Melatonin: A potential protective multifaceted force for sepsis-induced cardiomyopathy.

Sepsis is a life-threatening condition manifested by organ dysfunction caused by a dysregulated host response to infection. Lung, brain, liver, kidney, and heart are among the affected organs. Sepsis-induced cardiomyopathy is a common cause of death among septic patients. Sepsis-induced cardiomyopathy is characterized by an acute and reversible significant decline in biventricular both systolic and diastolic function. This is accompanied by left ventricular dilatation. The pathogenesis underlying sepsis-induced cardiomyopathy is multifactorial. Hence, targeting an individual pathway may not be effective in halting the extensive dysregulated immune response. Despite major advances in sepsis management strategies, no effective pharmacological strategies have been shown to treat or even reverse sepsis-induced cardiomyopathy. Melatonin, namely, N-acetyl-5-methoxytryptamine, is synthesized in the pineal gland of mammals and can also be produced in many cells and tissues. Melatonin has cardioprotective, neuroprotective, and anti-tumor activity. Several literature reviews have explored the role of melatonin in preventing sepsis-induced organ failure. Melatonin was found to act on different pathways that are involved in the pathogenesis of sepsis-induced cardiomyopathy. Through its antimicrobial, anti-inflammatory, and antioxidant activity, it offers a potential role in sepsis-induced cardiomyopathy. Its antioxidant activity is through free radical scavenging against reactive oxygen and nitrogen species and modulating the expression and activity of antioxidant enzymes. Melatonin anti-inflammatory activities control the overactive immune system and mitigate cytokine storm. Also, it mitigates mitochondrial dysfunction, a major mechanism involved in sepsis-induced cardiomyopathy, and thus controls apoptosis. Therefore, this review discusses melatonin as a promising drug for the management of sepsis-induced cardiomyopathy.

Can instrumentation kinematics affect postoperative pain and substance P levels? A randomized controlled trial.

BACKGROUND: This study aimed to assess the influence of continuous rotation and reciprocation kinematics on postoperative pain (POP) levels and substance P (SP) levels in patients diagnosed with irreversible pulpitis and symptomatic apical periodontitis (SAP). MATERIALS AND SUBJECTS: A total of twenty patients were randomly assigned into two groups: Continuous Rotation Group (CRG) (n = 10), subjected to mechanical preparation with the EdgeEndox7 rotary system (Albuquerque, NM, USA), and Reciprocation Group (RG) (n = 10), treated with the EdgeOne Fire reciprocating system (Albuquerque, NM, USA). Apical fluid (AF) samples were collected, and SP levels were quantified through radioimmunoassay. POP was assessed using the Numerical Rating Scale (NRS) at various time intervals (preoperatively, 6 h, 12 h, 24 h, 48 h, and 72 h). Data were statistically analyzed utilizing the independent t-test, Mann-Whitney U test, Friedman's test, and Nemenyi post hoc test. RESULTS: There was a significant increase in SP levels in the reciprocating group compared to the continuous rotation group (P ≤ 0.05). Additionally, patients in the reciprocating group reported significantly higher POP levels (P ≤ 0.05) at all measured intervals (6 h, 12 h, 24 h, and 48 h), with both groups exhibiting similar pain level reductions at the 72-hour mark. CONCLUSION: Our findings suggest that continuous rotation kinematics in root canal preparation leads to a considerable reduction in SP expression and POP. TRIAL REGISTRATION: The study protocol was retrospectively registered on the www. CLINICALTRIALS: gov database (NCT06081335) at (13/10/2023) after the approval of the Ethics Committee, Faculty of Dentistry, Ain Shams University (FDASU-RecIM012135).

Effects of histone acetyltransferase (HAT) and histone deacetylase (HDAC) inhibitors on proliferative, differentiative, and regenerative functions of Toll-like receptor 2 (TLR-2)-stimulated human dental pulp cells (hDPCs).

OBJECTIVES: This in vitro study aimed to modify TLR-2-mediated effects on the paracrine, proliferative, and differentiation potentials of human dental pulp-derived cells using histone acetyltransferase (HAT) and histone deacetylase (HDAC) inhibitors. MATERIALS AND METHODS: Cell viability was assessed using the XTT assay. Cells were either treated with 10 µg/ml Pam3CSK4 only, or pre-treated with valproic acid (VPA) (3 mM), trichostatin A (TSA) (3 µM), and MG-149 (3 µM) for a total of 4 h and 24 h. Control groups included unstimulated cells and cells incubated with inhibitors solvents only. Transcript levels for NANOG, OCT3-4, FGF-1 and 2, NGF, VEGF, COL-1A1, TLR-2, hßD-2 and 3, BMP-2, DSPP, and ALP were assessed through qPCR. RESULTS: After 24 h, TSA pre-treatment significantly upregulated the defensins and maintained the elevated pro-inflammatory cytokines, but significantly reduced healing and differentiation genes. VPA significantly upregulated the pro-inflammatory cytokine levels, while MG-149 significantly downregulated them. Pluripotency genes were not significantly affected by any regimen. CONCLUSIONS: At the attempted concentrations, TSA upregulated the defensins gene expression levels, and MG-149 exerted a remarkable anti-inflammatory effect; therefore, they could favorably impact the immunological profile of hDPCs. CLINICAL RELEVANCE: Targeting hDPC nuclear function could be a promising option in the scope of the biological management of inflammatory pulp diseases.

Nose to brain delivery of naringin-loaded chitosan nanoparticles for potential use in oxaliplatin-induced chemobrain in rats: impact on oxidative stress, cGAS/STING and HMGB1/RAGE/TLR2/MYD88 inflammatory axes.

OBJECTIVES: Oxaliplatin induces chemobrain in cancer patients/survivors. Nutraceutical naringin has antioxidant and anti-inflammatory properties with low oral bioavailability. Our aim was to formulate naringin in chitosan nanoparticles for nose to brain delivery and assess its neuroprotective effect against oxaliplatin-induced chemobrain in rats. METHODS: Naringin chitosan nanoparticles were prepared by ionic gelation. Rats were administered oral naringin (80 mg/kg), intranasal naringin (0.3 mg/kg) or intranasal naringin-loaded chitosan nanoparticles (0.3 mg/kg). Naringin's neuroprotective efficacy was assessed based on behavioral tests, histopathology, and measuring oxidative stress and inflammatory markers. RESULTS: Selected nanoparticles formulation showed drug loading of 5%, size of 150 nm and were cationic. Intranasal naringin administration enhanced memory function, inhibited hippocampal acetylcholinesterase activity, and corrected oxaliplatin-induced histological changes. Moreover, it reduced malondialdehyde and elevated reduced glutathione hippocampal levels. Furthermore, it decreased levels of inflammatory markers: NF-kB and TNF-α by 1.25-fold. Upstream to this inflammatory status, intranasal naringin downregulated the hippocampal protein levels of two pathways: cGAS/STING and HMGB1/RAGE/TLR2/MYD88. CONCLUSION: Intranasal naringin-loaded chitosan nanoparticles showed superior amelioration of oxaliplatin-induced chemobrain in rats at a dose 267-fold lower to that administered orally. The potential involvement of cGAS/STING and HMGB1/RAGE/TLR2/MYD88 pathways in the mechanistic process of either oxaliplatin-induced chemobrain or naringin-mediated neuroprotection was evidenced.

Effect of renin angiotensin blockers on angiotensin converting enzyme 2 level in cardiovascular patients.

BACKGROUND: Renin-angiotensin-aldosterone system (RAAS) is hypothesized to be in the center of COVID pathophysiology as the angiotensin converting enzyme 2 (ACE2) represents the main entrance of the virus, thus there is a need to address the effect of chronic use of RAAS blockers, as in case of treatment of cardiovascular diseases, on the expression of ACE2. Accordingly, this study aimed to clarify the effect of ACE inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) on ACE2 and to assess the correlation between ACE2 and several anthropometric and clinic-pathological factors. METHODS: A total of 40 healthy controls and 60 Egyptian patients suffering from chronic cardiovascular diseases were enrolled in this study. Patients were divided into 40 patients treated with ACEIs and 20 patients treated with ARBs. Serum ACE2 levels were assessed by ELISA. RESULTS: Assessment of serum ACE2 level in different groups showed a significant difference between ACEIs and healthy groups and ACEIs and ARBs group, while there was no difference between ARBs and healthy. Multivariate analysis using ACE2 level as constant and age, female sex, ACEIs use and myocardial infarction (MI) showed that there was a significant effect of female sex and ACEIs use on ACE2 level with no effect of age, MI and diabetes. CONCLUSION: ACE2 levels varied between ACEIs and ARBs. It tends to be lower in ACEIs group and there is a strong positive association between ACE2 level and the female sex. This needs to be considered in Future studies to further understand the relationship between gender, sex hormones and ACE2 level. TRIAL REGISTRATION: Retrospectively registered ClinicalTrials.gov ID: NCT05418361 (June 2022).

MicroRNA-146a-5p and microRNA-210-3p Correlate with T Regulatory Cells Frequency and Predict Asthma Severity in Egyptian Pediatric Population.

Background: Severe bronchial asthma (BA) affects 5-10% of children, which imposes socioeconomic burden. Therefore, it is crucial to identify biomarkers for risk stratification in children with BA. T regulatory cells (Tregs) play a balancing role in allergic response regulation. We aimed to investigate the relationship between Treg, miR-210-3p, and miR-146a-5p in relation to asthma phenotypes in search of novel biomarkers of disease severity. Methods: This study included 50 children with BA classified into Group 1 (n = 25) children with mild to moderate asthma and Group 2 (n = 25) children with severe asthma. In addition to 26 control subjects. Flow cytometry was used to detect Tregs. Plasma miR-210-3p and miR-146a levels were determined using quantitative real-time PCR. Patients' FEV1 (Forced Expiratory Volume in the first second) was measured. Results: miR-210-3p level correlated negatively with Treg frequency (r = -0.828, P < 0.001) and FEV1 (r = -0.621, P < 0.001). The level of miR-146a-5p positively correlated positively with Treg% (r = 0.303, P = 0.032). ROC curve analysis revealed that miR-210-3p was the most sensitive biomarker of severity, with the area under curve (AUC) = 0.923, 96% sensitivity, and 60% specificity. According to multivariate analysis, miR-210-3p is an independent risk factor for BA severity [OR =3.119, P = 0.030], while miR-146a-5p is a protective factor [OR =0.811, P = 0.049]. Conclusion: Treg frequency is linked to FEV1, miR-146a-5p and miR-210-3p in childhood BA. Upregulation of miR-210-3p is a sensitive biomarker and an independent risk factor for BA severity in Egyptian children.

Cost-Effectiveness of the Pharmacist-Managed Warfarin Therapy vs. Standard Care for Patients With Mechanical Mitral Valve Prostheses: An Egyptian Healthcare Perspective.

Background: Despite warfarin therapy had been used for decades for patients with mechanical mitral valve prostheses (MMVPs), serious and life-threatening complications are still reported worldwide with a significant economic burden. This study is aimed at assessing the clinical and the cost-effectiveness of adopting pharmacist-managed warfarin therapy (PMWT) services for optimizing warfarin treatment in Egypt. Methods: A prospective randomized trial in which 59 patients with MMVPs were randomly assigned to receive the PMWT services or the standard care and followed up for 1 year. The primary outcome was percentage time in the therapeutic range (TTR). For the cost-effectiveness analysis, a Markov cohort process model with nine mutually exclusive health states was developed from a medical provider's perspective. A lifetime horizon was applied. All costs and outcomes were discounted at 3.5% annually. Results: The study results revealed a significantly higher median TTR in the intervention group as compared to the control group; 96.8% [interquartile range (IQR) 77.9-100%] vs. 73.1% (52.7-95.1%), respectively, p = 0.008. A significant association between standard care and poor anticoagulation control (p = 0.021) was demonstrated by the multivariate regression analysis. For the cost-effectiveness analysis, the total cumulative quality-adjusted life-years (QALYs) and total costs per patient were 21.53 and 10.43; 436.38 and 1,242.25 United States dollar (USD) in the intervention and the control groups, respectively, with an incremental cost-effectiveness ratio (ICER) of -72.5796 for the intervention group. Conclusion: The PMWT strategy was proven to provide a significantly better anticoagulation control and to be a cost-saving approach in Egyptian patients with MMVPs. Nevertheless, the dominance of this strategy is sustained by maintaining the therapeutic International Normalized Ratio (INR) control within the recommended range. Our findings will benefit Egyptian policy-makers who may seek novel health strategies for better resource allocation. Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT04409613].

The effects of theatre-based vocal empowerment on young Egyptian women's vocal and language characteristics.

This study investigates the impact of a theatre-based vocal empowerment program on the vocal and language characteristics and the self-perceptions of young bilingual Egyptian women. The program used applied theatre, a dramatic practice that promotes civic action by utilizing improvisational techniques to engage participants in exploring solutions to self-identified community concerns. These techniques supported participants' pursuit of vocal empowerment: the ability to comfortably express their intended content with a clear audible voice, accompanied by the belief that what they had to say was worthwhile. The program was implemented in Alexandria and Aswan, two Egyptian cities in different regions of the country, with distinct socio-economic profiles. Thirty-six young women from Aswan and nineteen from Alexandria participated. The program was facilitated in Arabic, for 90 minutes per day over twelve consecutive days in 2018. Participants in both groups spoke Arabic as a home language and studied English in school settings but differed in their educational experiences and English proficiency. The vocal and language characteristics of each participant were tested in Arabic and English pre- and post- program using a spontaneous speech task and a reading aloud task. Their self-perceptions were evaluated through a vocal self-perception survey. Results indicated that participants responded differently in each city. In Alexandria, participants showed significant improvement in language skills (e.g., mean length of utterance). In contrast, participants in Aswan showed a significant change in fundamental frequency. Overall, the self-surveys indicated that all participants experienced an increased sense of confidence, a stronger belief in self-authorship, and an increased desire to voice their opinions clearly in public; however, there were subtle differences between the groups. In analyzing these results, we conclude that to design effective vocal empowerment outreach programs internationally, it is necessary to consider participants' cultural backgrounds, language diversity, and socio-economic status.

Changes in the Pharmacokinetics and Pharmacodynamics of Sildenafil in Cigarette and Cannabis Smokers.

Sildenafil citrate, a widely-used oral therapy for erectile dysfunction, is a cytochrome P3A4 (CYP3A4) enzyme substrate. Studies have reported that this substrate has an inhibitory effect on CYP3A4 enzymes in long-term cigarette and cannabis smokers, which predominantly mediate the hepatic elimination of sildenafil. Cigarette and/or cannabis smoking could therefore alter the exposure of sildenafil. The aim of this study was to examine the effect of smoking cigarettes and/or cannabis on the pharmacokinetics, pharmacodynamics, safety and tolerability of sildenafil. Thirty-six healthy human subjects were equally divided into three groups: non-smokers, cigarette smokers and cannabis smokers. Each group was administered a single dose of sildenafil (50 mg tablets). The primary outcome measures included the maximum concentration of sildenafil in plasma (Cmax), the elimination half-life (t1/2) and the area under the plasma concentration time curve from zero to time (AUC0-t). The pharmacodynamics were assessed by the International Index of Erectile Function (IIEF-5). The exposure of sildenafil (AUC0-t) showed a statistically significant increase in cigarette smokers (1156 ± 542 ng·h/mL) of 61% (p < 0.05) while in cannabis smokers (967 ± 262 ng·h/mL), a non-significant increase in AUC0-t of 35% (p > 0.05) was observed relative to non-smokers (717 ± 311 ng·h/mL). Moreover, the Cmax of sildenafil increased by 63% (p < 0.05) and 22% (p > 0.05) in cigarette smokers and cannabis smokers, respectively. Cigarette smoking increases the exposure of sildenafil to a statistically significant level with no effect on its pharmacodynamics, safety and tolerability.

Investigation of the regenerative potential of necrotic mature teeth following different revascularisation protocols.

This study aimed to assess the revascularisation potential of necrotic mature teeth in a dog model following different protocols. Periapical infection was induced in 54 mature premolars. Teeth were distributed into seven groups: (1) Double-antibiotic-paste/Blood clot, (2) Ciprofloxacin/collagen, (3) Double-antibiotic-paste/Collagen, (4) Modified Tri-antibiotic-paste /collagen, (5) Ciprofloxacin/Gelfoam, (6) Double-antibiotic-paste/Gelfoam, and (7) Modified Triantibiotic- paste/Gelfoam. Positive and negative controls included infected and healthy teeth, respectively, (n = 12 roots/group). Canals were apically shaped to size 0.6 mm then disinfected for 1 month. Intra-canal bleeding was induced then scaffolds were applied for another month. Teeth and supporting bone were surgically sampled. Tissues were histologically scored and vimentin immuno-intensity was estimated. Ciprofloxacin and Double-antibiotic paste/Collagen resulted in significantly better corono-apical tissue ingrowths, vascularity, cementum formation and significantly lower inflammatory extents (P < 0.05).These groups also showed significantly higher Vimentin intensities, (P < 0.05). The applied protocols revascularised necrotic mature canals and reduced inflammation particularly in the Ciprofloxacin/collagen and Double-antibiotic-paste/collagen groups.

Crisis resolution and home treatment: stakeholders' views on critical ingredients and implementation in England.

BACKGROUND: Crisis resolution teams (CRTs) can provide effective home-based treatment for acute mental health crises, although critical ingredients of the model have not been clearly identified, and implementation has been inconsistent. In order to inform development of a more highly specified CRT model that meets service users' needs, this study used qualitative methods to investigate stakeholders' experiences and views of CRTs, and what is important in good quality home-based crisis care. METHOD: Semi-structured interviews and focus groups were conducted with service users (n = 41), carers (n = 20) and practitioners (CRT staff, managers and referrers; n = 147, 26 focus groups, 9 interviews) in 10 mental health catchment areas in England, and with international CRT developers (n = 11). Data were analysed using thematic analysis. RESULTS: Three domains salient to views about optimal care were identified. 1. The organisation of CRT care: Providing a rapid initial responses, and frequent home visits from the same staff were seen as central to good care, particularly by service users and carers. Being accessible, reliable, and having some flexibility were also valued. Negative experiences of some referral pathways, and particularly lack of staff continuity were identified as problematic. 2. The content of CRT work: Emotional support was at the centre of service users' experiences. All stakeholder groups thought CRTs should involve the whole family, and offer a range of interventions. However, carers often feel excluded, and medication is often prioritised over other forms of support. 3. The role of CRTs within the care system: Gate-keeping admissions is seen as a key role for CRTs within the acute care system. Service users and carers report that recovery is quicker compared to in-patient care. Lack of knowledge and misunderstandings about CRTs among referrers are common. Overall, levels of stakeholder agreement about the critical ingredients of good crisis care were high, although aspects of this were not always seen as achievable. CONCLUSIONS: Stakeholders' views about optimal CRT care suggest that staff continuity, carer involvement, and emotional and practical support should be prioritised in service improvements and more clearly specified CRT models.

Development of a measure of model fidelity for mental health Crisis Resolution Teams.

BACKGROUND: Crisis Resolution Teams (CRTs) provide short-term intensive home treatment to people experiencing mental health crisis. Trial evidence suggests CRTs can be effective at reducing hospital admissions and increasing satisfaction with acute care. When scaled up to national level however, CRT implementation and outcomes have been variable. We aimed to develop and test a fidelity scale to assess adherence to a model of best practice for CRTs, based on best available evidence. METHODS: A concept mapping process was used to develop a CRT fidelity scale. Participants (n = 68) from a range of stakeholder groups prioritised and grouped statements (n = 72) about important components of the CRT model, generated from a literature review, national survey and qualitative interviews. These data were analysed using Ariadne software and the resultant cluster solution informed item selection for a CRT fidelity scale. Operational criteria and scoring anchor points were developed for each item. The CORE CRT fidelity scale was then piloted in 75 CRTs in the UK to assess the range of scores achieved and feasibility for use in a 1-day fidelity review process. Trained reviewers (n = 16) rated CRT service fidelity in a vignette exercise to test the scale's inter-rater reliability. RESULTS: There were high levels of agreement within and between stakeholder groups regarding the most important components of the CRT model. A 39-item measure of CRT model fidelity was developed. Piloting indicated that the scale was feasible for use to assess CRT model fidelity and had good face validity. The wide range of item scores and total scores across CRT services in the pilot demonstrate the measure can distinguish lower and higher fidelity services. Moderately good inter-rater reliability was found, with an estimated correlation between individual ratings of 0.65 (95% CI: 0.54 to 0.76). CONCLUSIONS: The CORE CRT Fidelity Scale has been developed through a rigorous and systematic process. Promising initial testing indicates its value in assessing adherence to a model of CRT best practice and to support service improvement monitoring and planning. Further research is required to establish its psychometric properties and international applicability.

Dentin wettability enhancement for three irrigating solutions and their effect on push out bond strength of gutta percha / AH Plus.

BACKGROUND: The aim of this study was to investigate the effect of wettability enhancement for 17% EDTA, 2.5% sodium hypochlorite and 7% maleic acid solutions on push out bond strength of gutta percha /AH Plus to root dentin. MATERIAL AND METHODS: One hundred and eight extracted single rooted human lower premolars were instrumented up to Protaper Universal F5 then irrigated with 3ml of 2.5% NaOCl after each file. Irrigants were prepared and a pilot study for determination of Tween 80 concentration yielding the lowest surface tension value in every solution was conducted. Samples were randomly divided into a control group and two experimental groups (17% EDTA and 7% Maleate), further split into eight subgroups (n=12), according to Tween 80 implementation sequence. Roots were obturated using gutta percha and AH plus by lateral condensation. Bond strength was measured by push out test. Mode of failure was then evaluated quantitatively by stereomicroscopy. Data were statistically analyzed using one way ANOVA followed by Tukey-Kramer for multiple comparisons. RESULTS: Control group showed the lowest values. Maleic acid subgroups showed significantly higher overall values than EDTA subgroups (P<0.05). Protocols implementing surfactant containing NaOCl showed significantly lower values than plain counterparts. Failure pattern was predominantly cohesive for plain regimens and the ones implementing Tween 80 in maleic acid solutions with plain NaOCl. CONCLUSIONS: Tween 80 addition to demineralizing irrigants increased the bond strength values. Surfactant containing NaOCl solutions yielded lower bond strength than plain ones. Key words:Wettability enhancement for three irrigants vs. corresponding gutta percha/AH Plus bonding.

The relationship between therapeutic alliance and service user satisfaction in mental health inpatient wards and crisis house alternatives: a cross-sectional study.

BACKGROUND: Poor service user experiences are often reported on mental health inpatient wards. Crisis houses are an alternative, but evidence is limited. This paper investigates therapeutic alliances in acute wards and crisis houses, exploring how far stronger therapeutic alliance may underlie greater client satisfaction in crisis houses. METHODS AND FINDINGS: Mixed methods were used. In the quantitative component, 108 crisis house and 247 acute ward service users responded to measures of satisfaction, therapeutic relationships, informal peer support, recovery and negative events experienced during the admission. Linear regressions were conducted to estimate the association between service setting and measures, and to model the factors associated with satisfaction. Qualitative interviews exploring therapeutic alliances were conducted with service users and staff in each setting and analysed thematically. RESULTS: We found that therapeutic alliances, service user satisfaction and informal peer support were greater in crisis houses than on acute wards, whilst self-rated recovery and numbers of negative events were lower. Adjusted multivariable analyses suggest that therapeutic relationships, informal peer support and negative experiences related to staff may be important factors in accounting for greater satisfaction in crisis houses. Qualitative results suggest factors that influence therapeutic alliances include service user perceptions of basic human qualities such as kindness and empathy in staff and, at service level, the extent of loss of liberty and autonomy. CONCLUSIONS AND IMPLICATIONS: We found that service users experience better therapeutic relationships and higher satisfaction in crisis houses compared to acute wards, although we cannot exclude the possibility that differences in service user characteristics contribute to this. This finding provides some support for the expansion of crisis house provision. Further research is needed to investigate why acute ward service users experience a lack of compassion and humanity from ward staff and how this could be changed.