Association between Adherence to Nutritional Guidelines,the Metabolic Syndrome and Adiposity Markers in a French Adult General Population

Introduction

Few studies have focused on the association between diet quality scores and the Metabolic Syndrome (MetS), a multi-component condition predictive of cardiovascular diseases (CVD) and death. The present study aims at investigating, in a cross-sectional design, the association between adherence to the French dietary guidelines through an a priori score – the French Nutrition and Health Program-Guideline Score (PNNS-GS) – and cardiovascular risk factors (CVRF) including the MetS and adiposity markers.

Methods

7902 French adults participating in the NutriNet-Santé study (an on-going web-based cohort study) attended a clinical and biological examination between January 2011 and November 2012: a fasting blood sample was drawn, blood pressure and body composition (bio-impedance) were measured. Multivariate linear and logistic regression models were used to assess the association between PNNS-GS and CVRF or the MetS.

Results

An increase of PNNS-GS was significantly negatively associated with waist circumference (WC), systolic and diastolic blood pressure (SBP and DBP) and serum triglycerides concentrations. From bottom to top quartile of PNNS-GS, SBP decreased from 129.9 to 128.8 mm Hg, DBP from 76.7 to 75.9 mm Hg, serum triglycerides concentrations from 110.8 to 104.6 mg/dL and WC from 94.8 to 90.1 cm for men and 81.3 to 78.9 cm for women. All adiposity markers (waist and hip circumference, % body fat, % trunk fat, % leg fat) were markedly reduced across quartiles of PNNS-GS and linearly. Individuals with a better PNNS-GS (quartile 4 vs quartile 1) were less likely to have the MetS (OR=0.71, 95% CI: 0.56-0.89).

Conclusion

The negative association between a higher adherence to the French dietary guidelines and a number of CVRF, the MetS prevalence and regional adiposity supports the importance of promoting the PNNS dietary guidelines in the population for the prevention of cardiometabolic abnormalities and hence, cardiovascular diseases.     

Interim analysis of safety and efficacy of ruxolitinib in patients with myelofibrosis and low platelet counts

Background

Ruxolitinib, a Janus kinase 1 and 2 inhibitor, demonstrated improvements in spleen volume, symptoms, and survival over placebo and best available therapy in intermediate-2 or high-risk myelofibrosis patients with baseline platelet counts ≥100?×?10⁹/L in phase III studies. The most common adverse events were dose-dependent anemia and thrombocytopenia, which were anticipated because thrombopoietin and erythropoietin signal through JAK2. These events were manageable, rarely leading to treatment discontinuation. Because approximately one-quarter of MF patients have platelet counts <100?×?10⁹/L consequent to their disease, ruxolitinib was evaluated in this subset of patients using lower initial doses. Interim results of a phase II study of ruxolitinib in myelofibrosis patients with baseline platelet counts of 50-100?×?10⁹/L are reported.

Methods

Ruxolitinib was initiated at a dose of 5 mg twice daily (BID), and doses could be increased by 5 mg once daily every 4 weeks to 10 mg BID if platelet counts remained adequate. Additional dosage increases required evidence of suboptimal efficacy. Assessments included measurement of spleen volume by MRI, MF symptoms by MF Symptom Assessment Form v2.0 Total Symptom Score [TSS]), Patient Global Impression of Change (PGIC); EORTC QLQ-C30, and safety/tolerability.

Results

By week 24, 62% of patients achieved stable doses ≥10 mg BID. Median reductions in spleen volume and TSS were 24.2% and 43.8%, respectively. Thrombocytopenia necessitating dose reductions and dose interruptions occurred in 12 and 8 patients, respectively, and occurred mainly in patients with baseline platelet counts ≤75?×?10⁹/L. Seven patients experienced platelet count increases ≥15?×?10⁹/L. Mean hemoglobin levels remained stable over the treatment period. Two patients discontinued for adverse events: 1 for grade 4 retroperitoneal hemorrhage secondary to multiple and suspected pre-existing renal artery aneurysms and 1 for grade 4 thrombocytopenia.

Conclusions

Results suggest that a low starting dose of ruxolitinib with escalation to 10 mg BID may be appropriate in myelofibrosis patients with low platelet counts.

Trial registration

ClinicalTrials.gov:NCT01348490.

     

Molecular Dynamics Reveal Binding Mode of Glutathionylspermidine by Trypanothione Synthetase

The trypanothione synthetase (TryS) catalyses the two-step biosynthesis of trypanothione from spermidine and glutathione and is an attractive new drug target for the development of trypanocidal and antileishmanial drugs, especially since the structural information of TryS from Leishmania major has become available. Unfortunately, the TryS structure was solved without any of the substrates and lacks loop regions that are mechanistically important. This contribution describes docking and molecular dynamics simulations that led to further insights into trypanothione biosynthesis and, in particular, explains the binding modes of substrates for the second catalytic step. The structural model essentially confirm previously proposed binding sites for glutathione, ATP and two Mg²⁺ ions, which appear identical for both catalytic steps. The analysis of an unsolved loop region near the proposed spermidine binding site revealed a new pocket that was demonstrated to bind glutathionylspermidine in an inverted orientation. For the second step of trypanothione synthesis glutathionylspermidine is bound in a way that preferentially allows N¹-glutathionylation of N⁸-glutathionylspermidine, classifying N⁸-glutathionylspermidine as the favoured substrate. By inhibitor docking, the binding site for N⁸-glutathionylspermidine was characterised as druggable.     

Depletion of the thioredoxin homologue tryparedoxin impairs antioxidative defence in African trypanosomes

In trypanosomes, the thioredoxin-type protein TXN (tryparedoxin) is a multi-purpose oxidoreductase that is involved in the detoxification of hydroperoxides, the synthesis of DNA precursors and the replication of the kinetoplastid DNA. African trypanosomes possess two isoforms that are localized in the cytosol and in the mitochondrion of the parasites respectively. Here we report on the biological significance of the cTXN (cytosolic TXN) of Trypanosoma brucei for hydroperoxide detoxification. Depending on the growth phase, the concentration of the protein is 3-7-fold higher in the parasite form infecting mammals (50-100 microM) than in the form hosted by the tsetse fly (7-34 microM). Depletion of the mRNA in bloodstream trypanosomes by RNA interference revealed the indispensability of the protein. Proliferation and viability of cultured trypanosomes were impaired when TXN was lowered to 1 muM for more than 48 h. Although the levels of glutathione, glutathionylspermidine and trypanothione were increased 2-3.5-fold, the sensitivity against exogenously generated H2O2 was significantly enhanced. The results prove the essential role of the cTXN and its pivotal function in the parasite defence against oxidative stress.     

Sachet water consumption as a risk factor for cholera in urban settings: Findings from a case control study in Kinshasa,Democratic Republic of the Congo during the 2017–2018 outbreak

BackgroundBehavioural risk factors for cholera are well established in rural and semi-urban contexts, but not in densely populated mega-cities in Sub-Saharan Africa. In November 2017, a cholera epidemic occurred in Kinshasa, the Democratic Republic of the Congo, where no outbreak had been recorded for nearly a decade. During this outbreak, we investigated context-specific risk factors for cholera in an urban setting among a population that is not frequently exposed to cholera.Methodology/Principal findingsWe recruited 390 participants from three affected health zones of Kinshasa into a 1:1 matched case control study. Cases were identified from cholera treatment centre admission records, while controls were recruited from the vicinity of the cases’ place of residence. We used standardized case report forms for the collection of socio-demographic and behavioural risk factors. We used augmented backward elimination in a conditional logistic regression model to identify risk factors.The consumption of sachet water was strongly associated with the risk of being a cholera case (p-value 0.019), which increased with increasing frequency of consumption from rarely (OR 2.2, 95% CI 0.9–5.2) to often (OR 4.0, 95% CI 1.6–9.9) to very often (OR 4.1, 95% CI 1.0–16.7). Overall, more than 80% of all participants reported consumption of this type of drinking water. The risk factors funeral attendance and contact with someone suffering from diarrhoea showed a p-value of 0.09 and 0.08, respectively. No socio-demographic characteristics were associated with the risk of cholera.Conclusions/SignificanceDrinking water consumption from sachets, which are sold informally on the streets in most Sub-Saharan African cities, are an overlooked route of infection in urban cholera outbreaks. Outbreak response measures need to acknowledge context-specific risk factors to remain a valuable tool in the efforts to achieve national and regional targets to reduce the burden of cholera in Sub-Saharan Africa.     

Extant and potential vegetation of an old-growth maritime Ilex opaca forest

The extant and potential (seed bank) vegetation of a rare maritime holly forest on Fire Island, New York was described to assess whether treefall gaps act as a mechanism for the persistence of the species composition of this plant community over time. The Sunken Forest overstory is dominated by Ilex opaca, Amelanchier canadensis and Sassafras albidum. A survey of canopy gaps indicated canopy openings compose 11.3% of the land within the Sunken Forest (16 ha). The composition and density of the seed bank were described using the emergence method. Germination from soil samples placed in the greenhouse was monitored over 2 years. Sixteen species germinated with an average propagule density of 215±41 germinants per square metre. An early successional species (Rhus copallinum) dominated the seed bank, but the late-successional, shade-tolerant I. opaca was also present. Though only one species in the seed bank did not appear in the current vegetation, species abundance differed between vegetation strata. The mean cover and density of the ground-layer flora were higher beneath treefall gaps than closed canopy. Sapling density did not differ between the two canopy conditions, but the dominant species differed with A. canadensis occupying several closed canopy plots and P. serotina saplings appearing more often in gap plots. Most of the dominant canopy species are present in the seed bank and ground layer but are not present in the shrub and sapling layer, with the exception of A. canadensis. Current (2002) sapling density is lower than three decades ago for all species except P. serotina, which is now the dominant woody species in the Sunken Forest understory. The results of this study indicate that if the cause of the sapling reduction is lessened or removed, the characteristic species of the overstory of this unusual plant community may rebound and redevelop a sapling and shrub layer akin to that present before the increase in Odocoileus virginianus on the island.     

Caspase-15 is autoprocessed at two sites that contain an aspartate residue in the P1' position

Our recent characterization of porcine caspase-15 suggested that the amino terminus of the small catalytic subunit is formed by proteolytic processing between the consecutive aspartate residues D277 and D278. Since a charged residue (D278) is highly unusual in the P1' position of a caspase cleavage site, we further characterized the mechanism of caspase-15 autoproteolysis. Amino acid sequence alignments showed that D277 and D278 as well as another pair of aspartates, D270 and D271, were evolutionarily conserved among species of the mammalian clade Laurasiatheria. Site-directed mutations of these four residues and analysis of recombinant proteins showed that D270 was crucial for autoproteolysis whereas the three other aspartates were dispensable for separation of the catalytic subunits. Mutation of D270 prevented catalytic activation and abolished subsequent processing at D277. Together with previous reports, our results show that caspase-15, unlike all other caspases, efficiently cleaves sites with an aspartate in the P1' position.     

Can dim light melatonin onset be predicted by the timing of sleep in patients with possible circadian sleep-wake rhythm disorders?

Dim Light Melatonin Onset (DLMO) is a reliable marker of the endogenous circadian rhythm. To determine if sleep timing can predict DLMO, we investigated the relationship between sleep timing and DLMO in patients in various circadian sleep-wake rhythm disorders (CSWRDs), ages and genders. We found that correlations were only moderate between DLMO and sleep-onset in the complete data-set, but they increased in patients with delayed sleep-wake phase disorder (DSWPD), DSWPD patients with a regular sleep pattern and patients with advanced sleep-wake phase disorder (ASWPD); the levels of correlation were r = 0.542, 0.657, 0.728 and 0.814, respectively. In DSWPD patients with a regular sleep pattern, mid-sleep strongly correlated (r = 0.839) with DLMO. Correlation in other CSRWDs was not significant. DLMO, sleep-onset and age were most discriminated factors between the various CSRWDs. Estimation of DLMO is only possible in patients with ASWPD and in DSWPD patients with a regular sleep pattern.     

Fiber Swap between Adenovirus Subgroups B and C Alters Intracellular Trafficking of Adenovirus Gene Transfer Vectors

Following receptor binding and internalization, intracellular trafficking of adenovirus (Ad) among subgroups B and C is different, with significant amounts of Ad serotype 7 (Ad7) (subgroup B) virions found in cytoplasm during the initial hours of infection while Ad5 (subgroup C) virions rapidly translocate to the nucleus. To evaluate the role of the fiber in these differences, we examined intracellular trafficking of Ad5, Ad7, and Ad5f7 (a chimeric vector composed of the Ad5 capsid with the fiber replaced by the Ad7 fiber) by conjugating Ad capsids directly with Cy3 fluorescent dye, permitting the trafficking of the capsids to be examined by fluorescence microscopy. The human lung carcinoma cell line A549 was infected with Cy3-conjugated viruses for 10 min followed by a 1-h incubation. Ad5 virions rapidly translocated to the nucleus (within 1 h of infection), while Ad7 virions were widely distributed in the cytoplasm at the same time point. Interestingly, chimeric Ad5f7 virions behaved similarly to Ad7 but not Ad5. In this regard, the percentages of nuclear localization of Ad5, Ad7, and Ad5f7 at 1 h following infection were 72% +/- 4%, 32% +/- 6%, and 38% +/- 2%, respectively. Consistent with these observations, fluorescence in situ hybridization demonstrated that most of the Ad5 DNA was detected at the nucleus after 1 h, but at the same time point, DNA of Ad7 and Ad5f7 was distributed in both the nucleus and cytoplasm. Quantification of the kinetics of Ad genomic DNA delivery to the nucleus using a fluorogenic probe-based PCR assay (TaqMan PCR) demonstrated that the percentages of nuclear association of Ad5 DNA and Ad5f7 DNA at 1 h postinfection were 80% +/- 13% and 43% +/- 1%, respectively. Although it has been generally accepted that Ad fiber protein mediates attachment of virions to cells and that fibers dissociate during endocytic uptake, these data suggest that in addition to mediating binding to the cell surface, fiber likely modulates intracellular trafficking as well.     

Trees and streams: the efficiency of branching patterns

Extending the analysis of branching patterns of the drainage net of rivers, originated by Horton, the relation of average numbers and lengths of tree branches to size of branch was investigated. Size of branch was defined by branch order, or its position in the hierarchy of tributaries. It was found that, as in river drainage nets, there is a definite logarithmic relation between branch order and lengths and numbers.