Late response to anti-TNF-alpha therapy in refractory mucocutaneous lesions of Beh double dagger et`s disease

Beh double dagger et`s disease (BD) is a multisystem chronic inflammatory disorder characterized by oral and genital ulceration and ocular involvement. Recurrent oral and genital ulcers are the most common symptoms of BD and occur in more than 80% of patients. The treatments of these disease manifestations include colchicine, corticosteroids and immunosuppressive drugs in severe cases. Anti-TNF-alpha therapy may be useful in refractory severe BD, particularly for ocular, central nervous system, gastrointestinal and refractory mucocutaneous lesions. During a 2-year period, 280 patients suffering from rheumatic diseases received anti-TNF-alpha agents at the infusion center of our University Hospital. Two patients (0.7%) presented BD; one of them had celiac disease as well, with recalcitrant mucocutaneous lesions that were not responsive to immunosuppressive drugs. We reported those patients who were successfully treated with infliximab and adalimumab, despite their late response.

Notopronocephalus peekayi gen. et sp. n. (Digenea: Pronocephalidae) from Australian freshwater turtles

Notopronocephalus peekayi gen, et sp, n. is described from the intestine of Elseya latisternum Gray, 1867, E. dentata (Gray, 1863) and Emydura signata Ahl, 1932 from rivers in Queensland. The new genus is distinguished by the absence of ventral glands, simple (neither diverticulate nor sinuous) caeca terminating at the anterior margin of the testes, excretory arms not uniting in forebody, single ovary, two opposite testes close to the posterior end of the body, intracaecal genital pore, vitelline follicles anterior to the testes, cirrus-sac orientated obliquely and not divided into two portions, and the uterus intracaecal. This is the first pronocephalid to be described from an Australian freshwater turtle and the first from the family Chelidae.

Impact of short-term preconceptional exposure to particulate air pollution on treatment outcome in couples undergoing in vitro fertilization and embryo transfer (IVF/ET)

To assess the potential effects of short-term exposure to particulate air pollution during follicular phase on clinical, laboratory, and pregnancy outcomes of women undergoing IVF/ET. Retrospective cohort study of 400 first IVF/ET cycles of women exposed to ambient particulate matter during follicular phase. Particulate matter (PM) was categorized into quartiles (Q(1): a parts per thousand currency sign30.48 A mu g/m(3), Q(2): 30.49-42.00 A mu g/m(3), Q(3): 42.01-56.72 A mu g/m(3), and Q(4): > 56.72 A mu g/m(3)). Clinical, laboratory, or treatment variables were not affected by follicular phase PM exposure periods. Women exposed to Q(4) period during the follicular phase of conception cycles had a higher risk of miscarriage (odds ratio, 5.05; 95% confidence interval: 1.04-25.51) when compared to women exposed to Q(1-3) periods. Our results show an association between brief exposure to high levels of ambient PM during the preconceptional period and early pregnancy loss, although no effect of this exposure on clinical, laboratory, and treatment outcomes was observed.

Targeting endothelin ET(A) and ET(B) receptors inhibits antigen-induced neutrophil migration and mechanical hypernociception in mice

Endothelin may contribute to the development of inflammatory events such as leukocyte recruitment and nociception. Herein, we investigated whether endothelin-mediated mechanical hypernociception (decreased nociceptive threshold, evaluated by electronic pressure-meter) and neutrophil migration (myeloperoxidase activity) are inter-dependent in antigen challenge-induced Th1-driven hind-paw inflammation. In antigen challenge-induced inflammation, endothelin (ET) ET(A) and ET(B) receptor antagonism inhibited both hypernociception and neutrophil migration. Interestingly, ET-1 peptide-induced hypernociception was not altered by inhibiting neutrophil migration or endothelin ET(B) receptor antagonism, but rather by endothelin ET(A) receptor antagonism. Furthermore, endothelin ET(A), but not ET(B), receptor antagonism inhibited antigen-induced PGE(2) production, whereas either selective or combined blockade of endothelin ET(A) and/or ET(B) receptors reduced hypernociception and neutrophil recruitment caused by antigen challenge. Concluding, this study advances knowledge into the role for endothelin in inflammatory mechanisms and further supports the potential of endothelin receptor antagonists in controlling inflammation.

Activation of the ET-1/ETA Pathway Contributes to Erectile Dysfunction Associated with Mineralocorticoid Hypertension

The cavernosal tissue is highly responsive to endothelin-1 (ET-1), and penile smooth muscle cells not only respond to but also synthesize ET-1. Considering that ET-1 is directly involved in end-organ damage in salt-sensitive forms of hypertension, we hypothesized that activation of the ET-1/ET(A) receptor pathway contributes to erectile dysfunction (ED) associated with mineralocorticoid hypertension. Wistar rats were uninephrectomized and submitted to deoxycorticosterone acetate (DOCA)-salt treatment for 5 weeks. Control (Uni [uninephrectomized control]) animals were uninephrectomized and given tap water. Uni and DOCA-salt rats were simultaneously treated with vehicle or atrasentan (ET(A) receptor antagonist, 5 mg/Kg/day). Cavernosal reactivity to ET-1, phenylephrine (PE), ET(B) receptor agonist (IRL-1620) and electric field stimulation (EFS) were evaluated in vitro. Expression of ROCK alpha, ROCK beta, myosin phosphatase target subunit 1 (MYPT-1), and extracellular signal-regulated kinase 1/2 (ERK 1/2) were evaluated by western blot analysis. ET-1 and ET(A) receptor mRNA expression was evaluated by real-time reverse-transcriptase polymerase chain reaction. Voltage-dependent increase in intracavernosal pressure/mean arterial pressure (ICP/MAP) was used to evaluate erectile function in vivo. ET(A) receptor blockade prevents DOCA-salt-associated ED. Cavernosal strips from DOCA-salt rats displayed augmented preproET-1 expression, increased contractile responses to ET-1 and decreased relaxation to IRL-1620. Contractile responses induced by EFS and PE were enhanced in cavernosal tissues from DOCA-salt hypertensive rats. These functional changes were associated with increased activation of the RhoA/Rho-kinase and ERK 1/2 pathways. Treatment of rats with atrasentan completely prevented changes in cavernosal reactivity in DOCA-salt rats and restored the decreased ICP/MAP, completely preventing ED in DOCA-salt rats. Activation of the ET-1/ET(A) pathway contributes to mineralocorticoid hypertension-associated ED. ET(A) receptor blockade may represent an alternative therapeutic approach for ED associated with salt-sensitive hypertension and in pathological conditions where increased levels of ET-1 are present. Carneiro FS, Nunes KP, Giachini FRC, Lima VV, Carneiro ZN, Nogueira EF, Leite R, Ergul A, Rainey WE, Webb RC, and Tostes RC. Activation of the ET-1/ETA pathway contributes to erectile dysfunction associated with mineralocorticoid hypertension. J Sex Med **;**:**-**.

Endothelin-1 Induces Contraction of Female Rat Internal Pudendal and Clitoral Arteries through ET(A) Receptor and Rho-Kinase Activation

Introduction. Endothelin-1 (ET-1), a potent vasoconstrictor peptide, acts mainly through the Gprotein-coupled ET(A) receptor (ET(A)R). Increased vascular ET-1 production and constrictor sensitivity have been observed in various cardiovascular diseases, including hypertension, as well as erectile dysfunction. The internal pudendal artery (IPA) supplies blood to the vagina and clitoris. Inadequate blood flow through the IPA may lead to insufficient vaginal engorgement and clitoral tumescence. Aim. Characterize the effects of ET-1 on the IPA and clitoral artery (CA). Methods. IPA and CA from female Sprague Dawley rats (225-250 g) were mounted in myograph chambers. Arterial segments were submitted to increasing concentrations of ET-1 (10-10-10-6 M). Segments were incubated with the ET(A)R antagonist, atrasentan (10-8 M) or the Rho-kinase inhibitor, Y-27632 (10-6 M) 30 minutes prior to agonist exposure. All E(max) values are expressed as % KCl-induced maximal contraction. ET(A)R, RhoA, and Rho-kinase expression from IPA was evaluated by Western blot. mRNA of preproET-1, ET(A)R, ET(B)R, RhoA, and Rho-kinase were measured by real time PCR. Main Outcome Measures. ET-1 constrictor sensitivity in IPA and CA, protein expression and messenger RNA levels of ET-1-mediated constriction components. Results. ET-1 concentration-dependently contracted IPA (% Contraction and pD2, respectively: 156 +/- 18, 8.2 +/- 0.1) and CA (163 +/- 12, 8.8 +/- 0.08), while ET(A)R antagonism reduced ET-1-mediated contraction (IPA: 104 +/- 23, 6.4 +/- 0.2; CA: 112 +/- 17, 6.6 +/- 0.08). Pretreatment with Y-27632 significantly shifted ET-1 pD2 in IPA (108 +/- 24, 7.9 +/- 0.1) and CA (147 +/- 58 and 8.0 +/- 0.25). Protein expression of ET(A)R, ET(B)R, RhoA, and Rho-kinase were detected in IPA. IPA and CA contained preproET-1, ET(A)R, ET(B)R, RhoA, and Rho-kinase message. Conclusion. We observed that the IPA and CA are sensitive to ET-1, signaling through the ET(A)R and Rho-kinase pathway. These data indicate that ET-1 may play a role in vaginal and clitoral blood flow and may be important in pathologies where ET-1 levels are elevated. Allahdadi KJ, Hannan JL, Tostes RC, and Webb RC. Endothelin-1 induces contraction of female rat internal pudendal and clitoral arteries through ETA receptor and Rho-kinase activation. J Sex Med 2010;7:2096-2103.

ReoPro rules: results from the 'DoTirofiban and ReoPro give similar efficacy trial' (TARGET) - A Key Paper Evaluation (Topol, Ej et al)

In the treatment of atherosclerotic disease, stenting in the presence of a glycoprotein (GP) IIb/IIIa antagonist is becoming an increasingly common procedure. The ‘Do Tirofiban and ReoPro Give Similar Efficacy Trial’ (TARGET) was designed to determine whether the cheaper tirofiban was as effective and safe as abciximab in the prevention of ischaemic events with stenting. Unexpectedly, abciximab was shown to be superior to tirofiban. Tirofiban is a selective GP IIb/IIIa antagonist whereas abciximab has additional anti-inflammatory actions, which may contribute to its superiority.