Imidazole Carbamates as a Promising Alternative for Treating Trichomoniasis: In Vitro Effects on the Growth and Gene Expression of Trichomonas vaginalis.

Metronidazole (MTZ) is the most common drug used against Trichomonas vaginalis (T. vaginalis) infections; however, treatment failures and high rates of recurrence of trichomoniasis have been reported, suggesting the presence of resistance in T. vaginalis to MTZ. Therefore, research into new therapeutic options against T. vaginalis infections has become increasingly urgent. This study investigated the trichomonacidal activity of a series of five imidazole carbamate compounds (AGR-1, AGR-2, AGR-3, AGR-4, and AGR-5) through in vitro susceptibility assays to determine the IC50 value of each compound. All five compounds demonstrated potent trichomonacidal activity, with IC50 values in the nanomolar range and AGR-2 being the most potent (IC50 400 nM). To gain insight into molecular events related to AGR-induced cell death in T. vaginalis, we analyzed the expression profiles of some metabolic genes in the trophozoites exposed to AGR compounds and MTZ. It was found that both AGR and MTZ compounds reduced the expression of the glycolytic genes (CK, PFK, TPI, and ENOL) and genes involved in metabolism (G6PD, TKT, TALDO, NADHOX, ACT, and TUB), suggesting that disturbing these key metabolic genes alters the survival of the T. vaginalis parasite and that they probably share a similar mechanism of action. Additionally, the compounds showed low cytotoxicity in the Caco-2 and HT29 cell lines, and the results of the ADMET analysis indicated that these compounds have pharmacokinetic properties similar to those of MTZ. The findings offer significant insights that can serve as a basis for future in vivo studies of the compounds as a potential new treatment against T. vaginalis.

Delayed hip arthroscopy for femoroacetabular impingement syndrome does not increase revision but does increase rates of chronic opiate use.

Introduction: In recent years, the utilization of hip arthroscopy to treat femoroacetabular impingement syndrome (FAIS) has increased due to its low complication rates, positive impact on patient-reported outcomes (PROs), and association with faster rehabilitation. Despite this, there are high rates of revision and conversion to total hip arthroplasty (THA) in some of these patients. It is unclear whether time from initial FAIS diagnosis to surgery is a risk factor for poor outcomes. In this study, we examined the relationship between timing of hip arthroscopy for FAIS and rates of 2-year revision hip procedures, 2-year conversion to total hip arthroplasty (THA), post-operative medical complications, and opioid prescriptions. Methods: This is a retrospective cohort study utilizing the PearlDiver database. Current Procedural Terminology (CPT) and International Classification of Diseases (ICD) codes were used to identify patients who had surgery for FAIS with minimum 2 years follow-up available. Patients were stratified by 3-month intervals into 5 groups based on time from diagnosis of FAIS to hip arthroscopy. Multivariate logistic regression was performed to determine factors independently associated with continued opiate use and subsequent surgeries. Results: A total of 14,677 patients were included in the study. The 2-year rate of revision hip arthroscopy was 4.2%. As time from diagnosis to surgery increased, even in multivariate regression analysis, there was a higher risk of filling an opioid prescription 90 days after surgery (P < 0.001). Regression analysis demonstrated that timing of surgery was not associated with 2-year revision hip arthroscopy or conversion to THA. Age, sex, obesity, and tobacco use were significant predictors of revision hip arthroscopy and conversion to THA (p < 0.001). Conclusion: There is no significant difference between timing of surgery for FAIS and odds of revision or conversion to THA. Prolonged opiate use after hip arthroscopy was significantly higher as duration from initial FAIS diagnosis to surgery increased. Age, sex, obesity, and tobacco use are significant predictors for revision, conversion to THA, and continued opiate prescriptions.

New candidate SNPs for genetic association with Alzheimer's disease: a linkage disequilibrium analysis for the FCGRIIB and PILRA genes.

Background: Two new SNPs have been recently associated to Alzheimer's disease in African American populations: FCGRIIB rs1050501 C/T, and PILRA rs1859788 A/G. The risk of Alzheimer's disease in FCGRIIB C and PILRA A allele carriers is three times higher than in non-carriers. However, the association between these and other single nucleotide polymorphisms (SNPs) has not been assessed. Methods: Linkage disequilibrium analysis, with r= 0.8 as a threshold value, was used to impute new candidate SNPs, on genomic data from both genes in 26 populations worldwide (n= 2504) from the 1000Genomes database. Results: Four SNPs (rs13376485, rs3767640, rs3767639 and rs3767641) were linked to rs1050501 and one (rs2405442) to rs1859788 in the whole sample. Conclusions: Five novel SNPs could be associated with Alzheimer's disease susceptibility and play a causal role, even if none of them are exon variants since their potential roles in the regulation of gene expression.

Antecedentes: Recientemente se han asociado dos nuevos polimorfismos de un solo nucleótido (SNP) a la enfermedad de Alzheimer en poblaciones afroamericanas: FCGRIIB rs1050501 C/T, y PILRA rs1859788 A/G. El riesgo de enfermedad de Alzheimer en los portadores de los alelos FCGRIIB C y PILRA A es tres veces mayor que en los no portadores. Sin embargo, no se ha evaluado la asociación entre estos y otros SNP. Métodos: Se utilizó el análisis de desequilibrio de ligamiento, con r2= 0,8 como valor umbral, para imputar nuevos SNPs candidatos, sobre datos genómicos de ambos genes en 26 poblaciones de todo el mundo (n= 2504) de la base de datos 1000Genomes. Resultados: Cuatro SNPs (rs13376485, rs3767640, rs3767639 y rs3767641) se vincularon al rs1050501 y uno (rs2405442) al rs1859788 en toda la muestra. Conclusiones: Cinco nuevos SNP podrían estar asociados con la susceptibilidad a la enfermedad de Alzheimer y desempeñar un papel causal, aunque ninguno de ellos sea una variante de exón, dado su papel potencial en la regulación de la expresión génica.

New candidate SNPs for genetic association with Alzheimer's disease: a linkage disequilibrium analysis for the FCGRIIB and PILRA genes

Background Two new SNPs have been recently associated to Alzheimer's disease in African American populations: FCGRIIB rs1050501 C/T, and PILRA rs1859788 A/G. The risk of Alzheimer's disease in FCGRIIB C and PILRA A allele carriers is three times higher than in non-carriers. However, the association between these and other single nucleotide polymorphisms (SNPs) has not been assessed. Methods Linkage disequilibrium analysis, with r= 0.8 as a threshold value, was used to impute new candidate SNPs, on genomic data from both genes in 26 populations worldwide (n= 2504) from the 1000Genomes database. Results Four SNPs (rs13376485, rs3767640, rs3767639 and rs3767641) were linked to rs1050501 and one (rs2405442) to rs1859788 in the whole sample. Conclusions Five novel SNPs could be associated with Alzheimer's disease susceptibility and play a causal role, even if none of them are exon variants since their potential roles in the regulation of gene expression.

Antecedentes Recientemente se han asociado dos nuevos polimorfismos de un solo nucleótido (SNP) a la enfermedad de Alzheimer en poblaciones afroamericanas: FCGRIIB rs1050501 C/T, y PILRA rs1859788 A/G. El riesgo de enfermedad de Alzheimer en los portadores de los alelos FCGRIIB C y PILRA A es tres veces mayor que en los no portadores. Sin embargo, no se ha evaluado la asociación entre estos y otros SNP. Métodos Se utilizó el análisis de desequilibrio de ligamiento, con r2= 0,8 como valor umbral, para imputar nuevos SNPs candidatos, sobre datos genómicos de ambos genes en 26 poblaciones de todo el mundo (n= 2504) de la base de datos 1000Genomes. Resultados Cuatro SNPs (rs13376485, rs3767640, rs3767639 y rs3767641) se vincularon al rs1050501 y uno (rs2405442) al rs1859788 en toda la muestra. Conclusiones Cinco nuevos SNP podrían estar asociados con la susceptibilidad a la enfermedad de Alzheimer y desempeñar un papel causal, aunque ninguno de ellos sea una variante de exón, dado su papel potencial en la regulación de la expresión génica.

Inferring co-expression networks of Arabidopsis thaliana genes during their interaction with Trichoderma spp.

Fungi of the Trichoderma genus are called "biostimulants" because they promote plant growth and development and induce disease resistance. We used conventional transcriptome and gene co-expression analyses to understand the molecular response of the plant Arabidopsis thaliana to inoculation with Trichoderma atroviride or Trichoderma virens. The transcriptional landscape of the plant during the interaction with these fungi showed a reduction in functions such as reactive oxygen species production, defense mechanisms against pathogens, and hormone signaling. T. virens, as opposed to T. atroviride, was more effective at downregulating genes related to terpenoid metabolism, root development, and chemical homeostasis. Through gene co-expression analysis, we found functional gene modules that closely link plant defense with hypoxia. Notably, we found a transcription factor (locus AT2G47520) with two functional domains of interest: a DNA-binding domain and an N-terminal cysteine needed for protein stability under hypoxia. We hypothesize that the transcription factor can bind to the promoter sequence of the GCC-box that is connected to pathogenesis by positioned weight matrix analysis.

Covid- 19 Vaccine-induced Myocarditis.

Myocarditis and pericarditis are rare adverse reactions, more commonly seen in young males after receiving the second dose of an mRNA vaccine. However, the benefits of vaccination heavily outweigh the risk of these side effects. In addition, vaccination boosters are effective against the newest, more infective variants. Therefore we expect more vaccines to be administered in the following years. The objective of this study is to review the current understanding of the mechanism, diagnosis, and treatment of myocarditis and pericarditis. Proposed mechanisms include molecular mimicry against the S protein and hypersensitivity reactions with mRNA vaccines and platelet aggregation and thrombus formation in cardiac blood vessels with adenoviral vaccines. Diagnosis of myocarditis is based on clinical findings, cardiac enzymes, ECG, MRI, and echocardiographic findings. Management includes NSAIDs and cardiovascular support in selected cases with ventricular dysfunction. Most patients have a mild presentation with preservation of cardiac function and recover entirely within seven days; the average hospital stay is three days. Long-term complications are infrequent.

Healthcare provider-targeted mobile applications to diagnose, screen, or monitor communicable diseases of public health importance in low- and middle-income countries: A systematic review.

Communicable diseases remain a leading cause of death and disability in low- and middle-income countries (LMICs). mHealth technologies carry considerable promise for managing these disorders within resource-poor settings, but many existing applications exclusively represent digital versions of existing guidelines or clinical calculators, communication facilitators, or patient self-management tools. We thus systematically searched PubMed, Web of Science, and Cochrane Central for studies published between January 2007 and October 2019 involving technologies that were mobile phone- or tablet-based; able to screen for, diagnose, or monitor a communicable disease of importance in LMICs; and targeted health professionals as primary users. We excluded technologies that digitized existing paper-based tools or facilitated communication (i.e., knowledge-based algorithms). Extracted data included disease category, pathogen type, diagnostic method, intervention purpose, study/target population, sample size, study methodology, development stage, accessory requirement, country of development, operating system, and cost. Given the search timeline, studies involving COVID-19 were not included in the analysis. Of 13,262 studies identified by the screen, 33 met inclusion criteria. 12% were randomized clinical trials (RCTs), with 58% of publications representing technical descriptions. 62% of studies had 100 or fewer subjects. All studied technologies involved diagnosis or screening steps; none addressed the monitoring of infections. 52% focused on priority diseases (HIV, malaria, tuberculosis), but only 12% addressed a neglected tropical disease. Although most reported studies were priced under 20USD at time of publication, two thirds of the records did not yet specify a cost for the study technology. We conclude that there are only a small number of mHealth technologies focusing on innovative methods of screening and diagnosing communicable diseases potentially of use in LMICs. Rigorous RCTs, analyses with large sample size, and technologies assisting in the monitoring of diseases are needed.

Human Triosephosphate Isomerase Is a Potential Target in Cancer Due to Commonly Occurring Post-Translational Modifications.

Cancer involves a series of diseases where cellular growth is not controlled. Cancer is a leading cause of death worldwide, and the burden of cancer incidence and mortality is rapidly growing, mainly in developing countries. Many drugs are currently used, from chemotherapeutic agents to immunotherapy, among others, along with organ transplantation. Treatments can cause severe side effects, including remission and progression of the disease with serious consequences. Increased glycolytic activity is characteristic of cancer cells. Triosephosphate isomerase is essential for net ATP production in the glycolytic pathway. Notably, some post-translational events have been described that occur in human triosephosphate isomerase in which functional and structural alterations are provoked. This is considered a window of opportunity, given the differences that may exist between cancer cells and their counterpart in normal cells concerning the glycolytic enzymes. Here, we provide elements that bring out the potential of triosephosphate isomerase, under post-translational modifications, to be considered an efficacious target for treating cancer.

Triceps Rupture After Olecranon Fixation with Proximal Ulna Plate and Suture Augmentation: A Case Report.

CASE: Olecranon fractures treated with proximal ulna plate fixation and repairing the triceps with suture augmentation to the plate decrease the risk of "olecranon escape," but may lead to failure through triceps rupture. In this case report, a rare complication of triceps rupture occurred, and the patient underwent triceps repair. CONCLUSION: When fixing olecranon fractures, surgeons should minimize triceps dissection for hardware placement. If subjected to significant force, a surgical insult to the tendon footprint for a better plate contact on the bone and the presence of suture augmentation may change the construct failure mechanism and result in triceps rupture as opposed to fracture redisplacement.

Repurposing of rabeprazole as an anti-Trypanosoma cruzi drug that targets cellular triosephosphate isomerase.

Trypanosoma cruzi is the causative agent of American trypanosomiasis, which mainly affects populations in Latin America. Benznidazole is used to control the disease, with severe effects in patients receiving this chemotherapy. Previous studies have demonstrated the inhibition of triosephosphate isomerase from T. cruzi, but cellular enzyme inhibition has yet to be established. This study demonstrates that rabeprazole inhibits both cell viability and triosephosphate isomerase activity in T. cruzi epimastigotes. Our results show that rabeprazole has an IC50 of 0.4 µM, which is 14.5 times more effective than benznidazole. Additionally, we observed increased levels of methyl-glyoxal and advanced glycation end products after the inhibition of cellular triosephosphate isomerase by rabeprazole. Finally, we demonstrate that the inactivation mechanisms of rabeprazole on triosephosphate isomerase of T. cruzi can be achieved through the derivatization of three of its four cysteine residues. These results indicate that rabeprazole is a promising candidate against American trypanosomiasis.

Developing Hypoimmunogenic Human iPSC-Derived Oligodendrocyte Progenitor Cells as an Off-The-Shelf Cell Therapy for Myelin Disorders.

Demyelinating disorders are among the most common and debilitating diseases in neurology. Canavan disease (CD) is a lethal demyelinating disease caused by mutation of the aspartoacylase (ASPA) gene, which leads to the accumulation of its substrate N-acetyl-l-aspartate (NAA), and consequently demyelination and vacuolation in the brain. In this study, hypoimmunogenic human induced pluripotent stem cell (iPSC)-derived oligodendrocyte progenitor cells (OPC) are developed from a healthy donor as an "off-the-shelf" cell therapy. Hypoimmunogenic iPSCs are generated through CRISPR/Cas9 editing of the human leukocyte antigen (HLA) molecules in healthy donor-derived iPSCs and differentiated into OPCs. The OPCs are engrafted into the brains of CD (nur7) mice and exhibit widespread distribution in the brain. The engrafted OPCs mature into oligodendrocytes that express the endogenous wildtype ASPA gene. Consequently, the transplanted mice exhibit elevated human ASPA expression and enzymatic activity and reduced NAA level in the brain. The transplanted OPCs are able to rescue major pathological features of CD, including defective myelination, extensive vacuolation, and motor function deficits. Moreover, the hypoimmunogenic OPCs exhibit low immunogenicity both in vitro and in vivo. The hypoimmunogenic OPCs can be used as "off-the-shelf" universal donor cells to treat various CD patients and many other demyelinating disorders, especially autoimmune demyelinating diseases, such as multiple sclerosis.

Prevalencia del haplotipo de riesgo GA de los polimorfismos rs1554483 y rs4864548 del gen CLOCK asociados a la obesidad y el sobrepeso en 26 poblaciones / Prevalence of the GA risk haplotype of the rs1554483 and rs4864548 polymorphisms of the CLOCK gene associated with obesity and overweight in 26 populations

Introducción: el haplotipo GA de los polimorfismos rs1554483 y rs4864548 se ha asociado con componentes del síndrome metabólico como la hipertensión arterial y los niveles de triglicéridos. Sus portadores presentan un riesgo de obesidad 1,5 veces mayor que el resto de la población. Metodología: se obtuvieron los SNP rs1554483 y rs4864548 de 2504 individuos desde la base de datos “1000genomes phase 3”. Los datos se agruparon en cinco macropoblaciones (África, Asia Oriental, Asia Meridional, Europa y Latinoamérica) cubriendo un total de 26 poblaciones. Se analizaron las diferencias en la frecuencia del haplotipo entre las macropoblaciones y las poblaciones, para lo cual se utilizó el estadístico F de Fisher. Resultados: la macropoblación de África presentó la menor frecuencia (17,9 %) y la del Este de Asia la mayor (57,4 %). Dentro de las poblaciones existe una relativa homogeneidad en las frecuencias, excepto en el caso de las que componen la macropoblación de Latinoamérica, donde la población peruana de Lima y la puertorriqueña presentan frecuencias mucho mayores que el resto. Conclusiones: el haplotipo GA presenta heterogeneidad entre las macropoblaciones, lo que sugiere procesos microevolutivos altamente diferenciados entre los continentes. Se propone estudiar la asociación del haplotipo GA con otros polimorfismos, como rs3749474, rs11932595 y rs6859524, que también se han asociado con el riesgo de obesidad y factores asociados al síndrome metabólico. (AU)

Introduction: the GA haplotype of polymorphisms rs1554483 and rs4864548 has been associated with components of the metabolic syndrome such as high blood pressure and triglyceride levels; its carriers have a risk of obesity, 1.5 times higher than the rest of the population. Methodology: SNP rs1554483 and rs4864548 were obtained from 2504 individuals from the "1000genomes phase 3" database. Data were grouped into five macro populations (Africa, East Asia, South Asia, Europe and Latin America) covering a total of 26 populations. Differences in haplotype frequency between macro populations and populations were analyzed, for which Fisher's F statistic was used. Results: the macro population of Africa presented the lowest frequency (17.9 %) and that of East Asia the highest (57.4 %). Within the populations there is a relative homogeneity in the frequencies, except in the case of those that make up the macro population of Latin America where the Peruvian population of Lima and the Puerto Rican population present much higher frequencies than the rest. Conclusions: the GA haplotype presents heterogeneity between macro populations, which suggests highly differentiated micro evolutionary processes between continents. We propose to study the association of the GA haplotype with other polymorphisms such as rs3749474, rs11932595 and rs6859524 that have also been associated with risk of obesity and factors associated with metabolic syndrome. (AU)