Rosmarinic acid turned α-syn oligomers into non-toxic species preserving microtubules in Raw 264.7 cells.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide, and the therapeutic is focused on several approaches including the inhibition of fibril formation by small compounds, avoiding the formation of cytotoxic oligomers. Thus, we decided to explore the capacity of compounds carrying catechol moieties to inhibit the progression of α-synuclein. Overall, the compounds rosmarinic acid (1), carnosic acid (2), carnosol (3), epiisorosmanol (4), and rosmanol (5) avoid the progression of fibril formation assessed by Thiofavine T (ThT), and atomic force microscopy images showed that morphology is influenced for the actions of compounds over fibrillization. Moreover, ITC experiments showed a Kd varying from 28 to 51 µM, the ΔG showed that the reaction between compounds and α-syn is spontaneous, and ΔH is associated with an exothermic reaction, suggesting the interactions of hydrogen bonds among compounds and α-syn. Docking experiments reinforce this idea showing the intermolecular interactions are mostly hydrogen bonding within the sites 2, 9, and 3/13 of α-synuclein, and compounds 1 and 5. Thus, compound 1, rosmarinic acid, interestingly interacts better with site 9 through catechol and Lysines. In cultured Raw 264. 7 cells, the presence of compounds showed that most of them can promote cell differentiation, especially rosmarinic acid, and rosmanol, both preserving tubulin cytoskeleton. However, once we evaluated whether or not the aggregates pre-treated with compounds could prevent the disruption of microtubules of Raw 264.7 cells, only pre-treated aggregates with rosmarinic acid prevented the disruption of the cytoskeleton. Altogether, we showed that especially rosmarinic acid not only inhibits α-syn but stabilizes the remaining aggregates turning them into not-toxic to Raw 264.7 cells suggesting a main role in cell survival and antigen processing in response to external α-syn aggregates.

Does an increase in energy return and/or longitudinal bending stiffness shoe features reduce the energetic cost of running?

PURPOSE: This study focused on the effects of shoe energy return and shoe longitudinal bending stiffness on the energetic cost and biomechanics of running. METHODS: The energetic cost of running and biomechanical variables altering running economy (ground contact times, stride frequency, vertical and leg stiffness, ground reaction force impulses, alignment between the resultant ground reaction force and the leg) were measured for nineteen male recreational runners. Participants ran overground under their ventilatory anaerobic threshold (10.8 ± 1.1 km h-1 on average) using four shoe prototypes with features combining low or high magnitudes of energy return and longitudinal bending stiffness. RESULTS: Neither the energy return, nor the longitudinal bending stiffness, or the interaction of these shoe features altered the energetic cost of running. High energy return shoes induced significant increased ground contact time from 274.5 ± 18.3 to 277.1 ± 18.7 ms, and significant decreased stride frequency from 1.34 ± 0.05 to 1.33 ± 0.05 Hz. High bending stiffness shoes induced significant increased ground contact time from 273.8 ± 18.2 to 277.9 ± 18.7 ms, significant increased vertical stiffness from 23.2 ± 3.4 to 23.8 ± 3.0 kN m-1, and significant decreased net vertical impulse from 245.4 ± 17.2 to 241.7 ± 17.5 BW ms. CONCLUSIONS: Increased energy return and longitudinal bending stiffness induced subtle changes in the running biomechanics, but did not induce any decrease in the energetic cost of running.

Diabetes, periodontitis, and cardiovascular disease: towards equity in diabetes care.

Type 2 diabetes and its associated cardiovascular risk is an escalating epidemic that represents a significant public health burden due to increased morbidity and mortality, disproportionately affecting disadvantaged communities. Poor glycaemic control exacerbates this burden by increasing retinal, renal, and cardiac damage and raising healthcare costs. This predicament underscores the urgent need for research into cost-effective approaches to preventing diabetes complications. An important but often overlooked strategy to improve metabolic control in diabetic patients is the treatment of periodontitis. Our aim is to assess whether the inclusion of periodontitis treatment in diabetes management strategies can effectively improve metabolic control, and to advocate for its inclusion from an equity perspective. We conducted a comprehensive review of the literature from 2000 to 2023. We analyzed the pathophysiological links between periodontitis, diabetes, and atherosclerotic cardiovascular disease, all of which have inflammation as a central component. We also examined the inequalities in health care spending in this context. Our findings suggest that incorporating routine screening and treatment of periodontitis into national health programs, with coordinated efforts between physicians and dentists, is a cost-effective measure to improve metabolic control, reduce complications and improve the overall quality of life of people with diabetes.

Circulating tumor DNA in unresectable pancreatic cancer is a strong predictor of first-line treatment efficacy: The KRASCIPANC prospective study.

BACKGROUND: There is no robust predictor of response to chemotherapy (CT) in unresectable pancreatic adenocarcinomas (UPA). The objective of the KRASCIPANC study was to analyze the kinetics of cell-free DNA (cfDNA)/circulating tumor DNA (ctDNA) as a predictor of response to CT in UPA. METHODS: Blood samples were collected just before first CT and at day 28. The primary endpoint was the kinetics of KRAS-mutated ctDNA by digital droplet PCR between D0 and D28 as a predictor of progression-free survival (PFS). RESULTS: We analyzed 65 patients with a KRAS-mutated tumor. A high level of cfDNA and KRAS-mutated ctDNA at D0, as well as the presence of KRAS-mutated ctDNA at D28, were strongly associated with lower centralized disease control rate (cDCR), shorter cPFS and OS in multivariate analysis. A score combining cfDNA level at diagnosis ≥ or <30 ng/mL and presence or not of KRAS-mutated ctDNA at D28 was an optimal predictor of cDCR (OR=30.7, IC95% 4.31-218 P=.001), PFS (HR=6.79, IC95% 2.76-16.7, P<.001) and OS (HR=9.98, IC95% 4.14-24.1, P<.001). CONCLUSION: A combined score using cfDNA level at diagnosis and KRAS-mutated ctDNA at D28 is strongly associated with patient survival/response to chemotherapy in UPA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04560270.

The stiff plate location into the shoe influences the running biomechanics.

The changes in running biomechanics induced by an increased longitudinal bending stiffness (stiff plates added into the shoes) have been well investigated, but little is known concerning the effects of the stiff plate location into the shoe on running biomechanics. Fourteen male recreational runners ran at two participant-specific running speeds (3.28 ± 0.28 m/s and 4.01 ± 0.27 m/s) with two shoe conditions where a stiff plate was added either in high (under the insole) or low location (between the midsole and outsole). Ground reaction forces, lower limb joint angles, net joint torques and work, as well as alignment between the resultant ground reaction force and the leg were analysed. Among the running speeds performed by the runners, the high location significantly decreased propulsive ground reaction forces, increased metatarsophalangeal joint dorsiflexion and ankle plantarflexion, induced an increased alignment between the resultant ground reaction force and the runner's leg, thus decreasing all the lower limb joint torques and the positive work at the knee joint compared to the low location. The results suggested that the high stiff plate location into the shoe should be considered for running performance perspectives, but care should be taken to not alter the perceived comfort and/or increase injury risks.

Implementación de un Programa Multidisciplinario de Evaluación para pacientes con Trastorno del Espectro Autista. Experiencia chilena en un hospital público; resultados preliminares / plementation of a Multidisciplinary Evaluation Program for Patients with Autism Spectrum Disorder. Chilean Experience in a Public Hospital; Preliminary Results.

El aumento en la prevalencia de los Trastornos del Espectro Autista (TEA) ha influido en la necesidad de contar con equipos de experiencia formada para su evaluación. En este esfuerzo es que en la unidad de salud mental ambulatoria del Hospital Exequiel González Cortés se implementó un programa de evaluación multidisciplinario para pacientes con sospecha de TEA. Entre los meses de abril y julio del presente año han sido evaluados 15 pacientes, en su mayoría varones con una edad media entre 6 a 10 años, encontrando que un 30% correspondía a un TEA y un 57% a otros diagnósticos como Retraso Global del Desarrollo y Trastornos Emocionales, entre otros. Los resultados confirman la importancia de contar con profesionales competentes con las habilidades para realizar el diagnóstico de estos pacientes.

The increase in the prevalence of the Autism Spectrum Disorders (ASD) influenced the need of having trained experienced teams for its evaluation. In this effort a multidisciplinary evaluation program for patients with suspected ASD was implemented in the Ambulatory Mental Health Unit of the Exequiel González Cortés Hospital. Between the months of april and july of 2020, 15 patients have been evaluated, mostly male, with an range of 6 to 10 years of age. We found that 30% corresponded to an ASD and 57% to other diagnoses such as Global Development Delay and Emotional Disorders, among others. The results confirm the importance of counting with trained teams with the skills to make the diagnosis in these patients.

Guía de atención remota para pacientes pediátricos con covid-19 / Covid-19: a remote assessment for pediatric patients

En China a finales del 2019 se puso en conocimiento esta nueva enfermedad denominada SARS-CoV-2, múltiples centros mundiales encargados de la salud pública entre ellos el Centers of Disease Control and Prevention (CDC) de Atlanta, Estados Unidos y la Orgaizacion Mundial de la Salud (OMS) publicaron diferentes clasificaciones acordes a cada grupo etáreo, dando mucha importancia a la población pediátrica, el riesgo comparativo en adultos/niños, la importancia de pruebas laboratoriales (prueba en cadena a la polimerasa (PCR) y anticuerpos), y finalmente, se discuten los tratamientos acorde al caso y la gravedad de los pacientes. Por la alta demanda de pacientes y el colapso de los sitemas de salud en todo el mundo y especialmente en los países de latinoamerica donde los sistemas de salud son muy frágiles se llegas a recurrir de herramientas técnológicas como la “Teleconsulta”, recomendada por la OMS. En el presente artículo de revisión se plantea múltiples conceptos clínicos propios de la enfermedad en niños, imágenológicos, tipo de presentación de la enfermedad incluyendo factores de riesgo. Criterios de hospitalización y tratamiento. Medidas de bioseguridad, aislamiento y supervisión médica. Y como pilar fundamental de atención la Telemedicina en la era COVID-19.

In China at the end of 2019, this new disease called SARS-CoV-2 was made known, multiple world centers in charge of public health, including the Centers of Disease Control and Prevention (CDC) of Atlanta USA and the world health organization (WHO), published different classifications according to each age group, with more emphasis on the pediatric population. Comparative risk in adults/children. In addition to the results of laboratory tests (Polymerase Chain Reaction (PCR) and antibodies). And later its treatment is denoted according to the case and the severity. Where, due to the demand of patients, technological tools are resorted to through “Teleconsultation”, recommended by the WHO. In this review article, multiple clinical concepts typical of the disease in children, imaging, type of presentation of the disease including risk factors are proposed. Criteria for hospitalization and treatment. Biosecurity measures, isolation, and medical supervision. And as a pillar of Telemedicine Care in the COVID-19 era.

Implementación de un Programa Multidisciplinario de Evaluación para pacientes con Trastorno del Espectro Autista. Experiencia Chilena en un Hospital Público; resultados preliminares / Implementation of a Multidisciplinary Evaluation Program for Patients with Autism Spectrum Disorder. Chilean Experience in a Public Hospital; Preliminary Results

El aumento en la prevalencia de los Trastornos del Espectro Autista (TEA) ha influído en la necesidad de contar con equipos de experiencia formada para su evaluación. En este esfuerzo es que en la unidad de salud mental ambulatoria del Hospital Exequiel González Cortés se implementó un programa de evaluación multidisciplinario para pacientes con sospecha de TEA. Entre los meses de abril y julio de 2019 han sido evaluados 15 pacientes en su mayoría varones con una edad media entre 6 a 10 años, encontrando que un 30% correspondía a un TEA y un 57% a otros diagnósticos como Retraso global del desarrollo y trastornos emocionales entre otros. Los resultados confirman la importancia de contar con profesionales competentes con las habilidades para realizar el diagnóstico de estos pacientes.Palabras Claves: Trastornos del Espectro Autista (TEA), Equipo multidisciplinario, Evaluación TEA, Programa Asistencial TEA, Hospital Público .

Abstract: The increase in the prevalence of Autism Spectrum Disorder (ASD) has caused a need of having trained teams for its diagnosis. For this purpose, a multidisciplinary evaluation program for patients with suspected ASD was implemented in the Ambulatory Mental Health Unit of the Exequiel González Cortés Hospital. Between the months of April and July of 2019, 15 patients have been evaluated, mostly male, with a range of ages between 6 and 10 years. It was found that 30% corresponded to an ASD and 57% to other diagnoses such as Global Development Delay and Emotional Disorders, among others. The results confirm the importance of counting with competent teams with the skills to diagnose these patients. Keywords: Autism Spectrum Disorders (ASD), Multidisciplinary Team, ASD evaluation, ASD Assistance Program, Public Hospital.

Phase I/II clinical study of Tosedostat, an inhibitor of aminopeptidases, in patients with acute myeloid leukemia and myelodysplasia.

PURPOSE: To identify the maximum-tolerated dose (MTD) and to evaluate the antileukemic activity of tosedostat (formerly CHR-2797), an orally bioavailable aminopeptidase inhibitor. PATIENTS AND METHODS: In phase I, the MTD of once daily oral doses of tosedostat in hematologic malignancies was defined. In phase II, the therapeutic activity of the maximum-acceptable dose (MAD) of tosedostat was evaluated in elderly and/or relapsing patients with acute myeloid leukemia (AML) or myelodysplastic syndrome. RESULTS: In phase I, 16 patients were treated in four cohorts with tosedostat (60 mg to 180 mg) for 28 days. Three patients reported dose-limiting toxicities: two with reversible thrombocytopenia (> 75% reduction in platelet count) at 180 mg (MTD) and one with a Common Toxicity Criteria (CTC) grade 3 ALT elevation at 130 mg (MAD). In phase II, 41 patients were treated with 130 mg tosedostat. In phases I and II, the most common severe (CTC grades 3 to 5) adverse event was a reduction in the platelet count. Of the 51 AML patients in this study, seven reached complete marrow response (< 5% marrow blasts), with three achieving complete remission, and a further seven patients reaching a partial marrow response (between 5% and 15% marrow blasts). The overall response rate was therefore 27%. All responders were age > 60 years, and 79% had either relapsed or refractory AML. CONCLUSION: This phase I/II study demonstrates that oral once daily dosing with 130 mg tosedostat is well tolerated and has significant antileukemic activity. The favorable risk-benefit profile suggests that further clinical trials are warranted.

CHR-2797: an antiproliferative aminopeptidase inhibitor that leads to amino acid deprivation in human leukemic cells.

CHR-2797 is a novel metalloenzyme inhibitor that is converted into a pharmacologically active acid product (CHR-79888) inside cells. CHR-79888 is a potent inhibitor of a number of intracellular aminopeptidases, including leucine aminopeptidase. CHR-2797 exerts antiproliferative effects against a range of tumor cell lines in vitro and in vivo and shows selectivity for transformed over nontransformed cells. Its antiproliferative effects are at least 300 times more potent than the prototypical aminopeptidase inhibitor, bestatin. However, the mechanism by which inhibition of these enzymes leads to proliferative changes is not understood. Gene expression microarrays were used to profile changes in mRNA expression levels in the human promyelocytic leukemia cell line HL-60 treated with CHR-2797. This analysis showed that CHR-2797 treatment induced a transcriptional response indicative of amino acid depletion, the amino acid deprivation response, which involves up-regulation of amino acid synthetic genes, transporters, and tRNA synthetases. These changes were confirmed in other leukemic cell lines sensitive to the antiproliferative effects of CHR-2797. Furthermore, CHR-2797 treatment inhibited phosphorylation of mTOR substrates and reduced protein synthesis in HL-60 cells, both also indicative of amino acid depletion. Treatment with CHR-2797 led to an increase in the concentration of intracellular small peptides, the substrates of aminopeptidases. It is suggested that aminopeptidase inhibitors, such as CHR-2797 and bestatin, deplete sensitive tumor cells of amino acids by blocking protein recycling, and this generates an antiproliferative effect. CHR-2797 is orally bioavailable and currently undergoing phase II clinical investigation in the treatment of myeloid leukemia.

A multicentre, randomised prospective trial comparing three intravesical adjuvant therapies for intermediate-risk superficial bladder cancer: low-dose bacillus Calmette-Guerin (27 mg) versus very low-dose bacillus Calmette-Guerin (13.5 mg) versus mitomycin C.

OBJECTIVE: The primary aim was to search for lower doses of Bacillus Calmette-Guerin (BCG) that are effective and have lower toxicity. METHODS: A low dose of BCG 27 mg was compared with BCG 13.5mg, using mitomycin C (MMC) 30 mg as the third arm of comparison. A total of 430 patients with intermediate-risk superficial bladder cancer were randomised into three groups. Instillations were repeated once a week for 6 wk followed by another six instillations given once every 2 wk during 12 wk. RESULTS: There was a significantly longer disease-free interval for BCG 27 mg versus MMC 30 mg (p=0.006). There were no statistically significant differences between BCG 27 mg and BCG 13.5mg (p=0.165) or between BCG 13.5mg and MMC 30 mg (p=0.183). Cox proportional hazards regression showed that disease-free interval in the multivariate analysis was significantly better for primary disease and treatment with BCG 27 mg. There were no significant differences among the three groups with regards to time to progression and cancer-specific survival time. Local and systemic toxicity were higher in both BCG treatment groups. CONCLUSIONS: One third of the standard dose, BCG 27 mg, seems to be the minimum effective dose as adjuvant treatment for intermediate-risk superficial bladder cancer, being more effective than MMC 30 mg. One sixth of the standard dose, BCG 13.5mg, has the same efficacy as MMC 30 mg but it is more toxic.

Has a 3-fold decreased dose of bacillus Calmette-Guerin the same efficacy against recurrences and progression of T1G3 and Tis bladder tumors than the standard dose? Results of a prospective randomized trial.

PURPOSE: We determined if a third of the dose of intravesical bacillus Calmette-Guerin (BCG) has the same efficacy than a standard dose for decreasing the risk of recurrence and progression after transurethral resection in patients with superficial high risk (stages T1G3 and carcinoma in situ) bladder cancer. Also, we evaluated toxic side effects. MATERIAL AND METHODS: A total of 155 patients with a mean age +/- SD of 67 +/- 10.1 years with superficial bladder cancer, including stages T1G3 in 90, a Tis primary tumor in 23 and associated Tis disease in 42, were enrolled and randomly assigned to be treated after transurethral resection of all visible lesions with intravesical BCG, Connaught strain (weekly x 6 and fortnightly x 6 thereafter) with the standard dose of 81 mg or with the decreased dose of 27 mg. RESULTS: Median followup was 61 months (range 3 to 102). Disease recurred in 32 patients (39%) treated with the standard dose and in 33 (45%) treated with the decreased dose. Median time to recurrence was not attained in the standard dose arm and it was 63 months in the decreased dose arm. Kaplan-Meier estimates for time to recurrence did not reveal differences between the 2 doses (p = 0.405). Tumor progressed in 20 patients (24.7%) with the standard dose and in 19 (26%) with the decreased dose. Four patients (6.1%) with Tis had local extension into the prostatic urethra and ducts, including 3 (8.3%) treated with the standard dose and 1 (3.4%) treated with the decreased dose. Median time to progression was not attained in either arm. Kaplan-Meier estimates for time to progression did not differ significantly (p = 0.7997). Deferred cystectomy for progression was performed in 7 patients (8.4%) treated with the standard dose and in 7 (9.5%) of those treated with the decreased dose. Subgroup analysis by patient age, tumor status, number, size and T stage (T1G3 vs Tis) did not differ significantly. The groups did not differ in disease specific mortality, which was 12.2% in the standard dose arm and 16.4% in the decreased dose arm. Mean disease specific survival +/- SE was 86.96 +/- 4.14 and 83.73 +/- 4.73 months, respectively. CONCLUSIONS: Our results suggest that a 3-fold decreased dose of intravesical BCG is as effective as the standard dose against progression in patients with high risk stages T1G3 and Tis superficial bladder carcinoma but with significantly less toxicity.