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Nanomedicine : Nanotechnology, Biology,... Jul 2024To address the adverse side effects associated with systemic high-dose methylprednisolone (MP) therapy for acute spinal cord injury (SCI), we have developed a...
Neuroprotective macromolecular methylprednisolone prodrug nanomedicine prevents glucocorticoid-induced muscle atrophy and osteoporosis in a rat model of spinal cord injury.
To address the adverse side effects associated with systemic high-dose methylprednisolone (MP) therapy for acute spinal cord injury (SCI), we have developed a N-2-hydroxypropyl methacrylamide copolymer-based MP prodrug nanomedicine (Nano-MP). Intravenous Nano-MP selectively targeted to the inflamed SCI lesion and significantly improved neuroprotection and functional recovery after acute SCI. In the present study, we comprehensively assessed the potential adverse side effects associated with the treatment in the SCI rat models, including reduced body weight and food intake, impaired glucose metabolism, and reduced musculoskeletal mass and integrity. In contrast to free MP treatment, intravenous Nano-MP after acute SCI not only offered superior neuroprotection and functional recovery but also significantly mitigated or even eliminated the aforementioned adverse side effects. The superior safety features of Nano-MP observed in this study further confirmed the clinical translational potential of Nano-MP as a highly promising drug candidate for better clinical management of patients with acute SCI.
PubMed: 38960364
DOI: 10.1016/j.nano.2024.102773 -
American Journal of Preventive Medicine Jul 2024Dental care is a critical component of healthy aging; however, emerging evidence suggests that having been previously incarcerated is a risk factor for not using dental...
INTRODUCTION
Dental care is a critical component of healthy aging; however, emerging evidence suggests that having been previously incarcerated is a risk factor for not using dental care services. This study investigates the relationship between prior incarceration and dental care among older adults and assesses whether wealth and dental insurance explain this relationship.
METHODS
Data are from the Health and Retirement Study, a nationally representative sample of community-dwelling older adults in the United States, collected in 2012 and 2014. Multivariable logistic regression is used to assess the relationship between a history of incarceration and dental care. Mediation analyses were conducted using the Karlson-Holm-Breen method of indirect effects in non-linear models. Statistical analyses were conducted from February to April 2024.
RESULTS
Adjusting for potential confounding variables, a respondent's prior incarceration is associated with a 25% lower odds of dental care use (adjusted odds ratio [aOR] = .748, 95% CI = .624, .896). The relationship between incarceration and dental care use is fully mediated-over 90% is explained by-wealth and having dental care insurance. Prior incarceration decreased the likelihood of dental care only among non-Hispanic White respondents.
CONCLUSIONS
The findings offer new evidence that prior incarceration is a risk factor for lacking the ability to utilize dental care among older adults and suggest that broader consequences of incarceration for wealth accumulation and access to dental insurance underpin this relationship. These results suggest the urgent need to expand access to affordable dental care services for older adults with a history of incarceration.
PubMed: 38960292
DOI: 10.1016/j.amepre.2024.06.023 -
International Journal of Biological... Jul 2024Bone defects resulting from trauma, illness or congenital abnormalities represent a significant challenge to global health. Conventional treatments such as autographs... (Review)
Review
Bone defects resulting from trauma, illness or congenital abnormalities represent a significant challenge to global health. Conventional treatments such as autographs and allografts have limitations, leading to the exploration of bone tissue engineering (BTE) as an alternative approach. This review aims to provide a comprehensive analysis of bone regeneration mechanisms with a focus on the role of chitosan-based biomaterials and mesenchymal stem cells (MSCs) in BTE. In addition, the physiochemical and biological properties of chitosan, its potential for bone regeneration when combined with other materials and the mechanisms through which MSCs facilitate bone regeneration were investigated. In addition, different methods of scaffold development and the incorporation of MSCs into chitosan-based scaffolds were examined. Chitosan has remarkable biocompatibility, biodegradability and osteoconductivity, making it an attractive choice for BTE. Interactions between transcription factors such as Runx2 and Osterix and signaling pathways such as the BMP and Wnt pathways regulate the differentiation of MSCs and bone regeneration. Various forms of scaffolding, including porous and fibrous injections, have shown promise in BTE. The synergistic combination of chitosan and MSCs in BTE has significant potential for addressing bone defects and promoting bone regeneration, highlighting the promising future of clinical challenges posed by bone defects.
PubMed: 38960259
DOI: 10.1016/j.ijbiomac.2024.133502 -
Neurobiology of Disease Jul 2024Clinical and preclinical evidence has demonstrated an increased risk for neuropsychiatric disorders following prenatal cannabinoid exposure. However, given the...
Clinical and preclinical evidence has demonstrated an increased risk for neuropsychiatric disorders following prenatal cannabinoid exposure. However, given the phytochemical complexity of cannabis, there is a need to understand how specific components of cannabis may contribute to these neurodevelopmental risks later in life. To investigate this, a rat model of prenatal cannabinoid exposure was utilized to examine the impacts of specific cannabis constituents (Δ9-tetrahydrocannabinol [THC]; cannabidiol [CBD]) alone and in combination on future neuropsychiatric liability in male and female offspring. Prenatal THC and CBD exposure were associated with low birth weight. At adolescence, offspring displayed sex-specific behavioural changes in anxiety, temporal order and social cognition, and sensorimotor gating. These phenotypes were associated with sex and treatment-specific neuronal and gene transcriptional alterations in the prefrontal cortex, and ventral hippocampus, regions where the endocannabinoid system is implicated in affective and cognitive development. Electrophysiology and RT-qPCR analysis in these regions implicated dysregulation of the endocannabinoid system and balance of excitatory and inhibitory signalling in the developmental consequences of prenatal cannabinoids. These findings reveal critical insights into how specific cannabinoids can differentially impact the developing fetal brains of males and females to enhance subsequent neuropsychiatric risk.
PubMed: 38960101
DOI: 10.1016/j.nbd.2024.106588 -
Journal of Stomatology, Oral and... Jul 2024Immune checkpoint inhibitors (ICIs) are widely adapted for recurrent or metastatic head and neck cancer (RM-HNC), and various studies on its prognostic factors have been...
BACKGROUND
Immune checkpoint inhibitors (ICIs) are widely adapted for recurrent or metastatic head and neck cancer (RM-HNC), and various studies on its prognostic factors have been reported. We aimed to elucidate the prognostic factors of ICI treatment for RM oral cancer (RM-OC) in a retrospective study.
METHODS
We retrospectively reviewed patients with RM-OC treated with ICIs (nivolumab and pembrolizumab) at our department from May 2017 to February 2023. The objective response rate (ORR) for ICI treatment and the relationship between several potential prognostic factors, progression-free survival (PFS), and overall survival (OS) were analyzed statistically.
RESULTS
The investigation enrolled 31 patients, 16 with nivolumab and 15 with pembrolizumab. There were no significant differences in the ORR or disease control rate between the nivolumab and pembrolizumab groups (p = 0.4578 and 0.2524). In multivariate analysis, the prognostic nutritional index (PNI) and C-reactive protein to albumin ratio (CAR) exhibited statistical correlations with PFS, whereas the use of antibiotics and proton pump inhibitors (PPIs), neutrophil to lymphocyte ratio (NLR), and PNI demonstrated statistical associations with OS.
CONCLUSION
Our findings imply that the use of antibiotics and PPIs, which can modify the gut microbiota, may also serve as a prognostic determinant for ICI treatment in RM-OC, consistent with previous studies. Additionally, PNI may be essential in affecting the survival rates of both PFS and OS and could be an exceedingly valuable inflammatory biomarker for RM-OC.
PubMed: 38960025
DOI: 10.1016/j.jormas.2024.101961 -
Free Radical Biology & Medicine Jul 2024Abnormal polarization of adipose tissue macrophages (ATMs) results in low-grade systemic inflammation and insulin resistance (IR), potentially contributing to the...
Excessive palmitic acid disturbs macrophage α-ketoglutarate/succinate metabolism and causes adipose tissue insulin resistance associated with Gestational Diabetes Mellitus.
Abnormal polarization of adipose tissue macrophages (ATMs) results in low-grade systemic inflammation and insulin resistance (IR), potentially contributing to the development of diabetes. However, the underlying mechanisms that regulate the polarization of ATMs associated with gestational diabetes mellitus (GDM) remain unclear. Thus, we aimed to determine the effects of abnormal fatty acids on macrophage polarization and development of insulin resistance in GDM. Levels of fatty acids and inflammation were assessed in the serum samples and adipose tissues of patients with GDM. An in vitro cell model treated with palmitic acid was established, and the mechanisms of palmitic acid in regulating macrophage polarization was clarified. The effects of excessive palmitic acid on the regulation of histone methylations and IR were also explored in the high-fat diet induced GDM mice model. We found that pregnancies with GDM were associated with increased levels of serum fatty acids, and inflammation and IR in adipose tissues. Increased palmitic acid could induce mitochondrial dysfunction and excessive ROS levels in macrophages, leading to abnormal cytoplasmic and nuclear metabolism of succinate and α-ketoglutarate (αKG). Specifically, a decreased nuclear αKG/succinate ratio could attenuate the enrichment of H3K27me3 at the promoters of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, leading to cytokine secretion. Importantly, GDM mice treated with GSK-J4, an inhibitor of histone lysine demethylase, were protected from abnormal pro-inflammatory macrophage polarization and excessive production of pro-inflammatory cytokines. Our findings highlight the importance of the metabolism of αKG and succinate as transcriptional modulators in regulating the polarization of ATMs and the insulin sensitivity of adipose tissue, ensuring a normal pregnancy. This novel insight sheds new light on gestational fatty acid metabolism and epigenetic alterations associated with GDM.
PubMed: 38960008
DOI: 10.1016/j.freeradbiomed.2024.06.029 -
Virus Research Jul 2024Enterococci are robust Gram-positive bacteria that pose a significant threat in healthcare settings due to antibiotic resistance, with vancomycin-resistant enterococci...
Enterococci are robust Gram-positive bacteria that pose a significant threat in healthcare settings due to antibiotic resistance, with vancomycin-resistant enterococci (VRE) most prominent. To tackle this issue, bacteriophages (bacterial viruses) can be exploited as they specifically and efficiently target bacteria. Here, we successfully isolated and characterised a set of novel phages: SHEF10, SHEF11, SHEF13, SHEF14, and SHEF16 which target E. faecalis (SHEF10,11,13), or E. faecium (SHEF13, SHEF14 & SHEF16) strains including a range of clinical and VRE isolates. Genomic analysis shows that all phages are strictly lytic and diverse in terms of genome size and content, quickly and effectively lysing strains at different multiplicity of infections. Detailed analysis of the broad host-range SHEF13 phage revealed the crucial role of the enterococcal polysaccharide antigen (EPA) variable region in its infection of E. faecalis V583. In parallel, the discovery of a carbohydrate-targeting domain (CBM22) found conserved within the three phage genomes indicates a role in cell surface interactions that may be important in phage-bacterial interactons. These findings advance our comprehension of phage-host interactions and pave the way for targeted therapeutic strategies against antibiotic-resistant enterococcal infections.
PubMed: 38960003
DOI: 10.1016/j.virusres.2024.199426 -
Journal of Dentistry Jul 2024The presence of insufficient peri-implant supracrestal tissue height (STH) may increase marginal bone resorption. This study aims to evaluate the effect of STH on...
OBJECTIVES
The presence of insufficient peri-implant supracrestal tissue height (STH) may increase marginal bone resorption. This study aims to evaluate the effect of STH on marginal bone level changes (ΔMBC) in platform-switched posterior implants placed crestally and subcrestally.
METHODS
A total of 80 implants were included in this study. There were two main groups in the study; STH≤2 mm (A) and STH> 2 mm (B) and four subgroups according to the implant placement level, crestally (I) and subcrestally (II): A-I, A-II, B-I, and B-II. Intraoperatively, STH and placement depths of implants were measured from mesial and distal aspects. The mesial and distal peri-implant marginal bone levels were measured on periapical radiographs at immediately (T0), 6 months (T1), 9 months (T2), and 12 months (T3) after functional loading, and the difference between the marginal bone levels was calculated as the ΔMBC.
RESULTS
Statistically significantly more mesial ΔMBC was detected in the A-I than in the B-I at the time of T0-T1. In the group with STH greater than 2 mm, the difference in ΔMBC between the crestally and subcrestally placements was not statistically significant.
CONCLUSIONS
This study was found that STH is effective at protecting the marginal bone in the early period, and in cases where the STH is insufficient, subcrestally placement may increase long-term implant success by preventing marginal bone loss from occurring beyond the implant shoulder. The clinical trial number is NCT05595746.
CLINICAL SIGNIFICANCE
In this study, it was demonstrated that an STH greater than 2 mm is important for marginal bone stabilization, regardless of crestal and subcrestal levels, and that subcrestally placement is beneficial in cases of insufficient STH.
PubMed: 38960001
DOI: 10.1016/j.jdent.2024.105219 -
Journal of Dentistry Jul 2024Periodontal disease constitutes a widely prevalent category of non-communicable diseases and ranks among the top 10 causes of disability worldwide. Little however is...
BACKGROUND
Periodontal disease constitutes a widely prevalent category of non-communicable diseases and ranks among the top 10 causes of disability worldwide. Little however is known about diagnostic errors in dentistry. In this work, by retrospectively deploying an electronic health record (EHR)-based trigger tool, followed by gold standard manual review, we provide epidemiological estimates on the rate of diagnostic misclassification in dentistry through a periodontal use case.
METHODS
An EHR-based trigger tool (a retrospective record review instrument that uses a list of triggers (or clues), i.e., data elements within the health record, to alert reviewers to the potential presence of a wrong diagnosis) was developed, tested and run against the EHR at the two participating sites to flag all cases having a potential misdiagnosis. All cases flagged as potentially misdiagnosed underwent extensive manual reviews by two calibrated domain experts. A subset of the non-flagged cases was also manually reviewed.
RESULTS
A total of 2,262 patient charts met the study's inclusion criteria. Of these, the algorithm flagged 1,124 cases as potentially misclassified and 1,138 cases as potentially correctly diagnosed. When the algorithm identified a case as potentially misclassified, compared to the diagnosis assigned by the gold standard, the kappa statistic was 0.01. However, for cases the algorithm marked as potentially correctly diagnosed, the review against the gold standard showed a kappa statistic of 0.9, indicating near perfect agreement. The observed proportion of diagnostic misclassification was 32%. There was no significant difference by clinic or provider characteristics.
CONCLUSION
Our work revealed that about a third of periodontal cases are misclassified. Diagnostic errors have been reported to happen more frequently than other types of errors, and to be more preventable. Benchmarking diagnostic quality is a first step. Subsequent research endeavor will delve into comprehending the factors that contribute to diagnostic errors in dentistry and instituting measures to prevent them.
CLINICAL SIGNIFICANCE
This study sheds light on the significance of diagnostic excellence in the delivery of dental care, and highlights the potential role of technology in aiding diagnostic decision-making at the point of care.
PubMed: 38960000
DOI: 10.1016/j.jdent.2024.105221 -
Cell Metabolism Jun 2024A mechanistic connection between aging and development is largely unexplored. Through profiling age-related chromatin and transcriptional changes across 22 murine cell...
A mechanistic connection between aging and development is largely unexplored. Through profiling age-related chromatin and transcriptional changes across 22 murine cell types, analyzed alongside previous mouse and human organismal maturation datasets, we uncovered a transcription factor binding site (TFBS) signature common to both processes. Early-life candidate cis-regulatory elements (cCREs), progressively losing accessibility during maturation and aging, are enriched for cell-type identity TFBSs. Conversely, cCREs gaining accessibility throughout life have a lower abundance of cell identity TFBSs but elevated activator protein 1 (AP-1) levels. We implicate TF redistribution toward these AP-1 TFBS-rich cCREs, in synergy with mild downregulation of cell identity TFs, as driving early-life cCRE accessibility loss and altering developmental and metabolic gene expression. Such remodeling can be triggered by elevating AP-1 or depleting repressive H3K27me3. We propose that AP-1-linked chromatin opening drives organismal maturation by disrupting cell identity TFBS-rich cCREs, thereby reprogramming transcriptome and cell function, a mechanism hijacked in aging through ongoing chromatin opening.
PubMed: 38959897
DOI: 10.1016/j.cmet.2024.06.006