Pharmacokinetics of ivermectin in sheep following pretreatment with Escherichia coli endotoxin.

The comparative pharmacokinetics of ivermectin (IVM), between healthy and in Escherichia coli lipopolysaccharides (LPS) injected sheep, was investigated after an intravenous (IV) administration of a single dose of 0.2 mg/kg. Ten Suffolk Down sheep, 55 ± 3.3 kg, were distributed in two experimental groups: Group 1 (LPS): treated with three doses of 1 µg LPS/kg bw at -24, -16, and -0.75 hr before IVM; group 2 (Control): treated with saline solution (SS). An IV dose of 0.2 mg IVM/kg was administered 45 min after the last injection of LPS or SS. Plasma concentrations of IVM were determined by liquid chromatography. Pharmacokinetic parameters were calculated based on non-compartmental modeling. In healthy sheep, the values of the pharmacokinetic parameters were as follows: elimination half-life (2.85 days), mean residence time (MRT) (2.27 days), area under the plasma concentration curve over time (AUC, 117.4 ng day-1 ml-1 ), volume of distribution (875.6 ml/kg), and clearance (187.1 ml/day). No statistically significant differences were observed when compared with the results obtained from the group of sheep treated with LPS. It is concluded that the acute inflammatory response (AIR) induced by the intravenous administration of E. coli LPS in adult sheep produced no changes in plasma concentrations or in the pharmacokinetic behavior of IVM, when it is administered intravenously at therapeutic doses.

Mechanical stretch increases L-type calcium channel stability in cardiomyocytes through a polycystin-1/AKT-dependent mechanism.

The L-type calcium channel (LTCC) is an important determinant of cardiac contractility. Therefore, changes in LTCC activity or protein levels could be expected to affect cardiac function. Several studies describing LTCC regulation are available, but only a few examine LTCC protein stability. Polycystin-1 (PC1) is a mechanosensor that regulates heart contractility and is involved in mechanical stretch-induced cardiac hypertrophy. PC1 was originally described as an unconventional Gi/o protein-coupled receptor in renal cells. We recently reported that PC1 regulates LTCC stability in cardiomyocytes under stress; however, the mechanism underlying this effect remains unknown. Here, we use cultured neonatal rat ventricular myocytes and hypo-osmotic stress (HS) to model mechanical stretch. The model shows that the Cavß2 subunit is necessary for LTCC stabilization in cardiomyocytes during mechanical stretch, acting through an AKT-dependent mechanism. Our data also shows that AKT activation depends on the G protein-coupled receptor activity of PC1, specifically its G protein-binding domain, and the associated Gßγ subunit of a heterotrimeric Gi/o protein. In fact, over-expression of the human PC1 C-terminal mutant lacking the G protein-binding domain blunted the AKT activation-induced increase in Cav1.2 protein in cardiomyocytes. These findings provide novel evidence that PC1 is involved in the regulation of cardiac LTCCs through a Gißγ-AKT-Cavß2 pathway, suggesting a new mechanism for regulation of cardiac function.

Mooren's ulcer: 30 years of follow-up. / Úlcera de Mooren: 30 años de seguimiento.

CASE REPORT: A 33-year-old Caucasian female presented with epiphora, ocular pain, and foreign body sensation in both eyes for one month. Examination revealed bilateral peripheral corneal ulcers. The patient had been treated with immunomodulators, and she was treated in the left eye with peripheral semi-circular keratoplasty, penetrating keratoplasty, conjunctival-corneal-scleroplasty, buccal mucosal graft, tibial osteo-keratoprosthesis and finally, retinal detachment. DISCUSSION: Mooren's ulcer is an immunological corneal disease. This lesion must be treated initially with immunomodulators. Surgical treatment should be considered when a risk of corneal perforation is present, when the perforation appears, or under acute necrosis.

Similarities between the Binding Sites of SB-206553 at Serotonin Type 2 and Alpha7 Acetylcholine Nicotinic Receptors: Rationale for Its Polypharmacological Profile.

Evidence from systems biology indicates that promiscuous drugs, i.e. those that act simultaneously at various protein targets, are clinically better in terms of efficacy, than those that act in a more selective fashion. This has generated a new trend in drug development called polypharmacology. However, the rational design of promiscuous compounds is a difficult task, particularly when the drugs are aimed to act at receptors with diverse structure, function and endogenous ligand. In the present work, using docking and molecular dynamics methodologies, we established the most probable binding sites of SB-206553, a drug originally described as a competitive antagonist of serotonin type 2B/2C metabotropic receptors (5-HT2B/2CRs) and more recently as a positive allosteric modulator of the ionotropic α7 nicotinic acetylcholine receptor (nAChR). To this end, we employed the crystal structures of the 5-HT2BR and acetylcholine binding protein as templates to build homology models of the 5-HT2CR and α7 nAChR, respectively. Then, using a statistical algorithm, the similarity between these binding sites was determined. Our analysis showed that the most plausible binding sites for SB-206553 at 5-HT2Rs and α7 nAChR are remarkably similar, both in size and chemical nature of the amino acid residues lining these pockets, thus providing a rationale to explain its affinity towards both receptor types. Finally, using a computational tool for multiple binding site alignment, we determined a consensus binding site, which should be useful for the rational design of novel compounds acting simultaneously at these two types of highly different protein targets.

Comparación de la estabilización precoz versus tardía en el trauma raquimedular / Comparison of early versus delayed stabilization in spinal cord injury

El Trauma Raquimedular (TRM) es el resultado del daño18, 19 producido por lesiones traumáticas vertebrales a cualquier nivel y que comprometen a las diferentes estructuras que componen la columna vertebral, particularmente la médula espinal o sus raíces. Su incidencia14, 16 varía entre 11.5 y 53.4 por cada millón de habitantes y la causa más frecuente en nuestro país son las caídas. La región cervical es la más afectada seguida de la unión toracolumbar. Los segmentos torácicos y lumbares se comprometen con menor frecuencia, siendo similar en ambos niveles. Es una patología catastrófica para los pacientes y sus familias, ya que habitualmente los afectados son personas jóvenes en edad productiva17. Conjuntamente con el inmenso problema social, esta patología constituye un gran problema económico15 para los sistemas de salud debido al alto costo que implica su tratamiento tanto en la fase aguda como su posterior rehabilitación. El tratamiento del TRM se debe iniciar desde el momento en que se sospecha una lesión medular. Con el fin de evitar el daño medular secundario, además de la inmovilización precoz1,2,3,4,5,6,9, 20 se han probado distintos protocolos de tratamientos farmacológicos7,8,10,12,13, sin resultados que avalen su uso. Los protocolos basados en los estudios NASCIS21,22,23,24 utilizados en la actualidad emplean metilprednisolona en dosis de 30 mg/kg en bolo infundido en 15 minutos, seguido de una infusión en dosis de 5.4 mg/kg/hora. Dependiendo si el tiempo transcurrido desde la lesión es menor a 3 horas la infusión se mantiene por 23 horas y si la lesión se encuentra entre 3 y 8 horas se mantiene por 47 horas. Del mismo modo se han utilizado TRH26, Gaciclidina, Naloxona22, Tirilizad24, Nimodipino25 y más recientemente se ha propuesto el tratamiento de células madres27,28. Por otra parte una serie de trabajos11 sugieren que la descompresión y estabilización precoz en TRM disminuye el daño medular así como las complicaciones médicas...

Spinal Cord Injury (SCI) is due to traumatic lesions involving spine, specially spinal cord and its roots. This is a catastrophic neurological disorder for the patients which are usually young people in productive age. The incidente range is from 11.5 to 53.4 per million people. Besides the great social problem it brings another important issue for health systems due to high costs involved. Different pharmacologic protocols have been proposed to avoid a possible further damage, without results supporting their use. Otherwise multiple studies suggest that early spine decompression and stabilization diminish secondary spinal cord damage as well as medical complications and period of hospitalization. Our study retrospectively evaluated a group of patients who received a late decompression and stabilization and one that received an early within the first 72 hours focusing in pre and post surgical stay and associated medical complications. The data were obtained of the Neurosurgical Department of The Rancagua Regional Hospital database and includes 233 patients with spinal cord injury between May 1997 and October 2009. Cervical Spinal Cord Injury is more prevalent and more common in middle age men. Patients who underwent early decompression were hospitalized less time and suffer less medical complications.

Case report: Conservative management of an arteriovenous fistula of the inferior epigastric artery.

We present a case of pseudoaneurysm and arteriovenous fistula of the inferior epigastric artery secondary to the placement of a drain during a surgical intervention. We stress the utility of colour Doppler ultrasound and arteriography embolisation in diagnosis and treatment, respectively.

Intestinal perforation by foreign bodies.

OBJECTIVE: To present our experience of patients who presented with intestinal perforation by foreign bodies to our hospital between 1980 and 1998. DESIGN: Retrospective study. SETTING: University hospital, Spain. SUBJECTS: 21 patients who presented with intestinal perforation by foreign bodies. MAIN OUTCOME MEASURES: Size of perforations, nature of foreign bodies, clinical symptoms, radiological findings, treatment and outcome. RESULTS: The most common location was the terminal ileum (n = 11), followed by the rectosigmoid junction (n = 5). The objects were mainly bone fragments and toothpicks. The diagnosis was generally made at operation, and only 4 of the 21 patients had signs of pneumoperitoneum on the preoperative abdominal film. The most common treatment was simple suture of the defect. CONCLUSIONS: Intestinal perforation by a foreign body is uncommon, and normally affects the ileocaecal and rectosigmoid regions, in which it is unusual to find pneumoperitoneum preoperatively. It must be considered in the differential diagnosis of such conditions as acute appendicitis and diverticulitis.

Esophageal candidiasis in HIV-negative patients.

UNLABELLED: Candida esophagitis is the most frequent esophageal infection in HIV seropositive as well as in seronegative patients. AIM: this retrospective study was designed to determine the characteristics of this disease in HIV negative patients in a general hospital. DESIGN: clinical records of all HIV negative patients with Candida esophagitis, which was endoscopically diagnosed and microscopically confirmed (biopsy and/or cytology of esophageal mucosa), were studied. RESULTS: thirty-one patients (23 men, 8 women, mean age: 65.4 +/- 14.3 years, median 71) fulfilled the criteria (0.56% of the diagnostic esophagogastroduodenal endoscopies). The most common clinical symptoms were dysphagia with or without odynophagia and pain (retrosternal, epigastric or xiphoid). Fourteen patients (45%) had no esophageal signs; in nine of them (29%) the disease was diagnosed in the course of an endoscopic exam to investigate the sources of acute or chronic anaemia. The most frequent predisposing factors were diabetes mellitus, oral or aerosolized corticotherapy, malignancies, treatment with broad-spectrum antibiotics and liver cirrhosis. Nine patients (29%) presented no known predisposing factors. The most common endoscopic appearance was grade II (51%). Sixty-one per cent of the patients exhibited at least one other esophagogastroduodenal endoscopic lesion associated with the mycosis. Three patients died of their underlying diseases within one week of the diagnosis of the candidiasis. Only one patient presented persistence of candidiasis one week after initiating treatment with oral nystatine. CONCLUSIONS: esophageal candidiasis is infrequent and does not always present with suspicious symptoms or known predisposing factors. Aerosolized corticotherapy may be a risk factor for the development of esophageal candidiasis.

Forceps and vacuum injuries to the cornea: histopathologic features of twelve cases and review of the literature.

Histopathologic and ultrastructural features were examined from 11 cases of corneal injury from obstetrical forceps and one case from vacuum extraction. Four major types of histopathologic features were observed. Type I (n = 4) included large tears of Descemet's membrane with a fragment of Descemet's membrane extending into the anterior chamber at one end of the tear and scroll formation at the other end. Type II (n = 6) consisted of scrolls of Descemet's membrane at each margin of the original break. Type III (n = 2) included those with small breaks in Descemet's membrane and healing by fibrosis at and posterior to the original tear. Type IV (n = 1) contained a small break in Descemet's membrane with minimal fibrosis. Transmission electron microscopy revealed Descemet's scrolls and retrocorneal fibrous tissue. Scanning electron microscopy revealed folds in Descemet's membrane and attenuation or absence of endothelium. Spindle- and stellate-shaped cells and pigment granules were present in the area of the tear in most cases. A review of the literature is presented.