Synthesis and evaluation of tylosin-related macrolides modified at the aldehyde function: a new series of orally effective antibiotics

Modification of the aldehyde group in tylosin and related macrolide antibiotics dramatically enhanced the oral efficacy of the derivatives against experimental infections caused by susceptible bacteria in laboratory animals. A large number and wide variety of aldehyde-modified macrolide derivatives were prepared, utilizing the Mitsunobu reaction and other chemical transformations. Evaluation of in vitro and in vivo antimicrobial activity indicated that derivatives of demycarosyltylosin (desmycosin) combined the broadest spectrum of antimicrobial activity with the best efficacy and bioavailability after oral administration.     

Contamination of breast milk with organochlorine compounds in comparison with cow's milk and selected milk products in the new federal districts

400 human milk, 280 cowmilk, 56 milkpowder and 305 butter samples were examined concerning there content of chloroorganic compounds. In human milk the highest concentration had DDE, followed by PCB, DDT and HCB, the lowest values were measured for HCH. Only total DDT in human milk but no compound in the milk product samples was above the maximal tolerated limit. There is a strong reduction in comparison to the values measured in 1979 (ten times for total HCH, one half for total DDT and to one sixth for HCB) but the PCB concentration didn't change.     

DHPLC mutation analysis of phenylketonuria

Denaturing high-performance liquid chromatography (DHPLC) is a sensitive and fast method for the detection of mutations which has been successfully used for mutation screening in several disease-related genes. Phenylketonuria (PKU, OMIM* 261600; McKusick 1986) is one of the most common autosomal recessive disorders in Europe. Mutations in the PAH gene mainly involve point mutations. In this study we report the successful use of DHPLC to analyse rapidly the complete coding sequence of the PAH gene in a total of 125 unrelated patients with PKU.     

Apparent homology of expressed genes from wood-forming tissues of loblolly pine (Pinus taeda L.) with Arabidopsis thaliana

Pinus taeda L. (loblolly pine) and Arabidopsis thaliana differ greatly in form, ecological niche, evolutionary history, and genome size. Arabidopsis is a small, herbaceous, annual dicotyledon, whereas pines are large, long-lived, coniferous forest trees. Such diverse plants might be expected to differ in a large number of functional genes. We have obtained and analyzed 59,797 expressed sequence tags (ESTs) from wood-forming tissues of loblolly pine and compared them to the gene sequences inferred from the complete sequence of the Arabidopsis genome. Approximately 50% of pine ESTs have no apparent homologs in Arabidopsis or any other angiosperm in public databases. When evaluated by using contigs containing long, high-quality sequences, we find a higher level of apparent homology between the inferred genes of these two species. For those contigs 1,100 bp or longer, approximately 90% have an apparent Arabidopsis homolog (E value < 10-10). Pines and Arabidopsis last shared a common ancestor approximately 300 million years ago. Few genes would be expected to retain high sequence similarity for this time if they did not have essential functions. These observations suggest substantial conservation of gene sequence in seed plants.     

Recent derivatives from smaller classes of fermentation-derived antibacterials

INTRODUCTION: New antibiotics, without cross-resistance to existing agents, are needed to treat infections caused by increasingly resistant pathogens and to improve the safety and efficacy of older agents. Renewed investigations of several older but smaller or underexploited classes of fermentation-derived antibiotics have generated active new derivatives and analogs that resulted from medicinal chemistry programs and/or manipulations of the biosynthetic pathways of producing microbes. Several of these programs have now produced clinical candidates undergoing preclinical studies or early clinical trials. AREAS COVERED: This review surveys the recent patent and journal literature for relevant new antibacterial derivatives from about 2007 until the present. EXPERT OPINION: Following the regulatory approvals of daptomycin and retapamulin for human use, these renewed investigations of underdeveloped fermentation-derived classes have demonstrated the further potential to discover new clinical candidates. However, many other classes of natural product antibiotics still remain underinvestigated and are thus available for renewed examinations. This strategy is one means for finding new antibiotics to add to the physician's armamentarium for treating resistant pathogens.     

A tiered approach to the use of alternatives to animal testing for the safety assessment of cosmetics: Skin irritation

Evaluation of the skin irritancy and corrosivity potential of an ingredient is a necessity in the safety assessment of cosmetic ingredients. To date, there are two formally validated alternatives to the rabbit Draize test for skin corrosivity in place, namely the rat skin transcutaneous electrical resistance (TER) assay and the Human Skin Model Test using EpiSkin™, EpiDerm™ and SkinEthic™ reconstructed human epidermal equivalents. For skin irritation, EpiSkin™, EpiDerm™ and SkinEthic™ are validated as stand-alone test replacements for the rabbit Draize test. Data from these tests are rarely considered in isolation and are evaluated in combination with other factors to establish the overall irritating or corrosive potential of an ingredient. In light of the deadlines established in the Cosmetics Directive for cessation of animal testing for cosmetic ingredients, a COLIPA scientific meeting was held in Brussels on 30th January, 2008 to review the use of alternative approaches and to set up a decision tree approach for their integration into tiered testing strategies for hazard and safety assessment of cosmetic ingredients and their use in products. In conclusion, the safety assessments for skin irritation/corrosion of new chemicals for use in cosmetics can be confidently accomplished using exclusively alternative methods.     

A tiered approach to the use of alternatives to animal testing for the safety assessment of cosmetics: Eye irritation

The need for alternative approaches to replace the in vivo rabbit Draize eye test for evaluation of eye irritation of cosmetic ingredients has been recognised by the cosmetics industry for many years. Extensive research has lead to the development of several assays, some of which have undergone formal validation. Even though, to date, no single in vitro assay has been validated as a full replacement for the rabbit Draize eye test, organotypic assays are accepted for specific and limited regulatory purposes. Although not formally validated, several other in vitro models have been used for over a decade by the cosmetics industry as valuable tools in a weight of evidence approach for the safety assessment of ingredients and finished products. In light of the deadlines established in the EU Cosmetics Directive for cessation of animal testing for cosmetic ingredients, a COLIPA scientific meeting was held in Brussels on 30th January, 2008 to review the use of alternative approaches and to set up a decision-tree approach for their integration into tiered testing strategies for hazard and safety assessment of cosmetic ingredients and their use in products. Furthermore, recommendations are given on how remaining data gaps and research needs can be addressed.     

Provider and Consumer Perceptions of Trauma Informed Practices and Services for Substance Use and Mental Health Problems

Both trauma-informed practices and trauma-specific services have been developed to meet the needs of individuals seeking services for mental health and substance use disorders. These approaches involve an acknowledgement of an individual’s inter-related experiences of trauma, mental health, and substance use problems in all aspects of service delivery, and focus on enhancing consumer safety and control. Although trauma-informed practices and trauma-specific interventions have been repeatedly identified as critical to service provision in this area, there is little understanding of how these practices and interventions are delivered and experienced from the perspectives of service users and providers. The purpose of this study was to explore facilitators and barriers in implementing trauma-informed practices and delivering trauma-specific services in mental health and addiction service settings through qualitative interviews with service providers, consumers and research experts. Based on thematic analysis of in-depth interviews with 19 participants (including service providers, research experts and consumers), a number of key facilitators and challenges to implementation of trauma-informed practices and services emerged. Key facilitators included: organizational support, community partnerships, staff awareness of trauma, a safe environment, peer support, the quality of consumer-provider relationships, consumer and provider readiness to change, and staff supports. Challenges included: provider reluctance to address trauma, lack of accessible services, limited funding for programs/services, and staff burnout. Key areas of change identified in the study point to the need for increased intersectoral collaboration and support, greater system-wide trauma awareness and provider training in order to enhance the ability of trauma-informed practices and -specific services to meet the complex needs of this population.