with more robust clinical and diagnostic parameters. A more robust global consensus and stringent guidelines are needed to fight against resistant microbes and maintain the longevity of current antimicrobial therapies.     

Identification of a novel homozygous UNC80 variant in a child with infantile hypotonia with psychomotor retardation and characteristic facies-2 (IHPRF2)

Metabolic Brain Disease - The UNC80 gene encodes for a large component of the NALCN sodium-leak channel complex that regulates the basal excitability of the nervous system. In this study, we report...     

Practical guidelines for screening and treatment of retinopathy of prematurity in Saudi Arabia

Retinopathy of Prematurity (ROP) is one of the leading causes of bilateral blindness in childhood. Early detection and effective treatment can prevent blindness. Efficient and timely screening examination of the retina by an experienced ophthalmologist who deals with preterm neonates with ROP is the mainstay in the management of this disease. All neonatologists and pediatricians who care for these at-risk preterm neonates should also be aware of this timing. This practical guideline intends to provide guidance to ophthalmologists, neonatologists and allied health care professionals in Saudi Arabia on current indications for screening and management of retinopathy of prematurity to prevent or minimize subsequent complications. This practical guideline was led by the National Eye Health Program (NEHP) and Neonatology Services Improvement Program at Ministry of Health (MOH), furthermore it has been solicited and endorsed from both Saudi Ophthalmological Society (SOS) and Saudi Neonatology Society (SNS).     

Behavioral risk factors and their relationship to tumor characteristics in Hispanic and non-Hispanic white long-term breast cancer survivors

Hispanics are more likely to be diagnosed with breast cancer at a younger age, with more advanced stage at diagnosis, hormone receptor-negative tumors, and worse prognosis than non-Hispanic whites (NHW). Little is known regarding the association between behavioral risk factors and breast tumor characteristics and whether these associations vary by race/ethnicity. We evaluated the association between several behavioral risk factors and tumor phenotype in a population-based study of Hispanics and NHWs. Participants are cases (846 Hispanic and 1,625 NHW women) diagnosed with breast cancer between 1999 and 2004 in Arizona, Colorado, New Mexico, or Utah. The association between breast cancer characteristics and obesity, physical activity, smoking, alcohol intake, and reproductive factors was examined. Logistic regression was used to compute the ethnic-specific odds ratios for the association between these risk factors and estrogen receptor (ER) status, tumor size, and histologic grade. Hispanics had more ER-negative tumors (28 vs. 20%), tumors >2 cm (39 vs. 27%), and poorly differentiated tumors (84 vs. 77%) than NHW. Among premenopausal women, obesity was associated with more ER-negative cancers among NHW [OR = 2.47 (95% CI: 1.08, 5.67)] but less ER-negative cancers among Hispanics [OR = 0.29 (0.13, 0.66)]. Obesity was associated with larger tumors among NHW [OR = 1.58 (1.09, 2.29)], but not among Hispanics. Never using mammography was associated with larger tumors in both ethnic groups. Moderate alcohol drinking and moderate and vigorous physical activity were weakly associated with smaller tumors in both ethnic groups. Our findings suggest that the association of obesity and other behavioral risk factors with breast cancer characteristics differ by ethnicity. We observed a divergent pattern between Hispanic and NHW cases in the association between obesity and ER status and tumor size. These observations suggest that a complex set of metabolic and hormonal factors related to estrogen and insulin pathways influence tumor characteristics.     

Phase II trial of syncopated thalidomide, lenalidomide, and weekly dexamethasone in patients with newly diagnosed multiple myeloma

IntroductionOver the past decade, the novel agents thalidomide, lenalidomide, and bortezomib have emerged as effective treatment in patients with multiple myeloma (MM). Initially used in the relapse setting, these agents have been incorporated into frontline treatment algorithms. They have been combined in doublets with corticosteroids, in triplets with alkylators, or with each other. Because thalidomide and lenalidomide have different clinical activity and toxicity profiles, we designed a trial to evaluate a syncopated schedule of thalidomide and lenalidomide with weekly dexamethasone in patients with newly diagnosed MM to determine response and toxicity.Patients and MethodsTwenty-two patients with newly diagnosed MM were treated with syncopated thalidomide (200 mg on days 1-7 and 15-21), lenalidomide (25 mg on days 8-14 and 22-28 for the first cycle and 50 mg on the same schedule for subsequent cycles) with weekly dexamethasone (40 mg). Each cycle lasted 28 days. MM parameters were assessed at the end of each cycle. It was intended that the patients proceed to stem cell mobilization and autologous transplantation after 4 cycles of therapy.ResultsThe median number of cycles administered was 3.5. The overall response was 68%. The regimen was well tolerated by the majority of the patients; only patient discontinued treatment because of toxicity.ConclusionWe conclude that a syncopated schedule of thalidomide and lenalidomide with weekly dexamethasone was tolerated well, with no unexpected toxicities. However the response rate, even using lenalidomide at 50 mg, was not superior to standard dosing of thalidomide or lenalidomide plus dexamethasone.     

Clinical trials on corticosteroids for diabetic macular edema

Diabetic macular edema (DME) is a common cause of visual impairment in diabetic patients. It is caused by an increase in the permeability of the perifoveal capillaries and a disruption of the blood retinal-barrier. The pathogenesis of DME is multifactorial. Several therapeutic modalities have been proposed for the treatment of DME. Corticosteroid treatments have emerged as an alternative therapy for persistent DME or refractory to conventional laser photocoagulation and other modalities, due to anti-inflammatory, anti-vascular endothelial growth factor and anti-proliferative effects. Many studies have demonstrated the beneficial therapeutic effect of corticosteroids with improvement to both retinal thickness and visual acuity in short-term on the treatment of DME. Peribulbar and intravitreal injections have been used to deliver steroids for DME with frequent injections due to the chronic and recurrent nature of the disease. Steroid-related side effects include elevated intraocular pressure, cataract, and injection related complications such as endophthalmitis, vitreous hemorrhage, and retinal detachment particularly with intravitreal steroid injections. In order to reduce the risks, complications and frequent dosing of intravitreal steroids, intravitreal implants have been developed recently to provide sustained release of corticosteroids and reduce repeated intravitreal injections for the management of DME.     

The association of systemic disorders with Vogt–Koyanagi–Harada and sympathetic ophthalmia

Background  

The aim of this work is to determine the systemic diseases and malignancy associated with Vogt–Koyanagi–Harada (VKH) disease compared to sympathetic ophthalmia (SO).