Control of the subthalamic innervation of the rat globus pallidus by D2/3 and D4 dopamine receptors

The effects of activating dopaminergic D(2/3) and D(4) receptors during activation of the subthalamic projection to the globus pallidus (GP) were explored in rat brain slices using the whole cell patch-clamp technique. Byocitin labeling and both orthodromic and antidromic activation demonstrated the integrity of some subthalamopallidal connections in in vitro parasagittal brain slices. Excitatory postsynaptic currents (EPSCs) that could be blocked by CNQX and AP5 were evoked onto pallidal neurons by local field stimulation of the subthalamopallidal pathway in the presence of bicuculline. Bath application of dopamine and quinpirole, a dopaminergic D(2)-class receptor agonist, reduced evoked EPSCs by about 35%. This effect was only partially blocked by sulpiride, a D(2/3) receptor antagonist. The sulpiride-sensitive reduction of the subthalamopallidal EPSC was associated with an increase in the paired-pulse ratio (PPR) and a reduction in the frequency but not the mean amplitude of spontaneous EPSCs (sEPSCs), indicative of a presynaptic site of action, which was confirmed by variance-mean analysis. The sulpiride-resistant EPSC reduction was mimicked by PD 168,077 and blocked by L-745,870, selective D(4) receptor agonist and antagonist, respectively, suggesting the involvement of D(4) receptors. The reduction of EPSCs produced by PD 168,077 was not accompanied by changes in PPR or the frequency of sEPSCs; however, it was accompanied by a reduction in mean sEPSC amplitude, indicative of a postsynaptic site of action. These results show that dopamine modulates subthalamopallidal excitation by presynaptic D(2/3) and postsynaptic D(4) receptors. The importance of this modulation is discussed.     

Periodontal 5'-deiodination on forced-induced root resorption--the protective effect of thyroid hormone administration

The present investigation was designed to study the protective effect given by thyroid hormone (TH) on root resorption: (1) whether intra-peritoneal versus oral TH administration had the same efficiency; and (2) whether this effect involved local or systemic mechanisms. For this purpose, circulating T3 levels, systemic alkaline phosphatase (APase) activity, and 5'deiodinase (5'D) activity were evaluated in the periodontal area of 80 Sprague-Dawley rats, 8 weeks of age, in which orthodontic appliances had been inserted. The results showed that TH-treated animals (intra-peritoneal or oral) had significantly less force-induced root resorptive lesions compared with a control group, without apparent changes in T3 or APase levels, and that periodontal remodelling was accompanied by a significant increase in local T3 generation as a result of T4 deiodination. This 5'D activity was higher in those animals that received exogenous TH. These results suggest that this protective TH mechanism may be achieved at a local level and that administration of low doses of TH may play a protective role on the root surface either during orthodontic treatment or in those patients that present spontaneous root resorptive lesions.     

Antineoplastic effect of iodine in mammary cancer: participation of 6-iodolactone (6-IL) and peroxisome proliferator-activated receptors (PPAR)

Introduction  

Studies in mammary cancer demonstrated that moderately high concentrations of molecular iodine (I₂) have a antiproliferative and apoptotic effect either in vivo as in vitro, however the cellular intermediated involved in these effects has not been elucidated.     

c-Abl activates p38 MAPK independently of its tyrosine kinase activity: Implications in cisplatin-based therapy

Activation of p38 MAPK is a critical requisite for the therapeutics activity of the antitumor agent cisplatin. In this sense, a growing body of evidences supports the role of c-Abl as a major determinant of p38 MAPK activation, especially in response to genotoxic stress when triggered by cisplatin. Here, we demonstrate that p38 MAPK activation in response to cisplatin does not require the tyrosine kinase activity of c-Abl. Indeed, c-Abl can activate the p38 MAPK signaling pathway by a mechanism that is independent of its tyrosine kinase activity, but that instead involves the ability of c-Abl to increase the stability of MKK6. Similar results were obtained in chronic myeloid leukemia-derived cell lines, in which a chimeric Bcr/Abl protein mimics the effects of c-Abl overexpression on p38 MAPK activation. These findings may explain why a clinically used c-Abl inhibitor, imatinib mesylate, fails to inhibit the p38 MAPK pathway alone or in combination with cisplatin, and provide evidence of a novel signaling mechanism in which these antitumor agents act.     

SARS-CoV-2 Variants in Paraguay: Detection and Surveillance with an Economical and Scalable Molecular Protocol

SARS-CoV-2 variant detection relies on resource-intensive whole-genome sequencing methods. We sought to develop a scalable protocol for variant detection and surveillance in Paraguay, pairing rRT-PCR for spike mutations with Nanopore sequencing. A total of 201 acute-phase nasopharyngeal samples were included. Samples were positive for the SARS-CoV-2 N2 target and tested with the Spike SNP assay to detect mutations associated with the following variants: alpha (501Y), beta/gamma (417variant/484K/501Y), delta (452R/478K), and lambda (452Q/490S). Spike SNP calls were confirmed using amplicon (Sanger) sequencing and whole-genome (Nanopore) sequencing on a subset of samples with confirmed variant lineages. Samples had a mean N2 Ct of 20.8 (SD 5.6); 198/201 samples (98.5%) tested positive in the Spike SNP assay. The most common genotype was 417variant/484K/501Y, detected in 102/198 samples (51.5%), which was consistent with the P.1 lineage (gamma variant) in Paraguay. No mutations (K417 only) were found in 64/198 (32.3%), and K417/484K was identified in 22/198 (11.1%), consistent with P.2 (zeta). Seven samples (3.5%) tested positive for 452R without 478K, and one sample with genotype K417/501Y was confirmed as B.1.1.7 (alpha). The results were confirmed using Sanger sequencing in 181/181 samples, and variant calls were consistent with Nanopore sequencing in 29/29 samples. The Spike SNP assay could improve population-level surveillance for mutations associated with SARS-CoV-2 variants and inform the judicious use of sequencing resources.     

Virtual Seminar on Coronavirus 2019 for the US-Mexico Border Region: Building Opportunities for Communication and Collaboration

While the US-Mexico border region has had increasing restrictions due to coronavirus 2019 (COVID-19), the economically and socially integrated region continues to facilitate necessary movement between the two countries. Binational partners representing universities, government, and health delivery worked together to develop a COVID-19 Virtual Seminar for the US-Mexico Border Region, which consisted of weekly sessions in Spanish designed to better facilitate communication and collaborative systems between border states. In total 835 participants registered for the virtual seminar with attendance ranging from 394 in Session 1 to 269 in Session 6. From evaluation surveys (n?=?297), organizers observed a large plurality of healthcare professionals, followed by students, researchers, and government employees. The seminar’s contribution to increasing collaborative and communication systems identified major needs in the region surrounding surveillance and monitoring; increased resources for migrant shelters to control outbreaks; an increase in personal protective equipment; tracking binational cases.

     

APOA1 (-75 G>A and 83 C>T) and APOB (2488 C>T) polymorphisms and their association with myocardial infarction,lipids and apolipoproteins in patients with type 2 diabetes mellitus

IntroductionThe increased risk of myocardial infarction (MI) in type 2 diabetes mellitus (T2DM) is well documented. Polymorphisms in APOA1 and APOB genes allow us to identify new genetic markers in the Mexican population with T2DM and MI.Material and methodsWe studied 135 patients with DMT2 and MI (DI); another 85 non-infarcted diabetic individuals with DMT2 but without previous ischemic events (NID) and 242 healthy subjects (HS). All three groups were selected with the aim to investigate the association between the polymorphisms and infarction when T2DM is present or absent.Results-75 G>A polymorphism: Differences were found in genotype distribution between DI and NID individuals (OR = 2.01, 95% CI: 1.117–3.623, p = 0.019) with an increased risk for A in the dominant model (OR = 1.77, 95% CI: 1.020–3.084, p = 0.042); also concentrations of ApoA-I for A/A were lower in comparison with G/A (p = 0.038) and LDL-C and HDL-C levels were lower in G/A compared to G/G carriers. 83 C>T polymorphism of APOA1: For DI individuals, HDL-C was lower in T/T compared to C/C and triglyceride levels were lower in C/T compared to C/C carriers.ConclusionsThe -75 G>A APOA1 polymorphism could be considered as a susceptibility factor for myocardial infarction in individuals with T2DM and 2488 C>T APOB polymorphism is associated with changes in HDL-C and LDL-C and triglycerides in the same group.