Enhanced Gene Delivery Triggered by Dual pH/Redox Responsive Host-Guest Dimerization of Cyclooligosaccharide Star Polycations.

A robust strategy is reported to build perfectly monodisperse star polycations combining a trehalose-based cyclooligosaccharide (cyclotrehalan, CT) central core onto which oligoethyleneimine radial arms are installed. The architectural perfection of the compounds is demonstrated by a variety of physicochemical techniques, including NMR, MS, DLS, TEM, and GPC. Key to the strategy is the possibility of customizing the cavity size of the macrocyclic platform to enable/prevent the inclusion of adamantane motifs. These properties can be taken into advantage to implement sequential levels of stimuli responsiveness by combining computational design, precision chemistry and programmed host-guest interactions. Specifically, it is shown that supramolecular dimers implying a trimeric CT-tetraethyleneimine star polycation and purposely designed bis-adamantane guests are preorganized to efficiently complex plasmid DNA (pDNA) into transfection-competent nanocomplexes. The stability of the dimer species is responsive to the protonation state of the cationic clusters, resulting in dissociation at acidic pH. This process facilitates endosomal escape, but reassembling can take place in the cytosol then handicapping pDNA nuclear import. By equipping the ditopic guest with a redox-sensitive disulfide group, recapturing phenomena are prevented, resulting in drastically improved transfection efficiencies both in vivo and in vitro.

Trifaceted Mickey Mouse Amphiphiles for Programmable Self-Assembly, DNA Complexation and Organ-Selective Gene Delivery.

Instilling segregated cationic and lipophilic domains with an angular disposition in a trehalose-based trifaceted macrocyclic scaffold allows engineering patchy molecular nanoparticles leveraging directional interactions that emulate those controlling self-assembling processes in viral capsids. The resulting trilobular amphiphilic derivatives, featuring a Mickey Mouse architecture, can electrostatically interact with plasmid DNA (pDNA) and further engage in hydrophobic contacts to promote condensation into transfectious nanocomplexes. Notably, the topology and internal structure of the cyclooligosaccharide/pDNA co-assemblies can be molded by fine-tuning the valency and characteristics of the cationic and lipophilic patches, which strongly impacts the transfection efficacy in vitro and in vivo. Outstanding organ selectivities can then be programmed with no need of incorporating a biorecognizable motif in the formulation. The results provide a versatile strategy for the construction of fully synthetic and perfectly monodisperse nonviral gene delivery systems uniquely suited for optimization schemes by making cyclooligosaccharide patchiness the focus.

Active Breaks Initiative During Hospital Rounds in the Surgical ICU to Improve Wellness of Healthcare Providers: An Observational Descriptive Study.

BACKGROUND: Healthcare professionals in the intensive care unit (ICU) confront stressful working conditions. Morning rounds involve several hours of prolonged standing and uninterrupted concentration each day and require both mental and physical endurance from the entire care team. There is concern that work-related fatigue among ICU practitioners will compromise their ability to safely and effectively care for their patients. To address this concern, the surgical intensive care unit (SICU) at Long Island Jewish Medical Center implemented an initiative to promote provider wellness through "active breaks" during rounds. MATERIALS AND METHODS: Between October and December 2019, 30 physicians, physician assistants, nurses, and students collectively engaged in active breaks during SICU rounds and then completed a 7-question, post-test survey to assess their experience. The survey consisted of both closed-end and open-ended questions. The data were then analyzed using simple statistics. RESULTS: In response to closed-ended questioning, the majority of participants agreed that active breaks relieved stress (27/30; 90%), promoted wellness (29/30; 96.7%), and improved team morale (29/30; 93.1%). When given the options of tricep dips, squats or push-ups, squats were the favored activity during breaks (17/30; 56.7%). Most of the participants (27/30; 90%) considered the active breaks to be appropriate for the working environment; two participants had no opinion on this matter. Approximately 90% of the respondents were interested in maintaining active breaks as part of the routine of morning rounds. CONCLUSIONS: Our assessment suggests active breaks during rounds are a healthy outlet to address the inherent stress associated with critical care. This initiative also potentially protects healthcare providers from burnout and, consequentially, improves the quality of patient care.

Kinetics of formation and reactivity of the persulfide in the one-cysteine peroxiredoxin from Mycobacterium tuberculosis.

Hydrogen sulfide (H2S) participates in prokaryotic metabolism and is associated with several physiological functions in mammals. H2S reacts with oxidized thiol derivatives (i.e. disulfides and sulfenic acids) and thereby forms persulfides, which are plausible transducers of the H2S-mediated signaling effects. The one-cysteine peroxiredoxin alkyl hydroperoxide reductase E from Mycobacterium tuberculosis (MtAhpE-SH) reacts fast with hydroperoxides, forming a stable sulfenic acid (MtAhpE-SOH), which we chose here as a model to study the interactions between H2S and peroxiredoxins (Prx). MtAhpE-SOH reacted with H2S, forming a persulfide (MtAhpE-SSH) detectable by mass spectrometry. The rate constant for this reaction was (1.4 ± 0.2) × 103 m-1 s-1 (pH 7.4, 25 °C), six times higher than that reported for the reaction with the main low-molecular-weight thiol in M. tuberculosis, mycothiol. H2S was able to complete the catalytic cycle of MtAhpE and, according to kinetic considerations, it could represent an alternative substrate in M. tuberculosis. MtAhpE-SSH reacted 43 times faster than did MtAhpE-SH with the unspecific electrophile 4,4'-dithiodipyridine, a disulfide that exhibits no preferential reactivity with peroxidatic cysteines, but MtAhpE-SSH was less reactive toward specific Prx substrates such as hydrogen peroxide and peroxynitrite. According to molecular dynamics simulations, this loss of specific reactivity could be explained by alterations in the MtAhpE active site. MtAhpE-SSH could transfer its sulfane sulfur to a low-molecular-weight thiol, a process likely facilitated by the low pKa of the leaving thiol MtAhpE-SH, highlighting the possibility that Prx participates in transpersulfidation. The findings of our study contribute to the understanding of persulfide formation and reactivity.

Short-term clinical outcomes of percutaneous coronary intervention of unprotected left main coronary disease in cardiogenic shock.

BACKGROUND: Percutaneous coronary intervention (PCI) of left main (LM) disease in patients with cardiogenic shock (CS) represents a clinical challenge. Evidence on clinical outcomes according to revascularization strategies in this scenario remains scarce. The objective was to investigate the short-term outcomes according to treatment strategies for this population. METHODS: We retrospectively analyzed 78 consecutive patients who underwent PCI of LM in established CS at two experienced centers. Characteristics of PCI and short-term clinical outcomes were assessed. RESULTS: LM stenosis was considered the culprit lesion in 49 patients (62.8%). In the remaining cases, LM stenosis was treated after successful PCI of the culprit vessel because of persistent CS. The majority of patients presented complex coronary anatomy (43.6% had Syntax score > 32). Complete revascularization was performed in 34.6%; a 2-stents technique in the LM bifurcation was used in 12.8% and intra-aortic balloon pump (IABP) in 73.1%. In-hospital mortality was 48.7%. At 90 days follow-up it was 50% without differences between 1 or 2 stent LM bifurcation-techniques (p = .319). Mortality was higher in patients with partial revascularization and residual Syntax score ≥ 15 (p < .05 by univariate analysis), and in those with TIMI flow<3 in the left coronary artery at the end of PCI (p < .05 by multivariate analysis). There were no significant differences in the use of IABP in relation to 90-day mortality (p = .92). CONCLUSIONS: In patients presenting with cardiogenic shock and LM disease, neither 2-stents strategy in the LM nor use of IABP displayed a reduced short-term mortality. However, patients with final TIMI flow <3 presented higher short-term mortality in our series.

Trehalose-polyamine/DNA nanocomplexes: impact of vector architecture on cell and organ transfection selectivity.

A novel family of precision-engineered gene vectors with well-defined structures built on trehalose and trehalose-based macrocycles (cyclotrehalans) comprising linear or cyclic polyamine heads have been synthesized through procedures that exploit click chemistry reactions. The strategy was conceived to enable systematic structural variations and, at the same time, ensuring that enantiomerically pure vectors are obtained. Notably, changes in the molecular architecture translated into topological differences at the nanoscale upon co-assembly with plasmid DNA, especially regarding the presence of regions with short- or long-range internal order as observed by TEM. In vitro and in vivo experiments further evidenced a significant impact on cell and organ transfection selectivity. Altogether, the results highlight the potential of trehalose-polyamine/pDNA nanocomplex monoformulations to achieve targeting transfection without the need for any additional cell- or organ-sorting component.

Characteristics, treatment and prognosis of patients with chronic heart failure according to ejection fraction. Results of an Ecuadorian registry.

BACKGROUND: In Ecuador, there are few data about the clinical behaviour of heart failure (HF). This study aims to analyse the clinical characteristics, treatment and prognosis according to the current classification based on left ventricular ejection fraction (EF). METHODS: A retrospective observational study was carried out in patients with chronic HF from the 'Los Ceibos' registry during the period January 2017-December 2022. Patients were classified into HF with preserved EF (HFpEF) [EF ≥ 50%], HF with mildly reduced EF (HFmrEF) [EF:41-49%], and HF with reduced (HFrEF) [EF ≤ 40%]. The patients were followed up for a mean time of 2.28 (IQR 1.25-3.49) years. RESULTS: A total of 711 patients were included, 333 (46.8%) with HFrEF, 109 patients (15.3%) with HFmrEF and 269 patients (37.8%) with HFpEF. The average age was 69.8 ± 13.1 years, 31.4% were women. The main comorbidity was arterial hypertension (92.7%). Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were used in 74.5%, beta-blockers in 82.3%, and mineralocorticoid receptor antagonists in 51.3%. 58.3% of patients with HFrEF received three drugs of the so-called foundational quadruple therapy. A lower all-cause (24.5%) and cardiovascular mortality rate (11,2%) was observed in the HFpEF group compared to HFmrEF (47.4% and 25,7%) and HFrEF (45.3% and 25,8%), p < 0.001. CONCLUSIONS: In the 'Los Ceibos' registry, a higher prevalence of HFrEF was observed. The main comorbidity was HTN. Half of the patients with HFrEF received three drugs of the foundational therapy. At four years of follow-up, lower all-cause and cardiovascular mortality rate was observed in the HFpEF group.

Predictors of poor prognosis in healthy, young, individuals with SARS-CoV-2 infections.

OBJECTIVES: To identify predictors of poor prognosis in previously healthy young individuals admitted to hospital with coronavirus disease 2019 (COVID-19). METHODS: We studied a cohort of patients hospitalized with COVID-19. All patients without co-morbidities, without usual treatments and ≤65 years old were selected from an international registry (HOPE-COVID-19, NCT04334291). We focused on baseline variables-symptoms and signs at admission-to analyse risk factors for poor prognosis. The primary end point was a composite of major adverse clinical events during hospitalization including mortality, mechanical ventilation, high-flow nasal oxygen therapy, prone, sepsis, systemic inflammatory response syndrome and embolic events. RESULTS: Overall, 773 healthy young patients were included. The primary composite end point was observed in 29% (225/773) and the overall mortality rate was 3.6% (28/773). In the combined event group, 75% (168/225) of patients were men and the mean age was 49 (±11) years, whereas in the non-combined event group, the prevalence of male gender was 43% (238/548) and the mean age was 42 (±13) years (p < 0.001 for both). On admission, respiratory insufficiency and cough were described in 51.4% (114/222) and 76% (170/223) of patients, respectively, in the combined event group, versus 7.9% (42/533) and 56% (302/543) of patients in the other group (p < 0.001 for both). The strongest independent predictor for the combined end point was desaturation (Spo2 <92%) (OR 5.40; 95% CI 3.34-8.75; p < 0.001), followed by tachypnoea (OR 3.17; 95% CI 1.93-5.21; p < 0.001), male gender (OR 3.01; 95% CI 1.96-4.61; p < 0.001) and pulmonary infiltrates on chest X-ray at admission (OR 2.21; 95% CI 1.18-4.16; p 0.014). CONCLUSIONS: Major adverse clinical events were unexpectedly high considering the baseline characteristics of the cohort. Signs of respiratory compromise at admission and male gender, were predictive for poor prognosis among young healthy patients hospitalized with COVID-19.

Development of atrioventricular and intraventricular conduction disturbances in patients undergoing transcatheter aortic valve replacement with new generation self-expanding valves: A real world multicenter analysis.

BACKGROUND: High degree cardiac conduction disturbances (HDCD) remain a major complication after transcatheter aortic valve replacement (TAVR), especially with self-expandable valves (SEV). Our aim was to investigate peri-procedural and in-hospital modification of atrioventricular and intracardiac conduction associated to new generation SEV implantation, and the development of new HDCD resulting in permanent pacemaker implantation (PPM) in patients undergoing TAVR. METHODS AND RESULTS: Three-hundred forty-four consecutive patients with severe aortic stenosis who underwent TAVR with a new generation SEV [Evolut-R/Pro (n = 130), Acurate-neo (n = 79), Portico (n = 75) and Allegra (n = 60)] were included. An analysis of baseline, post-TAVR and pre-discharge ECG and procedural aspects were centrally performed. A significant increase in baseline PR interval (169.6 ± 28.2 ms) and QRS complex width (101.7 ± 25.9 ms) was noted immediately post-TAVR (188.04 ± 34.49; 129.55 ± 30.02 ms), with a partial in-hospital reversal (179.4 ± 30.1; 123.06 ± 30.94 ms), resulting in a net increase at hospital discharge of 12.6 ± 38.8 ms and 21.4 ± 31.6 ms (p < 0.001), respectively. The global incidence of new onset persistent HDCD at hospital discharge was 46.3%, with 17.7% of patients requiring PPM. Independent predictors of new onset HCDC at hospital discharge were valve recapture (OR: 2.8; 95% IC: 1.1-7.2, p = 0.033) and implantation depth ≥ 6 mm (OR: 1.9 05% IC 1.1-3.3, p = 0.015), while higher implantation (<3 mm (OR: 0.3, 95% IC 0.1-0.7, p = 0.014) and use of Acurate-Neo valve (OR: 0.4; 95% IC 0.2-0.8, p = 0.009) were protective factor. CONCLUSIONS: New generation self-expanding aortic valves were associated with a significant increase in PR and QRS interval at hospital discharge leading to a very high rate of HDCD. While valve recapture and implantation depth were independent predictors for the occurrence of HDCD, use of Accurate-Neo valve was a protective factor.

Antiplatelet therapy and outcome in COVID-19: the Health Outcome Predictive Evaluation Registry.

BACKGROUND: Standard therapy for COVID-19 is continuously evolving. Autopsy studies showed high prevalence of platelet-fibrin-rich microthrombi in several organs. The aim of the study was therefore to evaluate the safety and efficacy of antiplatelet therapy (APT) in hospitalised patients with COVID-19 and its impact on survival. METHODS: 7824 consecutive patients with COVID-19 were enrolled in a multicentre international prospective registry (Health Outcome Predictive Evaluation-COVID-19 Registry). Clinical data and in-hospital complications were recorded. Data on APT, including aspirin and other antiplatelet drugs, were obtained for each patient. RESULTS: During hospitalisation, 730 (9%) patients received single APT (93%, n=680) or dual APT (7%, n=50). Patients treated with APT were older (74±12 years vs 63±17 years, p<0.01), more frequently male (68% vs 57%, p<0.01) and had higher prevalence of diabetes (39% vs 16%, p<0.01). Patients treated with APT showed no differences in terms of in-hospital mortality (18% vs 19%, p=0.64), need for invasive ventilation (8.7% vs 8.5%, p=0.88), embolic events (2.9% vs 2.5% p=0.34) and bleeding (2.1% vs 2.4%, p=0.43), but had shorter duration of mechanical ventilation (8±5 days vs 11±7 days, p=0.01); however, when comparing patients with APT versus no APT and no anticoagulation therapy, APT was associated with lower mortality rates (log-rank p<0.01, relative risk 0.79, 95% CI 0.70 to 0.94). On multivariable analysis, in-hospital APT was associated with lower mortality risk (relative risk 0.39, 95% CI 0.32 to 0.48, p<0.01). CONCLUSIONS: APT during hospitalisation for COVID-19 could be associated with lower mortality risk and shorter duration of mechanical ventilation, without increased risk of bleeding. TRIAL REGISTRATION NUMBER: NCT04334291.

Miltefosine: A Miracle Drug for Meningoencephalitis Caused by Free-Living Amoebas.

Meningoencephalitis caused by free-living amoebas (FLA) has a high mortality rate, and most treatments are ineffective. FLA includes Naegleria, Fowleri, Acanthamoeba, and Balamuthia mandrillaris (M). We explore the use of miltefosine in the treatment of one of these infections. The concerning mortality of the infection obligates us to look for more effective treatments for meningoencephalitis caused by FLA. During this review, we will consolidate the knowledge of using miltefosine in these three infections. We will investigate the mechanism by which the drug is effective in these infections as well. After this comprehensive review, we should assess if miltefosine improves the mortality and prognosis of the infection with the information collected. We used a Medical Subject Headings (MeSH) search on PubMed. Inclusion criteria included papers written in the English language and human subjects research for the past 25 years. Until today, there are no definitive guidelines to be followed when treating such patients. However, miltefosine has demonstrated promising results. Miltefosine decreases the usual mortality rate in the three infections; however, there are few reports due to the low frequency of these infections. Almost all cases we documented have survived. More information needs to be gathered for the use of miltefosine for these infections.

Strategies for cancer gene-delivery improvement by non-viral vectors.

Lack of selectivity together with severe side effects in conventional cancer treatment have afforded the development of new strategies based on gene therapy. Nowadays, gene therapy is employed through both viral and non-viral vectors. In spite of the high transfection activity of viral vectors, some drawbacks have pointed out to non-viral vectors as a safer alternative. To overcome low efficiency as well as other issues associated with the use of non-viral vectors, complexes formed by lipids and polymers with DNA, named lipoplexes and polyplexes respectively, have been modified in order to improve its features. Suitability of cancer gene therapy also requires the capacity to distinguish between normal and tumoral cells. This requirement has been solved by the addition of specific ligands that enable receptor binding and subsequent endocytosis. In this article we review the most recent approaches in structure modification of non-viral vectors through different methods comprising conjugation, addition of helper lipids or changes in design and synthesis as well as the strategy based on exploiting receptors that are usually overexpressed in malignancies. Such improvements confer specificity, efficient gene delivery, condensation, protection of DNA and low levels of toxicity avoiding off-target effects which turn into a potential tool to treat cancer.

Sepsis of Patients Infected by SARS-CoV-2: Real-World Experience From the International HOPE-COVID-19-Registry and Validation of HOPE Sepsis Score.

Background: Patients with sepsis with a concomitant coronavirus (COVID-19) infection are related to a high morbidity and mortality rate. We investigated a large cohort of patients with sepsis with a concomitant COVID-19, and we developed a risk score for the estimation of sepsis risk in COVID-19. Methods: We conducted a sub-analysis from the international Health Outcome Predictive Evaluation Registry for COVID-19 (HOPE-COVID-19-Registry, NCT04334291). Out of 5,837 patients with COVID-19, 624 patients were diagnosed with sepsis according to the Sepsis-3 International Consensus. Results: In multivariable analysis, the following risk factors were identified as independent predictors for developing sepsis: current smoking, tachypnoea (>22 breath per minute), hemoptysis, peripheral oxygen saturation (SpO2) <92%, blood pressure (BP) (systolic BP <90 mmHg and diastolic BP <60 mmHg), Glasgow Coma Scale (GCS) <15, elevated procalcitonin (PCT), elevated troponin I (TnI), and elevated creatinine >1.5 mg/dl. By assigning odds ratio (OR) weighted points to these variables, the following three risk categories were defined to develop sepsis during admission: low-risk group (probability of sepsis 3.1-11.8%); intermediate-risk group (24.8-53.8%); and high-risk-group (58.3-100%). A score of 1 was assigned to current smoking, tachypnoea, decreased SpO2, decreased BP, decreased GCS, elevated PCT, TnI, and creatinine, whereas a score of 2 was assigned to hemoptysis. Conclusions: The HOPE Sepsis Score including nine parameters is useful in identifying high-risk COVID-19 patients to develop sepsis. Sepsis in COVID-19 is associated with a high mortality rate.

Mortality risk assessment in Spain and Italy, insights of the HOPE COVID-19 registry.

Recently the coronavirus disease (COVID-19) outbreak has been declared a pandemic. Despite its aggressive extension and significant morbidity and mortality, risk factors are poorly characterized outside China. We designed a registry, HOPE COVID-19 (NCT04334291), assessing data of 1021 patients discharged (dead or alive) after COVID-19, from 23 hospitals in 4 countries, between 8 February and 1 April. The primary end-point was all-cause mortality aiming to produce a mortality risk score calculator. The median age was 68 years (IQR 52-79), and 59.5% were male. Most frequent comorbidities were hypertension (46.8%) and dyslipidemia (35.8%). A relevant heart or lung disease were depicted in 20%. And renal, neurological, or oncological disease, respectively, were detected in nearly 10%. Most common symptoms were fever, cough, and dyspnea at admission. 311 patients died and 710 were discharged alive. In the death-multivariate analysis, raised as most relevant: age, hypertension, obesity, renal insufficiency, any immunosuppressive disease, 02 saturation < 92% and an elevated C reactive protein (AUC = 0.87; Hosmer-Lemeshow test, p > 0.999; bootstrap-optimist: 0.0018). We provide a simple clinical score to estimate probability of death, dividing patients in four grades (I-IV) of increasing probability. Hydroxychloroquine (79.2%) and antivirals (67.6%) were the specific drugs most commonly used. After a propensity score adjustment, the results suggested a slight improvement in mortality rates (adjusted-ORhydroxychloroquine 0.88; 95% CI 0.81-0.91, p = 0.005; adjusted-ORantiviral 0.94; 95% CI 0.87-1.01; p = 0.115). COVID-19 produces important mortality, mostly in patients with comorbidities with respiratory symptoms. Hydroxychloroquine could be associated with survival benefit, but this data need to be confirmed with further trials. Trial Registration: NCT04334291/EUPAS34399.

[Importance of breastfeeding in the prevalence of metabolic syndrome and degree of childhood obesity]. / Importancia de la lactancia materna en la prevalencia de síndrome metabólico y en el grado de obesidad infantil.

OBJECTIVES: To evaluate the relationship between breastfeeding and the prevalence of obesity and metabolic syndrome in a group of obese children and adolescents. MATERIAL AND METHODS: We performed a retrospective study in obese children and adolescents treated at the Endocrinology and Nutrition Service of the Hospital de Getafe (Madrid). The variables studied were age, sex, height, weight, body mass index (BMI), waist circumference, waist-height ratio, blood pressure, triglycerides, high-density lipoprotein and fasting glucose. Information was also collected on food received in the first months of life. Breastfeeding was defined as feeding with maternal milk for at least 3 months. The SPSS v.15 statistical package was used. RESULTS: A total of 126 patients with obesity were recruited (71 boys and 55 girls) with a mean age of 11.94 +/- 3.12 years. Of these, 117 (92.86%) were morbidly obese (BMI > 97th percentile for age and sex). All patients had a waist circumference > 90th percentile for age and sex. Of the 126 patients evaluated, 36.8% were breastfed for more than 3 months and 63.2% were fed with artificial milk only. Compared with patients fed with artificial milk, those who were breast fed had a lower BMI (31.53 +/- 5.77 vs 32.08 +/- 6.78) and lower waist circumference (95.02 +/- 3.4 vs. 95.69 +/- 3.2 cm), although this difference was not statistically significant. The prevalence of metabolic syndrome in the study population was 19.8%. Within this group, 64% had not been breast fed compared with 36% who had been fed with artificial milk. CONCLUSIONS: Breast feeding for at least 3 months was associated with lower levels of obesity, smaller waist circumference and fewer complications related to metabolic syndrome in childhood and adolescence. Sixty-four percent of children with complete metabolic syndrome had received artificial feeding. Further studies are needed to ascertain the impact of breastfeeding on the development of obesity and cardiometabolic risk.

Rapid peroxynitrite reduction by human peroxiredoxin 3: Implications for the fate of oxidants in mitochondria.

Mitochondria are main sites of peroxynitrite formation. While at low concentrations mitochondrial peroxynitrite has been associated with redox signaling actions, increased levels can disrupt mitochondrial homeostasis and lead to pathology. Peroxiredoxin 3 is exclusively located in mitochondria, where it has been previously shown to play a major role in hydrogen peroxide reduction. In turn, reduction of peroxynitrite by peroxiredoxin 3 has been inferred from its protective actions against tyrosine nitration and neurotoxicity in animal models, but was not experimentally addressed so far. Herein, we demonstrate the human peroxiredoxin 3 reduces peroxynitrite with a rate constant of 1 × 107 M-1 s-1 at pH 7.8 and 25 °C. Reaction with hydroperoxides caused biphasic changes in the intrinsic fluorescence of peroxiredoxin 3: the first phase corresponded to the peroxidatic cysteine oxidation to sulfenic acid. Peroxynitrite in excess led to peroxiredoxin 3 hyperoxidation and tyrosine nitration, oxidative post-translational modifications that had been previously identified in vivo. A significant fraction of the oxidant is expected to react with CO2 and generate secondary radicals, which participate in further oxidation and nitration reactions, particularly under metabolic conditions of active oxidative decarboxylations or increased hydroperoxide formation. Our results indicate that both peroxiredoxin 3 and 5 should be regarded as main targets for peroxynitrite in mitochondria.

Chemistry and Redox Biology of Mycothiol.

SIGNIFICANCE: Mycothiol (MSH, AcCys-GlcN-Ins) is the main low-molecular weight (LMW) thiol of most Actinomycetes, including the human pathogen Mycobacterium tuberculosis that affects millions of people worldwide. Strains with decreased MSH content show increased susceptibilities to hydroperoxides and electrophilic compounds. In M. tuberculosis, MSH modulates the response to several antituberculosis drugs. Enzymatic routes involving MSH could provide clues for specific drug design. Recent Advances: Physicochemical data argue against a rapid, nonenzymatic reaction of MSH with oxidants, disulfides, or electrophiles. Moreover, exposure of the bacteria to high concentrations of two-electron oxidants resulted in protein mycothiolation. The recently described glutaredoxin-like protein mycoredoxin-1 (Mrx-1) provides a route for catalytic reduction of mycothiolated proteins, protecting critical cysteines from irreversible oxidation. The description of MSH/Mrx-1-dependent activities of peroxidases helped to explain the higher susceptibility to oxidants observed in Actinomycetes lacking MSH. Moreover, the first mycothiol-S-transferase, member of the DinB superfamily of proteins, was described. In Corynebacterium, both the MSH/Mrx-1 and the thioredoxin pathways reduce methionine sulfoxide reductase A. A novel tool for in vivo imaging of the MSH/mycothiol disulfide (MSSM) status allows following changes in the mycothiol redox state during macrophage infection and its relationship with antibiotic sensitivity. CRITICAL ISSUES: Redundancy of MSH with other LMW thiols is starting to be unraveled and could help to rationalize the differences in the reported importance of MSH synthesis observed in vitro versus in animal infection models. FUTURE DIRECTIONS: Future work should be directed to establish the structural bases of the specificity of MSH-dependent enzymes, thus facilitating drug developments. Antioxid. Redox Signal. 28, 487-504.

Nivel de conocimiento sobre parasitosis intestinal en madres, padres y cuidadores, Cotopaxi, Ecuador

Introducción: La parasitosis intestinal constituye un problema de salud a nivel mundial. Sus complicaciones en niños menores de 5 años abordan tanto la esfera física como social y psicológica; al ser un problema de salud es necesario mantener un adecuado conocimiento sobre sus características. Objetivo: Identificar el nivel de conocimiento que sobre la parasitosis tienen los padres y cuidadores de niñas y niños menores de cinco años que asisten al Centro de Salud Tipo C Lasso, Cotopaxi, diciembre 2021-febrero 2022. Métodos: Investigación básica, no experimental, descriptiva y de corte transversal que tuvo como universo a 156 padres y cuidadores de niños menores de 5 años. La muestra quedó conformada por 96 personas. Se aplicó una encuesta para identificar las características generales de las personas y su nivel de conocimiento relacionado con algunos elementos referentes a la parasitosis. Resultados: Promedio de edad de 27,18 años; predominio de personas femeninas (85,42 %); con nivel de escolaridad de secundaria (76,04 %), amas de casa (83,33 %) y con nivel de ingresos bajos (88,54 %). Se identificaron niveles de conocimientos inadecuados en relación al tipo de parásitos (62,50 %), manifestaciones clínicas (85,42 %), complicaciones (76,04 %) y prevención (60,42 %). Solo en relación a las formas de transmisión del parasitismo se identificó un nivel de conocimiento predominante adecuado (63,54 %). Conclusiones: Los resultados del estudio muestran que el nivel de conocimiento predominante en los padres y cuidadores de los niños y niñas de las comunidades Tanicuchí, Guaytacama y Pastocalle sobre la parasitosis intestinal es inadecuado.

Introduction: Intestinal parasitosis is a global health problem. Its complications in children under 5 years of age address both the physical and social and psychological spheres; Being a health problem, it is necessary to maintain an adequate knowledge of its characteristics. Objective: To identify the level of knowledge that parents and caregivers of children under five years of age who attend the Type C Lasso Health Center, Cotopaxi, have on parasitism, December 2021-February 2022. Methods: Basic, non-experimental, descriptive and cross-sectional research that included 156 parents and caregivers of children under 5 years of age. The sample was made up of 96 people. A survey was applied to identify the general characteristics of the people and their level of knowledge related to some elements related to parasitosis. Results: Average age of 27.18 years; predominance of female persons (85.42 %); with a secondary education level (76.04 %), housewives (83.33%) and with a low income level (88.54 %). Inadequate levels of knowledge were identified in relation to the type of parasites (62.50 %), clinical manifestations (85.42 %), complications (76.04 %) and prevention (60.42 %). Only in relation to the forms of transmission of parasitism, a predominantly adequate level of knowledge was identified (63.54 %). Conclusions: The results of the study show that the predominant level of knowledge in the parents and caregivers of the children of the Tanicuchí, Guaytacama and Pastocalle communities about intestinal parasitism is inadequate.

Síndrome ansioso depresivo en pacientes con enfermedades reumáticas

Introducción: Las enfermedades reumáticas son conocidas por su carácter sistémico, afectando distintos órganos y sistemas de órganos. La afectación neuropsiquiátrica es frecuente y condiciona discapacidad adicional. El síndrome ansioso depresivo constituye una de las principales expresiones de afectación del sistema nervioso. Objetivo: Describir las características clínicas y epidemiológicas de presentación del síndrome ansioso depresivo en pacientes con enfermedades reumáticas. Métodos: Se realizó una investigación básica, con diseño no experimental, descriptivo, transversal y de campo. El universo estuvo constituido por 557 pacientes con diagnóstico de enfermedades reumáticas atendidos en el Hospital Clínica Metropolita de la ciudad de Riobamba durante el periodo enero 2020 - diciembre 2022. La muestra quedó constituida por un total de 229 pacientes. Resultados: Promedio de edad de 53,48 años, predominio de pacientes femeninas (72,49 %) y con comorbilidades asociadas (56,77 %). El hipotiroidismo (39,23 %), la hipertensión arterial (33,08 %) y la diabetes mellitus (21,54 %) fueron las comorbilidades más representadas. La artritis reumatoide (67,68 %) fue la enfermedad reumática que con mayor frecuencia fue identificada. El 42,36 % de los pacientes presentó manifestaciones de ansiedad y el 36,68 % manifestaciones clínicas compatibles con depresión. Conclusiones: Se identificaron porcentajes elevados de pacientes con enfermedades reumáticas y manifestaciones clínicas compatibles con ansiedad y depresión; en los pacientes con lupus eritematoso sistémico fue donde se identificó un mayor porcentaje de presentación de estas manifestaciones.

Introduction: Rheumatic diseases are known for their systemic nature, affecting different organs and organ systems. Neuropsychiatric involvement is frequent and conditions additional disability. Anxious-depressive syndrome is one of the main expressions of affectation of the nervous system. Objective: To describe the clinical and epidemiological characteristics of the presentation of the anxious-depressive syndrome in patients with rheumatic diseases. Methods: A basic investigation was carried out, with a non-experimental, descriptive, cross-sectional and field design. The universe consisted of 557 patients diagnosed with rheumatic diseases treated at the Hospital Clinica Metropolitana in the city of Riobamba during the period January 2020 - December 2022. The sample was made up of a total of 229 patients. Results: Average age of 53.48 years, predominance of female patients (72.49 %) and with associated comorbidities (56.77 %). Hypothyroidism (39.23%), arterial hypertension (33.08 %) and diabetes mellitus (21.54 %) were the most represented comorbidities. Rheumatoid arthritis (67.68 %) was the rheumatic disease that was most frequently identified. 42.36 % of the patients presented manifestations of anxiety and 36.68 % clinical manifestations compatible with depression. Conclusions: High percentages of patients with rheumatic diseases and clinical manifestations compatible with anxiety and depression were identified; a higher percentage of presentation of these manifestations was identified in patients with systemic lupus erythematosus.

El RCP Lázaro como alternativa al perfeccionamiento de la reanimación cardiopulmonar

Introducción: el paro cardiorrespiratorio de la situación más peligrosa que puede enfrentar un ser humano; para su recuperación se necesita actuar inmediatamente y de forma correcta. El tiempo de comienzo de la reanimación cardiopulmonar es vital para lograr la supervivencia del paciente. Objetivo: socializar las ventajas que ofrece el RCP Lázaro en la asistencia de urgencia a pacientes con parada cardiorrespiratoria. Métodos: se realizó una investigación aplicada, con diseño experimental que parte de la identificación de una necesidad de salud y se procede a la ideación, diseño y creación de un prototipo de equipo de reanimación cardiopulmonar asistida denominado RCP Lázaro. Se confeccionó un equipo multidisciplinario que permitió obtener los planos mecánicos, ergonómicos y eléctricos que permiten un funcionamiento adecuado bajo el mando de un software diseñado específicamente para el equipo. Después de terminada la fase de modelación y diseño se realizaron pruebas funcionales que finalmente fueron superadas. Resultado: El RCP Lázaro es un prototipo superior en varios sentidos a los modelos previos existentes en el mercado. Presenta un diseño ergonómico que permite un mejor ajuste a la complexión física de los pacientes; puede ser utilizado en niños y adultos; presenta posibilidad de acople de desfibrilador; presenta 4 ciclos de compresiones/respiraciones; reajustable la altura del pistón para garantizar adaptación previa a las compresiones torácicas; batería de 6 horas de duración, entendible en modo ahorro de energía hasta 8 horas y facilidades para ensamblaje, transporte y acoplamiento al paciente. Conclusiones: El RCP Lázaro paso de forma satisfactoria las pruebas de validación, mostrando parámetros de funcionamiento adecuado para la función que está diseñada; corresponde entonces proceder a la prueba de campo antes de iniciar su producción en serie.

Introduction: cardiorespiratory arrest is the most dangerous situation that a human being can face; for your recovery you need to act immediately and correctly. The start time of cardiopulmonary resuscitation is vital to achieve patient survival. Objective: to socialize the advantages offered by Lazarus CPR in emergency care for patients with cardiorespiratory arrest. Methods: an applied investigation was carried out, with an experimental design that starts from the identification of a health need and proceeds to the ideation, design and creation of a prototype of assisted cardiopulmonary resuscitation equipment called Lazarus CPR. A multidisciplinary team was created that allowed obtaining the mechanical, ergonomic and electrical plans that allow proper operation under the command of software specifically designed for the equipment. After the modeling and design phase was completed, functional tests were carried out that were finally passed. Result: The Lazarus CPR is a superior prototype in several ways to the previous models on the market. It presents an ergonomic design that allows a better adjustment to the physical complexion of the patients; it can be used in children and adults; presents the possibility of defibrillator coupling; presents 4 cycles of compressions/breaths; the height of the piston can be readjusted to guarantee adaptation prior to chest compressions; 6-hour battery life, understandable in energy saving mode up to 8 hours and facilities for assembly, transport and coupling to the patient. Conclusions: The Lazarus CPR satisfactorily passed the validation tests, showing adequate operating parameters for the function that is designed; It is then appropriate to proceed to the field test before starting its production in series.