WITHDRAWN: Photobuforin II, a fluorescent photoswitchable peptide.

The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1016/j.bbadva.2023.100106. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/policies/article-withdrawal.

Photobuforin II, a fluorescent photoswitchable peptide.

Antimicrobial peptide buforin II translocates across the cell membrane and binds to DNA. Its sequence is identical to a portion of core histone protein H2A making it a highly charged peptide. Buforin II has a proline residue in the middle of its sequence that creates a helix-hinge-helix motif which has been found to play a key role in its ability to translocate across the cell membrane. To explore the structure-function relationship of this proline residue this study has replaced P11 with a meta-substituted azobenzene amino acid (Z). The resultant peptide, photobuforin II, retained the secondary structure and membrane activity of the naturally occurring peptide while gaining new spectroscopic properties. Photobuforin II can be isomerized from its trans to cis isomer upon irradiation with ultra-violet (UV) light and from its cis to trans isomer upon irradiation with visible (VL). Photobuforin II is also fluorescent with an emission peak at 390 nm. The intrinsic fluorescence of the peptide was used to determine binding to the membrane and to DNA. VL-treated photobuforin II has a 2-fold lower binding constant compared to UV-treated photobuforin and causes 11-fold more membrane leakage in 3:1 POPC:POPG vesicles. Photobuforin II provides insights into the importance of structure function relationships in membrane active peptides while also demonstrating that azobenzene can be used in certain peptide sequences to produce intrinsic fluorescence.

Electro-Acupuncture Effects Measured by Functional Magnetic Resonance Imaging-A Systematic Review of Randomized Clinical Trials.

INTRODUCTION: Electro-acupuncture, an innovative adaptation of traditional acupuncture, combines electrical stimulation with acupuncture needles to enhance therapeutic effects. While acupuncture is widely used, its biological mechanisms remain incompletely understood. Recent research has explored the neurophysiological aspects of acupuncture, particularly through functional magnetic resonance imaging (fMRI) to investigate its effects on brain activity. METHODS: In this systematic review, we conducted an extensive search for randomized clinical trials examining electro-acupuncture effects measured by fMRI. We employed strict eligibility criteria, quality assessment, and data extraction. RESULTS: Five studies met our inclusion criteria and were analyzed. The selected studies investigated electro-acupuncture in various medical conditions, including carpal tunnel syndrome, fibromyalgia, Crohn's disease, irritable bowel syndrome, and obesity. Notably, electro-acupuncture was found to modulate brain activity and connectivity in regions associated with pain perception, emotional regulation, and cognitive processing. These findings align with the holistic approach of traditional Chinese medicine, emphasizing the interconnectedness of body and mind. DISCUSSION: In carpal tunnel syndrome, electro-acupuncture at both local and distal sites showed neurophysiological improvements, suggesting distinct neuroplasticity mechanisms. In fibromyalgia, somatosensory electro-acupuncture correlated with reduced pain severity, enhanced brain connectivity, and increased gamma-aminobutyric acid levels. For Crohn's disease, electro-acupuncture influenced the homeostatic afferent processing network, potentially mitigating gut inflammation. Electro-acupuncture for irritable bowel syndrome led to decreased activity in the anterior cingulate cortex, offering pain relief, while electro-acupuncture for obesity impacted brain regions associated with dietary inhibition and emotional regulation. CONCLUSION: This systematic review provides evidence that electro-acupuncture can positively impact a range of medical conditions, possibly by modulating brain activity and connectivity. While the quality of the reviewed studies is generally good, further research with larger sample sizes and longer-term assessments is needed to better understand the mechanisms and optimize electro-acupuncture protocols for specific health conditions. The limited number of studies in this review emphasizes the need for broader investigations in this promising field. The research protocol was registered in PROSPERO (CRD42023465866).

Mental Health Benefits of a Traditional Vegetative Biofeedback Therapy Online Program during the COVID-19 Lockdown: A Controlled Trial.

Mandatory lockdown resulting from a pandemic may be effective against the physical impact of the virus; however, the resulting mental strains can lead to the development of several mental disturbances. Taijiquan and Qigong are considered traditional vegetative biofeedback therapies that allow the practitioner to control the functions and processes of the body through specific movements or stances, breathing techniques, and meditative exercises. This study aims to understand if these techniques can be applied as an online distance therapeutic option to reduce the psychological impact of home confinement and social distancing. Sixty-four participants were recruited and allocated to three groups. The experienced and novice Taijiquan and Qigong participants' groups received the intervention for 8 weeks while the control group did not receive any intervention. The outcomes were psychological well-being and psychological distress levels and were assessed by the Mental Health Inventory and a written interview. The experienced Taijiquan and Qigong participants achieved significant improvements in psychological well-being and psychological distress. Novice Taijiquan and Qigong participants achieved a significant improvement in anxiety levels. Additionally, the control group showed a significant decrease in psychological well-being. This study suggests that this distance online program of Taijiquan and Qigong is feasible and may benefit the mental health of participants during a lockdown.

Perfil sociodemográfico y clínico de las personas atendidas en el programa “Código Riesgo Suicidio de Cataluña” / Sociodemographic and clinical profile of people attended in the “Catalonia Suicide Risk Code” program

Introducción. El suicidio es un problema de un gran impacto en la salud pública. Por esta razón, el protocolo del Código de Riesgo Suicidio se desarrolló en Cataluña en 2015. El objetivo de este trabajo es examinar el perfil sociodemográfico y clínico de los pacientes para los que se activó este protocolo entre 2016 y 2017 en nuestra población de referencia. Metodología. Estudio descriptivo retrospectivo de datos registrados sobre el Código de Riesgo de Suicidio de nuestra población atendida (n = 246 en 2016 y n = 391 en 2017) en los centros de salud mental de adultos del Parc Sanitari Sant Joan de Déu que han sido previamente atendidos en urgencias de alguno de los hospitales del área de referencia. Resultados. El perfil más frecuente en 2016 y 2017 fue el de una mujer entre 40 y 55 años con acontecimientos vitales estresantes. El método más utilizado fue el abuso de sustancias. Conclusiones. Los datos sugieren que la tarea asistencial debería ajustarse al perfil de mayor riesgo observado para nuestra población de referencia, considerando los acontecimientos vitales estresantes como factor de riesgo significativos que deben ser considerados.(AU)

Introduction. Suicide is an issue with a great impact on public health. For this reason, the Catalonia Suicide Risk Code (CSRC) protocol was developed in 2015. The aim of this paper is to examine the sociodemographic and clinical profile of patients for whom this protocol was activated between 2016 and 2017 in our reference population. Methodology. Retrospective descriptive study of recorded data on Suicide Risk Code of our population attended (n=246 in 2016 and n=391 in 2017) in the mental health outpatient services of the Parc Sanitari Sant Joan de Déu being attended previously in the emergency services of any of the hospitals of reference. Results. The most prevalent profile in both 2016 and 2017 was woman between 40 and 55 years of age with stressful life events. The most prevalent method used was substance abuse. Conclusions. The data suggest that the health care task should be adjusted to the highest risk profile observed in our reference population, considering stressful live events as significant risk factors which should be taken into account.(AU)

Substituting azobenzene for proline in melittin to create photomelittin: A light-controlled membrane active peptide.

In this article we present the synthesis and characterization of a new form of the membrane active peptide melittin: photomelittin. This peptide was created by substituting the proline residue in melittin for a synthetic azobenzene amino acid derivative. This azobenzene altered the membrane activity of the peptide while retaining much of the secondary structure. Furthermore, the peptide demonstrates added light-dependent activity in leakage assays. There is a 1.5-fold increase in activity when exposed to UV light as opposed to visible light. The peptides further exhibit light-dependent hemolytic activity against human red blood cells. This will enable future studies optimizing photomelittin and other azobenzene-containing membrane active peptides for uses in medicine, drug delivery, and other biotechnological applications.

Applications and evolution of melittin, the quintessential membrane active peptide.

Melittin, the main venom component of the European Honeybee, is a cationic linear peptide-amide of 26 amino acid residues with the sequence: GIGAVLKVLTTGLPALISWIKRKRQQ-NH2. Melittin binds to lipid bilayer membranes, folds into amphipathic α-helical secondary structure and disrupts the permeability barrier. Since melittin was first described, a remarkable array of activities and potential applications in biology and medicine have been described. Melittin is also a favorite model system for biophysicists to study the structure, folding and function of peptides and proteins in membranes. Melittin has also been used as a template for the evolution of new activities in membranes. Here we overview the rich history of scientific research into the many activities of melittin and outline exciting future applications.

Risk factors for ischemic antiphospholipid syndrome: A case-control study.

OBJECTIVE: The objective of this study was to identify clinical and laboratory risk factors for ischemic stroke (IS) in primary antiphospholipid syndrome (APS) patients. MATERIALS AND METHODS: We performed a case-control study with consecutive primary APS patients divided into two groups, those who presented with IS, vs. those with no history of stroke. Demographics, vascular risk factors, therapeutic approaches, laboratory, imaging and functional outcomes were recorded. RESULTS: Fifty-three confirmed primary APS patients with IS and sixty-six non-stroke primary APS controls were recruited. Most patients were female (65.5 %), with a median age of 33 years. The main vascular risk factors for primary APS-associated stroke were hypertension (11.3 %), diabetes (11.3 %) and hypercholesterolemia (9.4 %). Among patients with stroke, median NIHSS score was 6; 15.1 % of these patients presented a recurrent stroke, and 88.8 % had a good functional outcome at the final follow-up. Positive lupus anticoagulant (OR = 6.1, 95 %CI 2.7-13.5), anti-ß2 glycoprotein IgG (OR = 3.6, 95 %CI 1.7-7.9), and anticardiolipin IgG (OR = 2.8, 95 %CI 1.3-5.9) were more prevalent in non-stroke primary APS, with a triple-positive antibody presence in 46.4 % of controls vs. 22.2 % of patients with stroke (OR = 3.0, 95 %CI 1.3-6.7). At the time of the index event (arterial or venous), 14 known primary APS patients were using vitamin K antagonists, but only 35.7 % of them had achieved therapeutic INR. CONCLUSION: Patients with primary APS and IS have similar vascular risk factors and lower antibody positivity than those with extracranial thrombosis.

The role of left atrial enlargement and age in the prediction of recurrence in embolic strokes of undetermined source.

Objectives: Left atrial disease is an independent risk factor for ischemic stroke and can be used to predict atrial fibrillation (AF). We examine whether left atrial enlargement (LAE) could predict stroke recurrence in patients with embolic stroke of undetermined source (ESUS). Materials and methods: Sixty-four patients with a confirmed diagnosis of ESUS were followed for a median of 22 months. Clinical data and echocardiogram findings were recorded. The echocardiogram interpretation was performed centrally and blindly. The Brown ESUS - AF score was used to categorize patients into high (human resource planning [HRP]: score > 2) and low-risk patients (non-HRP score 0-1). Stroke recurrence was the primary outcome. Results: The median age was 62 years (range: 22-85 years); and 33 (51.6%) were men. The median initial NIHSS score was three points (range: 0-27). Twelve (18.8%) patients were categorized as HRP. We found a significant tendency toward recurrence among HRP versus non-HRP patients. Three (25%) HRP versus 2 (3.8%) non-HRP experienced recurrence (OR: 8.3 95% CI 1.2-57; p=0.042); this association was related to severe atrial dilatation (OR: 14.5 95% CI 0.78-277, p = 0.02) and age > 75 years (OR: 12.7 95% CI 1.7-92.2, p = 0.03). We found no differences in recurrence in a univariate analysis. Conclusions: Patients with severe LAE who are 75 years old or older have a significant tendency to experience stroke recurrence.

Objetivos: La patología atrial izquierda es factor de riesgo independiente para infarto cerebral y puede utilizarse para predecir fibrilación auricular. Examinamos si el crecimiento aurícular izquierdo puede predecir recurrencia en pacientes con infarto embolico de origen indeterminado (ESUS). Materiales y métodos: Sesenta y cuatro pacientes con diagnóstico confirmado de ESUS fueron seguidos por una mediana de seguimiento de 22 meses. Registramos los datos clínicos y ecocardiográficos. La interpretación ecocardiográfica fue centralizada y cegada. La escala de Brown ESUS ­ AF fue utilizada para categorizar a los pacientes en riesgo alto (HRP puntaje > 2) y bajo riesgo (no-HRP: puntaje 0-1). El descenlace primario fue recurrencia de infarto cerebral. Resultados: Mediana de edad fue de 62 años (rango: 22-85 años); 33 (51.6%) fueron hombres. La mediana inicial de la escala de NIHSS fue de 3 putnos (rango de 0 a 27). 12 (18.8%) pacientes fueron de alto riesgo (HRP) y 52 (81.3%) de bajo riesgo (non- HRP). El grupo HRP mostró tendencia significatica hacia mayor recurrencia. Tres (25%) HRP versus 2 (3.8%) no-HRP experimentaron recurrencia (OR: 8.3 IC 95% 1.2-57; p = 0.042); esta asociación se relacionó con dilatación auricular severa (OR: 14.5 IC 95% 0.78-277, p = 0.02) y edad > 75 años (OR: 12.7 IC 95% 1.7-92.2, p = 0.03). En el análisis multivarioado, no encontramos significativas. Conclusiones: El crecimiento auricular izquierdo severo y la edad mayor de 75 años mostraron tendencia significativa a recurrencia de infarto cerebral.

The role of left atrial enlargement and age in the prediction of recurrence in embolic strokes of undetermined source / El papel del crecimiento auricular izquierdo y la edad como predictores de recurrencia en infarto cerebral embólicos de origen indeterminado

Abstract Objectives: Left atrial disease is an independent risk factor for ischemic stroke and can be used to predict atrial fibrillation (AF). We examine whether left atrial enlargement (LAE) could predict stroke recurrence in patients with embolic stroke of undetermined source (ESUS). Materials and methods: Sixty-four patients with a confirmed diagnosis of ESUS were followed for a median of 22 months. Clinical data and echocardiogram findings were recorded. The echocardiogram interpretation was performed centrally and blindly. The Brown ESUS – AF score was used to categorize patients into high (human resource planning [HRP]: score > 2) and low-risk patients (non-HRP score 0-1). Stroke recurrence was the primary outcome. Results: The median age was 62 years (range: 22-85 years); and 33 (51.6%) were men. The median initial NIHSS score was three points (range: 0-27). Twelve (18.8%) patients were categorized as HRP. We found a significant tendency toward recurrence among HRP versus non-HRP patients. Three (25%) HRP versus 2 (3.8%) non-HRP experienced recurrence (OR: 8.3 95% CI 1.2-57; p=0.042); this association was related to severe atrial dilatation (OR: 14.5 95% CI 0.78-277, p = 0.02) and age > 75 years (OR: 12.7 95% CI 1.7-92.2, p = 0.03). We found no differences in recurrence in a univariate analysis. Conclusions: Patients with severe LAE who are 75 years old or older have a significant tendency to experience stroke recurrence.

Resumen Objetivos: La patología atrial izquierda es factor de riesgo independiente para infarto cerebral y puede utilizarse para predecir fibrilación auricular. Examinamos si el crecimiento aurícular izquierdo puede predecir recurrencia en pacientes con infarto embolico de origen indeterminado (ESUS). Materiales y métodos: Sesenta y cuatro pacientes con diagnóstico confirmado de ESUS fueron seguidos por una mediana de seguimiento de 22 meses. Registramos los datos clínicos y ecocardiográficos. La interpretación ecocardiográfica fue centralizada y cegada. La escala de Brown ESUS – AF fue utilizada para categorizar a los pacientes en riesgo alto (HRP puntaje > 2) y bajo riesgo (no-HRP: puntaje 0-1). El descenlace primario fue recurrencia de infarto cerebral. Resultados: Mediana de edad fue de 62 años (rango: 22-85 años); 33 (51.6%) fueron hombres. La mediana inicial de la escala de NIHSS fue de 3 putnos (rango de 0 a 27). 12 (18.8%) pacientes fueron de alto riesgo (HRP) y 52 (81.3%) de bajo riesgo (non- HRP). El grupo HRP mostró tendencia significatica hacia mayor recurrencia. Tres (25%) HRP versus 2 (3.8%) no-HRP experimentaron recurrencia (OR: 8.3 IC 95% 1.2-57; p = 0.042); esta asociación se relacionó con dilatación auricular severa (OR: 14.5 IC 95% 0.78-277, p = 0.02) y edad > 75 años (OR: 12.7 IC 95% 1.7-92.2, p = 0.03). En el análisis multivarioado, no encontramos significativas. Conclusiones: El crecimiento auricular izquierdo severo y la edad mayor de 75 años mostraron tendencia significativa a recurrencia de infarto cerebral.

Synergies with and Resistance to Membrane-Active Peptides.

Membrane-active peptides (MAPs) have long been thought of as the key to defeating antimicrobial-resistant microorganisms. Such peptides, however, may not be sufficient alone. In this review, we seek to highlight some of the common pathways for resistance, as well as some avenues for potential synergy. This discussion takes place considering resistance, and/or synergy in the extracellular space, at the membrane, and during interaction, and/or removal. Overall, this review shows that researchers require improved definitions of resistance and a more thorough understanding of MAP-resistance mechanisms. The solution to combating resistance may ultimately come from an understanding of how to harness the power of synergistic drug combinations.

Cinnamic Derivatives as Antitubercular Agents: Characterization by Quantitative Structure-Activity Relationship Studies.

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains one of the top ten causes of death worldwide and the main cause of mortality from a single infectious agent. The upsurge of multi- and extensively-drug resistant tuberculosis cases calls for an urgent need to develop new and more effective antitubercular drugs. As the cinnamoyl scaffold is a privileged and important pharmacophore in medicinal chemistry, some studies were conducted to find novel cinnamic acid derivatives (CAD) potentially active against tuberculosis. In this context, we have engaged in the setting up of a quantitative structure-activity relationships (QSAR) strategy to: (i) derive through multiple linear regression analysis a statistically significant model to describe the antitubercular activity of CAD towards wild-type Mtb; and (ii) identify the most relevant properties with an impact on the antitubercular behavior of those derivatives. The best-found model involved only geometrical and electronic CAD related properties and was successfully challenged through strict internal and external validation procedures. The physicochemical information encoded by the identified descriptors can be used to propose specific structural modifications to design better CAD antitubercular compounds.

Alterações de neuropsicológicas decorrentes de substâncias psicoativas: prejuízos cognitivos e implicações para o tratamento / Neuropsychological alterations from psychoactive substances use: cognitive impairment and implications for treatment

O consumo abusivo de substâncias psicoativas (SPA) está associado a prejuízos no funcionamento das áreas frontais, especificamente do córtex pré-frontal sendo de grande importância o entendimento e descrição das alterações comportamentais, emocionais e cognitivas visando diagnóstico bem como prever o curso de tratamento adequado através da investigação neuropsicológica. Este trabalho teve o objetivo de identificar quais os impactos neuropsicológicos em decorrência do uso abusivo de substâncias psicoativas e analisar de que forma esses prejuízos influenciam no tratamento da dependência de substâncias psicoativas. A partir dos artigos analisados foi possível identificar a importância da avaliação neuropsicológica para o diagnóstico prognóstico do uso de substâncias psicoativas, além de identificar as alterações corticais (de córtex pré-frontal) afetadas pelo uso indevido de SPA bem como reflexo dessas alterações no desempenho e comportamento dos usuários de SPA. A realização desta pesquisa permite apontar que compreender esse contexto tem impacto direto no tratamento uma vez que as intervenções devem observar as capacidades e necessidades individuais dos usuários dos serviços de atenção objetivando a adesão ao tratamento e remissão dos sintomas. (AU)

Psychoactive substances (PAS) abusive use is associated with losses in the frontal areas function, specifically the prefrontal cortex. Thus the understanding and description of behavioral, emotional and cognitive changes aimed at diagnosing and predicting the course of appropriate treatment through neuropsychological research is of great importance. This work had the objective of identifying the Neuropsychological impacts from abusive use of psychoactive substances, and of examining how this impairment influences in the treatment of addiction to psychoactive substances. Based on the articles analyzed, it was possible to identify the importance of neuropsychological assessment for the prognostic diagnostic of psychoactive substances use, in addition to identify the cortical changes (prefrontal cortex) affected by the misuse of PAS, as well as the reflection of these changes on performance and behavior of PAS users. The results of this research show that understanding this context has a direct impact on the treatment, given the fact that interventions must observe the capacities and needs of individual users of care services aiming at adherence to treatment and remission of symptoms. (AU)

Programa de soporte a la primaria: Un análisis descriptivo y de concordancia diagnóstica entre médico/a de atención primaria y psicólogo/a / Program support to primary: A descriptive analysis and diagnostic concordance between primary care physician and psychologist

Objetivos: Describir las características del Programa de Soporte a la Primaria (PSP) y analizar la concordancia diagnóstica entre Médicos de Atención Primaria (MAP) y Psicólogos/as del programa. Metodología: Estudio descriptivo longitudinal realizado en 2010 en 7 CAPs de Barcelona. La muestra son 769 pacientes derivados a psicología. Se utilizan estadísticos descriptivos para analizar las variables sociodemográficas y la kappa de Cohen para valorar la concordancia. Resultados: El tiempo de espera medio entre derivación y primera visita es 28 días. La media de intervenciones por paciente es 3 visitas. Un 27% son dados de alta, un 20% abandonan. Existe una baja concordancia global entre MAP y Psicólogo/a. El diagnóstico más frecuentemente realizado por los MAP es Trastorno de Ansiedad. Los psicólogos/as diagnostican con igual frecuencia Trastornos Ansiosos (21%), Depresión (20.2%) y Trastornos Adaptativos (19.6%). Conclusiones: El PSP ofrece intervenciones breves y especializadas desde Atención Primaria. La baja concordancia indica la necesidad de aumentar espacios de interconsulta (AU)

Background: The objective is to describe characteristics of Program Support to Primary (PSP) and analyze diagnostic concordance between Primary Care Physicians (PCP) and psychologists. Method: A descriptive, longitudinal study conducted in 2010 in 7 Barcelona’s primary care centers. The sample of 769 patients referred to psychology (referral form issued by doctors). Descriptive statistics, Cohen’s kappa and percentage agreement were used to analyze demographic variables, to assess agreement. Results: The average waiting time between referral and first visit is 28 days. Mean interventions per patient is 3 visits. 27% of patients are discharged, 20% drop. It is a low overall concordance between PCP and psychologist, the most common diagnosis made by the PCP is anxiety disorder. Psychologists diagnosed with the same frequency anxiety disorders (21%), depression (20.2 %) and adaptive disorders (19.6 %). Conclusions: PSP offers brief and specialized interventions in Primary Care. Low concordance indicates a need to increase opportunities for communication between professionals through tools such as consultation (AU)

Molecular details of INH-C10 binding to wt KatG and Its S315T mutant.

Isoniazid (INH) is still one of the two most effective antitubercular drugs and is included in all recommended multitherapeutic regimens. Because of the increasing resistance of Mycobacterium tuberculosis to INH, mainly associated with mutations in the katG gene, new INH-based compounds have been proposed to circumvent this problem. In this work, we present a detailed comparative study of the molecular determinants of the interactions between wt KatG or its S315T mutant form and either INH or INH-C10, a new acylated INH derivative. MD simulations were used to explore the conformational space of both proteins, and results indicate that the S315T mutation did not have a significant impact on the average size of the access tunnel in the vicinity of these residues. Our simulations also indicate that the steric hindrance role assigned to Asp137 is transient and that electrostatic changes can be important in understanding the enzyme activity data of mutations in KatG. Additionally, molecular docking studies were used to determine the preferred modes of binding of the two substrates. Upon mutation, the apparently less favored docking solution for reaction became the most abundant, suggesting that S315T mutation favors less optimal binding modes. Moreover, the aliphatic tail in INH-C10 seems to bring the hydrazine group closer to the heme, thus favoring the apparent most reactive binding mode, regardless of the enzyme form. The ITC data is in agreement with our interpretation of the C10 alkyl chain role and helped to rationalize the significantly lower experimental MIC value observed for INH-C10. This compound seems to be able to counterbalance most of the conformational restrictions introduced by the mutation, which are thought to be responsible for the decrease in INH activity in the mutated strain. Therefore, INH-C10 appears to be a very promising lead compound for drug development.

Design, synthesis and biological evaluation of novel isoniazid derivatives with potent antitubercular activity.

The disturbing emergence of multidrug-resistant strains of Mycobacterium tuberculosis (Mtb) has been driving the scientific community to urgently search for new and efficient antitubercular drugs. Despite the various drugs currently under evaluation, isoniazid is still the key and most effective component in all multi-therapeutic regimens recommended by the WHO. This paper describes the QSAR-oriented design, synthesis and in vitro antitubercular activity of several potent isoniazid derivatives (isonicotinoyl hydrazones and isonicotinoyl hydrazides) against H37Rv and two resistant Mtb strains. QSAR studies entailed RFs and ASNNs classification models, as well as MLR models. Strict validation procedures were used to guarantee the models' robustness and predictive ability. Lipophilicity was shown not to be relevant to explain the activity of these derivatives, whereas shorter N-N distances and lengthy substituents lead to more active compounds. Compounds 1, 2, 4, 5 and 6, showed measured activities against H37Rv higher than INH (i.e., MIC ≤ 0.28 µM), while compound 9 exhibited a six fold decrease in MIC against the katG (S315T) mutated strain, by comparison with INH (i.e., 6.9 vs. 43.8 µM). All compounds were ineffective against H37RvINH (ΔkatG), a strain with a full deletion of the katG gene, thus corroborating the importance of KatG in the activation of INH-based compounds. The most potent compounds were also shown not to be cytotoxic up to a concentration 500 times higher than MIC.

QSAR based design of new antitubercular compounds: improved isoniazid derivatives against multidrug-resistant TB.

Tuberculosis (TB) is the second cause of death from a single infectious agent, the M. tuberculosis bacillus. Nearly two billion people are infected and about 8.7 million new cases and 1.4 million deaths were reported by the World Health Organization (WHO) in 2013. Despite the availability of effective treatment, the alarming emergence of multidrug resistant (MDR) strains (with 310.000 estimated cases in 2011 among notified patients with pulmonary TB), simultaneously resistant to the two most effective anti-TB drugs, isoniazid (INH) and rifampicin, has urged the need to develop new molecular scaffolds, either structurally original or based on old and active drugs. The aim of this review is to summarize the current status of different QSAR based strategies for the design of novel anti-TB drugs based upon the most active anti-TB agent known, INH. A case study puts in evidence that the judicious application of quantitative structure- activity relationships can be successfully used to rationally design new INH-based derivatives, active against INH-resistant strains harboring mutations in the most frequent resistance related target (katG), and therefore develop candidate-compounds against MDR-TB, thus revisiting the unique effectiveness of INH against TB.

Comparison of Multiple Linear Regressions and Neural Networks based QSAR models for the design of new antitubercular compounds.

The performance of two QSAR methodologies, namely Multiple Linear Regressions (MLR) and Neural Networks (NN), towards the modeling and prediction of antitubercular activity was evaluated and compared. A data set of 173 potentially active compounds belonging to the hydrazide family and represented by 96 descriptors was analyzed. Models were built with Multiple Linear Regressions (MLR), single Feed-Forward Neural Networks (FFNNs), ensembles of FFNNs and Associative Neural Networks (AsNNs) using four different data sets and different types of descriptors. The predictive ability of the different techniques used were assessed and discussed on the basis of different validation criteria and results show in general a better performance of AsNNs in terms of learning ability and prediction of antitubercular behaviors when compared with all other methods. MLR have, however, the advantage of pinpointing the most relevant molecular characteristics responsible for the behavior of these compounds against Mycobacterium tuberculosis. The best results for the larger data set (94 compounds in training set and 18 in test set) were obtained with AsNNs using seven descriptors (R(2) of 0.874 and RMSE of 0.437 against R(2) of 0.845 and RMSE of 0.472 in MLRs, for test set). Counter-Propagation Neural Networks (CPNNs) were trained with the same data sets and descriptors. From the scrutiny of the weight levels in each CPNN and the information retrieved from MLRs, a rational design of potentially active compounds was attempted. Two new compounds were synthesized and tested against M. tuberculosis showing an activity close to that predicted by the majority of the models.

Punção da artéria axilar para intervenções percutâneas em lactentes portadores de cardiopatias congênitas: "à procura de um caminho mais curto e mais seguro" / Axillary artery access for percutaneous interventions in infants with congenital heart disease: \"in search of a shorter and safer pathway"

INTRODUÇÃO: O acesso através da punção da artéria axilar (AAx) tem sido utilizado em adultos com bons resultados, porém seu uso em neonatos e lactentes jovens tem sido pouco relatado. Nosso objetivo foi relatar a experiência inicial com o uso desse acesso em diferentes intervenções nessa faixa etária de pacientes. Método: De janeiro de 2009 a setembro de 2010 foram incluídas 11 crianças submetidas a diferentes procedimentos intervencionistas realizados através de punção da AAx. O procedimento foi realizado com agulha 21 G, sendo utilizados introdutores 4 F ou 5 F pediátricos. Resultados: A média de idade foi de 26 + - 12 dias e o peso médio de 4,2 +- 1,7 kg. Os procedimentos intervencionistas realizados foram: implante de stent no canal arterial (6) valvoplastia aórtica (1) angioplastia aórtica (2), implante de stent em Blalock-Taussig (1), e redilatação do stent do canal arterial (!). A punção da AAx direita foi realizada com sucesso em todos os pacientes e sem dificuldade técnica. Os tempos médios do procedimento...

BACKGROUND: Axillary artery access (AxA) has been used in adults with good results, however, its use in neonates and infants has not been extensively reported. This study was aimed at reporting our initial experience using this access in different cardiac interventions in this age group. METHOD: From January 2009 to September 2010, 11 children were submitted to different cardiac interventions using AxA. The procedure was performed with a 21 G needle followed by the insertion of a 4 F or a 5 F pediatric sheats. RESULTS: Mean age was 26 ± 12 days and mean weight was 4.2 ± 1.7 Kg. The cardiac interventions performed were: stenting of the arterial duct (6), aortic valvoplasty (1), aortic angioplasty (2), stent implantation in a Blalock-Taussig shunt (1) and stent redilation in the arterial duct (1). Right AxA puncture was successfully obtained in all patients without technical difficulties. Mean procedure and fluoroscopy times were 52 ± 15 minutes and 13 ± 4 minutes, respectively. Pneumothorax without hemodynamic involvement was the single complication in one patient. The other patients did not have any abnormalities. There were no ischemic or neurologic complications in the ipsilateral limb. Mean time of Intensive Care Unit (ICU) stay was 48 ± 16 hours. There were no deaths during the interventional procedures and one patient died of sepsis at the ICU 5 days after the procedure. CONCLUSION: In our experience AxA proved to be a safe and effective alternative for different interventional procedures in neonates and infants with congenital heart diseases.