Adenosine A<Subscript>2A</Subscript> Receptor Blockade or Deletion Diminishes Fibrocyte Accumulation in the Skin in a Murine Model of Scleroderma,Bleomycin-induced Fibrosis

Peripheral blood fibrocytes are a newly identified circulating leukocyte subpopulation that migrates into injured tissue where it may display fibroblast-like properties and participate in wound healing and fibrosis of skin and other organs. Previous studies in our lab demonstrated that A_2A receptor-deficient and A_2A antagonist-treated mice were protected from developing bleomycin-induced dermal fibrosis, thus the aim of this study was to determine whether the adenosine A_2A receptor regulates recruitment of fibrocytes to the dermis in this bleomycin-induced model of dermal fibrosis. Sections of skin from normal mice and bleomycin-treated wild type, A_2A knockout and A_2A antagonist-treated mice were stained for Procollagen α2 Type I and CD34 and the double stained cells, fibrocytes, were counted in the tissue sections. There were more fibrocytes in the dermis of bleomycin-treated mice than normal mice and the increase was abrogated by deletion or blockade of adenosine A_2A receptors. Because fibrocytes play a central role in tissue fibrosis these results suggest that diminished adenosine A_2A receptor-mediated recruitment of fibrocytes into tissue may play a role in the pathogenesis of fibrosing diseases of the skin. Moreover, these results provide further evidence that adenosine A_2A receptors may represent a new target for the treatment of such fibrosing diseases as scleroderma or nephrogenic fibrosing dermopathy.     

Multiple interactions between the alpha<Subscript>2C</Subscript>- and beta<Subscript>1</Subscript>-adrenergic receptors influence heart failure survival

Background  

Persistent stimulation of cardiac β₁-adrenergic receptors by endogenous norepinephrine promotes heart failure progression. Polymorphisms of this gene are known to alter receptor function or expression, as are polymorphisms of the α_2C-adrenergic receptor, which regulates norepinephrine release from cardiac presynaptic nerves. The purpose of this study was to investigate possible synergistic effects of polymorphisms of these two intronless genes (ADRB1 and ADRA2C, respectively) on the risk of death/transplant in heart failure patients.     

Cervical human papillomavirus (HPV) infection and HPV type 16 antibodies in South African women

There is a high incidence of cervical cancer in South African women. No large studies to assess human papillomavirus virus (HPV) infection or HPV type 16 (HPV-16) exposure have occurred in the region, a requirement for policy making with regards to HPV screening and the introduction of vaccines. Control women (n = 1,003) enrolled in a case control study of hormonal contraceptives and cervical cancer were tested for 27 cervical HPV types by reverse line blot analysis. The seroprevalence of HPV-16 immunoglobulin G (IgG) and IgA antibodies was assessed by a virus-like particle-based enzyme-linked immunoassay of 908 and 904 control women, respectively, and of 474 women with cervical cancer. The cervical HPV prevalence was 26.1%. The HPV-16 IgG seroprevalence was 44.4% and the HPV-16 IgA seroprevalence was 28.7% in control women, and these levels were significantly higher (61.8% and 52.7%, respectively) for women with cervical cancer (odds ratio [OR], 2.1 and 2.8, respectively). The cervical HPV prevalence showed an association with cervical disease, and the HPV-16 IgG prevalence decreased while the HPV-16 IgA prevalence increased with increasing age (P < 0.05). The prevalence of oncogenic HPV types (including HPV-16) decreased with age, whereas nononcogenic HPV types showed limited association with age. Multivariate analysis revealed cervical HPV infection to be associated with herpes simplex virus type 2 infection (OR, 1.7) and increasing years of education (OR, 1.9). HPV-16 IgG antibodies were inversely associated with current smoking status (OR, 0.6), and the presence of HPV-16 IgA antibodies was inversely associated with the use of alcohol (OR, 2.1) and inversely associated with the use of oral contraceptives (OR, 0.6). High levels of exposure to HPV, and particularly HPV-16, were evident in this population. The apparent increase of serum HPV-16 IgA with increasing age requires further investigation.     

Effects of 4 Weeks Recombinant Human Growth Hormone Administration on Insulin Resistance of Skeletal Muscle in Rats

Purpose

Effect of recombinant human growth hormone (rhGH) administration on lipid storage, and its subsequent effect on insulin sensitivity have not yet been adequately examined. Thus, we investigated the effects of rhGH treatment on muscle triglyceride (TG) and ceramide content, and insulin sensitivity after 4 weeks of rhGH administration in rats.

Materials and Methods

Fourteen rats were randomly assigned to two groups: rhGH injection group (GH, n = 7) and saline injection group (CON, n = 7). GH received rhGH by subcutaneous injections (130 µg·kg^-1·day^-1, 6 days·week^-1) for 4 weeks, while CON received saline injections that were equivalent in volume to GH group. Intramuscular TG and ceramide content and hepatic TG content were measured. To determine insulin sesitivity, oral glucose tolerance test (OGTT) and muscle incubation for glucose transport rate were performed in rats, and used as indicators of insulin sensitivity. We also examined plasm lipid profiles.

Results

After 4 weeks of rhGH treatment, the GH group had higher muscle and liver TG contents than the CON (p < 0.05). Ceramide content in GH was significantly greater than that in CON (p < 0.05). GH also had higher plasma levels of FFA (p < 0.05), glucose and insulin responses during OGTT (p < 0.05), and lower glucose transport rates in submaximal insulin concentration (p < 0.05) as compared with CON. Results indicate that rhGH treatment is associated with insulin resistance in rats.

Conclusion

rhGH treatment elevated muscle TG and ceramide content, and hepatic TG content. Thus, elevation of these compounde by rhGH treatment could contribute to the development of insulin resistance in rats.     

Effect of accessory ostia on maxillary sinus ventilation: A computational fluid dynamics (CFD) study

We evaluated, by CFD simulation, effects of accessory ostium (AO) on maxillary sinus ventilation. A three-dimensional nasal model was constructed from an adult CT scan with two left maxillary AOs (sinus I) and one right AO (sinus II), then compared to an identical control model with all AOs sealed (sinuses III and IV). Transient simulations of quiet inspiration and expiration at 15L/min, and nasal blow at 48L/min, were calculated for both models using low-Reynolds-number turbulent analysis. At low flows, ventilation rates in sinuses with AOs (I≈0.46L/min, II≈0.54L/min), were both more than a magnitude higher than sinuses without AOs (III≈0.019L/min, IV≈0.020L/min). Absence of AO almost completely prevented sinus ventilation. Increased ventilation of sinuses with AOs is complex. Under high flow conditions mimicking nose blowing, in sinuses II, III, and IV, the sinus flow rate increased. In contrast, the airflow direction through sinus I reversed between inspiration and expiration, while it remained almost constant throughout the respiration cycle in sinus II. CFD simulation demonstrated that AOs markedly increase maxillary sinus airflow rates and alter sinus air circulation patterns. Whether these airflow changes impact maxillary sinus physiology or pathophysiology is unknown.     

Interleukin-22 Protects Intestinal Stem Cells from Immune-Mediated Tissue Damage and Regulates Sensitivity to Graft versus Host Disease

Little is known about the maintenance of intestinal stem cells (ISCs) and progenitors during immune-mediated tissue damage or about the susceptibility of transplant recipients to tissue damage mediated by the donor immune system during graft versus host disease (GVHD). We demonstrate here that deficiency of recipient-derived IL-22 increased acute GVHD tissue damage and mortality, that ISCs were eliminated during GVHD, and that ISCs as well as their downstream progenitors expressed the IL-22 receptor. Intestinal IL-22 was produced after bone marrow transplant by IL-23-responsive innate lymphoid cells (ILCs) from the transplant recipients, and intestinal IL-22 increased in response to pretransplant conditioning. However, ILC frequency and IL-22 amounts were decreased by GVHD. Recipient IL-22 deficiency led to increased crypt apoptosis, depletion of ISCs, and loss of epithelial integrity. Our findings reveal IL-22 as a critical regulator of tissue sensitivity to GVHD and a protective factor for ISCs during inflammatory intestinal damage.     

Central chemoreceptor modulation of breathing via multipath tuning in medullary ventrolateral respiratory column circuits

Ventrolateral respiratory column (VRC) circuits that modulate breathing in response to changes in central chemoreceptor drive are incompletely understood. We employed multielectrode arrays and spike train correlation methods to test predictions of the hypothesis that pre-B?tzinger complex (pre-B?tC) and retrotrapezoid nucleus/parafacial (RTN-pF) circuits cooperate in chemoreceptor-evoked tuning of ventral respiratory group (VRG) inspiratory neurons. Central chemoreceptors were selectively stimulated by injections of CO(2)-saturated saline into the vertebral artery in seven decerebrate, vagotomized, neuromuscularly blocked, and artificially ventilated cats. Among sampled neurons in the B?tzinger complex (B?tC)-to-VRG region, 70% (161 of 231) had a significant change in firing rate after chemoreceptor stimulation, as did 70% (101 of 144) of the RTN-pF neurons. Other responsive neurons (24 B?tC-VRG; 11 RTN-pF) had a change in the depth of respiratory modulation without a significant change in average firing rate. Seventy B?tC-VRG chemoresponsive neurons triggered 189 offset-feature correlograms (96 peaks; 93 troughs) with at least one responsive B?tC-VRG cell. Functional input from at least one RTN-pF cell could be inferred for 45 B?tC-VRG neurons (19%). Eleven RTN-pF cells were correlated with more than one B?tC-VRG target neuron, providing evidence for divergent connectivity. Thirty-seven RTN-pF neurons, 24 of which were chemoresponsive, were correlated with at least one chemoresponsive B?tC-VRG neuron. Correlation linkage maps and spike-triggered averages of phrenic nerve signals suggest transmission of chemoreceptor drive via a multipath network architecture: RTN-pF modulation of pre-B?tC-VRG rostral-to-caudal excitatory inspiratory neuron chains is tuned by feedforward and recurrent inhibition from other inspiratory neurons and from "tonic" expiratory neurons.     

FDA oversight of cell therapy clinical trials

The U.S. Food and Drug Administration applies regulatory flexibility to balance benefits and risks to subjects in cell-therapy clinical trials.     

Emotional targets: evaluative categorization as a function of context and content

Event-related potential (ERP) studies of early evaluative categorization have often used variants of an oddball paradigm to assess attention to target stimuli as a function of content (i.e., valence) and context (e.g., presentation among non-targets differing in valence). However, most previous studies have not fully crossed content and context, and have not examined the time-course of these effects. The purpose of the current study was to investigate these two issues in an effort to further clarify the nature of evaluative categorization as reflected in the late positive potential (LPP). Pleasant, neutral, and unpleasant images served as both targets and non-targets in an emotional oddball task. Results indicate additive effects of emotional content and target status on the early portion of the LPP; however, the LPP did not differ between pleasant and unpleasant stimuli. Only target status modulated the later portion of the LPP, suggesting different contributions of cognitive-affective processes over time during evaluative categorization.     

WNT3A induces a contractile and secretory phenotype in cultured vascular smooth muscle cells that is associated with increased gap junction communication

Evidence suggests a role for Wnt signaling in vascular wound repair and remodeling events. Despite this, very little is known about the effect of Wnt ligands on the structure and function of vascular cells. In this study, we treated vascular smooth muscle cells with 250?ng/ml of recombinant Wnt3a for 72?h and observed changes in the cell phenotype. Our data suggest Wnt3a completely alters the phenotype of vascular smooth muscle cells. The Wnt3a-treated cells appeared larger and had increased formation of stress fibers. These cells also had increased expression of the smooth muscle contractile proteins, calponin and smooth muscle α-actin, and contracted a collagen lattice faster than control cells. The Wnt3a-treated smooth muscle cells displayed increased extracellular matrix synthesis, as measured by collagen I and III mRNA expression, along with increased expression of MMP2 and MMP9, but decreased TIMP2 levels. The Wnt3a-induced change in cell phenotype was associated with increased expression of the gap junction protein connexin 43. Consistent with this, Wnt3a-treated smooth muscle cells displayed enhanced intercellular communication, as measured by the scrape-loading dye transfer technique. The canonical Wnt antagonist, dickkopf-related protein 1, completely reversed the contractile protein and connexin 43 expression seen in the Wnt3a-treated cells, suggesting these changes were dependent on canonical Wnt signaling. Collectively, this data suggest Wnt3a promotes a contractile and secretory phenotype in vascular smooth muscle cells that is associated with increased gap junction communication.