Trypanosoma cruzi antigen that interacts with the beta1-adrenergic receptor and modifies myocardial contractile activity

Previously, we have demonstrated that plasma membranes from the parasite Trypanosoma cruzi (T. cruzi) recognize and adhere to host cells through parasite surface attachment molecules that have affinity for beta(1)-adrenergic receptors (beta(1)-ARs) on target organs. In this report we identify a parasite protein that not only interacts with beta(1)-ARs, but also displays beta-agonist-like activity. We demonstrate that a recombinant maltose binding protein fusion of Tc13 Tul (MBP-Tc13 Tul), a member of the T. cruzi antigen 13 family of surface antigen proteins, competes for binding sites with the beta-adrenergic receptor antagonist [125I]-CYP on membranes purified both from CHO cells expressing human beta(1)-ARs and from rat atria. The competition is prevented by pre-treating MBP-Tc13 Tul with antibodies directed against the EPKSA repeat domain of Tc13 Tul, implicating this portion of the molecule in binding to the beta(1)-AR. Furthermore, MBP-Tc13 Tul activates rat myocardial beta(1)-ARs, resulting in synthesis of cyclic adenosine monophosphate (cAMP) and an increase in cardiac contractility. These biological effects are selectively suppressed by the beta(1)-AR antagonist atenolol, by a synthetic peptide corresponding to the second extracellular loop of the human beta(1)-AR, and by the anti-EPKSA repeat antibodies. These results imply that the Tc13 Tul cell-surface antigen of T. cruzi plays a central role in misregulating the beta(1)-AR following parasite infection, and may be a causative factor of dysautonomic syndrome described in Chagas' disease.     

Molar incisor hypomineralization in HIV‐infected children and adolescents

The objective was to determine the prevalence of molar incisor hypomineralization (MIH) among individuals between 7 and 15 years old infected or noninfected with human immunodeficiency virus (HIV). The study was conducted with 33 HIV‐infected individuals (study group; SG) and 66 non‐HIV‐infected schoolchildren (control group; CG), paired by gender and age. Data collection was based on medical records (SG), a questionnaire for caregivers and oral examination for diagnosis of MIH (European Academy of Pediatric Dentistry criteria) and caries (DMFT index and ICDAS). Data were analyzed with Mann‐Whitney, chi‐square, and Fisher's exact tests and logistic regression. In SG, MIH (45.5%) and caries (87.9%) had higher prevalence. MIH was associated with use of protease inhibitors in SG (OR: 2.14; 95% CI: 1.21 to 3.77) and incubator need in CG (OR: 2.80; 95% CI: 1.71 to 9.10). HIV‐infected patients had a higher prevalence of MIH and dental caries in the permanent dentition.     

Prevención de ictus en pacientes con diabetes mellitus tipo 2 o prediabetes. Recomendaciones del Grupo de Estudio de Enfermedades Cerebrovasculares de la Sociedad Española de Neurología

ObjectiveTo update the Spanish Society of Neurology's guidelines for stroke prevention in patients with type 2 diabetes or prediabetes, analysing the available evidence on the effect of metabolic control and the potential benefit of antidiabetic drugs with known vascular benefits in addition to conventional antidiabetic treatments in stroke prevention.DevelopmentPICO-type questions (Patient, Intervention, Comparison, Outcome) were developed to identify practical issues in the management of stroke patients and to establish specific recommendations for each of them. Subsequently, we conducted systematic reviews of the PubMed database and selected those randomised clinical trials evaluating stroke as an independent variable (primary or secondary). Finally, for each of the PICO questions we developed a meta-analysis to support the final recommendations.ConclusionsWhile there is no evidence that metabolic control reduces the risk of stroke, some families of antidiabetic drugs with vascular benefits have been shown to reduce these effects when added to conventional treatments, both in the field of primary prevention in patients presenting type 2 diabetes and high vascular risk or established atherosclerosis (GLP-1 agonists) and in secondary stroke prevention in patients with type 2 diabetes or prediabetes (pioglitazone).     

The translational repressor eIF4E-binding protein 2 (4E-BP2) correlates with selective delayed neuronal death after ischemia

Transient brain ischemia induces an inhibition of translational rates and causes delayed neuronal death in selective regions and cognitive deficits, whereas these effects do not occur in resistant areas. The translational repressor eukaryotic initiation factor (eIF) 4E-binding protein-2 (4E-BP2) specifically binds to eIF4E and is critical in the control of protein synthesis. To link neuronal death to translation inhibition, we study the eIF4E association with 4E-BP2 under ischemia reperfusion in a rat model of transient forebrain ischemia. Upon reperfusion, a selective neuronal apoptosis in the hippocampal cornu ammonis 1 (CA1) region was induced, while it did not occur in the cerebral cortex. Confocal microscopy analysis showed a decrease in 4E-BP2/eIF4E colocalization in resistant cortical neurons after reperfusion. In contrast, in vulnerable CA1 neurons, 4E-BP2 remains associated to eIF4E with a higher degree of 4E-BP2/eIF4E colocalization and translation inhibition. Furthermore, the binding of a 4E-BP2 peptide to eIF4E induced neuronal apoptosis in the CA1 region. Finally, pharmacological-induced protection of CA1 neurons inhibited neuronal apoptosis, decreased 4E-BP2/eIF4E association, and recovered translation. These findings documented specific changes in 4E-BP2/eIF4E association during ischemic reperfusion, linking the translation inhibition to selective neuronal death, and identifying 4E-BP2 as a novel target for protection of vulnerable neurons in ischemic injury.     

Effects of Sarcoma 180 Growth on Interleukin-1 and Circulating Immune Complexes

Cultured splenic mononuclear adherent cells (SMAc) from normal BALB/c mice as well as those from mice bearing 10-day sarcoma 180 (S180), exhibited a marked increase in Escherichia coli lipopolysaccharide-stimulated interleukin-1 (IL-1) production, when compared to spontaneous values. On days 20 and 30 following S180 challenge, a decrease in this effect on IL-1 production in treated and untreated SMAc was observed. Concomitantly with the alterations in the regulation of IL-1 production during tumor growth, an increase in the levels of prostaglandin E₂ and serum immune complexes could be detected. These data suggest that the immunosuppression associated with later stages of tumor development may be due to direct effects on monocytes, by means of a down-regulation of IL-1 production.     

Role of nitric oxide/cyclic GMP in myocardial adenosine A1 receptor-inotropic response

In this study we have determined the different signalling pathways involved in adenosine A(1)-receptor (A(1)-receptor)-dependent inhibition of contractility in rat isolated atria. N-cyclopentyladenosine (CPA) stimulation of A(1)-receptor exerts: negative inotropic response, inositol phosphates accumulation, stimulation of nitric oxide synthase (NOS), increased production of nitric oxide (NO) and cyclic GMP. Inhibitors of phospholipase C (PLC), protein kinase C (PKC), calcium/calmodulin, NOS and guanylate cyclase shifted the dose-response curve of CPA on contractility to the right. Those inhibitors also attenuated the A(1)-receptor-dependent increase in cyclic GMP and activation of NOS. These results suggest that CPA activation of A(1)-receptors exerts a negative inotropic effect associated with increased production of nitric oxide and cyclic GMP. The mechanism appears to occur secondarily to stimulation of phosphoinositide turnover via PLC activation. This, in turn, triggers cascade reactions involving calcium/calmodulin and PKC, leading to activation of NOS and soluble guanylate cyclase.     

Novel insight into the mechanisms involved in the regulation of the m1 muscarinic receptor,iNOS and nNOS mRNA levels

In this paper we have determined the different signaling pathways involved in M(1) muscarinic acetylcholine receptor (mAChR)-dependent stimulation of m1 mAChRs, neural and inducible isoforms of nitric oxide synthase (nNOS and iNOS)-mRNA gene expression of rat frontal cortex. Carbachol-stimulation of M(1) mAChRs exerts an increase in m1 mAChR-mRNA, activation of phosphoinositide (PI) turnover, translocation of protein kinase C (PKC) and stimulation of NOS activity. Inhibitors of phospholipase C (PLC), calcium/calmodulin and NOS, but not guanylate cyclase, prevent the carbachol-dependent increase of m1 mAChR-mRNA levels. These inhibitors also attenuate the muscarinic receptor-dependent increase in nNOS and iNOS mRNA levels. These results suggest that carbachol-activation of M(1) mAChRs increases m1 mAChR, nNOS and iNOS mRNA levels associated with increased production of nitric oxide (NO). The mechanism appears to occur secondarily to stimulation of PI turnover via PLC activation. This in turn, triggers a cascade reaction involving calcium/calmodulin and PKC, leading to activation of NOS. On the basis of our results, the activation of M(1) mAChRs appears to induce nNOS and iNOS expression and, reciprocally, the activator of NOS up-regulates m1 mAChR gene expression. These results may contribute to a better understanding of the effects and side effects of cholinomimetic treatment in patients with neurodegenerative diseases.     

The elusive link between coronary lesion morphology and dobutamine stress echocardiography results

Background. Coronary lesion angiographic morphology of the complex type is associated to enhanced susceptibility to ischemia during vasodilator adenosinergic stress testing and attributed to the reduced vasodilatory capacity of the damaged endothelium. Whether coronary lesion morphology can also influence the results of adrenergic pharmacologic stress test remains unknown. The aim of our study was to assess the relationship between coronary plaque morphology and dobutamine-atropine stress echocardiography (DASE) results. Methods and results. We analyzed DASE (up to 40 mcg/kg/min plus atropine) and coronary angiography data of 42 patients with single vessel disease and no totally occluded vessel at angiography. 7 patients had angina, 35 had previous infarction. A diagnostic DASE was performed in all patients within 1–10 (mean 4.7 ± 3.4) days before coronary angiography. An angiographic lesion was considered complex when irregular borders and/or intraluminal lucencies, suggestive of ulcer and/or thrombus were present. According to the angiographic lesion morphology (Ambrose classification), 2 groups were identified: Group I, with simple lesion; Group II with complex lesion. The two groups were similar for number of patients (n= 21), age (I=55 ± 11 vs II=53 ± 7 years, p=ns), coronary stenosis severity expressed as% diameter reduction (I=77 ± 14 vs II=78 ± 15%, p=ns), presence of previous infarction (I=17 vs II=18 pts, p=ns). No difference was found in the prevalence of positivity between the two groups (I=72 vs II=62%, p=ns). The two groups achieved a similar peak dobutamine dose (I=32 ± 9 vs II=33 ± 9 mcg/kg/min, p=ns) and peak Wall Motion Score Index (I=1.5 ± 0.26 vs II=1.45 ± 0.28, p=ns). Conclusions. In patients with non occlusive single vessel disease, coronary morphology of complex type is not associated with greater vulnerability to dobutamine induced ischemia.