Johnson & Johnson (France)

The incidence of tuberculosis has been increasing substantially on a worldwide basis over the past decade, but no tuberculosis-specific drugs have been discovered in 40 years. We identified a diarylquinoline, R207910, that potently inhibits both drug-sensitive and drug-resistant Mycobacterium tuberculosis in vitro (minimum inhibitory concentration 0.06 mug/ml). In mice, R207910 exceeded the bactericidal activities of isoniazid and rifampin by at least 1 log unit. Substitution of drugs included in the World Health Organization's first-line tuberculosis treatment regimen (rifampin, isoniazid, and pyrazinamide) with R207910 accelerated bactericidal activity, leading to complete culture conversion after 2 months of treatment in some combinations. A single dose of R207910 inhibited mycobacterial growth for 1 week. Plasma levels associated with efficacy in mice were well tolerated in healthy human volunteers. Mutants selected in vitro suggest that the drug targets the proton pump of adenosine triphosphate (ATP) synthase.

Within days after birth, rapid surface colonization of infant skin coincides with significant functional changes. Gradual maturation of skin function, structure, and composition continues throughout the first years of life. Recent reports have revealed topographical and temporal variations in the adult skin microbiome. Here we address the question of how the human skin microbiome develops early in life. We show that the composition of cutaneous microbial communities evolves over the first year of life, showing increasing diversity with age. Although early colonization is dominated by Staphylococci, their significant decline contributes to increased population evenness by the end of the first year. Similar to what has been shown in adults, the composition of infant skin microflora appears to be site specific. In contrast to adults, we find that Firmicutes predominate on infant skin. Timely and proper establishment of healthy skin microbiome during this early period might have a pivotal role in denying access to potentially infectious microbes and could affect microbiome composition and stability extending into adulthood. Bacterial communities contribute to the establishment of cutaneous homeostasis and modulate inflammatory responses. Early microbial colonization is therefore expected to critically affect the development of the skin immune function. Within days after birth, rapid surface colonization of infant skin coincides with significant functional changes. Gradual maturation of skin function, structure, and composition continues throughout the first years of life. Recent reports have revealed topographical and temporal variations in the adult skin microbiome. Here we address the question of how the human skin microbiome develops early in life. We show that the composition of cutaneous microbial communities evolves over the first year of life, showing increasing diversity with age. Although early colonization is dominated by Staphylococci, their significant decline contributes to increased population evenness by the end of the first year. Similar to what has been shown in adults, the composition of infant skin microflora appears to be site specific. In contrast to adults, we find that Firmicutes predominate on infant skin. Timely and proper establishment of healthy skin microbiome during this early period might have a pivotal role in denying access to potentially infectious microbes and could affect microbiome composition and stability extending into adulthood. Bacterial communities contribute to the establishment of cutaneous homeostasis and modulate inflammatory responses. Early microbial colonization is therefore expected to critically affect the development of the skin immune function. National Center for Biotechnology Information operational taxonomic unit principal component analysis

Functional differences between infant and adult skin may be attributed to putative differences in skin microstructure. The purpose of this study was to examine infant skin microstructure in vivo and to compare it with that of adult skin. The lower thigh area of 20 healthy mothers (ages 25-43) and their biological children (ages 3-24 months) was examined using in vivo noninvasive methods including fluorescence spectroscopy, video microscopy, and confocal laser scanning microscopy. Stratum corneum and supra-papillary epidermal thickness as well as cell size in the granular layer were assessed from the confocal images. Adhesive tapes were used to remove corneocytes from the outer-most layer of stratum corneum and their size was computed using image analysis. Surface features showed differences in glyph density and surface area. Infant stratum corneum was found to be 30% and infant epidermis 20% thinner than in adults. Infant corneocytes were found to be 20% and granular cells 10% smaller than adult corneocytes indicating a more rapid cell turnover in infants. This observation was confirmed by fluorescence spectroscopy. Dermal papillae density and size distribution also differed. Surprisingly, a distinct direct structural relationship between the stratum corneum morphology and the dermal papillae was observed exclusively in infant skin. A change in reflected signal intensity at approximately 100 mum indicating the transition between papillary and reticular dermis was evident only in adult skin. We demonstrate in vivo qualitative and quantitative differences in morphology between infant and adult skin. These differences in skin microstructure may help explain some of the reported functional differences.

Infant skin is often presented as the cosmetic ideal for adults. However, compared to adult skin it seems to be more prone to develop certain pathological conditions, such as atopic dermatitis and irritant contact dermatitis. Therefore, understanding the physiology of healthy infant skin as a point of reference is of interest both from the cosmetic as well as from the clinical point of view. Clinical research on healthy infants is, however, limited because of ethical considerations of using invasive methods and therefore until recently data has been scarce. Technical innovations and the availability of non-invasive in vivo techniques, such as evaporimetry, electrical impedance measurement, in vivo video and confocal microscopy, and in vivo fibre-optic based spectroscopy, opened up the field of in vivo infant skin physiology research. Studies incorporating such methods have demonstrated that compared to adult, infant skin continues to develop during the first years of life. Specifically, infant skin appears to have thinner epidermis and stratum corneum (SC) as well as smaller corneocytes at least until the second year of life. The water-handling properties are not fully developed before the end of the first year and infant SC contains more water and less amounts of natural moisturizing factors. Such findings re-evaluate the old notions that skin is fully matured at birth. Armed with this knowledge, we are in a position not only to better understand infant dermatological conditions but also to design better skin care products respecting the distinct qualities of infant skin.

BACKGROUND AND OBJECTIVE: The facial appearance of a person does not always reflect the chronological age; some people look younger or older than they really are. Many studies have described the changes in skin properties (colour, wrinkles, sagging, micro relief, etc.) with age, but few of them have analysed their influence on the perceived age. The primary objective of this study was to assess the contribution of individual skin attributes of the face on the perceived age of Caucasian women. Secondary objectives were to assess the influence of age and gender of graders with regard to the age perception. SUBJECTS AND METHOD: A random sample of 173 subjects of 20 to 74 years of age was taken from a database of more than 5000 healthy Caucasian women. A trained grader performed visual assessment of facial skin attributes (using a visual analogue scale), and a front face photograph was taken from each subject. Photographs were shown to 48 graders (20 men and 28 women, aged 22-64 years) who were asked to estimate the age of the subjects. Graders were classified as young (less than 35 years), middle age (35-50 years) and seniors (older than 50 years). Partial Least Square regression models were built to predict the chronological and the perceived age from the measured facial individual attributes. The contribution of each attribute within the regression model enabled to measure the relevance of this attribute with regards to age prediction. RESULTS: The eye area and the skin colour uniformity were the main attributes related to perceived age. For age prediction, older graders' estimations were more driven by lips border definition shape and eyes opening, whereas younger graders' (older than 50 years) estimations were more driven by dark circles, nasolabial fold and brown spots. There were statistically significant differences in graders' age perception between gender and among age ranges. Our findings suggest that female graders are more accurate than male, and younger graders (under 35 years) are more accurate than older (over 50 years) to predict Caucasian women age from facial photographs. CONCLUSIONS: Different skin attributes influence the estimation of age. These attributes have a different weight in the evaluation of the perceived age, depending on the age and of the observer. The most important attributes to estimate age are eyes, lips and skin colour uniformity.

Consumer safety is a prerequisite for any cosmetic product. Worldwide, there is an ever-increasing desire to bring safe products to market without animal testing, which requires a new approach to consumer safety. ‘Next Generation Risk Assessment’ (NGRA), defined as an exposure-led, hypothesis driven risk assessment approach that integrates in silico, in chemico and in vitro approaches, provides such an opportunity. The bespoke nature of each NGRA means that the development of a prescriptive list of tests to assure safety is not possible, nor appropriate. The International Cooperation on Cosmetics Regulation (ICCR) therefore tasked a group of scientists from regulatory authorities and the Cosmetic Industry to agree on and outline the principles for incorporating these new approaches into risk assessments for cosmetic ingredients. This ICCR group determined the overall goals of NGRA (to be human-relevant, exposure-led, hypothesis-driven and designed to prevent harm); how an NGRA should be conducted (using a tiered and iterative approach, following an appropriate literature search and evaluation of the available data, and using robust and relevant methods and strategies); and how the assessment should be documented (transparent and explicit about the logic of the approach and sources of uncertainty). Those working on the risk assessment of cosmetics have a unique opportunity to lead progress in the application of novel approaches, and cosmetic risk assessors are encouraged to consider these key principles when conducting or evaluating such assessments.

In recent years, there have been continuing efforts to understand the effects of baby skin care routines and products on the healthy development of baby skin. Such efforts aim ultimately to determine the best infant skin care practices. The pediatric and dermatologic communities have not reached consensus on what constitutes an appropriate cleansing practice. In the United States, guidelines for neonatal skin care have been developed, propagated, and implemented. The accumulated knowledge has promoted evidence-based clinical practices and, therefore, may help to improve clinical outcomes, although these guidelines primarily cover the care of preterm newborns and the treatment of those with other health problems. High-level, long-term clinical evidence of the effective and safe cleansing of healthy, full-term newborns and infants is scarce. This review presents a comprehensive analysis of the scientific literature on baby skin development, cleansing practices, and related products (for healthy newborns and babies) since 1970. The evidence drawn from the reviewed literature can be summarized as follows: Bathing immersed in water seems generally superior to washing alone. Bathing or washing with synthetic detergents (syndets) or mild liquid baby cleansers seems comparable with or even superior to water alone. Nevertheless, larger randomized clinical trials with age-defined cohorts of babies as well as more-defined parameters are required to identify optimal practices and products for skin cleansing of healthy infants. These parameters may include standardized skin function parameters such as transepidermal water loss, stratum corneum hydration, skin surface pH, and sebum production. Clinical skin scores such as the Neonatal Skin Condition Score may be employed as outcome measures.

BACKGROUND/PURPOSE: The Stratum Corneum (SC) barrier function mainly depends on the SC structure at the tissue level, its composition, and the organization of intercellular lipidic cement at the molecular level. The goal of this study was to assess the age-dependent changes of the SC barrier function and the associated physiological parameters. METHODS: This study was conducted on 40 French women divided into four groups of age. Measurements were done on three sites: cheek, protected, and exposed arm sites. SC composition (water, lipid/protein ratio, cholesterol, and ceramides) was measured using Raman confocal microspectroscopy, skin surface hydration using skin conductance, and barrier function through transepidermal water loss (TEWL) measurements. RESULTS: Transepidermal water loss decreases slightly with age, which is partially explained by the age-dependent increase in SC thickness. This decrease is faster for the face compared to both arm sites. The lipid to protein ratio and lipid compactness decrease significantly with age only for the arm sites. Water concentration profiles only decrease very close to the skin surface. At all ages tested, the SC on the cheek showed significantly higher TEWL, water and lipid content and less thickness compared to the arm sites. Comparison of the exposed to unexposed arm site showed difference only for the lipid compactness at the older group studied. CONCLUSION: Skin aging, body site and environmental exposure can affect the SC barrier function, its structure, and its lipid content. The thickening of the SC with age compensates for the decrease of the quantity and ordering of the lipidic cement.

Pediatricians and parents report diaper dermatitis (DD) to be one of the most common skin diseases that affects almost every child at some point during the early months and years of life. Diapered skin is exposed to friction and excessive hydration, has a higher pH than nondiapered skin, and is repeatedly soiled with feces that contains enzymes with high irritation potential for the skin. The combination of these factors frequently results in skin damage, leading to visible erythematous lesions that can be irritating and painful to the child. Behavioral changes such as increased crying and agitation and changes in eating and sleeping patterns indicate emotional distress. Appropriate skin care can help to prevent the occurrence of DD and to speed up the healing of affected skin. This includes frequent diaper changes and aeration, gentle cleansing, and the use of a barrier cream. Mild to moderate cases usually resolve after a few days of following this routine, but the use of harsh cleaning products can exacerbate DD.

Infections with Mycobacterium tuberculosis are substantially increasing on a worldwide scale and new antibiotics are urgently needed to combat concomitantly emerging drug-resistant mycobacterial strains. The diarylquinoline TMC207 is a highly promising drug candidate for treatment of tuberculosis. This compound kills M. tuberculosis by binding to a new target, mycobacterial ATP synthase. In this study we used biochemical assays and binding studies to characterize the interaction between TMC207 and ATP synthase. We show that TMC207 acts independent of the proton motive force and does not compete with protons for a common binding site. The drug is active on mycobacterial ATP synthesis at neutral and acidic pH with no significant change in affinity between pH 5.25 and pH 7.5, indicating that the protonated form of TMC207 is the active drug entity. The interaction of TMC207 with ATP synthase can be explained by a one-site binding mechanism, the drug molecule thus binds to a defined binding site on ATP synthase. TMC207 affinity for its target decreases with increasing ionic strength, suggesting that electrostatic forces play a significant role in drug binding. Our results are consistent with previous docking studies and provide experimental support for a predicted function of TMC207 in mimicking key residues in the proton transfer chain and blocking rotary movement of subunit c during catalysis. Furthermore, the high affinity of TMC207 at low proton motive force and low pH values may in part explain the exceptional ability of this compound to efficiently kill mycobacteria in different microenvironments.

Diarylquinolines (DARQs) are a new class of potent inhibitors of the ATPase of Mycobacterium tuberculosis. We have created a homology model of a binding site for this class of compounds located on the contact area of the a-subunit (gene atpB) and c-subunits (gene atpE) of Mycobacterium tuberculosis ATPase. The binding pocket that was identified from the analysis of the homology model is formed by 4 helices of three c-subunits and 2 helices of the a-subunit. The lead compound of the DARQ series, R207910, was docked into the pocket using a simulated annealing, multiple conformer, docking algorithm. Different stereoisomers were treated separately. The best docking pose for each stereoisomer was optimized by molecular dynamics simulation on the 5300 atoms of the binding region and ligand. The interaction energies in the computed complexes enable us to rank the different stereoisomers in order of interaction strength with the ATPase binding pockets. We propose that the activity of R207910 against Mycobacterium tuberculosis is based on interference of the compound with the escapement geometry of the proton transfer chain. Upon binding the compound mimics the conserved Arg-186 residue of the a-subunit and interacts in its place with the conserved acidic residue Glu-61 of the c-subunit. This mode of action is corroborated by the good agreement between the computed interaction energies and the observed pattern of stereo-specificity in the model of the binding region.

Abstract The discovery that post‐translational farnesylation of Ras oncoprotein was an essential step in exercising its biological effect led to the design of farnesyl protein transferase inhibitors (FTIs) in order to control growth of tumors bearing Ras mutations. Pre‐clinical studies on murine models have confirmed their inhibitory effect on tumor growth and enabled clinical development. R115777 (ZARNESTRA TM ) is currently undergoing clinical evaluation and recent studies have confirmed its antitumor potential and low toxicity. We wish to describe here the chemical synthesis routes that our group have developed to access ZARNESTRA TM . (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Infant skin is different from adult in structure, function, and composition. Despite these differences, the skin barrier is competent at birth in healthy, full-term neonates. The primary focus of this paper is on the developing skin barrier in healthy, full-term neonates and infants. Additionally, a brief discussion of the properties of the skin barrier in premature neonates and infants with abnormal skin conditions (i.e., atopic dermatitis and eczema) is included. As infant skin continues to mature through the first years of life, it is important that skin care products (e.g., cleansers and emollients) are formulated appropriately. Ideally, products that are used on infants should not interfere with skin surface pH or perturb the skin barrier. For cleansers, this can be achieved by choosing the right type of surfactant, by blending surfactants, or by blending hydrophobically-modified polymers (HMPs) with surfactants to increase product mildness. Similarly, choosing the right type of oil for emollients is important. Unlike some vegetable oils, mineral oil is more stable and is not subject to oxidation and hydrolysis. Although emollients can improve the skin barrier, more studies are needed to determine the potential long-term benefits of using emollients on healthy, full-term neonates and infants.

BACKGROUND: Various physical, chemical and biological insults, including exposure to ultraviolet (UV) radiation, cause erythema and change in pigmentation in human skin. These reactions provide an important measure of the cutaneous response to the insult. OBJECTIVES: To present a new implementation of a method for objective in vivo measurement of erythema and pigmentation. METHODS: The method is based on acquisition of reflectance spectra in the visible range using a commercially available spectrophotometer. The probe of this instrument incorporates an integrating sphere that captures the light remitted from the skin in a wide range of angles. We corrected the acquired reflectance spectra for the contribution of specular reflections by an amount given by the Fresnel equation and verified this correction experimentally. This correction is particularly important when measurements are performed on heavily pigmented skin. The corrected reflectance spectra are then transformed into absorbance spectra. To analyse these spectra, we developed an algorithm which can be used to calculate apparent concentrations of oxyhaemoglobin, deoxyhaemoglobin and melanin. This method was tested in clinical studies of skin reactions induced by exposure to UV radiation. These experiments involved three groups of subjects with progressively darker complexion (constitutive pigmentation). Each group consisted of 10 subjects. Erythema was measured 1 day after UV exposure, and pigmentation (melanin content) 1 week later. Results Distinct apparent absorbance spectra were obtained for dark, intermediate and fair skin. There was good agreement between reconstructed spectra and experimental data at relevant wavelengths. Difference absorption spectra were able to show the dose dependence of UV-induced responses, and erythema and pigmentation values obtained by the spectroscopic method showed good correlation with those derived by subjective visual grading. CONCLUSIONS: The results demonstrate that the presented methodology provides an objective noninvasive way of measuring UV-induced reactions independently of the level of constitutive pigmentation.

A preceding paper (Bonfanti et al. J. Med Chem. 2007, 50, 4572-4584) reported the optimization of the pharmacokinetic profile of substituted benzimidazoles by reducing their tissue retention. However, the modifications that were necessary to achieve this goal also led to a significant drop in anti-RSV activity. This paper describes a molecular modeling study followed by a lead optimization program that led to the recovery of the initial potent antiviral activity and the selection of TMC353121 as a clinical candidate.

Diaper dermatitis (DD) is one of the most common skin conditions in neonates and infants, with a peak between the ages of 9 and 12 months. Appropriate skin care practices that support skin barrier function and protect the buttocks skin from urine and feces are supposed to be effective in the prevention of DD. Despite many recommendations for parents and caregivers on proper diaper skin care, there is no up-to-date synthesis of the available evidence to develop recommendations for DD prevention practice. Therefore we performed a systematic literature review on the efficacy of nonmedical skin care practices on the diapered area of healthy, full-term infants ages 0 to 24 months. We identified 13 studies covering skin care practices such as cleansing, bathing, and application of topical products. DD prevalence and incidence and physiologic skin parameters were used as efficacy parameters. The results of this review indicate that cleansing of the diaper area using baby wipes or water and a washcloth have comparable effects on diapered skin. Bathing with a liquid baby cleanser twice weekly seems comparable with water alone. The application of ointments containing zinc oxide or petrolatum with or without vitamin A seems to have comparable effects on DD severity. There seems to be no information on whether single skin care practices such as cleansing, bathing, and application of topical preparations can prevent DD. High-quality randomized clinical trials are needed to show the effectiveness of skin care practices for controlling and preventing DD.

To achieve and maintain skin architecture and homeostasis, keratinocytes must intricately balance growth, differentiation, and polarized motility known to be governed by calcium. Orai1 is a pore subunit of a store-operated Ca(2+) channel that is a major molecular counterpart for Ca(2+) influx in nonexcitable cells. To elucidate the physiological significance of Orai1 in skin, we studied its functions in epidermis of mice, with targeted disruption of the orai1 gene, human skin sections, and primary keratinocytes. We demonstrate that Orai1 protein is mainly confined to the basal layer of epidermis where it plays a critical role to control keratinocyte proliferation and polarized motility. Orai1 loss of function alters keratinocyte differentiation both in vitro and in vivo. Exploring underlying mechanisms, we show that the activation of Orai1-mediated calcium entry leads to enhancing focal adhesion turnover via a PKCβ-Calpain-focal adhesion kinase pathway. Our findings provide insight into the functions of the Orai1 channel in the maintenance of skin homeostasis.

Over 4 million patients suffer nosocomial infections annually in the European Union. This study aimed to estimate the healthcare burden associated with healthcare-associated infections (HAIs) following surgery in France, and explore the potential impact of infection control strategies and interventions on the clinical and economic burden of disease. Data on the frequency of HAIs were gathered from the 2010 Programme de Médicalisation des Systèmes d'Information (PMSI), and cost data were taken from the 2009 Echelle Nationale de Coûts à Méthodologie Commune (ENCC). It was estimated that 3% of surgical procedures performed in 2010 in France resulted in infection, resulting in an annual cost of €57 892 715. Patients experiencing a HAI had a significantly increased mortality risk (4.15-fold) and an increased length of hospital stay (threefold). Scenario analysis in which HAI incidence following surgery was reduced by 8% (based on a study of the effectiveness of triclosan-coated sutures), suggested that, annually, 20 205 hospital days and €4 588 519 could be saved. Analyses of 20% and 30% reductions in incidence (based on an estimate of the number of preventable nosocomial infections) suggested that annual savings of €11 548 057 and €17 334 696, respectively, could be made. New infection control interventions which reduce HAI incidence during hospitalization for surgery have the potential to provide valuable cost savings to healthcare providers.

The skin is increasingly recognized as a component of the innate immune response, in addition to its role as a physical barrier. Although the deleterious effects of solar ultraviolet radiation (UVR), including immunosuppression and cutaneous tumorigenesis, are widely acknowledged, most studies to date have concentrated on adult skin. Despite the more sensitive nature of infant and toddler skin, little is known about its responses to UVR exposure, whether acute or long-term. Accumulating evidence suggests not only that the skin's barrier protection remains immature throughout at least the first 2 years of life but also that accumulation of UVR-induced changes in the skin may begin as early as the first summer of life. Such evidence not only affirms the importance of sun protection during the infant and toddler years but underscores the need for more research to establish evidence-based standards of care in this area. In this article we review recent studies in which differences between the skin properties of infants and young children and those of adults were compared, and we discuss the implications of these differences for sun-protection practices.

All-trans-retinoic acid is a potent inhibitor of cell proliferation and inducer of differentiation. However, the clinical use of all-trans-retinoic acid in the treatment of cancer is significantly hampered by its toxicity and the prompt emergence of resistance, believed to be caused by increased all-trans-retinoic acid metabolism. Inhibitors of all-trans-retinoic acid metabolism may therefore prove valuable in the treatment of cancer. In this study, we characterize R116010 as a new anticancer drug that is a potent inhibitor of all-trans-retinoic acid metabolism. In vitro, R116010 potently inhibits all-trans-retinoic acid metabolism in intact T47D cells with an IC(50)-value of 8.7 nM. In addition, R116010 is a selective inhibitor as indicated by its inhibition profile for several other cytochrome P450-mediated reactions. In T47D cell proliferation assays, R116010 by itself has no effect on cell proliferation. However, in combination with all-trans-retinoic acid, R116010 enhances the all-trans-retinoic acid-mediated antiproliferative activity in a concentration-dependent manner. In vivo, the growth of murine oestrogen-independent TA3-Ha mammary tumours is significantly inhibited by R116010 at doses as low as 0.16 mg kg(-1). In conclusion, R116010 is a highly potent and selective inhibitor of all-trans-retinoic acid metabolism, which is able to enhance the biological activity of all-trans-retinoic acid, thereby exhibiting antitumour activity. R116010 represents a novel and promising anticancer drug with an unique mechanism of action.