Hemodynamics of pancreatic ischemia in cardiogenic shock in pigs

BACKGROUND & AIMS: Previous studies have shown that the renin-angiotensin axis plays a pivotal role in vasoconstriction of the gastric, intestinal, and hepatic circulations during cardiogenic shock. The aim of this study was to evaluate the fundamental hemodynamic mechanism of pancreatic ischemia during cardiogenic shock induced by pericardial tamponade. METHODS: Cardiogenic shock was induced by pericardial tamponade. Cardiac output (and total peripheral vascular resistance) was determined by thermodilution. Pancreatic blood flow (and vascular resistance) was determined with radiolabeled microspheres. RESULTS: Graded increases in pericardial pressure produced corresponding decreases in cardiac output to 42% +/- 1% and arterial pressure to 67% +/- 3% of baseline and increases in total peripheral vascular resistance to 146% +/- 5% of baseline. Pancreatic blood flow decreased disproportionately to 30% +/- 3% of baseline, because of a disproportionate increase in pancreatic vascular resistance to 220% +/- 19% of baseline. Previously confirmed blockade of the renin-angiotensin axis ablated this response, whereas confirmed blockade of the alpha-adrenergic system or vasopressin system had no significant effect. Without shock, central intravenous infusions of angiotensin II closely mimicked this selective vasoconstriction. CONCLUSIONS: Angiotensin-mediated selective pancreatic vasoconstriction results in significant pancreatic ischemia during cardiogenic shock.     

Endothelial cells potentiate oxidant-mediated Kupffer cell phagocytic killing

Phagocytosis and killing of circulating organisms by Kupffer cells (KCs) are discrete, important components of host defense. However, the killing mechanism(s) are not fully understood, and the potential role of adjacent nonparenchymal cells such as hepatic endothelial cells has not been defined. Rat KCs -/+ an hepatic endothelial cell enriched cellular fraction (HECEF) were incubated with Candida parapsilosis and assayed for phagocytosis and phagocytic killing by validated fluorochromatic vital staining. The role of reactive oxygen metabolites in KC phagocytic functions was examined by inhibition with superoxide dismutase and/or catalase. Diphenyleneiodonium and allopurinol were used to examine the potential roles of NADPH oxidase and xanthine oxidase, respectively, in generating these toxic oxidants. Coculture with HECEF increased KC phagocytic activity (from 75% to 88%) and candidacidal activity (from 20% to 31%). Superoxide dismutase, catalase, diphenyleneiodonium, or allopurinol caused inhibition of candidacidal activity, but did not affect phagocytosis, and did not block the potentiation of phagocytosis or of killing caused by coculture with HECEF. Reactive oxygen intermediates generated by both NADPH oxidase and xanthine oxidase-dependent pathways are important in KC killing of Candida parapsilosis. In vitro, KC phagocytosis and killing are potentiated (via a non-oxidant-mediated mechanism) by coculture with a preparation of hepatic non-parenchymal cells composed primarily of endothelial cells.     

Observations of structure development during crystallisation of oriented poly(ethylene terephthalate)

Two types of SAXS and WAXS experiments have been made using synchrotron radiation to observe the transformation from smectic to crystalline phases in oriented poly(ethylene terephthalate) (PET). In step-anneal experiments, PET was drawn slowly at 30 °C and then observed after annealing at 5 °C steps up to 100 °C. In the other experiments, time-resolved observations were made while drawing at 90 °C at rates up to 10 s⁻¹. Up to 70 °C the WAXS data in the step-anneal experiments showed the smectic meridional reflection reducing in lateral width, indicating an increase in lateral long range order with annealing. Between 70 and 100 °C, there was a reduction in the intensity of the smectic reflection which correlated with an increase in the intensity of crystalline reflections. The SAXS from the step-anneal experiments showed an intense equatorial streak which has a correlation peak around 20 nm and which diminishes with annealing above 70 °C. It is concluded that this feature is a characteristic of the presence of the mesophase in oriented PET and is due to elongated domains of smectic mesophase with a length >75 nm and with an interdomain spacing of around 20 nm. Between 70 and 100 °C the SAXS data showed additional diffuse diffraction which correlated quantitatively with the crystalline phase and evolved from a cross-like appearance to a well resolved four-point pattern. The time-resolved drawing experiments were limited by the time resolution of the SAXS detector. They showed the same development of four-point diffuse SAXS patterns as was observed in the step-anneal experiments and a very weak equatorial streak. Differences in phase transformation kinetics between the two types of experiment are attributed to the different chain relaxation processes available under different conditions.     

Modulation of methylnitrosourea-induced breast cancer in Sprague Dawley rats by dehydroepiandrosterone: dose-dependent inhibition, effects of limited exposure, effects on peroxisomal enzymes, and lack of effects on levels of Ha-Ras mutations

Although bile salts play an important role in the secretion of biliary lipid, little is known about the relationship between bile salt hydrophobicity and the selection of lecithin species to be secreted into bile. We therefore investigated whether bile salts modulate the selection of biliary lecithin subspecies. Rats that were depleted of the bile salt pool were infused with taurocholate (50, 100, 200, and 400 nmol/min/100 g body weight), taurochenodeoxycholate (25, 50, 100, and 200 nmol/min/100 g body weight), tauroursodeoxycholate (100, 200, 400, and 800 nmol/min/100 g body weight), or taurobetamuricholate (100, 200, 400, and 800 nmol/min/100 g body weight). Bile was collected to analyze bile flow, bile acid output, cholesterol levels, and lecithin levels. The hydrophobic-hydrophilic balance of the bile salts and biliary lecithin species was assessed by determining the retention times during reverse-phase high-performance liquid chromatography. Biliary lecithin secretion rates correlated with the hydrophobicity index of the biliary bile salts administered. Thus, biliary lecithin hydrophobicity increased with increasing bile salt hydrophobicity, whereas the molar cholesterol-lecithin ratio in the bile decreased. In conclusion, bile salt hydrophobicity regulates the selection of biliary lecithin subspecies during biliary secretion and thereby modulates, at least in part, bile cholesterol metastability. Thus, bile salt hydrophobicity accounts for the physicochemical conditions determining bile lipid metastability.     

Heregulin and agonistic anti-p185(c-erbB2) antibodies inhibit proliferation but increase invasiveness of breast cancer cells that overexpress p185(c-erbB2): increased invasiveness may contribute to poor prognosis

Overexpression of p185(c-erbB2) (p185/NEU/HER2) by tumor cells is associated with a poor prognosis in many but not all studies of breast and ovarian cancer. The poor prognosis associated with overexpression of p185(c-erbB2) could result from an increased growth rate or increased invasive potential. The p185(c-erbB2) tyrosine kinase receptor can be activated with agonistic antibodies directed against p185(c-erbB2) or with the ligand heregulin through a combinatorial interaction with erbB3 or erbB4. Consequently, we have asked whether heregulin or agonistic antibodies increase anchorage-independent growth or invasiveness of the SKBr3 breast cancer cell line, which overexpresses p185(c-erbB2). Incubation of SKBr3 breast cancer cells with heregulin inhibited anchorage-independent growth while enhancing tyrosine phosphorylation of p185(c-erbB2). Heregulin treatment also increased adhesion of SKBr3 cells to plastic and increased invasiveness of tumor cells into Matrigel membranes while increasing expression of the CD44 (HCAM) and CD54 (ICAM-1) adhesion molecules. Tumor cell invasion of Matrigel membranes was partially blocked by either anti-CD44 or anti-CD54 antibodies, indicating a role for these adhesion molecules in the invasion process. Compatible with the increased invasiveness, heregulin increased expression of the matrix metalloproteinase 9. In contrast, the agonistic anti-p185(c-erbB2) antibody ID5 induced only a subset of the responses induced by heregulin. ID5 induced tyrosine phosphorylation of p185(c-erbB2), increased invasiveness, and increased expression of CD44. Despite the similarity of effects of ID5 and heregulin on some outcomes, the ID5 antibody failed to increase adhesion to plastic, expression of CD54, or production of matrix metalloproteinase 9. Thus, the ID5 agonistic anti-p185(c-erbB2) antibody mimics rather than antagonizes some but not all of the actions of heregulin. Moreover, the poor prognosis of breast and ovarian cancers that overexpress p185(c-erbB2) could relate in part to enhanced invasiveness rather than to increased proliferative capacity.     

Comparison of hexachlorocyclohexane-induced oxidative stress in the testis of immature and adult rats

1. The acute effect of hexachlorocyclohexane (HCH) administration (i.p.) on testicular antioxidant system and lipid peroxidation (LPX) in immature and mature rats (15- and 90-day-old, respectively) were compared. 2. In both the age groups, the level of LPX in crude homogenate of testis (endogenous, as well as FeSO4, and ascorbic acid-stimulated) was increased after 6 hr of HCH treatment and remained high till 24 hr. However, FeSO4 and ascorbic acid-stimulated LPX was higher in 90-day-old rats in comparison to 15-day-old rats. HCH treatment also resulted in elevation of LPX level in testicular subcellular (nuclear, mitochondrial and microsomal) fractions by 6 hr of treatment. However, the magnitude of increase was greater in case of 90-day-old rats. 3. Activities of testicular cytosolic superoxide dismutases (total and CN(-)-resistant) of rats of 15- and 90-day-old age groups decreased significantly after 6 hr of HCH treatment, and remained decreased till 24 hr of the pesticide treatment. The percentage of decrease was higher in 15-day-old rats than 90-day-old rats. CN(-)-sensitive SOD activity of testis was found to decrease by 12 and 24 hr after the pesticide treatment in 15- and 90-day-old rats, respectively. The activity of catalase decreased 6 hr after the pesticide treatment in both the age groups. However, the magnitude of decrease was similar for both age groups of rats. 4. Testicular glutathione content, as well as levels of glutathione metabolizing enzymes (glutathione peroxidase and glutathione reductase), did not change in response to HCH treatment, whereas ascorbic acid content decreased by 12 and 6 hr after HCH treatment in 15- and 90-day-old rats, respectively. The level of H2O2 was found to be elevated after 6 hr of the pesticide treatment in both age groups. 5. Total epididymal sperm number was comparable in all experimental groups. However, the percentage of dead and damaged spermatozoa was significantly enhanced in HCH treated rats. 6. Acute HCH administration to rats results in induction of oxidative stress in the testis which depends upon the age of the animal.