Search

Crystal structure, microstructure, electrical conductivity, and electrochemical performance of a family of iron perovskites with the generAl formula Ln0.5M0.5FeO3-δ (Ln = La and Pr; M = Sr, Ca, and Ba) has been studied as functions of mean A cation rAdius (rA). All the samples have a rhombohedrAl structure (space group: R¯3c). Scanning electron microscope images show that the averAge grAin size decreases with increasing (rA). The dc four-probe measurements indicate that all samples have high electrical conductivity, increasing with (rA). The electrochemical behavior of these cathode materials was evaluated by using current-voltage curve measurements and ac impedance spectroscopy over three-electrode electrolyte supported cells. The results show an improvement in cathode performance and a significant decrease in polarization resistance with increasing mean A cation rAdius (rA). [ABSTRACT FROM AUTHOR]

Cysteamine, an aminothiol, is the only available treatment for cystinosis, an incurable metabolic recessive disease characterized by detrimental symptoms at the renal, ocular, and muscular levels. Cystinosis is due to mutations in the CTNS gene encoding for the lysosomal symporter cystinosine. Cysteamine treatment only delays the symptoms, presents undesirable side effects and the patients depend on it for life. Thus, it is of paramount importance to find new complementary therapeutic targets for the disease, as well as to understand, at the molecular level, both the beneficial and detrimental effects of cysteamine. Here, we have used ZenoSWATH DIA proteomics and clustering analysis to unravel the differences between cystinotic and non-cystinotic skin fibroblasts, and to study the effect of increasing concentrations of cysteamine. Cystinotic cells present significant differences in proteins related to extracellular matrix structure and detoxification. Only a subset of those proteins is reversed by cysteamine in a dose-dependent manner, partially providing an explanation for its therapeutic benefits. Finally, cysteamine per se alters the levels of a group of lysosomal proteins that are not modulated in basal conditions. Our results will be helpful to understand the benefits, deficiencies, and detrimental effects of the cysteamine treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Heterozygous mutations in the TBK1 gene can cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The majority of TBK1-ALS/FTD patients carry deleterious loss-of-expression mutations, and it is still unclear which TBK1 function leads to neurodegeneration. We investigated the impact of the pathogenic TBK1 missense variant p.E696K, which does not abolish protein expression, but leads to a selective loss of TBK1 binding to the autophagy adaptor protein and TBK1 substrate optineurin. Using organelle-specific proteomics, we found that in a knock-in mouse model and human iPSC-derived motor neurons, the p.E696K mutation causes presymptomatic onset of autophagolysosomal dysfunction in neurons precipitating the accumulation of damaged lysosomes. This is followed by a progressive, age-dependent motor neuron disease. Contrary to the phenotype of mice with full Tbk1 knock-out, RIPK/TNF-α-dependent hepatic, neuronal necroptosis, and overt autoinflammation were not detected. Our in vivo results indicate autophagolysosomal dysfunction as a trigger for neurodegeneration and a promising therapeutic target in TBK1-ALS/FTD., (© 2024 Brenner et al.)

Outpatient parenteral antimicrobial therapy (OPAT) with continuous infusion pumps is postulated as a very promising solution to treat complicated infections, such as endocarditis or osteomyelitis, that require patients to stay in hospital during extended periods of time, thus reducing their quality of life and increasing the risk of complications. However, stability studies of drugs in elastomeric devices are scarce, which limits their use in OPAT. Therefore, we evaluated the stability of ampicillin in sodium chloride 0.9% at two different concentrations, 50 and 15 mg/mL, in an elastomeric infusion pump when stored in the refrigerator and subsequently in real-life conditions at two different temperatures, 25 and 32 °C, with and without the use of a cooling device. The 15 mg/mL ampicillin is stable for up to 72 h under refrigeration, allowing subsequent dosing at 25 °C for 24 h with and without a cooling device, but at 32 °C its concentration drops below 90% after 8 h. In contrast, 50 mg/mL ampicillin only remains stable for the first 24 h under refrigeration, and subsequent administration at room temperature is not possible, even with the use of a cooling system. Our data support that 15 mg/mL AMP is suitable for use in OPAT if the volume and rate of infusion are tailored to the dosage needs of antimicrobial treatments.

Biological drugs, especially those targeting anti-tumour necrosis factor α (TNFα) molecule, have revolutionized the treatment of patients with non-infectious uveitis (NIU), a sight-threatening condition characterized by ocular inflammation that can lead to severe vision threatening and blindness. Adalimumab (ADA) and infliximab (IFX), the most widely used anti-TNFα drugs, have led to greater clinical benefits, but a significant fraction of patients with NIU do not respond to these drugs. The therapeutic outcome is closely related to systemic drug levels, which are influenced by several factors such as immunogenicity, concomitant treatment with immunomodulators, and genetic factors. Therapeutic drug monitoring (TDM) of drug and anti-drug antibody (ADAbs) levels is emerging as a resource to optimise biologic therapy by personalising treatment to bring and maintain drug concentration within the therapeutic range, especially in those patients where a clinical response is less than expected. Furthermore, some studies have described different genetic polymorphisms that may act as predictors of response to treatment with anti-TNFα agents in immune-mediated diseases and could be useful in personalising biologic treatment selection. This review is a compilation of the published evidence in NIU and in other immune-mediated diseases that support the usefulness of TDM and pharmacogenetics as a tool to guide clinicians' treatment decisions leading to better clinical outcomes. In addition, findings from preclinical and clinical studies, assessing the safety and efficacy of intravitreal administration of anti-TNFα agents in NIU are discussed.

Age-related macular degeneration (AMD) is a common ocular disease characterized by degeneration of the central area of the retina in the elderly population. Progression and response to treatment are influenced by genetic and non-genetic factors. Proteomics is a powerful tool to study, at the molecular level, the mechanisms underlying the progression of the disease, to identify new therapeutic targets and to establish biomarkers to monitor progression and treatment effectiveness. In this work, we systematically review the use of proteomics-based approaches for the study of the molecular mechanisms underlying the development of AMD, as well as the progression of the disease and on-treatment patient monitoring. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) reporting guidelines were followed. Proteomic approaches have identified key players in the onset of the disease, such as complement components and proteins involved in lipid metabolism and oxidative stress, but also in the progression to advanced stages, including factors related to extracellular matrix integrity and angiogenesis. Although anti-vascular endothelial growth factor (anti-VEGF)-based therapy has been crucial in the treatment of neovascular AMD, it is necessary to deepen our understanding of the underlying disease mechanisms to move forward to next-generation therapies for later-stage forms of this multifactorial disease.

Cystinosis is a rare genetic disorder characterized by the accumulation of cystine crystals in different tissues and organs causing, among other symptoms, severe ocular manifestations. Cysteamine eye drops are prepared in hospital pharmacy departments to facilitate access to treatment, for which vehicles that provide adequate biopermanence, as well as adaptable containers that maintain its stability, are required. Difficulties related to cysteamine preparation, as well as its tendency to oxidize to cystamine, show the importance of conducting rigorous galenic characterization studies. This work aims to develop and characterize an ophthalmic compounded formulation of cysteamine prepared with hyaluronic acid and packaged in innovative single-dose systems. For this task, the effect of different storage temperatures and the presence/absence of nitrogen on the physicochemical stability of the formulation and its packaging was studied in a scaled manner, until reaching the optimal storage conditions. The results showed that 0.55% cysteamine, prepared with hyaluronic acid and packaged in single-dose containers, is stable for 30 days when stored at -20 °C. In addition, opening vials every 4 h at room temperature after 30 days of freezing maintains the stability of the cysteamine formulation for up to 16 h. Moreover, ocular biopermanence studies were conducted using molecular imaging, concluding that the biopermanence offered by the vehicle is not affected by the freezing process, where a half-life of 31.11 min for a hyaluronic acid formulation stored for 30 days at -20 °C was obtained, compared with 14.63 min for 0.9% sodium chloride eye drops.

In the last decades, personalized medicine has been increasing its presence in different fields of medicine, including ophthalmology. A new factor that can help us direct medicine towards the challenge of personalized treatments is the microbiome. The gut microbiome plays an important role in controlling immune response, and dysbiosis has been associated with immune-mediated diseases such as non-infectious uveitis (NIU). In this review, we gather the published evidence, both in the pre-clinical and clinical studies, that support the possible role of intestinal dysbiosis in the pathogenesis of NIU, as well as the modulation of the gut microbiota as a new possible therapeutic target. We describe the different mechanisms that have been proposed to involve dysbiosis in the causality of NIU, as well as the potential pharmacological tools that could be used to modify the microbiome (dietary supplementation, antibiotics, fecal microbiota transplantation, immunomodulators, or biologic drugs) and, consequently, in the control of the NIU. Furthermore, there is increasing scientific evidence suggesting that the treatment with anti-TNF not only restores the composition of the gut microbiota but also that the study of the composition of the gut microbiome will help predict the response of each patient to anti-TNF treatment.

Patients with rheumatoid arthritis (RA) show autoantibodies against post-translational protein modifications (PTMs), such as anti-citrullinated protein antibodies. However, the range of recognized PTMs is unknown. Here, we addressed four PTMs: chlorination, non-enzymatic glycation, nitration, and homocysteinylation, identified as targets of atypical RA autoantibodies in studies whose protocols we have followed. The modified antigens included collagen type II, an extract of synovial proteins and a selection of peptides. We interpreted the results according to the optical density (OD) obtained in an enzyme-linked immunosorbent assay ( ELISA) with the modified antigen and the corrected OD obtained after subtracting the reactivity against the unmodified antigen. The results showed evidence of specific antibodies against glycated collagen type II, as the corrected ODs were higher in the 182 patients with RA than in the 164 healthy controls ( p = 0.0003). However, the relevance of these antibodies was doubtful because the magnitude of the specific signal was small (median OD = 0.072 vs. 0.027, respectively). There were no specific antibodies against any of the other three PTMs. Therefore, our results showed that the four PTMs are not inducing a significant autoantibody response in patients with RA. These results indicated that the repertoire of PTM autoantigens in RA is restricted.

Two opposite phenomena have been found in territorial animals, the "dear enemy'' and the "nasty neighbour'', which refer to individuals that show less aggression toward neighbours than toward strangers and vice versa. However, the need to maintain territory should differ for males and females because sexual reproduction is the result of the different adaptive strategies of the sexes. In this study, we explore territorial behaviour in the context of dear-enemy and nasty neighbour effects in the Mexican volcano mouse (Neotomodon alstoni). Patterns of spatial relationships between individuals and the degrees of agonistic behaviour among neighbours were analysed for a period of one year. Results exhibit a greater spatial proximity between male pairs during the non-reproductive period than during the reproductive period, and greater spatial proximity between pairs of females during the reproductive period than during the non-reproductive period. The analysis of agonistic behaviour showed that there is less tolerance for distant neighbours than for nearest neighbours. However, there is a greater frequency of aggression between male pairs than between females, while females appear to exhibit non-aggressive avoidance among individuals. The results support the theory that Mexican volcano mouse exhibits the "dear enemy phenomenon"., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The patients with RA benefit from early identification soon after the first clinical symptoms appear. The 2010 ACR/EULAR classification criteria were developed to fulfill this need and their application has been demonstrated to be effective. However, there is still room for improvement. Therefore, we aimed to evaluate the potential of the concordant presence of RF, anti-CCP and anti-carbamylated protein antibodies to improve current RA classification among early arthritis (EA) patients., Methods: Data from the first visit of 1057 patients in two EA prospective cohorts were used. The serological scores from the 2010 ACR/EULAR criteria and the concordant presence of the three RA autoantibodies were assessed relative to a gold standard consisting of the RA classification with the 1987 ACR criteria at the 2 years of follow-up., Results: The concordant presence of three antibodies showed predictive characteristics allowing for direct classification as RA (positive predictive value = 96.1% and OR = 80.9). They were significantly better than the corresponding to the high antibody titers defined as in the 2010 classification criteria (PPV = 88.8%, OR = 26.1). In addition, the concordant presence of two antibodies was also very informative (PPV = 82.3%, OR = 15.1). These results allowed devising a scoring system based only on antibody concordance that displayed similar overall performance as the serological scoring system of the 2010 criteria. However, the best classification was obtained combining the concordance and 2010 serological systems, a combination with a significant contribution from each of the two systems., Discussion: The concordant presence of RA autoantibodies showed an independent contribution to the classification of EA patients that permitted increased discrimination and precision.

We report a case of de novo partial duplication of the distal segment of the long arm of chromosome 5 (q31--> qter). The patient showed dysmorphic features (flat face, short and horizontal palpebral fissures, depressed and broad nasal bridge, wide nose with hypoplastic alae nasae, short and flat philtrum, high arched palate, micrognathia, anomalies of the ears), redundant adipose panniculus of the neck, proximal shortening of the limbs, flexion contractures, long and distally widened fingers, bilateral clubfoot, single umbilical artery, hypoplasia of lung and pulmonary arteries, atrial septal defect and patent ductus arteriosus. She died 23 hours after birth from respiratory failure. Chromosome analysis with high resolution GTG bands showed 46,XX,1p1, which was interpreted as a partial duplication of the distal long arm of chromosome 5 (q31--> qter). Fluorescence in situ hybridization analyses with whole chromosome painting technique for chromosome 5 proved that this extra region belonged to chromosome 5. Our case is the first to have a de novo partial duplication of this chromosome segment.

We report two cases of agenesis of corpus callosum in which high resolution G-band cytogenetic study revealed inverted duplication of the short arm of chromosome 8. The application of hybridization techniques with fluorescence in situ hybridization (FISH) confirmed chromosomal alteration in both cases. The definitive karyotype was 46, XY or XX inv dup del (8) (qter-p23.1::p23.1-p11.2).ish (WCP 8 ) (tel 8p-).

We report a new case of partial trisomy 18q due to a balanced reciprocal translocation 4;18 in the mother. The female infant had a partial trisomy of the long arm of chromosome 18 associated with a partial monosomy of distal 4q. The infant showed many of the main clinical features of trisomy 18, such as dysmorphic face, congenital heart defect, crossing of the second and fifth fingers over the third and fourth with flexion contractures, and abnormal genitalia. We believe that the trisomy 18 phenotype requires a large region of 18q and that the greater the trisomic fragment, the more severe the expression. We stress the importance of genetic counseling to carriers of balanced translocations. The risk for each case should be evaluated and information should be given on the possibility of prenatal diagnosis.