Cellular and Structural Changes in Achilles and Patellar Tendinopathies: A Pilot In Vivo Study.

Tendinopathies continue to be a challenge for both patients and the medical teams providing care as no universal clinical practice guidelines have been established. In general, tendinopathies are typically characterized by prolonged, localized, activity-related pain with abnormalities in tissue composition, cellularity, and microstructure that may be observed on imaging or histology. In the lower limb, tendinopathies affecting the Achilles and the patellar tendons are the most common, showing a high incidence in athletic populations. Consistent diagnosis and management have been challenged by a lack of universal consensus on the pathophysiology and clinical presentation. Current management is primarily based on symptom relief and often consists of medications such as non-steroidal anti-inflammatories, injectable therapies, and exercise regimens that typically emphasize progressive eccentric loading of the affected structures. Implementing the knowledge of tendon stem/progenitor cells (TSPCs) and assessing their potential in enhancing tendon repair could fill an important gap in this regard. In the present pilot in vivo study, we have characterized the structural and cellular alterations that occur soon after tendon insult in models of both Achilles and patellar tendinopathy. Upon injury, CD146+ TSPCs are recruited from the interfascicular tendon matrix to the vicinity of the paratenon, whereas the observed reduction in M1 macrophage polarization is related to a greater abundance of reparative CD146+ TSPCs in situ. The robust TSPCs' immunomodulatory effects on macrophages were also demonstrated in in vitro settings where TSPCs can effectively polarize M1 macrophages towards an anti-inflammatory therapeutic M2 phenotype. Although preliminary, our findings suggest CD146+ TSPCs as a key phenotype that could be explored in the development of targeted regenerative therapies for tendinopathies.

Economic losses caused by mastitis and the influence of climate variation on the occurrence of the disease in a dairy cattle farm in southern Brazil.

This study evaluated the economic impacts caused by mastitis in a small dairy farm with similar characteristics and production to most dairy farms in southern Brazil and investigated if climatic variations influenced mastitis occurrence in the region. A farm with, on average, 45 lactating Holstein cattle was monitored from November 2021 to October 2022, and data on mastitis cases, bulk tank milk somatic cell count, animal treatment costs, milk production, animal disposal costs, and production losses were collected. Monthly averages of temperature, relative humidity (RH), and rainfall in the region were obtained. The greatest loss was related to the drop in milk production, resulting in 63.8% of total losses, followed by animal disposal (29.5%), milk disposal (4.6%), and treating animals with mastitis (2.0%), totaling a 10.6% reduction in the annual gross income. There were negative correlations between the clinical mastitis rate and monthly RH and between subclinical mastitis and temperature; the occurrence of subclinical mastitis and average RH were positively correlated. Our findings showed that mastitis negatively impacted the economy and that climate influenced mastitis occurrence.

Development of cobalt (Co)-doped monetites for bone regeneration.

Cobalt-doped monetite powders were synthesized by coprecipitation method under a cobalt nominal content between 2 and 20 mol % of total cation. Structural characterization of samples was performed by using X-ray diffraction (XRD), Fourier transform infrared spectroscopy, scanning electron microscopy, and energy dispersive X-ray spectroscopy. XRD results indicated that the Co-doped samples exhibited a monetite single-phase with the cell parameters and crystallite size dependent on the amount of substitutional element incorporated into the triclinic crystalline structure. Cell viability and adhesion assays using pre-osteoblastic cells showed there is no toxicity and the RTqPCR analysis showed significant differences in the expression for osteoblastic phenotype genes, showing a potential material for the bone regeneration.

Guidelines for Evaluating the Comparability of Down-Sampled GWAS Summary Statistics.

Proprietary genetic datasets are valuable for boosting the statistical power of genome-wide association studies (GWASs), but their use can restrict investigators from publicly sharing the resulting summary statistics. Although researchers can resort to sharing down-sampled versions that exclude restricted data, down-sampling reduces power and might change the genetic etiology of the phenotype being studied. These problems are further complicated when using multivariate GWAS methods, such as genomic structural equation modeling (Genomic SEM), that model genetic correlations across multiple traits. Here, we propose a systematic approach to assess the comparability of GWAS summary statistics that include versus exclude restricted data. Illustrating this approach with a multivariate GWAS of an externalizing factor, we assessed the impact of down-sampling on (1) the strength of the genetic signal in univariate GWASs, (2) the factor loadings and model fit in multivariate Genomic SEM, (3) the strength of the genetic signal at the factor level, (4) insights from gene-property analyses, (5) the pattern of genetic correlations with other traits, and (6) polygenic score analyses in independent samples. For the externalizing GWAS, although down-sampling resulted in a loss of genetic signal and fewer genome-wide significant loci; the factor loadings and model fit, gene-property analyses, genetic correlations, and polygenic score analyses were found robust. Given the importance of data sharing for the advancement of open science, we recommend that investigators who generate and share down-sampled summary statistics report these analyses as accompanying documentation to support other researchers' use of the summary statistics.

Efficacy Evaluation of a Commercial Formulation With Duddingtonia Flagrans in Equine Gastrointestinal Nematodes.

The indiscriminate use of antiparasitics for the treatment of helminths in horses has caused the ineffectiveness of commonly used chemical active principles, therefore, new alternatives such as the use of helminthophagous fungi have been studied. In this context, this study aimed to evaluate the in vitro efficacy of the commercial formulation Bioverm, composed of the fungus Duddingtonia flagrans strain AC001, in the reduction of gastrointestinal nematode larvae in equine feces. In coproculture, the genus Cyathostomum sp. was the most prevalent in the analyzed samples. The commercial formulation with D. flagrans demonstrated effectiveness in the predation of Cyathostomum sp. in tests. The recommended dose of 0.4 g, containing 105 chlamydospores per gram of product, reduced larvae by 44.23%, while the extrapolated dose of 1.0 g with the same concentrations of chlamydospores (105/g) resulted in a reduction of 57.20%, indicating the effectiveness of the product in controlling infective larvae.

ICAM-1-decorated extracellular vesicles loaded with miR-146a and Glut1 drive immunomodulation and hinder tumor progression in a murine model of breast cancer.

Tumor-associated immune cells play a crucial role in cancer progression. Myeloid-derived suppressor cells (MDSCs), for example, are immature innate immune cells that infiltrate the tumor to exert immunosuppressive activity and protect cancer cells from the host's immune system and/or cancer-specific immunotherapies. While tumor-associated immune cells have emerged as a promising therapeutic target, efforts to counter immunosuppression within the tumor niche have been hampered by the lack of approaches that selectively target the immune cell compartment of the tumor, to effectively eliminate "tumor-protecting" immune cells and/or drive an "anti-tumor" phenotype. Here we report on a novel nanotechnology-based approach to target tumor-associated immune cells and promote "anti-tumor" responses in a murine model of breast cancer. Engineered extracellular vesicles (EVs) decorated with ICAM-1 ligands and loaded with miR-146a and Glut1, were biosynthesized (in vitro or in vivo) and administered to tumor-bearing mice once a week for up to 5 weeks. The impact of this treatment modality on the immune cell compartment and tumor progression was evaluated via RT-qPCR, flow cytometry, and histology. Our results indicate that weekly administration of the engineered EVs (i.e., ICAM-1-decorated and loaded with miR-146a and Glut1) hampered tumor progression compared to ICAM-1-decorated EVs with no cargo. Flow cytometry analyses of the tumors indicated a shift in the phenotype of the immune cell population toward a more pro-inflammatory state, which appeared to have facilitated the infiltration of tumor-targeting T cells, and was associated with a reduction in tumor size and decreased metastatic burden. Altogether, our results indicate that ICAM-1-decorated EVs could be a powerful platform nanotechnology for the deployment of immune cell-targeting therapies to solid tumors.

SIRSi-vaccine dynamical model for the Covid-19 pandemic.

Covid-19, caused by severe acute respiratory syndrome coronavirus 2, broke out as a pandemic during the beginning of 2020. The rapid spread of the disease prompted an unprecedented global response involving academic institutions, regulatory agencies, and industries. Vaccination and nonpharmaceutical interventions including social distancing have proven to be the most effective strategies to combat the pandemic. In this context, it is crucial to understand the dynamic behavior of the Covid-19 spread together with possible vaccination strategies. In this study, a susceptible-infected-removed-sick model with vaccination (SIRSi-vaccine) was proposed, accounting for the unreported yet infectious. The model considered the possibility of temporary immunity following infection or vaccination. Both situations contribute toward the spread of diseases. The transcritical bifurcation diagram of alternating and mutually exclusive stabilities for both disease-free and endemic equilibria were determined in the parameter space of vaccination rate and isolation index. The existing equilibrium conditions for both points were determined in terms of the epidemiological parameters of the model. The bifurcation diagram allowed us to estimate the maximum number of confirmed cases expected for each set of parameters. The model was fitted with data from São Paulo, the state capital of SP, Brazil, which describes the number of confirmed infected cases and the isolation index for the considered data window. Furthermore, simulation results demonstrate the possibility of periodic undamped oscillatory behavior of the susceptible population and the number of confirmed cases forced by the periodic small-amplitude oscillations in the isolation index. The main contributions of the proposed model are as follows: A minimum effort was required when vaccination was combined with social isolation, while additionally ensuring the existence of equilibrium points. The model could provide valuable information for policymakers, helping define disease prevention mitigation strategies that combine vaccination and non-pharmaceutical interventions, such as social distancing and the use of masks. In addition, the SIRSi-vaccine model facilitated the qualitative assessment of information regarding the unreported infected yet infectious cases, while considering temporary immunity, vaccination, and social isolation index.

Guidelines for Evaluating the Comparability of Down-Sampled GWAS Summary Statistics.

Proprietary genetic datasets are valuable for boosting the statistical power of genome-wide association studies (GWASs), but their use can restrict investigators from publicly sharing the resulting summary statistics. Although researchers can resort to sharing down-sampled versions that exclude restricted data, down-sampling reduces power and might change the genetic etiology of the phenotype being studied. These problems are further complicated when using multivariate GWAS methods, such as genomic structural equation modeling (Genomic SEM), that model genetic correlations across multiple traits. Here, we propose a systematic approach to assess the comparability of GWAS summary statistics that include versus exclude restricted data. Illustrating this approach with a multivariate GWAS of an externalizing factor, we assessed the impact of down-sampling on (1) the strength of the genetic signal in univariate GWASs, (2) the factor loadings and model fit in multivariate Genomic SEM, (3) the strength of the genetic signal at the factor level, (4) insights from gene-property analyses, (5) the pattern of genetic correlations with other traits, and (6) polygenic score analyses in independent samples. For the externalizing GWAS, down-sampling resulted in a loss of genetic signal and fewer genome-wide significant loci, while the factor loadings and model fit, gene-property analyses, genetic correlations, and polygenic score analyses are robust. Given the importance of data sharing for the advancement of open science, we recommend that investigators who share down-sampled summary statistics report these analyses as accompanying documentation to support other researchers' use of the summary statistics.

Beyond ecology: ecosystem restoration as a process for social-ecological transformation.

Ecosystem restoration conventionally focuses on ecological targets. However, while ecological targets are crucial to mobilizing political, social, and financial capital, they do not encapsulate the need to: integrate social, economic, and ecological dimensions and systems approaches; reconcile global targets and local objectives; and measure the rate of progress toward multiple and synergistic goals. Restoration is better conceived as an inclusive social-ecological process that integrates diverse values, practices, knowledge, and restoration objectives across temporal and spatial scales and stakeholder groups. Taking a more process-based approach will ultimately enable greater social-ecological transformation, greater restoration effectiveness, and more long-lasting benefits to people and nature across time and place.

Ti-15Zr and Ti-15Zr-5Mo Biomaterials Alloys: An Analysis of Corrosion and Tribocorrosion Behavior in Phosphate-Buffered Saline Solution.

It is crucial for clinical needs to develop novel titanium alloys feasible for long-term use as orthopedic and dental prostheses to prevent adverse implications and further expensive procedures. The primary purpose of this research was to investigate the corrosion and tribocorrosion behavior in the phosphate buffered saline (PBS) of two recently developed titanium alloys, Ti-15Zr and Ti-15Zr-5Mo (wt.%) and compare them with the commercially pure titanium grade 4 (CP-Ti G4). Density, XRF, XRD, OM, SEM, and Vickers microhardness analyses were conducted to give details about the phase composition and the mechanical properties. Additionally, electrochemical impedance spectroscopy was used to supplement the corrosion studies, while confocal microscopy and SEM imaging of the wear track were used to evaluate the tribocorrosion mechanisms. As a result, the Ti-15Zr (α + α' phase) and Ti-15Zr-5Mo (α″ + ß phase) samples exhibited advantageous properties compared to CP-Ti G4 in the electrochemical and tribocorrosion tests. Moreover, a better recovery capacity of the passive oxide layer was observed in the studied alloys. These results open new horizons for biomedical applications of Ti-Zr-Mo alloys, such as dental and orthopedical prostheses.

Safety of Stromal Vascular Fraction Cell Therapy for Chronic Kidney Disease of Unknown Cause (Mesoamerican Nephropathy).

Chronic kidney disease of unknown cause (CKDu), also known as Mesoamerican nephropathy, typically presents as an ischemic nephropathy with chronic tubulointerstitial fibrosis in normotensive patients, rapidly progressing to kidney failure. In this first-in-human, open-label, safety study, we followed 18 patients with CKDu (stages 3-5) for 36 months after receiving a single infusion of angiogenic/anti-fibrotic autologous adipose-derived stromal vascular fraction (SVF) cells into their kidneys bilaterally via renal artery catheterization. SVF therapy was safe and well tolerated. There were no SVF-related serious adverse events and no procedural complications. Color Doppler evaluation at 2 months demonstrated increased perfusion to the interlobar and/or arcuate artery levels in each kidney evaluated (36/36) with a reduction in resistance index at the hilar artery (35/36) kidneys. Beyond 12 months, patients with initial eGFR <30 mL/minute/1.73 m2 deteriorated, whereas those ≥30 mL/minute/1.73 m2 further sustained their renal function, suggesting a possible renal protective effect in that group.

Effectiveness of ozonized saline solution in the treatment of Proteus spp. bacterial cystitis.

Bacterial cystitis is a common clinical problem among cats and dogs and is one of the main reasons for the administration of antimicrobials. This can cause serious damage to public and animal health, as this practice facilitates the selection of bacteria that are multidrug-resistant to antibiotics. In this context, it is urgent to understand and validate therapeutic modalities that complement antimicrobial treatment in cystitis cases. Ozone therapy has been proposed by scientists owing to the various mechanisms of action in a range of pathologies, both in human and animal medicine. This paper describes the bactericidal action of two different protocols of bladder irrigation with ozonized saline solution (59 µg/mL) in a paraplegic canine with recurrent bacterial cystitis caused by Proteus spp. In the first protocol, the bladder instillations were applied once a day for three consecutive days while in the second, successive lavages were performed throughout the day until a significant reduction in the presence of bacteria in the urine sediment. In this study, we were able to demonstrate that repeated bladder instillation within 24 hours was the most effective treatment for Proteus compared to a single instillation on successive days.

Neurofibromatosis tipo 1 y manifestación en el Territorio Maxilofacial: Reporte de un caso y Revisión de la Literatura

Introducción: El neurofibroma corresponde a un tumor benigno que compromete la vaina neural del tejido nervioso, asociándose íntimamente a la neurofibromatosis. Debido al compromiso de nervios periféricos y/o centrales, su expresión clínica es muy variada producto de la compresión y/o desplazamiento de estructuras vecinas dificultando así su diagnóstico. Objetivo: El objetivo de este artículo, es el de realizar una revisión de la literatura en relación con la neurofibromatosis y sus manifestaciones en el territorio máxilofacial en conjunto con la presentación de un caso de hipercondilismo mandibular asociado a un neurofibroma en la región de la articulación temporomandibular en un paciente con antecedentes de neurofibromatosis. Métodos: Se presenta el caso de un paciente con laterognasia y antecedentes de Neurofibromatosis tipo I (NF1). Por medio de estudio imagenológico, se confirma Hipercondilismo derecho y presencia de una zona radiolúcida relacionada con el cuello del cóndilo comprometido, cuyo resultado histopatológico confirmo el diagnóstico de neurofibroma. Conclusiones: Existe una muy variada clínica en pacientes con NF1, presentando una predisposición a la formación de neurofibromas y alteraciones oseas que pudiesen comprometer el territorio máxilofacial y causar asimetrías faciales. Debido a esto, resulta imprescindible tener conocimiento y consideración de ambas patologías para una correcta planificación del tratamiento de los pacientes.

Introduction: Neurofibroma is a benign tumor that compromises the neural sheath of nerve tissue, intimately associated with Neurofibromatosis. Due to the involvement of peripheral and/or central nerves, its clinical expression is wide as a result of compression and/or displacement of neighboring structures, making its diagnosis difficult. Objective: The aim of this article is to review the literature on Neurofibromatosis and its manifestations in the maxillofacial territory, along with the presentation of a case of mandibular Hyperchondylism associated with a neurofibroma in the temporomandibular joint region in a patient with a history of Neurofibromatosis. Methods: We present the case of a patient with laterogenesis and a history of Neurofibromatosis type I (NF1). By imaging study, a right Hyperchondylism is detected along with the presence of a radiolucent area related to the neck of the compromised condyle, whose histopathological result confirmed the diagnosis of neurofibroma. Conclusions: There is a diverse clinical picture in patients with NF1, presenting a pre-disposition to neurofibromas development and bone abnormalities, leading to the compromise of the maxillofacial territory and causing facial asymmetries. Because of this, it is essential to have knowledge and consideration of both pathologies for the right planning of patient treatment.

Preparation and characterization of novel as-cast Ti-Mo-Nb alloys for biomedical applications.

Ti and its alloys are the most used metallic biomaterials devices due to their excellent combination of chemical and mechanical properties, biocompatibility, and non-toxicity to the human body. However, the current alloys available still have several issues, such as cytotoxicity of Al and V and high elastic modulus values, compared to human bone. ß-type alloys, compared to α-type and (α + ß)-type Ti alloys, have lower elastic modulus and higher mechanical strength. Then, new biomedical ß-type alloys are being developed with non-cytotoxic alloying elements, such as Mo and Nb. Therefore, Ti-5Mo-xNb system alloys were prepared by argon arc melting. Chemical composition was evaluated by EDS analysis, and the density measurements were performed by Archimedes' method. The structure and microstructure of the alloys were obtained by X-ray diffraction and optical and scanning electron microscopy. Microhardness values were analyzed, and MTT and crystal violet tests were performed to assess their cytotoxicity. As the Nb concentration increases, the presence of the ß-Ti phase also grows, with the Ti-5Mo-30Nb alloy presenting a single ß-Ti phase. In contrast, the microhardness of the alloys decreases with the addition of Nb, except the Ti-5Mo-10Nb alloy, which has its microhardness increased probably due to the ω phase precipitation. Biological in-vitro tests showed that the alloys are not cytotoxic.

Understanding signatures of positive natural selection in human zinc transporter genes.

Zinc is an essential micronutrient with a tightly regulated systemic and cellular homeostasis. In humans, some zinc transporter genes (ZTGs) have been previously reported as candidates for strong geographically restricted selective sweeps. However, since zinc homeostasis is maintained by the joint action of 24 ZTGs, other more subtle modes of selection could have also facilitated human adaptation to zinc availability. Here, we studied whether the complete set of ZTGs are enriched for signals of positive selection in worldwide populations and population groups from South Asia. ZTGs showed higher levels of genetic differentiation between African and non-African populations than would be randomly expected, as well as other signals of polygenic selection outside Africa. Moreover, in several South Asian population groups, ZTGs were significantly enriched for SNPs with unusually extended haplotypes and displayed SNP genotype-environmental correlations when considering zinc deficiency levels in soil in that geographical area. Our study replicated some well-characterized targets for positive selection in East Asia and sub-Saharan Africa, and proposes new candidates for follow-up in South Asia (SLC39A5) and Africa (SLC39A7). Finally, we identified candidate variants for adaptation in ZTGs that could contribute to different disease susceptibilities and zinc-related human health traits.

Glosoplastía con Técnica de Harada, en un Paciente con Macroglosia por Amiloidosis

RESUMEN: La Macroglosia, corresponde a un cuadro caracterizado por un aumento de tamaño lingual, pudiendo causar alteraciones estéticas y funcionales, llegando incluso a comprometer la vía aérea. Es una de las manifestaciones temprana de la amiloidosis, que a su vez se encuentra asociada a algunos casos de Mieloma Múltiple. Se presenta caso clínico de paciente sexo masculino de 73 años de edad, que presenta macroglosia en servicio de Cirugía Maxilofacial del Hospital del Carmen Maipú, Santiago de Chile. Donde se determinó que la macroglosia estaba en contexto de una amiloidosis, se describe diagnóstico y tratamiento quirúrgico realizado, además de complicación caracterizada por obstrucción de vía aérea, requiriendo Glosoplastía mediante técnica de Harada.

ABSTRACT: Macroglossia corresponds to a condition characterized by an increase in lingual size, which can cause aesthetic and functional alterations, even compromising the airway. It is one of the early manifestations of amyloidosis, which is associated with some cases of Multiple Myeloma. Presented a clinical case of a 73-year-old male patient, presenting macroglossia in the Maxillofacial Surgery service of the Hospital del Carmen Maipú, Santiago de Chile, where it was determined that the macroglossia was in the context of amyloidosis. The diagnosis and surgical treatment performed is described, as a complication characterized by airway obstruction requiring Glossoplasty using the Harada technique.

Designer Extracellular Vesicles Modulate Pro-Neuronal Cell Responses and Improve Intracranial Retention.

Gene/oligonucleotide therapies have emerged as a promising strategy for the treatment of different neurological conditions. However, current methodologies for the delivery of neurogenic/neurotrophic cargo to brain and nerve tissue are fraught with caveats, including reliance on viral vectors, potential toxicity, and immune/inflammatory responses. Moreover, delivery to the central nervous system is further compounded by the low permeability of the blood brain barrier. Extracellular vesicles (EVs) have emerged as promising delivery vehicles for neurogenic/neurotrophic therapies, overcoming many of the limitations mentioned above. However, the manufacturing processes used for therapeutic EVs remain poorly understood. Here, we conducted a detailed study of the manufacturing process of neurogenic EVs by characterizing the nature of cargo and surface decoration, as well as the transfer dynamics across donor cells, EVs, and recipient cells. Neurogenic EVs loaded with Ascl1, Brn2, and Myt1l (ABM) are found to show enhanced neuron-specific tropism, modulate electrophysiological activity in neuronal cultures, and drive pro-neurogenic conversions/reprogramming. Moreover, murine studies demonstrate that surface decoration with glutamate receptors appears to mediate enhanced EV delivery to the brain. Altogether, the results indicate that ABM-loaded designer EVs can be a promising platform nanotechnology to drive pro-neuronal responses, and that surface functionalization with glutamate receptors can facilitate the deployment of EVs to the brain.