Synthesis, docking and evaluation of novel fused pyrimidine compounds as possible lead compounds with antibacterial and antitumor activities

Reaction of a series of hydrazonoyl chlorides with substituted aminopyrimidines afforded good selectivity in most cases leading either to formation of new imidazo[1,2-a]pyrimidine derivatives, or regioisomeric hydrazonamide adducts. The compounds were evaluated for antibacterial and anticancer activities. Screening against 'E. Coli', 'P. aeruginosa', 'S. aureus', 'S. epidermidis', 'B. subtilis' and 'K. rhizophila' did identify several different compound types with MIC of 0.1-0.4 mg/mL. Anticancer evaluation against a HeLa cell line identified one imidazo[1,2-a]pyrimidine lead. An 'in silico' target fishing analysis suggest three possible high value protein targets, Tankyrase-2 (Tank-2), Cyclin-dependent kinase (CDK2) and Epidermal growth factor tyrosine kinase receptor (EGFR), with modelling fit against co-crystallized known ligands. This provides a new structural family lead for further investigation of molecular targets and potential SAR activity development

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

A 5-Year Satisfaction Outcome Study of Patients Receiving Six-Implant-Supported Fixed Prosthesis

The aim of the study was to analyze the satisfaction of patients treated with a protocol of six-implant-supported fixed prosthesis (6IFP) throughout 5 years of service. This retrospective study collected the data of all patients who had full-arch rehabilitations using 6IFP and followed them for 5 years. After applying the research inclusion/exclusion strategy, 37 cases were finally included in the study. All the patients had no previous complete dentures because they were partially edentulous, not interested in pursuing complete denture rehabilitation, had immediate dental extractions, implantation used the 2-stage protocol, and there was minor peri-implant socket grafting. Cases with severe bone loss that required extensive grafting were excluded. A total number of 222 implants were placed in the maxillary or mandibular arches in a total of 37 patients. The data presented the satisfaction outcomes concerning mastication, phonetics, and comfort during the first 5 years of the recall plan. The former was achieved based on the clinical record reviews, follow-up visits, and recall phone calls at the preoperative stage as well as annually thereafter. The mean satisfaction rate was 94.5%, with a mean record of 8.21 ± 1.7 out of 10, there was no gender predilection significance, and no age range variation significance was validated. Regarding the smoking status, the t-test score exhibited no significant effect on phonetics and mastication (p = 0.12, p = 0.16, respectively), whereas comfort was found to be significantly affected (p = 0.03). The comfort level was found to be slightly less at the immediate postoperative period among smokers when compared to non-smokers. In conclusion, partially edentulous patients who received the rehabilitation plan of arch dental extractions, six immediate implantations, and delayed prosthetic loading were found to be highly satisfied

Efficacy of Vazirani Akinosi and Gow Gates Technique in Inferior Alveolar Nerve Block: A Comparative Study

Aim: The purpose of this study is to evaluate the onset of anesthesia, anesthetic success and incidence of positive aspiration during administration of local anesthetic solution using the Vazirani Akinosi and Gow Gates techniques. Methodology: The study involves 100 subjects, divided into two different groups of 50 subjects each receiving Gow Gates, Vazirani Akinosi&nbsp; nerve blocks. The onset of anesthesia, positive aspiration and anesthetic success was evaluated. Results: In Vazirani Akinosi technique group, patients showed highest anesthetic success of 95.71%; there was a significant difference seen between the Gow Gates and Vazirani Akinosi techniques (p = 0.0241). The mean value of the onset of anesthesia in Gow Gates technique showed the longest 343.71 ± 153.20 s and in Vazirani Akinosi technique it was 192.86 ± 61.20 s. Conclusion: The Vazirani Akinosi technique was found to be significantly better than GG techniques with respect to both onset and success of anesthesia

The Growth Factors and Cytokines of Dental Pulp Mesenchymal Stem Cell Secretome May Potentially Aid in Oral Cancer Proliferation

Background: Growth factors and cytokines responsible for the regenerative potential of the dental pulp mesenchymal stem cell secretome (DPMSC-S) are implicated in oral carcinogenesis. The impact and effects of these secretory factors on cancer cells must be understood in order to ensure their safe application in cancer patients. Objective: We aimed to quantify the growth factors and cytokines in DPMSC-S and assess their effect on oral cancer cell proliferation. Materials and methods: DPMSCs were isolated from patients with healthy teeth (n = 5) that were indicated for extraction for orthodontic reasons. The cells were characterized using flow cytometry and conditioned medium (DPMSC-CM) was prepared. DPMSC-CM was subjected to a bead-based array to quantify the growth factors and cytokines that may affect oral carcinogenesis. The effect of DPMSC-CM (20%, 50%, 100%) on the proliferation of oral cancer cells (AW123516) was evaluated using a Ki-67-based assay at 48 h. AW13516 cultured in the standard growth medium acted as the control. Results: VEGF, HCF, Ang-2, TGF-α, EPO, SCF, FGF, and PDGF-BB were the growth factors with the highest levels in the DPMSC-CM. The highest measured pro-inflammatory cytokine was TNF-α, followed by CXCL8. The most prevalent anti-inflammatory cytokine in the DPMSC-CM was IL-10, followed by TGF-β1 and IL-4. Concentrations of 50% and 100% DPMSC-CM inhibited Ki-67 expression in AW13516, although the effect was non-significant. Moreover, 20% DPMSC-CM significantly increased Ki-67 expression compared to the control. Conclusions: The increased Ki-67 expression of oral cancer cells in response to 20% DPMSC-CM indicates the potential for cancer progression. Further research is needed to identify their effects on other carcinogenic properties, including apoptosis, stemness, migration, invasion, adhesion, and therapeutic resistance

Role of Stem Cells in Augmenting Dental Implant Osseointegration: A Systematic Review

Dental implants are a widely used treatment modality for oral rehabilitation. Implant failures can be a result of many factors, with poor osseointegration being the main culprit. The present systematic review aimed to assess the effect of stem cells on the osseointegration of dental implants. An electronic search of the MEDLINE, LILACS, and EMBASE databases was conducted. We examined quantitative preclinical studies that reported on the effect of mesenchymal stem cells on bone healing after implant insertion. Eighteen studies that fulfilled the inclusion criteria were included. Various surface modification strategies, sites of placement, and cell origins were analyzed. The majority of the selected studies showed a high risk of bias, indicating that caution must be exercised in their interpretation. All the included studies reported that the stem cells used with graft material and scaffolds promoted osseointegration with higher levels of new bone formation. The mesenchymal cells attached to the implant surface facilitated the expression of bio-functionalized biomaterial surfaces, to boost bone formation and osseointegration at the bone–implant interfaces. There was a promotion of osteogenic differentiation of human mesenchymal cells and osseointegration of biomaterial implants, both in vitro and in vivo. These results highlight the significance of biomodified implant surfaces that can enhance osseointegration. These innovations can improve the stability and success rate of the implants used for oral rehabilitation

Malondialdehyde, an Oxidative Stress Marker in Oral Squamous Cell Carcinoma—A Systematic Review and Meta-Analysis

Objective: To qualitative and quantitatively review published literature assessing the oxidative stress marker malondialdehyde (MDA) in oral squamous cell carcinoma (OSCC). Methodology: Pubmed (MeSH), Science Direct, Scopus, Web of Science, Willey Online Library, Cochrane, and Cross Reference were searched for studies assessing MDA levels in OSCC samples. Results: From the 1008 articles identified, 849 were excluded based on title and abstract screening due to duplication and irrelevance to the topic of interest. Full-text assessment of the remaining 159 articles led to the inclusion of only 46 articles that satisfied the selection criteria. Of these, only 26 studies had data compatible for quantitative analysis. The MDA levels in OSCC groups are significantly increased (p &lt; 0.00001) in plasma, serum, and saliva samples in the majority of the studies evaluated. In contrast, MDA levels in OSCC tissue samples are significantly attenuated (p &lt; 0.00001) compared to healthy controls, supported by fewer studies. Conclusions: The augmented MDA levels in plasma, serum, and saliva samples of the OSCC reflect the heightened oxidative stress level accurately. Further studies are required to understand the attenuated MDA levels in the tissue samples of OSCC. Correlation analysis between MDA levels with established clinicopathological prognostic markers could aid in formulating oxidative stress-based prognostication and treatment planning

Use of Collagen Membrane in the Treatment of Periodontal Defects Distal to Mandibular Second Molars Following Surgical Removal of Impacted Mandibular Third Molars: A Comparative Clinical Study

The study aims to assess the efficacy of using collagen membrane in the treatment of distal periodontal defects of mandibular second molars following the removal of mesioangularly or horizontally impacted mandibular third molars surgically. Forty sites in twenty patients with bilaterally impacted mandibular third molars (mesioangular or horizontal) were considered for the study. In 20 test sites (Group A), after surgical removal of the mandibular third molar, a resorbable collagen membrane barrier was placed on the distal aspect of the mandibular second molar to cover the post-surgical bone defect. In the other control 20 sites (Group B), the same surgical procedure was repeated without placing any membrane barrier. The clinical parameters recorded were Oral Hygiene Index Simplified (OHI-S), Probing pocket depth (PPD), Clinical attachment level (CAL), and radiographic assessment of alveolar bone level (ABL). OHI-S score of most of the patients was observed to be satisfactory. Group A was observed to achieve a statistically significant reduction in PPD, CAL, and ABL gain compared to Group B. The improvements indicated that the use of collagen membrane facilitates early wound stabilization and promotes primary closure of the defect. This recovery is achieved through its unique property to assist fibrinogenesis over osteoconduction. Further longitudinal studies are needed to confirm the present findings