Vocal convergence and social proximity shape the calls of the most basal Passeriformes, New Zealand Wrens.

Despite extensive research on avian vocal learning, we still lack a general understanding of how and when this ability evolved in birds. As the closest living relatives of the earliest Passeriformes, the New Zealand wrens (Acanthisitti) hold a key phylogenetic position for furthering our understanding of the evolution of vocal learning because they share a common ancestor with two vocal learners: oscines and parrots. However, the vocal learning abilities of New Zealand wrens remain unexplored. Here, we test for the presence of prerequisite behaviors for vocal learning in one of the two extant species of New Zealand wrens, the rifleman (Acanthisitta chloris). We detect the presence of unique individual vocal signatures and show how these signatures are shaped by social proximity, as demonstrated by group vocal signatures and strong acoustic similarities among distantly related individuals in close social proximity. Further, we reveal that rifleman calls share similar phenotypic variance ratios to those previously reported in the learned vocalizations of the zebra finch, Taeniopygia guttata. Together these findings provide strong evidence that riflemen vocally converge, and though the mechanism still remains to be determined, they may also suggest that this vocal convergence is the result of rudimentary vocal learning abilities.

Intravenous versus Partial Oral Antibiotic Therapy in the Treatment of Uncomplicated Bloodstream Infection Due to Streptococcus Species.

This retrospective cohort study examines effectiveness of partial oral antibiotic regimens in uncomplicated bloodstream infections (BSIs) due to Streptococcus species compared to standard intravenous therapy. Adult patients with uncomplicated streptococcal BSIs from April 2016 to June 2020 in seven hospitals in South Carolina, USA, were evaluated. Multivariate Cox proportional hazards regression was used to examine the time to treatment failure within 90 days of a BSI after adjustment for the propensity to receive partial oral therapy. Multivariate linear regression was used to examine the hospital length of stay (HLOS). Among the 222 patients included, 99 received standard intravenous antibiotics and 123 received partial oral therapy. Of the standard intravenous therapy group, 46/99 (46.5%) required outpatient parenteral antibiotic therapy (OPAT). There was no difference in the risk of treatment failure between partial oral and standard intravenous therapy (hazards ratio 0.53, 95% CI 0.18, 1.60; p = 0.25). Partial oral therapy was independently associated with a shorter HLOS after adjustments for the propensity to receive partial oral therapy and other potential confounders (-2.23 days, 95% CI -3.53, -0.94; p < 0.001). Transitioning patients to oral antibiotics may be a reasonable strategy in the management of uncomplicated streptococcal BSIs. Partial oral therapy does not seem to have a higher risk of treatment failure and may spare patients from prolonged hospitalizations and OPAT complications.

Characterization of a mutant samhd1 zebrafish model implicates dysregulation of cholesterol biosynthesis in Aicardi-Goutières syndrome.

Aicardi-Goutières syndrome (AGS1-9) is a genetically determined encephalopathy that falls under the type I interferonopathy disease class, characterized by excessive type I interferon (IFN-I) activity, coupled with upregulation of IFN-stimulated genes (ISGs), which can be explained by the vital role these proteins play in self-non-self-discrimination. To date, few mouse models fully replicate the vast clinical phenotypes observed in AGS patients. Therefore, we investigated the use of zebrafish as an alternative species for generating a clinically relevant model of AGS. Using CRISPR-cas9 technology, we generated a stable mutant zebrafish line recapitulating AGS5, which arises from recessive mutations in SAMHD1. The resulting homozygous mutant zebrafish larvae possess a number of neurological phenotypes, exemplified by variable, but increased expression of several ISGs in the head region, a significant increase in brain cell death, microcephaly and locomotion deficits. A link between IFN-I signaling and cholesterol biosynthesis has been highlighted by others, but not previously implicated in the type I interferonopathies. Through assessment of neurovascular integrity and qPCR analysis we identified a significant dysregulation of cholesterol biosynthesis in the zebrafish model. Furthermore, dysregulation of cholesterol biosynthesis gene expression was also observed through RNA sequencing analysis of AGS patient whole blood. From this novel finding, we hypothesize that cholesterol dysregulation may play a role in AGS disease pathophysiology. Further experimentation will lend critical insight into the molecular pathophysiology of AGS and the potential links involving aberrant type I IFN signaling and cholesterol dysregulation.

Tumor Microenvironment CD14+ Cells Correlate with Poor Overall Survival in Patients with Early-Stage Lung Adenocarcinoma.

Patients with early-stage lung adenocarcinoma have a high risk of recurrent or metastatic disease despite undergoing curative intent therapy. We hypothesized that increased CD14+ cells within the tumor microenvironment (TME) could stratify patient outcomes. Immunohistochemistry for CD14 was performed on 189 specimens from patients with lung adenocarcinoma who underwent curative intent surgery. Outcomes and associations with clinical and pathologic variables were determined. In vitro studies utilized a coculture system to model the lung cancer TME containing CD14+ cells. Patients with high levels of TME CD14+ cells experienced a median overall survival of 5.5 years compared with 8.3 and 10.7 years for those with moderate or low CD14 levels, respectively (p < 0.001). Increased CD14+ cell tumor infiltration was associated with a higher stage at diagnosis and more positive lymph nodes at the time of surgery. This prognostic capacity remained even for patients with early-stage disease. Using an in vitro model system, we found that CD14+ cells reduced chemotherapy-induced cancer cell death. These data suggest that CD14+ cells are a biomarker for poor prognosis in early-stage lung adenocarcinoma and may promote tumor survival. CD14+ cell integration into the lung cancer TME can occur early in the disease and may be a promising new therapeutic avenue.

Perivascular Adipose Tissue Anticontractile Function Is Mediated by Both Endothelial and Neuronal Nitric Oxide Synthase Isoforms.

BACKGROUND: The mechanism of the perivascular adipose tissue (PVAT) anticontractile effect is well characterized in rodent visceral vascular beds; however, little is known about the mechanism of PVAT anticontractile function in subcutaneous vessels. In addition, we have previously shown that PVAT anticontractile function is nitric oxide synthase (NOS) dependent but have not investigated the roles of NOS isoforms. OBJECTIVE: Here, we examined PVAT anticontractile function in the mouse gracilis artery, a subcutaneous fat depot, in lean control and obese mice and investigated the mechanism in comparison to a visceral depot. METHOD: Using the wire myograph, we generated responses to noradrenaline and electrical field stimulation in the presence of pharmacological tools targeting components of the known PVAT anticontractile mechanism. In addition, we performed ex vivo "fat transplants" in the organ bath. RESULTS: The mechanism of PVAT anticontractile function is similar between subcutaneous and visceral PVAT depots. Both endothelial and neuronal NOS isoforms mediated the PVAT anticontractile effect. Loss of PVAT anticontractile function in obesity is independent of impaired vasoreactivity, and function can be restored in visceral PVAT by NOS activation. CONCLUSIONS: Targeting NOS isoforms may be useful in restoring PVAT anticontractile function in obesity, ameliorating increased vascular tone, and disease.

Understanding the Needs and Priorities of People Living with Persistent Pain and Long-Term Musculoskeletal Conditions during the COVID-19 Pandemic-A Public Involvement Project.

BACKGROUND: Critiques of public involvement (PI) are associated with failing to be inclusive of under-represented groups, and this leads to research that fails to include a diversity of perspectives. AIM: The aim of this PI project was to understand the experiences and priorities of people from three seldom-heard groups whose musculoskeletal pain may have been exacerbated or treatment delayed due to COVID-19. Engaging representatives to report diverse experiences was important, given the goal of developing further research into personalised and integrated care and addressing population health concerns about access and self-management for people with musculoskeletal pain. METHODS: The project was approved via Sheffield Hallam University Ethics but was exempt from further HRA approval. A literature review was conducted, followed by informal individual and group discussions involving professionals and people with lived experience of (a) fibromyalgia pain, (b) those waiting for elective surgery and (c) experts associated with the care home sector. Findings from the literature review were combined with the insights from the public involvement. Resulting narratives were developed to highlight the challenges associated with persistent pain and informed the creation of consensus statements on the priorities for service improvement and future research. The consensus statements were shared and refined with input from an expert steering group. RESULTS: The narratives describe pain as a uniformly difficult experience to share with professionals; it is described as exhausting, frustrating and socially limiting. Pain leads to exclusion from routine daily activities and often resigns people to feeling and being unwell. In all cases, there are concerns about accessing and improving services and critical issues associated with optimising physical activity, functional wellbeing and managing polypharmacy. Exercise and/or mobilisation are important and commonly used self-management strategies, but opportunity and advice about safe methods are variable. Services should focus on personalised care, including self-management support and medication management, so that people's views and needs are heard and validated by health professionals. CONCLUSIONS: More research is needed to explore the most effective pain management strategies, and public involvement is important to shape the most relevant research questions. Health and care systems evaluation is also needed to address the scale of the population health need. The pandemic appears to have highlighted pre-existing shortcomings in holistic pain management.

Prediction of mortality in Staphylococcus aureus bloodstream infection using quick Pitt bacteremia score.

OBJECTIVES: The quick Pitt bacteremia score (qPitt) predicts mortality in patients with serious infections due to gram-negative bacteria. This retrospective cohort study examines utility of qPitt to predict mortality in patients with Staphylococcus aureus bloodstream infection (SAB). METHODS: Multivariate logistic regression was used to examine risk factors for 28-day mortality in hospitalized adults with SAB at four Prisma Health hospitals in South Carolina, USA from January 2015 to December 2017. Area under receiver operating characteristic curve (AUROC) was used to examine model discrimination. RESULTS: Among 692 patients with SAB, 305 (44%) had methicillin-resistant S. aureus (MRSA), and 129 (19%) died within 28 days. After adjustment for age, comorbidities, and MRSA, each component of the qPitt was associated with 28-day mortality. There was a 3-fold increase in the risk of 28-day mortality for each one-point increase in qPitt. Predicted 28-day mortality was 3%, 9%, 22%, 45%, and 70% for qPitt of 0, 1, 2, 3, and ≥4, respectively. AUROC of the qPitt in predicting 28-day, 14-day, and in-hospital mortality were 0.80, 0.81, and 0.80, respectively. CONCLUSIONS: The qPitt predicts mortality with good discrimination in SAB. These results support using qPitt as a measure of acute severity of illness in future studies.

Community-Acquired, Extended-Spectrum ß-Lactamase-Producing and Extensively Drug-Resistant Escherichia coli in a 28-Year-Old Pyelonephritis Patient Lacking Risk Factors.

While Escherichia coli is a common cause of urinary tract infections and pyelonephritis, there are few documented cases of extended-spectrum ß-lactamase (ESBL)-producing and extensively drug-resistant (XDR) isolates from the community resulting in infection requiring hospitalization, especially in individuals lacking risk factors. In the United States, exposure to ESBL-producing E. coli is typically nosocomial, whereas patients from developing countries often encounter ESBL-producing E. coli in the community through the consumption of contaminated food or water. Considering the rarity at which XDR E. coli isolates are encountered, there is also a scarcity of literature describing the successful treatment of ESBL-producing XDR E. coli. Here we present a case of an otherwise healthy 28-year-old female delicatessen worker infected with ESBL-producing and XDR E. coli without recent travel, antibiotic use, or healthcare contact, who required admission to the intensive care unit (ICU) with pyelonephritis and septic shock. Treatment with intravenous meropenem through a peripherally inserted central catheter (PICC) line at home was curative and follow up thereafter unremarkable. Given the patient's lack of obvious exposure to and risk factors for an ESBL-producing XDR E. coli infection and the specific lack of risk factors for severe pyelonephritis requiring hospitalization, this case represents a unique addition to the literature and is of value to clinicians by describing successful treatment.

Genetic divergence between isolated populations of the North Island New Zealand Rifleman (Acanthisitta chloris granti) implicates ancient biogeographic impacts rather than recent habitat fragmentation.

This research investigates the extent and causal mechanisms of genetic population divergence in a poorly flighted passerine, the North Island Rifleman or Titipounamu (Acanthisitta chloris granti). While this species has a historically widespread distribution, anthropogenic forest clearance has resulted in a highly fragmented current distribution. We conducted analyses of mitochondrial DNA (COI and Control Region) and 12 nuclear DNA microsatellites to test for population divergence and estimate times of divergence. diyabc and biogeobears were then used to assess likely past dispersal scenarios based on both mtDNA and nDNA. The results reveal several significantly divergent lineages across the North Island of New Zealand and indicate that some populations have been isolated for extensive periods of time (0.7-4.9 mya). Modeling indicated a dynamic history of population connectivity, with a drastic restriction in gene flow between three geographic regions, followed by a more recent re-establishment of connectivity. Our analyses indicate the dynamic influence of key geological and climatological events on the distribution of genetic diversity in this species, including support for the genetic impact of old biogeographic boundaries such as the Taupo Line and Cockayne's Line, rather than recent anthropogenic habitat fragmentation. These findings present a rare example of an avian species with a genetic history more like that of flightless taxa and so provide new general insights into vicariant processes affecting populations of passerines with limited dispersal.

Restoring Perivascular Adipose Tissue Function in Obesity Using Exercise.

PURPOSE: Perivascular adipose tissue (PVAT) exerts an anti-contractile effect which is vital in regulating vascular tone. This effect is mediated via sympathetic nervous stimulation of PVAT by a mechanism which involves noradrenaline uptake through organic cation transporter 3 (OCT3) and ß3-adrenoceptor-mediated adiponectin release. In obesity, autonomic dysfunction occurs, which may result in a loss of PVAT function and subsequent vascular disease. Accordingly, we have investigated abnormalities in obese PVAT, and the potential for exercise in restoring function. METHODS: Vascular contractility to electrical field stimulation (EFS) was assessed ex vivo in the presence of pharmacological tools in ±PVAT vessels from obese and exercised obese mice. Immunohistochemistry was used to detect changes in expression of ß3-adrenoceptors, OCT3 and tumour necrosis factor-α (TNFα) in PVAT. RESULTS: High fat feeding induced hypertension, hyperglycaemia, and hyperinsulinaemia, which was reversed using exercise, independent of weight loss. Obesity induced a loss of the PVAT anti-contractile effect, which could not be restored via ß3-adrenoceptor activation. Moreover, adiponectin no longer exerts vasodilation. Additionally, exercise reversed PVAT dysfunction in obesity by reducing inflammation of PVAT and increasing ß3-adrenoceptor and OCT3 expression, which were downregulated in obesity. Furthermore, the vasodilator effects of adiponectin were restored. CONCLUSION: Loss of neutrally mediated PVAT anti-contractile function in obesity will contribute to the development of hypertension and type II diabetes. Exercise training will restore function and treat the vascular complications of obesity.

Impaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine.

The structure of proline prevents it from adopting an optimal position for rapid protein synthesis. Poly-proline-tract (PPT) associated ribosomal stalling is resolved by highly conserved eIF5A, the only protein to contain the amino acid hypusine. We show that de novo heterozygous EIF5A variants cause a disorder characterized by variable combinations of developmental delay, microcephaly, micrognathia and dysmorphism. Yeast growth assays, polysome profiling, total/hypusinated eIF5A levels and PPT-reporters studies reveal that the variants impair eIF5A function, reduce eIF5A-ribosome interactions and impair the synthesis of PPT-containing proteins. Supplementation with 1 mM spermidine partially corrects the yeast growth defects, improves the polysome profiles and restores expression of PPT reporters. In zebrafish, knockdown eif5a partly recapitulates the human phenotype that can be rescued with 1 µM spermidine supplementation. In summary, we uncover the role of eIF5A in human development and disease, demonstrate the mechanistic complexity of EIF5A-related disorder and raise possibilities for its treatment.

Revisiting promising preclinical intracerebral hemorrhage studies to highlight repurposable drugs for translation.

Intracerebral hemorrhage is a devastating global health burden with limited treatment options and is responsible for 49% of 6.5 million annual stroke-related deaths comparable to ischemic stroke. Despite the impact of intracerebral hemorrhage, there are currently no effective treatments and so weaknesses in the translational pipeline must be addressed. There have been many preclinical studies in intracerebral hemorrhage models with positive outcomes for potential therapies in vivo, but beyond advancing the understanding of intracerebral hemorrhage pathology, there has been no translation toward successful clinical application. Multidisciplinary preclinical research, use of multiple models, and validation in human tissue are essential for effective translation. Repurposing of therapeutics for intracerebral hemorrhage may be the most promising strategy to help relieve the global health burden of intracerebral hemorrhage. Here, we have reviewed the existing literature to highlight repurposable drugs with successful outcomes in preclinical models of intracerebral hemorrhage that have realistic potential for development into the clinic for intracerebral hemorrhage.

Interleukin-33 rescues perivascular adipose tissue anticontractile function in obesity.

Perivascular adipose tissue (PVAT) depots are metabolically active and play a major vasodilator role in healthy lean individuals. In obesity, they become inflamed and eosinophil-depleted and the anticontractile function is lost with the development of diabetes and hypertension. Moreover, eosinophil-deficient ΔdblGATA-1 mice lack PVAT anticontractile function and exhibit hypertension. Here, we have investigated the effects of inducing eosinophilia on PVAT function in health and obesity. Control, obese, and ΔdblGATA-1 mice were administered intraperitoneal injections of interleukin-33 (IL-33) for 5 days. Conscious restrained blood pressure was measured, and blood was collected for glucose and plasma measurements. Wire myography was used to assess the contractility of mesenteric resistance arteries. IL-33 injections induced a hypereosinophilic phenotype. Obese animals had significant elevations in blood pressure, blood glucose, and plasma insulin, which were normalized with IL-33. Blood glucose and insulin levels were also lowered in lean treated mice. In arteries from control mice, PVAT exerted an anticontractile effect on the vessels, which was enhanced with IL-33 treatment. In obese mice, loss of PVAT anticontractile function was rescued by IL-33. Exogenous application of IL-33 to isolated arteries induced a rapidly decaying endothelium-dependent vasodilation. The therapeutic effects were not seen in IL-33-treated ΔdblGATA-1 mice, thereby confirming that the eosinophil is crucial. In conclusion, IL-33 treatment restored PVAT anticontractile function in obesity and reversed development of hypertension, hyperglycemia, and hyperinsulinemia. These data suggest that targeting eosinophil numbers in PVAT offers a novel approach to the treatment of hypertension and type 2 diabetes in obesity.NEW & NOTEWORTHY In this study, we have shown that administering IL-33 to obese mice will restore PVAT anticontractile function, and this is accompanied by normalized blood pressure, blood glucose, and plasma insulin. Moreover, the PVAT effect is enhanced in control mice given IL-33. IL-33 induced a hypereosinophilic phenotype in our mice, and the effects of IL-33 on PVAT function, blood pressure, and blood glucose are absent in eosinophil-deficient mice, suggesting that the effects of IL-33 are mediated via eosinophils.

A Multi-Model Pipeline for Translational Intracerebral Haemorrhage Research.

Apart from acute and chronic blood pressure lowering, we have no specific medications to prevent intracerebral haemorrhage (ICH) or improve outcomes once bleeding has occurred. One reason for this may be related to particular limitations associated with the current pre-clinical models of ICH, leading to a failure to translate into the clinic. It would seem that a breakdown in the 'drug development pipeline' currently exists for translational ICH research which needs to be urgently addressed. Here, we review the most commonly used pre-clinical models of ICH and discuss their advantages and disadvantages in the context of translational studies. We propose that to increase our chances of successfully identifying new therapeutics for ICH, a bi-directional, 2- or 3-pronged approach using more than one model species/system could be useful for confirming key pre-clinical observations. Furthermore, we highlight that post-mortem/ex-vivo ICH patient material is a precious and underused resource which could play an essential role in the verification of experimental results prior to consideration for further clinical investigation. Embracing multidisciplinary collaboration between pre-clinical and clinical ICH research groups will be essential to ensure the success of this type of approach in the future.

MiRNAs as Novel Adipokines: Obesity-Related Circulating MiRNAs Influence Chemosensitivity in Cancer Patients.

Adipose tissue is an endocrine organ, capable of regulating distant physiological processes in other tissues via the release of adipokines into the bloodstream. Recently, circulating adipose-derived microRNAs (miRNAs) have been proposed as a novel class of adipokine, due to their capacity to regulate gene expression in tissues other than fat. Circulating levels of adipokines are known to be altered in obese individuals compared with typical weight individuals and are linked to poorer health outcomes. For example, obese individuals are known to be more prone to the development of some cancers, and less likely to achieve event-free survival following chemotherapy. The purpose of this review was twofold; first to identify circulating miRNAs which are reproducibly altered in obesity, and secondly to identify mechanisms by which these obesity-linked miRNAs might influence the sensitivity of tumors to treatment. We identified 8 candidate circulating miRNAs with altered levels in obese individuals (6 increased, 2 decreased). A second literature review was then performed to investigate if these candidates might have a role in mediating resistance to cancer treatment. All of the circulating miRNAs identified were capable of mediating responses to cancer treatment at the cellular level, and so this review provides novel insights which can be used by future studies which aim to improve obese patient outcomes.

Inpatient Antibiotic Stewardship Interventions in the Adult Oncology and Hematopoietic Stem Cell Transplant Population: A Review of the Literature.

Objective: To review the use of antibiotic stewardship interventions in the adult oncology and hematopoietic cell transplantation (HCT) populations. Data Sources: A literature search of PubMed was performed from inception to October 31, 2019. The general search terms used were oncology, cancer, hematologic malignancy, antimicrobial stewardship, antibiotic stewardship, febrile neutropenia, neutropenic fever, de-escalation, discontinuation, prophylaxis, practice guidelines, clinical pathway, rapid diagnostics, Filmarray, Verigene, MALDI-TOF, antibiotic allergy, and antimicrobial resistance. Study Selection and Data Extraction: Relevant English-language studies describing interventions supported by the Infectious Diseases Society of America guidelines on "Implementing an Antibiotic Stewardship Program" were included. Data Synthesis: Antibiotic stewardship publications in the oncology population have increased in recent years. Studies have described the impact of stewardship interventions, including preauthorization, prospective audit and feedback, implementation of clinical pathways, de-escalation of empirical antibiotics for febrile neutropenia (FN) prior to neutrophil recovery, allergy assessments, and use of rapid diagnostic testing. Many of these interventions have been shown to decrease antibiotic use without increased negative consequences, such as affecting length of stay or mortality. Relevance to Patient Care and Clinical Practice: This review synthesizes available evidence for implementing antibiotic stewardship interventions, particularly de-escalation of antibiotics for FN and implementation of clinical pathways for FN and sepsis, in oncology patients and HCT recipients. Summary tables highlight studies and specific research needs for clinicians. Conclusions: Immunocompromised populations, including oncology patients, have often been excluded from stewardship studies. Antibiotic stewardship is effective in reducing antibiotic consumption and improving outcomes in this patient population, although more quality data are needed.

Perivascular Adipose Tissue Contributes to the Modulation of Vascular Tone in vivo.

BACKGROUND: Perivascular adipose tissue (PVAT) reduces vascular tone in isolated arteries in vitro, however there are no studies of PVAT effects on vascular tone in vivo. In vitro adipocyte ß3-adrenoceptors play a role in PVAT function via secretion of the vasodilator adiponectin. OBJECTIVE: We have investigated the effects of PVAT on vessel diameter in vivo, and the contributions of ß3-adrenoceptors and adiponectin. METHOD: In anaesthetised rats, sections of the intact mesenteric bed were visualised and the diameter of arteries was recorded. Arteries were stimulated with electrical field stimulation (EFS), noradrenaline (NA), arginine-vasopressin (AVP), and acetylcholine (Ach). RESULTS: We report that in vivo, stimulation of PVAT with EFS, NA, and AVP evokes a local anti-constrictive effect on the artery, whilst PVAT exerts a pro-contractile effect on arteries subjected to Ach. The anti-constrictive effect of PVAT stimulated with EFS and NA was significantly reduced using ß3-adrenoceptor inhibition, and activation of ß3-adrenoceptors potentiated the anti-constrictive effect of vessels stimulated with EFS, NA, and AVP. The ß3-adrenoceptor agonist had no effect on mesenteric arteries with PVAT removed. A blocking peptide for adiponectin receptor 1 polyclonal antibody reduced the PVAT anti-constrictive effect in arteries stimulated with EFS and NA, indicating that adiponectin may be the anti-constrictive factor released upon ß3-adrenoceptor activation. CONCLUSIONS: These results clearly demonstrate that PVAT plays a paracrine role in regulating local vascular tone in vivo, and therefore may contribute to the modulation of blood pressure. This effect is mediated via adipocyte ß3-adrenoceptors, which may trigger release of the vasodilator adiponectin.

Mechanistic Links Between Obesity, Diabetes, and Blood Pressure: Role of Perivascular Adipose Tissue.

Obesity is increasingly prevalent and is associated with substantial cardiovascular risk. Adipose tissue distribution and morphology play a key role in determining the degree of adverse effects, and a key factor in the disease process appears to be the inflammatory cell population in adipose tissue. Healthy adipose tissue secretes a number of vasoactive adipokines and anti-inflammatory cytokines, and changes to this secretory profile will contribute to pathogenesis in obesity. In this review, we discuss the links between adipokine dysregulation and the development of hypertension and diabetes and explore the potential for manipulating adipose tissue morphology and its immune cell population to improve cardiovascular health in obesity.

Emerging Roles of Sympathetic Nerves and Inflammation in Perivascular Adipose Tissue.

Perivascular adipose tissue (PVAT) is no longer recognised as simply a structural support for the vasculature, and we now know that PVAT releases vasoactive factors which modulate vascular function. Since the discovery of this function in 1991, PVAT research is rapidly growing and the importance of PVAT function in disease is becoming increasingly clear. Obesity is associated with a plethora of vascular conditions; therefore, the study of adipocytes and their effects on the vasculature is vital. PVAT contains an adrenergic system including nerves, adrenoceptors and transporters. In obesity, the autonomic nervous system is dysfunctional; therefore, sympathetic innervation of PVAT may be the key mechanistic link between increased adiposity and vascular disease. In addition, not all obese people develop vascular disease, but a common feature amongst those that do appears to be the inflammatory cell population in PVAT. This review will discuss what is known about sympathetic innervation of PVAT, and the links between nerve activation and inflammation in obesity. In addition, we will examine the therapeutic potential of exercise in sympathetic stimulation of adipose tissue.

ß3 -Adrenoceptor stimulation of perivascular adipocytes leads to increased fat cell-derived NO and vascular relaxation in small arteries.

BACKGROUND AND PURPOSE: In response to noradrenaline, healthy perivascular adipose tissue (PVAT) exerts an anticontractile effect on adjacent small arterial tissue. Organ bath solution transfer experiments have demonstrated the release of PVAT-derived relaxing factors that mediate this function. The present studies were designed to investigate the mechanism responsible for the noradrenaline-induced PVAT anticontractile effect. EXPERIMENTAL APPROACH: In vitro rat small arterial contractile function was assessed using wire myography in the presence and absence of PVAT and the effects of sympathomimetic stimulation on the PVAT environment explored using Western blotting and assays of organ bath buffer. KEY RESULTS: PVAT elicited an anticontractile effect in response to noradrenaline but not phenylephrine stimulation. In arteries surrounded by intact PVAT, the ß3 -adrenoceptor agonist, CL-316243, reduced the vasoconstrictor effect of phenylephrine but not noradrenaline. Kv 7 channel inhibition using XE 991 reversed the noradrenaline-induced anticontractile effect in exogenously applied PVAT studies. Adrenergic stimulation of PVAT with noradrenaline and CL-316243, but not phenylephrine, was associated with increased adipocyte-derived NO production, and the contractile response to noradrenaline was augmented following incubation of exogenous PVAT with L-NMMA. PVAT from eNOS-/- mice had no anticontractile effect. Assays of adipocyte cAMP demonstrated an increase with noradrenaline stimulation implicating Gαs signalling in this process. CONCLUSIONS AND IMPLICATIONS: We have shown that adipocyte-located ß3 -adrenoceptor stimulation leads to activation of Gαs signalling pathways with increased cAMP and the release of adipocyte-derived NO. This process is dependent upon Kv 7 channel function. We conclude that adipocyte-derived NO plays a central role in anticontractile activity when rodent PVAT is stimulated by noradrenaline.