Colchicine exerts anti-atherosclerotic and -plaque-stabilizing effects targeting foam cell formation.

Colchicine is a broad-acting anti-inflammatory agent that has attracted interest for repurposing in atherosclerotic cardiovascular disease. Here, we studied its ability at a human equivalent dose of 0.5 mg/day to modify plaque formation and composition in murine atherosclerosis and investigated its actions on macrophage responses to atherogenic stimuli in vitro. In atherosclerosis induced by high-cholesterol diet, Apoe-/- mice treated with colchicine had 50% reduction in aortic oil Red O+ plaque area compared to saline control (p = .001) and lower oil Red O+ staining of aortic sinus lesions (p = .03). In vitro, addition of 10 nM colchicine inhibited foam cell formation from murine and human macrophages after treatment with oxidized LDL (ox-LDL). Mechanistically, colchicine downregulated glycosylation and surface expression of the ox-LDL uptake receptor, CD36, and reduced CD36+ staining in aortic sinus plaques. It also decreased macrophage uptake of cholesterol crystals, resulting in lower intracellular lysosomal activity, inhibition of the NLRP3 inflammasome, and reduced secretion of IL-1ß and IL-18. Colchicine's anti-atherosclerotic actions were accentuated in a mouse model of unstable plaque induced by carotid artery tandem stenosis surgery, where it decreased lesion size by 48% (p = .01), reduced lipid (p = .006) and necrotic core area (p = .007), increased collagen content and cap-to-necrotic core ratio (p = .05), and attenuated plaque neutrophil extracellular traps (p < .001). At low dose, colchicine's effects were not accompanied by the evidence of microtubule depolymerization. Together, these results show that colchicine exerts anti-atherosclerotic and plaque-stabilizing effects at low dose by inhibiting foam cell formation and cholesterol crystal-induced inflammation. This provides a new framework to support its repurposing for atherosclerotic cardiovascular disease.

Breaking prolonged sitting increases 24-h physical activity and self-perceived energy levels but does not acutely affect cognition in healthy adults.

INTRODUCTION: It is unknown whether predetermined (un)interrupted sitting within a laboratory setting will induce compensatory changes in human behaviours (energy intake and physical activity) once people return to a free-living environment. The effects of breaking up prolonged sitting on cognition are also unclear. METHODS: Twenty-four (male = 13) healthy participants [age 31 ± 8 y, BMI 22.7 ± 2.3 kg/m2 (mean ± SD)] completed 320 min mixed-feeding trials under prolonged sitting (SIT) or with 2 min walking at 6.4 km/h every 20 min (ACTIVE), in a randomised crossover design. Human behaviours were recorded post-trial under free-living conditions until midnight. Cognitive performance was evaluated before and immediately after SIT and ACTIVE trials. Self-perceived sensations (appetite, energy and mood) and finger prick blood glucose levels were collected at regular intervals throughout the trials. RESULTS: There were no differences between trials in eating behaviour and spontaneous physical activity (both, p > 0.05) in free-living conditions, resulting in greater overall total step counts [11,680 (10740,12620) versus 6049 (4845,7253) steps] and physical activity energy expenditure (PAEE) over 24-h period in ACTIVE compared to SIT (all, p < 0.05). Greater self-perceived levels of energy and lower blood glucose iAUC were found in ACTIVE trial compared to SIT trial (both, p < 0.05). No differences were found in cognitive performance between trials (all, p > 0.05). CONCLUSION: Breaking up sitting does not elicit subsequent behavioural compensation, resulting in greater 24-h step counts and PAEE in healthy adults. Breaking up sitting reduces postprandial glucose concentrations and elicits greater self-perceived energy levels, but these positive effects do not acutely translate into improved cognitive function.

Effects of acute and chronic stair-climbing exercise on metabolic health: A systematic review.

Stair climbing exercise (SE) provides a feasible approach to elevate physical activity, but the effects on metabolic health are unclear. We systematically reviewed the currently available evidence on the effects of SE on fasting and postprandial glycaemia and lipidaemia. Studies were included if they investigated the effects of acute or chronic (at least 2 weeks) SE on fasting and/or postprandial glycaemic (insulin and glucose) and lipidaemic (triacylglycerols and non-esterified fatty acids) responses in healthy, prediabetic or type 2 diabetic adult populations. PubMed, Web of Science and Scopus were searched for eligible studies until July 2022. A total of 25 studies (14 acute and 11 chronic) were eligible for review. Acute bout(s) of SE can reduce postprandial glycaemia in individuals with prediabetes and type 2 diabetes (8 of 9 studies), but not in normoglycemic individuals. The effects of acute SE on postprandial lipidaemic responses and SE training on both fasting and postprandial glycaemia/lipidaemia were unclear. Acute SE may reduce postprandial glucose concentrations in people with impaired glycaemic control, but high-quality studies are needed. More studies are needed to determine the effect of chronic SE training on postprandial glucose and lipid responses, and the acute effects of SE on lipid responses.

Risk comparison of osteonecrosis of the jaw in osteoporotic patients treated with bisphosphonates vs. denosumab: a multi-institutional retrospective cohort study in Taiwan.

In this multi-institutional retrospective cohort study, we compared the long-term risk of osteonecrosis of the jaw following the use of denosumab vs. bisphosphonates in osteoporotic patients. After 2-year use, the likelihood of osteonecrosis of the jaw is lower with denosumab compared to bisphosphonates, and the difference increases with time. PURPOSE: To compare the long-term risk of osteonecrosis of the jaw (ONJ) between osteoporotic patients treated with bisphosphonates (BPs) and denosumab. METHODS: This multi-institutional retrospective cohort study included patients aged > 40 years with osteoporosis between January 2010 and December 2018. Patients who met the eligibility criteria were divided into BPs and denosumab groups by propensity score matching (PSM). The risk of ONJ of denosumab vs. BPs was estimated using a Cox proportional hazards model and was described by the cumulative incidence rate using the Kaplan-Meier method. RESULTS: A total of 84,102 patients with osteoporosis were enrolled, among whom, 8962 were eligible for inclusion based on their first-line drug use (denosumab, n = 3,823; BPs, n = 5,139). Following PCM matching (1:1), the BPs and denosumab groups included 3665 patients each. The incidence density of ONJ in the denosumab and BPs matching groups was 1.47 vs. 2.49 events (per 1000 person-years), respectively. The hazard ratio of ONJ in the denosumab vs. BPs group was estimated as 0.581 (95% confidence interval: 0.33-1.04, p = 0.07). The cumulative incidence rates of ONJ in both groups were similar for the first and second years of drug use (p = 0.062), but significantly different from the third year onwards (p = 0.022). The severity of ONJ was not significantly different between the two groups. CONCLUSION: In osteoporotic patients, after 2 years of use, the likelihood of ONJ being induced by denosumab is lower than that of BPs, and the difference increases with time.

Divergent immunometabolic changes in adipose tissue and skeletal muscle with ageing in healthy humans.

KEY POINTS: Ageing is associated with increased systemic inflammation and metabolic dysfunction that contributes to the development of age-associated diseases. The role of adipose tissue in immunometabolic alterations that take place with ageing is unknown in humans. We show, in healthy, active and lean older adults, that adipose tissue, but not skeletal muscle, displays considerable pro-inflammatory transcriptomic, cellular and secretory changes, as well as a reduction in insulin signalling proteins compared to younger adults. These findings indicate that adipose tissue undergoes substantial immunometabolic alterations with ageing, and that these changes are tissue-specific and more profound than those observed in skeletal muscle or in the circulation. These results identify adipose tissue as an important tissue in the biological ageing process in humans, which may exhibit signs of immunometabolic dysfunction prior to systemic manifestation. ABSTRACT: Ageing and obesity are both characterized by inflammation and a deterioration in metabolic health. It is now clear that adipose tissue plays a major role in inflammation and metabolic control in obesity, although little is known about the role of adipose tissue in human ageing. To understand how ageing impacts adipose tissue, we characterized subcutaneous adipose tissue and skeletal muscle samples from twelve younger (27 ± 4 years [Young]) and twelve older (66 ± 5 years [Old]) active/non-obese males. We performed a wide-range of whole-body and tissue measures, including RNA-sequencing and multicolour flow cytometry. We also measured a range of inflammatory and metabolic proteins in the circulation and their release by adipose tissue, ex vivo. Both adipose tissue and muscle had ∼2-fold more immune cells per gram of tissue with ageing. In adipose tissue, this immune cell infiltration was driven by increased memory/effector T-cells, whereas, in muscle, the accumulation was driven by memory/effector T-cells and macrophages. Transcriptomic analysis revealed that, with ageing, adipose tissue, but not muscle, was enriched for inflammatory transcripts/pathways related to acquired and innate immunity. Ageing also increased the adipose tissue pro-inflammatory secretory profile. Insulin signalling protein content was reduced in adipose tissue, but not muscle. Our findings indicate that adipose tissue undergoes substantial immunometabolic changes with ageing in humans, and that these changes are tissue-specific and more profound than those observed in the circulation and skeletal muscle.

3D-Printed Micro Lens-in-Lens for In Vivo Multimodal Microendoscopy.

Multimodal microendoscopes enable co-located structural and molecular measurements in vivo, thus providing useful insights into the pathological changes associated with disease. However, different optical imaging modalities often have conflicting optical requirements for optimal lens design. For example, a high numerical aperture (NA) lens is needed to realize high-sensitivity fluorescence measurements. In contrast, optical coherence tomography (OCT) demands a low NA to achieve a large depth of focus. These competing requirements present a significant challenge in the design and fabrication of miniaturized imaging probes that are capable of supporting high-quality multiple modalities simultaneously. An optical design is demonstrated which uses two-photon 3D printing to create a miniaturized lens that is simultaneously optimized for these conflicting imaging modalities. The lens-in-lens design contains distinct but connected optical surfaces that separately address the needs of both fluorescence and OCT imaging within a lens of 330 µm diameter. This design shows an improvement in fluorescence sensitivity of >10x in contrast to more conventional fiber-optic design approaches. This lens-in-lens is then integrated into an intravascular catheter probe with a diameter of 520 µm. The first simultaneous intravascular OCT and fluorescence imaging of a mouse artery in vivo is reported.

Influence of hemoglobin on blood pressure among people with GP.Mur blood type☆.

BACKGROUND/PURPOSE: GP.Mur is a clinically important red blood cell (RBC) type. GP.Mur and band 3 interact on the RBCs. We previously observed that healthy adults with GP.Mur type present slightly higher blood pressure (BP). Because band 3 and Hb comodulate nitric oxide (NO)-dependent vasodilation and hemoglobin (Hb) is positively associated with BP, we aimed to test whether these could contribute to higher BP in GP.Mur+ people. METHODS: We recruited 989 non-elderly adults (21% GP.Mur) free of catastrophic illness and not on cardiovascular or anti-hypertensive medication. Their body indices, blood lab data and lifestyle data were collected for analyses of potential BP-related factors (BMI, age, smoking, Hb, and GP.Mur). RESULTS: BMI and age remained the most significant contributors to BP. GP.Mur slightly increased systolic BP (SBP). The direct correlation between Hb and BP was only found in Taiwanese non-anemic men, not women. After age and BMI adjusted, we estimated an increase of 1.8 mmHg and 2.6 mmHg of SBP by 1 g/dL Hb among men without and with GP.Mur type, respectively. Hb was generally lower among people expressing GP.Mur, which likely limited their larger impact on BP. CONCLUSION: GP.Mur contributed to BP in both Hb-dependent and Hb-independent fashion. A pronounced impact of hemoglobin on BP likely requires sufficient Hb, as GP.Mur increased the sensitivity of SBP to Hb only in non-anemic Taiwanese men, and not in Taiwanese women or anemic men. The mechanism through which GP.Mur affected BP independent of Hb is unknown.

Effects of backhand stroke styles on bone mineral content and density in postmenopausal recreational tennis players: a cross-sectional pilot investigation.

BACKGROUND: One-handed backhand (OB) and two-handed backhand (TB) styles are commonly used in tennis, but only TB generates loadings on the non-dominant arm and a greater extension torque on the rear leg, leading to a greater axial torque involving rotation of the hip and trunk. The current study investigated whether those effects can further affect bone area (BA), bone mineral content (BMC) and density (BMD) in postmenopausal recreational tennis players. METHODS: BA, BMC and BMD of the lumbar spine, hip and distal radius were assessed using dual-energy X-ray absorptiometry in TB, OB, and swimmers' group as a control (SG) (all participants self-reported for at least 5 years of exercise history, n = 14 per group). Muscular strength was assessed with a hand dynamometer. Among these three groups, the BA, BMC and BMD of distal radius and muscle strength were assessed using one-way ANOVA, and those of the lumbar region and the hip joint were tested by one-way ANCOVA. RESULTS: TB showed higher BMC and BMD for both lumbar spine and femoral neck than SG (all, p < 0.05). Both OB and TB showed greater BMD inter-trochanter than SG (both, p < 0.05). OB demonstrated greater inter-arm differences in the distal radius, which involved 1/3 distal for BMC and mid-distal radius for BMD compared to the TB and SG (all, p < 0.05). In addition, greater inter-arm asymmetry of grip strength was found in OB compared to TB and SG (both, p < 0.05). CONCLUSION: For postmenopausal women, performing two-handed backhand strokes, leads to higher BMC and BMD in the non-dominant arm, the lumbar region, and hips, indicating potential benefit to maintain bone health and strength. Whether this result leads to reducing the risk of osteoporosis needs to be investigated in further research.

Anti-carcinogenic effects of exercise-conditioned human serum: evidence, relevance and opportunities.

Regular physical activity reduces the risk of several site-specific cancers in humans and suppresses tumour growth in animal models. The mechanisms through which exercise reduces tumour growth remain incompletely understood, but an intriguing and accumulating body of evidence suggests that the incubation of cancer cells with post-exercise serum can have powerful effects on key hallmarks of cancer cell behaviour in vitro. This suggests that exercise can impact tumour biology through direct changes in circulating proteins, RNA molecules and metabolites. Here, we provide a comprehensive narrative overview of what is known about the effects of exercise-conditioned sera on in vitro cancer cell behaviour. In doing so, we consider the key limitations of the current body of literature, both from the perspective of exercise physiology and cancer biology, and we discuss the potential in vivo physiological relevance of these findings. We propose key opportunities for future research in an area that has the potential to identify key anti-oncogenic protein targets and optimise physical activity recommendations for cancer prevention, treatment and survivorship.

Glucose control upon waking is unaffected by hourly sleep fragmentation during the night, but is impaired by morning caffeinated coffee.

Morning coffee is a common remedy following disrupted sleep, yet each factor can independently impair glucose tolerance and insulin sensitivity in healthy adults. Remarkably, the combined effects of sleep fragmentation and coffee on glucose control upon waking per se have never been investigated. In a randomised crossover design, twenty-nine adults (mean age: 21 (sd 1) years, BMI: 24·4 (sd 3·3) kg/m2) underwent three oral glucose tolerance tests (OGTT). One following a habitual night of sleep (Control; in bed, lights-off trying to sleep approximately 23.00-07.00 hours), the others following a night of sleep fragmentation (as Control but waking hourly for 5 min), with and without morning coffee approximately 1 h after waking (approximately 300 mg caffeine as black coffee 30 min prior to OGTT). Individualised peak plasma glucose and insulin concentrations were unaffected by sleep quality but were higher following coffee consumption (mean (normalised CI) for Control, Fragmented and Fragmented + Coffee, respectively; glucose: 8·20 (normalised CI 7·93, 8·47) mmol/l v. 8·23 (normalised CI 7·96, 8·50) mmol/l v. 8·96 (normalised CI 8·70, 9·22) mmol/l; insulin: 265 (normalised CI 247, 283) pmol/l; and 235 (normalised CI 218, 253) pmol/l; and 310 (normalised CI 284, 337) pmol/l). Likewise, incremental AUC for plasma glucose was higher in the Fragmented + Coffee trial compared with Fragmented. Whilst sleep fragmentation did not alter glycaemic or insulinaemic responses to morning glucose ingestion, if a strong caffeinated coffee is consumed, then a reduction in glucose tolerance can be expected.

Co-ingestion of whey protein hydrolysate with milk minerals rich in calcium potently stimulates glucagon-like peptide-1 secretion: an RCT in healthy adults.

PURPOSE: To examine whether calcium type and co-ingestion with protein alter gut hormone availability. METHODS: Healthy adults aged 26 ± 7 years (mean ± SD) completed three randomized, double-blind, crossover studies. In all studies, arterialized blood was sampled postprandially over 120 min to determine GLP-1, GIP and PYY responses, alongside appetite ratings, energy expenditure and blood pressure. In study 1 (n = 20), three treatments matched for total calcium content (1058 mg) were compared: calcium citrate (CALCITR); milk minerals rich in calcium (MILK MINERALS); and milk minerals rich in calcium plus co-ingestion of 50 g whey protein hydrolysate (MILK MINERALS + PROTEIN). In study 2 (n = 6), 50 g whey protein hydrolysate (PROTEIN) was compared to MILK MINERALS + PROTEIN. In study 3 (n = 6), MILK MINERALS was compared to the vehicle of ingestion (water plus sucralose; CONTROL). RESULTS: MILK MINERALS + PROTEIN increased GLP-1 incremental area under the curve (iAUC) by ~ ninefold (43.7 ± 11.1 pmol L-1 120 min; p < 0.001) versus both CALCITR and MILK MINERALS, with no difference detected between CALCITR (6.6 ± 3.7 pmol L-1 120 min) and MILK MINERALS (5.3 ± 3.5 pmol L-1 120 min; p > 0.999). MILK MINERALS + PROTEIN produced a GLP-1 iAUC ~ 25% greater than PROTEIN (p = 0.024; mean difference: 9.1 ± 6.9 pmol L-1 120 min), whereas the difference between MILK MINERALS versus CONTROL was small and non-significant (p = 0.098; mean difference: 4.2 ± 5.1 pmol L-1 120 min). CONCLUSIONS: When ingested alone, milk minerals rich in calcium do not increase GLP-1 secretion compared to calcium citrate. Co-ingesting high-dose whey protein hydrolysate with milk minerals rich in calcium increases postprandial GLP-1 concentrations to some of the highest physiological levels ever reported. Registered at ClinicalTrials.gov: NCT03232034, NCT03370484, NCT03370497.

A Novel Epigenetic Drug-Eluting Balloon Angioplasty Device: Evaluation in a Large Animal Model of Neointimal Hyperplasia.

PURPOSE: Drug-eluting balloon catheters (DEBc) coated with paclitaxel (PTX) have been associated with potential safety concerns. An efficacious but less toxic balloon coating may reduce these outcomes. We evaluated a novel DEBc, Epi-Solve, coated with metacept-3 (MCT-3), a member of the histone deacetylase inhibitor (HDACi) class of epigenetic agents, in a large animal model of neointimal hyperplasia (NIH). METHODS: Plain balloon angioplasty (PABA) catheters were ultrasonically coated with MCT-3 to generate Epi-Solve DEBc. An ovine model of NIH formation was established utilising partial left common carotid artery (LCA) ligation. Twenty-eight days post neointima (NI) induction, PABA, Epi-Solve or PTX-coated DEBc were deployed at the site of induced NI formation. Twenty-eight days post-intervention, ligated vessels were evaluated for attenuation of NI formation, gene expression profiles and immunohistochemical analysis. RESULTS: Epi-Solve DEBc demonstrated attenuation of NIH over no intervention and a trend to inhibition of NIH over PABA. Gene expression analysis and immunohistochemical studies identified significant anti-proliferative and anti-inflammatory signatures and reduced vascular endothelial cell activation compared to PABA. CONCLUSIONS: Epi-Solve is a novel HDACi-coated DEBc which demonstrates significant anti-proliferative and anti-inflammatory signatures and reduced vascular endothelial cell activation compared to PABA in an ovine model and may afford endothelial protection.

Dual-Targeted Theranostic Delivery of miRs Arrests Abdominal Aortic Aneurysm Development.

Abdominal aortic aneurysm (AAA) is an often deadly disease without medical, non-invasive treatment options. The upregulation of vascular cell adhesion molecule-1 (VCAM-1) on aortic endothelium provides an early target epitope for a novel biotechnological theranostic approach. MicroRNA-126 was used as a therapeutic agent, based on its capability to downregulate VCAM-1 expression in endothelial cells and thereby reduces leukocyte adhesion and exerts anti-inflammatory effects. Ultrasound microbubbles were chosen as carriers, allowing both molecular imaging as well as targeted therapy of AAA. Microbubbles were coupled with a VCAM-1-targeted single-chain antibody (scFvmVCAM-1) and a microRNA-126 mimic (M126) constituting theranostic microbubbles (TargMB-M126). TargMB-M126 downregulates VCAM-1 expression in vitro and in an in vivo acute inflammatory murine model. Most importantly, using TargMB-M126 and ultrasound-guided burst delivery of M126, the development of AAA in an angiotensin-II-induced mouse model can be prevented. Overall, we describe a unique biotechnological theranostic approach with the potential for early diagnosis and long-sought-after medical therapy of AAA.

Myeloperoxidase is a potential molecular imaging and therapeutic target for the identification and stabilization of high-risk atherosclerotic plaque.

Aims: As the inflammatory enzyme myeloperoxidase (MPO) is abundant in ruptured human atherosclerotic plaques, we aimed to investigate the role of MPO as a potential diagnostic and therapeutic target for high-risk plaque. Methods and results: We employed the tandem stenosis model of atherosclerotic plaque instability in apolipoprotein E gene knockout (Apoe-/-) mice. To test the role of MPO, we used Mpo-/-Apoe-/- mice and the 2-thioxanthine MPO inhibitor AZM198. In vivo MPO activity was assessed by liquid chromatography-tandem mass spectrometry detection of 2-chloroethidium generation from hydroethidine and by bis-5HT-DTPA-Gd (MPO-Gd) molecular magnetic resonance imaging (MRI), while plaque phenotype was verified histologically. Myeloperoxidase activity was two-fold greater in plaque with unstable compared with stable phenotype. Genetic deletion of MPO significantly increased fibrous cap thickness, and decreased plaque fibrin and haemosiderin content in plaque with unstable phenotype. AZM198 inhibited MPO activity and it also increased fibrous cap thickness and decreased fibrin and haemosiderin in plaque with unstable phenotype, without affecting lesion monocytes and red blood cell markers or circulating leukocytes and lipids. MPO-Gd MRI demonstrated sustained enhancement of plaque with unstable phenotype on T1-weighted imaging that was two-fold greater than stable plaque and was significantly attenuated by both AZM198 treatment and deletion of the Mpo gene. Conclusion: Our data implicate MPO in atherosclerotic plaque instability and suggest that non-invasive imaging and pharmacological inhibition of plaque MPO activity hold promise for clinical translation in the management of high-risk coronary artery disease.

Venous blood provides lower glucagon-like peptide-1 concentrations than arterialized blood in the postprandial but not the fasted state: Consequences of sampling methods.

NEW FINDINGS: What is the central question of this study? Glucagon-like peptide-1 (GLP-1) is an important obesity/diabetes target, with effects dependent on circulating GLP-1 concentrations. Peripheral tissues extract GLP-1; therefore, sampling venous versus arterialized blood might provide different GLP-1 concentrations. This study examined whether arterialization alters GLP-1 concentrations during fasting and feeding. What is the main finding and its importance? This study demonstrates that venous blood provides lower postprandial but not fasting GLP-1 concentrations versus arterialized blood. Therefore, when accurate assessment of postprandial peripheral availability of GLP-1 is required, blood sampling methods should be considered carefully, reported clearly, and arterialization is recommended. ABSTRACT: Glucagon-like peptide-1 (GLP-1) displays concentration-dependent effects on metabolism, appetite and angiogenesis; therefore, accurate determination of circulating GLP-1 concentrations is important. In this study, we compared GLP-1 concentrations in venous versus arterialized blood in both fasted and fed conditions. Venous and arterialized blood samples were obtained simultaneously from 10 young, healthy men before and 30, 60 and 120 min after ingestion of 75 g glucose. Plasma GLP-1 concentrations increased in response to glucose ingestion (time effect, P < 0.01) and to a lesser extent in venous versus arterialized plasma (time × arterialization interaction, P < 0.01). Accordingly, the plasma incremental area under the curve was lower in venous versus arterialized plasma (974 ± 88 versus 1214 ± 115 pmol l (120 min)-1 , respectively, P = 0.049). In the postprandial state, there was a positive relationship between arterialized GLP-1 concentrations and the venous-arterialized difference in GLP-1 concentrations (r2  = 0.51; P < 0.01). Both arterialized and venous peak GLP-1 concentrations showed positive relationships with peak arterialized insulin concentrations (both r2  > 0.6, P < 0.01). Venous sampling results in lower concentrations of GLP-1 in the postprandial but not the fasted state compared with arterialized blood. This absolute difference is biologically meaningful and is magnified when GLP-1 availability is high. Therefore, sampling from arterialized blood may provide a better chance of detecting small differences in postprandial GLP-1 availability with interventions. If absolute GLP-1 concentrations are of interest, the blood sampling method should be considered carefully and reported clearly.

Feeding influences adipose tissue responses to exercise in overweight men.

Feeding profoundly affects metabolic responses to exercise in various tissues, but the effect of feeding status on human adipose tissue responses to exercise has never been studied. Ten healthy overweight men aged 26 ± 5 yr (mean ± SD) with a waist circumference of 105 ± 10 cm walked at 60% of maximum oxygen uptake under either fasted or fed conditions in a randomized, counterbalanced design. Feeding comprised 648 ± 115 kcal 2 h before exercise. Blood samples were collected at regular intervals to examine changes in metabolic parameters and adipokine concentrations. Adipose tissue samples were obtained at baseline and 1 h after exercise to examine changes in adipose tissue mRNA expression and secretion of selected adipokines ex vivo. Adipose tissue mRNA expression of pyruvate dehydrogenase kinase isozyme 4 (PDK4), adipose triglyceride lipase, hormone-sensitive lipase (HSL), fatty acid translocase/CD36, glucose transporter type 4 (GLUT4), and insulin receptor substrate 2 (IRS2) in response to exercise were lower in fed compared with fasted conditions (all P ≤ 0.05). Postexercise adipose IRS2 protein was affected by feeding (P ≤ 0.05), but Akt2, AMPK, IRS1, GLUT4, PDK4, and HSL protein levels were not different. Feeding status did not impact serum and ex vivo adipose secretion of IL-6, leptin, or adiponectin in response to exercise. This is the first study to show that feeding before acute exercise affects postexercise adipose tissue gene expression, and we propose that feeding is likely to blunt long-term adipose tissue adaptation to regular exercise.

[Factors and Medical Costs Associated With Fall Events in Hospitalized Patients].

BACKGROUND: Patient falls are a common, adverse event in hospitals that may result in economic and care burdens on the patient and his/her family afterward. PURPOSE: To analyze the factors that relate to falls among inpatients and to estimate the associated days of hospitalization and medical costs. METHODS: The present study used a retrospective matched case-control design to analyze inpatient fall data for 2009 to 2011 from a regional teaching hospital in northern Taipei. We matched fallers and controls according to gender, age ∓ 5 years, and ICD-9-CM (International Classification of Diseases, Ninth Revision, Clinical Modification) code. Data were analyzed using descriptive and inferential statistics. RESULTS: A total of 160 inpatients participated in the present study (80 fallers in the fall group and 80 nonfallers in the control group). The results revealed that fallers had more previous fall experiences and longer hospital stay than nonfallers. Multiple logistic regression analysis revealed that the risk factors that were significantly associated with inpatient falls included: no family accompaniment, use of more than 3 fall-related medications, and no intravenous catheter placement. Results further found that medical costs increased with the degree of injury. Third-degree injuries bore the highest post-fall medical costs of all of the injury-degree categories. The average medical cost for patients with third-degree injuries was 18,257 New Taiwan dollars. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: The findings provide a reference for hospitals to promote patient safety, to prevent the occurrence of inpatient falls, and, ultimately, to reduce fall-associated medical costs.

Coinhibitory suppression of T cell activation by CD40 protects against obesity and adipose tissue inflammation in mice.

BACKGROUND: Costimulatory cascades such as the CD40L-CD40 dyad enhance immune cell activation and inflammation during atherosclerosis. Here, we tested the hypothesis that CD40 directly modulates traits of the metabolic syndrome in diet-induced obesity in mice. METHODS AND RESULTS: To induce the metabolic syndrome, wild-type or CD40(-/-) mice consumed a high-fat diet for 20 weeks. Unexpectedly, CD40(-/-) mice exhibited increased weight gain, impaired insulin secretion, augmented accumulation of inflammatory cells in adipose tissue, and enhanced proinflammatory gene expression. This proinflammatory and adverse metabolic phenotype could be transplanted into wild-type mice by reconstitution with CD40-deficient lymphocytes, indicating a major role for CD40 in T or B cells in this context. Conversely, therapeutic activation of CD40 signaling by the stimulating antibody FGK45 abolished further weight gain during the study, lowered glucose levels, improved insulin sensitivity, and suppressed adipose tissue inflammation. Mechanistically, CD40 activation decreased the expression of proinflammatory cytokines in T cells but not in B cells or macrophages. Finally, repopulation of lymphocyte-free Rag1(-/-) mice with CD40(-/-) T cells provoked dysmetabolism and inflammation, corroborating a protective role of CD40 on T cells in the metabolic syndrome. Finally, levels of soluble CD40 showed a positive association with obesity in humans, suggesting clinical relevance of our findings. CONCLUSIONS: We present the surprising finding that CD40 deficiency on T cells aggravates whereas activation of CD40 signaling improves adipose tissue inflammation and its metabolic complications. Therefore, positive modulation of the CD40 pathway might describe a novel therapeutic concept against cardiometabolic disease.

A novel mouse model of atherosclerotic plaque instability for drug testing and mechanistic/therapeutic discoveries using gene and microRNA expression profiling.

RATIONALE: The high morbidity/mortality of atherosclerosis is typically precipitated by plaque rupture and consequent thrombosis. However, research on underlying mechanisms and therapeutic approaches is limited by the lack of animal models that reproduce plaque instability observed in humans. OBJECTIVE: Development and use of a mouse model of plaque rupture that reflects the end stage of human atherosclerosis. METHODS AND RESULTS: On the basis of flow measurements and computational fluid dynamics, we applied a tandem stenosis to the carotid artery of apolipoprotein E-deficient mice on high-fat diet. At 7 weeks postoperatively, we observed intraplaque hemorrhage in ≈50% of mice, as well as disruption of fibrous caps, intraluminal thrombosis, neovascularization, and further characteristics typically seen in human unstable plaques. Administration of atorvastatin was associated with plaque stabilization and downregulation of monocyte chemoattractant protein-1 and ubiquitin. Microarray profiling of mRNA and microRNA (miR) and, in particular, its combined analysis demonstrated major differences in the hierarchical clustering of genes and miRs among nonatherosclerotic arteries, stable, and unstable plaques and allows the identification of distinct genes/miRs, potentially representing novel therapeutic targets for plaque stabilization. The feasibility of the described animal model as a discovery tool was established in a pilot approach, identifying a disintegrin and metalloprotease with thrombospondin motifs 4 (ADAMTS4) and miR-322 as potential pathogenic factors of plaque instability in mice and validated in human plaques. CONCLUSIONS: The newly described mouse model reflects human atherosclerotic plaque instability and represents a discovery tool toward the development and testing of therapeutic strategies aimed at preventing plaque rupture. Distinctly expressed genes and miRs can be linked to plaque instability.