Chlorpromazine-Polypyrrole Drug Delivery System Tailored for Neurological Application.

Nowadays, drug delivery systems (DDSs) are gaining more and more attention. Conducting polymers (CPs) are efficiently used for DDS construction as such systems can be used in therapy. In this research, a well-known CP, polypyrrole (PPy), was synthesized in the presence of the polysaccharide heparin (HEP) and chlorpromazine (CPZ) using sodium dodecyl sulfate (SDS) as electrolyte on a steel substrate. The obtained results demonstrate the successful incorporation of CPZ and HEP into the polymer matrix, with the deposited films maintaining stable electrochemical parameters across multiple doping/dedoping cycles. Surface roughness, estimated via AFM analysis, revealed a correlation with layer thickness-decreasing for thinner layers and increasing for thicker ones. Moreover, SEM images revealed a change in the morphology of PPy films when PPy is electropolymerized in the presence of CPZ and HEP, while FTIR confirmed the presence of CPZ and HEP within PPy. Due to its lower molecular mass compared to HEP, CPZ was readily integrated into the thin polymer matrix during deposition, with diffusion being unimpeded, as opposed to films with greater thickness. Finally, the resulting system exhibited the ability to release CPZ, enabling a dosing range of 10 mg to 20 mg per day, effectively covering the therapeutic concentration range.

Challenges of Implementing a Human Multi-Tissue Bank in a Public Hospital in the Interior of São Paulo: Under the Light of the Quality Management System.

BACKGROUND: Human multi-tissue banks (HMTB) are important health institutions specialized in the capture, processing, and distribution of human tissues for transplants and research, aiming for safety and quality in the supply of their products, intended for reconstructive surgeries and injury repair, in addition to contributing to the advancement of research developed in regenerative medicine. This study aims to report and share the experience of implementing an HMTB, as well as creating an institution's own quality management system. METHODS: This is a descriptive study, an experience report type, which identifies historical aspects of an HMTB's actions in the 5 years of implementing and operating the service. RESULTS: Initially, a musculoskeletal tissue bank was established in collaboration with the Department of Orthopedics at the State University of Campinas, São Paulo, Brazil, in June 2018. In 2023, through a management model and associated technologies, the banks of human musculoskeletal and ocular tissues at the institution established the HC-UNICAMP Human Multi-tissue Bank. CONCLUSIONS: The implementation of the HMTB with modern and technological infrastructure, associated with the development and operation of the quality management system, allowed us to provide excellent organization of work processes, as well as obtain the necessary health license to begin activities. It is believed that this report can be an important source of information and recommendations applicable to the implementation of other human HMTBs.

Comparison between digital superimposition and microcomputed tomography methods of fit assessment of removable partial denture frameworks.

STATEMENT OF PROBLEM: The fit of removable partial denture frameworks should be assessed to optimize clinical adaptation. Potential discrepancies between framework and supporting structures are typically precisely measured with negative subtracts and high-resolution equipment. The growth of computer-aided engineering technology allows the development of new methods for the direct evaluation of discrepancies. However, how the methods compare is unclear. PURPOSE: The purpose of this in vitro study was to compare 2 digital methods of fit assessment based on direct digital superimposition and microcomputed tomography indirect analysis. MATERIAL AND METHODS: Twelve cobalt chromium removable partial denture frameworks were fabricated by conventional lost-wax casting or additive manufacturing techniques. The thickness of the gap between occlusal rests and respective definitive cast rest seats (n=34) was evaluated by using 2 different digital methods. Silicone elastomer impressions of the gaps were obtained, and microcomputed tomography measurements were used as controls for validation purposes. Digitization of the framework, the respective definitive cast, and the combination was followed by digital superimposition and direct measurements with the Geomagic Control X software program. Because normality and homogeneity of variance were not verified (Shapiro-Wilk and Levene tests, P<.05), the data were analyzed with Wilcoxon signed rank and Spearman correlation tests (α=.05). RESULTS: The thicknesses measured by microcomputed tomography (median=242 µm) and digital superimposition (median=236 µm) did not reveal statistically significant differences (P=.180). A positive correlation (ρ=0.612) was detected between the 2 methods of assessing fit. CONCLUSIONS: The frameworks presented median gap thicknesses under the limit of clinical acceptability without differences between the proposed methods. The digital superimposition method was determined to be as acceptable as the high-resolution microcomputed tomography method for assessing removable partial denture framework fit.

Understanding the Mechanical, Surface, and Color Behavior of Oral Bioactive Prosthetic Polymers under Biodegradation Processes.

Changes in the properties of resin-based polymers exposed to the oral environment can emerge when chlorhexidine (CHX) is incorporated to develop bioactive systems for treating denture stomatitis. Three reline resins loaded with CHX were prepared: 2.5 wt% in Kooliner (K), 5 wt% in Ufi Gel Hard (UFI), and Probase Cold (PC). A total of 60 specimens were submitted to physical aging (1000 cycles of thermal fluctuations, 5-55 °C) or chemical aging (28 days of pH fluctuations in artificial saliva, 6 h at pH = 3, 18 h at pH = 7). Knoop microhardness (30 s, 98 mN), 3-point flexural strength (5 mm/min), and surface energy were tested. Color changes (ΔE) were determined using the CIELab system. Data were submitted to non-parametric tests (α = 0.05). After aging, bioactive K and UFI specimens were not different from the controls (resins without CHX) in mechanical and surface properties. Thermally aged CHX-loaded PC specimens showed decreased microhardness and flexural strength but not under adequate levels for function. The color change was observed in all CHX-loaded specimens that underwent chemical aging. The long-term use of CHX bioactive systems based on reline resins generally does not impair removable dentures' proper mechanical and aesthetic functions.

Development of a chlorhexidine delivery system based on dental reline acrylic resins.

The high recurrence rate of common denture stomatitis after antifungal treatment is still concerning. This condition is caused by low patient compliance and incomplete local elimination of the main etiological factor - Candida albicans, often associated with other microorganisms, such as Streptococcus species. Impregnating denture materials with antimicrobials for local delivery is a strategy that can overcome the side effects and improve the efficacy of conventional treatments (topical and/or systemic). In this work, we describe the development of three hard autopolymerizing reline acrylic resins (Kooliner, Ufi Gel Hard, and Probase Cold) loaded with different percentages of chlorhexidine (CHX). The novel formulations were characterized based on their antimicrobial activity, mechanical, morphological and surface properties, in-vitro drug release profiles, and cytotoxicity. The addition of CHX in all resins did not change their chemical and mechanical structure. Among all the tested formulations, Probase Cold loaded with 5 wt% CHX showed the most promising results in terms of antimicrobial activity and lack of serious detrimental mechanical, morphological, surface, and biological properties.

Should local drug delivery systems be used in dentistry?

In dentistry, the use of biomaterial-based drug delivery systems (DDS) aiming the release of the active compounds directly to the site of action is slowly getting more awareness among the scientific and medical community. Emerging technologies including nanotechnological platforms are offering novel approaches, but the majority are still in the proof-of-concept stage. This study critically reviews the potential use of DDS in anesthesiology, oral diseases, cariology, restorative dentistry, periodontics, endodontics, implantology, fixed and removable prosthodontics, and orthodontics with a special focus on infections. It also stresses the gaps and challenges faced. Despite numerous clinical and pharmacological advantages, some disadvantages of DDS pose an obstacle to their widespread use. The biomaterial's biofunctionality may be affected when the drug is incorporated and may cause an additional risk of toxicity. Also, the release of sub-therapeutic levels of drugs such as antibiotics may lead to microbial resistance. Multiple available techniques for the manufacture of DDS may affect drug release profiles and their bioavailability. If the benefits outweigh the costs, DDS may be potentially used to prevent or treat oral pathologies as an alternative to conventional strategies. A case-by-case approach must be followed.

Determinants and prognostic implication of periprocedural myocardial injury after successful recanalization of coronary chronic total occlusion.

Periprocedural myocardial injury (PMI) has been generally associated with major adverse cardiac events (MACE), however, limited studies addressed its clinical implications following chronic total occlusion (CTO) percutaneous coronary intervention (PCI). To evaluate the determinants and prognostic implication of PMI following CTO-PCI. Retrospective single-centre study of 125 consecutive patients undergoing CTO-PCI was attempted between December 2013 and December 2017. Angiographic success was achieved in 115 patients (92.0%) and cTn-I values were obtained 12-24 h following PCI. PMI was defined as an elevation of cTn-I above 5 times the 99th-percentile upper reference limit. Baseline demographic, clinical, angiographic and procedural characteristics were compared. Multivariate analysis was performed to determine the predictors of PMI and the correlates of PMI and 1-year MACE, a composite of all-cause death, non-fatal myocardial infarction, and target lesion revascularization. Overall, mean age was 67 ± 17 years; 25 patients (21.7%) were female; and PMI occurred in 41 patients (35.7%). Multivessel coronary artery disease (MVD) (odds ratio [OR], 3.41; 95% confidence interval [CI], 1.09-10.67; p = 0.04) and procedural complications (a composite of iatrogenic coronary artery dissection/haematoma or perforation) (OR, 19.08; 95% CI, 3.77-96.65; p < 0.01) predicted PMI. Significant collateralization (Rentrop 3) (hazard ratio, [HR], 0.19; 95% CI, 0.06-0.64; p < 0.01) and procedural complications (HR, 8.86; 95% CI, 2.66-29.46; p < 0.01) were independently associated with 1-year MACE, while PMI was not (p = 0.26). In this contemporary cohort, PMI following successful CTO-PCI was a common finding and was predicted by MVD and procedural complications. PMI was not independently associated with 1-year MACE.

11p15 ICR1 Partial Deletions Associated with IGF2/H19 DMR Hypomethylation and Silver-Russell Syndrome.

The 11p15 region harbors the IGF2/H19 imprinted domain, implicated in fetal and postnatal growth. Silver-Russell syndrome (SRS) is characterized by fetal and postnatal growth failure, and is caused principally by hypomethylation of the 11p15 imprinting control region 1 (ICR1). However, the mechanisms leading to ICR1 hypomethylation remain unknown. Maternally inherited genetic defects affecting the ICR1 domain have been associated with ICR1 hypermethylation and Beckwith-Wiedemann syndrome (an overgrowth syndrome, the clinical and molecular mirror of SRS), and paternal deletions of IGF2 enhancers have been detected in four SRS patients. However, no paternal deletions of ICR1 have ever been associated with hypomethylation of the IGF2/H19 domain in SRS. We screened for new genetic defects within the ICR1 in a cohort of 234 SRS patients with hypomethylated IGF2/H19 domain. We report deletions close to the boundaries of ICR1 on the paternal allele in one familial and two sporadic cases of SRS with ICR1 hypomethylation. These deletions are associated with hypomethylation of the remaining CBS, and decreased IGF2 expression. These results suggest that these regions are most likely required to maintain methylation after fertilization. We estimate these anomalies to occur in about 1% of SRS cases with ICR1 hypomethylation.

Hypercortisolism due to a Pituitary Adenoma Associated with Beckwith-Wiedemann Syndrome.

BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome with an increased risk of cancer. Most BWS patients show a molecular defect in the 11p15 region that contains imprinted genes. BWS has been associated with malignant neoplasms during infancy. Descriptions of benign tumors, especially in adult patients, are rarer. METHODS/RESULTS: We report the case of a BWS patient with pituitary adenoma caused by loss of methylation (LOM) at ICR2 (locus CDKN1C/KCNQ1OT1). The patient was referred to an endocrinology unit for suspicion of Cushing's disease due to a history of macroglossia and hemihyperplasia. Biological tests led to the diagnosis of ACTH-dependent hypercortisolism. MRI showed a microadenoma of the pituitary gland, confirming the diagnosis of Cushing's disease. DNA methylation analysis revealed LOM at ICR2 that was in a mosaic state in the patient's leukocytes, but was present in nearly all cells of the pituitary adenoma. The epigenetic defect was associated with a somatic USP8 mutation in the adenoma. CONCLUSION: Pituitary adenoma rarely occurs in patients with BWS. However, BWS should be considered in cases of pituitary adenoma with minor and/or major signs of BWS. The association between ICR2 LOM and USP8 mutation in the adenoma is questionable. © 2016 S. Karger AG, Basel.

Control of crystallite and particle size in the synthesis of layered double hydroxides: Macromolecular insights and a complementary modeling tool.

Zinc-aluminum layered double hydroxides with nitrate intercalated (Zn(n)Al-NO3, n=Zn/Al) is an intermediate material for the intercalation of different functional molecules used in a wide range of industrial applications. The synthesis of Zn(2)Al-NO3 was investigated considering the time and temperature of hydrothermal treatment. By examining the crystallite size in two different directions, hydrodynamic particle size, morphology, crystal structure and chemical species in solution, it was possible to understand the crystallization and dissolution processes involved in the mechanisms of crystallite and particle growth. In addition, hydrogeochemical modeling rendered insights on the speciation of different metal cations in solution. Therefore, this tool can be a promising solution to model and optimize the synthesis of layered double hydroxide-based materials for industrial applications.

Exhaustive methylation analysis revealed uneven profiles of methylation at IGF2/ICR1/H19 11p15 loci in Russell Silver syndrome.

BACKGROUND: The structural organisation of the human IGF2/ICR1/H19 11p15 domain is very complex, and the mechanisms underlying its regulation are poorly understood. The Imprinted Center Region 1 (ICR1) contains seven binding sites for the zinc-finger protein CTCF (CBS: CTCF Binding Sites); three additional differentially methylated regions (DMR) are located at the H19 promoter (H19DMR) and two in the IGF2 gene (DMR0 and DMR2), respectively. Loss of imprinting at the IGF2/ICR1/H19 domain results in two growth disorders with opposite phenotypes: Beckwith-Wiedemann syndrome and Russell Silver syndrome (RSS). Despite the IGF2/ICR1/H19 locus being widely studied, the extent of hypomethylation across the domain remains not yet addressed in patients with RSS. METHODS: We assessed a detailed investigation of the methylation status of the 11p15 ICR1 CBS1-7, IGF2DMR0 and H19DMR (H19 promoter) in a population of controls (n=50) and RSS carrying (n=104) or not (n=65) carrying a hypomethylation at the 11p15 ICR1 region. RESULTS: The methylation indexes (MI) were balanced at all regions in the control population and patients with RSS without any as yet identified molecular anomaly. Interestingly, patients with RSS with ICR1 hypomethylation showed uneven profiles of methylation among the CBSs and DMRs. Furthermore, normal MIs at CBS1 and CBS7 were identified in 9% of patients. CONCLUSIONS: The hypomethylation does not spread equally throughout the IGF2/ICR1/H19 locus, and some loci could have normal MI, which may lead to underdiagnosis of patients with RSS with ICR1 hypomethylation. The uneven pattern of methylation suggests that some CBSs may play different roles in the tridimensional chromosomal looping regulation of this locus.

Complex tissue-specific epigenotypes in Russell-Silver Syndrome associated with 11p15 ICR1 hypomethylation.

Russell-Silver Syndrome (RSS) is a prenatal and postnatal growth retardation syndrome caused mainly by 11p15 ICR1 hypomethylation. Clinical presentation is heterogeneous in RSS patients with 11p15 ICR1 hypomethylation. We previously identified a subset of RSS patients with 11p15 ICR1 and multilocus hypomethylation. Here, we examine the relationships between IGF2 expression, 11p15 ICR1 methylation, and multilocus imprinting defects in various cell types from 39 RSS patients with 11p15 ICR1 hypomethylation in leukocyte DNA. 11p15 ICR1 hypomethylation was more pronounced in leukocytes than in buccal mucosa cells. Skin fibroblast IGF2 expression was correlated with the degree of ICR1 hypomethylation. Different tissue-specific multilocus methylation defects coexisted in 38% of cases, with some loci hypomethylated and others hypermethylated within the same cell type in some cases. Our new results suggest that tissue-specific epigenotypes may lead to clinical heterogeneity in RSS.

Extensive investigation of the IGF2/H19 imprinting control region reveals novel OCT4/SOX2 binding site defects associated with specific methylation patterns in Beckwith-Wiedemann syndrome.

Isolated gain of methylation (GOM) at the IGF2/H19 imprinting control region 1 (ICR1) accounts for about 10% of patients with BWS. A subset of these patients have genetic defects within ICR1, but the frequency of these defects has not yet been established in a large cohort of BWS patients with isolated ICR1 GOM. Here, we carried out a genetic analysis in a large cohort of 57 BWS patients with isolated ICR1 GOM and analyzed the methylation status of the entire domain. We found a new point mutation in two unrelated families and a 21 bp deletion in another unrelated child, both of which were maternally inherited and affected the OCT4/SOX2 binding site in the A2 repeat of ICR1. Based on data from this and previous studies, we estimate that cis genetic defects account for about 20% of BWS patients with isolated ICR1 GOM. Methylation analysis at eight loci of the IGF2/H19 domain revealed that sites surrounding OCT4/SOX2 binding site mutations were fully methylated and methylation indexes declined as a function of distance from these sites. This was not the case in BWS patients without genetic defects identified. Thus, GOM does not spread uniformly across the IGF2/H19 domain, suggesting that OCT4/SOX2 protects against methylation at local sites. These findings add new insights to the mechanism of the regulation of the ICR1 domain. Our data show that mutations and deletions within ICR1 are relatively common. Systematic identification is therefore necessary to establish appropriate genetic counseling for BWS patients with isolated ICR1 GOM.

Short- and long-term distribution and toxicity of gold nanoparticles in the rat after a single-dose intravenous administration.

Surface chemistry plays an important role in gold nanoparticles (AuNPs) stability and biocompatibility, which are crucial for their implementation into the clinical setting. We evaluated short- (30 min) and long-term (28 days) biodistribution and toxicity of ~20 nm citrate- and pentapeptide CALNN-coated AuNPs after a single intravenous injection in rats. The pattern of AuNPs distribution in Cit- and CALNN-AuNPs-injected rats was very similar in the assessed time-points. Both AuNPs were quickly removed from the bloodstream and preferentially accumulated in the liver. At 28 days liver remained the main accumulation site but at significantly lower levels compared to those found at 30 min. Spleen atrophy and hematological findings compatible with mild anemia were observed in CALNN-AuNPs-administered rats. Under our experimental conditions, surface coating had more impact on toxicity rather than on biodistribution of the AuNPs. Improvements in the design of capping peptides need to be done to increase biomedical applicability of peptide-coated AuNPs. FROM THE CLINICAL EDITOR: The biodistribution and toxicity of ~ 20 nm citrate- and pentapeptide CALNN-coated gold nanoparticles was investigated after a single intravenous injection in rats. Rapid clearance and hepatic accumulation was found at 30-minutes, whereas mild anemia and spleen atrophy was seen 28 days post injection. The authors also concluded that the toxicity was related to the capping proteins as opposed to the biodistribution of the particles, providing important suggestion for future design of gold nanoparticles.

Ethanol postpolymerization treatment for improving the biocompatibility of acrylic reline resins.

OBJECTIVE: To evaluate the effect of postpolymerization treatment based on ethanol-aqueous solutions on the residual monomer (RM) content, flexural strength, microhardness, and cytotoxicity of hard chairside reline resins (Kooliner, Ufi Gel Hard). METHODS: After polymerization, specimens were immersed in water, 20%, 50%, or 70% ethanol solutions at 23°C or 55°C for 10 minutes. Controls were left untreated. HPLC was used for the determination of RM content. Specimens were submitted to Vickers microhardness and 3-point loading flexural strength tests. Cytotoxicity of resin eluates was determined on human fibroblasts by assessing cellular mitochondrial function and lactate dehydrogenase release. RESULTS: Higher concentrations of ethanol promoted lower RM content at 55°C in both materials. The mechanical properties were maintained after 50% and 20% ethanol treatments in Kooliner and Ufi Gel Hard, respectively. Specimens submitted to those treatments showed significant reduction on cytotoxicity compared to immersion in hot water, the treatment of choice in the recent literature. SIGNIFICANCE: Immersion of relined dentures in specific ethanol solutions at 55°C for 10 minutes can be considered an effective postpolymerization treatment contributing to increase materials biocompatibility. The proposed protocol is expeditious and easy to achieve with simple equipment in a dental office.

Improved model systems for bacterial membranes from differing species: the importance of varying composition in PE/PG/cardiolipin ternary mixtures.

Steady-state fluorescence anisotropy and dynamic light scattering (DLS) were used to determine the thermotropic properties of lipid systems that act as models for bacterial membranes of Yersinia kristensenii and Proteus mirabilis. Lipid proportions of PE:PG:CL of 0.60:0.20:0.20 and 0.80:0.15:0.05, were used in order to mimic these two membranes respectively. We observed that the introduction of cardiolipin (CL) as a third lipid component of any PE:PG mixture, changes the system's properties considerably. The results obtained by these two techniques show that the main transition temperatures obtained are undoubtedly CL-dependent. Additionally AFM experiments were performed and these results show that even at small concentration CL produces important changes not only in the membrane thermotropic properties, but also in the bilayer structure. In summary, we were able to compare how low and high CL concentration affect bacterial membrane model system properties which can provide a further explanation for the different antibiotic susceptibilities reported for Y. kristensenii and P. mirabilis.

Nanoparticles in molecular diagnostics.

The aim of this chapter is to provide an overview of the available and emerging molecular diagnostic methods that take advantage of the unique nanoscale properties of nanoparticles (NPs) to increase the sensitivity, detection capabilities, ease of operation, and portability of the biodetection assemblies. The focus will be on noble metal NPs, especially gold NPs, fluorescent NPs, especially quantum dots, and magnetic NPs, the three main players in the development of probes for biological sensing. The chapter is divided into four sections: a first section covering the unique physicochemical properties of NPs of relevance for their utilization in molecular diagnostics; the second section dedicated to applications of NPs in molecular diagnostics by nucleic acid detection; and the third section with major applications of NPs in the area of immunoassays. Finally, a concluding section highlights the most promising advances in the area and presents future perspectives.

New insights into the use of magnetic force microscopy to discriminate between magnetic and nonmagnetic nanoparticles.

Magnetic force microscopy (MFM) is a very powerful technique, which can potentially be used to detect and localize the magnetic fields arising from nanoscopic magnetic domains, such as magnetic nanoparticles. However, in order to achieve this, we must be able to use MFM to discriminate between magnetic forces arising from the magnetic nanoparticles and nonmagnetic forces from other particles and sample features. Unfortunately, MFM can show a significant response even for nonmagnetic nanoparticles, giving rise to potentially misleading results. The literature to date lacks evidence for MFM detection of magnetic nanoparticles with nonmagnetic nanoparticles as a control. In this work, we studied magnetite particles of two sizes and with a silica shell, and compared them to nonmagnetic metallic and silica nanoparticles. We found that even on conducting, grounded substrates, significant electrostatic interaction between atomic force microscopy probes and nanoparticles can be detected, causing nonmagnetic signals that might be mistaken for a true MFM response. Nevertheless, we show that MFM can be used to discriminate between magnetic and nonmagnetic nanoparticles by using an electromagnetic shielding technique or by analysis of the phase shift data. On the basis of our experimental evidence we propose a methodology that enables MFM to be reliably used to study unknown samples containing magnetic nanoparticles, and correctly interpret the data obtained.

Biodegradation of acrylic based resins: A review.

OBJECTIVES: The development of different types of materials with application in dentistry is an area of intense growth and research, due to its importance in oral health. Among the different materials there are the acrylic based resins that have been extensively used either in restorations or in dentures. The objective of this manuscript was to review the acrylic based resins biodegradation phenomena. Specific attention was given to the causes and consequences of materials degradation under the oral environment. DATA AND SOURCES: Information from scientific full papers, reviews or abstracts published from 1963 to date were included in the review. Published material was searched in dental literature using general and specialist databases, like the PubMED database. STUDY SELECTION: Published studies regarding the description of biodegradation mechanisms, in vitro and in vivo release experiments and cell based studies conducted on acrylic based resins or their components were evaluated. Studies related to the effect of biodegradation on the physical and mechanical properties of the materials were also analyzed. CONCLUSIONS: Different factors such as saliva characteristics, chewing or thermal and chemical dietary changes may be responsible for the biodegradation of acrylic based resins. Release of potential toxic compounds from the material and change on their physical and mechanical properties are the major consequences of biodegradation. Increasing concern arises from potential toxic effects of biodegradation products under clinical application thus justifying an intensive research in this area.