Pentamidine Is Not a Permeant but a Nanomolar Inhibitor of the Trypanosoma brucei Aquaglyceroporin-2

The chemotherapeutic arsenal against human African trypanosomiasis, sleeping sickness, is limited and can cause severe, often fatal, side effects. One of the classic and most widely used drugs is pentamidine, an aromatic diamidine compound introduced in the 1940s. Recently, a genome-wide loss-of-function screen and a subsequently generated trypanosome knockout strain revealed a specific aquaglyceroporin, TbAQP2, to be required for high-affinity uptake of pentamidine. Yet, the underlying mechanism remained unclear. Here, we show that TbAQP2 is not a direct transporter for the di-basic, positively charged pentamidine. Even though one of the two common cation filters of aquaglyceroporins, i.e. the aromatic/arginine selectivity filter, is unconventional in TbAQP2, positively charged compounds are still excluded from passing the channel. We found, instead, that the unique selectivity filter layout renders pentamidine a nanomolar inhibitor of TbAQP2 glycerol permeability. Full, non-covalent inhibition of an aqua(glycero)porin in the nanomolar range has not been achieved before. The remarkable affinity derives from an electrostatic interaction with Asp265 and shielding from water as shown by structure-function evaluation and point mutation of Asp265. Exchange of the preceding Leu264 to arginine abolished pentamidine-binding and parasites expressing this mutant were pentamidine-resistant. Our results indicate that TbAQP2 is a high-affinity receptor for pentamidine. Taken together with localization of TbAQP2 in the flagellar pocket of bloodstream trypanosomes, we propose that pentamidine uptake is by endocytosis

110 Years of Avipoxvirus in the Galapagos Islands

The role of disease in regulating populations is controversial, partly owing to the absence of good disease records in historic wildlife populations. We examined birds collected in the Galapagos Islands between 1891 and 1906 that are currently held at the California Academy of Sciences and the Zoologisches Staatssammlung Muenchen, including 3973 specimens representing species from two well-studied families of endemic passerine birds: finches and mockingbirds. Beginning with samples collected in 1899, we observed cutaneous lesions consistent with Avipoxvirus on 226 (6.3%) specimens. Histopathology and viral genotyping of 59 candidate tissue samples from six islands showed that 21 (35.6%) were positive for Avipoxvirus, while alternative diagnoses for some of those testing negative by both methods were feather follicle cysts, non-specific dermatitis, or post mortem fungal colonization. Positive specimens were significantly nonrandomly distributed among islands both for mockingbirds (San Cristobal vs. Espanola, Santa Fe and Santa Cruz) and for finches (San Cristobal and Isabela vs. Santa Cruz and Floreana), and overall highly significantly distributed toward islands that were inhabited by humans (San Cristobal, Isabela, Floreana) vs. uninhabited at the time of collection (Santa Cruz, Santa Fe, Espanola), with only one positive individual on an uninhabited island. Eleven of the positive specimens sequenced successfully were identical at four diagnostic sites to the two canarypox variants previously described in contemporary Galapagos passerines. We conclude that this virus was introduced late in 1890′s and was dispersed among islands by a variety of mechanisms, including regular human movements among colonized islands. At present, this disease represents an ongoing threat to the birds on the Galapagos Islands

Corrección en el artículo de B. Vera et al. « Un portal de cálculo para la evaluación de la vulnerabilidad sísmica de estructuras aporticadas mediante elementos finitos »

Peer Reviewe

Un portal de cálculo para la evaluación de la vulnerabilidad sísmica de estructuras aporticadas mediante elementos finitos

This paper describes a computing portal called “Portal de Pórticos” that contain a finite element program for the dynamic, nonlinear analysis of framed reinforced concrete structures. The program is based on Lumped Damage Mechanics which describes the behaviour of this type of structure. To access the “Portal de Pórticos” it is only necessary to have a personal computer with Internet connection through a commercial browser (explorer, Mozilla firefox, etc). To show the accuracy in the results of the program Portal de Pórticos, some numerical simulations of experimental tests are presented

Linfoma primario de páncreas en un paciente de 27 anos de edad. Reporte de un caso

Los linfomas representan una pequeña fracción de todas las neoplasias malignas de páncreas, siendo inferior al 1 o 2%, y es aún más extremadamente extraño en individuos menores de 35 años, por lo que presentamos caso de linfoma primario de páncreas en un paciente de 27 años de edad, que presentó ictericia y dolor abdominal, como única sintomatología. El ultrasonido abdominal solo reportó litiasis biliar mixta, por lo que se programó cirugía electiva para colecistectomía y exploración biliar. El hallazgo intraoperatorio inesperadamente indicó una tumoración a nivel de cabeza del páncreas, y se procedió a realizar una biopsia de la lesión, colecistectomía e inserción de tubo de Kher en la vía biliar principal, ante la imposibilidad de manejo endoscópico posterior con endoprotesis. Adicionalmente, se inicio un protocolo de estudio postoperatorio, hacia la búsqueda de marcadores tumorales y tomografía axial computarizada (TAC) abdomino-pélvica, esta última evidenció tumoración en cabeza de páncreas sin infiltración a órganos vecinos o estructuras vasculares. El estudio histopatológico mostro un linfoma de páncreas, por lo que se complementaron los estudios de extensión e inició tratamiento a base de quimioterapia. En la actualidad tiene 6 meses de tratamiento con adecuada respuesta al mismo, dada por una disminución en el tamaño del tumor corroborada por tomografía y desaparición de la ictericia. Debido a los pocos casos reportados de linfoma primario de páncreas en individuos menores de 35 años, decidimos reportar este caso a fin evidenciar la importancia de un diagnóstico preoperatorio correcto, para evitar terapéuticas inadecuadas. Primary Lymphoma of Pancreas in a 27 year-old patient. A case report Abstract Pancreatic lymphomas is a rare (less than 1-2%) pancreatic malignant neoplasms, but is extremely rare in under 35 yearsold. A rare case of Primary Lymphoma of Pancreas in a 27 years old patient is described, who was initially treated for abdominal pain and jaundice. Ultrasonographic images showed a mixt biliary stone disease, and he was taken to operation room for elective cholecystectomy and biliary exploration. We found a large tumor in pancreatic head, and we decided to take a biopsy specimen retrieval, cholecystectomy and Kher tube insertion in chodelocus. A serum oncologic markers and CT scan was performed as a postoperatory studies. A pancreatic head tumor without any evidence of adjacent or vascular structures infiltration was found. Pathology report showed a primary pancreatic lymphoma and adjuvant chemotherapy was initiated. Six months after surgery and chemotherapy treatment, a diminished size of the tumor was showed by CT and no jaundice was reported. Because of the exceedingly rare in patients younger than 35 year-old, we decided to report it, in order to accurate preoperative diagnosis and treatment

Cirugía del enfisema

La historia de esta enfermedad se remonta desdehace dos siglos. En la antigüedad, se conocían los aspectos clínicos más resaltantes. La tos, respiraciónlaboriosa y la disnea, eran comunes a otros padecimientos crónicos, no sólo del enfisema pulmonar. La palabra enfisema, se deriva del griego emphysema de emphysân, soplar y denota una característica típica de los enfermos afectos de este padecimiento