Objective. It remains a matter of debate whether TNF-α antagonists have favourable effects on the cardiovascular (CV) system. This systematic review evaluates the effect of TNF-α blockers on the ...progression of subclinical atherosclerosis and arterial stiffness in patients with inflammatory arthritis.
Methods. A search of the MEDLINE and Web of Knowledge databases was conducted to identify studies into the effect of TNF-α antagonists on subclinical atherosclerosis and arterial stiffness in patients with RA, AS and PsA. Carotid intima–media thickness (cIMT) was used to assess subclinical atherosclerosis. Two methods were used to assess arterial stiffness: pulse wave velocity (PWV) and aortic augmentation index (AIx). Twenty-three studies matching the search criteria were included for analysis.
Results. TNF-α blockers probably are effective in preventing (7/13 studies) or even reversing (5/13 studies) the progression of IMT in patients with RA, AS and PsA who are responding to treatment. With regard to arterial stiffness, PWV was either significantly reduced (7/13 studies) or remained unchanged (6/13 studies) following TNF-α antagonist treatment. Nonetheless, most studies in RA (7/10) reported significant improvement of PWV. AIx remained unchanged in 10 of 13 studies.
Conclusion. The balance of evidence suggests that TNF-α antagonists may have a beneficial effect on preventing the progression of subclinical atherosclerosis and arterial stiffness. It remains unknown whether this effect is specific to TNF-α antagonists or relates to better control of inflammation irrespective of the disease modification strategy by which this is achieved.
Cell-to-cell communication and long-distance signaling play a key role in the response of plants to pests, mechanical wounding, and extreme environmental conditions. Here, we report on a rapid ...systemic signal in Arabidopsis thaliana that traveled at a rate of 8.4 centimeters per minute and was dependent on the respiratory burst oxidase homolog D (RbohD) gene. Signal propagation was accompanied by the accumulation of reactive oxygen species (ROS) in the extracellular spaces between cells and was inhibited by the suppression of ROS accumulation at locations distant from the initiation site. The rapid systemic signal was triggered by wounding, heat, cold, high-intensity light, and salinity stresses. Our results reveal the profound role that ROS play in mediating rapid, long-distance, cell-to-cell propagating signals in plants.
Dendritic cells (DCs), monocytes, macrophages, and neutrophils are myeloid-derived phagocytes critical to controlling bacterial infections, and these cells have complementary functions to ensure host ...survival. Recent data have shed light on the dynamics and function of myeloid cells at the early stage of infection. In particular, murine infection models with Salmonella enterica serovar Typhimurium have been useful for understanding the host response required to develop immunity to systemic salmonellosis. This review summarizes the early cellular responses in the intestinal lymphoid tissues to Salmonella and discusses Peyer's patch-dependent and -independent penetration of bacteria through the intestinal epithelium. Once Salmonella accesses host tissue, phagocytes respond by recruitment, redistribution, and activation in intestinal tissues. Recruited monocytes are specialized in controlling bacterial replication by producing anti-microbial molecules but are poor antigen-presenting cells. In contrast, DCs undergo maturation by direct (bacteria-mediated) and indirect (cytokine-mediated) pathways in vivo to optimize their antigen presentation capacity, and directly matured DCs have unique mechanisms to ensure T-cell stimulation. Toll-like receptor signaling is critical to DC maturation and myeloid cell recruitment during Salmonella infection, and the role of myeloid differentiation factor 88 (MyD88)-dependent and MyD88-independent pathways as well as proinflammatory cytokines and type 1 interferons in these processes are discussed.
While a primary genital tract infection with C. trachomatis stimulates partial-protection against re-infection, it may also result in severe inflammation and tissue destruction. Here we have ...dissected whether functional compartments exist in the genital tract that restrict Th1-mediated protective immunity. Apart from the Th1-subset, little is known about the role of other CD4(+) T cell subsets in response to a genital tract chlamydial infection. Therefore, we investigated CD4(+) T cell subset differentiation in the genital tract using RT-PCR for expression of critical transcription factors and cytokines in the upper (UGT) and lower genital tract (LGT) of female C57BL/6 mice in response to C. trachomatis serovar D infection. We found that the Th1 subset dominated the UGT, as IFN-γ and T-bet mRNA expression were high, while GATA-3 was low following genital infection with C. trachomatis serovar D. By contrast, IL-10 and GATA-3 mRNA dominated the LGT, suggesting the presence of Th2 cells. These functional compartments also attracted regulatory T cells (Tregs) differently as increased FoxP3 mRNA expression was seen primarily in the UGT. Although IL-17A mRNA was somewhat up-regulated in the LGT, no significant change in RORγ-t mRNA expression was observed, suggesting no involvement of Th17 cells. The dichotomy between the LGT and UGT was maintained during infection by IL-10 because in IL-10-deficient mice the distinction between the two compartments was completely lost and a dramatic shift to the predominance of Th1 cells in the LGT occurred. Unexpectedly, the major source of IL-10 was CD11c(+) CD11b(+) DC, probably creating an anti-inflammatory privileged site in the LGT.
A dominant appetite for protein drives increased energy intake in humans when the proportion of protein in the diet is reduced down to approximately 10% of total energy. Compensatory feeding for ...protein is apparent over a 1–2 d period but the mechanisms driving this regulation are not fully understood. Fibroblast growth factor-21 (FGF-21) has been identified as a candidate protein signal as levels increase in the circulation when dietary protein is low. The aim of this randomised controlled trial was to assess whether changes in percent dietary protein over a 4 d ad libitum experimental period in lean, healthy participants influenced energy intake, metabolic health, circulating FGF-21 and appetite regulating hormones including ghrelin, glucagon like peptide-1 and cholecystokinin. Twenty-two lean, healthy participants were fed ad libitum diets containing 10, 15 and 25% protein, over three, 4 d controlled, in-house experimental periods. Reduced dietary protein intake from 25% to 10% over a period of 4 d was associated with 14% increased energy intake (p = 0.02) as previously reported, and a 6-fold increase in fasting circulating plasma FGF-21 levels (p<0.0001), a 1.5-fold increase in serum triglycerides (p<0.0001), and a 0.9-fold decrease in serum total cholesterol (p = 0.02). Serum HDL cholesterol was reduced with a reduction in dietary protein from 15% to 10% (p = 0.01) over 4 d but not from 25% to 10% (p = 0.1) and the change from baseline was not different between diets. Plasma fasting insulin levels following the 4 d study period were significantly lower following the 25% ad libitum study period compared to the 15% protein period (p = 0.014) but not the 10% protein period (p = 0.2). Variability in interstitial glucose during each study period increased with a decrease in dietary protein from 25% to 15% and 10% (p = 0.001 and p = 0.04, respectively). Ghrelin, glucagon-like peptide-1 and cholecystokinin were unchanged. Increases in energy intake, plasma FGF-21 and serum triglycerides were associated with reductions in percent dietary protein from 25% to 10% energy over a 4 d ad libitum in-house feeding period and may be important in regulation of dietary protein intake.
Australia New Zealand Clinical Trials Registry ACTRN12616000144415.
Inflammatory bowel disease (IBD) is prevalent, but the mechanisms underlying disease development remain elusive. We identify a role for the E3 ubiquitin ligase RNF5 in IBD. Intestinal epithelial ...cells (IECs) express a high level of RNF5, while the colon of Rnf5−/− mice exhibits activated dendritic cells and intrinsic inflammation. Rnf5−/− mice exhibit severe acute colitis following dextran sodium sulfate (DSS) treatment. S100A8 is identified as an RNF5 substrate, resulting in S100A8 ubiquitination and proteasomal-dependent degradation that is attenuated upon inflammatory stimuli. Loss of RNF5 from IECs leads to enhanced S100A8 secretion, which induces mucosal CD4+ T cells, resulting in Th1 pro-inflammatory responses. Administration of S100A8-neutralizing antibodies to DSS-treated Rnf5−/− mice attenuates acute colitis development and increases survival. An inverse correlation between RNF5 and S100A8 protein expression in IECs of IBD patients coincides with disease severity. Collectively, RNF5-mediated regulation of S100A8 stability in IECs is required for the maintenance of intestinal homeostasis.
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•Severe intestinal inflammation resembling acute colitis in DSS-treated Rnf5−/− mice•RNF5 regulates S100A8 stability and pro-inflammatory responses•Neutralizing S100A8 antibodies attenuate acute colitis in DSS-treated Rnf5−/− mice•Inverse expression of RNF5 and S100A8 in IBD patients coincides with disease severity
Fujita et al. show that RNF5 regulation of S100A8 stability in intestinal epithelial cells defines the degree of pro-inflammatory response, culminating in severe intestinal inflammation following DSS treatment to Rnf5−/− mice. Neutralizing S100A8 antibodies attenuates acute colitis phenotypes, and inverse RNF5/S100A8 expression coincides with clinical severity in IBD patients.
AKT signaling is important for proliferation and survival of tumor cells. The clinical significance of AKT activation in diffuse large B-cell lymphoma (DLBCL) is not well analyzed. Here, we assessed ...expression of phosphorylated AKT (p-AKT) in 522 DLBCL patients. We found that high levels of p-AKT nuclear expression, observed in 24.3% of the study cohort, were associated with significantly worse progression-free survival and Myc and Bcl-2 overexpression. However, multivariate analysis indicated that AKT hyperactivation was not an independent factor. miRNA profiling analysis demonstrated that 63 miRNAs directly or indirectly related to the phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin pathway were differentially expressed between DLBCLs with high and low p-AKT nuclear expression. We further targeted AKT signaling using a highly selective AKT inhibitor MK-2206 in 26 representative DLBCL cell lines and delineated signaling alterations using a reverse-phase protein array. MK-2206 treatment inhibited lymphoma cell viability, and MK-2206 sensitivity correlated with AKT activation status in DLBCL cells. On MK-2206 treatment, p-AKT levels and downstream targets of AKT signaling were significantly decreased, likely because of the decreased feedback repression; Rictor and phosphatidylinositol 3-kinase expression and other compensatory pathways were also induced. This study demonstrates the clinical and therapeutic implications of AKT hyperactivation in DLBCL and suggests that AKT inhibitors need to be combined with other targeted agents for DLBCL to achieve optimal clinical efficacy.
The orosensory responses elicited by nicotine are relevant for the development and maintenance of addiction to tobacco products. However, although nicotine is described as bitter tasting, the ...molecular and neural substrates encoding the taste of nicotine are unclear. Here, rats and mice were used to determine whether nicotine activates peripheral and central taste pathways via TRPM5-dependent mechanisms, which are essential for responses to other bitter tastants such as quinine, and/or via nicotinic acetylcholine receptors (nAChRs). When compared with wild-type mice, Trpm5⁻/⁻ mice had reduced, but not abolished, chorda tympani (CT) responses to nicotine. In both genotypes, lingual application of mecamylamine, a nAChR-antagonist, inhibited CT nerve responses to nicotine and reduced behavioral responses of aversion to this stimulus. In accordance with these findings, rats were shown to discriminate between nicotine and quinine presented at intensity-paired concentrations. Moreover, rat gustatory cortex (GC) neural ensemble activity could also discriminate between these two bitter tastants. Mecamylamine reduced both behavioral and GC neural discrimination between nicotine and quinine. In summary, nicotine elicits taste responses through peripheral TRPM5-dependent pathways, common to other bitter tastants, and nAChR-dependent and TRPM5-independent pathways, thus creating a unique sensory representation that contributes to the sensory experience of tobacco products.
Systolic (Sa) and diastolic (Ea) myocardial velocities measured by tissue Doppler (TD) imaging (TDI) recently were shown to be decreased in subjects who have mutations causing hypertrophic ...cardiomyopathy (HCM) but who do not have left ventricular (LV) hypertrophy. By studying these subjects at a later date, we sought to determine whether TDI predicts the subsequent evolution of the HCM phenotype.
Serial 2D and Doppler echocardiography were performed in 12 subjects (age range, 17 to 51 years) with HCM-causing mutations on 2 occasions: before development of hypertrophy and 2 years later. Twelve age- and gender-matched family members without mutations were included as control subjects. In those with mutations, mean septal thickness and LV mass were 1.07+/-0.14 cm and 103.0+/-11 g at baseline, respectively, and increased to 1.30+/-0.36 cm and 193.0+/-78 g at follow-up (P<0.01), with 6 subjects satisfying HCM diagnostic criteria. Sa and Ea velocities in those with mutations were lower compared with control subjects at baseline and follow-up (lateral Sa, 15+/-1.2 versus 8.2+/-2.1 cm/s; lateral Ea, 16.5+/-2.8 versus 8.1+/-2.3 cm/s; P<0.01). At 2 years, left atrial volume and pulmonary venous flow indices of LV filling pressures increased, whereas TD early and late diastolic velocities decreased (all P<0.05) in those with the mutations. Control subjects had no significant interval changes of the above parameters.
Subsequent development of HCM in subjects with initially reduced TD velocities establishes TDI as a reliable method for early identification of HCM mutation carriers.
Infantile epileptic spasm syndrome (IESS) is an age-dependent epileptic encephalopathy with a significant risk of developmental regression. This study investigates the association between heart rate ...variability (HRV) in infants at risk of IESS and the clinical onset of IESS.
Sixty neonates at risk of IESS were prospectively followed from birth to 12 months with simultaneous electroencephalogram (EEG) and electrocardiogram recordings for 60 min at every 2-month interval. HRV metrics were calculated from 5 min time-epoch during sleep including frequency domain measures, Poincare analysis including cardiac vagal index (CVI) and cardiac sympathetic index (CSI), and detrended fluctuation analysis (DFA α1, DFA α2). To assess the effect of each HRV metric at the 2-month baseline on the time until the first occurrence of either hypsarrhythmia on EEG and/or clinical spasm, univariate cox-proportional hazard models were fitted for each HRV metric.
Infantile epileptic spasm syndrome was diagnosed in 20/60 (33%) of the cohort in a 12-month follow-up and 3 (5%) were lost to follow-up. The median age of developing hypsarrhythmia was 25 (7-53) weeks and clinical spasms at 24 (8-40) weeks. Three (5%) patients had clinical spasms without hypsarrhythmia, and 5 (8%) patients had hypsarrhythmia before clinical spasms at the initial presentation. The infants with high CSI (hazard ratio 2.5, 95% CI 1.2-5.2,
= 0.01) and high DFA α1 (hazard ratio 16, 95% CI 1.1-240,
= 0.04) at 2 months were more likely to develop hypsarrhythmia by the first year of age. There was a trend toward decreasing CSI and DFA α1 and increasing CVI in the first 8 months of age.
Our data suggest that relative sympathetic predominance at an early age of 2 months may be a potential predictor for developing IESS. Hence, early HRV patterns may provide valuable prognostic information in children at risk of IESS allowing early detection and optimization of cognitive outcomes. Whether early intervention to restore sympathovagal balance
would provide clinical benefit must be addressed by future studies.
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