Integrated decision strategies for skin sensitization hazard

One of the top priorities of the Interagency Coordinating Committee for the Validation of Alternative Methods (ICCVAM) is the identification and evaluation of non‐animal alternatives for skin sensitization testing. Although skin sensitization is a complex process, the key biological events of the process have been well characterized in an adverse outcome pathway (AOP) proposed by the Organisation for Economic Co‐operation and Development (OECD). Accordingly, ICCVAM is working to develop integrated decision strategies based on the AOP using in vitro, in chemico and in silico information. Data were compiled for 120 substances tested in the murine local lymph node assay (LLNA), direct peptide reactivity assay (DPRA), human cell line activation test (h‐CLAT) and KeratinoSens assay. Data for six physicochemical properties, which may affect skin penetration, were also collected, and skin sensitization read‐across predictions were performed using OECD QSAR Toolbox. All data were combined into a variety of potential integrated decision strategies to predict LLNA outcomes using a training set of 94 substances and an external test set of 26 substances. Fifty‐four models were built using multiple combinations of machine learning approaches and predictor variables. The seven models with the highest accuracy (89–96% for the test set and 96–99% for the training set) for predicting LLNA outcomes used a support vector machine (SVM) approach with different combinations of predictor variables. The performance statistics of the SVM models were higher than any of the non‐animal tests alone and higher than simple test battery approaches using these methods. These data suggest that computational approaches are promising tools to effectively integrate data sources to identify potential skin sensitizers without animal testing. Published 2016. This article has been contributed to by US Government employees and their work is in the public domain in the USA.     

The ostrich syndrome: obstetrician gynecologists and human immunodeficiency virus exposure

Obstetrician-gynecologists and midwives as well as surgical and labor and delivery staff are at risk for contact with human immunodeficiency virus (HIV), but measures can be taken to reduce the risk of exposure and transmission. Physician denial of exposure is common. Prompt identification of exposure, including rapid testing of index patients of unknown HIV status, combined with prompt initiation of prophylactic medication, may reduce transmission by 81%.     

Long-term outcomes: what should the focus be?

The neonatal intervention trials of the 1980s and early 1990s focused primarily on short-term outcomes. Contemporary clinical trials have recognized the importance of longer-term outcomes but have rarely been powered to achieve that aim. This review discusses important and clinically relevant outcomes that future trials should be powered to address and identifies the challenges facing the neonatal clinical trials community. These challenges include consensus definitions of relevant outcomes that are objective and validated, variability among centers in populations and practices, and the need for predictive surrogate markers of long-term outcomes. Future trials must be designed and powered to address the potential for harm as well as the prospect of benefit.     

Do Bach flower remedies have a role to play in pain control?: A critical analysis investigating therapeutic value beyond the placebo effect,and the potential of Bach flower remedies as a psychological method of pain relief

This paper explores the potentiality of Bach flower remedies as a means of pain relief through a retrospective case-study analysis to establish how clients suffering with painful conditions responded to the therapy. RESULTS: Of 384 subjects, 41 suffered pain. Of these, 46% felt treatment had relieved their pain; in 49% the physical outcome was unknown. About 88% of all subjects reported an improvement in their emotional outlook. DISCUSSION: The role of placebo and its influence on the study's key features: focus shift from physical pain to emotional outlook, and the importance of the client-practitioner relationship and belief in the therapy. CONCLUSION: The use of Bach flower remedies has brought about positive emotional changes in the majority of clients in this study. Whilst it is difficult to draw a definitive conclusion as to significance of the therapeutic value of these remedies in relation to pain above that of a placebo, the results are encouraging. In particular, relief of negative emotions and promotion of positive thought including how clients opened up about, and dealt with, emotional issues. The indication is that potential for Bach flower remedies as a therapeutic agent in the relief of pain does exist and is worthy of further qualitative and quantitative investigation through robust, purpose-designed studies to replicate and progress the results shown here.     

Evidence of depot‐specific regulation of all‐trans‐retinoic acid biosynthesis in human adipose tissue

The prevalence of obesity continues to rise, underscoring the need to better understand the pathways mediating adipose tissue (AT) expansion. All‐trans‐retinoic acid (atRA), a bioactive vitamin A metabolite, regulates adipogenesis and energy metabolism, and, in rodent studies, aberrant vitamin A metabolism appears a key facet of metabolic dysregulation. The relevance of these findings to human disease is unknown, as are the specific enzymes implicated in vitamin A metabolism within human AT. We hypothesized that in human AT, family 1A aldehyde dehydrogenase (ALDH1A) enzymes contribute to atRA biosynthesis in a depot‐specific manner. To test this hypothesis, parallel samples of subcutaneous and omental AT from participants (n = 15) were collected during elective abdominal surgeries to quantify atRA biosynthesis and key atRA synthesizing enzymes. ALDH1A1 was the most abundant ALDH1A isoform in both AT depots with expression approximately twofold higher in omental than subcutaneous AT. ALDH1A2 was detected only in omental AT. Formation velocity of atRA was approximately threefold higher (p = 0.0001) in omental AT (9.8 [7.6, 11.2]) pmol/min/mg) than subcutaneous AT (3.2 [2.1, 4.0] pmol/min/mg) and correlated with ALDH1A2 expression in omental AT (β‐coefficient = 3.07, p = 0.0007) and with ALDH1A1 expression in subcutaneous AT (β‐coefficient = 0.13, p = 0.003). Despite a positive correlation between body mass index (BMI) and omental ALDH1A1 protein expression (Spearman r = 0.65, p = 0.01), BMI did not correlate with atRA formation. Our findings suggest that ALDH1A2 is the primary mediator of atRA formation in omental AT, whereas ALDH1A1 is the principal atRA‐synthesizing enzyme in subcutaneous AT. These data highlight AT depot as a critical variable for defining the roles of retinoids in human AT biology.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Rodent data suggest that dysregulated production of all‐trans‐retinoic acid (atRA), the primary bioactive metabolite of vitamin A, may contribute to body weight gain and its complications. However, the key enzymes responsible for atRA biosynthesis in human adipose tissue have not been identified, nor has the relationship between body weight and adipose tissue atRA biosynthesis been evaluated in humans.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study sought to identify the key enzymes involved in atRA biosynthesis in human omental and subcutaneous adipose tissue. This study also quantified atRA formation velocity and explored the potential relationship between body mass index (BMI) and atRA biosynthesis in both adipose tissue depots.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study establishes that among the aldehyde dehydrogenase (ALDH) isoforms, ALDH1A1 and ALDH1A2 both contribute to atRA biosynthesis in human omental adipose tissue, whereas only ALDH1A1 contributes to atRA biosynthesis in subcutaneous adipose tissue. Both ALDH1A1 expression and atRA formation velocity are substantially higher in omental than subcutaneous adipose tissue. Omental ALDH1A1 protein expression exhibits a positive correlation with BMI, but atRA formation velocity in both omental and subcutaneous adipose tissue shows no correlation with BMI. Thus, these findings highlight discrepancies between human and rodent adipose tissue biology and, moreover, reveal depot‐specific regulation of vitamin A metabolism in human adipose tissue.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This line of research ultimately is intended to define the roles of vitamin A metabolites in the regulation of tissue remodeling and energy partitioning in human adipose tissue. This knowledge could contribute to the delineation of mechanisms underlying progressive obesity and its complications.     

Changes in psychiatric admission MMPI profiles over a period of 15 to 20 years

An attempt was made to compare admission MMPI profiles of a matched sample of psychiatric inpatients over a 15- to 20-year period. For both males and females, significant decreases in MMPI indices of psychopathology occurred. Possible reasons for this decrease are presented.