Myofibrillar myopathy hallmarks associated with ZAK deficiency.

The ZAK gene encodes two functionally distinct kinases, ZAKα and ZAKß. Homozygous loss of function mutations affecting both isoforms causes a congenital muscle disease. ZAKß is the only isoform expressed in skeletal muscle and is activated by muscle contraction and cellular compression. The ZAKß substrates in skeletal muscle or the mechanism whereby ZAKß senses mechanical stress remains to be determined. To gain insights into the pathogenic mechanism, we exploited ZAK-deficient cell lines, zebrafish, mice and a human biopsy. ZAK-deficient mice and zebrafish show a mild phenotype. In mice, comparative histopathology data from regeneration, overloading, ageing and sex conditions indicate that while age and activity are drivers of the pathology, ZAKß appears to have a marginal role in myoblast fusion in vitro or muscle regeneration in vivo. The presence of SYNPO2, BAG3 and Filamin C (FLNC) in a phosphoproteomics assay and extended analyses suggested a role for ZAKß in the turnover of FLNC. Immunofluorescence analysis of muscle sections from mice and a human biopsy showed evidence of FLNC and BAG3 accumulations as well as other myofibrillar myopathy markers. Moreover, endogenous overloading of skeletal muscle exacerbated the presence of fibres with FLNC accumulations in mice, indicating that ZAKß signalling is necessary for an adaptive turnover of FLNC that allows for the normal physiological response to sustained mechanical stress. We suggest that accumulation of mislocalized FLNC and BAG3 in highly immunoreactive fibres contributes to the pathogenic mechanism of ZAK deficiency.

Glucuronoxylomannan intranasal challenge prior to Cryptococcus neoformans pulmonary infection enhances cerebral cryptococcosis in rodents.

The encapsulated fungus Cryptococcus neoformans is the most common cause of fungal meningitis, with the highest rate of disease in patients with AIDS or immunosuppression. This microbe enters the human body via inhalation of infectious particles. C. neoformans capsular polysaccharide, in which the major component is glucuronoxylomannan (GXM), extensively accumulates in tissues and compromises host immune responses. C. neoformans travels from the lungs to the bloodstream and crosses to the brain via transcytosis, paracytosis, or inside of phagocytes using a "Trojan horse" mechanism. The fungus causes life-threatening meningoencephalitis with high mortality rates. Hence, we investigated the impact of intranasal exogenous GXM administration on C. neoformans infection in C57BL/6 mice. GXM enhances cryptococcal pulmonary infection and facilitates fungal systemic dissemination and brain invasion. Pre-challenge of GXM results in detection of the polysaccharide in lungs, serum, and surprisingly brain, the latter likely reached through the nasal cavity. GXM significantly alters endothelial cell tight junction protein expression in vivo, suggesting significant implications for the C. neoformans mechanisms of brain invasion. Using a microtiter transwell system, we showed that GXM disrupts the trans-endothelial electrical resistance, weakening human brain endothelial cell monolayers co-cultured with pericytes, supportive cells of blood vessels/capillaries found in the blood-brain barrier (BBB) to promote C. neoformans BBB penetration. Our findings should be considered in the development of therapeutics to combat the devastating complications of cryptococcosis that results in an estimated ~200,000 deaths worldwide each year.

Mode of Onset Modifies the Effect of Time to Endovascular Reperfusion on Clinical Outcomes after Acute Ischemic Stroke: An Analysis of the DAWN Trial.

OBJECTIVE: We aimed to assess the impact of time to endovascular thrombectomy (EVT) on clinical outcomes in the DAWN trial, while also exploring the potential effect modification of mode of stroke onset on this relationship. METHODS: The association between every 1-h treatment delay with 90-day functional independence (modified Rankin Scale [mRS] score 0-2), symptomatic intracranial hemorrhage, and 90-day mortality was explored in the overall population and in three modes of onset subgroups (wake-up vs. witnessed vs. unwitnessed). RESULTS: Out of the 205 patients, 98 (47.8%) and 107 (52.2%) presented in the 6 to 12 hours and 12 to 24 hours time window, respectively. Considering all three modes of onset together, there was no statistically significant association between time last seen well to randomization with either functional independence or mortality at 90 days in either the endovascular thrombectomy (mRS 0-2 1-hour delay OR 1.07; 95% CI 0.93-1.24; mRS 6 OR 0.84; 95% CI 0.65-1.03) or medical management (mRS 0-2 1-hour delay OR 0.98; 95% CI 0.80-1.14; mRS 6 1-hour delay OR 0.94; 95% CI 0.79-1.09) groups. Moreover, there was no significant interaction between treatment effect and time (p = 0.439 and p = 0.421 for mRS 0-2 and 6, respectively). However, within the thrombectomy group, the models that tested the association between time last seen well to successful reperfusion (modified Treatment in Cerebral Infarction ≥2b) and 90-day functional independence showed a significant interaction with mode of presentation (p = 0.013). This appeared to be driven by a nominally positive slope for both witnessed and unwitnessed strokes versus a significantly (p = 0.018) negative slope in wake-up patients. There was no association between treatment times and symptomatic intracranial hemorrhage. INTERPRETATION: Mode of onset modifies the effect of time to reperfusion on thrombectomy outcomes, and should be considered when exploring different treatment paradigms in the extended window. ANN NEUROL 2024;96:356-364.

On the speech envelope in the cortical tracking of speech.

The synchronization between the speech envelope and neural activity in auditory regions, referred to as cortical tracking of speech (CTS), plays a key role in speech processing. The method selected for extracting the envelope is a crucial step in CTS measurement, and the absence of a consensus on best practices among the various methods can influence analysis outcomes and interpretation. Here, we systematically compare five standard envelope extraction methods the absolute value of Hilbert transform (absHilbert), gammatone filterbanks, heuristic approach, Bark scale, and vocalic energy), analyzing their impact on the CTS. We present performance metrics for each method based on the recording of brain activity from participants listening to speech in clear and noisy conditions, utilizing intracranial EEG, MEG and EEG data. As expected, we observed significant CTS in temporal brain regions below 10 Hz across all datasets, regardless of the extraction methods. In general, the gammatone filterbanks approach consistently demonstrated superior performance compared to other methods. Results from our study can guide scientists in the field to make informed decisions about the optimal analysis to extract the CTS, contributing to advancing the understanding of the neuronal mechanisms implicated in CTS.

An integrated docking and molecular dynamics simulation approach to discover potential inhibitors of activin receptor-like kinase 1.

Activin receptor-like kinase 1 (ALK1) is a transmembrane receptor involved in crucial signaling pathways associated with angiogenesis and vascular development. Inhibition of ALK1 signaling has emerged as a promising therapeutic strategy for various angiogenesis-related diseases, including cancer and hereditary hemorrhagic telangiectasia. This study aimed to investigate the potential of phytoconstituents as inhibitors of ALK1 using a combined approach of virtual screening and molecular dynamics (MDs) simulations. Phytoconstituents from the IMPPAT 2.0 database underwent virtual screening to identify potential inhibitors of ALK1. The compounds were initially filtered based on physicochemical parameters, following Lipinski's rules and the PAINS filter. Subsequently, compounds demonstrating high binding affinities in docking analysis were further analyzed. Additional assessments, including ADMET, PAINS, and PASS evaluations, were conducted to identify more potent hits. Through interaction analysis, a phytoconstituent, Candidine, exhibited appreciable affinity and specific interactions with the ALK1 active site. To validate the results, MD simulations and principal components analysis were performed. The MD simulations demonstrated that Candidine stabilized the ALK1 structure and reduced conformational fluctuations. In conclusion, Candidine shows promising potential as binding partners of ALK1. These findings provide a foundation for further exploration and development of Candidine as a lead molecule for therapeutic interventions targeting ALK1-associated diseases.

Integrated spectroscopic and computational analyses unravel the molecular interaction of pesticide azinphos-methyl with bovine beta-lactoglobulin.

Organophosphorus are typically hazardous chemicals used in the pharmaceutical, agricultural, and other industries. They pose a serious risk to human life and can be fatal upon direct exposure. Hence, studying the interaction between such compounds with proteins is crucial for environmental, health, and food safety. In this study, we investigated the interaction mechanism between azinphos-methyl (AZM) and ß-lactoglobulin (BLG) at pH 7.4 using a combination of biophysical techniques. Intrinsic fluorescence investigations revealed that BLG fluorescence was quenched in the presence of increasing AZM concentrations. The quenching mechanism was identified as static, as evidenced by a decrease in the fluorescence quenching constant (1.25 × 104, 1.18 × 104, and 0.86 × 104 M-1) with an increase in temperatures. Thermodynamic calculations (ΔH > 0; ΔS > 0) affirmed the formation of a complex between AZM and BLG through hydrophobic interactions. The BLG's secondary structure was found to be increased due to AZM interaction. Ultraviolet -visible spectroscopy data showed alterations in BLG conformation in the presence of AZM. Molecular docking highlighted the significant role of hydrophobic interactions involving residues such as Val43, Ile56, Ile71, Val92, Phe105, and Met107 in the binding between BLG and AZM. A docking energy of -6.9 kcal mol-1, and binding affinity of 1.15 × 105 M-1 suggest spontaneous interaction between AZM and BLG with moderate to high affinity. These findings underscore the potential health risks associated with the entry of AZM into the food chain, emphasizing the need for further consideration of its impact on human health.

Higher Procedural Volumes Are Associated with Faster Treatment Times, Better Functional Outcomes, and Lower Mortality in Patients Undergoing Endovascular Treatment for Acute Ischemic Stroke.

OBJECTIVE: We aimed to characterize the association of hospital procedural volumes with outcomes among acute ischemic stroke (AIS) patients undergoing endovascular therapy (EVT). METHODS: This was a retrospective, observational cohort study using data prospectively collected from January 1, 2016 to December 31, 2019 in the Get with the Guidelines-Stroke registry. Participants were derived from a cohort of 60,727 AIS patients treated with EVT within 24 hours at 626 hospitals. The primary cohort excluded patients with pretreatment National Institutes of Health Stroke Scale (NIHSS) < 6, onset-to-treatment time > 6 hours, and interhospital transfers. There were 2 secondary cohorts: (1) the EVT metrics cohort excluded patients with missing data on time from door to arterial puncture and (2) the intravenous thrombolysis (IVT) metrics cohort only included patients receiving IVT ≤4.5 hours after onset. RESULTS: The primary cohort (mean ± standard deviation age = 70.7 ± 14.8 years; 51.2% female; median [interquartile range] baseline NIHSS = 18.0 [13-22]; IVT use, 70.2%) comprised 21,209 patients across 595 hospitals. The EVT metrics cohort and IVT metrics cohort comprised 47,262 and 16,889 patients across 408 and 601 hospitals, respectively. Higher procedural volumes were significantly associated with higher odds (expressed as adjusted odds ratio [95% confidence interval] for every 10-case increase in volume) of discharge to home (1.03 [1.02-1.04]), functional independence at discharge (1.02 [1.01-1.04]), and lower rates of in-hospital mortality (0.96 [0.95-0.98]). All secondary measures were also associated with procedural volumes. INTERPRETATION: Among AIS patients primarily presenting to EVT-capable hospitals (excluding those transferred from one facility to another and those suffering in-hospital strokes), EVT at hospitals with higher procedural volumes was associated with faster treatment times, better discharge outcomes, and lower rates of in-hospital mortality. ANN NEUROL 2023.

PI3K inhibitor "alpelisib" alleviates methotrexate induced liver injury in mice and potentiates its cytotoxic effect against MDA-MB-231 triple negative breast cancer cell line.

Hepatotoxicity is the main off-target effect of methotrexate (MTX) limiting its effective clinical use. Besides, MDA-MB231 breast cancer cells show chemoresistance, partly via PI3K/AKT pathway. Therefore, we investigated the ameliorative potentials of the PI3K inhibitor, alpelisib (ALP) on MTX-induced hepatotoxicity (in vivo) and the restraining potentials of ALP on MDA-MB231 chemoresistance to MTX (in vitro). Twenty-eight male BALB/c mice were divided into 4 groups. In treatment groups, mice were administered ALP (2.5 and 5 mg/kg) for 5 days and MTX (20 mg/kg) from day 2 till day 5. The results showed that ALP restored hepatic architecture, reduced immune cell infiltration (F4/80, Ly6G and MPO) and repressed the rise in liver enzymes (AST and ALT) induced by MTX. Additionally, ALP rectified the MTX-induced disruption of cellular oxidant status by boosting antioxidant defense systems (HO-1 and GSH) and repressing lipid peroxidation (MDA and 4-HNE). Finally, ALP curbed MTX-induced hepatocyte apoptosis (NF-κB and BAX) and shifted the cytokine milieu away from inflammation (IL-17, IL-22, IL-6 and IL- 10). The results of the in vitro experiments revealed that ALP alone and in combination with MTX, synergistically, reduced cancer cell viability (MTT assay), migration (wound healing assay) and their capacity to establish colonies (colony formation assay) as compared to MTX alone. RT-PCR revealed the antiproliferative (Bcl-2) and proapoptotic (BAX) potentials of ALP and ALP/MTX combination especially after 24 h. In conclusion, targeting PI3K/AKT pathway is a promising strategy in triple negative breast cancer patients by ameliorating hepatotoxicity and restraining chemoresistance to chemotherapy.

Aridity creates global thresholds in soil nitrogen retention and availability.

Identifying tipping points in the relationship between aridity and gross nitrogen (N) cycling rates could show critical vulnerabilities of terrestrial ecosystems to climate change. Yet, the global pattern of gross N cycling response to aridity across terrestrial ecosystems remains unknown. Here, we collected 14,144 observations from 451 15 N-labeled studies and used segmented regression to identify the global threshold responses of soil gross N cycling rates and soil process-related variables to aridity index (AI), which decreases as aridity increases. We found on a global scale that increasing aridity reduced soil gross nitrate consumption but increased soil nitrification capacity, mainly due to reduced soil microbial biomass carbon (MBC) and N (MBN) and increased soil pH. Threshold response of gross N production and retention to aridity was observed across terrestrial ecosystems. In croplands, gross nitrification and extractable nitrate were inhibited with increasing aridity below the threshold AI ~0.8-0.9 due to inhibited ammonia-oxidizing archaea and bacteria, while the opposite was favored above this threshold. In grasslands, gross N mineralization and immobilization decreased with increasing aridity below the threshold AI ~0.5 due to decreased MBN, but the opposite was true above this threshold. In forests, increased aridity stimulated nitrate immobilization below the threshold AI ~1.0 due to increased soil C/N ratio, but inhibited ammonium immobilization above the threshold AI ~1.3 due to decreased soil total N and increased MBC/MBN ratio. Soil dissimilatory nitrate reduction to ammonium decreased with increasing aridity globally and in forests when the threshold AI ~1.4 was passed. Overall, we suggest that any projected increase in aridity in response to climate change is likely to reduce plant N availability in arid regions while enhancing it in humid regions, affecting the provision of ecosystem services and functions.

Genetic Components Derived Parameters and Heterosis in Okra under Saudi Arabia Conditions.

Four parental genotypes of okra were crossed in complete diallel design to study the direction and extent of relative heterosis and heterobeltiosis for yield and its associated traits for utilization of existing genetic diversity to develop heterotic F1 hybrids in okra. The additive genetic component (D) was significant in all studied traits except average pod weight. Nonadditive (H1 and H2) components were found to be significant in all studied traits. However, the values of the dominant effect (H1) were smaller than the D components for no. of nodes/plant, no. of pods/plant, weight of medium pods, weight of large pods, and total fresh pod yield. The maximum significant MP heterosis in the desirable direction (149.9%) was recorded for the weight of large pods/plot. The maximum significant heterobeltiosis in the desirable direction (120.1%) was recorded for the weight of small pods/plot followed by total fresh pod yield (107.4%), the weight of large pods/plot (104.9%), weight of medium pods/plot (92.1%), average pod weight (51.8%), number of pods/plant (38.4%), and plant height (34.3%). It could be concluded that plant height, average pod weight, and the number of branches could be considered for the development of elite hybrids (heterosis breeding) or inbred lines (pure line selection) in succeeding generations. Therefore, these parameters can be considered for selecting genotypes to improve the pod yield of okra. The superior crosses identified through heterosis analysis were Egyptian Balady × Line 4.1.18 (30.8 ton/ha), Line 4.1.18 × Egyptian Balady (29.8 ton/ha), Dwarf Green Long Pod × Line 4.1.18 (28.3 ton/ha), and Egyptian Balady × Dwarf Green Long Pod (27.6 ton/ha) as these crosses had high performance as well as significant and higher estimates of heterobeltiosis for fruit yield per plant and yield attributing other characters.

Morphological, Biochemical, and Molecular Diversity Assessment of Egyptian Bottle Gourd Cultivars.

The genetic variability and relationships between ten bottle gourd cultivars were evaluated based on morphological, biochemical, and molecular parameters. The results displayed high variability among selected cultivars in terms of photosynthetic pigments, total free amino acids, total phenol content, isozymes pattern, and protein electrophoresis. Furthermore, differences in molecular markers were revealed by the SCoT technique. The peroxidase (POD) and polyphenyl oxidase (PPO) isozymes patterns did not detect significant differences in bands among cultivars. The protein patterns revealed seventeen bands ranging from 126 to 9 kDa and five polymorphic bands representing 29.41%. On the other hand, eight SCoT primers were used to evaluate the genetic variability and relationships between the ten Egyptian bottle gourd cultivars. The results of SCoT analysis detected 44 amplicons with 50% polymorphism. In addition, the results of the phylogenetic tree that is constructed based on the similarity coefficient revealed by SCoT analysis confirm the results of biochemical analysis indicating a genetic relationship between the most efficient bottle gourd cultivars (S1 and S2 cultivars). In addition, there is a genetic relationship among the less efficient bottle gourd cultivars (S4 and S5 cultivars). These results could be beneficial to distinguish among bottle gourd cultivars in the plant breeding programs.

Fates of a Nonwetting Slug in Tapered Microcapillaries under Gravity and Zero Gravity Conditions: Dynamics, Asymptotic Equilibrium Analysis, and Computational Fluid Dynamics Verifications.

It has been determined experimentally and numerically that a nonwetting slug in a tapered capillary tube, under the sole action of capillary force, self-propels itself toward the wider end of the tube until an equilibrium state is reached. The aim of this work is to highlight the state of the slug at equilibrium in terms of configuration and location. Furthermore, it turns out that gravity adds richness to this phenomenon, and more fates become possible. A modified Bond number is developed that determines the relative importance of gravity and capillarity for this system. According to the magnitude of the Bond number, three more fates are possible. Therefore, in a tapered capillary tube held vertically upward with its wider end at the top, in the absence of gravity or under microgravity conditions, the nonwetting slug moves upward toward the wider end of the tube until it reaches equilibrium with the two menisci part of a single sphere. The location of the slug at equilibrium in this case represents the farthest fate among the other fates. When gravity exists yet capillarity dominates, the slug still moves upward toward the wider end. However, in this case, the two menisci become parts of two different spheres of different curvatures. For this scenario, the slug climbs upward but reaches a lower level compared to the previous scenario. On the other hand, when gravity dominates, the slug experiences a net downward pull toward the narrower end of the tube and starts to move in the direction of gravity until capillary force establishes a balance, then it stops. When gravity sufficiently dominates, it pulls the slug downward until it completely drains off the tube. A computational fluid dynamics (CFD) analysis is conducted in order to build a framework for verification exercises. Excellent agreements between the results of the developed model and the CFD analysis are obtained. A fate map and a scheme are developed to identify these four fates based on two Bond numbers; namely, the initial Bond number and that associated with the slug when it is at the exit.

Association of ACE1 I/D polymorphism and susceptibility to COVID-19 in Egyptian children and adolescents.

BACKGROUND: Given the sparse data on the renin-angiotensin system (RAS) and its biological effector molecules ACE1 and ACE2 in pediatric COVID-19 cases, we investigated whether the ACE1 insertion/deletion (I/D) polymorphism could be a genetic marker for susceptibility to COVID-19 in Egyptian children and adolescents. METHODS: This was a case-control study included four hundred sixty patients diagnosed with COVID-19, and 460 well-matched healthy control children and adolescents. The I/D polymorphism (rs1799752) in the ACE1 gene was genotyped by polymerase chain reaction (PCR), meanwhile the ACE serum concentrations were assessed by ELISA. RESULTS: The ACE1 D/D genotype and Deletion allele were significantly more represented in patients with COVID-19 compared to the control group (55% vs. 28%; OR = 2.4; [95% CI: 1.46-3.95]; for the DD genotype; P = 0.002) and (68% vs. 52.5%; OR: 1.93; [95% CI: 1.49-2.5] for the D allele; P = 0.032). The presence of ACE1 D/D genotype was an independent risk factor for severe COVID-19 among studied patients (adjusted OR: 2.6; [95% CI: 1.6-9.7]; P < 0.001. CONCLUSIONS: The ACE1 insertion/deletion polymorphism may confer susceptibility to SARS-CoV-2 infection in Egyptian children and adolescents. IMPACT: Recent studies suggested a crucial role of renin-angiotensin system and its biological effector molecules ACE1 and ACE2 in the pathogenesis and progression of COVID-19. To our knowledge, ours is the first study to investigate the association of ACE1 I/D polymorphism and susceptibility to COVID-19 in Caucasian children and adolescents. The presence of the ACE1 D/D genotype or ACE1 Deletion allele may confer susceptibility to SARS-CoV-2 infection and being associated with higher ACE serum levels; may constitute independent risk factors for severe COVID-19. The ACE1 I/D genotyping help design further clinical trials reconsidering RAS-pathway antagonists to achieve more efficient targeted therapies.

Magnetic resonance imaging of pilonidal sinus disease: interobserver agreement and practical MRI reporting tips.

OBJECTIVE: To evaluate the interobserver agreement for the features of natal cleft pilonidal sinus disease (PSD) on magnetic resonance imaging (MRI) and propose a standardized checklist for reporting PSD on MRI. MATERIALS AND METHODS: Forty MRI studies of 39 discrete patients with PSD were retrospectively evaluated by five independent radiologists using a standardized checklist. Fleiss' Kappa (k) coefficients of agreement were used to test the agreement between categorical variables. The MRI features of the natal cleft sepsis associated with PSD were classified into four main categories: morphology, branching and extensions, external skin openings, and the relationship of the PSD to the coccyx. A survey was created and disseminated online among general surgeons who treat patients with PSD to assess the relevance of the MRI features proposed in the standardized checklist. RESULTS: The overall agreement regarding the identification of morphology of the natal cleft sepsis was moderate (k = 0.59). Lateral and caudal extensions interobserver agreement was substantial (k = 0.64 and 0.71, respectively). However, the overall agreement regarding the individual parts of anal sphincter involved was moderate (k = 0.47). Substantial interobserver agreement was found in assessing the proximity of the PSD to the coccyx (k = 0.62). CONCLUSION: Preoperative MRI can delineate the extensions and branching of PSD with substantial agreement. MRI is superior in describing the deep extensions of PSD with better reliability than assessing the number and locations of the external openings. Expert consensus agreement is needed to establish the MRI features necessary for optimal reporting of PSD. CLINICAL RELEVANCE STATEMENT: MRI can offer valuable information about the extent of sepsis associated with pilonidal sinus disease, particularly in cases with involvement of critical anatomical structures such as the coccyx and anal triangle. MRI can potentially contribute to more accurate patient stratification and surgical planning. KEY POINTS: • The interobserver agreement for assessing PSD's lateral and caudal extension on MRI is substantial. • MRI can describe deep extensions and branching of PSD with superior reliability than assessing the number and site of external openings. • Reporting the relationship between natal cleft sepsis in PSD and the anal region may influence the surgical approach and postoperative healing.

Green synthesis of zinc oxide nanoparticles using ethanolic extract of Gliricidia sepium (Jacq.) kunth. Ex. Walp., stem: Characterizations and their gastroprotective effect on ethanol-induced gastritis in rats.

The study presents a significant advancement in drug delivery and therapeutic efficacy through the successful synthesis of Gliricidia sepium(Jacq.) Kunth. ex. Walp., stem zinc oxide nanoparticles(GSS ZnONPs). The phenolic compounds present in Gliricidia sepium stem (GSS) particularly vanillic acid, apegnin-7-O-glucoside, syringic acid, and p-coumaric acid which were identified by HPLC. These compounds shown antioxidant and anti-inflammatory properties. GSS ZnONPs demonstrate pronounced gastroprotective effects against ethanol-induced gastritis, evidenced by the reduction in gastric lesions and mucosal injury upon its treatment. Histopathological evaluation and immunohistochemical analysis of nuclear factor erythroid 2-related factor 2 (Nrf2) expression further validate these results, revealing the amelioration of ethanol-induced gastritis and improved gastric tissue condition due to their treatment. Noteworthy is the dose-dependent response of GSS ZnONPs, showcasing their efficacy even at lower doses against ethanol-induced gastritis which is confirmed by different biomarkers. These findings have substantial implications for mitigating dosage-related adverse effects while preserving therapeutic benefits, offering a more favorable treatment approach. This study aims to investigate the potential gastroprotective activity of GSS ZnONPs against gastritis.

Hydroxytyrosol Alleviates Methotrexate-Induced Pulmonary Fibrosis in Rats: Involvement of TGF-ß1, Tissue Factor, and VEGF.

Methotrexate (MTX) is an indispensable drug used for the treatment of many autoimmune and cancerous diseases. However, its clinical use is associated with serious side effects, such as lung fibrosis. The main objective of this study is to test the hypothesis that hydroxytyrosol (HT) can mitigate MTX-induced lung fibrosis in rats while synergizing MTX anticancer effects. Pulmonary fibrosis was induced in the rats using MTX (14 mg/kg/week, per os (p.o.)). The rats were treated with or without HT (10, 20, and 40 mg/kg/d p.o.) or dexamethasone (DEX; 0.5 mg/kg/d, intraperitoneally (i.p.)) for two weeks concomitantly with MTX. Transforming growth factor beta 1 (TGF-ß1), interleukin-4 (IL-4), thromboxane A2 (TXA2), vascular endothelial growth factor (VEGF), 8-hydroxy-2-deoxy-guanosine (8-OHdG), tissue factor (TF) and fibrin were assessed using enzyme-linked immunosorbent assay (ELISA), immunofluorescence, and RT-PCR. Pulmonary fibrosis was manifested by an excessive extracellular matrix (ECM) deposition and a marked increase in TGF-ß1 and IL-4 in lung tissues. Furthermore, cotreatment with HT or dexamethasone (DEX) significantly attenuated MTX-induced ECM deposition, TGF-ß1, and IL-4 expression. Similarly, HT or DEX notably reduced hydroxyproline contents, TXA2, fibrin, and TF expression in lung tissues. Moreover, using HT or DEX downregulated the gene expression of TF. A significant decrease in lung contents of VEGF, IL-8, and 8-OHdG was also observed in HT + MTX- or DEX + MTX -treated animals in a dose-dependent manner. Collectively, the results of our study suggest that HT might represent a potential protective agent against MTX-induced pulmonary fibrosis.

Imaging of musculoskeletal tuberculosis.

Tuberculosis (TB) represents a major public health problem worldwide. Any tissue may be infected. Involvement of the musculoskeletal (MSK) system account for 1-3% of all tuberculous infections. MSK TB may manifest as tuberculous spondylitis, arthritis, osteomyelitis, and soft tissue infections. Although TB spondylitis may present with distinctive imaging features compared to pyogenic infections of the spine, the imaging semiology of extra-spinal TB infections is mostly nonspecific and may mimic other lesions. TB infections should therefore always be considered in the differential diagnosis, particularly in immunocompromised patients. The aim of this article is to review the imaging features of spinal and extra-spinal MSK TB. Magnetic resonance imaging is considered the modality of choice to make the diagnosis and to evaluate the extent of the disease.

Protective effects of gallic acid against nickel-induced kidney injury: impact of antioxidants and transcription factor on the incidence of nephrotoxicity.

Nickel (Ni) is a common metal with a nephrotoxic effect, damaging the kidneys. This study investigated the mechanism by which gallic acid (GA) protects mice kidneys against renal damage induced by Nickel oxide nanoparticles (NiO-NPs). Forty male Swiss albino mice were randomly assigned into four groups, each consisting of ten mice (n = 10/group): Group I the control group, received no treatment; Group II, the GA group, was administrated GA at a dosage of 110 mg/kg/day body weight; Group III, the NiO-NPs group, received injection of NiO-NPs at a concentration of 20 mg/kg body weight for 10 consecutive days; Group IV, the GA + NiO-NPs group, underwent treatment with both GA and NiO-NPs. The results showed a significant increase in serum biochemical markers and a reduction in antioxidant activities. Moreover, levels of 8-hydroxy-2'-deoxyguanosine (8-OH-dG), phosphorylated nuclear factor kappa B (p65), and protein carbonyl (PC) were significantly elevated in group III compared with group I. Furthermore, the western blot analysis revealed significant high NF-κB p65 expression, immunohistochemistry of the NF-κB and caspase-1 expression levels were significantly increased in group III compared to group I. Additionally, the histopathological inspection of the kidney in group III exhibited a substantial increase in extensive necrosis features compared with group I. In contrast, the concomitant coadministration of GA and NiO-NPs in group IV showed significant biochemical, antioxidant activities, immunohistochemical and histopathological improvements compared with group III. Gallic acid has a protective role against kidney dysfunction and renal damage in Ni-nanoparticle toxicity.

Early Discharge for Revision Total Knee and Hip Arthroplasty: Predictors of Success.

BACKGROUND: The rate of revision total joint arthroplasties is expected to increase drastically in the near future. Given the recent pandemic, there has been a general push toward early discharge. This study aimed to assess for predictors of early postoperative discharge after revision total knee arthroplasty (rTKA) and revision total hip arthroplasty (rTHA). METHODS: There were 77 rTKA and 129 rTHA collected between January 1, 2019 and December 31, 2021. Demographic data, comorbidities, a comorbidity index, the modified frailty index (mFI-5), and surgical history were collected. The Common Procedural Terminology codes for each case were assessed. Patients were grouped into 2 cohorts, early discharge (length of stay [LOS] <24 hours) and late discharge (LOS >24 hours). RESULTS: In the rTHA cohort, age >65 years, a history of cardiac or liver disease, an mFI-5 of >1, a comorbidity index of >2.7, a surgical time >122 minutes, and the need for a transfusion were predictors of prolonged LOS. Only the presence of a surgical time of >63 minutes or an mFI-5 >1 increased patient LOS in the rTKA cohort. In both rTHA and rTKA patients, periprosthetic joint infection resulted in a late discharge for all patients, mean 4.8 and 7.1 days, respectively. Dual component revision was performed in 70.5% of rTHA. Only 27.6% of rTKA were 2-component revisions or placements of an antibiotic spacer. CONCLUSIONS: Several patient and surgical factors preclude early discharge candidacy. For rTHA, an mFI-5 of >2/5, comorbidity index of >4, or a surgical time of >122 minutes is predictive of prolonged LOS. For rTKA, an mFI-5 of >2/5, Charlson Comorbidity Index of >5, or a surgical time of >63 minutes predicts prolonged LOS.

Potential anticancer effect of free and nanoformulated Deferasirox for breast cancer treatment: in-vitro and in-vivo evaluation.

BACKGROUND: Breast cancer (BC) stands as the second-leading cause of mortality among women worldwide. Many chemotherapeutic treatments for BC come with significant adverse effects. Additionally, BC is recognized as one of the most resistant forms of malignancy to treatment. Consequently, there exists a critical need for innovative therapeutic agents that are both highly effective and exhibit reduced toxicity and side effects for patients. Deferasirox (DFX), an iron-chelating drug approved by the FDA for oral use, emerges as a promising contender in the fight against BC proliferation. DFX, primarily administered orally, is utilized to address chronic iron excess resulting from blood transfusions, and it is the inaugural treatment for chronic iron overload syndrome. However, DFX encounters limitations due to its poor water solubility. AIM: This study aimed at incorporating DFX into lipid nanocapsules (DFX-LNCs) followed by investigating the anticancer effect of the DFX nanoform as compared to free DFX in-vitro and on an orthotopic BC mouse model in-vivo. METHODS: The DFX-LNCs was prepared and imaged using TEM and also characterized in terms of particle size (PS), zeta potential (ZP), and polydispersity index (PDI) using DLS. Moreover, drug release, cytotoxicity, and anticancer effect were assessed in-vitro, and in-vivo. RESULTS: The results revealed that DFX-LNCs are more cytotoxic than free DFX with IC50 of 4.417 µg/ml and 16.114 µg/ml, respectively, while the plain LNCs didn't show any cytotoxic effect on the 4T1 cell line (IC50 = 122.797 µg/ml). Besides, the apoptotic effect of DFX-LNCs was more pronounced than that of free DFX, as evidenced by Annexin V/PI staining, increased BAX expression, and decreased expression of BcL-2. Moreover, DFX-LNCs showed a superior antitumor effect in-vivo with potent antioxidant and anti-proliferative effects. CONCLUSION: The newly developed DFX nanoform demonstrated a high potential as a promising therapeutic agent for BC treatment.