Molecular characterization of the whole genome of H9N2 avian influenza virus isolated from Egyptian poultry farms.

H9N2 avian influenza viruses (AIVs) affect both poultry and humans on a global level, and they are especially prevalent in Egypt. In this study, we sequenced the entire genome of AIV H9N2 isolated from chickens in Egypt in 2021, using next-generation sequencing (NGS) technology. Phylogenetic analysis of the resulting sequences showed that the studied strain was generally monophyletic and grouped within the G1 sublineage of the Eurasian lineage. Four segments (polymerase basic 2 [PB2], polymerase basic 1 [PB1], polymerase acidic [PA], and non-structural [NS]) were related to Egyptian genotype II, while the nucleoprotein (NP), neuraminidase (NA), matrix (M), and haemagglutinin (HA) segments were related to Egyptian genotype I. Molecular analysis revealed that HA protein contained amino acid residues (191H and 234L) that suggested a predilection for attaching to human-like receptors. The antigenic sites of HA had two nonsynonymous mutations: V194I at antigenic site A and M40K at antigenic site B. Furthermore, the R403W and S372A mutations, which have been observed in H3N2 and H2N2 strains that caused human pandemics, were found in the NA protein of the detected strain. The internal proteins contained virulence markers: 504V in the PB2 protein, 622G, 436Y, 207K, and 677T in the PB1 protein, 127V, 550L, and 672L in PA protein, and 64F and 69P in the M protein. These results show that the detected strain had undergone intrasubtype reassortment. Furthermore, it contains changes in the viral proteins that make it more likely to be virulent, raising a question about the tendency of AIV H9N2 to become highly pathogenic in the future for both poultry and humans.

Ambroxol, a mucolytic agent, boosts HO-1, suppresses NF-κB, and decreases the susceptibility of the inflamed rat colon to apoptosis: A new treatment option for treating ulcerative colitis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease of unknown etiology that increases the risk of developing colorectal cancer and imposes a lifelong healthcare burden on millions of patients worldwide. Current treatment strategies are associated with significant risks and have been shown to be fairly effective. Hence, discovering new therapies that have better efficacy and safety profiles than currently exploited therapeutic strategies is challenging. It has been well delineated that NF-κB/Nrf2 crosstalk is a chief player in the interplay between oxidative stress and inflammation. Ambroxol hydrochloride, a mucolytic agent, has shown antioxidant and anti-inflammatory activity in humans and animals and has not yet been examined for the management of UC. Therefore, our approach was to investigate whether ambroxol could be effective to combat UC using the common acetic acid rat model. Interestingly, a high dose of oral ambroxol (200 mg/kg/day) reasonably improved the microscopic and macroscopic features of the injured colon. This was linked to low disease activity and a reduction in the colonic weight/length ratio. In the context of that, ambroxol boosted Nrf2 activity and upregulated HO-1 and catalase to augment the antioxidant defense against oxidative damage. Besides, ambroxol inactivated NF-κB signaling and its consequent target pro-inflammatory mediators, IL-6 and TNF-α. In contrast, IL-10 is upregulated. Consistent with these results, myeloperoxidase activity is suppressed. Moreover, ambroxol decreased the susceptibility of the injured colon to apoptosis. To conclude, our findings highlight the potential application of ambroxol to modify the progression of UC by its anti-inflammatory, antioxidant, and antiapoptotic properties.

Novel topoisomerase II/EGFR dual inhibitors: design, synthesis and docking studies of naphtho[2',3':4,5]thiazolo[3,2-a]pyrimidine hybrids as potential anticancer agents with apoptosis inducing activity.

Topoisomerases II are ubiquitous enzymes with significant genotoxic effects in many critical DNA processes. Additionally, epidermal growth factor receptor (EGFR) plays pivotal role in tumour growth and angiogenesis. A novel series of naphtho[2',3':4,5]thiazolo[3,2-a]pyrimidine hybrids have been designed, synthesised and evaluated for their topo IIα/EGFR inhibitory and apoptotic inducer activities. Cytotoxicity of the synthesised hybrids was evaluated against MCF-7, A549 and HCT-116 cell lines. Of the synthesised hybrids, 6i, 6a and 6c experienced superior cytotoxic activity compared to doxorubicin and erlotinib against the tested cancer cells. The molecular mechanism of these hybrids revealed their ability to successfully inhibit topo IIα and EGFR activities in micromolar concentration and may serve as topo II catalytic inhibitor. Moreover, these hybrids significantly arrested cell cycle at G2/M phase together with increased p53, caspae-7, caspase-9 levels and Bax/Bcl-2 ratio. The synthesised hybrids showed efficient binding pattern in molecular docking study and have acceptable drug likeness characters.

Analysis of Geographic and Environmental Factors and Their Association with Cutaneous Melanoma Incidence in Canada.

BACKGROUND: Over 90% of skin cancers including cutaneous melanoma (CM) are related directly to sun exposure. Despite extensive knowledge on ultraviolet radiation's (UVR) detrimental impact, many still fail to implement sun protection/sun avoidance. Human behavior, attitudes, and cultural norms of individuals and communities heavily depend on the surrounding climate/environment. In many instances, the climate shapes the culture/norms of the society. Canada has vast geographic/environmental differences. METHODS: In the current ecological study, we sought to examine the relationship between various geographic and environmental factors and the distribution of CM incidence by Forward Sortation Area (FSA) postal code across Canada. CM incidence data were extracted from the Canadian Cancer Registry, while environmental data were extracted from the Canadian Urban Environmental Health Research Consortium (greenspace, as measured by the normalized difference vegetation index; annual highest temperature; absolute number and average length of yearly heat events; annual total precipitation [rain and snow]; absolute number and average length of events with precipitation [rain and snow]; and summer UVR index). The above geographic/environmental data by FSA were correlated with the respective CM incidence employing negative binomial regression model. RESULTS: Our analysis highlights that increases in annual average temperature, summer UVR, and greenspace were associated with higher expected incidence of CM cases, while higher number of annual heat events together with highest annual temperature and higher average number of annual rain events were associated with a decrease in CM incidence rate. This study also highlights regional variation in environmental CM risk factors in Canada. CONCLUSIONS: This national population-based study presents clinically relevant conclusions on weather/geographic variations associated with CM incidence in Canada and will help refine targeted CM prevention campaigns by understanding unique weather/geographic variations in high-risk regions.

Drug-induced acanthosis nigricans: A systematic review and new classification.

Drug-induced acanthosis nigricans is an uncommon subtype of acanthosis nigricans and the data on this topic is not well understood by clinicians as it is presently limited in the literature. Previous reports of drug-induced acanthosis nigricans have simply consisted of a list of drugs possibly implicated in causing acanthosis nigricans. Several drugs listed are based on single case reports without biopsy confirmation, report of clearing on stopping the drug or reporting on whether acanthosis nigricans recurred with drug rechallenge. A comprehensive literature search was conducted using PubMed, EMBASE(Ovid), Cochrane Library, Scopus, and Web of Science electronic databases. The authors screened the initial result of the search strategy by title and abstract using the following inclusion criteria: eligible studies included those with patients who developed acanthosis nigricans secondary to a drug. This study is the first to comprehensively review the drugs that have been implicated in the development of acanthosis nigricans. A total of 38 studies were included in the systematic review, and a total of 13 acanthosis nigricans inducing drugs were identified. Nicotinic acid and insulin were the two most significant drugs that were reported to cause acanthosis nigricans. By using the results of this study, we created a revised classification system of drug-induced acanthosis nigricans which can be used as a concise framework for clinicians to refer to.

Design, Synthesis, Cytotoxic Screening and Molecular Docking Studies of Novel Hybrid Thiosemicarbazone Derivatives as Anticancer Agents.

Thiosemicarbazones have been the focus of scientists owing to their broad clinical anticancer range. Herein, A Series of new thiosemicarbazone derivatives 5-9 were synthesized and confirmed through the use of different spectroscopic techniques along with elemental analysis. The in vitro cytotoxic activity of compounds 5-9 against MCF-7 and A549 cell lines and normal breast cells were assessed. Several compounds were found to be active. The most active compound 7 caused MCF-7 cell cycle arrest at G1/ S phases; and induced apoptosis at the pre-G1 phase. The apoptosis-inducing activity of compound 7 was proofed by the elevation of caspase 3/7 activity and also by up-regulation of the expression of Bax and p53 proteins together with the down-regulation of the expression of the Bcl-2 protein. It also had a strong inhibitory effect topoisomerase IIß enzyme. Molecular Docking study revealed that the synthesized compounds had good docking scores compared to the standard drug Etoposide towards the topoisomerase IIß protein (3QX3). Overall, these findings confirmed that the new thiosemicarbazone derivatives could aid in the development of promising cancer drug candidates.

Warfarin induced leukocytoclastic vasculitis: an extraordinary side effect.

Warfarin is one of the most commonly used anticoagulants in the management of thromboembolic events. Herein we report a rare case of warfarin induced leukocytoclastic vasculitis in a patient with history of rheumatic heart disease and a mechanical mitral valve prosthesis who presented with heart failure and palpable purpura. Upon clinical suspicion of cutaneous small vessel vasculitis, a comprehensive laboratory panel was performed. Warfarin induced vasculitis was suspected when withdrawal of warfarin, due to rising INR, led to improvement of the skin lesions. The diagnosis was finally confirmed when re-instatement of warfarin reproduced the skin lesions and a skin biopsy showed evidence for leukocytoclastic vasculitis with eosinophilic infiltration. A third of cases of leukocytoclastic vasculitis are due to drug hypersensitivity which being a diagnosis of exclusion with varying manifestations, requires a high index of clinical suspicion. Since drug induced leukocytoclastic vasculitis may affect multiple organ systems and even cause mortality, clinicians must be aware of this rare adverse event, promptly discontinue the drug, and commence anti-inflammatory or immunosuppressive treatment when necessary.

Evolution of ARDS biomarkers: Will metabolomics be the answer?

To date, there is no clinically agreed-upon diagnostic test for acute respiratory distress syndrome (ARDS): the condition is still diagnosed on the basis of a constellation of clinical findings, laboratory tests, and radiological images. Development of ARDS biomarkers has been in a state of continuous flux during the past four decades. To address ARDS heterogeneity, several studies have recently focused on subphenotyping the disease on the basis of observable clinical characteristics and associated blood biomarkers. However, the strong correlation between identified biomarkers and ARDS subphenotypes has yet to establish etiology; hence, there is a need for the adoption of other methodologies for studying ARDS. In this review, we will shed light on ARDS metabolomics research in the literature and discuss advances and major obstacles encountered in ARDS metabolomics research. Generally, the ARDS metabolomics studies focused on identification of differentiating metabolites for diagnosing ARDS, but they were performed to different standards in terms of sample size, selection of control cohort, type of specimens collected, and measuring technique utilized. Virtually none of these studies have been properly validated to identify true metabolomics biomarkers of ARDS. Though in their infancy, metabolomics studies exhibit promise to unfold the biological processes underlying ARDS and, in our opinion, have great potential for pushing forward our present understanding of ARDS.

Folliculotropism Does Not Affect Overall Survival in Mycosis Fungoides: Results from a Single-Center Cohort and Meta-Analysis.

BACKGROUND: Folliculotropic mycosis fungoides (FMF) is a distinct subtype of mycosis fungoides (MF) with unique clinicopathological features. The medical literature suggests that FMF has a more aggressive course and worse survival than classic MF. Previous studies do not use standardized treatment, and no studies have reported an association between treatment response and overall survival (OS). OBJECTIVE: To compare OS for MF, FMF, and Sézary syndrome (SS) patients. METHODS: Data were collected retrospectively from 218 patients (171 MF, 15 SS, 32 FMF) treated in a single academic center between 1970 and 2016. RESULTS: Negative predictors of OS were age (OR = 1.07), male sex (OR = 1.63), and stage IIB, III, and IV (OR = 4.10, 5.42, and 7.54, respectively, vs. stage IA). Lack of initial PUVA response was strongly associated with negative OS (OR = 3.08). Kaplan-Meier analysis of age-, sex-, and stage-matched MF and FMF patients found similar OS between the 2 groups. The 5-year OS was 91% for FMF and 74% for MF. Meta-analysis of current data and 2 published studies where survival of FMF patients was compared to MF did not reveal statistically significant differences between these 2 diseases. CONCLUSIONS: When patients were matched for age, sex, and disease stage, folliculotropism did not affect OS in MF.

Eruptive syringomas with associated calcinosis cutis-A case report and literature review of this association.

We report the case of a 9-year-old boy presenting with eruptive syringomas and macroscopic lesions of calcinosis cutis resembling subepidermal calcified nodules. Literature review revealed eruptive syringomas can be associated with calcinosis cutis with several different presentations. In this report, we review the five different presentations and associations of eruptive syringomas and calcinosis cutis, which to our knowledge has not been categorized before.

Psoriasis knowledge gaps and misconceptions in the Middle East and North Africa (MENA) regions: patients' survey-based study.

BACKGROUND: Misconceptions among psoriatic patients often lead to a negative impact on disease outcomes. OBJECTIVES: Our main target was knowledge assessment among a sample of psoriatic patients in the Middle East and North Africa (MENA) region where data are scarce. METHODS: The present study is a cross-sectional descriptive survey. It consists of an online questionnaire comprising 19 questions designed to assess psoriasis knowledge and five demographic questions. The questionnaire link was posted on the official Facebook page of the Kasr Al Ainy Psoriasis Unit (KAPU). RESULTS: The questionnaire was taken by 527 participants, but only 396 responses were complete and adequate for analysis. The mean psoriasis knowledge score was higher in females (P = 0.005) and participants with advanced education degrees (P < 0.001). Patients reporting regular follow-ups with dermatologists were more likely to acknowledge joint involvement (P = 0.044) but also incorrectly assume biologics are a final cure (P = 0.038). In addition, they were more likely to assume psoriasis affects pregnancy (P = 0.013). Patients with a family history of psoriasis showed a better mean knowledge score than those without (P = 0.01). Only 54.55% of participants reported knowledge of possible disease exacerbation by drugs. A minority (26.77%) of our patients responded that a diet change could not permanently cure psoriasis. CONCLUSION: This study reports knowledge gaps in a cohort of Arabic-speaking psoriasis patients, especially regarding areas of extracutaneous involvement, the hereditary nature of the disease, and the effect of psoriasis on pregnancy and fertility. Most participants were unaware that biological therapy and a change in diet do not offer a permanent cure. Dermatologists in our region must reach out to their patients and correct the various misconceptions reported in this study.

Topical sodium valproate-loaded nanospanlastics versus conventional topical steroid therapy in alopecia areata: a randomized controlled study.

BACKGROUND: A myriad of therapeutic modalities for alopecia areata are available; however, none is of high level of evidence, creating an immense need for the evaluation of other treatment modalities, of which topical sodium valproate is of potential role via proposed decrease in beta-catenin breakdown, despite its well-known side effect of hair fall as an oral therapy. OBJECTIVE: Evaluating the efficacy and the safety of sodium valproate (SV)-loaded nanospanlastics, in comparison to topical corticosteroids, this is the currently available gold standard topical treatment for patchy AA. METHODOLOGY: A total of 66 patients with patchy AA were randomly assigned to receive either topical mometasone furoate lotion or topical SV applied twice daily to all patches except a control patch, which was left untreated. Clinical, trichoscopic and biochemical assessments of beta-catenin tissue levels and Axin-2 gene expression were carried out at baseline and after 3 months. RESULTS: Both therapeutic modalities were comparable. Potential efficacy was highlighted by significant improvement in the representative patch, the largest treated patch, to the control patch, the smallest untreated patch in both steroid and valproate groups (p = 0.027, 0.003 respectively). Both beta-catenin levels and Axin-2 gene expression were reduced after treatment, pointing to the inhibitory effect of dominating uncontrolled inflammatory milieu. Baseline beta-catenin was found to significantly negatively correlate with improvement in the representative patch in patients with baseline level above 0.42 ng/ml (p = - 0.042). CONCLUSION: Both topical SV and steroids are of comparable modest efficacy. Thus, further evaluation of SV is due in combination with intralesional steroids and other anti-inflammatory treatment modalities, together with developing individualized approaches based on baseline beta-catenin level. GOV IDENTIFIER: NCT05017454, https://clinicaltrials.gov/ct2/show/NCT05017454 .

Adipogenetic effects of retrofractamide A derivatives in 3T3-L1 cells.

In a previous study, retrofractamide A from the fruit of Piper chaba was shown to promote adipogenesis in 3T3-L1 cells. In the present study, retrofractamide A and its derivatives were synthesized, and their adipogenetic effects in 3T3-L1 cells were examined. Among the tested compounds, an amide composed of 9-(3',4'-methylenedioxyphenyl)-nona-2E,4E,8E-trienoic acid and an n-butyl or n-pentyl amine showed strongest activity. Moreover, the amide with the n-pentyl amine moiety significantly increased the uptake of 2-deoxyglucose into the cells, and also increased the mRNA levels of adiponectin, peroxisome proliferator-activated receptor γ2 (PPARγ2), glucose transporter 4 (GLUT4), fatty acid-binding protein (aP2), and CCAAT/enhancer-binding protein (C/EBP) α and ß in a similar manner as the PPARγ agonist troglitazone, although it had less agonistic activity against PPARγ.

Vesicular Darier's disease: a case report and review of the English literature of a rare disease variant.

Darier's disease is an autosomal dominant inherited skin disorder resulting from mutations in the ATP2A2 gene, which encodes SERCA2, an endoplasmic reticulum calcium ATPase. Darier's disease classically manifests as confluent hyperkeratotic brown-to-red papules that manifest and follow a seborrheic distribution, which include the chest, neck, trunk, and face. Vesicular Darier's disease is a rare variant of the disorder where patients develop numerous vesicles and bullae concurrently or independent of the more typical lesions found in Darier's disease.

Mitigating diagnostic performance bias in a skin-tone balanced dermatology curriculum.

INTRODUCTION: Individuals with skin of colour (SoC) have delayed diagnosis and poorer outcomes when presenting with some dermatologic conditions when compared to individuals with light skin (LS). The objective of this study was to determine if diagnostic performance bias can be mitigated by a skin-tone balanced dermatology curriculum. METHODOLOGY: A prospective randomised intervention study occurred over 2 weeks in 2020 at a Canadian medical school. A convenience sample of all first-year medical students (n = 167) was chosen. In week 1, all participants had access to dermatology podcasts and were randomly allocated to receive non-analytic training (NAT; online patient 'cards') on either SoC cases or LS cases. In week 2, all participants received combined training (CT; NAT and analytic training through workshops on how to apply dermatology diagnostic rules for all skin tones). Participating students completed two formative assessments after weeks 1 and 2. RESULTS: Ninety-two students participated in the study. After week 1, both groups had a lower diagnostic performance on SoC (p = 0.0002 and p = 0.002 for students who trained on LS 'cards' and SoC 'cards', respectively). There was a significant decrease in mean skin tone difference in both groups after week 2 (initial training on SoC: 5.8% (SD 12.2) pre, -1.4% (14.7) post, p = 0.007; initial training on LS: 7.8% (15.4) pre, -4.0% (11.8%) post, p = 0.0001). Five students participated in a post-study survey in 2023, and all found the curriculum enhanced their diagnostic skills in SoC. CONCLUSIONS: SoC performance biases of medical students disappeared after CT in a skin tone-balanced dermatology curriculum.

New Pyrazole-Clubbed Pyrimidine or Pyrazoline Hybrids as Anti-Methicillin-Resistant Staphylococcus aureus Agents: Design, Synthesis, In Vitro and In Vivo Evaluation, and Molecular Modeling Simulation.

Two hybrid series of pyrazole-clubbed pyrimidines 5a-c and pyrazole-clubbed pyrazoline compounds 6a,b and 7 were designed as attractive scaffolds to be investigated in vitro and in vivo for antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. From the results of the in vitro antibacterial screening, compound 5c showed excellent activity (minimal inhibitory concentration, MIC = 521 µM) when compared with that of the reference antibiotic levofloxacin (MIC = 346 µM). The inhibition of the target dihydrofolate reductase (DHFR) enzyme by compounds 4 and 5a-c (IC50 = 5.00 ± 0.23, 4.20 ± 0.20, 4.10 ± 0.19, and 4.00 ± 0.18 µM, respectively) was found to be better than the reference drug trimethoprim (IC50 = 5.54 ± 0.28 µM). Molecular modeling simulation results have justified the order of activity of all the newly synthesized compounds as DHFR enzyme inhibitors, and compound 5c exhibited the best binding profile (-13.6169386 kcal/mol). Hence, the most potent inhibitor of the DHFR enzyme, 5c, was chosen to be evaluated in vivo for its activity in treating MRSA-induced keratitis in rats and that, in turn, significantly (P < 0.0001) reduced infection in rats when compared to MRSA-treated group results.