Folic acid supplementation during the preconception period: A systematic review and meta-analysis.

Guidelines recommend that women take folic acid supplements in the preconception period to prevent neural tube defects (NTDs) in their offspring. Estimates of adherence to this recommendation across different countries worldwide have not been synthesized. Medline, CINAHL, and EMBASE were systematically searched to identify studies reporting the prevalence of preconception folic acid supplementation. Pooled prevalence estimates for each country (where data were available) were calculated; and differences based on demographic, methodological, and study quality characteristics were examined. Of 3372 titles and abstracts screened, 722 full-texts were reviewed and 105 articles that reported 106 estimates of preconception folic acid supplementation in 34 countries were included. Pooled prevalence estimates were 32-51% in North America, 9-78% in Europe, 21-46% in Asia, 4-34% in the Middle East, 32-39% in Australia/New Zealand, and 0% in Africa. No South American studies were identified. Higher supplementation prevalence was observed in studies that had more highly educated samples, were conducted in fertility clinics, and assessed folic acid use via self-report. Of note, only 32% and 28% of studies reported timing of folic acid use and adherence to folic acid, respectively. Preconception folic acid supplementation is highly variable worldwide and many women may not achieve sufficient folate levels to prevent NTDs. To better understand non-adherence, recommendations for future research include: more explicit reporting of methodology, more detailed assessment of folic acid use, assessment of variables potentially relevant to folic acid use, and surveillance of folic acid use in a greater diversity of countries, especially in the developing world.

Fuel poverty as a major determinant of perceived health: the case of France.

OBJECTIVES: The number of households in fuel poverty is growing. Individuals increasingly struggle to heat their homes, and therefore, a growing number of individuals are exposed to low temperatures, which can affect their health. This study sought to determine the link between a subjective measure of fuel poverty (self-reported feeling cold) and self-reported health. The impact of other particular individual and environmental features on self-reported health were also analysed. STUDY DESIGN: Econometric analysis. METHODS: The study method uses self-reported perception of thermal discomfort (self-reported feeling cold) as a proxy for fuel poverty. The French database of the Healthcare and Insurance survey carried by the Institute for Research and Information on Health Economics (IRDES) was used to estimate a dichotomous probit model. RESULTS: The estimation allows us to infer a negative impact of fuel poverty on self-reported health. Thus, a person in fuel poverty is 2.36 percentage points more likely to report poor or fair health status than a person who is not in fuel poverty. CONCLUSION: It may be appropriate to reduce the impacts of fuel poverty to provide support for the most vulnerable categories of individuals with respect to the health impacts of fuel poverty and cold homes, e.g., chronic patients who experience difficulty heating their homes.

In situ continuous monitoring of dissolved gases (N2, O2, CO2, H2) prior to H2 injection in an aquifer (Catenoy, France) by on-site Raman and infrared spectroscopies: instrumental assessment and geochemical baseline establishment.

The establishment of a baseline of gases from an aquifer appears to be an essential prerequisite for monitoring and securing underground storage operations such as the storage of carbon dioxide (carbon capture and storage: CCS), methane or hydrogen. This study describes an innovative metrological technique dedicated to the in situ and continuous quantification of dissolved gases (CO2, O2, N2, CH4 and H2) in a shallow aquifer, on the site of Catenoy (Paris Basin) with a water table at a depth of 13 m. Monitoring was carried out from May 7, 2019 to November 19, 2019, before the simulation of H2 injection. Gases as vapors were collected from the aquifer through a nine-meter long, half-permeable polymer membrane positioned below a packer in a 25-meter deep well. Collected gases were analyzed simultaneously at the surface by fiber Raman (CO2, O2, N2, CH4 and H2) and infrared sensors (CO2). Gas concentrations were determined from Raman and infrared data, and then converted into dissolved concentrations using Henry's law. The dissolved gas concentrations were about constant over the 6 months period with average values of 31-40 mg L-1 (CO2), 8 mg L-1 (O2), 17 mg L-1 (N2), and 0 mg L-1 (H2, CH4) indicating a very low variability in the aquifer. This is believed to allow for rapid detection of any possible abnormal concentration variation, in particular linked to an accidental arrival of gases such as hydrogen. Such an online gas measurement system can be deployed as is on any site type of underground storage without any need for adaptation.

The design of linear peptides that fold as monomeric beta-sheet structures.

Current knowledge about the determinants of beta-sheet formation has been notably improved by the structural and kinetic analysis of model peptides, by mutagenesis experiments in proteins and by the statistical analysis of the protein structure database (Protein Data Bank; PDB). In the past year, several peptides comprising natural and non-natural amino acids have been designed to fold as monomeric three-stranded beta-sheets. In all these cases, the design strategy has involved both the statistical analysis of the protein structure database and empirical information obtained in model beta-hairpin systems and in proteins. Only in one case was rotamer analysis performed to check for the compatibility of the sidechain packing. It is foreseeable that, in future designs, algorithms exploring the sequence and conformational space will be employed. For the design of small proteins (less than 30 amino acids), questions remain about the demonstration of two-state behavior, the formation of a well-defined network of mainchain hydrogen bonds and the quantification of the structured populations.

Steroid metabolism and steroid receptors in dimethylbenz(a)anthracene-induced rat mammary tumors.

Mammary tumors were induced in rats by treatment with dimethylbenz(a)anthracene. Cytosol receptors for 17 beta-estradiol and progesterone were estimated by means of sucrose density gradient centrifugation, and the metabolism of [14C]progesterone, [14C]testosterone, and 17 beta-[14C]estradiol by minced tumor tissue was studied. The estradiol receptor (ER) and progesterone receptor (PR) levels of the tumors varied considerably from less than 5 to 48 fmol/mg protein for ER and to 243 fmol/mg protein for PR. Considering a receptor level lower than 5 fmol/mg protein to be negative, four groups of tumors were found: ER-negative and PR-negative; ER-positive and PR-negative; ER-negative and PR-positive; ER-positive and PR-positive. In dimethylbenz(a)anthracene-induced tumor tissue, high 5 alpha-reductase and 20 alpha-hydroxysteroid dehydrogenase activities and somewhat lower 3 alpha-hydroxysteroid dehydrogenase and 6 alpha-hydroxylase activities were found. No aromatization was detectable. Steroids, especially estradiol, were also metabolized in a high degree to unextractable metabolites. It was concluded that steroid metabolism of dimethylbenz(a)anthracene-induced rat mammary tumors was not related to the ER and/or PR concentration of tumor tissue.

Elucidating the folding problem of alpha-helices: local motifs, long-range electrostatics, ionic-strength dependence and prediction of NMR parameters.

The information about the conformational behavior of monomeric helical peptides in solution, as well as the alpha-helix stability in proteins, has been previously utilized to derive a database with the energy contributions for various interactions taking place in an alpha-helix: intrinsic helical propensities, side-chain-side-chain interactions, main-chain-main-chain hydrogen bonds, and capping effects. This database was implemented in an algorithm based on the helix/coil transition theory (AGADIR). Here, we have modified this algorithm to include previously described local motifs: hydrophobic staple, Schellman motif and Pro-capping motif, new variants of these, and newly described side-chain-side-chain interactions. Based on recent experimental data we have introduced a position dependence of the helical propensities for some of the 20 amino acid residues. A new electrostatic model that takes into consideration all electrostatic interactions up to 12 residues in distance in the helix and random-coil conformations, as well as the effect of ionic strength, has been implemented. We have synthesized and analyzed several peptides, and used data from peptides already analysed by other groups, to test the validity of our electrostatic model. The modified algorithm predicts, with an overall standard deviation value of 6.6 (maximum helix is 100%), the helical, content of 778 peptides of which 223 correspond to wild-type and modified protein fragments. To improve the prediction potential of the algorithm and to have a direct comparison with nuclear magnetic resonance data, the algorithm now predicts the conformational shift of the CalphaH protons, 13Calpha and 3JalphaN values. We have found that for those peptides correctly predicted from the point of view of circular dichroism, the prediction of the NMR parameters is very good.

Amide hydrogen exchange and internal dynamics in the chemotactic protein CheY from Escherichia coli.

The backbone internal dynamics of the wild-type 129 amino acid alpha/beta parallel protein CheY and its double mutant F14N/P110G are analysed here by the hydrogen-exchange method. The F14N mutation is known to stabilise the protein and to accelerate refolding while P110G is destabilising and accelerates unfolding. We first assigned and characterised the double mutant by nuclear magnetic resonance (NMR), to try and discover any possible conformational change induced by the two mutations. The main difference between the two proteins is a favourable N-capping interaction of the newly introduced Asn14 side-chain at the beginning of the first alpha-helix (alpha-helix A). Second, we have measured the exchange rates in the wild-type and mutant CheY. In the first case the observed protection factors are slightly dispersed around an average value. According to their distribution in the structure, protein stability is highest on one face of the central beta-sheet, in the surroundings of the main hydrophobic core formed by side-chains of residues in beta-strands I, II and III and helices A and E. The mutations in the double mutant protein affect two distinct subdomains differently (from beta-strand I to III and from alpha-helix C to the end). In the second subdomain the number of protected protons is reduced with respect to those in the wild-type. This differential behaviour can be explained by a selective decrease in stability of the second folding subdomain produced by the P110G mutation and the opposite effect in the first subdomain, produced by the F14N mutation. alpha-Helix A, which is involved together with beta-strands I and III in the folding nucleus of CheY, shows the largest protection factors in both proteins.

Towards understanding a molecular switch mechanism: thermodynamic and crystallographic studies of the signal transduction protein CheY.

The signal transduction protein CheY displays an alpha/beta-parallel polypeptide folding, including a highly unstable helix alpha4 and a strongly charged active site. Helix alpha4 has been shown to adopt various positions and conformations in different crystal structures, suggesting that it is a mobile segment. Furthermore, the instability of this helix is believed to have functional significance because it is involved in protein-protein contacts with the transmitter protein kinase CheA, the target protein FliM and the phosphatase CheZ. The active site of CheY comprises a cluster of three aspartic acid residues and a lysine residue, all of which participate in the binding of the Mg(2+) needed for the protein activation. Two steps were followed to study the activation mechanism of CheY upon phosphorylation: first, we independently substituted the three aspartic acid residues in the active site with alanine; second, several mutations were designed in helix alpha 4, both to increase its level of stability and to improve its packing against the protein core. The structural and thermodynamic analysis of these mutant proteins provides further evidence of the connection between the active-site area and helix alpha 4, and helps to understand how small movements at the active site are transmitted and amplified to the protein surface.

Computer-aided design of beta-sheet peptides.

The design of beta-sheet proteins is still a challenge in the field of de novo protein design. Here, we have tested the validity of automatic design methods to create and/or improve beta-sheet peptides and proteins. We chose Betanova, a three-stranded beta-sheet peptide, as target system, and, as an automatic design tool, a protein design algorithm called PERLA (protein engineering rotamer library algorithm). PERLA was used to define both stabilising and destabilising single- and multiple-residue mutations of Betanova. Conformational analysis by NMR spectroscopy and far-UV circular dichroism (CD) allowed us to evaluate population differences among the set of designed peptides. Some of the new mutants are approximately 1 kcal/mol more stable than the wild-type peptide. Comparison of the scale of predicted and observed stabilities demonstrates that they are in good agreement for most peptides studied. Our results show that automatic design algorithms can be successfully applied to the design of beta-sheet peptides.

The N-linked oligosaccharides of the Fc epsilon receptors of rat basophilic leukemia cells.

This study was undertaken to investigate the nature and microheterogeneity of the carbohydrate moiety of the Fc epsilon receptors of RBL-CA10 and RBL-CA10.7 cells. Treatment using the glycosylation processing inhibitors, castanospermine (CN), 1-deoxymannojirimycin (DMJ), and swainsonine (SW) resulted in a decrease of the relative molecular mass (M(r)) of both the alpha-chain of the high affinity receptor for IgE, Fc epsilon RI(alpha), and the low affinity receptor for IgE, Fc epsilon RL. Exposure to DMJ had the greatest effect on the M(r), while CN seemed to lead to a decreased cell surface expression of Fc epsilon RI. Both receptors are largely resistant to endoglycosidase H as their M(r) decreased only by approximately 2 kDa. These results suggest that both receptors are composed primarily of complex oligosaccharides with a single high mannose, N-glycosylated site. Both Fc epsilon receptors become endoglycosidase H sensitive if first exposed to DMJ which indicates that the carbohydrate composition is indeed altered by this processing inhibitor presumably by blocking the formation of complex structures. When the Fc epsilon receptors were reduced and hydrolyzed by N-glycanase, the M(r) values for Fc epsilon RI(alpha) and Fc epsilon RL decreased to approximately 28 and 34-38 kDa respectively. In the case of Fc epsilon RI(alpha), this implies the presence of only a small amount of O-linked oligosaccharides.

Computational estimation of specific side chain interaction energies in alpha helices.

We have used a structure energy-based computer program developed for protein design, Perla, to provide theoretical estimates of all specific side chain-side chain interaction energies occurring in alpha helices. The computed side chain-side chain interaction energies were used as substitutes for the corresponding values used by the helix/coil transition algorithm, AGADIR. Predictions of peptide helical contents were nearly as successful as those obtained with the originally calibrated set of parameters; a correlation to experimentally observed alpha-helical populations of 0.91 proved that our theoretical estimates are reasonably correct for amino acid pairs that are frequent in our database of peptides. Furthermore, we have determined experimentally the previously uncharacterized interaction energies for Lys-Ile, Thr-Ile, and Phe-Ile amino acid pairs at i,i + 4 positions. The experimental values compare favorably with the computed theoretical estimates. Importantly, the computed values for Thr-Ile and Phe-Ile interactions are better than the energies based on chemical similarity, whereas for Lys-Ile they are similar. Thus, computational techniques can be used to provide precise energies for amino acid pairwise interactions, a fact that supports the development of structure energy-based computational tools for structure predictions and sequence design.

Computer-assisted re-design of spectrin SH3 residue clusters.

We have developed a protein design computer program, called Perla, which performs searches in sequence space to uncover optimal amino acid sequences for desired protein three-dimensional structures. Optimal sequences are localised at the minima of a sequence-structure energy landscape defined using a complex scoring function (an all-atom molecular mechanics force field plus statistical terms including entropy and solvation) measured with respect to a reference state simulating a denatured protein. Sequence choices eventually optimise side chain packing, secondary structure propensities, and hydrogen bonding and electrostatics interactions. Perla was used to re-design clusters of residues of the SH3 domain of alpha-spectrin. Several mutant proteins were produced and characterised. Some of our designed proteins have significantly higher stabilities (stability enhancements about 0.25, 0.70 and 1.0 kcal mol(-1)) than the wild-type protein. These successful protein re-designs, and similar examples found in the literature, establish the quality of the structure-based computational approach to protein design.

Kinetic study of HCG induced decrease of microsomal 7 alpha-hydroxylase activity in rat testes.

Microsomes from rat testes were incubated with varying concentrations of 14C labelled testosterone and androstenedione. The production of 7 alpha-hydroxytestosterone and 7 alpha-hydroxyandrostenedione was followed; Km and Vm values were calculated from Lineweaver-Burk curves. A sustained treatment of rats with HCG resulted in a considerable decrease of the maximal 7 alpha-hydroxylation rats (Vm) whereas the Km value was not changed. Vm of microsomes from normal rats, when incubated with microsomes from HCG-treated animals, was also decreased substantially. It is concluded that HCG-induced depression of 7 alpha-hydroxylation capacity of testicular microsomes is at least in part due to non-competitive inhibition of the enzyme.

Influence of age on the formation of 5alpha-androstanediol and 7alpha-hydroxy-testosterone by incubated rat testes.

Testes from rats of different ages were indubated with or without tritiated testosterone. The exogenously-added or endogenously-produced testosterone is mainly metabolized to 7alpha-hydroxylated testosterone in adult animals, and to 5alpha-reduced metabolites (especially 5alpha-androstanediol) in immature animals.

Effect of tamoxifen on the activity of enzymes of testicular steroidogenesis.

Testicular homogenates of tamoxifen-treated rats were incubated with labeled steroid precursors (progesterone, 17 alpha-hydroxyprogesterone, dehydroepiandrosterone, androstenedione or testosterone) in order to study the effect of tamoxifen on testicular steroidogenesis. The results indicate that a 9 day treatment with a daily dose of 1 mg tamoxifen produces a reduction of the synthesis of testosterone. Inhibition of the 17 alpha-hydroxylase and C17,20-desmolase enzyme systems was observed together with an increased 20 alpha-hydroxysteroid dehydrogenase activity.

Pre-exercise branched-chain amino acid administration increases endurance performance in rats.

This study investigated the effects of pre-exercise branched-chain amino acid (BCAA) administration on blood ammonia levels and on time to exhaustion during treadmill exercise in rats. Adult female Wistar rats were trained on a motor driven treadmill. After a 24-h fast, rats were injected intraperitoneally (i.p.) with 1 mL of placebo or BCAA (30 mg), 5 min before performing 30 min of submaximal exercise (N = 18) or running to exhaustion (N = 12). In both cases, rats were sacrificed immediately following exercise, and blood was collected for the measurement of glucose, nonesterified fatty acid (NEFA), lactic acid, BCAA, ammonia, and free-tryptophan (free-TRP) levels. Control values were obtained from sedentary rats that were subjected to identical treatments and procedures (N = 30). Plasma BCAA levels increased threefold within 5 min after BCAA administration. Mean run time to exhaustion was significantly longer (P < 0.01) after BCAA administration (99 +/- 9 min) compared with placebo (76 +/- 4 min). During exercise, blood ammonia levels were significantly higher (P < 0.01) in the BCAA treated compared with those in the placebo treated rats both in the 30-min exercise bout (113 +/- 25 mumol.L-1 (BCAA) vs 89 +/- 16 mumol.L-1) and following exercise to exhaustion (186 +/- 44 mumol.L-1 (BCAA) vs 123 +/- 19 mumol.L-1). These data demonstrate that BCAA administration in rats results in enhanced endurance performance and an increase in blood ammonia during exercise.

Multifunctionalized alpha,beta-cyclopentenones from C-2 and C-4-ulopyranosyl compounds: a stereospecific rearrangement initiated by base.

Base treatment of O-benzyl protected C-2- or C-4-ulopyranosyl compounds (4 alpha, 4 beta, and 11) by either 10% Et(3)N or 1% K(2)CO(3) in MeOH initiated a beta elimination to afford alpha,beta-unsaturated C-ulopyranosyl compounds (5 alpha, 5 beta, and 12), which further rearranged in a stereocontrolled manner to multifuctionalized alpha,beta-cyclopentenones (6 and 14) in 70-80% yield. Both C-alpha- and C-beta-2-ulosides (5 alpha and 5 beta) produced the same cyclopentenone 6, indicating that a 1,2-enolate is formed prior to the cleavage of the C-5--O bond. Because 6 is racemic, it was probably formed by the intramolecular cycloaldolization of two equally populated enantiomeric intermediates. When treated with 90% Et(3)N in MeOH, 5 alpha yielded almost exclusively 15 (isomer of 6), which was formed by a migration of the double bond in 5 alpha during the previously described rearrangement. Thus either 6 or 15 was the major product, depending on the base used.

Acute dysautonomia and arteriovenous malformation of the brain stem.

A patient with acute pure dysautonomia also suffered from several episodes of transient diplopia and hemiparesthesiae which were related to an arteriovenous malformation in the pons. The clinical presentations and the radiological diagnosis of arteriovenous malformations of the brain stem are reviewed, as well as the semiology and etiopathogeny of acute dysautonomia. No relationship was found between these two rare affections.

[From empirical 'dietetics' to rational dietetics]. / Van empirische 'dietetiek' naar rationele dietetiek.

From the outset, the terms 'dietetics' and 'diet' applied in their general acceptance to all the measures, whether or not alimentary, that can provide optimal living conditions for both the healthy and the diseased. In that meaning they are synonymous with hygiene or way of life. In their more restricted acceptance, which will be used henceforth, the terms apply to the choice of food and beverages which promotes or restores health of normal and sick people. In its most restricted meaning, the term 'diet' is confined to the nutrition of the sick, consisting either in a more or less drastic limitation of food intake, or in the prescription of specific foods. Due to the absence of scientific knowledge concerning the processes of life in general, and in particular concerning the physiology of the digestive system and the metabolism, the 'dietetic' rules and principles were governed until the middle of the nineteenth century by empiricism with a strong background of intuition, tradition, magic and religion. In his continuous struggle for life, man has been confronted with the dramatic consequences of the ingestion of toxic and spoiled food. Nausea, vomiting, diarrhea, cramps and eventually death have soon been linked with the ingestion of particular food, although the symptoms were attributed to supernatural forces. Intuitively and later by laws and prohibition, the use of certain foods was to be avoided or was forbidden. Moreover, with the development of cultures and civilizations food and food intake have acquired -besides their vital necessity-social and often magic-religious values which sometimes resulted in food taboos. In most civilizations these taboos have particulars in common: they are mainly directed against food of animal origin, more against meat than fish and particularly against red meat, which is being considered as symbol of strength and power and as endowed with exciting and stimulatory properties. The meat taboos are selective for some animals or parts of an animal, but what is allowed in some cultures is forbidden in others. More or less severe and long lasting abstinence from food or fasting was also self-inflicted or imposed to individuals or whole populations by religion, sometimes seemingly on hygienic grounds but in most cases without any logic reason. Since the earliest time, diets take-together with other dietetic measures-a prevailing place in the treatment of the sick and sickness. Most alimentary prescriptions are based on a more or less drastic restriction of food and - particularly in the seventeenth century with the iatrochemical school - also of fluids. The restrictions were not only quantitative, but also qualitative with restriction of meat consumption-particularly of red meat-and the prescription of more or less diluted decoctions of barley (infusions) or broth. The numerous works on 'dietetics' published-thanks to the development of printing-from the seventeenth on through the nineteenth century concern mainly the description of foodstuffs and beverages available at the time, and of the ways of preparing them. They also provide indications concerning the way these foodstuffs can improve health and/or list which of them can be prescribed or must be avoided in the treatment of the sick and of specific diseases. Some of these 'dietetical' prescriptions and maxims seem perfectly valid from a scientific and therapeutical point of view, - at least according to our actual knowledge - however, many are totally ineffective or are ridiculous and even dangerous. Except for the "dietetical" measures imposed by public hygiene or by religion to everyone, most of the dieteticotherapeutical prescriptions (food restrictions, clysters, purgation, bleeding) involved only the small fraction of the population that could afford medical assistance. The common people - the majority - could afford neither medical help, nor food abuse - except for an occasional feast - and had only access to a limited quantity and choi

[Comparative study of the ideas about causes, disease mechanisms and therapies of the plague on the basis of the plague treatises of the Medical Faculty of Paris (1348-1349), of Joannes de Vesalia (after 1454) and of Thomas Montanus (1669)]. / Vergelijkende studie van de opvattingen omtrent oorzaken, ziektemechanismen en therapieën van pest op basis van de pesttraktaten van de medische faculteit te Parijs (1348-1349), van Joannes de Vesalia (na 1454), en van Thomas Montanus (1669).

The comparison between the consilium of the Faculty of Paris (14th century), and the treatises by Joannes de Vesalia (15th century) and by Thomas Montanus (17th century) shows that the concepts with regard to the causes and the mechanisms of and the proposed preventive and curative measures against the plague did in essence not change for over three centuries. In fact this is not very surprising, since the development of modern physiology and physiopathology only started gradually in the second half of the 19th century. Furthermore, the plague bacillus has only been identified in 1894. However, the preventive and curative measures against plague that are proposed in the three treatises, do not result from an uncontrolled imagination. Most of these measures have a rational basis and are the result of--although erroneous--concepts with regard to the causes and mechanisms of the disease.