What if gastrointestinal complications in endurance athletes were gut injuries in response to a high consumption of ultra-processed foods? Please take care of your bugs if you want to improve endurance performance: a narrative review.

To improve performance and recovery faster, athletes are advised to eat more often than usual and consume higher doses of simple carbohydrates, during and after exercise. Sports energetic supplements contain food additives, such as artificial sweeteners, emulsifiers, acidity regulators, preservatives, and salts, which could be harmful to the gut microbiota and impair the intestinal barrier function. The intestinal barrier plays a critical function in bidirectionally regulation of the selective transfer of nutrients, water, and electrolytes, while preventing at the same time, the entrance of harmful substances (selective permeability). The gut microbiota helps to the host to regulate intestinal homeostasis through metabolic, protective, and immune functions. Globally, the gut health is essential to maintain systemic homeostasis in athletes, and to ensure proper digestion, metabolization, and substrate absorption. Gastrointestinal complaints are an important cause of underperformance and dropout during endurance events. These complications are directly related to the loss of gut equilibrium, mainly linked to microbiota dysbiosis and leaky gut. In summary, athletes must be cautious with the elevated intake of ultra-processed foods and specifically those contained on sports nutrition supplements. This review points out the specific nutritional interventions that should be implemented and/or discontinued depending on individual gut functionality.

Hyperfiltration can be detected by transcutaneous assessment of glomerular filtration rate in diabetic obese mice.

We addressed if hyperfiltration can be assessed transcutaneously in male diabetic obese mice (BTBRob/ob) at 12 and 24 wk and how this relates to glomerular parameters indicative for hyperfiltration. Transcutaneous assessment of FITC-Sinistrin clearance [transcutaneous assessment of glomerular filtration rate (tGFR)] was compared against classical plasma clearance. Kidney from SV620C-01-PEI perfused mice were harvested at 24 wk and processed for tissue clearing and classical histology. Perfusion patterns of glomerular capillaries, glomerular size, and vasodilation of the afferent arterioles were assessed. Although at 12 wk FITC-Sinistrin half-life (t1/2) for both tGFR and plasma clearance suggested hyperfiltration, this was not significant anymore at 24 wk. In kidneys of diabetic mice the diameter of the afferent arteriole was significantly larger and positively correlated with glomerular size. Glomerular perfusion pattern in these mice was heterogeneous ranging from non- to well-perfused glomeruli. Nonperfused glomerular areas displayed a strong periodic acid-Schiff's (PAS) positive staining. Collectively our data demonstrate that tGFR is a valid method to detect hyperfiltration. Hyperfiltration occurs early in BTBRob/ob mice and disappears with disease progression as a consequence of a reduced filtration surface. It remains to be assessed if tGFR is also a valid method in diabetic mice with severely compromised renal function.NEW & NOTEWORTHY tGFR measurement is a relatively new method to assess kidney function in conscious rodents, which can be repeated multiple times in the same animal to track the course of the disease and/or the effect of potential treatments. Since the literature was inconclusive on the suitability of this technique in obese mice, we validated it for the first time against classical plasma clearance in the commonly used BTBRob/ob mouse model.

Lipopolysaccharide Tolerance in Human Primary Monocytes and Polarized Macrophages.

Innate immune memory allows macrophages to adequately respond to pathogens to which they have been pre-exposed. To what extent different pattern recognition receptors, cytokines and resolution signals influence innate immune memory needs further elucidation. The present study assessed whether lipopolysaccharide (LPS) tolerance in monocytes and macrophages is affected by these factors. Human CD14+ cells were isolated from peripheral blood, stimulated by LPS and re-stimulated after 3 days of resting. Hereafter, immune-responsive gene 1 (IRG-1), heme oxygenase 1 (HO-1), tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) expression were assessed. Our study revealed the following findings: (1) While pre-stimulation with the Toll-like receptor 4 ligand LPS inhibits the induction of IRG-1, TNF-α and IL-6 expression, pre-stimulation with TLR 1/2 ligands only affects cytokine production but not IRG-1 expression upon subsequent TLR4 engagement. (2) Prior TNF-α stimulation does not affect LPS tolerance but rather increases LPS-mediated cytokine expression. (3) Dimethyl itaconate (DMI) inhibits the expression of IRG-1 in a dose-dependent manner but does not affect TNF-α or IL-6 expression. (4) Docosahexaenoic acid (DHA) partly inhibits IRG-1 expression in monocytes but not in M(IFNγ) and M(IL-4) polarized macrophages. LPS tolerance is not affected in these cells by DHA. The data presented in this study partly corroborate and extend previous findings on innate immune memory and warrant further studies on LPS tolerance to gain a better understanding of innate immune memory at the molecular level.

Adipose-Derived Mesenchymal Stem Cells Protect Endothelial Cells from Hypoxic Injury by Suppressing Terminal UPR In Vivo and In Vitro.

Adipose-derived stem cells (ASCs) have been used as a therapeutic intervention for peripheral artery disease (PAD) in clinical trials. To further explore the therapeutic mechanism of these mesenchymal multipotent stromal/stem cells in PAD, this study was designed to test the effect of xenogeneic ASCs extracted from human adipose tissue on hypoxic endothelial cells (ECs) and terminal unfolded protein response (UPR) in vitro and in an atherosclerosis-prone apolipoprotein E-deficient mice (ApoE-/- mice) hindlimb ischemia model in vivo. ASCs were added to Cobalt (II) chloride-treated ECs; then, metabolic activity, cell migration, and tube formation were evaluated. Fluorescence-based sensors were used to assess dynamic changes in Ca2+ levels in the cytosolic- and endoplasmic reticulum (ER) as well as changes in reactive oxygen species. Western blotting was used to observe the UPR pathway. To simulate an acute-on-chronic model of PAD, ApoE-/- mice were subjected to a double ligation of the femoral artery (DLFA). An assessment of functional recovery after DFLA was conducted, as well as histology of gastrocnemius. Hypoxia caused ER stress in ECs, but ASCs reduced it, thereby promoting cell survival. Treatment with ASCs ameliorated the effects of ischemia on muscle tissue in the ApoE-/- mice hindlimb ischemia model. Animals showed less muscle necrosis, less inflammation, and lower levels of muscle enzymes after ASC injection. In vitro and in vivo results revealed that all ER stress sensors (BIP, ATF6, CHOP, and XBP1) were activated. We also observed that the expression of these proteins was reduced in the ASCs treatment group. ASCs effectively alleviated endothelial dysfunction under hypoxic conditions by strengthening ATF6 and initiating a transcriptional program to restore ER homeostasis. In general, our data suggest that ASCs may be a meaningful treatment option for patients with PAD who do not have traditional revascularization options.

Influence of carnosine and carnosinase-1 on diabetes-induced afferent arteriole vasodilation: implications for glomerular hemodynamics.

Dysregulation in glomerular hemodynamics favors hyperfiltration in diabetic kidney disease (DKD). Although carnosine supplementation ameliorates features of DKD, its effect on glomerular vasoregulation is not known. We assessed the influence of carnosine and carnosinase-1 (CN1) on afferent glomerular arteriole vasodilation and its association with glomerular size, hypertrophy, and nephrin expression in diabetic BTBRob/ob mice. Two cohorts of mice including appropriate controls were studied: i.e., diabetic mice that received oral carnosine supplementation (cohort 1) and human (h)CN1 transgenic (TG) diabetic mice (cohort 2). The lumen area ratio (LAR) of the afferent arterioles and glomerular parameters were measured by conventional histology. Three-dimensional analysis using a tissue clearing strategy was also used. In both cohorts, LAR was significantly larger in diabetic BTBRob/ob versus nondiabetic BTBRwt/ob mice (0.41 ± 0.05 vs. 0.26 ± 0.07, P < 0.0001 and 0.42 ± 0.06 vs. 0.29 ± 0.04, P < 0.0001) and associated with glomerular size (cohort 1: r = 0.55, P = 0.001 and cohort 2: r = 0.89, P < 0.0001). LAR was partially normalized by oral carnosine supplementation (0.34 ± 0.05 vs. 0.41 ± 0.05, P = 0.004) but did not differ between hCN1 TG and wild-type BTBRob/ob mice. In hCN1 TG mice, serum CN1 concentrations correlated with LAR (r = 0.90, P = 0.006). Diabetic mice displayed decreased nephrin expression and increased glomerular hypertrophy. This was not significantly different in hCN1 TG BTBRob/ob mice (P = 0.06 and P = 0.08, respectively). In conclusion, carnosine and CN1 may affect intraglomerular pressure in an opposing manner through the regulation of afferent arteriolar tone. This study corroborates previous findings on the role of carnosine in the progression of DKD.NEW & NOTEWORTHY Dysregulation in glomerular hemodynamics favors hyperfiltration in diabetic kidney disease (DKD). Although carnosine supplementation ameliorates features of DKD, its effect on glomerular vasoregulation is not known. We assessed the influence of carnosine and carnosinase-1 (CN1) on afferent glomerular arteriole vasodilation and its association with glomerular size, hypertrophy, and nephrin expression in diabetic BTBRob/ob mice. Our results provide evidence that carnosine feeding and CN1 overexpression likely affect intraglomerular pressure through vasoregulation of the afferent arteriole.

The viscosity of dilute carbon nanotube (1D) and graphene oxide (2D) nanofluids.

Controlling the physicochemical properties of nanoparticles in fluids directly impacts on their liquid phase processing and applications in nanofluidics, thermal engineering, biomedicine and printed electronics. In this work, the temperature dependent viscosity of various aqueous nanofluids containing carbon nanotubes (CNTs) or graphene oxide (GO), i.e. 1D and 2D nanoparticles with extreme aspect ratios, is analyzed by empirical and predictive physical models. The focus is to understand how the nanoparticle shape, concentration, motion degrees and surface chemistry affect the viscosity of diluted dispersions. To this end, experimental results from capillary viscosimeters are first examined in terms of the energy of viscous flow and the maximum packing fraction applying the Maron-Pierce model. Next, a comparison of the experimental data with predictive physical models is carried out in terms of nanoparticle characteristics that affect the viscosity of the fluid, mostly their aspect ratio. The analysis of intrinsic viscosity data leads to a general understanding of motion modes for carbon nanoparticles, including those with extreme aspect ratios, in a flowing liquid. The resulting universal curve might be extended to the prediction of the viscosity for any kind of 1D and 2D nanoparticles in dilute suspensions.

Capacitive and Charge Transfer Effects of Single-Walled Carbon Nanotubes in TiO2 Electrodes.

The transfer of nanoscale properties from single-walled carbon nanotubes (SWCNTs) to macroscopic systems is a topic of intense research. In particular, inorganic composites of SWCNTs and metal oxide semiconductors are being investigated for applications in electronics, energy devices, photocatalysis, and electroanalysis. In this work, a commercial SWCNT material is separated into fractions containing different conformations. The liquid fractions show clear variations in their optical absorbance spectra, indicating differences in the metallic/semiconducting character and the diameter of the SWCNTs. Also, changes in the surface chemistry and the electrical resistance are evidenced in SWCNT solid films. The starting SWCNT sample and the fractions as well are used to prepare hybrid electrodes with titanium dioxide (SWCNT/TiO2 ). Raman spectroscopy reflects the optoelectronic properties of SWCNTs in the SWCNT/TiO2 electrodes, while the electrochemical behavior is studied by cyclic voltammetry. A selective development of charge transfer characteristics and double-layer behavior is achieved through the suitable choice of SWCNT fractions.

Identification and characterisation of carnostatine (SAN9812), a potent and selective carnosinase (CN1) inhibitor with in vivo activity.

Carnosinase 1 (CN1) has been postulated to be a susceptibility factor for developing diabetic nephropathy (DN). Although its major substrate, carnosine, is beneficial in rodent models of DN, translation of these findings to humans has been hampered by high CN1 activity in human serum resulting in rapid degradation of carnosine. To overcome this hurdle, we screened a protease-directed small-molecule library for inhibitors of human recombinant CN1. We identified SAN9812 as a potent and highly selective inhibitor of CN1 activity with a Ki of 11 nM. It also inhibited CN1 activity in human serum and serum of transgenic mice-overexpressing human CN1. Subcutaneous administration of 30 mg/kg SAN9812 led to a sustained reduction in circulating CN1 activity in human CN1 transgenic (TG) mice. Simultaneous administration of carnosine and SAN9812 increased carnosine levels in plasma and kidney by up to 100-fold compared to treatment-naïve CN1-overexpressing mice. To our knowledge, this is the first study reporting on a potent and selective CN1 inhibitor with in vivo activity. SAN9812, also called carnostatine, may be used to increase renal carnosine concentration as a potential therapeutic modality for renal diseases linked to glycoxidative conditions.

Detection of carnosinase-1 in urine of healthy individuals and patients with type 2 diabetes: correlation with albuminuria and renal function.

Low serum carnosinase (CN-1) concentrations are associated with low risk for development of diabetic nephropathy (DN) in patients with type 2 diabetes (T2D). Although CN-1 is expressed in the kidney, urinary CN-1 (CNU) excretion and its pathological relevance in patients with T2D have not been investigated to date. The present study therefore assessed the extent of CNU excretion in healthy subjects (n = 243) and in patients with T2D (n = 361) enrolled in the DIAbetes and LifEstyle Cohort Twente-1 (DIALECT-1) in relation to functional renal parameters. CNU was detected in a high proportion of healthy individuals, 180 (74%); median CNU excretion was 0.25 mg/24 h [(IQR 0-0.65 mg/24 h]. In patients with T2D the prevalence and extent of CNU increased in parallel with albuminuria (r = 0.59, p < 0.0001; median CNU 0.1 vs 0.2 vs 1.5 mg/24 h, p < 0.0001; prevalence of CNU 61 vs. 81 vs. 97% p < 0.05 in normo- (n = 241), micro- (n = 80) and macroalbuminuria (n = 40), respectively). Patients with estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73 m2 displayed higher median CNU excretion rates in comparison to patients with preserved eGFR (> 90 ml/min/1.73 m2) (1.36 vs 0.13 mg/24 h, p < 0.05). Backward stepwise multivariate linear regression analysis revealed albuminuria, eGFR and glycosuria to be independent factors of CNU excretion rates, all together explaining 37% of variation of CNU excretion rates (R2 = 0.37, p < 0.0001). These results show for the first time that CN-1 can be detected in urine and warrants prospective studies to assess the relevance of CNU for renal function deterioration in diabetes patients.

Carnosinase concentration, activity, and CNDP1 genotype in patients with type 2 diabetes with and without nephropathy.

This study assessed if serum carnosinase (CNDP1) activity and concentration in patients with type 2 diabetes mellitus (T2D) with diabetic nephropathy (DN) differs from those without nephropathy. In a cross-sectional design 127 patients with T2D with DN ((CTG)5 homozygous patients n = 45) and 145 patients with T2D without nephropathy ((CTG)5 homozygous patients n = 47) were recruited. Univariate and multivariate regression analyses were performed to predict factors relevant for serum CNDP1 concentration. CNDP1 (CTG)5 homozygous patients with T2D with DN had significantly lower CNDP1 concentrations (30.4 ± 18.3 vs 51.2 ± 17.6 µg/ml, p < 0.05) and activity (1.25 ± 0.5 vs 2.53 ± 1.1 µmol/ml/h, p < 0.05) than those without nephropathy. This applied for patients with DN on the whole, irrespective of (CTG)5 homozygosity. In the multivariate regression analyses, lower serum CNDP1 concentrations correlated with impaired renal function and to a lesser extend with the CNDP1 genotype (95% CI of regression coefficients: eGFR: 0.10-1.94 (p = 0.001); genotype: - 0.05 to 5.79 (p = 0.055)). Our study demonstrates that serum CNDP1 concentrations associate with CNDP1 genotype and renal function in patients with T2D. Our data warrant further studies using large cohorts to confirm these findings and to delineate the correlation between low serum CNDP1 concentrations and renal function deterioration in patients with T2D.

The Cholinergic Anti-Inflammatory Pathway as a Conceptual Framework to Treat Inflammation-Mediated Renal Injury.

BACKGROUND: The cholinergic anti-inflammatory pathway, positioned at the interface of the nervous and immune systems, is the efferent limb of the "inflammatory reflex" which mainly signals through the vagus nerve. As such, the brain can modulate peripheral inflammatory responses by the activation of vagal efferent fibers. Importantly, immune cells in the spleen express most cholinergic system components such as acetylcholine (ACh), choline acetyltransferase, acetylcholinesterase, and both muscarinic and nicotinic ACh receptors, making communication between both systems possible. In general, this communication down-regulates the inflammation, achieved through different mechanisms and depending on the cells involved. SUMMARY: With the awareness that the cholinergic anti-inflammatory pathway serves to prevent or limit inflammation in peripheral organs, vagus nerve stimulation has become a promising strategy in the treatment of several inflammatory conditions. Both pharmacological and non-pharmacological methods have been used in many studies to limit organ injury as a consequence of inflammation. Key Messages: In this review, we will highlight our current knowledge of the cholinergic anti-inflammatory pathway, with emphasis on its potential clinical use in the treatment of inflammation-triggered kidney injury.

Combined immunotherapy encompassing intratumoral poly-ICLC, dendritic-cell vaccination and radiotherapy in advanced cancer patients.

Background: Combination immunotherapy has the potential to achieve additive or synergistic effects. Combined local injections of dsRNA analogues (mimicking viral RNA) and repeated vaccinations with tumor-lysate loaded dendritic cells shows efficacy against colon cancer mouse models. In the context of immunotherapy, radiotherapy can exert beneficial abscopal effects. Patients and methods: In this two-cohort pilot phase I study, 15 advanced cancer patients received two 4-week cycles of four intradermal daily doses of monocyte-derived dendritic cells preloaded with autologous tumor lysate and matured for 24 h with poly-ICLC (Hiltonol), TNF-α and IFN-α. On days +8 and +10 of each cycle, patients received intratumoral image-guided 0.25 mg injections of the dsRNA-analogue Hiltonol. Cyclophosphamide 600 mg/m2 was administered 1 week before. Six patients received stereotactic ablative radiotherapy (SABR) on selected tumor lesions, including those injected with Hiltonol. Expression of 25 immune-relevant genes was sequentially monitored by RT-PCR on circulating peripheral blood mononuclear cell (PBMCs) and serum concentrations of a cytokine panel were sequentially determined before and during treatment. Pre- and post-treatment PBMC from patients achieving durable stable disease (SD) were studied by IFNγ ELISPOT-assays responding to tumor-lysate loaded DC and by TCRß sequencing. Results: Combined treatment was, safe and well tolerated. One heavily pretreated castration-resistant prostate cancer patient experienced a remarkable mixed abscopal response to SABR+ immunotherapy. No objective responses were observed, while nine patients presented SD (five of them in the six-patient radiotherapy cohort). Intratumoral Hiltonol increased IFN-ß and IFN-α mRNA in circulating PBMC. DC vaccination increased serum IL-12 and IL-1ß concentrations, especially in patients presenting SD. IFNγ-ELISPOT reactivity to tumor lysates was observed in two patients experiencing durable SD. Conclusions: This radio-immunotherapy combination strategy, aimed at resembling viral infection in tumor tissue in combination with a dendritic-cell vaccine and SABR, is safe and shows immune-associated activity and signs of preliminary clinical efficacy.

Carnosine Catalyzes the Formation of the Oligo/Polymeric Products of Methylglyoxal.

BACKGROUND/AIMS: Reactive dicarbonyl compounds, such as methylglyoxal (MG), contribute to diabetic complications. MG-scavenging capacities of carnosine and anserine, which have been shown to mitigate diabetic nephropathy, were evaluated in vitro and in vivo. METHODS: MG-induced cell toxicity was characterized by MTT and MG-H1-formation, scavenging abilities by Western Blot and NMR spectroscopies, cellular carnosine transport by qPCR and microplate luminescence and carnosine concentration by HPLC. RESULTS: In vitro, carnosine and anserine dose-dependently reduced N-carboxyethyl lysine (CEL) and advanced glycation end products (AGEs) formation. NMR studies revealed the formation of oligo/polymeric products of MG catalyzed by carnosine or anserine. MG toxicity (0.3-1 mM) was dose-dependent for podocytes, tubular and mesangial cells whereas low MG levels (0.2 mM) resulted in increased cell viability in podocytes (143±13%, p<0.001) and tubular cells (129±3%, p<0.001). Incubation with carnosine/anserine did not reduce MG-induced toxicity, independent of incubation times and across large ranges of MG to carnosine/anserine ratios. Cellular carnosine uptake was low (<0.1% in 20 hours) and cellular carnosine concentrations remained unaffected. The putative carnosine transporter PHT1 along with the taurine transporter (TauT) was expressed in all cell types while PEPT1, PEPT2 and PHT2, also belonging to the proton-coupled oligopeptide transporter (POT) family, were only expressed in tubular cells. CONCLUSION: While carnosine and anserine catalyze the formation of MG oligo/polymers, the molar ratios required for protection from MG-induced cellular toxicity are not achievable in renal cells. The effect of carnosine in vivo, to mitigate diabetic nephropathy may therefore be independent upon its ability to scavenge MG and/or carnosine is mainly acting extracellularly.

Donor Dopamine Does Not Affect Liver Graft Survival: Evidence of Safety From a Randomized Controlled Trial.

Treatment of donation after brain death (DBD) donors with low-dose dopamine improves the outcomes after kidney and heart transplantation. This study investigates the course of liver allografts from multiorgan donors enrolled in the randomized dopamine trial between 2004 and 2007 (clinicaltrials.gov identifier: NCT00115115). There were 264 hemodynamically stable DBDs who were randomly assigned to receive low-dose dopamine. Dopamine was infused at 4 µg/kg/minute for a median duration of 6.0 hours (interquartile range, 4.4-7.5 hours). We assessed the outcomes of 212 liver transplantations (LTs) performed at 32 European centers. Donors and recipients of both groups were very similar in baseline characteristics. Pretransplant laboratory Model for End-Stage Liver Disease score was not different in recipients of a dopamine-treated versus untreated graft (18 ± 8 versus 20 ± 8; P = 0.12). Mean cold ischemia time was 10.6 ± 2.9 versus 10.1 ± 2.8 hours (P = 0.24). No differences occurred in biopsy-proven rejection episodes (14.4% versus 15.7%; P = 0.85), requirement of hemofiltration (27.9% versus 31.5%; P = 0.65), the need for early retransplantation (5.8% versus 6.5%; P > 0.99), the incidence of primary nonfunction (7.7% versus 8.3%; P > 0.99), and in-hospital mortality (15.4% versus 14.8%; P > 0.99). Graft survival was 71.2% versus 73.2% and 59.6% versus 62.0% at 2 and 3 years (log-rank P = 0.71). Patient survival was 76.0% versus 78.7% and 65.4% versus 69.4% at 1 and 3 years (log-rank P = 0.50). In conclusion, donor pretreatment with dopamine has no short-term or longterm effects on outcome after LT. Therefore, low-dose dopamine pretreatment can safely be implemented as the standard of care in hemodynamically stable DBDs.

Dopamine in transplantation: Written off or comeback with novel indication?

Renal-dose dopamine has fallen out of favor in the intensive care unit (ICU) during past years due to its ineffectiveness to prevent impending or to ameliorate overt renal failure in the critically ill. By contrast, growing evidence indicates that low-dose dopamine administered to the stable organ donor after brain death confirmation improves the clinical course of transplanted organs after kidney and heart transplantation. Ensuring a thorough monitoring for potential circulatory side effects, employment of dopamine at a dose of 4 µg/kg/min is safe in the deceased donor. Among recipients, the advantageous effect is easy to achieve, inexpensive, and devoid of adverse side effects. The mode of action relies on dopamine's propensity to mitigate injury in various cell systems from isolated transplantable organs under cold storage conditions. The present review article summarizes the clinical evidence of dopamine donor pretreatment in solid organ transplantation and focuses on the underlying molecular mechanisms of cellular protection. Introducing the routine use of low-dose dopamine for the management of the brain-dead donor in the ICU before procurement provides an evidence-based strategy to improve graft outcome after kidney transplantation without conferring harm to non-renal grafts, namely to livers and hearts, in cases of multi-organ donation.

Trend differences in men and women in rural and urban U.S. settings.

BACKGROUND: Smoking prevalence is declining at a slower rate in rural than urban settings in the United States (U.S.), and known predictors of smoking do not readily account for this trend difference. Given that socioeconomic and psychosocial determinants of health disparities accumulate in rural settings and that life-course disadvantages are often greater in women than men, we examined whether smoking trends are different for rural and urban men and women. METHOD: We used yearly cross-sectional data (n = 303,311) from the U.S. National Survey on Drug Use and Health (NSDUH) from 2007 through 2014 to compare cigarette smoking trends in men and women across rural and urban areas. Current smoking status was modelled using logistic regression controlling for confounding risk factors. RESULTS: Regression derived graphs predicting unadjusted prevalence estimates and 95% confidence bands revealed that whereas the smoking trends of rural men, urban men, and urban women significantly declined from 2007 to 2014, the trend for rural women was flat. Controlling for demographic, socioeconomic and psychosocial predictors of smoking did not explain rural women's significantly different trend from those of the other three groups. CONCLUSION: Rural women lag behind rural men, urban men and urban women in decreasing smoking, a health disparity finding that supports the need for tobacco control and regulatory policies and interventions that are more effective in reducing smoking among rural women.

The adenosinergic system: a potential player in the pathogenesis of ANCA-associated vasculitis?

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a potentially lethal autoimmune disease whose pathology comprises disturbed T cell differentiation and functionality accompanied by dysfunctional autoreactive immunoglobulin development, culminating in destructive innate immune response as well. Purines, adenine nucleotides and adenosine in particular, have been elucidated as potent extracellular mediators for fine adjustment of these pivotal processes establishing human immunity. Therefore, the extracellular purinergic microenvironment is under control of ectonucleotidases CD39 and CD73 degrading pro-inflammatory adenosine triphosphate (ATP) to anti-inflammatory adenosine as well as adenosine deaminase bound to CD26 deactivating adenosine. Accordingly, the ATP P2X7 receptor was elicited to be responsible for promotion of inflammation, while predominantly the adenosine A2A receptor demonstrated the opposite. Recent reports pointed at the adenosinergic system to be crucially involved in AAV pathogenesis. Here, experimental evidence on ecto-enzymes controlling extracellular adenine nucleotide concentrations and purinergic signaling in the immune system with respect to its contribution to the AAV pathomechanism is reviewed besides unsolved problems being identified that require further investigation in order to develop new treatment strategies for AAV.

A growing geographic disparity: Rural and urban cigarette smoking trends in the United States.

Rural areas of the United States have a higher smoking prevalence than urban areas. However, no recent studies have rigorously examined potential changes in this disparity over time or whether the disparity can be explained by demographic or psychosocial characteristics associated with smoking. The present study used yearly cross sectional data from the National Survey on Drug Use and Health from 2007 through 2014 to examine cigarette smoking trends in rural versus urban areas of the United States. The analytic sample included 303,311 respondents. Two regression models were built to examine (a) unadjusted rural and urban trends in prevalence of current smoking and (b) whether differences remained after adjusting for demographic and psychosocial characteristics. Results of the unadjusted model showed disparate and diverging cigarette use trends during the 8-year time period. The adjusted model also showed diverging trends, initially with no or small differences that became more pronounced across the 8-year period. We conclude that differences reported in earlier studies may be explained by differences in rural versus urban demographic and psychosocial risk factors, while more recent and growing disparities appear to be related to other factors. These emergent differences may be attributable to policy-level tobacco control and regulatory factors that disproportionately benefit urban areas such as enforcement of regulations around the sale and marketing of tobacco products and treatment availability. Strong federal policies and targeted or tailored interventions may be important to expanding tobacco control and regulatory benefits to vulnerable populations including rural Americans.

Cardiovascular Risk Factors in Cluster Headache.

Background: Patients with cluster headache tend to have a dysregulation of systemic blood pressure such as increased blood pressure variability and decreased nocturnal dipping. This pattern of nocturnal nondipping is associated with end-organ damage and increased risk of cardiovascular disease. Objective: To determine if cluster headache is associated with a higher risk of cardiovascular disease. Methods: Cross-sectional study of 33 cluster headache patients without evidence of cardiovascular disease and 30 age- and gender-matched healthy controls. Ambulatory blood pressure monitoring was performed in all subjects. We evaluate anthropometric, hematologic, and structural parameters (carotid intima-media thickness and ankle-brachial index). Results: Of the 33 cluster headache patients, 16 (48.5%) were nondippers, a higher percentage than expected. Most of the cluster headache patients (69.7%) also presented a pathological ankle-brachial index. In terms of the carotid intima-media thickness values, 58.3% of the patients were in the 75th percentile, 25% were in the 90th percentile, and 20% were in the 95th percentile. In the control group, only five of the 30 subjects (16.7%) had a nondipper pattern ( P = 0.004), with 4.54% in the 90th and 95th percentiles ( P = 0.012 and 0.015). Conclusions: Compared with healthy controls, patients with cluster headache presented a high incidence (48.5%) of nondipper pattern, pathological ankle-brachial index (69.7%), and intima-media thickness values above the 75th percentile. These findings support the hypothesis that patients with cluster headache present increased risk of cardiovascular disease.

Medical Student Perspectives of Active Learning: A Focus Group Study.

Phenomenon: Medical student perspectives were sought about active learning, including concerns, challenges, perceived advantages and disadvantages, and appropriate role in the educational process. APPROACH: Focus groups were conducted with students from all years and campuses of a large U.S. state medical school. FINDINGS: Students had considerable experience with active learning prior to medical school and conveyed accurate understanding of the concept and its major strategies. They appreciated the potential of active learning to deepen and broaden learning and its value for long-term professional development but had significant concerns about the efficiency of the process, the clarity of expectations provided, and the importance of receiving preparatory materials. Most significantly, active learning experiences were perceived as disconnected from grading and even as impeding preparation for school and national examinations. Insights: Medical students understand the concepts of active learning and have considerable experience in several formats prior to medical school. They are generally supportive of active learning concepts but frustrated by perceived inefficiencies and lack of contribution to the urgencies of achieving optimal grades and passing United States Medical Licensing Examinations, especially Step 1.