N-Benzylated 5-Hydroxybenzothiophene-2-carboxamides as Multi-Targeted Clk/Dyrk Inhibitors and Potential Anticancer Agents.

Numerous studies have reported that Dyrk1A, Dyrk1B, and Clk1 are overexpressed in multiple cancers, suggesting a role in malignant disease. Here, we introduce a novel class of group-selective kinase inhibitors targeting Dyrk1A, Dyrk1B, and Clk1. This was achieved by modifying our earlier selective Clk1 inhibitors, which were based on the 5-methoxybenzothiophene-2-carboxamide scaffold. By incorporating a 5-hydroxy group, we increased the potential for additional hydrogen bond interactions that broadened the inhibitory effect to include Dyrk1A and Dyrk1B kinases. Within this series, compounds 12 and 17 emerged as the most potent multi-kinase inhibitors against Dyrk1A, Dyrk1B, and Clk1. Furthermore, when assessed against the most closely related kinases also implicated in cancer, the frontrunner compounds revealed additional inhibitory activity against Haspin and Clk2. Compounds 12 and 17 displayed high potency across various cancer cell lines with minimal effect on non-tumor cells. By examining the effect of these inhibitors on cell cycle distribution, compound 17 retained cells in the G2/M phase and induced apoptosis. Compounds 12 and 17 could also increase levels of cleaved caspase-3 and Bax, while decreasing the expression of the antiapoptotic Bcl-2 protein. These findings support the further study and development of these compounds as novel anticancer therapeutics.

"Ultrastructural changes of platelets in COVID-19 and chronic viral hepatitis patients ".

Platelet-viral interactions are evolving as a new concern. Coagulation disorder is a major consequence of the COVID-19 infection. In chronic hepatitis virus infections, defect in coagulation factors, thrombocytopenia and platelet function abnormalities are common. A SARS-CoV-2 infection on top of chronic viral hepatitis infection can be common in areas where viral hepatitis is endemic. Here, we investigate the platelet ultrastructural changes and estimate the serum platelet factor-4 (PF-4), ferritin, CRP, and D-dimer in COVID-19 patients (n = 60), COVID-19 patients with associated chronic viral hepatitis (n = 20), and healthy subjects (n = 20). Ultrastructural changes were demonstrated in all test groups, denoting platelet activation. In chronic viral hepatitis patients, Platelet ultrastrustural apoptotic changes were also seen. Significantly high levels of PF-4 were confirmed in moderate and severe COVID-19 patients (P.value <0.001), with a cut off value of 17 ng/ml for predicting disease severity. A positive correlation of PF-4 with the level of serum ferritin, CRP, and D-dimer (p value < 0.001) was noted, while negatively correlated with platelet count and platelet granule count (p value < 0.001). In our study, chronic viral hepatitis patients presented mild COVID-19 signs, and their PF-4 level was comparable with the subgroup of mild COVID-19 infection. The platelet's critical role in COVID-19 coagulopathy and chronic viral hepatitis is evidenced by the ultrastructural changes and the high levels of PF4. Moreover, a dual viral infection poses a substantial burden on the platelets, necessitating close monitoring of the patient's coagulation profile.

Ultrasound Hand and Wrist Findings in Children with Systemic Lupus Erythematosus.

BACKGROUND: Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease that can involve any organ system. SLE typically affects the musculoskeletal system to varying degrees, and patients are frequently most prone to have pain in the hand joints. OBJECTIVES: The study aims to assess by ultrasound the presence of joint inflammation in patients with juvenile Systemic Lupus Erythematosus (JSLE) not complaining of painful joints of the hand and wrist (asymptomatic) and compare the findings with those in JSLE patients complaining of painful hand and wrist joints (symptomatic) and in healthy controls. METHODS: This was a cross-sectional case control study on 37 JSLE patients. Thirty were asymptomatic for joint complaints. Ultrasound examined wrists and joints of both hands, 11 joints in each hand, to assess synovial hypertrophy, effusion and pathological vascularization (using power Doppler) (PD), and were given a score of 0-3. Patients were compared with 8 healthy controls. RESULTS: Ultrasound abnormalities (synovial hypertrophy and increased vascularity) were detected in 22/30 of the asymptomatic patients (73.3%) and in all 7 symptomatic patients (100%). In asymptomatic children, 29 joints were affected (4.4% of all joints), compared to 13 joints in the symptomatic patients (8.4% of all joints). Synovitis score was mild or moderate (1 or 2) in both symptomatic and asymptomatic patients, with all showing increased vascularity. In the control group, 5 joints (2.8% of all joints) showed synovial hypertrophy but no increased vascularity. CONCLUSION: Increased vascularity (PD more than 0) is a more reliable indicator of inflammation than synovial hypertrophy, which may be detected in healthy individuals.

Nutritional Related Knowledge of Cancer Prevention among Primary Health Care Physicians.

OBJECTIVES: To explore the cancer prevention-related nutrition knowledge of primary health care physicians towards nutrition and its relation to the development of cancer. MATERIALS AND METHODS: a cross-sectional study was conducted among family physicians in Riyadh, between November 2019 and April 2020. The participants in the current study were surveyed using a self-administered questionnaire. The questionnaire included socio-economic data and data related to the association between nutrition and cancer. RESULTS: The mean correct knowledge score for physicians is good but less than expected (26.5+5.8) 73.6%. Multiple regression revealed that age, position, and nationality to be significantly associated with knowledge of cancer prevention (P<0.05) among physicians. CONCLUSIONS: Primary care physicians have good knowledge about the relation between nutrition and cancer but not sufficient, they should have continuous nutrition educational training programs to ensure safe and sound nutritional advice to patients and for the public about the relation of nutrition and cancer.

A juvenile dermatomyositis: demographics, characteristics and disease outcome in an Egyptian cohort.

OBJECTIVES: To study the demographics, characteristics, management and disease outcome of Egyptian children with juvenile dermatomyositis (JDM). METHODS: Retrospective analysis of the records of 134 JDM patients attending two centres in Cairo, Egypt from January 2010 to December 2019. A total of 128 patients were included in the study, all of which fulfilled either the Bohan and Peter criteria and/or the EULAR/ACR classification criteria of 2017. RESULTS: The mean age of disease onset was 5.9±2.8 years and the follow-up duration were 6±3.2 years. Female to male ratio was 2.2:1. Constitutional manifestations and cutaneous skin ulcers were common, while gut vasculopathy was rare in our patients. Heliotrope rash was the commonest skin manifestation. Lactate dehydrogenase enzyme was more frequently elevated than creatine kinase. Electromyography was the most frequently used diagnostic procedure, while muscle biopsy and muscle MRI were not commonly done in our patients. Glucocorticoids, methotrexate, hydroxychloroquine, mycophenolate mofetil and IVIG were the most frequently used medications. Sixty (46.9 %) of the patients had clinically inactive disease, at the last follow-up visit. Chronic skin disease, residual muscle weakness, calcinosis and growth failure were among the most common cumulative damage manifestations. The mortality rate was 1.6% over the follow-up period, one death was due to severe infection, and the other due to respiratory failure. CONCLUSIONS: Although our patients shared several similarities with their peers in the Middle East and in Europe, there were some striking differences. These differences can be attributed to the ethnic and environmental disparities.

Assessment of Lupus Nephritis in a Multicenter Retrospective Egyptian Cohort: Initial Characteristics, Influence of Age and Gender, Outcome, and Potential Association with Disease Damage.

The study aimed to evaluate the association of demographic, clinical, and histopathologic characteristics with renal and disease outcomes. Persistent lack of partial or complete remission despite sequential induction therapy, chronic kidney disease (CKD) or endstage renal disease (ESRD), and/or mortality were determined as poor renal outcomes. Disease damage was investigated through the Systemic Lupus International Collaborating Clinics/ American College of Rheumatology Damage Index (SDI). Of 201 biopsy-proven lupus nephritis patients, a poor outcome was present in 56 (27.9%) patients, with nine (4.5%), 22 (10.9%), and 29 (14.4%) patients demonstrating lack of response, CKD, and ESRD, respectively, and the prevalence of mortality was 5.5% (11/201). The outcome was poor among males [29/201 (14.4%)] [P = 0.008; odds ratio (OR): 2.8; 95% confidence interval (CI): 1.2-6.4], yet comparable between adult- and juvenile-onset patients [80/201 (39.8%) (≤16 years)] (P = 0.6; OR: 0.8; 95% CI: 0.4-1.6). Hypertension (P <0.001; OR: 6.3; 95% CI: 2.6-14.9), elevated creatinine (P <0.001; OR: 5.2; 95% CI: 2.6-10.3), and hematuria (P <0.001; OR: 3.7; 95% CI: 1.9-7.5) at presentation, and fibrinoid necrosis [P <0.001; odds ratio (OR): 4.1; 95% confidence interval (CI): 2.1-8.1], wire loops (P = 0.006; OR: 2.4; 95% CI: 1.2-4.6), crescents (P <0.001; OR: 5.4 95% CI: 2.8-10.5), interstitial fibrosis (P = 0.001; OR: 2.7; 95% CI: 1.4-5.1), and acute vascular lesions (P = 0.004; OR: 3.6; 95% CI: 1.4-9.4) on biopsy were associated with a poor outcome. Chronic glomerular (P = 0.003) and acute vascular lesions (P <0.001), and a higher chronicity index (r = 0.1; P = 0.006) on biopsy, and frequent renal (r = 0.3; P <0.001) and extra-renal flares (r = 0.2; P <0.001) were associated with higher SDI scores. Among the studied renal and extra-renal parameters, independent predictors of higher disease damage solely included frequent renal flares (ᵝ= 1; P <0.001). To conclude, a poor renal outcome (27.9%) was associated with distinct features. Disease damage was associated with frequent renal flares.

Characteristics, evolution, and outcome of patients with non-infectious uveitis referred for rheumatologic assessment and management: an Egyptian multicenter retrospective study.

OBJECTIVE: To investigate the characteristics, evolution, and visual outcome of non-infectious uveitis. METHODOLOGY: Records of 201 patients with non-infectious uveitis (136 (67.7%) males and 84 (41.8%) juvenile-onset (≤ 16 years)) were retrospectively reviewed. Data were analyzed through Kruskal-Wallis and Mann-Whitney, chi-square (χ2) tests, and logistic regression. RESULTS: The median disease and follow-up durations were 36 (interquartile range (IQR) 24-70) and 24 (IQR 10-36) months, respectively. Fifty-eight (28.9%) patients had persistently idiopathic uveitis, and 143 (71.1%) were associated with rheumatic diseases, of whom uveitis heralded, coincided with, and succeeded the rheumatic manifestation(s) in 62/143 (43.4%), 37/143 (25.9%), and 44/143 (30.7%) patients, respectively. Established rheumatic diseases were Behçet's disease (103/201 (51.2%)), juvenile idiopathic arthritis (13/201 (6.5%)), sarcoidosis (8/201 (4%)), seronegative spondyloarthropathy (7/201 (3.5%)), and Vogt-Koyanagi-Harada (7/201 (3.5%)), and other diagnoses were present in 5/201 (2.5%) patients. Patients with idiopathic uveitis were characterized by a juvenile-onset (p < 0.001), lower male predominance (p = 0.01), prevalent granulomatous (p < 0.001), and anterior (p = 0.001) uveitis. The median visual acuity at last visit was 0.3 (IQR 0.05-0.6). Visual loss was present in 45/201 (22.3%) patients (36/201 (17.9%) unilateral and 9/201 (4.4%) bilateral). Apart from a longer disease duration (p = 0.002), lower educational level (p = 0.03), and prevalent panuveitis (p < 0.001), visual loss was not associated with any other studied ocular or extra-ocular characteristics. CONCLUSION: Behçet's disease (51.2%) and idiopathic uveitis (28.9%) were the most prevalent causes of non-infectious uveitis in our study. Visual loss (22.3%) was associated with a longer disease duration, lower education level, and prevalent panuveitis. Key Points • Most common causes of uveitis referred to rheumatologists were Behçet's disease and idiopathic uveitis. • Several rheumatic diseases initially presented only with uveitis, more commonly in adult and male patients. • Panuveitis was more frequent among patients with an established rheumatic disease, whereas granulomatous uveitis was uncommon. • Longer disease duration and presence of panuveitis were independently associated with visual loss.

A comparative study between the disease characteristics in adult-onset and childhood-onset systemic lupus erythematosus in Egyptian patients attending a large university hospital.

INTRODUCTION: Disease features and laboratory abnormalities differ among adult-onset and childhood-onset systemic lupus erythematosus (aSLE and cSLE). Socioeconomic status both independent of, and in combination with, ethnicity influences the disease phenotype and outcome. OBJECTIVE: To compare the various disease features among patients with cSLE and aSLE in a limited monetary income Egyptian cohort attending a large free-of-charge university hospital. Patients and methods: Retrospective analysis of the medical records of 714 SLE patients attending Cairo University Hospitals from January 2000 to December 2019. Of them 602 (400 with aSLE and 202 with cSLE) were enrolled in the study. RESULTS: The mean age of disease onset was 28.27 ± 10.55 among aSLE patients compared to 12.88 ± 4.26 years among cSLE patients. Disease duration was 12.03 ± 5.05 and 4.14 ± 3.18 years in aSLE and cSLE, respectively. Female to male ratio was 15:1 among patients with aSLE, as compared to 2.67:1 among cSLE (<0.001). Arthritis (69%), oral ulcers (48.5%), neuropsychiatric (18.3%) and thrombotic manifestations of antiphospholipid syndrome (12%) were significantly more frequent in aSLE. On the other hand, renal (67.8%), serositis (49.6%), fever (49%), lymphopenia (40.6%), hemolytic anemia (38.6%), and discoid lupus (13.4%) were significantly more frequent in cSLE. Weight loss, malar rash, photosensitivity, thrombocytopenia, leucopenia and lymphadenopathy were not significantly different between the two groups. Hypocomplementemia, proteinuria, urinary sediments, hematuria were significantly more frequent in cSLE. For those patients with renal involvement, who underwent renal biopsy (58.3% in aSLE and 63.5% in cSLE), there was no significant difference with regard to the different histopathological classes. Anti-Smith, anti-cardiolipin antibodies and rheumatoid factor were significantly more frequent among aSLE patients, while anti-La antibodies were more frequent among cSLE patients. CONCLUSION: Arthritis was the most common clinical manifestation over time in aSLE compared to renal involvement in cSLE. Renal disease tends to be more active in cSLE. The differences in disease manifestations between this cohort and other studies can be attributed to the ethnic and socioeconomic disparities.

Red Cell Distribution Width (RDW) as a Marker of Subclinical Inflammation in Children with Familial Mediterranean Fever.

BACKGROUND: Familial Mediterranean fever (FMF) is an autoinflammatory disease with potentially devastating effects on the kidney, and the chronic subclinical inflammation may also be deleterious. Further, proteinuria has been associated with chronic inflammatory states. OBJECTIVE: We aimed to probe whether red cell distribution width (RDW) can be used as a reliable indicator of subclinical disease in FMF patients. METHODS: Ninety-nine children with FMF, according to the new pediatric FMF criteria, were included in the present study. All were attack-free at the time of the study. They were compared with 44 healthy age-matched controls. For all patients and controls, the following tests were done: Complete blood count (in the form of red cell count, leukocyte count, platelet count, hemoglobin, RDW and MCV), CRP, ESR, creatinine and an estimated glomerular filtration rate (e-GFR). For patients, serum and urine albumin and albumin/creatinine ratio were also determined. Group 1 consisted of 61 patients, who were not suffering from microalbuminuria, and Group 2 consisted of 38 patients who had confirmed albuminuria. RESULTS: RDW and ESR were significantly higher in patients with FMF without microalbuminuria than in controls, while MCV was smaller in controls (p<0.05). CONCLUSION: RDW can be used as an indicator of subclinical inflammation in children with FMF. The tests are easy to perform and cheaper than more sophisticated tests. Microalbuminuria may be silent and occur on the background of normal levels of acute-phase reactants. All cases must be routinely checked for microalbuminuria.

Late-onset systemic lupus erythematosus: characteristics and outcome in comparison to juvenile- and adult-onset patients-a multicenter retrospective cohort.

INTRODUCTION: The aim of this study was to investigate the characteristics and outcome of systemic lupus erythematosus (SLE) among elderly-onset patients. METHODS: This study included 575 SLE patients managed at Cairo, Alexandria, and Helwan universities from August 2014 to 2018: of whom 49 (8.5%), 420 (73%), and 106 (18.4%) were elderly- (> 50 years), adult- (17-50 years), and juvenile- (≤ 16 years) onset patients, respectively. Cumulative characteristics were recorded. Disease activity at the last visit was investigated through the Systemic Lupus Erythematosus Disease Activity Index-2K (SLEDAI-2K), whereby lupus low disease activity (LLDA) was defined as a SLEDAI-2K score ≤ 4. The disease outcome was assessed through investigating disease damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI)) and the prevalence of mortality. Quantitative and categorical data were compared using Kruskal-Wallis and Mann-Whitney tests, and chi-square (χ2) test, respectively. RESULTS: Late-onset SLE (LSLE) patients demonstrated the lowest prevalence of constitutional and mucocutaneous manifestations (p < 0.001), serositis (p = 0.006), nephritis (p < 0.001), neuropsychiatric involvement (p < 0.001), and hypocomplementinemia (p < 0.001), but showed the highest prevalence of comorbidities and multimorbidity (comorbidities ≥ 2) (p < 0.001), and positive anti-ds DNA antibodies (p < 0.001). Elderly-onset patients demonstrated the lowest SLEDAI-2K and SDI scores, achieved LLDA the most (p < 0.001), and developed any damage (SDI ≥ 1) the least (p < 0.001). The prevalence of mortality was comparable across the three age groups (p = 0.6). CONCLUSIONS: Late-onset SLE patients (8.5%) showed the lowest prevalence of major organ involvement and the highest prevalence of comorbidities, and demonstrated more favorable disease activity and damage indices.Key Points• The disease characteristics and outcome among LSLE patients are characterized by being controversial, with studies from the Middle East being limited. Our cohort constituted of 8.5% elderly-onset SLE patients-who were characterized by the lowest prevalence of major organ involvement and the lowest activity and damage indices-making the disease pattern more favorable in this age group, despite being characterized by the highest prevalence of comorbidities.

Scalable Sonochemical Synthetic Strategy for Pyrazolo[1,5-a]pyridine Derivatives: First Catalyst-Free Concerted [3 + 2] Cycloaddition of Alkyne and Alkene Derivatives to 2-Imino-1H-pyridin-1-amines.

A highly efficient and convenient one-pot sonochemical synthetic strategy has been sophisticated for synthesizing a novel class of polysubstituted pyrazolo[1,5-a]pyridines via [3 + 2] cycloaddition of dialkyl acetylenedicarboxylates, ethyl propiolate, and alkenes to 2-imino-1H-pyridin-1-amines under catalyst-free conditions. A series of uniquely substituted pyrazolo[1,5-a]pyridines has been synthesized with a very good to excellent yield, and the mechanistic pathway that involves a [3 + 2] annulation process was also proposed. In this study, several spectroscopic tools of analyses were employed for structure elucidation, and the X-ray single-crystal technique was utilized to confirm the proposed mechanism and the regioselectivity.

An Unusual Presentation of a Rare Scleroderma Mimic: What is Behind the Scenes?

BACKGROUND: Scleroderma or systemic sclerosis (SSc) is a rare systemic autoimmune disease. Many conditions mimic the presentation of SSc, especially skin thickening and fibrosis. One of these conditions is scleredema, a rare collagen and mucin deposition disorder which was found to be associated with diabetes mellitus, streptococcal infection or monoclonal gammopathy. CASE PRESENTATION: A 55 years old female presented with insidious onset and progressive course of diffuse skin thickening of face, neck, arms, forearms, thighs, chest, back, and excluding both hands and feet of 6 years' duration associated with arthralgia, dysphagia and dyspnea on exertion of 1- year duration. There was no history of Raynaud's phenomenon. Erythrocyte sedimentation rate was 100 mm/1st h, autoantibodies for SSc were negative, nail fold capillaroscopy normal, pulmonary function tests showed restrictive pattern and high-resolution computed tomography showed interstitial lung fibrosis. Patient was not fulfilling the American collage of rheumatology/European League Against Rheumatism classification criteria for SSc. Skin biopsy was done and revealed histological appearance of scleredema. Investigations were done for disease association with scleredema. The patient was not diabetic, antistreptolysin O titer was normal, serum protein electrophoresis, immunofixation and bone marrow biopsy were done, and the patient was diagnosed as scleredema associated with immunoglobulin A kappa multiple myeloma. Treatment by combination of bortezomib, cyclophosphamide, and dexamethasone was started with marked clinical and hematological improvement. CONCLUSION: Many conditions mimic SSc including scleredema, which may be the initial presentation of multiple myeloma. Rheumatologists and dermatologists should be able to recognize these conditions to provide the suitable management and follow-up for these patients.

Serum Amyloid A Level in Egyptian Children with Familial Mediterranean Fever.

Background and Objectives. SAA is an acute-phase reactant detected during an FMF attack or other inflammatory conditions. High SAA levels may increase the risk of amyloidosis. The aim of the study is to measure the serum amyloid A (SAA) level in a group of Egyptian children with familial Mediterranean fever (FMF) and study its various correlates, if any. Methods. The study enrolled seventy-one children with FMF. Results. SAA level was high in 78.9% of the studied patients with a mean of 81.62 ± 31.6 mg/L, and CRP was positive in 31% of patients. There was no significant releation between SAA level and any demographic or clinical manifestation. High SAA was more frequent in V726A allele (16.9%) followed by M694V allele (12.3%). Elevated SAA levels were more frequent in patients on low colchicine doses. Forty-five percent (45%) of patients have low adherence to colchicine therapy. Interpretation and Conclusion. High SAA levels were detected two weeks after last FMF attack in a large percentage of Egyptian FMF children. This indicates that subclinical inflammation continues during attack-free periods, and SAA could be used as a marker of it.

A comparative study of the novel spectrophotometric methods versus conventional ones for the simultaneous determination of Esomeprazole magnesium trihydrate and Naproxen in their binary mixture.

Two novel simple, specific, accurate and precise spectrophotometric methods manipulating ratio spectra are developed and validated for simultaneous determination of Esomeprazole magnesium trihydrate (ESO) and Naproxen (NAP) namely; absorbance subtraction and ratio difference. The results were compared to that of the conventional spectrophotometric methods namely; dual wavelength and isoabsorptive point coupled with first derivative of ratio spectra and derivative ratio. The suggested methods were validated in compliance with the ICH guidelines and were successfully applied for determination of ESO and NAP in their laboratory prepared mixtures and pharmaceutical preparation. No preliminary separation steps are required for the proposed spectrophotometeric procedures. The statistical comparison showed that there is no significant difference between the proposed methods and the reported method with respect to both accuracy and precision.