SYNTHESIS, ANTITUMOR ACTIVITY, PHARMACOPHORE MODELING AND QSAR STUDIES OF NOVEL PYRAZOLES AND PYRAZOLO [1, 5-A] PYRIMIDINES AGAINST BREAST ADENOCARCINOMA MCF-7 CELL LINE

Objective: The present work aimed to synthesize New series of pyrazoles 3 and pyrazolo[1,5-a]pyrimidines 5, 7, 9 in order to evaluate their antiproliferative activity against human breast adenocarcinoma MCF-7cell line and study the cell cycle progression of the most active compounds. In addition, Pharmacophore modeling and QSAR Studies of these new compounds were done.Methods: The diazonium salt of 4-aminoacetophenone 1 was coupled with malononitrile in ethanol using sodium acetate affords 2-[(4-acetylphenyl)diazenyl] malononitrile Cycloaddition of hydrazine hydrate, in molar ratios 1:1 or 1:2, on compound 2, furnished 3,5-diaminopyrazolederivatives 3a and 3b respectively. Moreover, new pyrazolo[1,5-a]pyrimidine derivatives 5a-f were obtained upon cyclocondensation of 3a, b with different chalcones 4a-c in EtOH/piperidine,while compounds 7a-f were prepared via cycloaddition of 3a, b with various arylidene malononitriles 6a-c in the same reaction condition. Finally, treatment of 3a, b with ethyl 2-cyano-3-ethoxyacrylate 8a or 2-(ethoxymethylene)malononitrile 8b in EtOH/TEA yielded the novel pyrazolo[1,5-a]pyrimidine derivatives 9a, b respectively. These target compounds were screened for their cytotoxic activity against MCF-7 (human breast Cell Line) followed by study cell cycle of 7a. Finally, Pharmacophore modeling and QSAR Studies was carried out.Results: The pyrazolopyrimidine 7a was the most active compound (IC50 = 3.25 µM), whereas, some of the tested compounds exploited moderate growth inhibitory activity. Its effect was further studied on cell cycle progression; results showed that compound 7a induced cell cycle arrest at S-phase verifying this compound as a promising selective anticancer agent.Conclusion: Compound 7a was found to be the most active member against MCF-7 breast cancer (IC50= 3.25 μM), Further biological assessment of 7a using flow-cytometric analysis, revealed that it induced cell cycle arrest at S phase.Keywords: Pyrazole, Pyrazolo[1,5-a]pyrimidine, MCF-7 breast cancer cell line, Cell cycle profile, 3D pharmacophore,1 QSAR stud

Immunomodulatory effects of food

There is a strong consensus that nutrition plays a role in modulating immune function and that the immune system needs adequate supply of nutrients to function properly. The complexity of the immune system supports this idea because its optimal functioning involves a variety of biological activities including cell division and proliferation, energy metabolism, and production of proteins. The micronutrients most often cited as being important to immune function include vitamins A, C, E, and B6, folate, iron, zinc, and selenium. Other nutrients mentioned as playing a role in immune function include beta-carotene (a precursor to vitamin A), vitamin B12, and vitamin D. On the other hand, over-activation of the immune system can lead to detrimental effects such as chronic inflammation or autoimmune diseases. In persons with allergies, a normally harmless material can be mistaken as an antigen. Some individuals develop an exaggerated immune response to food through developing food allergy which may be IgE mediated, non-IgE mediated, or mixed. This review will highlight the interaction between the immune system and some foods and food components in terms of modulation of immune functions by a variety of mechanisms.Egypt J Pediatr Allergy Immunol 2011;9(1):3-1

Subclinical hypothyroidism among Egyptian children with systemic lupus erythematosus

Background: Thyroid autoimmune diseases have been associated with systemic lupus erythematosus (SLE). Both hypothyroidism and hyperthyroidism are seen, but hypothyroidism is the most common abnormality. Subclinical hypothyroidism (SCH) has been reported among adult lupus patients. SCH is not without risk as it might contribute to a proatherogenic state. Objectives: This study was aimed to assess the frequency of SCH in a group of Egyptian children with SLE and its effects on the serum lipids. Methods: Forty patients with pediatric SLE who regularly follow up at our center were enrolled in this study. They were subjected to routine laboratory investigations of SLE and measurement of serum lipids (serum triglycerides, cholesterol, LDL and HDL) as well as free thyroxine (T4), thyroid stimulating hormone (TSH) and anti-thyroperoxidase antibody (anti-TPO-ab) titre. SLE activity was assessed using the systemic lupus erythematosus disease activity index (SLEDAI). Results: Six patients (15%) were found to have SCH while the remaining 34 patients (85%) had normal thyroid function. Anti-TPO-abs were positive in 4 out of the 6 (66.6 %) SLE patients with SCH and in 20 out of the 34 (58.8%) SLE patients with normal thyroid function. In SLE patients with SCH, TSH correlated positively yet insignificantly with anti-TPO-ab titre and the duration of SLE (p = 0.17, p = 0.12, respectively). There were no statistically significant correlations between the serum lipids of SLE patients with SCH and their thyroid function or anti-TPO-ab titre. Conclusion: SCH is not uncommon among children with SLE. This SCH does not seem to affect serum lipids. However, further longitudinal studies on wider scales are needed to assess the long term effects of SCH in those patients.Keywords: SLE, anti-thyroperoxidase antibodies, subclinical hypothyroidismEgypt J Pediatr Allergy Immunol 2011;9(2):87-9

Interferon gamma: is it a co-player in the pathogenesis of idiopathic nephrotic syndrome

Introduction: Idiopathic nephrotic syndrome (INS), the most common form of NS in childhood, was considered 4 decades ago as a systemic disorder of T cells, mediated through its released cytokines. To date, the exact incriminated cytokine or immunological mediator is not properly defined. Interferon gamma (IFN-γ), a pro-inflammatory cytokine, is thought to have a role in the provocation of the T cell mediated INS relapse, through promotion of T helper1 (Th1) differentiation and suppression of regulatory T cells (Treg). Aim of the study: to evaluate the immunopathogenic role of IFN-γ in children with steroid sensitive idiopathic nephrotic syndrome (SSNS) through monitoring the changes in its levels with disease course. Methods: This study included twenty-five newly diagnosed children with SSINS. They were all given full dose prednisolone, evaluated at initial diagnosis and at full remission as regards the serum level of IFN-γ. Results: Serum levels of IFN-γ were lowermost at time of diagnosis and increased with remission on corticosteroids. Conclusions: this study points to a role for the lower serum IFN-γ at diagnosis, in the immunopathogenesis of INS than at remission and the rise in its serum level might be a marker of remission induction, however this awaits confirmation in larger scale studies. Studies on renal biopsy specimens are needed to determine the exact renal in situ levels and effects of IFN-

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Evaluation of serum undercarboxylated osteocalcin in premenopausal rheumatoid arthritis patients: its correlation with disease activity and bone mineral density

Background There is a definite role of vitamin K and undercarboxylated osteocalcin (ucOC) on bone mineral density (BMD) in rheumatoid arthritis (RA). Up to our knowledge, no other work has discussed the relationship between ucOC and BMD in premenopausal RA patients and its correlation with disease activity. Patients and methods Sixty premenopausal RA female patients and 30 healthy premenopausal controls of matched age were included. All were subjected to clinical examination, laboratory investigations including serum level of ucOC, disease activity measurement using DAS-28 score, and BMD measurement using dual-energy X-ray absorptiometry. Results The level of ucOC was significantly higher in patients with RA than in controls (P<0.001). BMD in patients was found to be significantly lower compared with controls in the spine, femoral neck, and distal radius areas. The most frequent osteoporotic site according to Z-score was the spine (16.7%), followed by the femoral neck (8.3%) and distal radius (6.7%). The most common commonest osteopenic site according to Z-score was the spine (31.7%), followed by the femoral neck (21.7%) and the distal radius (16.7%). Our work showed that ucOC level was found to be high in premenopausal RA patients with higher DAS values than in those with lower DAS value (P<0.001). In our work, BMD measured by means of dual-energy X-ray absorptiometry scan was found to be lower with higher DAS values and vice versa. Conclusion Serum level of ucOC (which is a mirror of vitamin K deficiency) was found to be higher in premenopausal RA patients than controls and correlated positively with disease activity and inversely with BMD measurement

Evaluation of serum undercarboxylated osteocalcin in premenopausal rheumatoid arthritis patients: its correlation with disease activity and bone mineral density

Background There is a definite role of vitamin K and undercarboxylated osteocalcin (ucOC) on bone mineral density (BMD) in rheumatoid arthritis (RA). Up to our knowledge, no other work has discussed the relationship between ucOC and BMD in premenopausal RA patients and its correlation with disease activity. Patients and methods Sixty premenopausal RA female patients and 30 healthy premenopausal controls of matched age were included. All were subjected to clinical examination, laboratory investigations including serum level of ucOC, disease activity measurement using DAS-28 score, and BMD measurement using dual-energy X-ray absorptiometry. Results The level of ucOC was significantly higher in patients with RA than in controls (P<0.001). BMD in patients was found to be significantly lower compared with controls in the spine, femoral neck, and distal radius areas. The most frequent osteoporotic site according to Z-score was the spine (16.7%), followed by the femoral neck (8.3%) and distal radius (6.7%). The most common commonest osteopenic site according to Z-score was the spine (31.7%), followed by the femoral neck (21.7%) and the distal radius (16.7%). Our work showed that ucOC level was found to be high in premenopausal RA patients with higher DAS values than in those with lower DAS value (P<0.001). In our work, BMD measured by means of dual-energy X-ray absorptiometry scan was found to be lower with higher DAS values and vice versa. Conclusion Serum level of ucOC (which is a mirror of vitamin K deficiency) was found to be higher in premenopausal RA patients than controls and correlated positively with disease activity and inversely with BMD measurement