Stereotactic Body Radiotherapy: is less fractionation more effective in adrenal and renal malignant lesions?

PURPOSE: Stereotactic body radiotherapy (SBRT) has become an excellent non-invasive alternative for many patients with primary renal cell carcinoma (RCC) and adrenal malignancies (AM). The aims of this study were to analyse how tumor-, patient- and treatment-related factors may influence the outcomes and side effects of SBRT and to assess its benefits as an alternative to surgery. METHODS: This retrospective, multicenter study included 25 lesions in 23 patients treated with SBRT using different devices (LINAC, CyberKnife® and Tomotherapy®). A multivariate linear regression was used for the statistical study. RESULTS: Local control time was higher than six months in more than 87% of patients and treatment response was complete for 73.68%. There was an overall 2-year survival of 40% and none of the deaths were secondary to renal or adrenal local progression. Patients treated with lower total radiation dose (mean [m] = 55 Gy) but less fractions with more dose per fraction (> 8.5 Gy) showed better outcome. Patients with previous chemotherapy and surgery treatments also showed higher complete response and disease-free survival (> 6 months). CONCLUSIONS: This study highlights the importance of ultra-hypofractionated regimens with higher doses per session. Thus, the referral of patients with RCC and AM to Radiotherapy and Oncology departments should be encouraged supporting the role of SBRT as a minimally invasive and outpatient treatment.

SOCS3 regulates pathological retinal angiogenesis through modulating SPP1 expression in microglia and macrophages.

Pathological ocular angiogenesis has long been associated with myeloid cell activation. However, the precise cellular and molecular mechanisms governing the intricate crosstalk between the immune system and vascular changes during ocular neovascularization formation remain elusive. In this study, we demonstrated that the absence of the suppressor of cytokine signaling 3 (SOCS3) in myeloid cells led to a substantial accumulation of microglia and macrophage subsets during the neovascularization process. Our single-cell RNA sequencing data analysis revealed a remarkable increase in the expression of the secreted phosphoprotein 1 (Spp1) gene within these microglia and macrophages, identifying subsets of Spp1-expressing microglia and macrophages during neovascularization formation in angiogenesis mouse models. Notably, the number of Spp1-expressing microglia and macrophages exhibited further elevation during neovascularization in mice lacking myeloid SOCS3. Moreover, our investigation unveiled the Spp1 gene as a direct transcriptional target gene of signal transducer and activator of transcription 3. Importantly, pharmaceutical activation of SOCS3 or blocking of SPP1 resulted in a significant reduction in pathological neovascularization. In conclusion, our study highlights the pivotal role of the SOCS3/STAT3/SPP1 axis in the regulation of pathological retinal angiogenesis.

Degradation kinetics of veterinary antibiotics and estrogenic hormones in a claypan soil.

Veterinary antibiotics and estrogens are excreted in livestock waste before being applied to agricultural lands as fertilizer, resulting in contamination of soil and adjacent waterways. The objectives of this study were to 1) investigate the degradation kinetics of the VAs sulfamethazine and lincomycin and the estrogens estrone and 17ß-estradiol in soil mesocosms, and 2) assess the effect of the phytochemical DIBOA-Glu, secreted in eastern gamagrass (Tripsacum dactyloides) roots, on antibiotic degradation due to the ability of DIBOA-Glu to facilitate hydrolysis of atrazine in solution assays. Mesocosm soil was a silt loam representing a typical claypan soil in portions of Missouri and the Central United States. Mesocosms (n = 133) were treated with a single target compound (antibiotic concentrations at 125 ng g-1 dw, estrogen concentrations at 1250 ng g-1 dw); a subset of mesocosms treated with antibiotics were also treated with DIBOA-Glu (12,500 ng g-1 dw); all mesocosms were kept at 60% water-filled pore space and incubated at 25 °C in darkness. Randomly chosen mesocosms were destructively sampled in triplicate for up to 96 days. All targeted compounds followed pseudo first-order degradation kinetics in soil. The soil half-life (t0.5) of sulfamethazine ranged between 17.8 and 30.1 d and ranged between 9.37 and 9.90 d for lincomycin. The antibiotics results showed no significant differences in degradation kinetics between treatments with or without DIBOA-Glu. For estrogens, degradation rates of estrone (t0.5 = 4.71-6.08 d) and 17ß-estradiol (t0.5 = 5.59-6.03 d) were very similar; however, results showed that estrone was present as a metabolite in the 17ß-estradiol treated mesocosms and vice-versa within 24 h. The antibiotics results suggest that sulfamethazine has a greater potential to persist in soil than lincomycin. The interconversion of 17ß-estradiol and estrone in soil increased their overall persistence and sustained soil estrogenicity. This study demonstrates the persistence of these compounds in a typical claypan soil representing portions of the Central United States.

The Supplementation of Sechium edule var. nigrum spinosum (Chayote) Promotes Nrf2-Mediated Antioxidant Protection in Older Adults with Metabolic Syndrome.

The aim was to determine the effect of Sechium edule var. nigrum spinosum (chayote) on gene expression related to antioxidant protection mechanisms and the inflammatory process in older adults with metabolic syndrome (MetS). A quasi-experimental study was carried out in a convenience sample of 46 older adults diagnosed with MetS: (i) placebo group (PG; n = 20); (ii) experimental group (EG; n = 26). The clinical, biochemical, anthropometric parameters and SOD, GPx, and CAT enzyme activity, alongside total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI), cytokines (IL-6, IL-8 and TNF-α), and mRNA expression of SOD, GPx, CAT, IL-6, IL-8, TNF-α, Nrf2, NFkB p50, and NFkB p65, were measured at baseline and 6 months post-intervention. A statistically significant decrease was observed in TOS (baseline, 28.9 ± 3.6 vs. post, 23.7 ± 3.4, p < 0.01) and OSI (baseline, 24.1 ± 3.8 vs. post, 17.7 ± 4), as well as an increase in IL-6 (baseline, 10.7 ± 1.1 vs. post, 12.3 ± 2, p = 0.03), SOD activity (baseline, 167.1 ± 11.9 vs. post, 180.6 ± 7.6, p < 0.05), CAT activity (baseline, 1.0 ± 0.2 vs. post, 1.3 ± 0.2, p < 0.01), and TAS (baseline, 1.1 ± 0.1 vs. post, 1.4 ± 0.1, p < 0.01) in the EG compared to the PG. Regarding the expression of Nrf2, SOD, and IL-6, the EG showed a significant increase vs. basal levels (47%, 44%, and 43%, respectively). Our findings suggest that Sechium edule supplementation promotes the antioxidant response and decreases oxidative stress via Nrf2.

Evaluation of Dosimetry Formalisms in Intraoperative Radiation Therapy of Glioblastoma.

PURPOSE: The intraoperative radiotherapy in newly diagnosed glioblastoma multiforme (INTRAGO) clinical trial assesses survival in patients with glioblastoma treated with intraoperative radiation therapy (IORT) using the INTRABEAM. Treatment planning for INTRABEAM relies on vendor-provided in-water depth dose curves obtained according to the TARGeted Intraoperative radioTherapy (TARGIT) dosimetry protocol. However, recent studies have shown discrepancies between the estimated TARGIT and delivered doses. This work evaluates the effect of the choice of dosimetry formalism on organs at risk (OAR) doses. METHODS AND MATERIALS: A treatment planning framework for INTRABEAM was developed to retrospectively calculate the IORT dose in 8 INTRAGO patients. These patients received an IORT prescription dose of 20 to 30 Gy in addition to external beam radiation therapy. The IORT dose was obtained using (1) the TARGIT method; (2) the manufacturer's V4.0 method; (3) the CQ method, which uses an ionization chamber Monte Carlo (MC) calculated factor; (4) MC dose-to-water; and (5) MC dose-to-tissue. The IORT dose was converted to 2 Gy fractions equivalent dose. RESULTS: According to the TARGIT method, the OAR dose constraints were respected in all cases. However, the other formalisms estimated a higher mean dose to OARs and revealed 1 case where the constraint for the brain stem was exceeded. The addition of the external beam radiation therapy and TARGIT IORT doses resulted in 10 cases of OARs exceeding the dose constraints. The more accurate MC calculation of dose-to-tissue led to the highest dosimetric differences, with 3, 3, 2, and 2 cases (out of 8) exceeding the dose constraint to the brain stem, optic chiasm, optic nerves, and lenses, respectively. Moreover, the mean cumulative dose to brain stem exceeded its constraint of 66 Gy with the MC dose-to-tissue method, which was not evident with the current INTRAGO clinical practice. CONCLUSIONS: The current clinical approach of calculating the IORT dose with the TARGIT method may considerably underestimate doses to nearby OARs. In practice, OAR dose constraints may have been exceeded, as revealed by more accurate methods.

Targeted siRNA lipid nanoparticles for the treatment of KRAS-mutant tumors.

K-RAS is a highly relevant oncogene that is mutated in approximately 90% of pancreatic cancers and 20-25% of lung adenocarcinomas. The aim of this work was to develop a new anti-KRAS siRNA therapeutic strategy through the engineering of functionalized lipid nanoparticles (LNPs). To do this, first, a potent pan anti-KRAS siRNA sequence was chosen from the literature and different chemical modifications of siRNA were tested for their transfection efficacy (KRAS knockdown) and anti-proliferative effects on various cancer cell lines. Second, a selected siRNA candidate was loaded into tLyp-1 targeted and non-targeted lipid nanoparticles (LNPs). The biodistribution and antitumoral efficacy of selected siRNA-loaded LNP-prototypes were evaluated in vivo using a pancreatic cancer murine model (subcutaneous xenograft CFPAC-1 tumors). Our results show that tLyp-1-tagged targeted LNPs have an enhanced accumulation in the tumor compared to non-targeted LNPs. Moreover, a significant reduction in the pancreatic tumor growth was observed when the anti-KRAS siRNA treatment was combined with a classical chemotherapeutic agent, gemcitabine. In conclusion, our work demonstrates the benefits of using a targeting approach to improve tumor accumulation of siRNA-LNPs and its positive impact on tumor reduction.

Overcoming Resistance to Osimertinib by T790M Loss and C797S Acquisition Using Gefitinib in a Patient With EGFR-Mutant NSCLC: A Case Report.

Limited strategies are available at disease progression on osimertinib for patients with EGFR-mutant NSCLC. The emergence of the on-target EGFR C797S mutation has been described as one of the most common mechanisms of resistance. In addition, loss of the EGFR T790M mutation has been mainly investigated as a resistance phenomenon to second-line osimertinib exposure. Remarkably, by studying the molecular profile at progression, it has been reported that the presence of the EGFR-sensitizing mutation, concurrently with the T790M, and C797S resulted in resistance to the current available EGFR tyrosine kinase inhibitors. Here, we report the first clinical evidence of gefitinib efficacy at EGFR exon 19 deletion/C797S mutation/T790M loss-mediated resistance to first-line osimertinib. Our findings highlight that dynamic genetic monitoring is a crucial approach in the evolution of EGFR-mutant NSCLC to understand the acquired molecular mechanisms for driving the best treatment strategy.

Prioritizing Pesticides of Potential Concern and Identifying Potential Mixture Effects in Great Lakes Tributaries Using Passive Samplers.

To help meet the objectives of the Great Lakes Restoration Initiative with regard to increasing knowledge about toxic substances, 223 pesticides and pesticide transformation products were monitored in 15 Great Lakes tributaries using polar organic chemical integrative samplers. A screening-level assessment of their potential for biological effects was conducted by computing toxicity quotients (TQs) for chemicals with available US Environmental Protection Agency (USEPA) Aquatic Life Benchmark values. In addition, exposure activity ratios (EAR) were calculated using information from the USEPA ToxCast database. Between 16 and 81 chemicals were detected per site, with 97 unique compounds detected overall, for which 64 could be assessed using TQs or EARs. Ten chemicals exceeded TQ or EAR levels of concern at two or more sites. Chemicals exceeding thresholds included seven herbicides (2,4-dichlorophenoxyacetic acid, diuron, metolachlor, acetochlor, atrazine, simazine, and sulfentrazone), a transformation product (deisopropylatrazine), and two insecticides (fipronil and imidacloprid). Watersheds draining agricultural and urban areas had more detections and higher concentrations of pesticides compared with other land uses. Chemical mixtures analysis for ToxCast assays associated with common modes of action defined by gene targets and adverse outcome pathways (AOP) indicated potential activity on biological pathways related to a range of cellular processes, including xenobiotic metabolism, extracellular signaling, endocrine function, and protection against oxidative stress. Use of gene ontology databases and the AOP knowledgebase within the R-package ToxMixtures highlighted the utility of ToxCast data for identifying and evaluating potential biological effects and adverse outcomes of chemicals and mixtures. Results have provided a list of high-priority chemicals for future monitoring and potential biological effects warranting further evaluation in laboratory and field environments. Environ Toxicol Chem 2023;42:340-366. Published 2022. This article is a U.S. Government work and is in the public domain in the USA. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Contractility of isolated colonic smooth muscle strips from rats treated with cancer chemotherapy: differential effects of cisplatin and vincristine.

Background: Certain antineoplastic drugs cause gastrointestinal disorders even after the end of treatment. Enteric neuropathy has been associated with some of these alterations. Our goal was to assess the impact of repeated treatment with cisplatin and vincristine on the contractility of circular and longitudinal muscle strips isolated from the rat colon. Methods: Two cohorts of male rats were used: in cohort 1, rats received one intraperitoneal (ip) injection of saline or cisplatin (2 mg kg-1 week-1) on the first day of weeks 1-5; in cohort 2, rats received two cycles of five daily ip injections (Monday to Friday, weeks 1-2) of saline or vincristine (0.1 mg kg-1 day-1). Body weight and food and water intake were monitored throughout the study. One week after treatment, responses of colonic smooth muscle strips to acetylcholine (10-9-10-5 M) and electrical field stimulation (EFS, 0.1-20 Hz), before and after atropine (10-6 M), were evaluated in an organ bath. Results: Both drugs decreased body weight gain. Compared to saline, cisplatin significantly decreased responses of both longitudinal and circular smooth muscle strips to EFS, whereas vincristine tended to increase them, although in a non-significant manner. No differences were observed in the muscle response to acetylcholine. Atropine abolished the contractile responses induced by acetylcholine, although those induced by EFS were only partially reduced in the presence of atropine. Conclusion: The findings suggest that although both drugs cause the development of enteric neuropathy, this seems to have a functional impact only in cisplatin-treated animals. Understanding the effects of chemotherapy on gastrointestinal motor function is vital for enhancing the quality of life of cancer patients.

Moderate exercise combined with metformin-treatment improves mitochondrial bioenergetics of the quadriceps muscle of old female Wistar rats.

Sarcopenia is a syndrome that leads to physical disability and that deteriorates elderly people´s life quality. The etiology of sarcopenia is multifactorial, but mitochondrial dysfunction plays a paramount role in this pathology. Our research group has shown that the combined treatment of metformin (MTF) and exercise has beneficial effects for preventing muscle loss and fat accumulation, by modulating the redox state. To get an insight into the mechanism of the combined treatment, the mitochondrial bioenergetics was studied in the mitochondria isolated from old female Wistar rats quadriceps muscles. The animals were divided into six groups; three performed exercise on a treadmill for 5 days/week for 20 months, and the other three were sedentary. Also, two groups of each were treated with MTF for 6 or 12 months. The rats were euthanized at 24 months. The mitochondria were isolated and supercomplexes formation along with oxygen consumption, ATP synthesis, and ROS generation were evaluated. Our results showed that the combined treatment for 12 months increased the complex I and IV activities associated with the supercomplexes, simultaneously, ATP synthesis increased while ROS production decreased, indicating a tightly coupled mitochondria. The role of exercise plus the MTF treatment against sarcopenia in old muscles is discussed.

Spontaneous Mutation in the Movement Protein of Citrus Leprosis Virus C2, in a Heterologous Virus Infection Context, Increases Cell-to-Cell Transport and Generates Fitness Advantage.

Previous results using a movement defective alfalfa mosaic virus (AMV) vector revealed that citrus leprosis virus C (CiLV-C) movement protein (MP) generates a more efficient local movement, but not more systemic transport, than citrus leprosis virus C2 (CiLV-C2) MP, MPs belonging to two important viruses for the citrus industry. Here, competition experiment assays in transgenic tobacco plants (P12) between transcripts of AMV constructs expressing the cilevirus MPs, followed by several biological passages, showed the prevalence of the AMV construct carrying the CiLV-C2 MP. The analysis of AMV RNA 3 progeny recovered from P12 plant at the second viral passage revealed the presence of a mix of progeny encompassing the CiLV-C2 MP wild type (MPWT) and two variants carrying serines instead phenylalanines at positions 72 (MPS72F) or 259 (MPS259F), respectively. We evaluated the effects of each modified residue in virus replication, and cell-to-cell and long-distance movements. Results indicated that phenylalanine at position 259 favors viral cell-to-cell transport with an improvement in viral fitness, but has no effect on viral replication, whereas mutation at position 72 (MPS72F) has a penalty in the viral fitness. Our findings indicate that the prevalence of a viral population may be correlated with its greater efficiency in cell-to-cell and systemic movements.

Correlation among Knee Muscle Strength and Self-Reported Outcomes Score, Anterior Tibial Displacement, and Time Post-Injury in Non-Coper Anterior Cruciate Ligament Deficient Patients: A Cross-Sectional Study.

Little attention has been paid to knee muscle strength after ACL rupture and its effect on prognostic outcomes and treatment decisions. We studied hamstrings (H) and quadriceps (Q) strength correlation with a patient-reported outcome measures score (International Knee Documentation Committee, IKDC), anterior tibial translation (ATT), and time post-injury in 194 anterior cruciate ligament deficient patients (ACLD) who required surgery after a failed rehabilitation program (non-copers). The correlation between knee muscle strength and ATT was also studied in 53 non-injured controls. ACLD patients showed decreased knee muscle strength of both the injured and non-injured limbs. The median (interquartile range) values of the H/Q ratio were 0.61 (0.52-0.81) for patients' injured side and 0.65 (0.57-0.8) for the non-injured side (p = 0.010). The median H/Q ratio for the controls was 0.52 (0.45-0.66) on both knees (p < 0.001, compared with the non-injured side of patients). The H/Q, ATT, and time post-injury were not significantly correlated with the IKDC score. ATT was significantly correlated with the H/Q of the injured and non-injured knees of patients, but not in the knees of the controls. Quadriceps strength and H/Q ratio were significantly correlated with ATT for both limbs of the patients. IKDC score correlated significantly with the quadriceps and hamstrings strengths of the injured limb but not with the H/Q ratio, ATT or time passed after injury.

Non-scarring Minimal Incision Neo-omphaloplasty in Abdominoplasty: The Alvarez Technique. A New Proposal.

BACKGROUND: Abdominoplasties are increasingly requested aesthetic, reconstructive surgical procedures that, in most cases, have shown the disadvantage of leaving an often-notorious periumbilical scar due to hypertrophy, keloid, or because it simply remains very visible over time, after surgery. The Alvarez technique (or nonscarring minimal-incision neo-omphaloplasty) is a completely new, unprecedented technique because it does not leave visible scars. This technique requires the generation of four small flaps and a purse-string suture system interacting with the aponeurosis of the rectus abdominis muscles, as well as the modification of the vertical abdominal plication, and management of the subcutaneous cellular tissue in the new umbilicus area, which, if executed correctly, provide adequate aesthetic results. METHODS: A multicentric case-series scientific study is presented with a total of 94 patients who underwent classical abdominoplasties and neo-omphaloplasties with the aforementioned technique from August 2018 to December 2020. Pre-surgical and postoperative photographic files were collected. RESULTS: Of the 94 patients, there were eight (8.5%) cases of seroma, which are not attributable to neo-omphaloplasty but inherent to the use of drains. There were five (5.3%) cases of umbilical dehiscence. In total, 89.2% (84 patients) showed a very high degree of long-term satisfaction, and 10.6% (10 patients) had a medium level of long-term satisfaction. CONCLUSIONS: The Alvarez technique provides good aesthetic results that are well accepted among patients and surgeons, in the short and long term. It is useful for those patients who wish to undergo an abdominoplasty but cannot stand a scar in the umbilical region.

The Role of Physiotherapy in Pediatric Palliative Care: A Systematic Review.

Pediatric palliative care (PPC) is a set of actions aimed at children who suffer from a severe or life-threatening disease to alleviate the symptoms of the disease and improve the quality of life of both the child and his/her family. One of the tools used to control symptoms is physiotherapy; however, its application in the child population has not been thoroughly studied. The main objective of this study was to gather, analyze, and critically evaluate the available scientific evidence on physiotherapy in children who require palliative care through a systematic review of the studies published in the last 10 years in the following databases: PubMed, Cochrane Library, PEDro, CINAHL, and Scopus. Of a total of 622 studies, the inclusion criteria were only met by seven articles, which were focused on the relationship between physiotherapy and PPC. This study analyzed: (1) the main pathologies treated, with a predominance of cerebral palsy and cancer; (2) the interventions applied, such as respiratory physiotherapy, neurological physiotherapy, therapeutic massage, and virtual reality; (3) the effects achieved in the child and his/her family, highlighting the control of symptoms and the improvement of the quality of life; and (4) the knowledge of the physiotherapists on PPC, observing that most of the professionals had not received training in this scope. The findings of this review indicate a lack of an adequate evidence foundation for physiotherapy in PPC.

Monte Carlo calculation of the TG-43 dosimetry parameters for the INTRABEAM source with spherical applicators.

OBJECTIVE: The relative TG-43 dosimetry parameters of the INTRABEAM (Carl Zeiss Meditec AG, Jena, Germany) bare probe were recently reported by Ayala Alvarezet al(2020Phys. Med. Biol.65245041). The current study focuses on the dosimetry characterization of the INTRABEAM source with the eight available spherical applicators according to the TG-43 formalism using Monte Carlo (MC) simulations. APPROACH: This report includes the calculated dose-rate conversion coefficients that determine the absolute dose rate to water at a reference point of 10 mm from the applicator surface, based on calibration air-kerma rate measurements at 50 cm from the source on its transverse plane. Since the air-kerma rate measurements are not yet provided from a standards laboratory for the INTRABEAM, the values in the present study were calculated with MC. This approach is aligned with other works in the search for standardization of the dosimetry of electronic brachytherapy sources. As a validation of the MC model, depth dose calculations along the source axis were compared with calibration data from the source manufacturer. MAIN RESULTS: The calculated dose-rate conversion coefficients were 434.0 for the bare probe, and 683.5, 548.3, 449.9, 376.5, 251.0, 225.6, 202.8, and 182.6 for the source with applicators of increasing diameter from 15 to 50 mm, respectively. The radial dose and the 2D anisotropy functions of the TG-43 formalism were also obtained and tabulated in this document. SIGNIFICANCE: This work presents the data required by a treatment planning system for the characterization of the INTRABEAM system in the context of intraoperative radiotherapy applications.

Monte Carlo calculation of the relative TG-43 dosimetry parameters for the INTRABEAM electronic brachytherapy source.

The INTRABEAM system (Carl Zeiss Meditec AG, Jena, Germany) is an electronic brachytherapy (eBT) device designed for intraoperative radiotherapy applications. To date, the INTRABEAM x-ray source has not been characterized according to the AAPM TG-43 specifications for brachytherapy sources. This restricts its modelling in commercial treatment planning systems (TPSs), with the consequence that the doses to organs at risk are unknown. The aim of this work is to characterize the INTRABEAM source according to the TG-43 brachytherapy dosimetry protocol. The dose distribution in water around the source was determined with Monte Carlo (MC) calculations. For the validation of the MC model, depth dose calculations along the source longitudinal axis were compared with measurements using a soft x-ray ionization chamber (PTW 34013) and two synthetic diamond detectors (microDiamond PTW TN60019). In our results, the measurements in water agreed with the MC model calculations within uncertainties. The use of the microDiamond detector yielded better agreement with MC calculations, within estimated uncertainties, compared to the ionization chamber at points of steeper dose gradients. The radial dose function showed a steep fall-off close to the INTRABEAM source ([Formula: see text]10 mm) with a gradient higher than that of commonly used brachytherapy radionuclides (192Ir, 125I and 103Pd), with values of 2.510, 1.645 and 1.232 at 4, 6 and 8 mm, respectively. The radial dose function partially flattens at larger distances with a fall-off comparable to that of the Xoft Axxent® (iCAD, Inc., Nashua, NH) eBT system. The simulated 2D polar anisotropy close to the bare probe walls showed deviations from unity of up to 55% at 10 mm and 155°. This work presents the MC calculated TG-43 parameters for the INTRABEAM, which constitute the necessary data for the characterization of the source as required by a TPS used in clinical dose calculations.

Nose-to-brain delivery of enveloped RNA - cell permeating peptide nanocomplexes for the treatment of neurodegenerative diseases.

Direct nose-to-brain (N-to-B) delivery enables the rapid transport of drugs to the brain, while minimizing systemic exposure. The objective of this work was to engineer a nanocarrier intended to enhance N-to-B delivery of RNA and to explore its potential utility for the treatment of neurological disorders. Our approach involved the formation of electrostatically driven nanocomplexes between a hydrophobic derivative of octaarginine (r8), chemically conjugated with lauric acid (C12), and the RNA of interest. Subsequently, these cationic nanocomplexes were enveloped (enveloped nanocomplexes, ENCPs) with different protective polymers, i.e. polyethyleneglycol - polyglutamic acid (PEG-PGA) or hyaluronic acid (HA), intended to enhance their stability and mucodiffusion across the olfactory nasal mucosa. These rationally designed ENCPs were produced in bulk format and also using a microfluidics-based technique. This technique enabled the production of a scalable nanoformulation, exhibiting; (i) a unimodal size distribution with a tunable mean size, (ii) the capacity to highly associate (100%) and protect RNA from degradation, (iii) the ability to preserve its physicochemical properties in biorelevant media and prevent the premature RNA release. Moreover, in vitro cell culture studies showed the capacity of ENCPs to interact and be efficiently taken-up by CHO cells. Finally, in vivo experiments in a mouse model of Alzheimer's disease provided evidence of a statistically significant increase of a potentially therapeutic miRNA mimic in the hippocampus area and its further effect on two mRNA targets, following its intranasal administration. Overall, these findings stress the value of the rational design of nanocarriers towards overcoming the biological barriers associated to N-to-B RNA delivery and reveal their potential value as therapeutic strategies in Alzheimer's disease.

Panorama epidemiológico de la fisura labiopalatina en Quito, Guayaquil y Cuenca. Ecuador, 2010-2018 / Epidemiological overview of the labiopalatine fisure in Quito, Guayaquil and Cuenca. Ecuador, 2010-2018

Objetivo: determinar la prevalencia de la fisura labio alveolo palatina (FLAP) en las prin-cipales ciudades del Ecuador: Quito, Guayaquil y Cuenca, en el período comprendido desde el año 2010 al 2018. Metodos: se realizó un estudio descriptivo, observacional de corte transversal y retrospectivo mediante la revisión de la base de datos de estudios realizados en medios hospitalarios de las ciudades de Quito, Guayaquil y Cuenca en pacientes con diagnóstico de FLAP nacidos en el periodo comprendido desde el año 2010 al 2018. La información mediante un formulario para el nacido vivo con FLAP sindrómico, no sindrómico y de la madre. Resultados: se encontró que la frecuencia de FLAP es 14.97 por cada 10,000 nacidos vivos, dato concordante con el de los países de la región. Según registros hospitalarios del sistema nacional de salud, 1132 pacientes con diagnostico FLAP fueron atendidos en el periodo 2010 a 2018. Con respecto al de edad de los niños que requirieron atención por FLAP, este fue de 3 años (DS: ±3.2). Su proporción por sexo fue 38.19% en mujeres vs. 61.68% en hombres. Conclusión: hasta ahora no se han encontrado estudios en el Ecuador que cuenten con criterios unifi-cados sobre diagnóstico y clasificación de las FLAP, para así aportar a la formulación políticas de salud pública y al mejoramiento de la calidad de vida del paciente fisurado.

Objective: To determine the prevalence of the cleft lip and palate (CLAP) in the main cities of Ecuador: Quito, Guayaquil and Cuenca, in the period from 2010 to 2018. Methods: A descriptive, observational, cross-sectional and retrospective study was carried out by reviewing the database of studies conducted in hospital settings in the cities of Quito, Guayaquil and Cuenca of patients diagnosed with FLAP born in the period from 2010 to 2018. The information was collected using a form for the live birth with syndromic, non-syndromic and mother CLAP. Results: The frequency of CLAP was found to be 14.97 per 10,000 live births, consistent with that of the countries in the region. 1132 patients diagnosed with CLAP were treated in the national health system according to hospital records, in the period 2010 to 2018; Regarding the average age of children who required CLAP care, it was 3 years (SD: ± 3.2). Their sex ratio was 38.19% women vs. 61.68% men Conclusion: No studies have been found in Ecuador that have unified criteria on diagnosis and classification of CLAPs that help formulate public health policies that improve the quality of life of the cracked patient.

Ultrasound localization of lacerated flexor tendon ends in the hand: a cadaveric study.

OBJECTIVE: Flexor tendon repair currently requires extensive exposure to locate and repair tendons. Ultrasound (US) has been used to identify lacerated tendon ends with little information on accuracy. This study was designed to measure the accuracy of US to localize tendon ends in zone II flexor tendon lacerations in a cadaveric model. MATERIALS AND METHODS: US was used to locate tendon ends in zone II lacerations of fingers of six cadaveric hands (96 tendon ends) by a musculoskeletal radiologist. The distance of each tendon end relative to the laceration was recorded. Specimens were dissected and tendon position was compared to US position. RESULTS: The radiologist correctly identified full-thickness lacerations of both superficial and deep tendons 99.0% (n = 05/96 tendons) of the time. The average difference between mean US predicted retraction and anatomic confirmed retraction for all digits all tendons was 3.5 mm of underestimation. US correctly identified the position of all tendon stumps to within 10 mm 92.7% (n = 89/96 tendons) of the time and 69.8% (n = 67/96 tendons) of the time to within 5 mm. Error tended to underestimate (61.5%; 59/96 tendons) rather than overestimate retraction (29.2%; 28/96 tendons). CONCLUSIONS: This fresh cadaveric study has demonstrated that with an experienced radiologist, there was 99.0% accuracy identifying a completed tendon tear and locating the tendon ends with US to within 1 cm was 92.7% accurate.