Population pharmacokinetics of nitroglycerin and of its two metabolites after a single 24-hour application of a nitroglycerin transdermal matrix delivery system

OBJECTIVES: To determine whether oxytocin exists in the cerebrospinal fluid (CSF) of dogs and whether the amount of oxytocin in the CSF of dogs with neck or back pain caused by spinal cord compression is significantly different than that in the CSF of clinically normal dogs. STUDY DESIGN: Prospective controlled study. ANIMAL POPULATION: A total of 15 purpose-bred beagles and 17 client-owned dogs. METHODS: CSF was collected by needle puncture of the cerebellar medullary cistern after induction of general anesthesia. Oxytocin levels within the samples were determined through radioimmunoassay. RESULTS: Dogs with spinal cord compression had significantly more oxytocin in their CSF than the clinically normal dogs (13.76 +/- 2.0 pg/mL and 3.61 +/- 0.63 pg/mL, respectively; P < .0001). Dogs with chronic signs (>7 days) had significantly more oxytocin in their CSF than dogs with acute signs (<7 days) (21.60 +/- 0.86 pg/mL and 6.80 +/- 0.81 pg/mL, respectively; P < .0001). Both acutely and chronically affected dogs had significantly more oxytocin in their CSF than the controls (P < .005 and P < .0001 respectively). CONCLUSIONS: Dogs with neck and back pain caused by spinal cord compression have significantly more oxytocin in their CSF than clinically normal dogs. Dogs with chronic clinical signs have significantly more oxytocin in their CSF than dogs with acute clinical signs. CLINICAL RELEVANCE: In humans, intrathecal injection of oxytocin is effective in treating low back pain for up to 5 hours. Intrathecal oxytocin may be a logical choice for perioperative analgesia in dogs undergoing myelography because the intrathecal space is accessed for injection of contrast agent.     

Ethanol-mediated neutrophil extravasation in feline pancreas

Ethanol is a common cause of both acute and chronic pancreatitis. Studies in other organs suggest that polymorphonuclear neutrophils activated by ethanol may cause tissue injury in a variety of conditions. The aim of this study was to investigate the effects of ethanol on neutrophil extravasation in the feline pancreas. Pancreata were isolated and perfused at different flow rates with varying concentrations of ethanol in either a physiological or neutrophil depleted perfusate. Neutrophil extravasation was assessed by measuring pancreatic tissue myeloperoxidase (MPO) activity. Ethanol at 2.5% (54.25 mmol/liter) was the lowest concentration that still caused significant neutrophil extravasation (3.1+/-0.8 vs 1.9+/-0.2 units, P<0.05) and was accompanied by an increase in vascular resistance of 15%. Reduction of pancreatic perfusion by 15% did not significantly increase neutrophil extravasation. (1.1+/-0.3 vs 1.6+/-0.2 units, NS) Perfusion of the pancreas with neutrophil-depleted blood containing either ethanol or saline, followed by perfusion with an ethanol-free perfusate, showed an increase in neutrophil extravasation in the ethanol group compared to the control group (3.2+/-0.9 vs 1.9+/-0.2 units, P<0.05). In conclusion, ethanol causes neutrophil extravasation in the feline pancreas independent of blood flow changes and occurs despite the absence of direct neutrophil exposure to ethanol.     

A sonographically guided technique for central venous access

OBJECTIVE: The internal jugular vein (IJV) is an important access to the central venous system. We compared sonographically guided technique with the traditional anatomic landmark technique for IJV catheterization. SUBJECTS AND METHODS: In a prospective randomized trial, 100 patients underwent routine catheterization of the IJV (50 patients in the sonography group and 50 patients in the anatomic landmark group). Access time, failure rates, and complication rates were evaluated. In addition, the physicians' number of years of experience with catheter insertion was recorded. RESULTS: Access time was markedly shorter with the sonographically guided technique (mean, 15.2 sec; range, 8-76 sec) than with the anatomic landmark technique (mean, 51.4 sec; range, 3-820 sec) (p = .001). The failure rate was significantly lower with the sonographically guided technique (p = .002). Complications were fewer with the sonographically guided technique (neck hematoma, 2% versus 10%; plexus irritation, 4% versus 6%; carotid artery puncture, 0% versus 12%). We found that the number of years of postgraduate clinical training was greater in the group of physicians using the anatomic landmark technique. CONCLUSION: The sonographically guided technique is associated with less risk and less inconvenience for patients, especially critically ill patients, for whom the technique provides fast, safe, and easy IJV catheterization.     

Mutant PCNA alleles are associated with cdc phenotypes and sensitivity to DNA damage in fission yeast

Twenty-eight site-directed mutations were introduced into the fission yeast gene (pcn1+) that encodes proliferating cell nuclear antigen (PCNA) and their in vivo effects analyzed in a strain with a null pcn1 background. Mutants defective in enhancing processivity of DNA polymerase delta have previously been identified. In this study, we assessed all of the mutants for their sensitivities to temperature, hydroxyurea, UV irradiation and methyl methanesulfonate (MMS), and specific mutants were also tested for sensitivity to gamma irradiation. One cold-sensitive allele, pcn1-3, was characterized in detail. This mutant had a recessive cold-sensitive cdc phenotype and showed sensitivity to hydroxyurea, UV, and gamma irradiation. At the non-permissive temperature pcn1-3 protein was able to form homotrimers in solution and showed increased stimulation of both synthetic activity and processivity of DNA polymerase delta relative to the wild-type Pcn1+ protein. Epistasis analyses indicated that pcn1-3 is defective in the repair pathway involving rad2+ but not defective in the classical nucleotide excision repair pathway involving rad13+. Furthermore, pcn1-3 is either synthetically or conditionally lethal in null checkpoint rad backgrounds and displays a mitotic catastrophe phenotype in these backgrounds. A model for how pcn1-3 defects may affect DNA repair and replication is presented.