Polymorphisms in the novel gene acyloxyacyl hydroxylase (AOAH) are associated with asthma and associated phenotypes

BACKGROUND: The gene encoding acyloxyacyl hydroxylase (AOAH), an enzyme that hydrolyzes secondary fatty acyl chains of LPS, is localized on chromosome 7p14-p12, where evidence for linkage to total IgE (tIgE) concentrations and asthma has been previously reported. OBJECTIVE: We hypothesized that variants in AOAH are associated with asthma and related phenotypes. Because both AOAH and soluble CD14 respond to LPS, we tested for gene-gene interaction. METHODS: We investigated the association between 28 single nucleotide polymorphisms throughout the AOAH gene and asthma, concentrations of tIgE, the ratio of IL-13/IFN-gamma, and soluble CD14 levels among 125 African Caribbean, multiplex asthmatic pedigrees (n = 834). Real-time PCR was used to assess whether AOAH cDNA expression differed with AOAH genotype. RESULTS: Significant effects were observed for all 4 phenotypes and AOAH markers in 3 distinct regions (promoter, introns 1-6, and the intron 12/exon 13 boundary/intron 13 region) by means of single-marker and haplotype analyses, with the strongest evidence for a 2-single-nucleotide-polymorphism haplotype and log[tIgE] (P = .006). There was no difference in AOAH expression levels by AOAH genotype for any of the markers. Comparing genotypic distributions at both the AOAH marker rs2727831 and CD14(-260)C >T raises the possibility of gene-gene interaction (P = .006-.036). CONCLUSION: Our results indicate that polymorphisms in markers within the AOAH gene are associated with risk of asthma and associated quantitative traits (IgE and cytokine levels) among asthmatic subjects and their families in Barbados, and there is an interactive effect on tIgE and asthma concentrations between an AOAH marker and the functional CD14(-260)C >T polymorphism. CLINICAL IMPLICATIONS: AOAH is a novel innate immunity candidate gene associated with asthma and related phenotypes in an African ancestry population.     

Interventions to reduce the incidence of falls in older adult patients in acute-care hospitals: a systematic review

Aim Falls can cause serious physical and emotional injuries to patients leading to poor quality of life and increased length of hospital stay. The aim of this study was to present the best available evidence regarding the effectiveness of risk assessment or other interventions that aimed to minimise the number of falls. Methods A systematic review of randomised controlled trials was undertaken to determine the effectiveness of interventions that were designed to reduce the incidence of falls in older acute-care patients. Only trials published between 1998 and 2008 were considered. Results Only seven studies were included in the review, indicating the evidence on this topic is sparse. There is some evidence to suggest that implementing the following interventions in acute hospitals may be effective in reducing the amount of falls of older adult inpatients: ? A multidisciplinary multifactorial intervention program consisting of falls risk alert card, an exercise program, an education program and the use of hip protectors after approximately 45?days ? A one-on-one patient education package entailing information on risk factors and preventative strategies for falls as well as goal setting ? A targeted fall risk factor reduction intervention that includes a fall risk factor screen, recommended interventions encompassing local advice and a summary of the evidence There is also some evidence to suggest that implementing a multidisciplinary multifactorial intervention that consists of systematic assessment and treatment of fall risk factors, as well as active management of postoperative complications, can reduce the amount of falls in patients following surgery for femoral neck fracture. Conclusion There is some evidence to suggest that certain multifactorial interventions are more effective than others and that increasing patient education or targeting fall risk factors may be of benefit. Further high-quality research is needed in order to ascertain effective fall-prevention strategies in acute-care facilities.     

Serotonin 5-hydroxytryptamine(2A) receptor activation suppresses tumor necrosis factor-alpha-induced inflammation with extraordinary potency

The G protein-coupled serotonin 5-hydroxytryptamine (5-HT)(2A) receptor is primarily recognized for its role in brain neurotransmission, where it mediates a wide variety of functions, including certain aspects of cognition. However, there is significant expression of this receptor in peripheral tissues, where its importance is largely unknown. We have now discovered that activation of 5-HT(2A) receptors in primary aortic smooth muscle cells provides a previously unknown and extremely potent inhibition of tumor necrosis factor (TNF)-alpha-mediated inflammation. 5-HT(2A) receptor stimulation with the agonist (R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(R)-DOI] rapidly inhibits a variety of TNF-alpha-mediated proinflammatory markers, including intracellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), and interleukin (IL)-6 gene expression, nitric-oxide synthase activity, and nuclear translocation of nuclear factor kappaB, with IC(50) values of only 10 to 20 pM. It is significant that proinflammatory markers can also be inhibited by (R)-DOI hours after treatment with TNF-alpha. With the exception of a few natural toxins, no current drugs or small molecule therapeutics demonstrate a comparable potency for any physiological effect. TNF-alpha-mediated inflammatory pathways have been strongly implicated in a number of diseases, including atherosclerosis, rheumatoid arthritis, psoriasis, type II diabetes, depression, schizophrenia, and Alzheimer's disease. Our results indicate that activation of 5-HT(2A) receptors represents a novel, and extraordinarily potent, potential therapeutic avenue for the treatment of disorders involving TNF-alpha-mediated inflammation. Note that because (R)-DOI can significantly inhibit the effects of TNF-alpha many hours after the administration of TNF-alpha, potential therapies could be aimed not only at preventing inflammation but also treating inflammatory injury that has already occurred or is ongoing.     

Drug delivery to the posterior segment of the eye

Delivery of drugs to the posterior eye is challenging, owing to anatomical and physiological constrains of the eye. There is an increasing need for managing rapidly progressing posterior eye diseases, such as age-related macular degeneration, diabetic retinopathy and retinitis pigmentosa. Drug delivery to the posterior segment of the eye is therefore compounded by the increasing number of new therapeutic entities (e.g. oligonucleotides, aptamers and antibodies) and the need for chronic therapy. Currently, the intravitreal route is widely used to deliver therapeutic entities to the retina. However, frequent administration of drugs via this route can lead to retinal detachment, endophthalmitis and increased intraocular pressure. Various controlled delivery systems, such as biodegradable and non-biodegradable implants, liposomes and nanoparticles, have been developed to overcome such adverse effects, with some success. The periocular route is a promising alternative, owing to the large surface area and the relatively high permeability of the sclera. Yet, the blood-retinal barrier and efflux transporters hamper the transport of therapeutic entities to the retina. As such, the efficient delivery of drugs to the posterior eye remains a major challenge facing the pharmaceutical scientist. In this review, we discuss the barriers of the posterior eye drug delivery and the various drug-delivery strategies used to overcome these barriers.     

The impact of trauma-informed suicide prevention approaches: A systematic review of evidence across the lifespan

Trauma is associated with an increased likelihood of experiencing suicidality, indicating the need for and potential value of trauma-informed suicide prevention strategies. The aim of this study is to systematically review published literature regarding trauma-informed approaches for suicide prevention, and the impact on suicide outcomes. Systematic searches were conducted in eight databases (Medline, Embase, PsycInfo, Emcare, Nursing, and JBI in the Ovid platform; as well as ProQuest Psychology Database and The Cochrane Library) in March 2022, with no publication date limit. Four studies met the inclusion criteria: two randomized controlled trials and two quasi-experimental studies. Two studies reported reductions in ideation, intent, and behaviour among youth and a cultural minority group. Few studies directly reporting suicide outcomes were identified, all were quantitative, and heterogeneity prevents generalizability across population groups. Currently, there is limited evidence focusing specifically on trauma-informed suicide prevention across the lifespan. Additional research, incorporating lived experience voices, is needed to understand the potential of this approach, as well as how mental health nurses can incorporate these approaches into their practice.