Developmental Changes in Hemodynamic Responses and Cardiovagal Modulation during Isometric Handgrip Exercise

The purpose of this study was to examine differences in pressor response and cardiovagal modulation during isometric handgrip exercise (IHG) between children and adults. Beat-to-beat heart rate (HR) and blood pressure were measured in 23 prepubertal children and 23 adults at baseline and during IHG. Cardiovagal modulation was quantified by analysis of HR variability. Mean arterial pressure responses to IHG were greater in adults compared to children (P < .05) whereas there were no group differences in HR responses (P > .05). Children had a greater reduction in cardiovagal modulation in response to IHG compared to adults (P < .05). Changes in mean arterial pressure during IHG were correlated with baseline cardiovagal modulation and force produced during isometric contraction (P < .05). In conclusion, differences in pressor reflex response between children and adults cannot be solely explained by differences in autonomic modulation and appear to be associated with factors contributing to the force produced during isometric contraction

Toll-like receptor 9 activation: a novel mechanism linking placenta-derived mitochondrial DNA and vascular dysfunction in pre-eclampsia

Emerging evidence suggests that in addition to being the 'power houses' of our cells, mitochondria facilitate effector responses of the immune system. Cell death and injury result in the release of mtDNA (mitochondrial DNA) that acts via TLR9 (Toll-like receptor 9), a pattern recognition receptor of the immune system which detects bacterial and viral DNA but not vertebrate DNA. The ability of mtDNA to activate TLR9 in a similar fashion to bacterial DNA stems from evolutionarily conserved similarities between bacteria and mitochondria. mtDNA may be the trigger of systemic inflammation in pathologies associated with abnormal cell death. PE (pre-eclampsia) is a hypertensive disorder of pregnancy with devastating maternal and fetal consequences. The aetiology of PE is unknown and removal of the placenta is the only effective cure. Placentas from women with PE show exaggerated necrosis of trophoblast cells, and circulating levels of mtDNA are higher in pregnancies with PE. Accordingly, we propose the hypothesis that exaggerated necrosis of trophoblast cells results in the release of mtDNA, which stimulates TLR9 to mount an immune response and to produce systemic maternal inflammation and vascular dysfunction that lead to hypertension and IUGR (intra-uterine growth restriction). The proposed hypothesis implicates mtDNA in the development of PE via activation of the immune system and may have important preventative and therapeutic implications, because circulating mtDNA may be potential markers of early detection of PE, and anti-TLR9 treatments may be promising in the management of the disease.National Institutes of HealthNational Institutes of Health [R01 HL071138, R01 DK083685, T32 HL066993-09]Society for Womens Health ResearchSociety for Women's Health ResearchNaito Foundation JapanNaito Foundation Japa

Gender differences in elite athletes heart rate dynamics following a supra maximal complex effort

Regarding the importance of recovery in sport performance, assessment of postexercise Heart Rate (HR) Dynamics has become a useful tool to understand such an individual process. Heart Rate Variability (HRV) analysis is widely used as a non-invasive marker of Autonomic Nervous System regulation of HR, where the nonlinear methods (Detrended Fluctuation Analysis (DFA)) have become a promising complementary analysis technique. In order to deepen on the effects of supra maximal complex efforts, integrating specific endurance and strength requirements on cardiac autonomic regulation, our research group is working in different protocols looking for the analysis of specific responses under supra maximal exertion. Therefore, our purpose was to analyze the immediate 10 min recovery timeline following a supra maximal specific Judo test in twenty-four judokas from the Spanish National Team (16 males and 8 females, 24.40 ± 0.97 years), deepening on gender differences. Consistent with previous research on supra maximal protocols, both HRV indices and Short-Term Scaling Exponent (α1), stemmed from DFA, appeared severely depressed after the test. Moreover, a negative correlation was found between final isometric pull-up drill and both lnTP (r=-0.457; p<0.05) and lnLF (r=-0.496; p<0.05), thus suggesting a crucial role for isometric strength requirements in cardiac autonomic recovery after exercise. At the same time, while performance showed a large gender difference (p<0.05; d=0.90), no significant gender differences were found either in HRV indices or in α1 . However, when analyzing distance scores to optimal value of α1 =1 (|1- α1|), men displayed significantly greater results, thus implying an improved recovery ability. Eventually, our results corroborate that nonlinear methods, compared to linear HRV indices, are capable of detecting subtler changes in HR behaviour

Caspase-3 dependent nitrergic neuronal apoptosis following cavernous nerve injury is mediated via RhoA and ROCK activation in major pelvic ganglion

Axonal injury due to prostatectomy leads to Wallerian degeneration of the cavernous nerve (CN) and erectile dysfunction (ED). Return of potency is dependent on axonal regeneration and reinnervation of the penis. Following CN injury (CNI), RhoA and Rho-associated protein kinase (ROCK) increase in penile endothelial and smooth muscle cells. Previous studies indicate that nerve regeneration is hampered by activation of RhoA/ROCK pathway. We evaluated the role of RhoA/ROCK pathway in CN regulation following CNI using a validated rat model. CNI upregulated gene and protein expression of RhoA/ROCK and caspase-3 mediated apoptosis in the major pelvic ganglion (MPG). ROCK inhibitor (ROCK-I) prevented upregulation of RhoA/ROCK pathway as well as activation of caspase-3 in the MPG. Following CNI, there was decrease in the dimer to monomer ratio of neuronal nitric oxide synthase (nNOS) protein and lowered NOS activity in the MPG, which were prevented by ROCK-I. CNI lowered intracavernous pressure and impaired non-adrenergic non-cholinergic-mediated relaxation in the penis, consistent with ED. ROCK-I maintained the intracavernous pressure and non-adrenergic non-cholinergic-mediated relaxation in the penis following CNI. These results suggest that activation of RhoA/ROCK pathway mediates caspase-3 dependent apoptosis of nitrergic neurons in the MPG following CNI and that ROCK-I can prevent post-prostatectomy ED

Co-evolution of NK receptors and HLA ligands in humans is driven by reproduction.

Allogeneic individuals co-exist during pregnancy in eutherian mammals. Maternal and fetal cells intermingle at the site of placental attachment in the uterus, where the arteries are remodeled to supply the fetus with oxygen and nutrients. This access by placental cells to the maternal supply line determines the growth and birth weight of the baby and is subject to stabilizing selection. Invading placental trophoblast cells express human leukocyte antigen class I ligands (HLA-E, HLA-G, and HLA-C) for receptors on maternal uterine natural killer (NK) and myelomonocytic cells, CD94/NKG2, leukocyte immunoglobulin-like receptor (LILR), and killer immunoglobulin receptor (KIR). Of these, only the KIR/HLA-C system is highly polymorphic. Different combinations of maternal KIR and fetal HLA-C variants are correlated with low birth weight and pre-eclampsia or high birth weight and obstructed labor, the two extremes of the obstetric dilemma. This situation has arisen because of the evolution of bipedalism and subsequently, in the last million years, larger brains. At this point, the human system began to reach a balance between KIR A and KIR B haplotypes and C1 and C2 epitopes of HLA-C alleles that reflects a functional compromise between the competing demands of immunity and reproduction.We are grateful for financial support from Centre for Trophoblast Research, University of Cambridge, King's College, Cambridge, and the Wellcome Trust.This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1111/imr.1232

Changes in T Cell and Dendritic Cell Phenotype from Mid to Late Pregnancy Are Indicative of a Shift from Immune Tolerance to Immune Activation.

During pregnancy, the mother allows the immunologically distinct fetoplacental unit to develop and grow. Opinions are divided as to whether this represents a state of fetal-specific tolerance or of a generalized suppression of the maternal immune system. We hypothesized that antigen-specific T cell responses are modulated by an inhibitory T cell phenotype and modified dendritic cell (DC) phenotype in a gestation-dependent manner. We analyzed changes in surface markers of peripheral blood T cells, ex vivo antigen-specific T cell responses, indoleamine 2,3-dioxygenase (IDO) activity (kynurenine/tryptophan ratio, KTR), plasma neopterin concentration, and the in vitro expression of progesterone-induced blocking factor (PIBF) in response to peripheral blood mononuclear cell culture with progesterone. We found that mid gestation is characterized by reduced antigen-specific T cell responses associated with (1) predominance of effector memory over other T cell subsets; (2) upregulation of inhibitory markers (programmed death ligand 1); (3) heightened response to progesterone (PIBF); and (4) reduced proportions of myeloid DC and concurrent IDO activity (KTR). Conversely, antigen-specific T cell responses normalized in late pregnancy and were associated with increased markers of T cell activation (CD38, neopterin). However, these changes occur with a simultaneous upregulation of immune suppressive mechanisms including apoptosis (CD95), coinhibition (TIM-3), and immune regulation (IL-10) through the course of pregnancy. Together, our data suggest that immune tolerance dominates in the second trimester and that it is gradually reversed in the third trimester in association with immune activation as the end of pregnancy approaches

<b>Supplementary Figure 2</b>— <b>Gating strategy for cell viability and cell death in BeWo trophoblast cells in response to oxidative stress.</b>

Two populations of cells were identified, and gating strategies were applied to each population. Histograms were used to determine A) cell viability by gating CC+, 7AAD-, and Apo- cells and B) the percentage of viable cells was determined by taking CC+, 77AD-, Apo- cell counts and dividing by total number of cell counts. C) Apoptosis (Q1+Q2) and necrosis (Q3) were determined with 7AAD on the x-axis and Apopoxin on the y-axis. D) The percentage of total apoptosis was calculated by summing Q1 and Q3 counts and dividing by the total number of cell counts. E) The percentage of total necrosis was determined by dividing Q4 by the total number of cell counts.</p

<b>Supplementary Figure 3</b>

Representative immunoblot membranes of SQSTM1/p62 (A-B) and LC3 (C-D) with respective Ponceau Stain. Area of analysis of total protein is indicated with rectangular boxes (A, C).</p

<b>Supplementary Figure 4</b>

The ratio of mtDNA to nDNA was increased in BeWo cells treated with antimycin A in both the A) membrane-bound (p=0.018) and B) non-membrane bound forms (p=0.006). Rotenone did not affect these ratios in the C) membrane-bound (p=0.64) or D) non-membrane bound form (p=0.99). These data were analyzed with one-way ANOVA (A,C) or non-parametric Kruskal Wallis test (B,D) for data that was not normally distributed. Means ± SD. n=5-7 independent observations.</p