The use of the SeDeM diagram expert system for the formulation of Captopril SR matrix tablets by direct compression

The SeDeM Diagram Expert System has been used to study excipients, Captopril and designed formulations for their galenic characterization and to ascertain the critical points of the formula affecting product quality to obtain suitable formulations of Captopril Direct Compression SR Matrix Tablets. The application of the Sedem Diagram Expert System enables selecting excipients with in order to optimize the formula in the preformulation and formulation studies. The methodology is based on the implementation of ICH Q8, establishing the design space of the formula with the use of experiment design, using the parameters of the SeDeM Diagram Expert System as system responses.

Prediction of direct and indirect genetic gains and genotypic correlations in rubber tree progenies

The objective of this work was to estimate the genetic parameters, genotypic and phenotypic correlations, and direct and indirect genetic gains among and within rubber tree (Hevea brasiliensis) progenies. The experiment was set up at the Municipality of Jaú, SP, Brazil. A randomized complete block design was used, with 22 treatments (progenies), 6 replicates, and 10 plants per plot at a spacing of 3x3 m. Three‑year‑old progenies were assessed for girth, rubber yield, and bark thickness by direct and indirect gains and genotypic correlations. The number of latex vessel rings showed the best correlations, correlating positively and significantly with girth and bark thickness. Selection gains among progenies were greater than within progeny for all the variables analyzed. Total gains obtained were high, especially for girth increase and rubber yield, which were 93.38 and 105.95%, respectively. Young progeny selection can maximize the expected genetic gains, reducing the rubber tree selection cycle.

Study of the impact of tissue density heterogeneities on 3-dimensional abdominal dosimetry: comparison between dose kernel convolution and direct monte carlo methods.

Dose kernel convolution (DK) methods have been proposed to speed up absorbed dose calculations in molecular radionuclide therapy. Our aim was to evaluate the impact of tissue density heterogeneities (TDH) on dosimetry when using a DK method and to propose a simple density-correction method. METHODS: This study has been conducted on 3 clinical cases: case 1, non-Hodgkin lymphoma treated with (131)I-tositumomab; case 2, a neuroendocrine tumor treatment simulated with (177)Lu-peptides; and case 3, hepatocellular carcinoma treated with (90)Y-microspheres. Absorbed dose calculations were performed using a direct Monte Carlo approach accounting for TDH (3D-RD), and a DK approach (VoxelDose, or VD). For each individual voxel, the VD absorbed dose, D(VD), calculated assuming uniform density, was corrected for density, giving D(VDd). The average 3D-RD absorbed dose values, D(3DRD), were compared with D(VD) and D(VDd), using the relative difference Δ(VD/3DRD). At the voxel level, density-binned Δ(VD/3DRD) and Δ(VDd/3DRD) were plotted against ρ and fitted with a linear regression. RESULTS: The D(VD) calculations showed a good agreement with D(3DRD). Δ(VD/3DRD) was less than 3.5%, except for the tumor of case 1 (5.9%) and the renal cortex of case 2 (5.6%). At the voxel level, the Δ(VD/3DRD) range was 0%-14% for cases 1 and 2, and -3% to 7% for case 3. All 3 cases showed a linear relationship between voxel bin-averaged Δ(VD/3DRD) and density, ρ: case 1 (Δ = -0.56ρ + 0.62, R(2) = 0.93), case 2 (Δ = -0.91ρ + 0.96, R(2) = 0.99), and case 3 (Δ = -0.69ρ + 0.72, R(2) = 0.91). The density correction improved the agreement of the DK method with the Monte Carlo approach (Δ(VDd/3DRD) < 1.1%), but with a lesser extent for the tumor of case 1 (3.1%). At the voxel level, the Δ(VDd/3DRD) range decreased for the 3 clinical cases (case 1, -1% to 4%; case 2, -0.5% to 1.5%, and -1.5% to 2%). No more linear regression existed for cases 2 and 3, contrary to case 1 (Δ = 0.41ρ - 0.38, R(2) = 0.88) although the slope in case 1 was less pronounced. CONCLUSION: This study shows a small influence of TDH in the abdominal region for 3 representative clinical cases. A simple density-correction method was proposed and improved the comparison in the absorbed dose calculations when using our voxel S value implementation.

Evaluation of respiratory and dermal occupational exposures to monoethanolamine during cleaning

Professional cleaning is a basic service occupation with a wide variety of tasks carried out in all kind of different sectors and workplaces by a large workforce. One important risk for cleaning workers is the exposure to chemical substances that are present in cleaning products.Monoethanolamine was found to be often present in cleaning products such as general purpose cleaners, bathroom cleaners, floor cleaners and kitchen cleaners. Monoethanolamine can injure the skin, and exposure to monoethanolamine was associated to asthma even when the air concentrations were low. It is a strong irritant and known to be involved in sensitizing mechanisms. It is very likely that the use of cleaning products containing monoethanolamine gives rise to respiratory and dermal exposures. Therefore there is a need to further investigate the exposures to monoethanolamine for both, respiratory and dermal exposure.The determination of monoethanolamine has traditionally been difficult and analytical methods available are little adapted for occupational exposure assessments. For monoethanolamine air concentrations, a sampling and analytical method was already available and could be used. However, a method to analyses samples for skin exposure assessments as well as samples of skin permeation experiments was missing. Therefore one main objective of this master thesis was to search an already developed and described analytical method for the measurement of monoethanolamine in water solutions, and to set it up in the laboratory. Monoethanolamine was analyzed after a derivatisation reaction with o-pthtaldialdehyde. The derivated fluorescing monoethanolamine was then separated with high performance liquid chromatography and detection took place with a fluorescent detector. The method was found to be suitable for qualitative and quantitative analysis of monoethanolamine. An exposure assessment was conducted in the cleaning sector to measure the respiratory and dermal exposures to monoethanolamine during floor cleaning. Stationary air samples (n=36) were collected in 8 companies and samples for dermal exposures (n=12) were collected in two companies. Air concentrations (Mean = 0.18 mg/m3, Standard Deviation = 0.23 mg/m3, geometric Mean = 0.09 mg/m3, Geometric Standard Deviation = 3.50) detected were mostly below 1/10 of the Swiss 8h time weighted average occupational exposure limit. Factors that influenced the measured monoethanolamine air concentrations were room size, ventilation system and the concentration of monoethanolamine in the cleaning product and amount of monoethanolamine used. Measured skin exposures ranged from 0.6 to 128.4 mg/sample. Some cleaning workers that participated in the skin exposure assessment did not use gloves and had direct contact with the solutions containing the cleaning product and monoethanolamine. During the entire sampling campaign, cleaning workers mostly did not use gloves. Cleaning workers are at risk to be regularly exposed to low air concentrations of monoethanolamine. This exposure may be problematic if a worker suffers from allergic reactions (e.g. Asthma). In that case a substitution of the cleaning product may be a good prevention measure as several different cleaning products are available for similar cleaning tasks. Currently there are no occupational exposure limits to compare the skin exposures that were found. To prevent skin exposures, adaptations of the cleaning techniques and the use of gloves should be considered. The simultaneous skin and airborne exposures might accelerate adverse health effects. Overall the risks caused by exposures to monoethanolamine are considered as low to moderate when the cleaning products are used correctly. Whenever possible, skin exposures should be avoided. Further research should consider especially the dermal exposure routes, as very high exposures might occur by skin contact with cleaning products. Dermatitis but also sensitization might be caused by skin exposures. In addition, new biomedical insights are needed to better understand the risks of the dermal exposure. Therefore skin permeability experiments should be considered.

Structural Insight into the Mode of Action of a Direct Inhibitor of Coregulator Binding to the Thyroid Hormone Receptor.

The development of nuclear hormone receptor antagonists that directly inhibit the association of the receptor with its essential coactivators would allow useful manipulation of nuclear hormone receptor signaling. We previously identified 3-(dibutylamino)-1-(4-hexylphenyl)-propan-1-one (DHPPA), an aromatic β-amino ketone that inhibits coactivator recruitment to thyroid hormone receptor β (TRβ), in a high-throughput screen. Initial evidence suggested that the aromatic β-enone 1-(4-hexylphenyl)-prop-2-en-1-one (HPPE), which alkylates a specific cysteine residue on the TRβ surface, is liberated from DHPPA. Nevertheless, aspects of the mechanism and specificity of action of DHPPA remained unclear. Here, we report an x-ray structure of TRβ with the inhibitor HPPE at 2.3-Å resolution. Unreacted HPPE is located at the interface that normally mediates binding between TRβ and its coactivator. Several lines of evidence, including experiments with TRβ mutants and mass spectroscopic analysis, showed that HPPE specifically alkylates cysteine residue 298 of TRβ, which is located near the activation function-2 pocket. We propose that this covalent adduct formation proceeds through a two-step mechanism: 1) β-elimination to form HPPE; and 2) a covalent bond slowly forms between HPPE and TRβ. DHPPA represents a novel class of potent TRβ antagonist, and its crystal structure suggests new ways to design antagonists that target the assembly of nuclear hormone receptor gene-regulatory complexes and block transcription.

Arthro-IRM directe en traction axiale: technique et intérêt [Technique and value of direct MR arthrography applying articular distraction]

Direct MR arthrography has a better diagnostic accuracy than MR imaging alone. However, contrast material is not always homogeneously distributed in the articular space. Lesions of cartilage surfaces or intra-articular soft tissues can thus be misdiagnosed. Concomitant application of axial traction during MR arthrography leads to articular distraction. This enables better distribution of contrast material in the joint and better delineation of intra-articular structures. Therefore, this technique improves detection of cartilage lesions. Moreover, the axial stress applied on articular structures may reveal lesions invisible on MR images without traction. Based on our clinical experience, we believe that this relatively unknown technique is promising and should be further developed.

Role of MT1-MMP in cancer dissemination : insights from the real time imaging of tumors

Abstract : Matrix metalloproteinases (MMPs) are thought to play a major role in the tumor dissemination process as they degrade all components of the extracellular matrix. However, failure of clinical trials testing broad MMP inhibitors in cancer led to the consensus that a better understanding of the MMP biology was required. Using intravital multiphoton laser scanning microscopy, we developed an in vivo model to observe tumor dissemination and extracellular matrix remodeling in real time. We show that the matrix-modifying hormone relaxin increases tumor associated fibroblast interaction with collagen fibers by inducing integrin beta-1 expression. This causes changes in the collagen network that are mediated by MMP-8 and MT1-MMP. Also, we show that MMP-mediated collagen remodeling in vivo requires a direct contact between stationary tumor associated fibroblasts (TAFs) and collagen fibers. As MMPs are expressed in the tumor and stromal compartment of breast cancers we determined the importance of Membrane-type 1 MMP (MT1-MMP) from each compartment for cancer progression. We find that tumor-MT1-MMP promotes the invasion of the blood vasculature and blood-borne metastasis in vivo by enhancing tumor cell migration and endothelial basement membrane degradation. Interestingly, stromal-MT1-MMP cannot compensate for the lack of tumor-MT1-MMP but promotes peritumor collagen I remodeling. Thus, the function of MT1-MMP is context dependent and we identify the different but complementary roles of tumor and stromal MT1-MMP for tumor dissemination. Finally, we translate our preclinical findings in to human breast cancer samples. We show that tumor-MT1-MMP expression correlates with tumor invasion of the blood vasculature in ER-PR-HER2- breast cancers and that MT1-MMP expression increases with cancer progression. MT1-MMP could thus represent an interesting therapeutic target for the prevention of blood vasculature invasion in these tumors. Resumé : Les matrix metalloproteinases (MMPs) semblent jouer un rôle majeur pour la dissémination tumorale en raison de leur capacité à dégrader l'ensemble des composants de la matrice extracellulaire (MEC). Néanmoins, les résultats décevants des études cliniques testant les inhibiteurs des MMP ont conduit à la notion qu'une compréhension plus précise de la biologie des MMP était requise. Dans ce travail de thèse, nous avons développé un modèle murin qui permet d'observer simultanément la dissémination tumorale ainsi que les modifications de la MEC en temps réel. Nous démontrons que le traitement de tumeurs par l'hormone relaxin augmente l'interaction des fibroblastes tumoraux avec les fibres de collagène via l'intégrine beta-1. Nous montrons que cette interaction favorise et est nécessaire à la dégradation des fibres de collagène par MMP-8 et MT1-MMP. Ensuite, étant donné que les MMPs sont exprimées dans les cellules tumorales et stromales des cancers du sein, nous nous sommes intéressés au rôle de la MMP membranaire type 1 (MT1-MMP) exprimée dans chacun de ces compartiments. Nous démontrons que MT1-MMP dérivant des cellules tumorales favorise leur invasion dans les vaisseaux sanguins par la dégradation de la membrane basale vasculaire. De manière inattendue, nous montrons que l'expression de MT1-MMP par le compartiment stromal ne peut compenser le manque de MT1-MMP dans le compartiment tumoral. Néanmoins, nos résultats prouvent que MT1-MMP dérivant du compartiment stromal est impliqué dans la dégradation de collagène peritumorale. La fonction de la protéine MT1-MMP varie donc selon le compartiment tumoral d'origine. Finalement, nous avons testé nos résultats pré cliniques chez l'humain. Dans des biopsies de cancer du sein nous montrons une corrélation entre l'expression de MT1-MMP dans les cellules tumorales et l'invasion de vaisseaux sanguins par des tumeurs ER-PR-HER2-. MT1-MMP pourrait donc être une cible intéressante pour la prévention de dissémination vasculaire de ces tumeurs

Medical and pharmacological direct costs of a 9-week smoking cessation programme.

Background: Medical and pharmacological direct costs of cigarette smoking cessation programmes are not covered by health insurance in several countries despite documented cost-effectiveness. Design: prospective cost identification study of a 9-week programme in Switzerland. Methods: A total of 481 smokers were followed-up for 9 weeks. Socio-demographic characteristics, number of outpatient visits, dosage and frequency of use of nicotine replacement therapy (NRT) as well as date of relapse were prospectively collected. Individual cost of care until relapse or programme end as well as cost per week of follow-up were computed. Comparisons were carried out between the groups with or without relapse at the end of the programme. Results: Of the 209 men and 272 women included, 347 patients (72%) finished the programme. Among them, 240 patients (70%) succeeded in quitting and 107 patients (30%) relapsed. As compared with the group relapsing by the end of the programme, the group succeeding in quitting was more often living in a couple (68% vs. 55%, p = 0.029). Their mean weekly costs of visits were higher (CHF 81.2 ± 6.1 vs. 78.4 ± 7.6, p = 0.001), while their mean weekly costs for NRT were similar (CHF 24.2 ± 12.6 vs. 25.4 ± 15.9, p = 0.711). Mean total costs per week were similar (CHF 105.4 ± 15.4 vs. 103.8 ± 19.4, p = 0.252). More intensive NRT at week 4 increased the probability not to relapse at the end of the programme. Conclusions: Over 9 weeks, medical and pharmacological costs of stopping smoking are low. Good medical and social support as well as adequate NRT seem to play a role in successful quitting.

Connexins: key mediators of endocrine function.

The appearance of multicellular organisms imposed the development of several mechanisms for cell-to-cell communication, whereby different types of cells coordinate their function. Some of these mechanisms depend on the intercellular diffusion of signal molecules in the extracellular spaces, whereas others require cell-to-cell contact. Among the latter mechanisms, those provided by the proteins of the connexin family are widespread in most tissues. Connexin signaling is achieved via direct exchanges of cytosolic molecules between adjacent cells at gap junctions, for cell-to-cell coupling, and possibly also involves the formation of membrane "hemi-channels," for the extracellular release of cytosolic signals, direct interactions between connexins and other cell proteins, and coordinated influence on the expression of multiple genes. Connexin signaling appears to be an obligatory attribute of all multicellular exocrine and endocrine glands. Specifically, the experimental evidence we review here points to a direct participation of the Cx36 isoform in the function of the insulin-producing β-cells of the endocrine pancreas, and of the Cx40 isoform in the function of the renin-producing juxtaglomerular epithelioid cells of the kidney cortex.

Mothers' experience of their contact with their stillborn infant: an interpretative phenomenological analysis.

BACKGROUND: Guidelines surrounding maternal contact with the stillborn infant have been contradictory over the past thirty years. Most studies have reported that seeing and holding the stillborn baby is associated with fewer anxiety and depressive symptoms among mothers of stillborn babies than not doing so. In contrast, others studies suggest that contact with the stillborn infant can lead to poorer maternal mental health outcomes. There is a lack of research focusing on the maternal experience of this contact. The present study aimed to investigate how mothers describe their experience of spending time with their stillborn baby and how they felt retrospectively about the decision they made to see and hold their baby or not. METHOD: In depth interviews were conducted with twenty-one mothers three months after stillbirth. All mothers had decided to see and the majority to hold their baby. Qualitative analysis of the interview data was performed using Interpretive Phenomenological Analysis. RESULTS: Six superordinate themes were identified: Characteristics of Contact, Physicality; Emotional Experience; Surreal Experience; Finality; and Decision. Having contact with their stillborn infant provided mothers with time to process what had happened, to build memories, and to 'say goodbye', often sharing the experience with partners and other family members. The majority of mothers felt satisfied with their decision to spend time with their stillborn baby. Several mothers talked about their fear of seeing a damaged or dead body. Some mothers experienced strong disbelief and dissociation during the contact. CONCLUSIONS: Results indicate that preparation before contact with the baby, professional support during the contact, and professional follow-up are crucial in order to prevent the development of maternal mental health problems. Fears of seeing a damaged or dead body should be sensitively explored and ways of coping discussed. Even in cases where mothers experienced intense distress during the contact with their stillborn baby, they still described that having had this contact was important and that they had taken the right decision. This indicates a need for giving parents an informed choice by engaging in discussions about the possible benefits and risks of seeing their stillborn baby.

Contact force transitions in regrasp tasks of planar objects

This paper presents a simple and fast solution to the problem of finding the time variations of the forces that keep the object equilibrium when a finger is removed from a three contact point grasp or a finger is added to a two contact point grasp, assuming the existence of an external perturbation force (that can be the object weight itself). The procedure returns force set points for the control system of a manipulator device in a regrasping action. The approach was implemented and a numerical example is included in the paper to illustrate how it works.

Anatomical exposure patterns of skin to sunlight: relative contributions of direct, diffuse and reflected ultraviolet radiation

Summary Background  The dose-response between ultraviolet (UV) exposure patterns and skin cancer occurrence is not fully understood. Sun-protection messages often focus on acute exposure, implicitly assuming that direct UV radiation is the key contributor to the overall UV exposure. However, little is known about the relative contribution of the direct, diffuse and reflected radiation components. Objective  To investigate solar UV exposure patterns at different body sites with respect to the relative contribution of the direct, diffuse and reflected radiation. Methods  A three-dimensional numerical model was used to assess exposure doses for various body parts and exposure scenarios of a standing individual (static and dynamic postures). The model was fed with erythemally weighted ground irradiance data for the year 2009 in Payerne, Switzerland. A year-round daily exposure (08:00-17:00 h) without protection was assumed. Results  For most anatomical sites, mean daily doses were high (typically 6·2-14·6 standard erythemal doses) and exceeded the recommended exposure values. Direct exposure was important during specific periods (e.g. midday during summer), but contributed moderately to the annual dose, ranging from 15% to 24% for vertical and horizontal body parts, respectively. Diffuse irradiation explained about 80% of the cumulative annual exposure dose. Acute diffuse exposures were also observed during cloudy summer days. Conclusions  The importance of diffuse UV radiation should not be underestimated when advocating preventive measures. Messages focused on avoiding acute direct exposures may be of limited efficiency to prevent skin cancers associated with chronic exposure.

Direct comparison of a radioiodinated intact chimeric anti-CEA MAb with its F(ab')2 fragment in nude mice bearing different human colon cancer xenografts.

Tumour localisation and tumour to normal tissue ratios of a chimeric anti-carcinoembryonic antigen (CEA) monoclonal antibody (MAb), in intact form and as an F(ab')2 fragment labelled with 125I and 131I, were compared in groups of nude mice bearing four different colon cancer xenografts, T380, Co112 or LoVo, of human origin, or a rat colon cancer transfected with human CEA cDNA, called '3G7'. For each tumour, three to four mice per time point were analysed 6, 12, 24, 48 and 96 h after MAb injection. In the different tumours, maximal localisation of intact MAb was obtained at 24 to 48 h, and of F(ab')2 fragment 12 to 24 h after injection. Among the different tumours, localisation was highest with colon cancer T380, with 64% of the injected dose per gram (% ID/g) for the intact MAb and 57% for its F(ab')2 fragment, while in the three other tumours, maximal localisation ranged from 14 to 22% ID g-1 for the intact MAb and was about 11% for the F(ab')2. Tumour to normal tissue ratios of intact MAb increased rapidly until 24 h after injection and remained stable or showed only a minor increase thereafter. In contrast, for the F(ab')2 fragment, the tumour to normal tissue ratios increased steadily up to 4 days after injection reaching markedly higher values than those obtained with intact MAb. For the four different xenografts, tumour to blood ratios of F(ab')2 were about 2, 3 and 5 to 16 times higher than those of intact antibodies at 12, 24 and 96 h after injection, respectively.

Direct mapping of 19F in 19FDG-6P in brain tissue at subcellular resolution using soft X-ray fluorescence

Low energy x-ray fluorescence (LEXRF) detection was optimized for imaging cerebral glucose metabolism by mapping the fluorine LEXRF signal of 19 F in 19 FDG, trapped as intracellular 19 F-deoxyglucose-6-phosphate ( 19 FDG-6P) at 1μm spatial resolution from 3μm thick brain slices. 19 FDG metabolism was evaluated in brain structures closely resembling the general cerebral cytoarchitecture following formalin fixation of brain slices and their inclusion in an epon matrix. 2-dimensional distribution maps of 19 FDG-6P were placed in a cytoarchitectural and morphological context by simultaneous LEXRF mapping of N and O, and scanning transmission x-ray (STXM) imaging. A disproportionately high uptake and metabolism of glucose was found in neuropil relative to intracellular domains of the cell body of hypothalamic neurons, showing directly that neurons, like glial cells, also metabolize glucose. As 19 F-deoxyglucose-6P is structurally identical to 18 F-deoxyglucose-6P, LEXRF of subcellular 19 F provides a link to in vivo 18 FDG PET, forming a novel basis for understanding the physiological mechanisms underlying the 18 FDG PET image, and the contribution of neurons and glia to the PET signal.