Reference Values for Fetal Cardiac Dimensions, Volumes, Ventricular Function and Left Ventricular Longitudinal Strain Using Doppler Ultrasound Gated Cardiac Magnetic Resonance Imaging in Healthy Third Trimester Fetuses.

BACKGROUND: Recent advances in hardware and software permit the use of cardiac MRI of late gestation fetuses, however there is a paucity of MRI-based reference values. PURPOSE: To provide initial data on fetal cardiac MRI-derived cardiac dimensions, volumes, ventricular function, and left ventricular longitudinal strain in healthy developing fetuses >30 weeks gestational age. STUDY TYPE: Prospective. POPULATION: Twenty-five third trimester (34 ± 1 weeks, range of 32-37 weeks gestation) women with healthy developing fetuses. FIELD STRENGTH/SEQUENCE: Studies were performed at 1.5 T and 3 T. Cardiac synchronization was achieved with a Doppler ultrasound device. The protocol included T2 single shot turbo spin echo stacks for fetal weight and ultrasound probe positioning, and multiplanar multi-slice cine balanced steady state free precession gradient echo sequences. ASSESSMENT: Primary analyses were performed by a single observer. Weight indexed right ventricular (RV) and left ventricular (LV) volumes and function were calculated from short axis (SAX) stacks. Cardiac dimensions were calculated from the four-chamber and SAX stacks. Single plane LV longitudinal strain was calculated from the four-chamber stack. Interobserver variability was assessed in 10 participants. Cardiac MRI values were compared against available published normative fetal echocardiogram data using z-scores. STATISTICAL TESTS: Mean and SDs were calculated for baseline maternal/fetal demographics, cardiac dimensions, volumes, ventricular function, and left ventricular longitudinal strain. Bland-Altman and intraclass correlation coefficient analysis was performed to test interobserver variability. RESULTS: The mean gestational age was 34 ± 1.4 weeks. The mean RV and LV end diastolic volumes were 3.1 ± 0.6 mL/kg and 2.4 ± 0.5 mL/kg respectively. The mean RV cardiac output was 198 ± 49 mL/min/kg while the mean LV cardiac output was 173 ± 43 mL/min/kg. DATA CONCLUSION: This paper reports initial reference values obtained by cardiac MRI in healthy developing third trimester fetuses. MRI generally resulted in slightly larger indexed values (by z-score) compared to reports in literature using fetal echocardiography. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

A compendium of RNA-binding motifs for decoding gene regulation.

RNA-binding proteins are key regulators of gene expression, yet only a small fraction have been functionally characterized. Here we report a systematic analysis of the RNA motifs recognized by RNA-binding proteins, encompassing 205 distinct genes from 24 diverse eukaryotes. The sequence specificities of RNA-binding proteins display deep evolutionary conservation, and the recognition preferences for a large fraction of metazoan RNA-binding proteins can thus be inferred from their RNA-binding domain sequence. The motifs that we identify in vitro correlate well with in vivo RNA-binding data. Moreover, we can associate them with distinct functional roles in diverse types of post-transcriptional regulation, enabling new insights into the functions of RNA-binding proteins both in normal physiology and in human disease. These data provide an unprecedented overview of RNA-binding proteins and their targets, and constitute an invaluable resource for determining post-transcriptional regulatory mechanisms in eukaryotes.

A double-blind, randomised trial of a polyphenolic-rich nail bed balm for chemotherapy-induced onycholysis: the UK polybalm study.

PURPOSE: Nail damage is common amongst patients receiving chemotherapy causing disfigurement and pain. This investigation evaluated whether a topical balm containing steam-extracted, bioactive polyphenolic-rich herbal oils blended with organic waxes could protect the nails via their reported anti-inflammatory, analgesic, anti-oxidant and anti-microbial properties. METHODS: 60 patients (23M, 37F) were randomised to apply (2-3/day) either the plant balm (PB) or a petroleum control (PC) to their nail beds. Demographics, type and number of chemotherapy cycles did not differ between the two groups, recruited between Sept 2015 and Sept 2016. An unpaired t test was used to test the differences in symptoms and physical nail damage between the two groups. RESULTS: Symptom scores recorded with the dermatology life quality questionnaire (DLQQ) were significantly better, between the start and end of chemotherapy, in the group applying the PB versus PC. Likewise, the mean fall in nail damage, scored with the Nail Psoriasis Index by the supervising physician, was also significantly different. CONCLUSION: The polyphenolic-rich essential oils and plant-based waxes in this nail bed balm profoundly reduced chemotherapy-related nail damage and improved nail-related quality of life, compared to a control. A further analysis is planned combining this balm with nail bed cooling.

Expression and enzyme activity of cytochrome P450 enzymes CYP3A4 and CYP3A5 in human skin and tissue-engineered skin equivalents.

CYP3A4 and CYP4A5 share specificity for a wide range of xenobiotics with the CYP3 subfamily collectively involved in the biotransformation of approximately 30% of all drugs. CYP3A4/5 mRNA transcripts have been reported in the skin, yet knowledge of their protein expression and function is lacking. In this study, we observed gene and protein expression of CYP3A4/5 in both human skin and tissue-engineered skin equivalents (TESEs), and enzyme activity was detected using the model substrate benzyl-O-methyl-cyanocoumarin. Mass spectrometric analysis of TESE lysates following testosterone application revealed a time-dependent increase in metabolite production, confirming the functional expression of these enzymes in skin.

Cooling of the oral mucosa to prevent adverse effects of chemotherapeutic agents: An in vitro study.

BACKGROUND: The cytotoxic effect of chemotherapeutic agents to the oral mucosa, as a side effect of cancer treatment, is a major problem. Cooling the oral mucosa using ice chips in conjunction with chemotherapy is known to reduce the severity of oral mucositis. However, although the use of ice chips is of clinical value, this method of cooling has inherent problems including discomfort for the patient, non-uniformity and fluctuations in cooling temperature throughout the oral cavity. Furthermore, despite being used clinically, it is not known what reduction in temperature is required to prevent oral mucositis. The aim of this study was therefore to determine in vitro if the cytotoxic effect of 5-fluorouracil (5-FU) on the oral mucosa could be reduced by lowering the temperature during chemotherapeutic treatment. METHODS: Tissue-engineered oral mucosal (TEOM) models were incubated at 20, 25, 30 or 35°C for 30 minutes followed by exposure to a clinically relevant concentration of 5-FU (162 µg/mL) for 2 hours and compared with untreated models (35°C). Cell viability and inflammatory cytokine production (IL-6 and TNF-α) were measured using PrestoBlue® and ELISA, respectively. RESULTS: TEOM models incubated at 20°C showed an increased cell viability and had a reduced IL-6 and TNF-α production compared to models treated with 5-FU incubated at 35°C. CONCLUSION: This study demonstrates a reduced cytotoxic effect to the TEOM by reducing the temperature of the tissue during chemotherapy treatment and suggests that decreasing the temperature to 20°C could have clinical advantages.

Designing equitable workplace dietary interventions: perceptions of intervention deliverers.

BACKGROUND: Workplaces are a good setting for interventions that aim to support workers in achieving a healthier diet and body weight. However, little is known about the factors that impact on the feasibility and implementation of these interventions, and how these might vary by type of workplace and type of worker. The aim of this study was to explore the views of those involved in commissioning and delivering the Better Health at Work Award, an established and evidence-based workplace health improvement programme. METHODS: One-to-one semi-structured interviews were conducted with 11 individuals in North East England who had some level of responsibility for delivering workplace dietary interventions. Interviews were transcribed verbatim and analysed using thematic framework analysis. RESULTS: A number of factors were felt to promote the feasibility and implementation of interventions. These included interventions that were cost-neutral (to employee and employer), unstructured, involved colleagues for support, took place at lunchtimes, and were well-advertised and communicated via a variety of media. Offering incentives, not necessarily monetary, was perceived to increase recruitment rates. Factors that militate against feasibility and implementation of interventions included worksites that were large in size and remote, working patterns including shifts and working outside of normal working hours that were not conducive to workers being able to access intervention sessions, workplaces without appropriate provision for healthy food on site, and a lack of support from management. CONCLUSIONS: Intervention deliverers perceived that workplace dietary interventions should be equally and easily accessible (in terms of cost and timing of sessions) for all staff, regardless of their job role. Additional effort should be taken to ensure those staff working outside normal working hours, and those working off-site, can easily engage with any intervention, to avoid the risk of intervention-generated inequalities (IGIs).

Comparative metabolomics in vegans and omnivores reveal constraints on diet-dependent gut microbiota metabolite production.

OBJECTIVE: The consumption of an agrarian diet is associated with a reduced risk for many diseases associated with a 'Westernised' lifestyle. Studies suggest that diet affects the gut microbiota, which subsequently influences the metabolome, thereby connecting diet, microbiota and health. However, the degree to which diet influences the composition of the gut microbiota is controversial. Murine models and studies comparing the gut microbiota in humans residing in agrarian versus Western societies suggest that the influence is large. To separate global environmental influences from dietary influences, we characterised the gut microbiota and the host metabolome of individuals consuming an agrarian diet in Western society. DESIGN AND RESULTS: Using 16S rRNA-tagged sequencing as well as plasma and urinary metabolomic platforms, we compared measures of dietary intake, gut microbiota composition and the plasma metabolome between healthy human vegans and omnivores, sampled in an urban USA environment. Plasma metabolome of vegans differed markedly from omnivores but the gut microbiota was surprisingly similar. Unlike prior studies of individuals living in agrarian societies, higher consumption of fermentable substrate in vegans was not associated with higher levels of faecal short chain fatty acids, a finding confirmed in a 10-day controlled feeding experiment. Similarly, the proportion of vegans capable of producing equol, a soy-based gut microbiota metabolite, was less than that was reported in Asian societies despite the high consumption of soy-based products. CONCLUSIONS: Evidently, residence in globally distinct societies helps determine the composition of the gut microbiota that, in turn, influences the production of diet-dependent gut microbial metabolites.

Exploring the dynamics of a free fruit at work intervention.

BACKGROUND: The workplace has been identified as an ideal setting for health interventions. However, few UK-based workplace intervention studies have been published. Fewer still focus on the practicalities and implications when running an intervention within the workplace setting. The objective of this paper was to qualitatively determine the perceived behaviour changes of participants in a free fruit at work intervention. Understanding the dynamics of a workplace intervention and establishing any limitations of conducting an intervention in a workplace setting were also explored. METHODS: Twenty-three face-to-face interviews were conducted with individuals receiving free fruit at work for 18 weeks (74 % female). The worksite was the offices of a regional local government in the North East of England. Analysis was guided theoretically by Grounded Theory research and the data were subjected to content analysis. The transcripts were read repeatedly and cross-compared to develop a coding framework and derive dominant themes. RESULTS: Topics explored included: the workplace food environment; the effect of the intervention on participants and on other related health behaviours; the effect of the intervention on others; participant's fruit consumption; reasons for not taking part in the intervention; expectations and sustainability post-intervention; and how to make the workplace healthier. Five emergent themes included: the office relationship with food; desk based eating; males and peer support; guilt around consumption of unhealthy foods; and the type of workplace influencing the acceptability of future interventions. CONCLUSION: Exploring the perceptions of participants offered valued insights into the dynamics of a free fruit workplace intervention. Findings suggest that access and availability are both barriers and facilitators to encouraging healthy eating in the workplace.

hnRNP U enhances caspase-9 splicing and is modulated by AKT-dependent phosphorylation of hnRNP L.

Caspase-9 has two splice variants, pro-apoptotic caspase-9a and anti-apoptotic caspase-9b, which are regulated by RNA trans-factors associated with exon 3 of caspase-9 pre-mRNA (C9/E3). In this study, we identified hnRNP U as an RNA trans-factor associated with C9/E3. Down-regulation of hnRNP U led to a decrease in the caspase-9a/9b mRNA ratio, demonstrating a novel enhancing function. Importantly, hnRNP U bound specifically to C9/E3 at an RNA cis-element previously reported as the binding site for the splicing repressor, hnRNP L. Phosphorylated hnRNP L interfered with hnRNP U binding to C9/E3, and our results demonstrate the importance of the phosphoinositide 3-kinase/AKT pathway in modulating the association of hnRNP U to C9/E3. Taken together, these findings show that hnRNP U competes with hnRNP L for binding to C9/E3 to enhance the inclusion of the four-exon cassette, and this splice-enhancing function is blocked by the AKT pathway via phosphorylation of hnRNP L.

Magnet Hospitals: Higher Rates of Patient Satisfaction.

Patient satisfaction with care is an important indicator of quality of care. As of 2013-2014, 30% of the Value-Based Purchasing score Medicare is using to determine hospital reimbursement is based on patient reports of care. This study determined whether significant relationships exists between Magnet (N = 160), Magnet-in-progress (N = 99), and non-Magnet hospital (N = 1,742) status and the highest ratings on the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey questions related to patient satisfaction with care. This study was a secondary analysis of data collected and compiled from three sources (the American Hospital Association, American Nurses Credentialing Center, and HCAHPS databases). Analysis revealed that Magnet and Magnet-in-progress hospitals have significantly (p < .007) higher scores than non-Magnet hospitals on six of the seven questions regarding patient-reported satisfaction with care. The implications of these results for nursing are discussed.

A new species of lizard in the genus Caledoniscincus (Reptilia: Scincidae) from southern New Caledonia and a review of Caledoniscincus atropunctatus (Roux).

A new species of skink, Caledoniscincus notialis sp. nov., is described from the ultramafic ranges in southern New Caledonia. It is most similar to, and has previously been referred to Caledoniscincus atropunctatus (Roux), a species with a widespread distribution throughout the Grand Terre and Loyalty Islands. The new species is distinct genetically from all other Caledoniscincus and can be distinguished by a unique pattern of dorsal coloration in males. Its range extends over much of the extensive ultramafic block in the south of the island, including the Goro Plateau and the mountain ranges at the southern edge of the Chaine Centrale north to Mt. Humboldt. It occurs mainly in humid forest habitat, much of which is now present only as isolated fragments in southern New Caledonia. Its preference for a habitat that has undergone a significant reduction in area of extent in a region under pressure from a range of anthropogenic threats suggests this new species is of conservation concern, and could be ranked as Vulnerable under IUCN listing. The genetic relationships of a redefined Caledoniscincus atropunctatus identifies two major subgroups, one located mainly in the northern and central-east regions of Grand Terre and the other in the southern and central-west regions and also including the population on the Loyalty Islands.

A disease-associated polymorphism alters splicing of the human CD45 phosphatase gene by disrupting combinatorial repression by heterogeneous nuclear ribonucleoproteins (hnRNPs).

Alternative splicing is typically controlled by complexes of regulatory proteins that bind to sequences within or flanking variable exons. The identification of regulatory sequence motifs and the characterization of sequence motifs bound by splicing regulatory proteins have been essential to predicting splicing regulation. The activation-responsive sequence (ARS) motif has previously been identified in several exons that undergo changes in splicing upon T cell activation. hnRNP L binds to this ARS motif and regulates ARS-containing exons; however, hnRNP L does not function alone. Interestingly, the proteins that bind together with hnRNP L differ for different exons that contain the ARS core motif. Here we undertake a systematic mutational analysis of the best characterized context of the ARS motif, namely the ESS1 sequence from CD45 exon 4, to understand the determinants of binding specificity among the components of the ESS1 regulatory complex and the relationship between protein binding and function. We demonstrate that different mutations within the ARS motif affect specific aspects of regulatory function and disrupt the binding of distinct proteins. Most notably, we demonstrate that the C77G polymorphism, which correlates with autoimmune disease susceptibility in humans, disrupts exon silencing by preventing the redundant activity of hnRNPs K and E2 to compensate for the weakened function of hnRNP L. Therefore, these studies provide an important example of the functional relevance of combinatorial function in splicing regulation and suggest that additional polymorphisms may similarly disrupt function of the ESS1 silencer.

Adaptive evolution of Toll-like receptor 5 in domesticated mammals.

BACKGROUND: Previous studies have proposed that mammalian toll like receptors (TLRs) have evolved under diversifying selection due to their role in pathogen detection. To determine if this is the case, we examined the extent of adaptive evolution in the TLR5 gene in both individual species and defined clades of the mammalia. RESULTS: In support of previous studies, we find evidence of adaptive evolution of mammalian TLR5. However, we also show that TLR5 genes of domestic livestock have a concentration of single nucleotide polymorphisms suggesting a specific signature of adaptation. Using codon models of evolution we have identified a concentration of rapidly evolving codons within the TLR5 extracellular domain a site of interaction between host and the bacterial surface protein flagellin. CONCLUSIONS: The results suggest that interactions between pathogen and host may be driving adaptive change in TLR5 by competition between species. In support of this, we have identified single nucleotide polymorphisms (SNP) in sheep and cattle TLR5 genes that are co-localised and co-incident with the predicted adaptive codons suggesting that adaptation in this region of the TLR5 gene is on-going in domestic species.

Stable isotope tracing in vivo reveals a metabolic bridge linking the microbiota to host histone acetylation.

The gut microbiota influences acetylation on host histones by fermenting dietary fiber into butyrate. Although butyrate could promote histone acetylation by inhibiting histone deacetylases, it may also undergo oxidation to acetyl-coenzyme A (CoA), a necessary cofactor for histone acetyltransferases. Here, we find that epithelial cells from germ-free mice harbor a loss of histone H4 acetylation across the genome except at promoter regions. Using stable isotope tracing in vivo with 13C-labeled fiber, we demonstrate that the microbiota supplies carbon for histone acetylation. Subsequent metabolomic profiling revealed hundreds of labeled molecules and supported a microbial contribution to host fatty acid metabolism, which declined in response to colitis and correlated with reduced expression of genes involved in fatty acid oxidation. These results illuminate the flow of carbon from the diet to the host via the microbiota, disruptions to which may affect energy homeostasis in the distal gut and contribute to the development of colitis.

Exploring awareness, attitudes, and perceived role among oral health providers regarding HPV-related oral cancers.

OBJECTIVES: Human Papillomavirus (HPV), the most common STI in the United States, is increasingly being associated with a number of cancers, including oral cancers (OC). This may change the approach of oral health providers (OHP) towards screening and identifying OC in their patients. METHODS: Five focus groups were conducted in February and March 2009 with dentists and dental hygienists. Participants were recruited via presentations at monthly meetings of local dental and dental hygiene professional associations, and through association mailing and telephone lists. RESULTS: A total of 38 OHP participated in the focus groups (17 dentists and 21 hygienists). Analysis of focus group data was framed by three general content areas regarding HPV-related OC and the HPV vaccine, including: (a) knowledge; (b) attitudes; and (c) perceived roles. Sub-themes that emerged included issues related to the HPV vaccine, the role of professional organizations, and concerns with gender roles and confidentiality. CONCLUSIONS: As public awareness of the link between HPV and OC increases, OHP play an important role in addressing this issue with their patients. The current study clearly identified areas that must be addressed among OHP in order for effective and comfortable communication regarding the HPV-OC link and the potential uses of the HPV vaccines to take place, including: (a) increasing knowledge of the HPV-OC link and HPV vaccine; and (b) clarifying screening procedures, role, and expectations.

Self-verification and social anxiety: preference for negative social feedback and low social self-esteem.

BACKGROUND: A self-verification model of social anxiety views negative social self-esteem as a core feature of social anxiety. This core feature is proposed to be maintained through self-verification processes, such as by leading individuals with negative social self-esteem to prefer negative social feedback. This model is tested in two studies. METHODS: In Study 1, questionnaires were administered to a college sample (N = 317). In Study 2, questionnaires were administered to anxiety disordered patients (N = 62) before and after treatment. RESULTS: Study 1 developed measures of preference for negative social feedback and social self-esteem, and provided evidence of their incremental validity in a college sample. Study 2 found that these two variables are not strongly related to fears of evaluation, are relatively unaffected by a treatment that targets such fears, and predict residual social anxiety following treatment. CONCLUSIONS: Overall, these studies provide preliminary evidence for a self-verification model of social anxiety.

Identification of 4'-Demethyltangeretin as a Major Urinary Metabolite of Tangeretin in Mice and Its Anti-inflammatory Activities.

The present study showed that oral administration of tangeretin (TAN) in mice resulted in the production of 4'-demethyltangeretin (4DT) as a major urinary metabolite. The anti-inflammatory efficacy of TAN and 4DT was determined in RAW 264.7 macrophages stimulated by lipopolysaccharides (LPS). 4DT produced considerably stronger inhibition on the overproduction of prostaglandin E2 and nitric oxide than TAN did at the same concentrations. Western blot and quantitative polymerase chain reaction analyses indicated that 4DT exerted more potent suppressive activity on the over-expression of interleukin-1ß, inducible nitric oxide synthase, and cyclooxygenase-2 than TAN. Treatments with TAN and 4DT diminished LPS-stimulated nuclear factor κB (NFκB) translocation via suppressing the degradation of inhibitor κB (IκBα). Furthermore, both compounds attenuated mitogen-activated protein kinases (MAPKs) and Akt signaling upregulated by LPS. Overall, our findings showed that TAN and 4DT inhibited the LPS-stimulated inflammatory response in macrophages by suppressing Akt/MAPKs/NFκB proinflammatory pathways, while 4DT showed more potent activity than TAN, its parent compound.

Optimization of Supercritical CO2 Extraction of Moringa oleifera Seed Oil Using Response Surface Methodological Approach and Its Antioxidant Activity.

Moringa (Moringa oleifera) seed oil is an edible vegetable oil rich in unsaturated fatty acids. In this study, the supercritical CO2 fluid extraction method was employed to obtain the maximum yield of moringa seed oil. The effects of temperature, time, and pressure, three characteristics of extractions, on the extraction rate of Moringa seed oil were investigated by single factor test and response surface methodological approach. The optimal process conditions of supercritical CO2 fluid extraction of moringa seed oil were determined as extraction temperature of 45°C, extraction time of 2.5 h, extraction pressure of 50 MPa, and CO2 flow rate of 240 L/h, resulting in a maximum yield of 38.54%. Composition analysis shows that the extracted moringa seed oil is rich in unsaturated fatty acids, including oleic acid, octadecanoic acid, palmitic acid, stearic acid, eicosanoic acid, etc. Furthermore, we found that Moringa seed oil exerted potent antioxidant activities on DPPH and hydroxyl radicals, and its efficacy was comparable to commercial peanut oil and tea oil. Overall, this novel extraction method of moringa seed oil may increase its potential value and application in the food and nutraceutical industries.

Mitochondrial dysfunction in inflammatory bowel disease alters intestinal epithelial metabolism of hepatic acylcarnitines.

As the interface between the gut microbiota and the mucosal immune system, there has been great interest in the maintenance of colonic epithelial integrity through mitochondrial oxidation of butyrate, a short-chain fatty acid produced by the gut microbiota. Herein, we showed that the intestinal epithelium could also oxidize long-chain fatty acids, and that luminally delivered acylcarnitines in bile could be consumed via apical absorption by the intestinal epithelium, resulting in mitochondrial oxidation. Finally, intestinal inflammation led to mitochondrial dysfunction in the apical domain of the surface epithelium that may reduce the consumption of fatty acids, contributing to higher concentrations of fecal acylcarnitines in murine Citrobacter rodentium-induced colitis and human inflammatory bowel disease. These results emphasized the importance of both the gut microbiota and the liver in the delivery of energy substrates for mitochondrial metabolism by the intestinal epithelium.

The collective power of women's organisations in Chuuk, FSM.

Achieving gender equality is a key component for improving global health, but how to do so remains a complex undertaking. Each community's experiences with gender inequality and vision for equality are historically and culturally specific, while also fitting larger global patterns. This is the case in Chuuk, Federated States of Micronesia, a group of islands suffering from the impacts of a long history integrating coloniser and locally formed patriarchal values. Chuukese women often see their roles as powerless and silent except when acting through women's groups. In recent decades, Chuukese women created an umbrella organisation for all women's groups, yielding more power to effect change. Derived from an ethnographic study of the Chuuk Women's Council (CWC), 1 focus group and 12 individual interviews were conducted with CWC members to explore women's experiences advancing gender equality on their terms. Findings demonstrate how the CWC lobbied for legal change, replaced inadequate health and social services, and changed community conversations about gender. The CWC received national and international resources, which became both supportive and disruptive to their efforts. Findings from this study have implications for global support of grassroots efforts to achieve gender equality, with lasting implications for gender equity in health.