Anti-Mycobacterium tuberculosis activity and cytotoxicity of Calophyllum brasiliense Cambess (Clusiaceae)

We evaluated the in vitro anti-Mycobacterium tuberculosis activity and the cytotoxicity of dichloromethane extract and pure compounds from the leaves of Calophyllum brasiliense. Purification of the dichloromethane extract yielded the pure compounds (-) mammea A/BB (1), (-) mammea B/BB (2) and amentoflavone (3). The compound structures were elucidated on the basis of spectroscopic and spectrometric data. The contents of bioactive compounds in the extracts were quantified using high performance liquid chromatography coupled to an ultraviolet detector. The anti-M. tuberculosis activity of the extracts and the pure compounds was evaluated using a resazurin microtitre assay plate. The cytotoxicity assay was performed in J774G.8 macrophages using the 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide colourimetric method. The quantification of the dichloromethane extract showed (1) and (2) at concentrations of 31.86 ± 2.6 and 8.24 ± 1.1 µg/mg of extract, respectively. The dichloromethane and aqueous extracts showed anti-M. tuberculosis H37Rv activity of 62.5 and 125 µg/mL, respectively. Coumarins (1) and (2) showed minimal inhibitory concentration ranges of 31.2 and 62.5 µg/mL against M. tuberculosis H37Rv and clinical isolates. Compound (3) showed no activity against M. tuberculosis H37Rv. The selectivity index ranged from 0.59-1.06. We report the activity of the extracts and coumarins from the leaves of C. brasiliense against M. tuberculosis.

Assessment of Physical Activity and Energy Expenditure by GPS Combined With Accelerometry in Real-Life Conditions.

Background: Physical activity (PA) and related energy expenditure (EE) is often assessed by means of a single technique. Because of inherent limitations, single techniques may not allow for an accurate assessment both PA and related EE. The aim of this study was to develop a model to accurately assess common PA types and durations and thus EE in free-living conditions, combining data from global positioning system (GPS) and 2 accelerometers. Methods: Forty-one volunteers participated in the study. First, a model was developed and adjusted to measured EE with a first group of subjects (Protocol I, n = 12) who performed 6 structured and supervised PA. Then, the model was validated over 2 experimental phases with 2 groups (n = 12 and n = 17) performing scheduled (Protocol I) and spontaneous common activities in real-life condition (Protocol II). Predicted EE was compared with actual EE as measured by portable indirect calorimetry. Results: In protocol I, performed PA types could be recognized with little error. The duration of each PA type could be predicted with an accuracy below 1 minute. Measured and predicted EE were strongly associated (r = .97, P < .001). Conclusion: Combining GPS and 2 accelerometers allows for an accurate assessment of PA and EE in free-living situations.

Alterations in phosphatidylinositol 3-kinase activity and PTEN phosphatase in the prefrontal cortex of depressed suicide victims.

BACKGROUND: Recent studies have reported alterations in protein kinase B (PKB)/Akt and in its downstream target, glycogen synthase kinase 3β, in depression and suicide. The aim of the present study was to investigate possible impairment of the upstream regulators, namely phosphatidylinositol 3-kinase (PI3K) and PTEN. METHODS: The ventral prefrontal cortex (Brodmann's area 11) of 24 suicide victims and 24 drug-free nonsuicide subjects was used. The antemortem diagnoses of major depression disorder were obtained from the institutional records or psychological autopsy, and toxicological analyses were performed. Protein levels of PI3K and PTEN were assayed using the immunoblot method, and the kinase activity of PI3K and Akt was determined by phosphorylation of specific substrates. RESULTS: A decrease was observed in the enzymatic activity of PI3K [ANOVA: F(3, 44) = 9.20; p < 0.001] and Akt1 [ANOVA: F(3, 44) = 13.59; p < 0.001], without any change in protein levels, in both depressed suicide victims and depressed nonsuicide subjects (p < 0.01 and p < 0.002, respectively). PTEN protein levels were increased in the same groups [ANOVA: F(3, 44) = 10.5; p < 0.001]. No change was observed in nondepressed suicide victims. CONCLUSION: This study concludes that attenuation of kinase activity of PKB/Akt in depressed suicide victims may be due to the combined dysregulation of PTEN and PI3K resulting in insufficient phosphorylation of lipid second messengers. The effect is associated with major depression rather than with suicide per se. Given the cellular deficits reported in major depression, the study of enzymes involved in cell survival and neuroplasticity is particularly relevant to neurotrophic factor dysregulation in depression.

State-Society Relationships, Social Trust and the Development of Labour Market Policies in Italy and Sweden

The first decade of the twenty-first century may be remembered for the rebirth of consensus on labour market policy. After three decades of bitter political and ideological controversy between a neo-liberal and a traditional social democratic approach, a new model, often labelled flexicurity, has emerged. This model is promoted by numerous political organisations since it promises to put an end to the old trade-off between equality and efficiency. Several countries are embracing the flexicurity model as a blueprint for labour market reform, but others, mostly belonging to the 'Mediterranean Rim', are clearly lagging behind. Why is it so difficult for these countries to implement the flexicurity model? This paper argues that the application of a flexicurity strategy in these countries is complicated by the lack of social trust between social partners and the state as well as political economy traditions that highlight the role of labour market regulation as a source of social protection.

Modulatory effect of iron chelators on adenosine deaminase activity and gene expression in Trichomonas vaginalis

Trichomonas vaginalis is a flagellate protozoan that parasitises the urogenital human tract and causes trichomoniasis. During the infection, the acquisition of nutrients, such as iron and purine and pyrimidine nucleosides, is essential for the survival of the parasite. The enzymes for purinergic signalling, including adenosine deaminase (ADA), which degrades adenosine to inosine, have been characterised in T. vaginalis. In the evaluation of the ADA profile in different T. vaginalisisolates treated with different iron sources or with limited iron availability, a decrease in activity and an increase in ADA gene expression after iron limitation by 2,2-bipyridyl and ferrozine chelators were observed. This supported the hypothesis that iron can modulate the activity of the enzymes involved in purinergic signalling. Under bovine serum limitation conditions, no significant differences were observed. The results obtained in this study allow for the assessment of important aspects of ADA and contribute to a better understanding of the purinergic system in T. vaginalis and the role of iron in establishing infection and parasite survival.

In vivo antileishmanial activity and chemical profile of polar extract from Selaginella sellowii

The polar hydroethanolic extract from Selaginella sellowii(SSPHE) has been previously proven active on intracellular amastigotes (in vitro test) and now was tested on hamsters infected with Leishmania (Leishmania) amazonensis (in vivo test). SSPHE suppressed a 100% of the parasite load in the infection site and draining lymph nodes at an intralesional dose of 50 mg/kg/day × 5, which was similar to the results observed in hamsters treated with N-methylglucamine antimonate (Sb) (28 mg/Kg/day × 5). When orally administered, SSPHE (50 mg/kg/day × 20) suppressed 99.2% of the parasite load in infected footpads, while Sb suppressed 98.5%. SSPHE also enhanced the release of nitric oxide through the intralesional route in comparison to Sb. The chemical fingerprint of SSPHE by high-performance liquid chromatography with diode-array detection and tandem mass spectrometry showed the presence of biflavonoids and high molecular weight phenylpropanoid glycosides. These compounds may have a synergistic action in vivo. Histopathological study revealed that the intralesional treatment with SSPHE induced an intense inflammatory infiltrate, composed mainly of mononuclear cells. The present findings reinforce the potential of this natural product as a source of future drug candidates for American cutaneous leishmaniasis.

Don't stop, don't stop: physical activity and adolescence.

The aim was to assess whether physical activity decreases during adolescence, whether this decrease depends on the gender, whether physical activity is related to personal, family, and school factors, and whether it is associated to healthy behaviors in a sample of adolescents. Data were drawn from a survey carried out in 2001 among in-school Catalan adolescents aged 14-19 years. Subjects were divided in two groups: physical activity (N=4,185, 43.5% females) and no-physical activity (N=2,743; 68.9% females). Personal, family, school and lifestyles' variables were compared. Chi-square and Odds Ratio were used to compare qualitative variables and Student's t to compare quantitative variables. For the multivariate analysis, all statistically significant variables in the univariate analysis in each of the four groups of variables (plus age) were introduced in a non-conditioned multiple regression. Analysis was performed separately by gender. Physical activity was significantly more frequent among males and decreased with age. Globally, physically active youth perceived themselves as healthier and happier with their body image, they showed a better relationship with their parents, were better connected to school, and exhibited healthier lifestyles. As physical activity has important benefits on health, health professionals dealing with adolescents should encourage adolescents to keep practicing. This message must be specially directed to females.

Activity and migration of Cory's shearwater

I describe some of the features that characterize the activity and migration of Cory’s shearwater during approximately one year. I also explore the influence of Moon, photoperiod, geographic position and life-history stage on the resulting patterns and the periodicity of the latter. I have principally used time series and regression analysis. Its use here is one of the first applications to the analysis of logger data in seabirds. An intriguing finding of this work is the lunar periodicity that pervades the annual cycle of this species.

The JNK binding domain of islet-brain 1 inhibits IL-1 induced JNK activity and apoptosis but not the transcription of key proapoptotic or protective genes in insulin-secreting cell lines.

The stress-activated protein kinase c-Jun NH2-terminal kinase (JNK) is a central signal for interleukin-1beta (IL-1beta)-induced apoptosis in insulin-producing beta-cells. The cell-permeable peptide inhibitor of JNK (JNKI1), that introduces the JNK binding domain (JBD) of the scaffold protein islet-brain 1 (IB1) inside cells, effectively prevents beta-cell death caused by this cytokine. To define the molecular targets of JNK involved in cytokine-induced beta-cell apoptosis we investigated whether JNKI1 or stable expression of JBD affected the expression of selected pro- and anti-apoptotic genes induced in rat (RIN-5AH-T2B) and mouse (betaTC3) insulinoma cells exposed to IL-1beta. Inhibition of JNK significantly reduced phosphorylation of the specific JNK substrate c-Jun (p&lt;0.05), IL-1beta-induced apoptosis (p&lt;0.001), and IL-1beta-mediated c-fos gene expression. However, neither JNKI1 nor JBD did influence IL-1beta-induced NO synthesis or iNOS expression or the transcription of the genes encoding mitochondrial manganese superoxide dismutase (MnSOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase rho (GSTrho), heat shock protein (HSP) 70, IL-1beta-converting enzyme (ICE), caspase-3, apoptosis-inducing factor (AIF), Bcl-2 or Bcl-xL. We suggest that the anti-apoptotic effect of JNK inhibition by JBD is independent of the transcription of major pro- and anti-apoptotic genes, but may be exerted at the translational or posttranslational level.

Moderate to vigorous physical activity and sedentary time and cardiometabolic risk factors in children and adolescents.

CONTEXT: Sparse data exist on the combined associations between physical activity and sedentary time with cardiometabolic risk factors in healthy children. OBJECTIVE: To examine the independent and combined associations between objectively measured time in moderate- to vigorous-intensity physical activity (MVPA) and sedentary time with cardiometabolic risk factors. DESIGN, SETTING, AND PARTICIPANTS: Pooled data from 14 studies between 1998 and 2009 comprising 20 871 children (aged 4-18 years) from the International Children's Accelerometry Database. Time spent in MVPA and sedentary time were measured using accelerometry after reanalyzing raw data. The independent associations between time in MVPA and sedentary time, with outcomes, were examined using meta-analysis. Participants were stratified by tertiles of MVPA and sedentary time. MAIN OUTCOME MEASURES: Waist circumference, systolic blood pressure, fasting triglycerides, high-density lipoprotein cholesterol, and insulin. RESULTS: Times (mean [SD] min/d) accumulated by children in MVPA and being sedentary were 30 (21) and 354 (96), respectively. Time in MVPA was significantly associated with all cardiometabolic outcomes independent of sex, age, monitor wear time, time spent sedentary, and waist circumference (when not the outcome). Sedentary time was not associated with any outcome independent of time in MVPA. In the combined analyses, higher levels of MVPA were associated with better cardiometabolic risk factors across tertiles of sedentary time. The differences in outcomes between higher and lower MVPA were greater with lower sedentary time. Mean differences in waist circumference between the bottom and top tertiles of MVPA were 5.6 cm (95% CI, 4.8-6.4 cm) for high sedentary time and 3.6 cm (95% CI, 2.8-4.3 cm) for low sedentary time. Mean differences in systolic blood pressure for high and low sedentary time were 0.7 mm Hg (95% CI, -0.07 to 1.6) and 2.5 mm Hg (95% CI, 1.7-3.3), and for high-density lipoprotein cholesterol, differences were -2.6 mg/dL (95% CI, -1.4 to -3.9) and -4.5 mg/dL (95% CI, -3.3 to -5.6), respectively. Geometric mean differences for insulin and triglycerides showed similar variation. Those in the top tertile of MVPA accumulated more than 35 minutes per day in this intensity level compared with fewer than 18 minutes per day for those in the bottom tertile. In prospective analyses (N = 6413 at 2.1 years' follow-up), MVPA and sedentary time were not associated with waist circumference at follow-up, but a higher waist circumference at baseline was associated with higher amounts of sedentary time at follow-up. CONCLUSION: Higher MVPA time by children and adolescents was associated with better cardiometabolic risk factors regardless of the amount of sedentary time.

Neurally Adjusted Ventilatory Assist (NAVA) improves the matching of diaphragmatic electrical activity and tidal volume in comparison to pressure support (PS) under non invasive ventilation

INTRODUCTION. Patient-ventilator asynchrony is a frequent issue in non invasivemechanical ventilation (NIV) and leaks at the patient-mask interface play a major role in itspathogenesis. NIV algorithms alleviate the deleterious impact of leaks and improve patient-ventilator interaction. Neurally adusted ventilatory assist (NAVA), a neurally triggered modethat avoids interferences between leaks and the usual pneumatic trigger, could further improvepatient-ventilator interaction in NIV patients.OBJECTIVES. To evaluate the feasibility ofNAVAin patients receiving a prophylactic postextubationNIV and to compare the respective impact ofPSVandNAVAwith and withoutNIValgorithm on patient-ventilator interaction.METHODS. Prospective study conducted in 16 beds adult critical care unit (ICU) in a tertiaryuniversity hospital. Over a 2 months period, were included 17 adult medical ICU patientsextubated for less than 2 h and in whom a prophylactic post-extubation NIV was indicated.Patients were randomly mechanically ventilated for 10 min with: PSV without NIV algorithm(PSV-NIV-), PSV with NIV algorithm (PSV-NIV+),NAVAwithout NIV algorithm (NAVANIV-)and NAVA with NIV algorithm (NAVA-NIV+). Breathing pattern descriptors, diaphragmelectrical activity, leaks volume, inspiratory trigger delay (Tdinsp), inspiratory time inexcess (Tiexcess) and the five main asynchronies were quantified. Asynchrony index (AI) andasynchrony index influenced by leaks (AIleaks) were computed.RESULTS. Peak inspiratory pressure and diaphragm electrical activity were similar in thefour conditions. With both PSV and NAVA, NIV algorithm significantly reduced the level ofleak (p\0.01). Tdinsp was not affected by NIV algorithm but was shorter in NAVA than inPSV (p\0.01). Tiexcess was shorter in NAVA and PSV-NIV+ than in PSV-NIV- (p\0.05).The prevalence of double triggering was significantly lower in PSV-NIV+ than in NAVANIV+.As compared to PSV,NAVAsignificantly reduced the prevalence of premature cyclingand late cycling while NIV algorithm did not influenced premature cycling. AI was not affectedby NIV algorithm but was significantly lower in NAVA than in PSV (p\0.05). AIleaks wasquasi null with NAVA and significantly lower than in PSV (p\0.05).CONCLUSIONS. NAVA is feasible in patients receiving a post-extubation prophylacticNIV. NAVA and NIV improve patient-ventilator synchrony in different manners. NAVANIV+offers the best patient-ventilator interaction. Clinical studies are required to assess thepotential clinical benefit of NAVA in patients receiving NIV.

A repeated GGA motif is critical for the activity and stability of the riboregulator RsmY of Pseudomonas fluorescens.

The riboregulator RsmY of Pseudomonas fluorescens strain CHA0 is an example of small regulatory RNAs belonging to the global Rsm/Csr regulatory systems controlling diverse cellular processes such as glycogen accumulation, motility, or formation of extracellular products in various bacteria. By binding multiple molecules of the small regulatory protein RsmA, RsmY relieves the negative effect of RsmA on the translation of several target genes involved in the biocontrol properties of strain CHA0. RsmY and functionally related riboregulators have repeated GGA motifs predicted to be exposed in single-stranded regions, notably in the loops of hairpins. The secondary structure of RsmY was corroborated by in vivo cleavage with lead acetate. RsmY mutants lacking three or five (out of six) of the GGA motifs showed reduced ability to derepress the expression of target genes in vivo and failed to bind the RsmA protein efficiently in vitro. The absence of GGA motifs in RsmY mutants resulted in reduced abundance of these transcripts and in a shorter half-life (< or = 6 min as compared with 27 min for wild type RsmY). These results suggest that both the interaction of RsmY with RsmA and the stability of RsmY strongly depend on the GGA repeats and that the ability of RsmY to interact with small regulatory proteins such as RsmA may protect this RNA from degradation.

Cytochrome P450 1A2 activity and inducibility: impact of smoking, smoking cessation and genetic polymorphisms

Aims: Cytochrome P4501A2 (CYP1A2) is involved in the metabolism of severaldrugs (clozapine, olanzapine, theopylline, caffeine, etc) and is induced by smoking.This can result in decreased plasma levels of drugs metabolized by thisisoenzyme, causing a decrease in therapeutic response. After quitting smoking,increased plasma levels can lead to adverse effects of the concerned drugs, such asconfusion and seizures, described under clozapine treatment. The present studyaimed to examine the variation of CYP1A2 activity in a large group of smokersbefore and after smoking cessation. Moreover, we aimed to determine whethergenetic polymorphisms of CYP1A2 gene could influence the inducibility ofCYP1A2. Methods: CYP1A2 activity was determined by the paraxanthine/caffeineratio in 194 smokers and in 118 of them being abstinent during a 4-weekperiod. Participants were genotyped for CYP1A2*1F (rs762551), *1D(rs35694136) and *1C (rs2069514) polymorphisms. Results: Smokers had higherCYP1A2 activity (1.55-fold; p < 0.0001). Individual change of CYP1A2 activityafter smoking cessation ranged from 1.0-fold (no change) to 7.3-fold decreasedactivity. In five participants with low initial CYP1A2 activity, an increase wasobserved after smoking cessation. During smoking, CYP1A2*1F (p = 0.005), CYP1A2*1D (p = 0.014), the number of cigarettes/day (p = 0.012), contraceptives use(p < 0.001) and - 163A/- 2467T/- 3860G haplotype (p = 0.002) influencedCYP1A2 activity, while after quitting smoking, CYP1A2*1F (p = 0.017) and contraceptives(p = 0.05) did. No influence of CYP1A2 polymorphisms on the inducibilityof CYP1A2 was observed. Conclusion: Higher CYP1A2 activity wasmeasured in smokers, but with a large interindividual variability of its inductionby smoking. Careful clinical management with the help of therapeutic drug monitoringis therefore needed for patients receiving drugs which are metabolized byCYP1A2, who stop or start smoking. Unidentified genetic variations in theCYP1A2 gene and/or in other genes controlling CYP1A2 activity and other environmentalfactors could be responsible of the observed differences in CYP1A2enzymatic activity and inducibility.