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Mohamed A Hendaus,1,2 Hibaq A Jama,1 Faisal J Siddiqui,1,3 Sohair A Elsiddig,1 Ahmed H Alhammadi1,2 1Department of Pediatrics, General Academic Pediatrics Section, Hamad Medical Corporation, Doha, 2Department of Clinical Pediatrics, Weill Cornell Medical College, 3Pediatric Residency Program, Hamad Medical Corporation, Doha, Qatar Objective: The objective of this study was to investigate parental preference for fluoride varnish in a country where the average percentage of dental caries in young children is up to ~73%. Consequently, the aim of this study, despite being a pilot, was to create a nationwide project in the State of Qatar to promote oral health in children. Methods: A cross-sectional perspective study was conducted at Hamad Medical Corporation in Qatar. Parents of children aged ≤5 years were offered an interview survey. A total of 200 questionnaires were completed (response rate =100%). The study was conducted between December 1, 2014 and March 30, 2015, and included all children aged >1 year and 90% of families were aware that dental health affects the health of the whole body. The study showed that ~70% of parents were not aware of the existence of fluoride varnish, but would allow a health provider to apply fluoride varnish. Furthermore, ~80% of parents would not stop brushing their child’s teeth and would not skip dentist appointments if varnish was to be applied. Approximately 40% of parents conveyed some concerns regarding the safety of fluoride varnish, despite being considered as a new concept. The main concern was that the child might swallow some of the fluoride. Another important concern expressed by parents was the availability of the fluoride varnish in all clinics. Conclusion: The robust positive attitude of parents in this sample suggests that introducing fluoride varnish is feasible and acceptable in our community. Actions to augment fluoride varnish acceptability in the developing world, such as focusing on safety, could be important in the disseminated implementation of fluoride varnish. Keywords: fluoride, parents, varnish, Qatar

Background: Fermentation of dietary fiber by the gut microbiota leads to the production of metabolites called short-chain fatty acids, which lower blood pressure and exert cardioprotective effects. Short-chain fatty acids activate host signaling responses via the functionally redundant receptors GPR41 and GPR43, which are highly expressed by immune cells. Whether and how these receptors protect against hypertension or mediate the cardioprotective effects of dietary fiber remains unknown., Methods: Cardiovascular phenotype was assessed in untreated and Ang II (angiotensin II) treated hypertensive wild-type and GPR41/43 knockout (KO) double knockout male mice fed diets with different levels of fiber content. Some mice received TLR4-antagonist treatment and bone marrow chimeras. Single-nucleotide polymorphisms associated with GPR41 and GPR43 expression were assessed in UK Biobank participants., Results: Untreated GPR41/43KO mice had unaltered blood pressure but had greater cardiac and renal collagen deposition with higher macrophage numbers in the kidney compared with wild-type mice. Ang II-treated GPR41/43KO mice showed higher systolic blood pressure, cardiorenal weights and collagen deposition, and increased gut permeability, which allows the translocation of gastrointestinal bacterial components such as lipopolysaccharides into the circulation. The use of an antagonist to the lipopolysaccharide receptor, TLR4, a potent proinflammatory signaling molecule, restored the cardiovascular phenotype in GPR41/43KO mice. The lack of GPR41/43 expression in the immune compartment was sufficient to lead to a worsened hypertensive phenotype. We also demonstrate that GPR41/43 is, at least partially, responsible for the blood pressure-lowering and cardioprotective effects of a high-fiber diet. Finally, using the UK Biobank, we provide translational evidence that variants associated with lower expression of both GPR41 and GPR43 are more prevalent in participants with hypertension., Conclusions: Our findings highlight that lack of short-chain fatty acid-receptor signaling via both GPR41 and GPR43 increases risk of high blood pressure, suggesting treatments that target these receptors could be a novel strategy to prevent or treat hypertension.

Introduction: Melanoma is one of the most dangerous and common types of cancer in humans. In order to minimize the toxicity and side effects of melanoma treatment, it is important to identify drug candidates that have strong anti-cancer activity and fewer side effects. Lobaric acid is a small molecule that has been found to have significant anti-cancer effects on various types of cancer cells., Methods: The study aimed to investigate the effects of lobaric acid on human melanoma cell lines (A-375, MDA-MB-435, G-361, and WM-115) and normal human epidermal melanocyte cells. The study also examined the regulation of cell cycle and apoptosis, as well as the gene expression level of apoptosis-related genes and regulatory proteins to induce apoptosis in melanoma cells., Results: The study suggests that lobaric acid may have an effect on the proliferation of A-375 melanoma cells, with results indicating a dose- and time-dependent manner. Additionally, the study found that the expression levels of 70 target genes out of 88 apoptosis- related genes in the primary apoptosis library panel were obtained. Out of these, 54 genes showed an increase in expression levels, while 16 genes showed a decrease. Moreover, it has been determined that the levels of apoptosis-related proteins, such as Casp3, Casp7, Casp9, and PARP, were increased. The results suggest that lobaric acid induces apoptosis through the extrinsic pathway by upregulating the expression of Caspases and PARP., Conclusion: The findings of this study provided a strong basis for the use of lobaric acid as a potential therapeutic agent in the treatment of melanoma., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The paternal environment prior to conception has been demonstrated to influence offspring physiology and behavior, with the sperm epigenome (including noncoding RNAs) proposed as a potential facilitator of non-genetic inheritance. Whilst the maternal gut microbiome has been established as an important influence on offspring development, the impact of the paternal gut microbiome on offspring development, health and behavior is largely unknown. Gut microbiota have major influences on immunity, and thus we hypothesized that they may be relevant to paternal immune activation (PIA) modulating epigenetic inheritance in mice. Therefore, male C57BL/6J mice (F0) were orally administered non-absorbable antibiotics via drinking water in order to substantially deplete their gut microbiome. Four weeks after administration of the antibiotics (gut microbiome depletion), F0 male mice were then mated with naïve female mice. The F1 offspring of the microbiome-depleted males had reduced body weight as well as altered gut morphology (shortened colon length). F1 females showed significant alterations in affective behaviors, including measures of anxiety and depressive-like behaviors, indicating altered development. Analysis of small noncoding RNAs in the sperm of F0 mice revealed that gut microbiome depletion is associated with differential expression of 8 different PIWI-interacting RNAs (piRNAs), each of which has the potential to modulate the expression of multiple downstream gene targets, and thus influence epigenetic inheritance and offspring development. This study demonstrates that the gut-germline axis influences sperm small RNA profiles and offspring physiology, with specific impacts on offspring affective and/or coping behaviors. These findings may have broader implications for other animal species with comparable gut microbiota, intergenerational epigenetics and developmental biology, including humans., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Institutional delivery has been considered one of the important strategies to improve maternal and child health and significantly reduce birth-related complications. However, it is still low in developing countries though there are some improvements. even among the community who has access to the health institutions weather health center and hospital including Somaliland. Hence, the aim of this study was to assess the level of institutional delivery service utilization and associated factors among women who gave birth in the last 12 months in Ga'an libah district, Marodijeh region, Somaliland., Methods: The community-based cross-sectional study was conducted among women who gave birth in the last 12 months from September to December 2022. A simple random sampling technique was employed to select study participants from a total of sample population. Data was collected using semi-structural administered questionnaire through interviewing women. Data was collected with online mobile data collection (Kobo collect). SPSS version 25.0 was used for data management, entering and analysis. Bivariate and multivariable logistic regression models were fitted to determine the presence of a statistically significant association between independent variables and the outcome variable with p-value < 0.05., Result: Level of Institutional delivery services utilization in Ga'an libah district was 53.9% [95% Cl 48.2-59.6] gave birth at health institutions. Women who can read and write local were (AOR 2.18, 95% CI 1.08-4.56, p<0.01), Women with their husband can be capable to read and write are [(AOR = 6.95, 95% Cl 2.82-21.58, p<0.002]). Additionally, ability to cost transportation for referral [AOR 5.21, 95% Cl 2.44-11.13, p<0.001]. not good services available [AOR 0.07, 95%Cl 0.01-0.10, p<0.02]. lack of maternal health and child knowledge [AOR 0.034, 95% Cl 0.02-0.57, p<0.01]. were observed associated with level of institutional deliver services utilization., Conclusion: The institutional delivery service utilization was relatively high compared to national demographic health services in the study area. A large proportion of women gave both at home without a skilled attendant. Therefore, this finding has important policy implications since changes in the cost of the health service and perceived quality would mean changes in client satisfaction as well as their choice, as well emphasize to expectant women can receive medical advice and ambulance for referrals., (© 2024. The Author(s).)

Background: The primary public health service system is indispensable for the implementation of the "Healthy China 2030" strategy, and primary healthcare workers, as the key drivers of this system, play a pivotal role in its development and establishment to ensure population well-being. In developing countries, such as China, primary public health systems are still weak, and in order to address this phenomenon, health system reform is needed, and primary public health personnel are crucial to health system reform. The current situation of primary public health workers in low-income and developing countries is characterized by varying degrees of problems that need improvement., Objectives: The purpose of this study is to understand the current situation of primary public health service workforce building, analyze the existing problems of the workforce, put forward suggestions for improvement and explore countermeasures, and provide Chinese wisdom and a reference basis for primary public health workforce building in the world, especially in developing countries., Methods: Combining the Work-Family Conflict Scale, Copenhagen Burnout Inventory, Minnesota Satisfaction Questionnaire, and Turnover Intention Scale, a relevant survey questionnaire was designed to quantitatively investigate the baseline characteristics of primary public health service institutions and their staff in four representative cities in the Huaihai Economic Zone: Xuzhou in Jiangsu Province, Linyi in Shandong Province, Shangqiu in Henan Province, and Huaibei in Anhui Province. The collected data were analyzed and processed using SPSS 25.0 statistical analysis software through univariate analysis and logistic regression analyses. Methods such as one-way ANOVA, Logistic regression analysis, and independent samples t -test were used to analyze the influencing factors of primary public health workforce development., Results: The current work intensity at the primary public health level is currently high, the salary and benefits cannot meet the needs of most primary public health personnel, and the competition between work and family in terms of time and resources is pronounced, and the majority of primary public health personnel are dissatisfied with the status quo of "doing more work for less reward" and the poor social security. Emotional exhaustion, depersonalization, and a sense of personal accomplishment were positively correlated with the tendency to leave (all p  < 0.01), and the burnout and emotional exhaustion of primary public health workers were intense., Conclusion: Primary public health personnel play an important role in providing primary public health services. However, the current working conditions of junior public health personnel in the Huaihai Economic Zone are influenced by factors such as workload, income level, and employment situation improvement, leading to low job satisfaction, significant work-family conflicts, and high turnover intention. In this context, based on the opinions of grassroots administrative departments and internationally relevant experiences, a series of suggestions have been proposed to improve the professional service level, job satisfaction, and occupational identity of staff members. These suggestions make valuable contributions to both the Huaihai Economic Zone and countries worldwide in safeguarding individual health and promoting national primary healthcare reform., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ni, Wang, Wen, Fang, Xu, Wu, Sawmadal and Jama.)

Objectives: The purpose of this paper is to explore the relationship between blood levels of cadmium, lead, and mercury and anxiety in American adults., Methods: Blood metals and self-reported anxiety days were extracted from laboratory data and questionnaire data, respectively, using NHANES data from 2007-2012. Weighted logistic regression was used to assess the relationship between cadmium, lead and mercury with anxiety. Restricted cubic spline was used to visualize the non-linear relationship between metal concentrations and anxiety. Weighted quantile sum (WQS) regression was used to investigate the effect of combined exposure to the three metals on anxiety., Results: The prevalence of anxiety in adults was 26.0%. After adjusting for potential confounding variables, cadmium levels in the highest quartile (Q4) were associated with a higher risk of anxiety compared to the lowest quartile (Q1) (OR = 1.279, 95% CI: 1.113-1.471, p < 0.01). Restricted cubic spline analysis indicated a positive association between blood cadmium levels and anxiety. Furthermore, co-exposure to multiple heavy metals was positively associated with anxiety risk (WQS positive: OR = 1.068, 95% CI: 1.016-1.160, p < 0.05), with cadmium contributing the most to the overall mixture effect. Compared to the Light RPA, the Vigorous/Moderate RPA group had a relatively low risk of anxiety after cadmium exposure., Conclusion: High levels of blood cadmium are positively associated with the development of anxiety disorders, which needs to be further verified in future studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Bai, Wen, Zhu, Jama, Sawmadal and Chen.)

According to several international, regional, and national guidelines on hypertension, lifestyle interventions are the first-line treatment to lower blood pressure (BP). Although diet is one of the major lifestyle modifications described in hypertension guidelines, dietary fiber is not specified. Suboptimal intake of foods high in fiber, such as in Westernized diets, is a major contributing factor to mortality and morbidity of noncommunicable diseases due to higher BP and cardiovascular disease. In this review, we address this deficiency by examining and advocating for the incorporation of dietary fiber as a key lifestyle modification to manage elevated BP. We explain what dietary fiber is, review the existing literature that supports its use to lower BP and prevent cardiovascular disease, describe the mechanisms involved, propose evidence-based target levels of fiber intake, provide examples of how patients can achieve the recommended targets, and discuss outstanding questions in the field. According to the evidence reviewed here, the minimum daily dietary fiber for adults with hypertension should be >28 g/day for women and >38 g/day for men, with each extra 5 g/day estimated to reduce systolic BP by 2.8 mm Hg and diastolic BP by 2.1 mm Hg. This would support a healthy gut microbiota and the production of gut microbiota-derived metabolites called short-chain fatty acids that lower BP. Awareness about dietary fiber targets and how to achieve them will guide medical teams on better educating patients and empowering them to increase their fiber intake and, as a result, lower their BP and cardiovascular disease risk., Competing Interests: Disclosures J. Muir works in a department that financially benefits from the sales of a digital application, booklets, cookbooks, online courses, and a food certification program on the low-fermentable oligosaccharides, disaccharides, monosaccharides, and polyols diet. Funds raised from these activities contribute to the research of the Department of Gastroenterology and Monash University. The salary of J. Muir is now 100% paid by these commercial activities. The other authors report no conflicts.

Objective: There have been proposals that vitamin D may be associated with a reduction in the incidence of anxiety disorders. However, the findings thus far have been inconsistent, warranting further investigation. The purpose of this paper is to explore the link between serum vitamin D and anxiety., Methods: Data are from the National Health and Nutrition Examination Survey (NHANES) in the United States from 2007 to 2012. Study included a total of 12,232 participants, and through the multivariate logistic regression to study the relationship between serum vitamin D and anxiety, smooth curve fitting is used to study the nonlinear relationship between serum vitamin D levels and anxiety., Results: Serum vitamin D levels demonstrated a negative correlation with anxiety ( p < 0.001). Vitamin D exhibited a significant impact on anxiety (Q4:OR = 0.774, 95% CI: 0.663-0.903, p < 0.01), and this effect remained significant even after adjusting for confounding variables (Q4:OR = 0.781, 95% CI: 0.669-0.912, p < 0.01). Smoothed curve fitting revealed a negative association between serum vitamin D levels and the risk of anxiety, and these findings persisted after accounting for confounding variables., Conclusion: Serum vitamin D levels were inversely associated with anxiety risk in US adults. In the future, more accurate prospective studies are needed to confirm this result., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wen, Bai, Wu, Chen, Jama and Sawmadal.)

Microbiome science has been one of the most exciting and rapidly evolving research fields in the past two decades. Breakthroughs in technologies including DNA sequencing have meant that the trillions of microbes (particularly bacteria) inhabiting human biological niches (particularly the gut) can be profiled and analysed in exquisite detail. This microbiome profiling has profound impacts across many fields of research, especially biomedical science, with implications for how we understand and ultimately treat a wide range of human disorders. However, like many great scientific frontiers in human history, the pioneering nature of microbiome research comes with a multitude of challenges and potential pitfalls. These include the reproducibility and robustness of microbiome science, especially in its applications to human health outcomes. In this article, we address the enormous promise of microbiome science and its many challenges, proposing constructive solutions to enhance the reproducibility and robustness of research in this nascent field. The optimisation of microbiome science spans research design, implementation and analysis, and we discuss specific aspects such as the importance of ecological principals and functionality, challenges with microbiome-modulating therapies and the consideration of confounding, alternative options for microbiome sequencing, and the potential of machine learning and computational science to advance the field. The power of microbiome science promises to revolutionise our understanding of many diseases and provide new approaches to prevention, early diagnosis, and treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Ferroptosis is a recently discovered type of cell death caused by the accumulation of iron-dependent lipid peroxides and reactive oxygen species that differs significantly from other cell death pathways such as apoptosis, necrosis, and autophagy. Ferroptosis is essential in developing and treating ischemia-reperfusion injury, neurological diseases, cancer, and other diseases. The ferroptosis mechanism, which can be induced by reagents like erastin and glutamate, and suppressed by antioxidants such as vitamin E and deferoxamine (DFO) chelators, can be regulated at the epigenetic, transcriptional, post-transcriptional, and post-translational levels. A recent study has determined many non-coding RNAs (lncRNA, miRNA, circRNA) that modulate ferroptotic cell death in cancer cells. Furthermore, some anti-cancer drugs (Sorafenib, Sulfasalazine, Acetominofen, Lanperisone, etc.) used in pre-clinical and clinical applications have been shown to induce ferroptosis in various cancer types. However, in addition to the studies in the literature, it is necessary to define novel molecules & non-coding RNAs and determine their effects on the ferroptosis mechanism. Thus, it will be possible to develop effective and safe treatment options., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Fibers remain undigested until they reach the colon, where some are fermented by gut microbiota, producing metabolites called short-chain fatty acids (SCFAs), such as acetate and butyrate 1 . SCFAs lower blood pressure in experimental models 2-5 , but their translational potential is unknown. Here we present the results of a phase II, randomized, placebo-controlled, double-blind cross-over trial (Australian New Zealand Clinical Trials Registry ACTRN12619000916145) using prebiotic acetylated and butyrylated high-amylose maize starch (HAMSAB) supplementation 6 . Twenty treatment-naive participants with hypertension were randomized to 40 g per day of HAMSAB or placebo, completing each arm for 3 weeks, with a 3-week washout period between them. The primary endpoint was a reduction in ambulatory systolic blood pressure. Secondary endpoints included changes to circulating cytokines, immune markers and gut microbiome modulation. Patients receiving the HAMSAB treatment showed a clinically relevant reduction in 24-hour systolic blood pressure independent of age, sex and body mass index without any adverse effects. HAMSAB increased levels of acetate and butyrate, shifted the microbial ecosystem and expanded the prevalence of SCFA producers. In summary, a prebiotic intervention with HAMSAB could represent a promising option to deliver SCFAs and lower blood pressure in patients with essential hypertension., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Elevated blood pressure (BP), or hypertension, is the main risk factor for cardiovascular disease. As a multifactorial and systemic disease that involves multiple organs and systems, hypertension remains a challenging disease to study. Models of hypertension are invaluable to support the discovery of the specific genetic, cellular and molecular mechanisms underlying essential hypertension, as well as to test new possible treatments to lower BP. Rodent models have proven to be an invaluable tool for advancing the field. In this review, we discuss the strengths and weaknesses of rodent models of hypertension through a systems approach. We highlight the ways how target organs and systems including the kidneys, vasculature, the sympathetic nervous system (SNS), immune system and the gut microbiota influence BP in each rodent model. We also discuss often overlooked hypertensive conditions such as pulmonary hypertension and hypertensive-pregnancy disorders, providing an important resource for researchers. LINKED ARTICLES: This article is part of a themed issue on Preclinical Models for Cardiovascular disease research (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.5/issuetoc., (© 2021 The British Pharmacological Society.)

Background: Hypertension is a prevalent chronic disease worldwide that remains poorly controlled. Recent studies support the concept that the gut microbiota is involved in the development of hypertension and that dietary fibre intake may act through the gut microbiota to lower blood pressure (BP). Resistant starch is a type of prebiotic fibre which is metabolised by commensal bacteria in the colon to produce short-chain fatty acids (SCFAs), including acetate, propionate, and butyrate. Previous work in pre-clinical models provides strong evidence that both prebiotic fibre as well as SCFAs (i.e. postbiotics) can prevent the development of hypertension. The aim of this clinical trial is to determine if acetylated and butyrylated modified resistant starch can decrease BP of hypertensive individuals via the modulation of the gut microbiota and release of high levels of SCFAs., Methods: This is a phase IIa double-blinded, randomised, cross-over, placebo controlled trial. Participants are randomly allocated to receive either a diet containing 40 g/day of the modified resistant starch or placebo (corn starch or regular flour) for 3 weeks on each diet, with a 3-week washout period between the two diets. BP is measured in the office, at home, and using a 24-h ambulatory device. Arterial stiffness is measured using carotid-to-femoral pulse wave velocity. Our primary endpoint is a reduction in ambulatory daytime systolic BP. Secondary endpoints include changes to circulating cytokines, immune markers, and modulation to the gut microbiome., Discussion: The findings of this study will provide the first evidence for the use of a combination of pre- and postbiotics to lower BP in humans. The results are expected at the end of 2021., Trial Registration: Australia and New Zealand Clinical Trial Registry ACTRN12619000916145 . Registered on 1 July 2019., (© 2021. The Author(s).)

There is increasing evidence of the influence of the gut microbiota on hypertension and its complications, such as chronic kidney disease, stroke, heart failure, and myocardial infarction. This is not surprising considering that the most common risk factors for hypertension, such as age, sex, medication, and diet, can also impact the gut microbiota. For example, sodium and fermentable fiber have been studied in relation to both hypertension and the gut microbiota. By combining second- and, now, third-generation sequencing with metabolomics approaches, metabolites, such as short-chain fatty acids and trimethylamine N-oxide, and their producers, have been identified and are now known to affect host physiology and the cardiovascular system. The receptors that bind these metabolites have also been explored with positive findings-examples include known short-chain fatty acid receptors, such as G-protein coupled receptors GPR41, GPR43, GPR109a, and OLF78 in mice. GPR41 and OLF78 have been shown to have inverse roles in blood pressure regulation, whereas GPR43 and GPR109A have to date been demonstrated to impact cardiac function. New treatment options in the form of prebiotics (eg, dietary fiber), probiotics (eg, Lactobacillus spp.), and postbiotics (eg, the short-chain fatty acids acetate, propionate, and butyrate) have all been demonstrated to be beneficial in lowering blood pressure in animal models, but the underlying mechanisms remain poorly understood and translation to hypertensive patients is still lacking. Here, we review the evidence for the role of the gut microbiota in hypertension, its risk factors, and cardiorenal complications and identify future directions for this exciting and fast-evolving field.

Increasing evidence supports a role for the gut microbiota in the development of cardiovascular diseases such as hypertension and its progression to heart failure (HF). Dietary fibre has emerged as a modulator of the gut microbiota, resulting in the release of gut metabolites called short-chain fatty acids (SCFAs), such as acetate. We have shown previously that fibre or acetate can protect against hypertension and heart disease in certain models. HF is also commonly caused by genetic disorders. In this study we investigated whether the intake of fibre or direct supplementation with acetate could attenuate the development of HF in a genetic model of dilated cardiomyopathy (DCM) due to overexpression of the cardiac specific mammalian sterile 20-like kinase (Mst1). Seven-week-old male mice DCM mice and littermate controls (wild-type, C57BL/6) were fed a control diet (with or without supplementation with 200 mM magnesium acetate in drinking water), or a high fibre diet for 7 weeks. We obtained hemodynamic, morphological, flow cytometric and gene expression data. The gut microbiome was characterised by 16S rRNA amplicon sequencing. Fibre intake was associated with a significant shift in the gut microbiome irrespective of mouse genotype. However, neither fibre or supplementation with acetate were able to attenuate cardiac remodelling or cardiomyocyte apoptosis in Mst1 mice. Furthermore, fibre and acetate did not improve echocardiographic or hemodynamic parameters in DCM mice. These data suggest that although fibre modulates the gut microbiome, neither fibre nor acetate can override a strong genetic contribution to the development of heart failure in the Mst1 model.

Background: High blood pressure (BP) continues to be a major, poorly controlled but modifiable risk factor for cardiovascular death. Among key Western lifestyle factors, a diet poor in fiber is associated with prevalence of high BP. The impact of lack of prebiotic fiber and the associated mechanisms that lead to higher BP are unknown. Here we show that lack of prebiotic dietary fiber leads to the development of a hypertensinogenic gut microbiota, hypertension and its complications, and demonstrate a role for G-protein coupled-receptors (GPCRs) that sense gut metabolites., Methods: One hundred seventy-nine mice including C57BL/6J, gnotobiotic C57BL/6J, and knockout strains for GPR41, GPR43, GPR109A, and GPR43/109A were included. C57BL/6J mice were implanted with minipumps containing saline or a slow-pressor dose of angiotensin II (0.25 mg·kg -1 ·d -1 ). Mice were fed diets lacking prebiotic fiber with or without addition of gut metabolites called short-chain fatty acids ([SCFA)] produced during fermentation of prebiotic fiber in the large intestine), or high prebiotic fiber diets. Cardiac histology and function, BP, sodium and potassium excretion, gut microbiome, flow cytometry, catecholamines and methylation-wide changes were determined., Results: Lack of prebiotic fiber predisposed mice to hypertension in the presence of a mild hypertensive stimulus, with resultant pathological cardiac remodeling. Transfer of a hypertensinogenic microbiota to gnotobiotic mice recapitulated the prebiotic-deprived hypertensive phenotype, including cardiac manifestations. Reintroduction of SCFAs to fiber-depleted mice had protective effects on the development of hypertension, cardiac hypertrophy, and fibrosis. The cardioprotective effect of SCFAs were mediated via the cognate SCFA receptors GPR43/GPR109A, and modulated L-3,4-dihydroxyphenylalanine levels and the abundance of T regulatory cells regulated by DNA methylation., Conclusions: The detrimental effects of low fiber Westernized diets may underlie hypertension, through deficient SCFA production and GPR43/109A signaling. Maintaining a healthy, SCFA-producing microbiota is important for cardiovascular health.

Hypertension is a complex and modifiable condition in which environmental factors contribute to both onset and progression. Recent evidence has accumulated for roles of diet and the gut microbiome as environmental factors in blood pressure regulation. However, this is complex because gut microbiomes are a unique feature of each individual reflecting that individual's developmental and environmental history creating caveats for both experimental models and human studies. Here, we describe guidelines for conducting gut microbiome studies in experimental and clinical hypertension. We provide a complete guide for authors on proper design, analyses, and reporting of gut microbiota/microbiome and metabolite studies and checklists that can be used by reviewers and editors to support robust reporting and interpretation. We discuss factors that modulate the gut microbiota in animal (eg, cohort, controls, diet, developmental age, housing, sex, and models used) and human studies (eg, blood pressure measurement and medication, body mass index, demographic characteristics including age, cultural identification, living structure, sex and socioeconomic environment, and exclusion criteria). We also provide best practice advice on sampling, storage of fecal/cecal samples, DNA extraction, sequencing methods (including metagenomics and 16S rRNA), and computational analyses. Finally, we discuss the measurement of short-chain fatty acids, metabolites produced by the gut microbiota, and interpretation of data. These guidelines should support better transparency, reproducibility, and translation of findings in the field of gut microbiota/microbiome in hypertension and cardiovascular disease.

Over the past decade, the immune system has emerged as an important component in the aetiology of hypertension. There has been a blooming interest in the contribution of the gut microbiota, the microbes that inhabit our small and large intestine, to blood pressure (BP) regulation. The gastrointestinal tract houses the largest number of immune cells in our body, thus, it is no surprise that its microbiota plays an important functional role in the appropriate development of the immune system through a co-ordinated sequence of events leading to immune tolerance of commensal bacteria. Importantly, recent evidence supports that the gut microbiota can protect or promote the development of experimental hypertension and is likely to have a role in human hypertension. One of the major modulators of the gut microbiota is diet: diets that emphasize high intake of fermentable fibre, such as the Mediterranean diet and the Dietary Approaches to Stop Hypertension, promote expansion of protective microbes that release gut metabolites such as short-chain fatty acids, which are immune-, BP-, and cardio-protective, likely acting through G-coupled protein receptors. In contrast, diets lacking fibre or high in salt and fat, such as the Western diet, reduce prevalence of commensal microbial species and support a pathogenic and pro-inflammatory environment, including the release of the pro-atherosclerotic trimethylamine N-oxide. Here, we review the current understanding of the gut microbiota-driven immune dysfunction in both experimental and clinical hypertension, and how these changes may be addressed through dietary interventions., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Kawasaki disease (KD) is a leading cause of pediatric heart disease, characterized by the emergence of life-threatening coronary vasculitis. Identifying which cytokines drive KD has been a major research goal, and both TNF and IL-1 have been identified as potential candidates. Using a murine model of KD induced by the injection of the water-soluble component of Candida albicans , we therefore undertook a mechanistic study to determine how and when these two cytokines mediate cardiac inflammation. In this study, we show that TNF signaling is active in the acute phase of cardiac inflammation, which is characterized by a diffuse myocarditis that precedes the development of coronary vasculitis. Mechanistically, TNF is produced by the myeloid cells and triggers acute cardiac inflammation by stimulating both stromal and immune compartments of the heart. In contrast to this early involvement for TNF, IL-1 signaling is dispensable for the development of acute myocarditis. Critically, although mice deficient in IL-1 signaling have extensive acute inflammation following C. albicans water-soluble complex challenge, they do not develop coronary vasculitis. Thus, TNF and IL-1 appear to play temporally distinct roles in KD, with TNF being active in acute cardiac inflammation and IL-1 in the subsequent development of coronary vasculitis. These observations have important implications for understanding the progression of cardiac pathology in KD and the relative therapeutic use of targeting these cytokines., (Copyright © 2019 by The American Association of Immunologists, Inc.)

The adult heart contains macrophages derived from both embryonic and adult bone marrow (BM)-derived precursors. This population diversity prompted us to explore how distinct macrophage subsets localize within the heart, and their relative contributions in cardiac disease. In this study, using the reciprocal expression of Lyve-1 and Ccr2 to distinguish macrophages with distinct origins, we show that, in the steady state, both embryonic (Lyve pos ) and BM-derived (Ccr2 pos ) macrophages populate the major vessels of the heart in mice and humans. However, cardiac macrophage populations are markedly perturbed by inflammation. In a mouse model of Kawasaki disease, BM-derived macrophages preferentially increase during acute cardiac inflammation and selectively accumulate around major cardiac vessels. The accumulation of BM-derived macrophages coincides with the loss of their embryonic counterparts and is an initiating, essential step in the emergence of subsequent cardiac vasculitis in this experimental model. Finally, we demonstrate that the accumulation of Ccr2 pos macrophages (and the development of vasculitis) occurs in close proximity to a population of Ccr2 chemokine ligand-producing epicardial cells, suggesting that the epicardium may be involved in localizing inflammation to cardiac vessels. Collectively, our findings identify the perivascular accumulation of BM-derived macrophages as pivotal in the pathogenesis of cardiac vasculitis and provide evidence about the mechanisms governing their recruitment to the heart., (Copyright © 2019 by The American Association of Immunologists, Inc.)

Purpose of Review: To summarize evidence supporting that microorganisms colonizing our gastrointestinal tract, collectively known as the gut microbiota, are implicated in the development and maintenance of hypertension in experimental models., Recent Findings: The use of gnotobiotic (germ-free) mice has been essential for advancement in this area: they develop higher blood pressure (BP) if they receive faecal transplants from hypertensive patients compared to normotensive donors, and germ-free mice have a blunted response to angiotensin II. Experimental hypertension is consistently accompanied by changes in the composition of the gut microbiota. This is combined with a shift in microbial diversity and the deterioration of the gut epithelial barrier commonly referred to as gut dysbiosis. Restoration of normal gut biosis and microbiota alleviates and protects against the development of hypertension in both genetic and pharmacological models. This has been achieved by the use of antibiotics, faecal transplants between normotensive and hypertensive strains, and the use of prebiotics (i.e. food stuff that feeds the microbiota), probiotics (i.e. live bacteria) and gut metabolites (i.e. short-chain fatty acids)., Summary: Research into experimental hypertension supports that the gut microbiota contributes to the regulation of BP. Manipulation of the microbiota might represent a new tool to prevent hypertension.

Disregulation of genes making up the mammalian circadian clock has been associated with different forms of cancer. This study aimed to address how the circadian clock genes behave over the course of treatment for both the acute and chronic forms of leukemia and whether any could be used as potential biomarkers as a read-out for therapeutic efficacy. Expression profiling for both core and ancillary clock genes revealed that the majority of clock genes are down-regulated in acute myeloid leukemia patients, except for Cry2, which is up-regulated towards the end of treatment. A similar process was seen in acute lymphocytic leukemia patients; however, here, Cry2 expression came back up towards control levels upon treatment completion. In addition, all of the core clock genes were down-regulated in both chronic forms of leukemia (chronic myeloid leukemia and chronic lymphocytic leukemia), except for Cry2, which was not affected when the disease was diagnosed. Furthermore, the NAD(+) - dependent protein deacetylase Sirt1 has been proposed to have a dual role in both control of circadian clock circuitry and promotion of cell survival by inhibiting apoptotic pathways in cancer. We used a pharmacological-based approach to see whether Sirt1 played a role in regulating the circadian clock circuitry in both acute and chronic forms of leukemia. Our results suggest that interfering with Sirt1 leads to a partial restoration of BMAL1 oscillation in chronic myeloid leukemia patient samples. Furthermore, interfering with Sirt1 activity led to both the induction and repression of circadian clock genes in both acute and chronic forms of leukemia, which makes it a potential therapeutic target to either augment existing therapies for chronic leukemia or to act as a means of facilitating chronotherapy in order to maximize both the effectiveness of existing therapies and to minimize therapy-associated toxicity.

Urogenital specimens from 445 patients, 174 women and 271 men, were tested for antigen to Chlamydia trachomatis by an enzyme amplified immunoassay, IDEIA. The test results for specimens stored at -20 degrees C for means of 9.6 weeks (from each of the first 376 patients) and eight months (from the remaining 69) were compared with results for specimens stored at 4 degrees C and tested within five days. Of 617 specimens (one from the urethra of each patient and one from the cervices of 172 women) cultured for C trachomatis, 90 (15%) gave positive results. The IDEIA results for specimens stored at -20 degrees C were identical with those of specimens analysed without such storage in 96.4% (595/617) of all cases. No difference was seen between urethral specimens from men or women or cervical specimens or between specimens stored for 9.6 weeks compared with those stored for eight months. In 22 cases in which the IDEIA results differed, culture positive results were missed in stored as well as unstored specimens. The median absorbance value above the cut off point for a positive IDEIA result in stored specimens was no lower than in those not stored. The few differences noted probably depended on the sampling technique rather than on the way of storing the specimens.