The effects of ethanol on pancreatic blood flow in awake and anesthetized dogs

The pathophysiology of alcohol-induced acute pancreatitis is not clear. Ischemic injury has been suggested as a possible mechanism. To examine the effects of ethanol on pancreatic and splanchnic blood flow, measurements were made in fasted, conditioned awake dogs before and after iv infusion of ethanol (1.7 g/kg). At 30 min blood ethanol concentration ranged between 60 and 150 mg/dl and at 60 min between 166 and 350 mg/dl. Although cardiac output, aortic pressure, left atrial pressure, and arterial pH did not change, pancreatic flow declined by 39 +/- 12 ml/min/100 g, P less than 0.05 (from 173 +/- 10 ml/min/100 g) at 30 min and was still depressed (by 27 +/- 12 ml/min/100 g, P less than 0.05) at 60 min. Concomitantly, hepatic arterial flow increased. While hepatic and pancreatic flow changed inversely, the correlation (r = -0.17) of these changes was not significant. At comparable blood ethanol concentrations in pentobarbital-anesthetized dogs hepatic arterial flow increased by 11 +/- 3 ml/min/100 g, P less than 0.01 (from 24 +/- 5 ml/min/100 g), but pancreatic flow did not change. Thus, in the awake dog at blood levels that would produce mild to moderate alcoholic intoxication in man, ethanol reduces pancreatic flow. Although hepatic flow increases concomitantly, the relationship of these changes appears to be independent.     

Implementation and evaluation of a clinical pathway for TRAM breast reconstruction

Among strategies recently proposed to reduce practice variation, promote quality, and control costs in health care delivery, the concept of the clinical pathway has received considerable attention. Because transverse rectus abdominis musculocutaneous (TRAM) breast reconstruction is a common and often costly intervention, this institution sought to evaluate cost and quality outcomes of a clinical pathways program for this procedure. The TRAM reconstruction clinical pathway was implemented in April of 1996 to standardize postoperative care in this patient population. Outcomes of consecutive pathway cases for the first 14 months of the program were assessed in a retrospective cohort design, by using all nonpathway TRAM cases from the 18 months immediately before pathway implementation as controls. Outcomes assessed included length of hospital stay, postoperative complications, total postoperative charges, and total postoperative costs in relative value units. Data on these dependent variables were collected from hospital charts and billing records. The effects of pathway implementation on the outcomes of interest were analyzed by using analysis of covariance to control for potential confounding by other independent variables, including surgical site (unilateral versus bilateral reconstructions), technique (pedicle versus free TRAMs), timing (immediate versus delayed reconstructions), and patient age. Finally, a comparison of variances in the outcomes of interest between the two groups was analyzed by using an Ftest. For all statistical tests, p values of < or = 0.05 were considered significant. Twenty-nine patients were treated in the TRAM pathway group, whereas the control population included 40 nonpathway patients. After implementation of the TRAM pathway, length of stay decreased from 6.0 to 5.2 days; total postoperative charges were reduced from $8587 to $7744; and total postoperative relative value unit utilization declined from 1686 to 1104. Analysis of covariance showed that the decreases in length of hospital stay and relative value units in the TRAM pathway were statistically significant (p = 0.05 and p = 0.007, respectively). By contrast, no significant increase in complications was observed after pathway implementation. Variability in the TRAM pathway group, as measured by SD, decreased significantly for both length of hospital stay (p = 0.039) and relative value units (p = 0.023). Implementation of the TRAM reconstruction clinical pathway resulted in significant declines in length of hospital stay and total costs. These decreases in resource utilization had no significant effect on postoperative complication rates. Although additional research is needed to further assess the impact of clinical pathways, this approach offers considerable promise for improving the cost-effectiveness of health care.     

Scorpion toxins for the reversal of BoNT-induced paralysis

The botulinum neurotoxins, characterized by their neuromuscular paralytic effects, are the most toxic proteins known to man. Due to their extreme potency, ease of production, and duration of activity, the BoNT proteins have been classified by the Centers for Disease Control as high threat agents for bioterrorism. In an attempt to discover effective BoNT therapeutics, we have pursued a strategy in which we leverage the blockade of K⁺ channels that ultimately results in the reversal of neuromuscular paralysis. Towards this end, we utilized peptides derived from scorpion venom that are highly potent K⁺ channel blockers. Herein, we report the synthesis of charybdotoxin, a 37 amino acid peptide, and detail its activity, along with iberiotoxin and margatoxin, in a mouse phrenic nerve hemidiaphragm assay in the absence and the presence of BoNT/A.     

Genetic analysis of sympatric char populations in western Alaska: Arctic char (Salvelinus alpinus) and Dolly Varden (Salvelinus malma) are not two sides of the same coin

The North Pacific Ocean has been of great significance to understanding biogeography and speciation in temperate faunas, including for two species of char (Salmonidae: Salvelinus) whose evolutionary relationship has been controversial. We examined the morphology and genetics (microsatellite and mitochondrial DNA) of Arctic char (Salvelinus alpinus) and Dolly Varden char (Salvelinus malma) in lake systems in western Alaska, the eastern and western Arctic, and south of the Alaskan Peninsula. Morphologically, each lake system contained two forms: one (Arctic char) largely confined to lake habitats and characterized by greater numbers of pyloric caeca, gill rakers, and shallower bodies, and another (Dolly Varden) predominated in adjacent stream habitats and was characterized by fewer pyloric caeca, gill rakers, and deeper bodies. MtDNA partial (550 bp) d-loop sequences of both taxa were interspersed with each other within a single 'Bering' clade and demographic inferences suggested historical gene flow from Dolly Varden to Arctic char had occurred. By contrast, the taxa were strongly differentiated in sympatry across nine microsatellite loci in both lakes. Our data show that the two taxa are highly genetically distinct in sympatry, supporting their status as valid biological species, despite occasional hybridization. The interaction between these species highlights the importance of the North Pacific, and Beringia in particular, as an evolutionary wellspring of biodiversity.     

A Combination of Radiation and the Hypoxia-Activated Prodrug Evofosfamide (TH-302) is Efficacious against a Human Orthotopic Pancreatic Tumor Model

This study was designed to investigate the effect of single-dose radiation therapy (RT) in combination with evofosfamide (TH-302), a hypoxia-activated prodrug, in a pre-clinical model of pancreatic cancer. AsPC1 tumors were implanted orthotopically in the pancreas of nude mice. Tumors were treated with 15 Gy of RT, using a 1 cm diameter field, and delivered as a continuous arc. Image-guidance to center the field on the tumor was based on CT imaging with intraperitoneal contrast. Evofosfamide (100 mg/kg, i.p.) was administered 3 hours before RT. Tumor volumes were measured using ultrasound, and regrowth curves were plotted. Tumor hypoxia and cell proliferation were measured using pimonidazole and the thymidine analog EdU, respectively. In vitro clonogenic assays were performed. Tumors were shown to contain substantial areas of hypoxia, as calculated by percent pimonidazole staining. Evofosfamide was active in these tumors, as demonstrated by a significant reduction in uptake of the thymidine analog EdU. This effect was visible in oxygenated tissue, consistent with the previously reported bystander effects of evofosfamide. RT produced significant regrowth delay, as did evofosfamide. The combination of both agents produced a growth delay that was at least equal to the sum of the two treatments given separately. The improvement in tumor response when evofosfamide is combined with RT supports the hypothesis that hypoxia is a cause of radioresistance in high dose RT for pancreatic cancer. Assessing the efficacy and safety of stereotactic radiation treatment and evofosfamide is warranted in patients with locally advanced pancreatic cancer.     

A proteomic analysis of liver after ethanol binge in chronically ethanol treated rats

ABSTRACT: BACKGROUND: Binge ethanol in rats after chronic ethanol exposure augments necrosis and steatosis in the liver. In this study, two-dimensional gel electrophoresis proteomic profiles of liver of control, chronic ethanol, control-binge, and chronic ethanol- binge were compared. RESULTS: The proteomic analysis identified changes in protein abundance among the groups. The levels of carbonic anhydrase isoform 3 (CA3) were decreased after chronic ethanol and decreased further after chronic ethanol-binge. Ethanol binge alone in control rats had no effect on this protein suggesting its possible role in increased susceptibility to injury by binge after chonic ethanol treatment. A protein spot, in which both cytosolic isocitrate dehydrogenase (IDH1) and glutamine synthetase (GS) were identified, showed a small decrease after chronic ethanol binge but western blot demonstrated significant decrease only for glutamine synthetase in chronic ethanol treated rats. Level of gluathione S-transferase mu isoform (GSTM1) increased after chronic ethanol but the levels were lower after chronic ethanol-binge compared to chronic ethanol treatment. The protein levels of basic form protein disulfide isomerase associated protein 3 (PDIA3) were significantly decreased and acidic forms were increased after chronic ethanol- binge but not in chronic ethanol treated rats or ethanol binge in control rats. CONCLUSIONS: Given the role of CA3, IDH1 and GST in oxidative stress; PDIA3 in protein quality, apoptosis and DNA repair; and decreased glutamine synthetase as a sensitive marker of pericentral liver injury; this proteome study of chronic ethanol-binge rat model identifies these proteins for the first time as molecular targets with potential role in progression of liver injury by binge ethanol drinking.     

BMP signaling in vascular development and disease

Genetic and functional studies indicate that common components of the bone morphogenetic protein (BMP) signaling pathway play critical roles in regulating vascular development in the embryo and in promoting vascular homeostasis and disease in the adult. However, discrepancies between in vitro and in vivo findings and distinct functional properties of the BMP signaling pathway in different vascular beds, have led to controversies in the field that have been difficult to reconcile. This review attempts to clarify some of these issues by providing an up to date overview of the biology and genetics of BMP signaling relevant to the intact vasculature.