Iron supplementation for unexplained fatigue in non-anaemic women: double blind randomised placebo controlled trial.

OBJECTIVE: To determine the subjective response to iron therapy in non-anaemic women with unexplained fatigue. DESIGN: Double blind randomised placebo controlled trial. SETTING: Academic primary care centre and eight general practices in western Switzerland. PARTICIPANTS: 144 women aged 18 to 55, assigned to either oral ferrous sulphate (80 mg/day of elemental iron daily; n=75) or placebo (n=69) for four weeks. MAIN OUTCOME MEASURES: Level of fatigue, measured by a 10 point visual analogue scale. RESULTS: 136 (94%) women completed the study. Most had a low serum ferritin concentration; <or= 20 microg/l in 69 (51%) women. Mean age, haemoglobin concentration, serum ferritin concentration, level of fatigue, depression, and anxiety were similar in both groups at baseline. Both groups were also similar for compliance and dropout rates. The level of fatigue after one month decreased by -1.82/6.37 points (29%) in the iron group compared with -0.85/6.46 points (13%) in the placebo group (difference 0.95 points, 95% confidence interval 0.32 to 1.62; P=0.004). Subgroups analysis showed that only women with ferritin concentrations <or= 50 microg/l improved with oral supplementation. CONCLUSION: Non-anaemic women with unexplained fatigue may benefit from iron supplementation. The effect may be restricted to women with low or borderline serum ferritin concentrations.

Monads in double categories

We extend the basic concepts of Street's formal theory of monads from the setting of 2-categories to that of double categories. In particular, we introduce the double category Mnd(C) of monads in a double category C and dene what it means for a double category to admit the construction of free monads. Our main theorem shows that, under some mild conditions, a double category that is a framed bicategory admits the construction of free monads if its horizontal 2-category does. We apply this result to obtain double adjunctions which extend the adjunction between graphs and categories and the adjunction between polynomial endofunctors and polynomial monads.

Lévy area for Gaussian processes: A double Wiener--Itô integral approach

"Vegeu el resum a l'inici del document del fitxer adjunt."

Bacterial overgrowth during treatment with omeprazole compared with cimetidine: a prospective randomised double blind study.

BACKGROUND: Gastric and duodenal bacterial overgrowth frequently occurs in conditions where diminished acid secretion is present. Omeprazole inhibits acid secretion more effectively than cimetidine and might therefore more frequently cause bacterial overgrowth. AIM: This controlled prospective study compared the incidence of gastric and duodenal bacterial overgrowth in patients treated with omeprazole or cimetidine. METHODS: 47 outpatients with peptic disease were randomly assigned to a four week treatment regimen with omeprazole 20 mg or cimetidine 800 mg daily. Gastric and duodenal juice were obtained during upper gastrointestinal endoscopy and plated for anaerobic and aerobic organisms. RESULTS: Bacterial overgrowth (> or = 10(5) cfu/ml) was present in 53% of the patients receiving omeprazole and in 17% receiving cimetidine (p < 0.05). The mean (SEM) number of gastric and duodenal bacterial counts was 6.0 (0.2) and 5.0 (0.2) respectively in the omeprazole group and 4.0 (0.2) and 4.0 (0.1) in the cimetidine group (p < 0.001 and < 0.01; respectively). Faecal type bacteria were found in 30% of the patients with bacterial overgrowth. Basal gastric pH was higher in patients treated with omeprazole compared with cimetidine (4.2 (0.5) versus 2.0 (0.2); p < 0.001) and in patients with bacterial overgrowth compared with those without bacterial overgrowth (5.1 (0.6) versus 2.0 (0.1); p < 0.0001). The nitrate, nitrite, and nitrosamine values in gastric juice did not increase after treatment with either cimetidine or omeprazole. Serum concentrations of vitamin B12, beta carotene, and albumin were similar before and after treatment with both drugs. CONCLUSIONS: These results show that the incidence of gastric and duodenal bacterial overgrowth is considerably higher in patients treated with omeprazole compared with cimetidine. This can be explained by more pronounced inhibition of gastric acid secretion. No patient developed signs of malabsorption or an increase of N-nitroso compounds. The clinical significance of these findings needs to be assessed in studies with long-term treatment with omeprazole, in particular in patients belonging to high risk groups such as HIV infected and intensive care units patients.

Replenish the source within: Rescuing tumor-infiltrating lymphocytes by double checkpoint blockade.

We have recently reported that the PD-1 and CTLA4 signaling pathways are active in both effector and regulatory T cells, causing profound immune dysfunctions in the tumor microenvironment. In line with this notion, the dual blockade of PD-1- and CTLA4-conveyed signals may exert robust therapeutic effects. Here, we discuss the mechanisms possibly underlying such a synergic interaction.

Relating the permeability of quartz sands to their grain size and spectral induced polarization characteristics

Recently, Revil & Florsch proposed a novel mechanistic model based on the polarization of the Stern layer relating the permeability of granular media to their spectral induced polarization (SIP) characteristics based on the formation of polarized cells around individual grains. To explore the practical validity of this model, we compare it to pertinent laboratory measurements on samples of quartz sands with a wide range of granulometric characteristics. In particular, we measure the hydraulic and SIP characteristics of all samples both in their loose, non-compacted and compacted states, which might allow for the detection of polarization processes that are independent of the grain size. We first verify the underlying grain size/permeability relationship upon which the model of Revil & Florsch is based and then proceed to compare the observed and predicted permeability values for our samples by substituting the grain size characteristics by corresponding SIP parameters, notably the so-called Cole-Cole time constant. In doing so, we also asses the quantitative impact of an observed shift in the Cole-Cole time constant related to textural variations in the samples and observe that changes related to the compaction of the samples are not relevant for the corresponding permeability predictions. We find that the proposed model does indeed provide an adequate prediction of the overall trend of the observed permeability values, but underestimates their actual values by approximately one order-of-magnitude. This discrepancy in turn points to the potential importance of phenomena, which are currently not accounted for in the model and which tend to reduce the characteristic size of the prevailing polarization cells compared to the considered model, such as, for example, membrane polarization, contacts of double-layers of neighbouring grains, and incorrect estimation of the size of the polarized cells because of the irregularity of natural sand grains.

Double gene deletion reveals the lack of cooperation between PPARalpha and PPARbeta in skeletal muscle.

The peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of most of the pathways linked to lipid metabolism. PPARalpha and PPARbeta isotypes are known to regulate muscle fatty acid oxidation and a reciprocal compensation of their function has been proposed. Herein, we investigated muscle contractile and metabolic phenotypes in PPARalpha-/-, PPARbeta-/-, and double PPARalpha-/- beta-/- mice. Heart and soleus muscle analyses show that the deletion of PPARalpha induces a decrease of the HAD activity (beta-oxidation) while soleus contractile phenotype remains unchanged. A PPARbeta deletion alone has no effect. However, these mild phenotypes are not due to a reciprocal compensation of PPARbeta and PPARalpha functions since double gene deletion PPARalpha-PPARbeta mostly reproduces the null PPARalpha-mediated reduced beta-oxidation, in addition to a shift from fast to slow fibers. In conclusion, PPARbeta is not required for maintaining skeletal muscle metabolic activity and does not compensate the lack of PPARalpha in PPARalpha null mice.

Double-oblique free-breathing high resolution three-dimensional coronary magnetic resonance angiography.

OBJECTIVES: The goal of the present study was to develop a strategy for three-dimensional (3D) volume acquisition along the major axes of the coronary arteries. BACKGROUND: For high-resolution 3D free-breathing coronary magnetic resonance angiography (MRA), coverage of the coronary artery tree may be limited due to excessive measurement times associated with large volume acquisitions. Planning the 3D volume along the major axis of the coronary vessels may help to overcome such limitations. METHODS: Fifteen healthy adult volunteers and seven patients with X-ray angiographically confirmed coronary artery disease underwent free-breathing navigator-gated and corrected 3D coronary MRA. For an accurate volume targeting of the high resolution scans, a three-point planscan software tool was applied. RESULTS: The average length of contiguously visualized left main and left anterior descending coronary artery was 81.8 +/- 13.9 mm in the healthy volunteers and 76.2 +/- 16.5 mm in the patients (p = NS). For the right coronary artery, a total length of 111.7 +/- 27.7 mm was found in the healthy volunteers and 79.3 +/- 4.6 mm in the patients (p = NS). Comparing coronary MRA and X-ray angiography, a good agreement of anatomy and pathology was found in the patients. CONCLUSIONS: Double-oblique submillimeter free-breathing coronary MRA allows depiction of extensive parts of the native coronary arteries. The results obtained in patients suggest that the method has the potential to be applied in broader prospective multicenter studies where coronary MRA is compared with X-ray angiography.

Double adjunctions

We characterize double adjunctions in terms of presheaves and universal squares, and then apply these characterizations to free monads and Eilenberg-Moore objects in double categories. We improve upon an earlier result of Fiore-Gambino-Kock in [7] to conclude: if a double category with cofolding admits the construction of free monads in its horizontal 2-category, then it also admits the construction of free monads as a double category horizontally and vertically, and also in its vertical 2-category. We also prove that a double category admits Eilenberg-Moore objects if and only if a certain parameterized presheaf is representable. Along the way, we develop parameterized presheaves on double categories and prove a double Yoneda Lemma.

Identification of Mycobacteria by Thin Layer Chromatographic Analysis of Mycolic Acids and Conventional Biochemical Method: Four Years of Experience

Mycolic acids analysis by thin-layer chromatography (TLC) has been employed by several laboratories worldwide as a method for fast identification of mycobacteria. This method was introduced in Brazil by our laboratory in 1992 as a routine identification technique. Up to the present, 861 strains isolated were identified by mycolic acids TLC and by standard biochemical tests; 61% out of these strains came as clinical samples, 4% isolated from frogs and 35% as environmental samples. Mycobacterium tuberculosis strains identified by classical methods were confirmed by their mycolic acids contents (I, III and IV). The method allowed earlier differentiation of M. avium complex - MAC (mycolic acids I, IV and VI) from M. simiae (acids I, II and IV), both with similar biochemical properties. The method also permitted to distinguish M. fortuitum (acids I and V) from M. chelonae (acids I and II) , and to detect mixed mycobacterial infections cases as M. tuberculosis with MAC and M. fortuitum with MAC. Concluding, four years experience shows that mycolic acids TLC is an easy, reliable, fast and inexpensive method, an important tool to put together conventional mycobacteria identification methods.

An approximate solution method for boundary layer flow of a power law fluid over a flat plate

The work in this paper deals with the development of momentum and thermal boundary layers when a power law fluid flows over a flat plate. At the plate we impose either constant temperature, constant flux or a Newton cooling condition. The problem is analysed using similarity solutions, integral momentum and energy equations and an approximation technique which is a form of the Heat Balance Integral Method. The fluid properties are assumed to be independent of temperature, hence the momentum equation uncouples from the thermal problem. We first derive the similarity equations for the velocity and present exact solutions for the case where the power law index n = 2. The similarity solutions are used to validate the new approximation method. This new technique is then applied to the thermal boundary layer, where a similarity solution can only be obtained for the case n = 1.

Cost of Illness and Contingent Valuation : Controlling for the Motivations of Expressed Preferences in an Attempt to Avoid Double-Counting

This paper addresses the issue of double counting of health impacts in the context of cost of illness valuation. Double counting occurs when estimates are jointly used, which rely on valuation techniques that overlap. As a solution, we propose to limit the scope of each of the valuation method to a specific range of impacts. In order to limit the contingentvaluation method to the exclusive valuation of intangible costs, we propose a three steps approach : (1) leave the respondents free to valuate the consequences which matter to them, (2) elicit respondent's motivations, (3) control for the influence motivations have on elicited values. This procedure was applied in a Swiss contingent-valuation. An econometric treatment was applied in order to limit the scope of the estimates of the contingent valuation method to intangibles,therefore the possibility to a combination of methods with the risk of double-counting and underestimating costs being kept to a minimum.

Effect of immunisation against angiotensin II with CYT006-AngQb on ambulatory blood pressure: a double-blind, randomised, placebo-controlled phase IIa study.

BACKGROUND: Hypertension can be controlled adequately with existing drugs such as angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. Nevertheless, treatment success is often restricted by patients not adhering to treatment. Immunisation against angiotensin II could solve this problem. We investigated the safety and efficacy of CYT006-AngQb-a vaccine based on a virus-like particle-that targets angiotensin II to reduce ambulatory blood pressure. METHODS: In this multicentre, double-blind, randomised, placebo-controlled phase IIa trial, 72 patients with mild-to-moderate hypertension were randomly assigned with a computer-generated randomisation list to receive subcutaneous injections of either 100 mug CYT006-AngQb (n=24), 300 mug CYT006-AngQb (24), or placebo (24), at weeks 0, 4, and 12. 24-h ambulatory blood pressure was measured before treatment and at week 14. The primary outcomes were safety and tolerability. Analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00500786. FINDINGS: Two patients in the 100 mug group, three in the 300 mug group, and none in the placebo group discontinued study treatment. All patients were included in safety analyses; efficacy analyses did not include the five dropouts, for whom no data were available at week 14. Five serious adverse events were reported (two in the 100 mug group, two in the 300 mug group, and one in the placebo group); none were deemed to be treatment related. Most side-effects were mild, transient reactions at the injection site. Mild, transient influenza-like symptoms were seen in three patients in the 100 mug group, seven in the 300 mug group, and none in the placebo group. In the 300 mug group, there was a reduction from baseline in mean ambulatory daytime blood pressure at week 14 by -9.0/-4.0 mm Hg compared with placebo (p=0.015 for systolic and 0.064 for diastolic). The 300 mug dose reduced the early morning blood-pressure surge compared with placebo (change at 0800 h -25/-13 mm Hg; p<0.0001 for systolic, p=0.0035 for diastolic). INTERPRETATION: Immunisation with CYT006-AngQb was associated with no serious adverse events; most observed adverse events were consistent with local or systemic responses similar to those seen with other vaccines. The 300 mug dose reduced blood pressure in patients with mild-to-moderate hypertension during the daytime, especially in the early morning. FUNDING: Cytos Biotechnology AG.

Antimicrobial susceptibility of Campylobacter jejuni subsp. jejuni assessed by E-test and double dilution agar method in Southern Chile

The susceptibility patterns of 108 Campylobacter jejuni subsp. jejuni clinical strains, to six antimicrobial agents was determined by using the E-test and the double dilution agar methods. Using both metods, no strain was found to be resistant to ciprofloxacin, erythromycin and gentamicin, but two (1.8%) were resistant to tetracycline and all to aztreonam. Seven (6.5%) strains were resistant to ampicillin by the E-test and five (4.6%) by the double dilution agar method and by both meyhods. No great discrepancies were observed between both methods.

Intracortical connectivity of layer VI pyramidal cells in the barrel cortex of mice

ABSTRACT : The whisker-to-barrel pathway of rodents is formed by a series of somatotopic projections from the mystacial whisker follicles to the layer IV of the primary somatosensory cortex such that each follicle corresponds to a cluster of cortical neurons called barrel. Barrels are present in layer IV but form part of functional columns that comprise the entire depth of the somatosensory cortex. Interestingly, the cortex of the barrelless mouse strain (BRL) is organized such a manner that thalamocortical afferents do not remodel their projections in layer IV and barrels fail to appear. Nevertheless, functionally, a columnar organization persists, indicating that functional columns are not only provided by thalamocortical projections and layer IV cells. Since in the visual cortex of cats, layer VI cells contribute to the response properties of layer IV neurons, we wonder whether layer VI pyramidal cells could contribute to the columnar organization of the primary somatosensory cortex of mice. To address -this question, we morphologically analyzed the distribution of intracortical axon collaterals of layer VI neurons after in-vivo juxtacellular injections of biocytin in the C2 barrel column. Injected hemispheres were tangentially serial cut and intracortical collaterals of individual layer VI neurons were reconstructed at the light microscopic level. The position of axonal boutons was recorded to evaluate the distribution of presumed synaptic contacts. In normal (NOR) mice, cluster analysis shows that layer VI pyramidal cells can be classified in four statistically different clusters of neurons. Moreover, we assume that two classes are formed by cortico-cortical neurons and two classes are formed by cortico-thalamic neurons. Looking at the direction of the main axon in the white matter, we noticed that its orientation correlates perfectly with the type of neuron: cortico-cortical neurons send main axon medially whereas cortico-thalamic neurons send main axon laterally. Performing the same study in the BRL strain, we showed that the BRL mutation affects layer VI pyramidal cells tangentially and radially: the effects of the mutation are illustrated by a significant decrease of the index of colurnnarization and a significant decrease of percentage of boutons in granular and supragranular layers comparing to NOR neurons. In spite of these differences, the same four classes of layer VI neurons have been found in BRL mice. Using a tangential analysis of the boutons distribution, we showed that putative synapses are distributed mainly in the C2 barrel column. This was observed for each layer, type of neuron, cluster or strain, indicating that layer VI pyramidal cells could participate to the functional columnar organization of the barrel cortex. To determine post-synaptic partners of layer VI neurons in layer IV, we conducted an ultrastructural analysis of layer VI-to-IV contacts. We showed that synapses principally occur on spines and spiny dendritic shafts, supposed to belong to excitatory neurons. We furthermore showed that pre-synaptic elements are significantly different between en passant and terminaux contacts, which support hypothesis that terminaux boutons should show longer duration of facilitation than en passant boutons. RÉSUMÉ : Le «whisker-to-barrel pathway» des rongeurs est caractérisé par une série de projections somatotopiques depuis les follicules des moustaches ('whiskers') jusqu'à la couche IV de l'aire somatosensorielle primaire, de telle façon que chaque follicule corresponde à un groupe de neurones corticaux appelés tonneaux (`barrels'). Les tonneaux sont seulement présents en couche IV mais font partie de colonnes fonctionnelles qui s'étendent sur toute la profondeur du cortex somatosensoriel. Chez les souris mutantes barrelless (BRL), le cortex somatosensoriel est organisé de façon telle que lés afférences thalamocorticales ne remodellent pas leurs projections en couche IV et que les tonneaux n'apparaissent pas. Fonctionnellement, pourtant, une organisation en colonnes persiste, ce qui indique que les colonnes fonctionnelles ne sont pas uniquement produites par les projections thalamocorticales et par les cellules de la couche IV. Puisque les cellules de la couche VI contribuent à influencer les réponses des cellules de la couche IV dans le cortex visuel du chat, nous nous sommes demandé si ces cellules ne pourraient pas aussi contribuer à l'organisation en colonnes du cortex somatosensoriel primaire de la souris. Pour répondre à cette question, nous avons analysé de façon morphologique la distribution intracorticale des collatéraux axonaux de neurones de la couche VI. Suite à des injections juxtacellulaires de biocytine in-vivo dans la colonne C2, les hémisphères cérébraux ont été tangentiellement coupés en série et les collatéraux intracorticaux des neurones de la couche VI ont été reconstruits en microscopie optique. La position des boutons axonaux a aussi été enregistrée pour évaluer la distribution des contacts synpptiques potentiels. Chez les souris NOR, une analyse multivariée montre que les cellules pyramidales de la couche VI sont distribuées en quatre classes. Deux de ces classes sont probablement formées de neurons cortico-corticaux, alors que les deux autres sont probablement formées de neurones corticothalamiques. En observant la direction de l'axone principal dans la matière blanche, nous avons noté que son orientation est parfaitement corrélée avec le type supposé de neurone : les neurones corticocorticaux envoient leurs axones principaux médiallement, alors que les neurons cortico-thalamiques envoient leurs axones principaux latéralement. En menant la même étude chez les souris BRL, nous avons montré que la mutation affecte les cellules pyramidales de la couche VI de façon tangentielle, mais aussi radiaire : les effets de 1a mutation se traduisent par une diminution significative de l'index de « columnarization » et de la connectivité en couches granulaire et supragranulaire. Malgré ces différences, les quatre mêmes classes de neurones ont été retrouvées. En utilisant une analyse tangentielle de la distribution des boutons, nous avons montré que les synapses potentielles sont distribuées principalement dans la colonne C2. Cette observation a été faite dans chaque couche, chaque type de neurones, chaque classe de neurones et chaque souche de souris, indicant que les cellules de la couche VI participent certainement à l'organisation en colonne du cortex somatosensoriel. Pour déterminer les partenaires post-synaptiques des cellules de la couche VI en couche IV, nous avons conduit une analyse ultrastructurelle de ces contacts. Nous avons montré que les synapses interviennent principalement sur les épines et sur les dendrites supposés appartenir à des cellules excitatrices. Nous avons aussi montré que les éléments pré-synaptiques de ces synapses sont significativement differents selon le type de bouton, en passant ou terminal, ce qui supporte l'hypothèse que les boutons terminaux seraient capables d'une plus longue facilitation.