Activation of muscarinic potassium currents by ATP gamma S in atrial cells

Intracellular perfusion of atrial myocytes with adenosine 5'-(gamma-thio) triphosphate (ATP gamma S), an ATP analog, elicits a progressive increase of the muscarinic potassium channel current, IK(M), in the absence of agonists. In this respect, ATP gamma S mimics the actions of guanosine triphosphate (GTP) analogs, which produce direct, persistent activation of the guanyl nucleotide-binding (G) protein controlling the K+(M) channel. The effect of ATP gamma S on IK(M), however, differs from that produced by GTP analogs in two aspects: it requires relatively large ATP gamma S concentrations, and it appears after a considerable delay, suggesting a rate-limiting step not present in similar experiments performed with guanosine 5'-(gamma-thio) triphosphate (GTP gamma S). Incubation of atrial homogenates with [35S]ATP gamma S leads to formation of significant amounts of [35S]GTP gamma S, suggesting that activation of IK(M) by ATP gamma S arises indirectly through its conversion into GTP gamma S by cellular enzymes. ATP gamma S is often used to demonstrate the involvement of protein phosphorylation in the control of various cellular processes. The finding that cytosolic application of ATP gamma S can also lead to G-protein activation implies that experiments with ATP gamma S must be interpreted with caution.     

An interlaboratory study of the pharmacokinetics of testosterone following intramuscular administration to Thoroughbred horses

Testosterone is an anabolic androgenic steroid (AAS) that is endogenously produced by both male and female horses that also has the potential for abuse when administered exogenously to race horses. To recommend appropriate withdrawal guidelines so that veterinarians can discontinue therapeutic use prior to competition, the pharmacokinetics and elimination of testosterone were investigated. An aqueous testosterone suspension was administered intramuscularly in the neck of Thoroughbred horses (n = 20). The disposition of testosterone from this formulation was characterized by an initial, rapid absorption phase followed by a much more variable secondary absorption phase. The median terminal half-life was 39 h. A second focus of this study was to compare the testosterone concentrations determined by two different laboratories using a percentage similarity model with a coefficient of variation of 16.5% showing good agreement between the two laboratories results. Based on the results of this study, a withdrawal period of 30 days for aqueous testosterone administered IM is recommended.     

Structural basis of toll-like receptor 3 signaling with double-stranded RNA

Toll-like receptor 3 (TLR3) recognizes double-stranded RNA (dsRNA), a molecular signature of most viruses, and triggers inflammatory responses that prevent viral spread. TLR3 ectodomains (ECDs) dimerize on oligonucleotides of at least 40 to 50 base pairs in length, the minimal length required for signal transduction. To establish the molecular basis for ligand binding and signaling, we determined the crystal structure of a complex between two mouse TLR3-ECDs and dsRNA at 3.4 angstrom resolution. Each TLR3-ECD binds dsRNA at two sites located at opposite ends of the TLR3 horseshoe, and an intermolecular contact between the two TLR3-ECD C-terminal domains coordinates and stabilizes the dimer. This juxtaposition could mediate downstream signaling by dimerizing the cytoplasmic Toll interleukin-1 receptor (TIR) domains. The overall shape of the TLR3-ECD does not change upon binding to dsRNA.     

Somatomedin-C mediates growth hormone negative feedback by effects on both the hypothalamus and the pituitary

Somatomedin-C stimulates somatostatin release to a maximum of 390 percent of basal release during short-term (20-minute) incubation of rat hypothalamus. It has no effect on basal or stimulated growth hormone release from primary cultures of rat adenohypophyseal cells during a 4-hour incubation, but inhibits stimulated release by more that 90 percent after 24 hours. These findings suggest that somatomedin-C participates in the growth hormone negative feedback loop with an immediate effect on hypothalamic somatostatin and a delayed effect on the anterior pituitary.     

Forest restitution and protected area effectiveness in post-socialist Romania

The effectiveness of protected areas can diminish during times of pronounced socio-economic and institutional change. Our goals were to assess the effectiveness of Romanian protected areas at stemming unsanctioned logging, and to assess post-socialist logging in their surrounding landscapes, during a time of massive socio-economic and institutional change. Our results suggest that forest cover remained fairly stable shortly before and after 1990, but forest disturbance rates increased sharply in two waves after 1995 and 2005. We found substantial disturbances inside protected areas, even within core reserve areas. Moreover, disturbances in the matrix surrounding protected areas were even lower than inside protected area boundaries. We suggest that these rates are largely the result of high logging rates, triggered by rapid ownership and institutional changes. These trends compromise the goals of Romania’s protected area network, lead to an increasing loss of forest habitat, and more isolated and more fragmented protected areas. The effectiveness of Romania’s protected area network in terms of its ability to safeguard biodiversity is therefore most likely decreasing.     

A new synthesis of natural pyrethrins

A synthesis route, based on a by-product of a prostaglandin synthesis, provides access to rethrolones and rethrins with the same stereochemistry at the ring C-4 position as the natural compounds. For cinerin I, the overall yield is good and the product is a mixture of side-chain E and Z isomers. The Z:E ratio varies from 3:1 to 10:1 depending on the conditions employed.     

Pharmacokinetics of azathioprine following single-dose intravenous and oral administration and effects of azathioprine following chronic oral administration in horses

OBJECTIVE: To determine pharmacokinetics of azathioprine (AZA) and clinical, hematologic, and serologic effects of i.v. and oral administration of AZA in horses. ANIMALS: 6 horses. PROCEDURE: In study phase 1, a single dose of AZA was administered i.v. (1.5 mg/kg) or orally (3.0 mg/kg) to 6 horses, with at least 1 week between treatments. Blood samples were collected for AZA and 6-mercaptopurine (6-MP) analysis 1 hour before and at predetermined time points up to 4 hours after AZA administration. In study phase 2, AZA was administered orally (3 mg/kg) every 24 hours for 30 days and then every 48 hours for 30 days. Throughout study phase 2, blood samples were collected for CBC determination and serum biochemical analysis. RESULTS: Plasma concentrations of AZA and its metabolite, 6-MP decreased rapidly from plasma following i.v. administration of AZA, consistent with the short mean elimination half-life of 1.8 minutes. Oral bioavailability of AZA was low, ranging from 1% to 7%. No horses had abnormalities on CBC determination or serum biochemical analysis, other than 1 horse that was lymphopenic on day 5 and 26 of daily treatment. This horse developed facial alopecia from which 1 colony of a Trichophyton sp was cultured; alopecia resolved within 1 month after the study ended. CONCLUSIONS AND CLINICAL RELEVANCE: Overall, no adverse effects were observed with long-term oral administration of AZA to horses, although 1 horse did have possible evidence of immunosuppression with chronic treatment. Further investigation of the clinical efficacy of AZA in the treatment of autoimmune diseases in horses is warranted.     

Rectum diverticulum/perineal hernia surgery through longitudinal contracting of the wall of the rectum

Older male dogs often exhibit the symptoms of rectum diverticulum and perineal hernia. In order to point out the often common reason of these disorders, the term "rectum diverticulum/perineal hernia complex" has been introduced. In a large group of such patients two methods of surgical correction of this problem were retrospectively evaluated. Only patients were included in this evaluation that were euthanized if recurrence occurred. In 21 patients (group 1) the often performed method of Bojrab was used, both in rectum diverticulum and in perineal hernia operations. In group 2 15 dogs were subjected to the same operation technique, but we performed an additional pleating contraction of the herniated gut wall layers. In case of visible recurrence at an age of at least 11 years the dogs were euthanized. Group 1 showed a postoperative survival time of 3.61 +/- 0.96 years until recurrence, group 2 revealed recurrence not before 4.93 +/- 0.93 years post operationem. The difference is significant (p < 0.05). It is the opinion of the authors that additional longitudinal contracting by pleating of the gut markedly prolonges the point of time when recurrence appears.     

Species susceptibility to the pulmonary toxicity of 3-furyl isoamyl ketone (perilla ketone): in vivo support for involvement of the lung monooxygenase system

To explore a possible relationship between metabolism and lethality, the acute toxicity of naturally occurring perilla ketone (PK), 1-(3-furyl)-4-methyl-pentan-1-one, was examined in the uninduced mouse, hamster, rabbit, dog and pig. The LD50 (+/- SE), determined using intraperitoneal (ip) injection, for the mouse and hamster were low at 5.0 +/- .3 and 13.7 +/- .9 mg/kg, respectively. The rabbit died from an ip dosage of near 14 mg/kg and estimated ip LD50 dosages were quite high for the dog and pig, being 106 +/- 25 mg/kg and over 158 mg/kg, respectively. Dogs and the pig that died from ip injections of PK displayed varying degrees of midzonal and centrilobular liver damage and dogs also had elevated serum alkaline phosphatase and glutamic-pyruvic transaminase activities. In contrast, rodents and rabbits display only pulmonary toxicity from this agent. Cytochromes P-450 and b5 concentrations and NADPH-cytochrome c reductase activity were determined for the lung, liver and kidney of mice, hamsters, rabbits, dogs, swine, sheep and cattle. High correlation between lethality and enzyme concentration further supports the hypothesis that enzymatic bioactivation of PK is required for toxicity in all species.     

Morphology, life cycle biology, and DNA sequence analysis of rust fungi on garlic and chives from california

ABSTRACT In the late 1990s, commercial garlic fields in California (CA) were devastated by an outbreak of rust caused by Puccinia allii. We compared collections of the pathogen from garlic (Allium sativum) and chives (A. schoenoprasum) in central CA and Oregon (OR) to collections from garlic and leek (A. porrum and A. ampeloprasum) in the Middle East. Teliospores from the CA and OR collections were smaller in length, width, and projected cross-sectional area compared with collections from the Middle East. CA and OR collections had a shortened life cycle, in which pycnia and aecia were not formed. Germinating teliospores produced a two-celled promycelium, resulting in two basidiospores, each initially with two nuclei, indicating that this rust was homothallic. In addition, the morphology of the substomatal vesicles was different between the CA-OR (fusiform) and the Middle Eastern (bulbous) collections. DNA sequence analysis of the nuclear ribosomal internal transcribed spacer region showed that the CA and OR rust collections formed a well-supported cluster distinct from the Middle Eastern and European samples. These results suggest that the rust on garlic and chives in CA and OR is a different species than the rust fungus on garlic and leek in the Middle East.