Des-acyl ghrelin fragments evoke endothelium-dependent vasodilatation of rat mesenteric vascular bed via activation of potassium channels

The mechanisms that subserve ghrelin-evoked vasodilatation have not been elucidated in previous studies. Changes in perfusion pressure evoked by ghrelin and its N-terminal fragments were examined ex vivo in phenylephrine-constricted perfused mesenteric vascular beds of male Sprague Dawley rats maintained at a constant flow rate. Both ghrelin (maximum effect [E(max)] 45%) and des-acyl ghrelin (E(max) 43%) evoked vasodilatation at concentrations between 10 pM and 1 nM, compared to acetylcholine (median effective concentration [EC(50)] 3 nM; E(max) 93%). Those responses were abolished in endothelium-denuded preparations, and in endothelium-intact preparations exposed to either calcium-activated potassium channel, or a depolarizing stimulus, or in the presence of a combination of either apamin and 1,2-chlorophenyl diphenylmethyl-1 H-pyrazole (triarylmethane-34 [TRAM-34]), or ouabain and barium. ATP-activated potassium channel blockade, or a combination of nitric oxide synthase and cyclooxygenase inhibition had no effect. The classical growth hormone secretagogue antagonist, [d-Lys(3)]-growth hormone-releasing peptide (10 nM), or several N-terminal fragments of des-acyl ghrelin, including the tripeptide glycine-serine-serine (G-S-S [1 nM]), showed endothelium-dependent vasodilatation like des-acyl ghrelin, while responses to glycine-serine or serine-serine were relatively lower. A higher concentration (100 muM) of l-serine, but not glycine, evoked vasodilatation of similar magnitude. The serine dense N-terminal sequence of des-acyl ghrelin mediates endothelium-dependent vasodilatation via activation of apamin+TRAM-34 sensitive small- and intermediate-conductance calcium-activated potassium channels present on the mesenteric endothelium. Thus, the vasodilator response to ghrelins in the perfused rat mesenteric vascular bed is not mediated by the classical growth hormone secretagogue receptor type 1a.     

Omega-3 fatty acids are protective against paclitaxel-induced peripheral neuropathy: A randomized double-blind placebo controlled trial

ABSTRACT: BACKGROUND: Axonal sensory peripheral neuropathy is the major dose-limiting side effect of paclitaxel.Omega-3 fatty acids have beneficial effects on neurological disorders from their effects on neurons cells and inhibition of the formation of proinflammatory cytokines involved in peripheral neuropathy. METHODS: This study was a randomized double blind placebo controlled trial to investigate the efficacy of omega-3 fatty acids in reducing incidence and severity of paclitaxel-induced peripheral neuropathy (PIPN). Eligible patients with breast cancer randomly assigned to take omega-3 fatty acid pearls, 640 mg t.i.d during chemotherapy with paclitaxel and one month after the end of the treatment or placebo. Clinical and electrophysiological studies were performed before the onset of chemotherapy and one month after cessation of therapy to evaluate PIPN based on "reduced Total Neuropathy Score". RESULTS: Twenty one patients (70 %) of the group taking omega-3 fatty acid supplement (n = 30) did not develop PN while it was 40.7 %( 11 patients) in the placebo group(n = 27). A significant difference was seen in PN incidence (OR = 0.3, .95 % CI = (0.10-0.88), p = 0.029). There was a non-significant trend for differences of PIPN severity between the two study groups but the frequencies of PN in all scoring categories were higher in the placebo group (0.95 % CI = ([MINUS SIGN]2.06 -0.02), p = 0.054). CONCLUSIONS: Omega-3 fatty acids may be an efficient neuroprotective agent for prophylaxis against PIPN. Patients with breast cancer have a longer disease free survival rate with the aid of therapeutical agents. Finding a way to solve the disabling effects of PIPN would significantly improve the patients' quality of life.Trial registrationThis trial was registered at ClinicalTrials.gov (NCT01049295).     

The Relationship Between Pediatric Combination Vaccines and Market Effects

We explored market factors that affect pediatric combination vaccine uptake in the US public-sector pediatric vaccine market. We specifically examined how Pediarix and Pentacel earned a place in the 2009–2012 lowest overall cost formulary.Direct competition between Pediarix and Pentacel is driven by the indirect presence of the Merck Haemophilus influenzae type b vaccine and the Recommended Childhood Immunization Schedule requirement for a hepatitis B birth dose.The resulting analysis suggests that Pentacel would never have earned a place in the lowest overall cost formulary for 2009–2012 federal contract prices for any cost of an injection unless the Merck H influenzae type b advantage was ignored and the hepatitis B birth dose administration cost was recognized by health care providers in designing the lowest overall cost formularies.A limited number of pharmaceutical companies manufacture vaccines for the US pediatric vaccine market. Over the past decade, numerous economic and regulatory factors have made vaccine manufacturing less profitable for such companies, resulting in many of them exiting the market.1 One consequence of this situation is that production problems often translate into vaccine shortages in the market. Because maintaining high immunization levels is a vital societal need, public health administrators are motivated to sustain an adequate supply of vaccines through public health policies that encourage new companies to enter the market.1The Centers for Disease Control and Prevention (CDC) in the United States is the primary public health organization responsible for developing and applying disease prevention and control. The Advisory Committee on Immunization Practices (ACIP) is an independent panel of vaccine stakeholder representatives from the CDC, vaccine manufacturers, scientists, and physician groups. The ACIP reviews technical data on new vaccines, and then makes recommendations after the vaccines are approved by the Food and Drug Administration (FDA) for sale in the United States. The ACIP is also responsible for adding the vaccines to the Recommended Childhood Immunization Schedule (RCIS; Figure 12). The RCIS represents the recommended sequence and timing of pediatric vaccines to protect children from pediatric diseases.Open in a separate windowFIGURE 1—United States 2012 Recommended Childhood Immunization Schedule for birth through age 6 years.Note. DTaP = diphtheria, tetanus, and pertussis; HepA = hepatitis A; HepB = hepatitis B; Hib = Haemophilus influenzae type b; IPV = inactivated poliovirus; MMR = measles, mumps, and rubella; PCV = pneumococcal conjugate vaccine; RV = rotavirus.Source. Centers for Disease Control and Prevention.The CDC is required by law to negotiate vaccine prices for the purchases made by state and local governments. The state and local government public health officials purchase vaccines for the immunization of the children in their administrative areas of responsibility. They seek to satisfy the RCIS for each child to ensure proper immunization coverage. They distribute the vaccines free of charge to the private physicians and public health clinics that are registered as Vaccines for Children (VFC) Program providers.3 The VFC Program is designed to provide vaccines (at no charge) to children whose parents or guardians are not able to afford them. Pediatric vaccines purchased at the federal contract prices, as negotiated by CDC, account for approximately 57% of total pediatric purchases by volume.3 Private vaccine providers who are not registered as VFC Program providers cannot purchase the vaccines through federal contract prices, and as such, purchase the vaccines at private-sector prices (typically higher than the federal contract prices). The private-sector prices are reported by vaccine manufacturers to the CDC.4 In this analysis, we focused on federal contract prices, though the methodology employed could be adapted to separately analyze the private sector.Vaccines are said to compete when 2 or more vaccine manufacturers produce the same vaccine or vaccines that contain the same antigen that can be administered to satisfy the immunization requirements in a given time period. There are 4 competitive antigens: diphtheria, tetanus, and pertussis (DTaP); hepatitis B (HepB); Haemophilus influenzae type b (Hib); and inactivated poliovirus (IPV). In the United States, 3 pharmaceutical companies (Merck, GlaxoSmithKline, and Sanofi Pasteur) manufacture all the competing vaccines.Pediarix (DTaP–HepB–IPV) was the first pentavalent combination vaccine to gain FDA approval (in 2002). In 2008, a second pentavalent combination vaccine, Pentacel (DTaP–IPV/Hib), gained FDA approval for the US market. As Pediarix and Pentacel are the only vaccines that immunize against 5 diseases in a single injection, health care providers welcome them as part of the formulary (defined as a set of pediatric vaccines stocked to satisfy the immunization needs for a pediatric population cohort, as defined by a given set of immunization requirements). On the basis of the RCIS structure, Pediarix and Pentacel are not compatible for use in a single vaccine formulary. By design, the market will gravitate toward the combination vaccine that provides the best value (i.e., yields the lowest overall cost formulary [LOCF], the set of vaccines that satisfies the RCIS at the lowest overall formulary cost5). Therefore, Pediarix and Pentacel are said to serve as the backbone of the LOCF. From the perspective of health care providers, the question to ask is: which pentavalent vaccine earns a place in the LOCF, given a fixed cost of an injection (defined as a constant vaccine administration cost)?Behzad et al.6 reported and discussed the LOCFs across 3 years (2009–2011) for several fixed cost of an injection values. From Behzad et al.,6 Pentacel was not competitively priced compared with Pediarix in 2009–2011 (i.e., Pentacel did not earn a place in the LOCF for any cost of an injection). According to data provided by the CDC7,8 (e-mail communication from Sarah Foster, Centers for Disease Control and Prevention, August 14, 2013), the net number of Pentacel doses distributed in 2009–2011 was greater than the number of Pediarix doses distributed. A natural question to ask is why the uptake by health care providers who administer Pediarix or Pentacel as the backbone of their pediatric formularies is not consistent with the results reported in Behzad et al.6This study answers this question by considering the effects of 2 issues: a special property of the Merck Hib (i.e., a month-6 dose of Hib is not required if Merck Hib is administered in months 2 and 4) and the HepB birth dose. Moreover, this study identifies the equilibrium cost of an injection (defined as the minimum cost of an injection for which Pentacel earns a place in the LOCF) for the 4 possible scenarios associated with recognizing or ignoring these 2 issues by health care providers in designing the LOCF. No attempt has been made before to characterize the effects of the special property of the Merck Hib and HepB birth dose on the uptake of Pediarix and Pentacel. Understanding the market factors that have an impact on the uptake of pediatric combination vaccines could interest those within the pediatric health care community, such as pharmaceutical companies seeking right pricing strategies for their products, as well as the CDC negotiating vaccine prices with manufacturers and government, and public health officials seeking the LOCF for the children in their administrative area.     

Implication of invalidation concept in fibromyalgia diagnosis

Clinical Rheumatology - The invalidation or social pain is an important but neglected issue in polysymptomatology of fibromyalgia (FM). This study sought whether tracing-perceived invalidation...     

Morphine and breast tumor metastasis: the role of matrix-degrading enzymes

Opioids including morphine are commonly used in pain management during and after cancer surgery but have been linked to a variety of pro- and anti-tumor effects. In the present study the effect of morphine administration on the localization and growth of breast tumor cells in lungs and the level of extracellular matrix (ECM) proteases were investigated. In a mouse syngeneic model of intravenously inoculated breast cancer cells, morphine administration led to a reduction in the localization and growth of tumors in the lungs and a reduction in circulating matrix metalloproteinase-9 (MMP-9) and urokinase-like plasminogen activator (uPA). To model the involvement of non-malignant cells of the tumor microenvironment in the changes we observed in the level of proteases, we co-cultured breast cancer cells with macrophages, endothelial cells and fibroblasts. We found a significant elevation of matrix proteases as well as matrix protease inhibitors in co-cultures of breast cancer cells with macrophages or endothelial cells. Interestingly, morphine treatment of these co-cultures reduced the level of MMP-9 and increased its endogenous inhibitor, TIMP-1, thereby altering the proteolytic profile. Morphine affected the level of enzymes in co-cultures but not in cells grown individually. This suggests that anti-tumor effects of morphine observed in our in vivo model could be mediated at least in part through modulation of paracrine communication between cancer cells and non-malignant cells in the tumor microenvironment.