USP19 regulates DNA methylation damage repair and confers temozolomide resistance through MGMT stabilization.

OBJECTIVE: To elucidate the relationship between USP19 and O(6)-methylguanine-DNA methyltransferase (MGMT) after temozolomide treatment in glioblastoma (GBM) patients with chemotherapy resistance. METHODS: Screening the deubiquitinase pannel and identifying the deubiquitinase directly interacts with and deubiquitination MGMT. Deubiquitination assay to confirm USP19 deubiquitinates MGMT. The colony formation and tumor growth study in xenograft assess USP19 affects the GBM sensitive to TMZ was performed by T98G, LN18, U251, and U87 cell lines. Immunohistochemistry staining and survival analysis were performed to explore how USP19 is correlated to MGMT in GBM clinical management. RESULTS: USP19 removes the ubiquitination of MGMT to facilitate the DNA methylation damage repair. Depletion of USP19 results in the glioblastoma cell sensitivity to temozolomide, which can be rescued by overexpressing MGMT. USP19 is overexpressed in glioblastoma patient samples, which positively correlates with the level of MGMT protein and poor prognosis in these patients. CONCLUSION: The regulation of MGMT ubiquitination by USP19 plays a critical role in DNA methylation damage repair and GBM patients' temozolomide chemotherapy response.

Antimicrobial Susceptibility and Resistance Genes in Streptococcus uberis Isolated from Bovine Mastitis in the Czech Republic.

Streptococcus uberis is one of the most important causative agents of mastitis and is a common reason for the use of antimicrobials in dairy cows. In this study, we assessed the antimicrobial susceptibility of 667 S. uberis isolates originating from 216 Czech dairy farms collected between 2019 and 2023 using the broth microdilution method. We tested 140 of the isolates for the presence of antimicrobial genes using whole-genome sequencing and evaluated their relationship with phenotypic resistance. Streptococcus uberis isolates showed high levels of resistance to tetracycline (59%), followed by streptomycin (38%) and clindamycin (29%). Although all of the isolates were susceptible to beta-lactams, a relatively high percentage of intermediately susceptible isolates was recorded for ampicillin (44%) and penicillin (18%). The isolates were mainly resistant to tetracycline alone (31.3%); the second most frequent occurrence of the phenotypic profile was simultaneous resistance to tetracycline, streptomycin, and clindamycin (16.6%). The occurrence of antibiotic resistance genes did not always match the phenotypic results; in total, 36.8% of isolates that possessed the ant(6)-Ia gene did not show phenotypic resistance to streptomycin. To a lesser extent, silent genes were also detected in clindamycin and tetracycline. This study confirmed the high susceptibility of S. uberis to penicillins used as first-line antimicrobials for S. uberis mastitis treatment.

A proposal of a new index of coronary microvascular resistance based on the duration of the transient ECG repolarization changes during coronary angiography.

Coronary microvascular dysfunction is present in the majority of patients with acute coronary syndromes, myocardial infarction with nonobstructive coronary arteries, and takotsubo syndrome. Assessment of the coronary microcirculation via a noninvasive index of coronary microvascular resistance (CMVR) based on coronary angiography is currently employed by many laboratories (AngioMVR). A proposal is presented herein of a new index of CMVR, based on the duration of the transient ECG repolarization changes during coronary angiography (ECGMVR), well known to occur in patients with and without coronary artery disease, and specific for the left and right coronary artery contrast injections, which have been widely documented, starting 60 years ago. It will be imperative for the index of ECGMVR to be correlated with the currently implemented AngioMVR and the TIMI frame count index, for the validation of the ECGMVR.

[Cardiovascular risk factors, haemostasis and antithrombotic treatment in retinal vessel occlusion]. / Kardiovaskuläre Risikofaktoren, Gerinnung und gerinnungswirksame Therapien bei retinalen Gefäßverschlusserkrankungen.

Venous and arterial retinal vascular occlusions are age-related disorders, generally associated with classical cardiovascular risk factors, rather than an isolated ocular disease. As affected patients often also have an increased general risk for other vascular diseases, such as ischemic stroke, an interdisciplinary clarification of cardiovascular risk factors and systemic comorbidities is essential for all patients. Extended hemostaseological investigations may be recommended in those patients who do not match the typical risk profile. Patients at a young age by the time of manifestation, without conventional risk factors as well as patients with an increased risk of developing antiphospholipid syndrome may require a selective clinical investigation including testing for thrombophilic risk factors. Recent studies have clearly demonstrated an association between coagulation and lipid metabolism disorders and the development of both retinal vein and artery occlusions in specific subgroups of patients. Therapeutic approaches to treat retinal vascular occlusions or reduce the long-term risk of recurrences with anticoagulant or antiplatelet drugs have not gained widespread acceptance. However, intravenous thrombolysis may be a valuable treatment option for central retinal artery occlusions within a short time to treatment therapeutic window. For defined disorders of the coagulation system, the administration of antithrombotic drugs to reduce the general vascular risk can be a reasonable approach. This article provides an overview of cardiovascular risk factors, the general vascular risk and the current state of knowledge on ophthalmologically relevant disorders of coagulation and lipid metabolism in patients with venous and arterial retinal vascular occlusions.

Genetic factors underlying tacrolimus intolerance after liver transplantation.

Background: Tacrolimus (FK506) is the cornerstone of immunosuppression after liver transplantation (LT), however, clinically, switching from FK506 to cyclosporine (SFTC) is common in LT patients with tacrolimus intolerance. The aim of this study was to investigate the genetic risk of patients with tacrolimus intolerance. Methods: A total of 114 LT patients were enrolled in this retrospective study. SNPs were genotyped using Infinium Human Exome-12 v1.2 BeadChip, and genome-wide gene expression levels were profiled using Agilent G4112F array. Results: SFTC was a potential risk factor of dyslipidemia (OR=4.774[1.122-20.311], p = 0.034) and insulin resistance (IR) (OR=6.25[1.451-26.916], p = 0.014), but did not affect the survival of LT patients. Differential expression analysis showed donor CYP3A5, CYP2C9, CFTR, and GSTP1, four important pharmacogenetic genes were significantly up-regulated in the tacrolimus intolerance group. Twelve SNPs of these four genes were screened to investigate the effects on tacrolimus intolerance. Regression analysis showed donor rs4646450 (OR=3.23 [1.22-8.60] per each A allele, p = 0.01), donor rs6977165 (OR=6.44 [1.09-37.87] per each C allele, p = 0.02), and donor rs776746 (OR=3.31 [1.25-8.81] per each A allele, p = 0.01) were independent risk factors of tacrolimus intolerance. Conclusions: These results suggested that SFTC was a potential risk factor for dyslipidemia and IR after LT. Besides, rs4646450, rs6977165, and rs776746 of CYP3A5 might be the underlying genetic risks of tacrolimus intolerance. This might help transplant surgeons make earlier clinical decisions about the use of immunosuppression.

Emergence of high colistin resistance in carbapenem resistant Acinetobacter baumannii in Pakistan and its potential management through immunomodulatory effect of an extract from Saussurea lappa.

Carbapenem resistant Acinetobacter baumannii has emerged as one of the most difficult to treat nosocomial bacterial infections in recent years. It was one of the major causes of secondary infections in Covid-19 patients in developing countries. The polycationic polypeptide antibiotic colistin is used as a last resort drug to treat carbapenem resistant A. baumannii infections. Therefore, resistance to colistin is considered as a serious medical threat. The purpose of this study was to assess the current status of colistin resistance in Pakistan, a country where carbapenem resistant A. bumannii infections are endemic, to understand the impact of colistin resistance on virulence in mice and to assess alternative strategies to treat such infections. Out of 150 isolates collected from five hospitals in Pakistan during 2019-20, 84% were carbapenem resistant and 7.3% were additionally resistant to colistin. There were two isolates resistant to all tested antibiotics and 83% of colistin resistant isolates were susceptible to only tetracycline family drugs doxycycline and minocycline. Doxycycline exhibited a synergetic bactericidal effect with colistin even in colistin resistant isolates. Exposure of A. baumannii 17978 to sub inhibitory concentrations of colistin identified novel point mutations associated with colistin resistance. Colistin tolerance acquired independent of mutations in lpxA, lpxB, lpxC, lpxD, and pmrAB supressed the proinflammatory immune response in epithelial cells and the virulence in a mouse infection model. Moreover, the oral administration of water extract of Saussuria lappa, although not showing antimicrobial activity against A. baumannii in vitro, lowered the number of colonizing bacteria in liver, spleen and lung of the mouse model and also lowered the levels of neutrophils and interleukin 8 in mice. Our findings suggest that the S. lappa extract exhibits an immunomodulatory effect with potential to reduce and cure systemic infections by both opaque and translucent colony variants of A. baumannii.

Infección urinaria producida por enterococo faecalis y enterococo faecium asociada a sonda vesical: factores de riesgo y evaluación de los patrones de resistencia / Urinary infection produced by enterococcus faecalis and enterococcus faecium associated with bladder catheterization: risk factors and evaluation of resistance patterns

Background and objectives: Urinary tract infection (UTI) is one of the most common infections in hospitalized and outpatients. Bladder catheterization is an important risk factor. The increase in antibiotic resistance can make the treatment of these infections a challenge. The main objective of this study is to analize the resistance and sensitivity rates of UTIs in catheterized patients caused by Enterococcus (E.faecium and E.faecalis). Associated riskfactors were also studied. Materials and methods: Retrospective observational study of patients with urinary infection associated to catheterization caused by E.faecium and E.faecalis during 2020 in al Internal Medicina Unit. Results: Ampicillin was the antibiotic with the highest resistance rate in the case of E.faecium (94.4%), while 93.05% of E.faecalis presented resistance to Gentamicin. Teicoplanin and Vancomycin were the ones with the lowest rates. Regarding risk factors, dementia, catheterization > 5 days, previous antibiotic therapy, immunosuppresion, and institutionalized patients were statistically significant. Conclusions: It is important to know the epidemiology of UTIs in each area, as well as the raties of resistance and risk factors in order to provide the most adequate treatment possible, and to avoid the increase in resistance. (AU)

Introducción y objetivos: La infección urinaria es una de las infecciones intra y extrahospitalarias más frecuentes, siendo el sondaje vesical uno de los principales factores de riesgo. El aumento de resistencias antibióticas al que estamos asistiendo hace que su tratamiento a veces suponga un reto. El objetivo principal del estudio pretende analizar las tasas de resistencia y sensibilidad de las principales infecciones urinarias producidas por Enterococos (E.faecium y E.faecalis) en pacientes sondados. También se estudiaron los factores de riesgo asociados. Material y métodos: Estudio retrospectivo observacional de pacientes con infección urinaria asociada a sondaje por E.faecium y E.faecalis durante el año 2020 en un servicio de Medicina Interna. Resultados: La ampicilina fue el antibiótico que mayor tasa de resistencia obtuvo en el caso de E.faecium (94.4%), mientras que el 93.05% de casos por E.faecalis presentó resistencias a gentamicina. Teicoplanina y vancomicina fueron los que menores tasas tuvieron. En cuanto a los factores de riesgo, la demencia, el sondaje > 5 días, la antibioterapia previa, la inmunodepresión y los pacientes institucionalizados fueron estadísticamente significativos. Conclusiones: Es importante conocer la epidemiología de las infecciones urinarias de la zona por áreas geográficas, así como las tasas de resistencias y los factores de riesgo con el fin de un tratamiento lo más adecuado posible, y evitar el aumento de resistencias. (AU)

Comparative Studies to Uncover Mechanisms of Action of N-(1,3,4-Oxadiazol-2-yl)benzamide Containing Antibacterial Agents.

Drug-resistant bacterial pathogens still cause high levels of mortality annually despite the availability of many antibiotics. Methicillin-resistant Staphylococcus aureus (MRSA) is especially problematic, and the rise in resistance to front-line treatments like vancomycin and linezolid calls for new chemical modalities to treat chronic and relapsing MRSA infections. Halogenated N-(1,3,4-oxadiazol-2-yl)benzamides are an interesting class of antimicrobial agents, which have been described by multiple groups to be effective against different bacterial pathogens. The modes of action of a few N-(1,3,4-oxadiazol-2-yl)benzamides have been elucidated. For example, oxadiazoles KKL-35 and MBX-4132 have been described as inhibitors of trans-translation (a ribosome rescue pathway), while HSGN-94 was shown to inhibit lipoteichoic acid (LTA). However, other similarly halogenated N-(1,3,4-oxadiazol-2-yl)benzamides neither inhibit trans-translation nor LTA biosynthesis but are potent antimicrobial agents. For example, HSGN-220, -218, and -144 are N-(1,3,4-oxadiazol-2-yl)benzamides that are modified with OCF3, SCF3, or SF5 and have remarkable minimum inhibitory concentrations ranging from 1 to 0.06 µg/mL against MRSA clinical isolates and show a low propensity to develop resistance to MRSA over 30 days. The mechanism of action of these highly potent oxadiazoles is however unknown. To provide insights into how these halogenated N-(1,3,4-oxadiazol-2-yl)benzamides inhibit bacterial growth, we performed global proteomics and RNA expression analysis of some essential genes of S. aureus treated with HSGN-220, -218, and -144. These studies revealed that the oxadiazoles HSGN-220, -218, and -144 are multitargeting antibiotics that regulate menaquinone biosynthesis and other essential proteins like DnaX, Pol IIIC, BirA, LexA, and DnaC. In addition, these halogenated N-(1,3,4-oxadiazol-2-yl)benzamides were able to depolarize bacterial membranes and regulate siderophore biosynthesis and heme regulation. Iron starvation appears to be part of the mechanism of action that led to bacterial killing. This study demonstrates that N-(1,3,4-oxadiazol-2-yl)benzamides are indeed privileged scaffolds for the development of antibacterial agents and that subtle modifications lead to changes to the mechanism of action.

Fisiología respiratoria: circulación pulmonar / Respiratory physiology: pulmonary circulation

El pulmón recibe sangre desde la circulación bronquial y pulmonar. La circulación pulmonar presenta importantes diferencias con la sistémica, sus vasos sanguíneos poseen características únicas que le permiten cumplir sus diferentes funciones, siendo la más importante el intercambio gaseoso. Existen múltiples factores, activos y pasivos, que están involucrados en la regulación de la resistencia vascular y flujo sanguíneo pulmonar.

The lung receives blood from the bronchial and the pulmonary circulation. The pulmonary circulation presents important differences with the systemic circulation, its blood vessels have unique characteristics that allow them to fulfill their different functions, the most important being gas exchange. There are multiple factors, active and passive, that are involved in the regulation of vascular resistance and pulmonary blood flow.

Variantes genéticas del SARS-CoV-2 y sus implicaciones clínicas / Genetic variants of SARS-CoV-2 and its clinical implications

El SARS-CoV-2, agente causal de la actual pandemia de la COVID-19, va sufriendo mutaciones como consecuencia de su ciclo evolutivo, lo que ha originado diferentes variantes genéticas, que han sido agrupadas en dos categorías: preocupante (alfa o británica, beta o sudafricana, gamma o brasileña y delta o india) y de interés (lamdba, mu, épsilon, eta, iota, kappa, zeta, theta); estas conllevan implicaciones clínicas en la transmisibilidad, virulencia y resistencia del SARS-CoV-2 a la inmunidad natural y adquirida, lo que representa un serio desafío para los servicios de salud en todo el mundo. En este artículo se describen dichas variantes genéticas, con énfasis en su probable impacto clínico, y además se plantea la posibilidad de que aparezcan otras, como fenómeno natural en la evolución de los virus.

The SARS-CoV-2, causal agent of the COVID-19 current pandemic, is suffering mutations as a consequence of its evolutive cycle, what has originated different genetic variants that have been grouped in two categories: worrying (alpha or British, beta or South African, gamma or Brazilian and delta or Indian) and of interest (lamdba, mu, epsilon, eta, iota, kappa, zed, theta); these categories bear clinical implications in the transmissibility, virulence and resistance from SARS-CoV-2 to the natural and acquired immunity, what represents a serious challenge in health services worldwide. These genetic variants are described in this work, with emphasis in its probable clinical impact, and the possibility that other variants could appear is also explained, as natural phenomenon in the evolution of viruses.

Nota clínica: Efecto antidepresivo de la EMTrdurante el embarazo en un caso de Depresión Mayor Resistente al Tratamiento Farmacológico / Clinical note: Antidepressant effect of rTMS during pregnancy in a case of drug-resistant major depression. during pregnancy in a case of Medication-Resistant Major Depression

El trastorno depresivo mayor (TDM) constituye una complicación común del embarazo y el período posparto. Aproximadamente un 5% de mujeres que presentan un TDM durante la gestación o el periodo postparto cumplen criterios paradepresión resistente, asociándose con un incremento de lamorbilidad tanto en el recién nacido como en la propia gestante. En la actualidad disponemos de diferentes opcionesterapéuticas para el tratamiento del TDM durante el embarazo si bien en los casos de resistencia durante el embarazolos criterios de tratamiento no se encuentran tan bien establecidos.Presentamos el caso de una mujer de 36 años de edadque desarrolló un episodio de depresión mayor resistente altratamiento farmacológico. Durante el episodio actual y trascuatro ciclos de tratamiento farmacológico fallido se quedóembarazada. A las 16 semanas de gestación fue tratada conestimulación magnética transcraneal repetitiva (EMTr) debaja frecuencia. Tras 30 sesiones de tratamiento, con buenatolerancia, la paciente presentó una recuperación completade la sintomatología depresiva, dando a luz a un recién nacido sano. La EMTr constituye una buena alternativa frente a laTerapia Electroconvulsiva en algunos casos de TDM resistentedurante la gestación. A pesar de estos hallazgos prometedores, se requiere de un mayor número de estudios controlados,doble ciego que incluyan muestras amplias de pacientes embarazadas, con parámetros EMTr bien diseñados, e inclusoestudios prospectivos (siguiendo a mujeres embarazadas ysus descendientes) para confirmar la ausencia de efectos secundarios a largo plazo. (AU)

Major depressive disorder (MDD) is a common complication of pregnancy and the postpartum period. Approximately 5% of women who have MDD during pregnancy orthe postpartum period meet criteria for resistant depression,associated with increased morbidity in both the newbornand the pregnant woman. Currently we have different therapeutic options for the treatment of MDD during pregnancy,although in cases of resistance during that period the treatment criteria are not that well established.We set out the case of a 36-year-old woman who presents an episode of major depression resistant to pharmacotherapy. During the current episode and after four cycles offailed pharmacological treatment she became pregnant. Inthe 16th week of gestation, she was treated with low-frequency repetitive transcranial magnetic stimulation (rTMS).After 30 treatment sessions, with good tolerance, the patient presented a complete recovery from the depressivesymptoms, giving birth to a healthy newborn. rTMS is a goodalternative to Electroconvulsive Therapy in some cases ofresistant MDD during pregnancy. Despite these promisingfindings, further double-blind controlled studies with broadsamples of pregnant women are required, with well-designed rTMS parameters, and even prospective studies (following pregnant women and their offspring) to confirm theabsence of long-term side effects. (AU)

Mechanobiology of cancerogenesis.

BACKGROUND: Within the tumour microenvironment, tumour cells are exposed to different mechanical stimuli such as compression stress, cell-cell and cell-extracellular matrix traction forces, interstitial fluid pressure, and shear stress. Cells actively sense and process this information by the mechanism of mechanotransduction to make decisions about their growth, motility, and differentiation. Indeed, the mechanical properties of the tumour microenvironment can deeply influence the behaviour of cancer cells and promote cancerogenesis. During tumour progression, desmoplasia arises and a positive feedback loop between the stiffening extracellular matrix and the properties enabling tumour expansion is established. Tumour cells can use mechanic stimuli to promote proliferation, increase their migratory and invasive potential, and induce therapeutic resistance. Mechanobio-logy is a progressive multidisciplinary field which studies how mechanical forces influence the behaviour of cells or tissues and may provide some interesting targets for cancer therapy. PURPOSE: In this review, we discuss the mechanical properties of cancer cells and describe the tumour promoting effect of the transformed extracellular matrix. We propose that the differences in the mechanobio-logy of cells and extracellular matrix are significant enough to facilitate tumorigenesis and may provide interesting targets for cancer therapy.

Prevalencia y patrones de resistencia adquirida a antirretrovirales en menores de 18 años en el Hospital de Especialidades Pediátricas "Omar Torrijos Herrera" / Prevalence and patterns of acquired resistance to antiretrovirals in children under 18 years of age

Introducción: La resistencia a antirretrovirales compromete la efectividad del tratamiento de pacientes con infección por VIH, llevando a falla virológica e inmunológica, deterioro clínico y comprometiendo tratamientos futuros. Los niños y adolescentes tienen mayor riesgo de desarrollo de resistencia asociados a terapias prolongadas, mala adherencia y limitadas opciones terapéuticas. Se desconoce la prevalencia y patrones de resistencia adquirida en población pediátrica panameña. Objetivos: Conocer la prevalencia y describir los patrones de resistencia adquirida en población pediátrica infectada con falla virológica en el período 2009-2019 Material y Método: Estudio descriptivo. Se incluyeron sujetos menores de 18 años de edad, con al menos un año de tratamiento, en falla virológica y que contaban con una prueba de genotipaje. Se realizó revisión de los expedientes clínicos para la obtención de los datos. Se describen las características demográficas, historial de tratamiento, resistencia a familias de antirretrovirales y mutaciones específicas Resultados y conclusiones: 13 pacientes fueron incluidos en el estudio de un total de 72 pacientes con infección de VIH atendidos en el período de estudio, para una prevalencia de resistencia del 18% de sujetos en terapia con resistencia. Se encontró 92% de resistencia a Inhibidores de la transcriptasa reversa análogo de nucleósidos, 61.5% a inhibidores de la transcriptasa reversa no análogos de nucleósidos y 23% de resistencia a Inhibidores de proteasa, las mutaciones M184V y K103N fueron las más frecuentes. Se requiere mantener la vigilancia de resistencia en niños con el fin de ajustar las recomendaciones de tratamiento.

Introduction: Antiretroviral resistance compromises the effectiveness of the treatment of patients with HIV infection, leading to virological and immunological failure, clinical deterioration and compromising future treatments. Children and adolescents are at increased risk of developing resistance associated with prolonged therapies, poor adherence, and limited therapeutic options. The prevalence and patterns of acquired resistance in the Panamanian pediatric population are unknown. Metodology Descriptive study. Subjects under 18 years of age, with at least one year of treatment, in virological failure and who had a genotyping test were included. A review of the clinical records was carried out to obtain the data. Demographic characteristics, treatment history, and at the time of genotyping, resistance to antiretroviral families and specific mutations are described. Conclusions: 13 patients were included in the study of a total of 72 patients with HIV infection attended in the study period, for a prevalence of 18% of subjects on antirretroviral therapy. It was found 92% resistance to nucleoside reverse transcriptase inhibitor, 61.5% to non- nucleoside reverse transcriptase inhibitor and 23% resistance to protease inhibitor. The M184V and K103N mutation were the most frequent. Surveillance of ARV resistance in children is required to adjust treatment recommendations.

Chronic Thromboembolic Pulmonary Hypertension - What Have We Learned From Large Animal Models.

Chronic thrombo-embolic pulmonary hypertension (CTEPH) develops in a subset of patients after acute pulmonary embolism. In CTEPH, pulmonary vascular resistance, which is initially elevated due to the obstructions in the larger pulmonary arteries, is further increased by pulmonary microvascular remodeling. The increased afterload of the right ventricle (RV) leads to RV dilation and hypertrophy. This RV remodeling predisposes to arrhythmogenesis and RV failure. Yet, mechanisms involved in pulmonary microvascular remodeling, processes underlying the RV structural and functional adaptability in CTEPH as well as determinants of the susceptibility to arrhythmias such as atrial fibrillation in the context of CTEPH remain incompletely understood. Several large animal models with critical clinical features of human CTEPH and subsequent RV remodeling have relatively recently been developed in swine, sheep, and dogs. In this review we will discuss the current knowledge on the processes underlying development and progression of CTEPH, and on how animal models can help enlarge understanding of these processes.

An assessment of the hemorheological profile in patients with subclinical carotid atherosclerosis divided in relation to the number of cardiovascular risk factors and different degrees of insulin resistance.

We present a cohort of 100 subjects [43 men and 57 women; median age 66.00(25)] who were tested using carotid ultrasound to identify subclinical carotid atherosclerosis (SCA). We have evaluated the behaviour of whole blood viscosity (WBV) at high (450 s-1) and low (0.51 s-1) shear rates, plasma viscosity (450-1), hematocrit and mean erythrocyte aggregation. When compared to normal control subjects, using the Mann-Whitney test, we observed in SCA patients a significant increase in WBV only. The results were substantial after having divided the SCA subjects according to the cardiovascular risk factors (CRFs) and the degree of insulin resistance; the research was performed using two surrogate indexes such as TG/HDL-C and TyG. With the division carried out according to CRFs, employing the Kruskal-Wallis test, results show a significant increase in WBV (at high and low shear rates), in plasma viscosity, in erythrocyte aggregation and plasma fibrinogen level. Whereas by dividing them into the median of TG/HDL-C and TyG, we noticed a significant increase in WBV (at high and low shear rates) and in erythrocyte aggregation in the two groups with high TG/HDL-C ratio and with high TyG; having found an increased level of plasma fibrinogen in the latter. The data underlines the role of the main hemorheologic aspects in subclinical carotid atherosclerosis being closely correlated to the CRFs and different degrees of insulin resistance.

A novel oral rabies vaccine enhances the immunogenicity through increasing dendritic cells activation and germinal center formation by expressing U-OMP19 in a mouse model.

Rabies remains a public health threat in most parts of the world. Dogs, especially stray dogs, are the main sources of rabies transmission in developing countries, while wild animals are primarily responsible for the spread of rabies in developed countries and play an emerging role in rabies transmission in developing countries. Oral vaccination is the most practical method for rabies control in these animals, and the greatest challenge for oral vaccination is the hostile environment and large quantity of proteases in the gastrointestinal tract. In the present study, a promising adjuvant with potential protease inhibitory activity, unlipidated outer membrane protein 19 (U-OMP19), was inserted into the genome of the recombinant rabies virus (rRABV) strain LBNSE, designated LBNSE-U-OMP19, and the immunogenicity of LBNSE-U-OMP19 was investigated. LBNSE-U-OMP19 could potentially protect viral glycoprotein from digestion by gastrointestinal fluids in vitro. The expression of U-OMP19 attenuated viral pathogenicity by restricting viral replication in the central nervous system (CNS) and repressing the production of inflammatory chemokines and cytokines. After oral vaccination, LBNSE-U-OMP19 recruited dendritic cells (DCs), follicular helper T (TFH) cells and germinal center (GC) B cells, promoted the formation of GCs, and increased the population of plasma cells in immunized mice, resulting in higher levels of RABV-neutralizing antibodies and better protection in mice immunized with LBNSE-U-OMP19 than in those immunized with the parent virus LBNSE. Together, our data suggest that LBNSE-U-OMP19 is a promising candidate for oral rabies vaccines.

Perfil de resistencia genotípica y fenotípica presente en bacterias aisladas a partir de fómites en Armenia, Quindío-Colombia período junio-julio 2019 / Genotypic and phenotypic resistance profile present in bacteria isolated from fomites in Armenia, Quindío-Colombia period June-July 2019

Resumen Introducción: La antibiótico-resistencia es un fenómeno por el cual las bacterias logran sobrevivir al tratamiento con antimicrobianos; con incidencia en ambientes intra y extrahospitalarios como: fuentes hídricas, sector agrario/ganadero y fómites. Objetivo: Describir bacterias presentes en fómites de alta circulación en una región centro-occidental de Colombia junto a su perfil de sensibilidad fenotípica y presencia de genes para betalactamasas tipo TEM-full, OXA-3 y SHV-full. Metodología: Se aislaron cepas bacterianas de billetes, pasamanos de escaleras eléctricas y botones de cajeros automáticos; se evaluó su perfil de sensibilidad fenotípica por medio de concentración mínima inhibitoria-técnica automatizada/Vitek2® y genes para betalactamasas tipo TEM-full, OXA-3 y SHV-full mediante PCR convencional. Resultados: Se obtuvo 30 aislados; Acinetobacter baumannii complex, fue la más común; el fómite con mayor aislados y resistencia fueron los billetes; el 53% portó al menos uno de los genes estudiados. Se identificaron bacterias gramnegativas con resistencia frente a: Imipinem, Piperacilina/Tazobactam, Colistina, Ceftazidima, Tigeciclina y Ceftriaxona; bacterias grampositivas con resistencia frente a: Quinupristina/Dalfopristina, Minociclina, Tetraciclina, Teicoplanina, Nitrofuratoina, Oxacilina, Clindamicina, Trimetropina-sulfametoxazol, y Minociclina. Conclusión: Teniendo en cuenta la circulación de cepas con estas resistencias, es importante la educación en la comunidad para evitar la adquisición o propagación de infecciones por manipulación inadecuada de fómites.

Abstract Introduction: Antibiotic-resistance is a phenomenon by which bacteria manage to survive antimicrobial treatment; with incidence in intra and extra hospital environments such as: water sources, agricultural / livestock sector and fomites. Aim: To describe bacteria present in high circulation fomites in a central-western region of Colombia, with their phenotypic sensitivity profile and presence of genes beta-lactamases (TEM, OXA3 and SHV). Methodology: We isolate bacterial strains from banknotes, escalator handrails and ATM buttons. We evaluated its phenotypic sensitivity profile by minimal inhibitory concentration automated technique using Vitek 2® and presence of genes for beta-lactamases type TEM-full, OXA-3 and SHV-full by conventional PCR. Results: A total of 30 isolates were obtained; Acinetobacter baumannii complex, was the most common; banknotes were the form with the highest number of isolates and resistance. Of the total isolates, 53% carried at least one of the genes studied. Phenotypically, gram-negative bacteria were identified with resistance against: Imipinem, Piperacillin / Tazobactam, Colistin, Ceftazidime, Tigecycline and Ceftriaxone; Gram-positive bacteria with resistance to: Quinupristin / Dalfopristin, Minocycline, Tetracycline, Teicoplanin, Nitrofuratoin, Oxacillin, Clindamycin, Trimethropine-sulfamethoxazole, and Minocycline. Conclusion: Taking into account the circulation of strains with these resistances, it is important to educate the community to avoid the acquisition or spread of infections due to the inappropriate handling of this type of inanimate elements.

[Antibiotic stewardship : Structure and implementation]. / Antibiotic Stewardship : Struktur und praktische Umsetzung.

Antibiotic resistance is a part of bacterial evolution and therefore unavoidable. Scarcity of novel treatment options requires prudent use of available antibiotics in order to decelerate the spread of resistance. This is the aim of antibiotic stewardship (ABS) programmes. The implementation of strategies that optimize antibiotic prescription and therapy necessitates the deployment of personnel as well as of structural resources. Necessary requirements for staff and strategies based on their evidence are described in the updated German S3 ABS Guideline. In the future, patients with infectious diseases will benefit from accelerated microbiological diagnostics as early adequate treatment not only reduces antibiotic consumption but also improves patient outcome. In addition, training of infectious disease specialists will substantially contribute to enhanced quality of care of patients with infectious disease.

SHP2 Inhibition Benefits Epidermal Growth Factor Receptor-mutated Non-Small Cell Lung Cancer Therapy.

EGFR-TKIs are confronted with big challenge of everlasting activated EGFR mutations which lack effective binding sites; this barrier is the dark side that largely limits the outcome of NSCLC patients in the clinic. Combination strategies show impressive anti-tumor efficacy that compared with EGFR-TKI mono-treatment, especially targeting both stem cells and non-stem cells. SHP2 (Src homology 2-containing phosphotyrosine phosphatase 2) plays an important role in regulating various malignant biology through hyper-activating intracellular pathways due to either overexpression or catalytical mutation. Some pathways, in which SHP2 was involved, were overlapped with EGFR downstream, and others were not subject to EGFR. Interestingly, SHP2 suppression was reported to destroy the stemness of cancer. Therefore, we hypothesize that SHP2 inhibitor might be a promising drug that could synergistically enhance or sensitize the anti-tumor efficacy of EGFR-TKIs in EGFR mutated NSCLC patients. Here, we summarized the mechanisms of SHP2 in regulating EGFR mutated NSCLC patients, and attempted to reveal the potential synergistic file://localhost/C/:Program%20Files%20(x86):Youdao:Dict:7.5.2.0:resultui:dict:%3Fkeyword=effects of SHP2 inhibitor combined with EGFR-TKIs.