A Direct Interaction between Cyclodextrins and TASK Channels Decreases the Leak Current in Cerebellar Granule Neurons.

Two pore domain potassium channels (K2P) are strongly expressed in the nervous system (CNS), where they play a central role in excitability. These channels give rise to background K+ currents, also known as IKSO (standing-outward potassium current). We detected the expression in primary cultured cerebellar granule neurons (CGNs) of TWIK-1 (K2P1), TASK-1 (K2P3), TASK-3 (K2P9), and TRESK (K2P18) channels by immunocytochemistry and their association with lipid rafts using the specific lipids raft markers flotillin-2 and caveolin-1. At the functional level, methyl-ß-cyclodextrin (MßCD, 5 mM) reduced IKSO currents by ~40% in CGN cells. To dissect out this effect, we heterologously expressed the human TWIK-1, TASK-1, TASK-3, and TRESK channels in HEK-293 cells. MßCD directly blocked TASK-1 and TASK-3 channels and the covalently concatenated heterodimer TASK-1/TASK-3 currents. Conversely, MßCD did not affect TWIK-1- and TRESK-mediated K+ currents. On the other hand, the cholesterol-depleting agent filipin III did not affect TASK-1/TASK-3 channels. Together, the results suggest that neuronal background K+ channels are associated to lipid raft environments whilst the functional activity is independent of the cholesterol membrane organization.

Consenso chileno de diagnóstico y manejo de neoplasias quísticas pancreáticas. Club de páncreas Chile-SCHGE / Chilean consensus on diagnosis and management of pancreatic cystic neoplasms

Pancreatic cystic neoplasms (PCN) are frequently detected on abdominal images performed for non-pancreatic indications. Their prevalence in asymptomatic population ranges from 2.7 to 24.8%, and increases with age. There are several types of pancreatic cysts. Some may contain cancer or have malignant potential, such as mucinous cystic neoplasms, including mucinous cystadenoma (MCN) and intraductal papillary mucinous neoplasms (IPMN). In contrast, others are benign, such as serous cystadenoma (SCA). However, even those cysts with malignant potential rarely progress to cancer. Currently, the only treatment for pancreatic cysts is surgery, which is associated with high morbidity and occasional mortality. The Board of the Chilean Pancreas Club of the Chilean Gastroenterology Society developed the first Chilean multidisciplinary consensus for diagnosis, management, and surveillance of PCN. Thirty experts were invited and answered 21 statements with five possible alternatives: 1) fully agree; 2) partially agree; 3) undecided; 4) disagree and 5) strongly disagree. A consensus was adopted when at least 80% of the sum of the answers "fully agree" and "partially agree" was reached. The consensus was approved by the Board of Directors of the Chilean Pancreas Club for publication.

Penicillin desensitization in allergic pregnant women with syphilis. Report of two cases.

Syphilis during pregnancy has a high risk of congenital transmission with disastrous fetal consequences. Penicillin (PNC) is the only effective antimicrobial for the treatment of pregnant women with syphilis. Chilean guidelines do not consider desensitization to PNC in these women. We report two cases of pregnant women aged 32 and 23 years, with immediate allergy to PNC and syphilis who were safely and successfully desensitized using a four-hour intravenous protocol in the critical care unit and who subsequently received benzathine G PNC. An electronic survey was conducted among approximately 100 Clinical Pharmacists (CP) in the country. Of these, 16 answered and 13 reported having experience in drug desensitization, in at least five cases with PNC and none reported deaths or cardiorespiratory arrest. Desensitization to PNC can be carried out safely and in Chile, this alternative should be incorporated to the management of pregnant women with syphilis and immediate allergy to PNC, instead of using erythromycin.

Penicillin desensitization in allergic pregnant women with syphilis. Report of two cases / Desensibilización a penicilina en mujeres embarazadas alérgicas. Informe de dos casos

ABSTRACT Syphilis during pregnancy has a high risk of congenital transmission with disastrous fetal consequences. Penicillin (PNC) is the only effective antimicrobial for the treatment of pregnant women with syphilis. Chilean guidelines do not consider desensitization to PNC in these women. We report two cases of pregnant women aged 32 and 23 years, with immediate allergy to PNC and syphilis who were safely and successfully desensitized using a four-hour intravenous protocol in the critical care unit and who subsequently received benzathine G PNC. An electronic survey was conducted among approximately 100 Clinical Pharmacists (CP) in the country. Of these, 16 answered and 13 reported having experience in drug desensitization, in at least five cases with PNC and none reported deaths or cardiorespiratory arrest. Desensitization to PNC can be carried out safely and in Chile, this alternative should be incorporated to the management of pregnant women with syphilis and immediate allergy to PNC, instead of using erythromycin.

La sífilis durante el embarazo tiene un alto riesgo de transmisión congénita con consecuencias desastrosas para el feto. La penicilina (PNC) es el único compuesto efectivo para el tratamiento de sífilis en una mujer embarazada.. En Chile, ante alergias de tipo inmediata, no se considera la desensibilización a la PNC en mujeres embarazadas por norma ministerial. Se comunican dos casos de mujeres embarazadas con alergia tipo inmediata y sífilis durante la gestación que fueron desensibilizadas a este compuesto con un protocolo endovenoso de 4 horas en la unidad de pacientes críticos, sin observar complicaciones, recibiendo posteriormente PNC G Benzatina. Se efectuó una encuesta electrónica a farmacéuticos clínicos del país que incluyó más de 100 profesionales. De ellos, 16 contestaron y 13 declararon poseer experiencia en desensibilización de fármacos, en al menos cinco casos con PNC y ninguno reportó muertes o paro cardiorrespiratorio. La desensibilización a PNC puede ser efectuada en forma segura en embarazadas con alergia de tipo inmediata a PNC que cursan con sífilis. En Chile se debería incorporar esta alternativa en el manejo de mujeres embarazadas con sífilis y alergia inmediata a PNC en lugar de solo considerar por norma el uso de eritromicina.

Discovery of potent and selective inhibitors of the Escherichia coli M1-aminopeptidase via multicomponent solid-phase synthesis of tetrazole-peptidomimetics.

The Escherichia coli neutral M1-aminopeptidase (ePepN) is a novel target identified for the development of antimicrobials. Here we describe a solid-phase multicomponent approach which enabled the discovery of potent ePepN inhibitors. The on-resin protocol, developed in the frame of the Distributed Drug Discovery (D3) program, comprises the implementation of parallel Ugi-azide four-component reactions with resin-bound amino acids, thus leading to the rapid preparation of a focused library of tetrazole-peptidomimetics (TPMs) suitable for biological screening. By dose-response studies, three compounds were identified as potent and selective ePepN inhibitors, as little inhibitory effect was exhibited for the porcine ortholog aminopeptidase. The study allowed for the identification of the key structural features required for a high ePepN inhibitory activity. The most potent and selective inhibitor (TPM 11) showed a non-competitive inhibition profile of ePepN. We predicted that both diastereomers of compound TPM 11 bind to a site distinct from that occupied by the substrate. Theoretical models suggested that TPM 11 has an alternative inhibition mechanism that doesn't involve Zn coordination. On the other hand, the activity landscape analysis provided a rationale for our findings. Of note, compound TMP 2 showed in vitro antibacterial activity against Escherichia coli. Furthermore, none of the three identified inhibitors is a potent haemolytic agent, and only two compounds showed moderate cytotoxic activity toward the murine myeloma P3X63Ag cells. These results point to promising compounds for the future development of rationally designed TPMs as antibacterial agents.

Microsatellite loci-based distribution of Trypanosoma cruzi genotypes from Chilean chronic Chagas disease patients and Triatoma infestans is concordant with a specific host-parasite association hypothesis.

The objective of this study was to investigate if there is specific host-parasite association in Chilean populations of Trypanosoma cruzi. For this purpose, two groups of parasites were analyzed, one from chronic chagasic patients, and the other from Triatoma infestans triatomines in three regions of the country. The first group consisted of four types of samples: parasites from peripheral blood of non-cardiopathic T. cruzi infected patients (NB); parasites from their corresponding xenodiagnosis (NX); parasites from peripheral blood of T. cruzi infected cardiopathic patients (CB) and parasites from their xenodiagnostics (CX). The T. infestans sample in turn was from three regions: III, V and M (Metropolitan). The genetic differentiation by the Fisher exact method, the lineage distribution of the samples, the molecular phylogeny and the frequency of multiclonality were analysed. The results show that not only are the groups of T. cruzi clones from Chagas disease patients and vectors genetically differentiated, but also all the sub-groups (NB, NX, CB and CX) from the III, V and M regions. The analysis of lineage distribution was concordant with the above results, because significant differences among the percentages of TcI, TcIII and hybrids (TcV or TcVI) were observed. The phylogenetic reconstruction with these Chilean T. cruzi samples was coherent with the above results because the four chagasic samples clustered together in a node with high bootstrap support, whereas the three triatomine samples (III, V and M) were located apart from that node. The topology of the tree including published T. cruzi clones and isolates was concordant with the known topology, which confirmed that the results presented here are correct and are not biased by experimental error. Taken together the results presented here are concordant with a specific host-parasite association between some Chilean T. cruzi populations.