PVAT (perivascular adipose tissue) has recently been recognized as a novel factor in vascular biology, with implications in the pathophysiology of cardiovascular disease. Composed mainly of ...adipocytes, PVAT releases a wide range of biologically active molecules that modulate vascular smooth muscle cell contraction, proliferation and migration. PVAT exerts an anti-contractile effect in various vascular beds which seems to be mediated by an as yet elusive PVRF PVAT-derived relaxing factor(s). Considerable progress has been made on deciphering the nature and mechanisms of action of PVRF, and the PVRFs proposed until now are reviewed here. However, complex pathways seem to regulate PVAT function and more than one mechanism is probably responsible for PVAT actions in vascular biology. The present review describes our current knowledge on the structure and function of PVAT, with a focus on its role in modulating vascular tone. Potential involvements of PVAT dysfunction in obesity, hypertension and atherosclerosis will be highlighted.
Toll-like receptors (TLRs) are components of the innate immune system that respond to exogenous infectious ligands (pathogen-associated molecular patterns, PAMPs) and endogenous molecules that are ...released during host tissue injury/death (damage-associated molecular patterns, DAMPs). Interaction of TLRs with their ligands leads to activation of downstream signaling pathways that induce an immune response by producing inflammatory cytokines, type I interferons (IFN), and other inflammatory mediators. TLR activation affects vascular function and remodeling, and these molecular events prime antigen-specific adaptive immune responses. Despite the presence of TLRs in vascular cells, the exact mechanisms whereby TLR signaling affects the function of vascular tissues are largely unknown. Cardiovascular diseases are considered chronic inflammatory conditions, and accumulating data show that TLRs and the innate immune system play a determinant role in the initiation and development of cardiovascular diseases. This evidence unfolds a possibility that targeting TLRs and the innate immune system may be a novel therapeutic goal for these conditions. TLR inhibitors and agonists are already in clinical trials for inflammatory conditions such as asthma, cancer, and autoimmune diseases, but their study in the context of cardiovascular diseases is in its infancy. In this article, we review the current knowledge of TLR signaling in the cardiovascular system with an emphasis on atherosclerosis, hypertension, and cerebrovascular injury. Furthermore, we address the therapeutic potential of TLR as pharmacological targets in cardiovascular disease and consider intriguing research questions for future study.
Characterization of temperature and thermal transport properties of the skin can yield important information of relevance to both clinical medicine and basic research in skin physiology. Here we ...introduce an ultrathin, compliant skin-like, or 'epidermal', photonic device that combines colorimetric temperature indicators with wireless stretchable electronics for thermal measurements when softly laminated on the skin surface. The sensors exploit thermochromic liquid crystals patterned into large-scale, pixelated arrays on thin elastomeric substrates; the electronics provide means for controlled, local heating by radio frequency signals. Algorithms for extracting patterns of colour recorded from these devices with a digital camera and computational tools for relating the results to underlying thermal processes near the skin surface lend quantitative value to the resulting data. Application examples include non-invasive spatial mapping of skin temperature with milli-Kelvin precision (±50 mK) and sub-millimetre spatial resolution. Demonstrations in reactive hyperaemia assessments of blood flow and hydration analysis establish relevance to cardiovascular health and skin care, respectively.
Mechanical assessment of soft biological tissues and organs has broad relevance in clinical diagnosis and treatment of disease. Existing characterization methods are invasive, lack microscale spatial ...resolution, and are tailored only for specific regions of the body under quasi-static conditions. Here, we develop conformal and piezoelectric devices that enable in vivo measurements of soft tissue viscoelasticity in the near-surface regions of the epidermis. These systems achieve conformal contact with the underlying complex topography and texture of the targeted skin, as well as other organ surfaces, under both quasi-static and dynamic conditions. Experimental and theoretical characterization of the responses of piezoelectric actuator-sensor pairs laminated on a variety of soft biological tissues and organ systems in animal models provide information on the operation of the devices. Studies on human subjects establish the clinical significance of these devices for rapid and non-invasive characterization of skin mechanical properties.
Aim
To assess the comparative efficacy and safety of sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors in adults with type 2 diabetes.
Methods
We electronically searched randomized controlled trials ...(≥24 weeks) including canagliflozin, dapagliflozin or empagliflozin that were published up to 3 November 2015. Data were collected on cardiometabolic and safety outcomes and synthesized using network meta‐analyses.
Results
A total of 38 trials (23 997 participants) were included. Compared with placebo, all SGLT2 inhibitors reduced glycated haemoglobin (HbA1c), fasting plasma glucose (FPG), body weight and blood pressure, and slightly increased HDL cholesterol. Canagliflozin 300 mg reduced HbA1c, FPG and systolic blood pressure and increased LDL cholesterol to a greater extent compared with other inhibitors at any dose. At their highest doses, canagliflozin 300 mg reduced: HbA1c by 0.2% 95% confidence interval (CI) 0.1–0.3 versus both dapagliflozin 10 mg and empagliflozin 25 mg; FPG by 0.6 mmol/l (95% CI 0.3–0.9) and 0.5 mmol/l (95% CI 0.1–0.8) versus dapagliflozin and empagliflozin, respectively; and systolic blood pressure by 2 mmHg (95% CI 1.0–3.0) versus dapagliflozin; and increased LDL cholesterol by 0.13 mmol/l (95% CI 0.03–0.23) and 0.15 mmol/l (95% CI 0.06–0.23) versus dapagliflozin and empagliflozin, respectively. The highest doses of inhibitors had similar effects on body weight reduction. Canagliflozin 300 and 100 mg increased the risk of hypoglycaemia versus placebo, dapagliflozin 10 mg and empagliflozin 10 mg odds ratios (ORs) 1.4–1.6. Dapagliflozin 10 mg increased the risk of urinary tract infection versus placebo and empagliflozin 25 mg (ORs 1.4). All inhibitors similarly increased the risk of genital infection (ORs 4–6 versus placebo).
Conclusions
Although they increase the risk of genital infection, SGLT2 inhibitors are effective in improving cardiometabolic markers in type 2 diabetes, with canagliflozin 300 mg performing better in this respect than other inhibitors. Further studies will clarify whether these differences are likely to translate into differing long‐term outcomes.
Circadian clocks provide a competitive advantage in an environment that is heavily influenced by the rotation of the Earth, by driving daily rhythms in behaviour, physiology and metabolism in ...bacteria, fungi, plants and animals. Circadian clocks comprise transcription-translation feedback loops, which are entrained by environmental signals such as light and temperature to adjust the phase of rhythms to match the local environment. The production of sugars by photosynthesis is a key metabolic output of the circadian clock in plants. Here we show that these rhythmic, endogenous sugar signals can entrain circadian rhythms in Arabidopsis thaliana by regulating the gene expression of circadian clock components early in the photoperiod, thus defining a 'metabolic dawn'. By inhibiting photosynthesis, we demonstrate that endogenous oscillations in sugar levels provide metabolic feedback to the circadian oscillator through the morning-expressed gene PSEUDO-RESPONSE REGULATOR 7 (PRR7), and we identify that prr7 mutants are insensitive to the effects of sucrose on the circadian period. Thus, photosynthesis has a marked effect on the entrainment and maintenance of robust circadian rhythms in A. thaliana, demonstrating that metabolism has a crucial role in regulation of the circadian clock.
Diabetes mellitus is a complex metabolic disorder associated with an increased risk of microvascular and macrovascular disease; its main clinical characteristic is hyperglycaemia. The last century ...has been characterised by remarkable advances in our understanding of the mechanisms leading to hyperglycaemia. The central role of insulin in glucose metabolism regulation was clearly demonstrated during the early 1920s, when Banting, Best, Collip and Macleod successfully reduced blood glucose levels and glycosuria in a patient treated with a substance purified from bovine pancreata. Later, during the mid-1930s, clinical observations suggested a possible distinction between 'insulin-sensitive' and 'insulin-insensitive' diabetes. Only during the 1950s, when a reliable measure of circulating insulin was available, was it possible to translate these clinical observations into pathophysiological and biochemical differences, and the terms 'insulin-dependent' (indicating undetectable insulin levels) and 'non-insulin-dependent' (normal or high insulin levels) started to emerge. The next 30 years were characterised by pivotal progress in the field of immunology that were instrumental in demonstrating an immune-mediated loss of insulin-secreting β-cells in subjects with 'insulin-dependent' diabetes. At the same time, new experimental techniques allowing measurement of insulin 'impedance' showed a reduced peripheral effect of insulin in subjects with 'non-insulin-dependent' diabetes (insulin resistance). The difference between the two types of diabetes emerging from decades of observations and experiments was further formally recognised in 1979, when the definitions 'type I' and 'type II' diabetes were introduced to replace the former 'insulin-dependent' and 'non-insulin-dependent' terms. In the following years, many studies elucidated the natural history and temporal contribution of insulin resistance and β-cell insulin secretion in 'type II' diabetes. Furthermore, a central role for insulin resistance in the development of a cluster of cardiometabolic alterations (dyslipidaemia, inflammation, high blood pressure) was suggested. Possibly as a consequence of the secular changes in diabetes risk factors, in the last 10 years the limitation of a simple distinction between 'type I' and 'type II' diabetes has been increasingly recognised, with subjects showing the coexistence of insulin resistance and immune activation against β-cells. With the advancement of our cellular and molecular understanding of diabetes, a more pathophysiological classification that overcomes the historical and simple 'glucocentric' view could result in a better patient phenotyping and therapeutic approach.
Background. Beta-lactam antibiotics are a commonly used treatment for severe sepsis, with intermittent bolus dosing standard therapy, despite a strong theoretical rationale for continuous ...administration. The aim of this trial was to determine the clinical and pharmacokinetic differences between continuous and intermittent dosing in patients with severe sepsis. Methods. This was a prospective, double-blind, randomized controlled trial of continuous infusion versus intermittent bolus dosing of piperacillin-tazobactam, meropenem, and ticarcillin-clavulanate conducted in 5 intensive care units across Australia and Hong Kong. The primary pharmacokinetic outcome on treatment analysis was plasma antibiotic concentration above the minimum inhibitory concentration (MIC) on days 3 and 4. The assessed clinical outcomes were clinical response 7–14 days after study drug cessation, ICU-free days at day 28 and hospital survival. Results. Sixty patients were enrolled with 30 patients each allocated to the intervention and control groups. Plasma antibiotic concentrations exceeded the MIC in 82% of patients (18 of 22) in the continuous arm versus 29% (6 of 21) in the intermittent arm (P = .001). Clinical cure was higher in the continuous group (70% vs 43%; P = .037), but ICU-free days (19.5 vs 17 days; P = .14) did not significantly differ between groups. Survival to hospital discharge was 90% in the continuous group versus 80% in the intermittent group (P = .47). Conclusions. Continuous administration of beta-lactam antibiotics achieved higher plasma antibiotic concentrations than intermittent administration with improvement in clinical cure. This study provides a strong rationale for further multicenter trials with sufficient power to identify differences in patient-centered endpoints.
Hypertension and COVID-19 Schiffrin, Ernesto L; Flack, John M; Ito, Sadayoshi ...
American journal of hypertension,
04/2020, Letnik:
33, Številka:
5
Journal Article
Aims
To compare efficacy and safety of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) in people with type 2 diabetes.
Materials and methods
We electronically searched, up to June 3, 2016, ...published randomized clinical trials lasting between 24 and 32 weeks that compared a GLP‐1RA (albiglutide, dulaglutide, twice‐daily exenatide and once‐weekly exenatide, liraglutide, lixisenatide, semaglutide and taspoglutide) with placebo or another GLP‐1RA. Data on cardiometabolic and safety outcomes were analysed using a mixed‐treatment comparison meta‐analysis.
Results
A total of 34 trials (14 464 participants) met the inclusion criteria; no published data for semaglutide were available. Compared with placebo, all GLP‐1RAs reduced glycated haemoglobin (HbA1c) and fasting plasma glucose (FPG) levels (reductions ranged from −0.55% and −0.73 mmol/L, respectively, for lixisenatide to −1.21% and −1.97 mmol/L, respectively, for dulaglutide). There were no differences within short‐acting (twice‐daily exenatide and lixisenatide) or long‐acting (albiglutide, dulaglutide, once‐weekly exenatide, liraglutide and taspoglutide) groups. Compared with twice‐daily exenatide, dulaglutide treatment was associated with the greatest HbA1c and FPG reduction (0.51% and 1.04 mmol/L, respectively), followed by liraglutide (0.45% and 0.93 mmol/L, respectively) and once‐weekly exenatide (0.38% and 0.85 mmol/L, respectively); similar reductions were found when these 3 agents were compared with lixisenatide. Compared with placebo, all GLP‐1RAs except albiglutide reduced weight and increased the risk of hypoglycaemia and gastrointestinal side effects, and all agents except dulaglutide and taspoglutide reduced systolic blood pressure. When all GLP‐1RAs were compared with each other, no clinically meaningful differences were observed in weight loss, blood pressure reduction or hypoglycaemia risk. Albiglutide had the lowest risk of nausea and diarrhoea and once‐weekly exenatide the lowest risk of vomiting.
Conclusions
The RCTs in the present analysis show that all GLP‐1RAs improve glycaemic control, reduce body weight and increase the risk of adverse gastrointestinal symptoms compared with placebo. Although there were no differences when short‐acting agents were compared with each other or when long‐acting agents were compared with each other, dulaglutide, liraglutide and once‐weekly exenatide were superior to twice‐daily exenatide and lixisenatide at lowering HbA1c and FPG levels. There were no differences in hypoglycaemia between these 3 agents, whilst once‐weekly exenatide had the lowest risk of vomiting. These results, along with patient's preferences and individualized targets, should be considered when selecting a GLP‐1RA.
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