Effect of a nutraceutical combination on sleep quality among people with impaired sleep: a randomised, placebo-controlled trial.

In this randomised, placebo-controlled trial, adults with impaired sleep (Pittsburgh Sleep Quality Index ≥ 5) were randomly assigned using a minimization algorithm to receive a formulation containing L-theanine plus lemon balm, valerian, and saffron extracts, or placebo, during 6 weeks. Objective sleep quality parameters were measured using an actigraphy device. We enrolled and randomised 64 individuals, 31 from the active group and 27 from the placebo group completed the 6 week follow-up. Mean sleep efficiency remained unmodified in the active group, and increased by 3% in the placebo group, the between-group difference in the change was not statistically significant (p = 0.49). Total sleep time also improved more with placebo (13.0 vs. 1.33 min, p = 0.66). Time wake after sleep onset (WASO) decreased more in the active group (4.6% vs. 2.4%), but the difference was not significant (p = 0.33). Mean PSQI decreased by 3.11 points (32.3%) in the active group, and by 3.86 points (39.5%) in the placebo group (p = 0.41). SF-36 increased more with placebo (+ 18.3 in active, + 32.1 in placebo, p = 0.68). Salivary cortisol remained unchanged in both groups. No serious adverse events were reported. Among adults with impaired sleep, a nutraceutical combination did not improve objective or subjective sleep parameters more than a placebo infusion.

Antileishmanial activity of tetra-cationic porphyrins with peripheral Pt(II) and Pd(II) complexes mediated by photodynamic therapy.

Leishmaniasis is a neglected disease that impacts more than one billion people in endemic areas of the globe. Several drawbacks are associated with the currently existing drugs for treatment such as low effectiveness, toxicity, and the emergence of resistant strains that demonstrate the importance of looking for novel therapeutic alternatives. Photodynamic therapy (PDT) is a promising novel alternative for cutaneous leishmaniasis treatment because its topical application avoids potential side effects generally associated with oral/parenteral application. A light-sensitive compound known as photosensitizer (PS) interacts with light and molecular oxygen to generate reactive oxygen species (ROS), which promote cell death by oxidative stress through PDT approaches. Here, for the first time, we demonstrate the antileishmanial effect of tetra-cationic porphyrins with peripheral Pt(II)- and Pd(II)-polypyridyl complexes using PDT. The isomeric tetra-cationic porphyrins in the meta positions, 3-PtTPyP, and 3-PdTPyP, exhibited the highest antiparasitic activity against promastigote (IC50-pro = 41.8 nM and 46.1 nM, respectively) and intracellular amastigote forms (IC50-ama = 27.6 nM and 38.8 nM, respectively) of L. amazonensis under white light irradiation (72 J cm-2) with high selectivity (SI > 50) for both forms of parasites regarding mammalian cells. In addition, these PS induced the cell death of parasites principally by a necrotic process in the presence of white light by mitochondrial and acidic compartments accumulation. This study showed that porphyrins 3-PtTPyP and 3-PdTPyP displayed a promising antileishmanial-PDT activity with potential application for cutaneous leishmaniasis treatment.

Dinámicas socioculturales y alternativas económicas de mujeres en un contexto de economía minera extractivista

Este artículo describe las dinámicas socioculturales presentes en Puerto Claver, El Bagre, Antioquia, a causa del contexto económico minero. El enfoque fenomenològico permitió un acercamiento a las realidades sociales a partir de la cotidianidad de las personas, de sus experiencias vitales y relatos. Un resultado es que la práctica extractiva de oro, arraigada en el corregimiento como la principal alternativa económica, genera desarraigo frente a otras formas de sobrevivencia, como la cosecha y siembra de alimentos y plantas medicinales, la pesca y la apicultura. Al transformarse las prácticas económicas y productivas, así como la relación con el medio ambiente, cambian también las relaciones sociales, las dinámicas socioculturales preexistentes y el tejido social y comunitario. En este contexto, las asociaciones de mujeres tienen un papel significativo en la resignificación y dinamización de procesos económicos alternativos a la práctica minera, a través de los cuales puedan transformar las relaciones sociales y comunitarias.

This article describes the socio-cultural dynamics present in the village of Puerto Claver, municipality of El Bagre, Antioquia, as a result of the mining economic context. The phenomenological approach allowed an approach to the social realities from the daily life of the people, their life experiences and stories. One result is that the practice of gold mining, rooted in the township as the main economic alternative, generates uprooting compared to other forms of survival, such as harvesting and planting food and medicinal plants, fishing and beekeeping. As economic and productive practices are transformed, as well as the relationship with the environment, social relations, pre-existing socio-cultural dynamics and the social and community fabric also change. In this context, women's associations have a significant role to play in re-signifying and energizing alternative economic processes to mining practices, through which they can transform social and community relations.

Novel Selective and Low-Toxic Inhibitor of LmCPB2.8ΔCTE (CPB) One Important Cysteine Protease for Leishmania Virulence.

Leishmaniasis is a highly prevalent, yet neglected disease caused by protozoan parasites of the genus Leishmania. In the search for newer, safer, and more effective antileishmanial compounds, we herein present a study of the mode of action in addition to a detailed structural and biological characterization of LQOF-G6 [N-benzoyl-N'-benzyl-N″-(4-tertbutylphenyl)guanidine]. X-ray crystallography and extensive NMR experiments revealed that LQOF-G6 nearly exclusively adopts the Z conformation stabilized by an intramolecular hydrogen bond. The investigated guanidine showed selective inhibitory activity on Leishmania major cysteine protease LmCPB2.8ΔCTE (CPB) with ~73% inhibition and an IC50-CPB of 6.0 µM. This compound did not show any activity against the mammalian homologues cathepsin L and B. LQOF-G6 has been found to be nontoxic toward both organs and several cell lines, and no signs of hepatotoxicity or nephrotoxicity were observed from the analysis of biochemical clinical plasma markers in the treated mice. Docking simulations and experimental NMR measurements showed a clear contribution of the conformational parameters to the strength of the binding in the active site of the enzyme, and thus fit the differences in the inhibition values of LQOF-G6 compared to the other guanidines. Furthermore, the resulting data render LQOF-G6 suitable for further development as an antileishmanial drug.

New Insights into the Mechanism of Action of the Cyclopalladated Complex (CP2) in Leishmania: Calcium Dysregulation, Mitochondrial Dysfunction, and Cell Death.

The current treatment of leishmaniasis is based on a few drugs that present several drawbacks, such as high toxicity, difficult administration route, and low efficacy. These disadvantages raise the necessity to develop novel antileishmanial compounds allied with a comprehensive understanding of their mechanisms of action. Here, we elucidate the probable mechanism of action of the antileishmanial binuclear cyclopalladated complex [Pd(dmba)(µ-N3)]2 (CP2) in Leishmania amazonensis. CP2 causes oxidative stress in the parasite, resulting in disruption of mitochondrial Ca2+ homeostasis, cell cycle arrest at the S-phase, increasing the reactive oxygen species (ROS) production and overexpression of stress-related and cell detoxification proteins, and collapsing the Leishmania mitochondrial membrane potential, and promotes apoptotic-like features in promastigotes, leading to necrosis, or directs programmed cell death (PCD)-committed cells toward necrotic-like destruction. Moreover, CP2 reduces the parasite load in both liver and spleen in Leishmania infantum-infected hamsters when treated for 15 days with 1.5 mg/kg body weight/day CP2, expanding its potential application in addition to the already known effectiveness on cutaneous leishmaniasis for the treatment of visceral leishmaniasis, showing the broad spectrum of action of this cyclopalladated complex. The data presented here bring new insights into the CP2 molecular mechanisms of action, assisting the promotion of its rational modification to improve both safety and efficacy.

Predicting early recovery of consciousness after cardiac arrest supported by quantitative electroencephalography.

OBJECTIVE: To determine the ability of quantitative electroencephalography (QEEG) to improve the accuracy of predicting recovery of consciousness by post-cardiac arrest day 10. METHODS: Unconscious survivors of cardiac arrest undergoing daily clinical and EEG assessments through post-cardiac arrest day 10 were studied in a prospective observational cohort study. Power spectral density, local coherence, and permutation entropy were calculated from daily EEG clips following a painful stimulus. Recovery of consciousness was defined as following at least simple commands by day 10. We determined the impact of EEG metrics to predict recovery when analyzed with established predictors of recovery using partial least squares regression models. Explained variance analysis identified which features contributed most to the predictive model. RESULTS: 367 EEG epochs from 98 subjects were analyzed in conjunction with clinical measures. Highest prediction accuracy was achieved when adding QEEG features from post-arrest days 4-6 to established predictors (area under the receiver operating curve improved from 0.81 ± 0.04 to 0.86 ± 0.05). Prediction accuracy decreased from 0.84 ± 0.04 to 0.79 ± 0.04 when adding QEEG features from post-arrest days 1-3. Patients with recovery of command-following by day 10 showed higher coherence across the frequency spectrum and higher centro-occipital delta-frequency spectral power by days 4-6, and globally-higher theta range permutation entropy by days 7-10. CONCLUSIONS: Adding quantitative EEG metrics to established predictors of recovery allows modest improvement of prediction accuracy for recovery of consciousness, when obtained within a week of cardiac arrest. Further research is needed to determine the best strategy for integration of QEEG data into prognostic models in this patient population.

Antileishmanial activity of amphiphilic chlorin derivatives mediated by photodynamic therapy.

Leishmaniasis is a serious and neglected disease that affects 14 million people around the World. The currently available drugs for treatment present several drawbacks such as low efficacy and severe side effects, contributing to patients' low compliance. Photodynamic therapy (PDT) is rising as a promising treatment of cutaneous leishmaniasis, mainly considering its topical administration that circumvents any potential adverse effects commonly related to oral/parenteral administration. PDT depends on the interaction between a light-sensitive compound (photosensitizer - PS), light and molecular oxygen. The reaction generates reactive oxygen species (ROS) which induce cell death by oxidative stress. The main goal of this study is to demonstrate the antileishmanial effect of three chlorin derivatives (CHL-OH-A, CHL-OH-B, CHL-TRISMA) using PDT, as well as to investigate their cell death pathway on Leishmania amazonensis promastigote forms after chlorin-PDT application. The chlorin derivatives herein studied did not exhibit aggregates in aqueous medium and showed fast accumulation in Leishmania acidic compartments. CHL-OH-A exhibited the highest antiparasitic activity at 24 h (0.33 µmol L-1) and 48 h (0.14 µmol L-1) after irradiation at 660 nm (6.0 Jcm-2). CHL-OH-A, CHL-OH-B and CHL-TRISMA molecules induced the cell death of parasites mainly by an apoptotic-like process in the presence of light. These chlorin derivatives are 80-fold more active against Leishmania when compared to other PSs reported in the literature. In this study, we have shown that these amphiphilic chlorins, and in particular, CHL-OH-A, exert an interesting leishmanicidal activity suggesting that the use of these PSs associated with PDT could be a promising strategy for treatment of cutaneous leishmaniasis.

Efficacy of photodynamic therapy using TiO2 nanoparticles doped with Zn and hypericin in the treatment of cutaneous Leishmaniasis caused by Leishmania amazonensis.

Since Leishmania parasites exhibit resistance outbreaks to drugs conventionally used in medical treatments, research of new antileishmanial compounds or alternative treatment therapies are essential. A focus of interest has been the implementation of light-based therapies such as photodynamic therapy, where inorganic compounds such as titanium dioxide have shown promising results as drug delivery carriers. In this work, nanoparticles of TiO2 doped with Zn (TiO2/Zn) were synthesized through solution combustion route and with hypericin (HY) in order to enhance its photodynamic activity in the visible light region. Scanning (SEM) and transmission (TEM) electron microscopy analyses showed particles of (TiO2/Zn) with sizes smaller than 20 nm and formation of aggregates smaller than 1 µm, whilst electron diffraction spectroscopy (EDS) analysis ensured the presence of Zn in the system. The association of the TiO2/Zn with HY (TiO2/Zn-HY) was further confirmed by fluorescence spectrometry. Measurements of its cellular uptake showed the presence of smaller molecules into promastigotes after 120 min incubation. TiO2/Zn-HY showed good antileishmanial activity (EC50 of 17.5 ± 0.2 µg mL-1) and low cytotoxicity against murine macrophages (CC50 35.2 ± 0.3 µg mL-1) in the visible light (22 mW cm-2; 52.8 J cm-2). Moreover, in the in vivo analysis, TiO2/Zn-HY decreased the parasite load of L. amazonensis - BALB/c infected mice by 43% - 58% after a combination of blue and red light presenting 22 mW cm-2 of intensity and 52.8 J cm-2 of fluency delivered. All together, these data indicate a new combined system of nanoparticles associated with a photosensitizer and PDT as alternative to amphotericin B for the treatment of cutaneous leishmaniasis.

N, N', N″-trisubstituted guanidines: Synthesis, characterization and evaluation of their leishmanicidal activity.

Leishmaniasis is a group of diseases caused by protozoan parasites from the genus Leishmania. There are estimated 1.3 million new cases annually with a mortality of 20,000-30,000 per year, when patients are left untreated. Current chemotherapeutic drugs available present high toxicity and low efficacy, the latter mainly due to the emergence of drug-resistant parasites, which makes discovery of novel, safe, and efficacious antileishmanial drugs mandatory. The present work reports the synthesis, characterization by ESI-MS, 1H and 13C NMR, and FTIR techniques as well as in vitro and in vivo evaluation of leishmanicidal activity of guanidines derivatives presenting lower toxicity. Among ten investigated compounds, all being guanidines containing a benzoyl, a benzyl, and a substituted phenyl moiety, LQOF-G2 (IC50-ama 5.6 µM; SI = 131.8) and LQOF-G7 (IC50-ama 7.1 µM; SI = 87.1) were the most active against L. amazonensis intracellular amastigote, showing low cytotoxicity to the host cells according to their selectivity index. The most promising compound, LQOF-G2, was further evaluated in an in vivo model and was able to decrease 60% of the parasite load in foot lesions at a dose of 0.25 mg/kg/day. Moreover, this guanidine derivative demonstrated reduced hepatotoxicity compared to other leishmanicidal compounds and did not show nephrotoxicity, as determined by the analyses of biomarkers of hepatic damage and renal function, which make this compound a potential new hit for therapy against leishmaniasis.

In vitro activities of glycoalkaloids from the Solanum lycocarpum against Leishmania infantum

ABSTRACT Leishmania infantum is an etiologic agent of visceral leishmaniasis. This disease is a neglected disease that can be fatal if not treated and additionally, the few therapeutic option present several drawbacks, including difficult route of administration and toxicity, which turn the search for new therapeutic alternatives necessary. Herein, we evaluated the leishmanicidal in vitro activity of the solanum extract from Solanum lycocarpum A. St.-Hil., Solanaceae, and the isolated alkaloids solasodine, solamargine and solasonine against promastigotes and intracellular amastigotes of L. infantum. Solasodine (IC50-pro = 4.7 µg/ml; IC50-ama = 10.8 µg/ml) and solamargine (IC50-pro = 8.1 µg/ml; IC50-ama = 3.0 µg/ml) exhibited interesting leishmanicidal ativity. Solasonine was approximately four-times (Selective Index 3.7) more selective to the parasite than to the host cells. This data suggest that solasonine might be considered as a potential drug candidate for leishmaniasis treatment.

Potential application of rLc36 protein for diagnosis of canine visceral leishmaniasis.

Visceral leishmaniasis (VL) is fatal if left untreated. Infected dogs are important reservoirs of the disease, and thus specific identification of infected animals is very important. Several diagnostic tests have been developed for canine VL (CVL); however, these tests show varied specificity and sensitivity. The present study describes the recombinant protein rLc36, expressed by Leishmania infantum, as potential antigen for more sensitive and specific diagnosis of CVL based on an immunoenzymatic assay. The concentration of 1.0 µg/mL of rLc36 enabled differentiation of positive and negative sera and showed a sensitivity of 85% and specificity of 71% (with 95% confidence), with an accuracy of 76%.

Intracortical electrophysiological correlates of blood flow after severe SAH: A multimodality monitoring study.

Subarachnoid hemorrhage (SAH) is a devastating form of stroke. Approximately one in four patients develop progressive neurological deterioration and silent infarction referred to as delayed cerebral ischemia (DCI). DCI is a complex, multifactorial secondary brain injury pattern and its pathogenesis is not fully understood. We aimed to study the relationship between cerebral blood flow (CBF) and neuronal activity at both the cortex and in scalp using electroencephalography (EEG) in poor-grade SAH patients undergoing multimodality intracranial neuromonitoring. Twenty patients were included, of whom half had DCI median 4.7 days (interquartile range (IQR): 4.0-5.6) from SAH bleed. The rate of decline in regional cerebral blood flow (rCBF) was significant in both those with and without DCI and occurred between days 4 and 7 post-SAH. The scalp EEG alpha-delta ratio declined early in those with DCI. In the group without DCI, CBF and cortical EEG alpha-delta ratio were correlated (r = 0.53; p < 0.01) and in the group without DCI, inverse neurovascular coupling was observed at CPP < 80 mmHg. We found preliminary evidence that as patients enter the period of highest risk for the development of DCI, the absence of neurovascular coupling may act as a possible pathomechanism in the development of ischemia following SAH.

Efficacy of a Binuclear Cyclopalladated Compound Therapy for Cutaneous Leishmaniasis in the Murine Model of Infection with Leishmania amazonensis and Its Inhibitory Effect on Topoisomerase 1B.

Leishmaniasis is a disease found throughout the (sub)tropical parts of the world caused by protozoan parasites of the Leishmania genus. Despite the numerous problems associated with existing treatments, pharmaceutical companies continue to neglect the development of better ones. The high toxicity of current drugs combined with emerging resistance makes the discovery of new therapeutic alternatives urgent. We report here the evaluation of a binuclear cyclopalladated complex containing Pd(II) and N,N'-dimethylbenzylamine (Hdmba) against Leishmania amazonensis The compound [Pd(dmba)(µ-N3)]2 (CP2) inhibits promastigote growth (50% inhibitory concentration [IC50] = 13.2 ± 0.7 µM) and decreases the proliferation of intracellular amastigotes in in vitro incubated macrophages (IC50 = 10.2 ± 2.2 µM) without a cytotoxic effect when tested against peritoneal macrophages (50% cytotoxic concentration = 506.0 ± 10.7 µM). In addition, CP2 was also active against T. cruzi intracellular amastigotes (IC50 = 2.3 ± 0.5 µM, selective index = 225), an indication of its potential for use in Chagas disease therapy. In vivo assays using L. amazonensis-infected BALB/c showed an 80% reduction in parasite load compared to infected and nontreated animals. Also, compared to amphotericin B treatment, CP2 did not show any side effects, which was corroborated by the analysis of plasma levels of different hepatic and renal biomarkers. Furthermore, CP2 was able to inhibit Leishmania donovani topoisomerase 1B (Ldtopo1B), a potentially important target in this parasite. (This study has been registered at ClinicalTrials.gov under identifier NCT02169141.).

Seizure burden in subarachnoid hemorrhage associated with functional and cognitive outcome.

OBJECTIVE: To assess the relationship between seizure burden on continuous EEG (cEEG) and functional as well as cognitive outcome 3 months after subarachnoid hemorrhage (SAH). METHODS: The study included all consecutive patients with a spontaneous SAH admitted to the Columbia University Medical Center Neurological Intensive Care Unit and monitored with cEEG between 1996 and 2013. Seizure burden was defined as the duration, in hours, of seizures on cEEG. Cognitive outcomes were measured with the Telephone Interview for Cognitive Status (TICS, ranging from 0 to 51, indicating poor to good global mental status). RESULTS: Overall, 402 patients with SAH were included with a median age of 58 years (interquartile range [IQR] 46-68 years). The median duration of cEEG monitoring was 96 hours (IQR 48-155 hours). Seizures were recorded in 50 patients (12%), in whom the median seizure burden was 6 hours (IQR 1-13 hours). At 3 months, in multivariate analysis, seizure burden was associated with unfavorable functional and cognitive outcome. Every hour of seizure on cEEG was associated with an odds ratio of 1.10 (95% confidence interval [CI] 1.01-1.21, p = 0.04) to 3-month disability and mortality, and the TICS-score decreased, on average, by 0.16 points (adjusted coefficient -0.19, 95% CI -0.33 to -0.05, p = 0.01). CONCLUSION: In this study, after adjusting for established predictors, seizure burden was associated with functional outcome and cognitive impairment 3 months after SAH.

Synthesis and evaluation of novel prenylated chalcone derivatives as anti-leishmanial and anti-trypanosomal compounds.

Chalcones form a class of compounds that belong to the flavonoid family and are widely distributed in plants. Their simple structure and the ease of preparation make chalcones attractive scaffolds for the synthesis of a large number of derivatives enabling the evaluation of the effects of different functional groups on biological activities. In this Letter, we report the successful synthesis of a series of novel prenylated chalcones via Claisen-Schmidt condensation and the evaluation of their effect on the viability of the Trypanosomatidae parasites Leishmania amazonensis, Leishmania infantum and Trypanosoma cruzi.

New drugs with antiprotozoal activity from marine algae: a review

The use of indigenous or remote popular knowledge to identify new drugs against diseases or infections is a well-known approach in medicine. The inhabitants of coastal regions are known to prepare algae extracts for the treatment of disorders and ailments such as wounds, fever and stomach aches, as for the prevention of arrhythmia. Recent trends in drug research from natural sources have indicated that marine algae are a promising source of novel biochemically active compounds, especially with antiprotozoal activity. Algae survive in a competitive environment and, therefore, developed defense strategies that have resulted in a significant level of chemical structural diversity in various metabolic pathways. The exploration of these organisms for pharmaceutical and medical purposes has provided important chemical candidates for the discovery of new agents against neglected tropical diseases, stimulating the use of sophisticated physical techniques. This current review describes the main substances biosynthesized by benthic marine algae with activity against Leishmania spp., Trypanosoma cruzi and Trypanosoma brucei; the causative agents of leishmaniasis, Chagas disease and African trypanosomiasis, respectively. Emphasis is given to secondary metabolites and crude extracts prepared from marine algae.

Synthesis and tripanocidal activity of ferrocenyl and benzyl diamines against Trypanosoma brucei and Trypanosoma cruzi.

Trypanosoma brucei and Trypanosoma cruzi are the etiologic agents of sleeping sickness and Chagas disease, respectively, two of the 17 preventable tropical infectious diseases (NTD) which have been neglected by governments and organizations working in the health sector, as well as pharmaceutical industries. High toxicity and resistance are problems of the conventional drugs employed against trypanosomiasis, hence the need for the development of new drugs with trypanocidal activity. In this work we have evaluated the trypanocidal activity of a series of N1,N2-dibenzylethane-1,2-diamine hydrochlorides (benzyl diamines) and N1-benzyl,N2-methyferrocenylethane-1,2-diamine hydrochlorides (ferrocenyl diamines) against T. brucei and T. cruzi parasite strains. We show that incorporation of the ferrocenyl group into the benzyl diamines increases the trypanocidal activity. The molecules exhibit potential trypanocidal activity in vitro against all parasite strains. Cytotoxicity assay was also carried out to evaluate the toxicity in HepG2 cells.

Contingencias de las estructuras familiares del milenio / Contingencies of the family structure of the millennium

La Familia como la máxima institución social, ha cambiado en su estructura, funcionamiento y ciclo vital. Es considerada como un sujeto prevalente de derechos y un nuevo actor social, a nivel nacional e internacional. En sus relaciones ecosistémicas, dinámicas, flexibles y adaptativas, es influenciada por los fenómenos socio-económicos, culturales y políticos del tercer milenio, que afectan todas la estructuras familiares, según su estrato socio-económico y condiciones. El artículo referencia algunos de los eventos, que debenser considerados en la formación profesional universitaria, en la formulación de política pública y en la modernización de las legislaciones que amparan a la familia o a susmiembros. Tales son: Modernización del Estado y reformas legislativas, Movilidad social. Remesas Familiares. Desplazamiento forzado. Desigualdad en el capital humano. Empresas familiarmente responsables. Desarrollo sustentable. Relación familia escuela. Homoparentalidad. TICS - Tecnologías de la información.

The family, as the maximum social institution, has changed in its structure, functioning and vital cycle. It is considered as a prevalentsubject of rights and a new social actor, nationally and internationally. In its ecosystemic, dynamic, flexible and adaptive relationships, it is influenced by the socioeconomic,cultural and political phenomena ofthe third millennium, which affect all the family structures; according to its socio-economic status and conditions. This article makes reference to some of the events, which must be taken into account in the college professionaltraining, in the formulation of a public policy and in the modernization of the legislations which protect the family or its members. Such legislations include: the Modernization of theState and legislative reforms, Social Mobility, Family Remittance, Forced Migration, Economic Inequality in the human capital, Responsible Family Enterprises, Sustainable Development, Family-School Relationship, Homoparentality, Information andCommunication Technology.