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Biomedical subjects

J Werner

Publications and source records attributed to J Werner.

At least 91 records · Page 5Linked to original sources
PubMed1998

Modulation of the vascular smooth muscle angiotensin subtype 2 (AT2) receptor by angiotensin II.

The angiotensin subtype 2 (AT2) receptor is scarce in most adult vascular tissues except after injury. Since angiotensin II (AngII) is released upon injury, we examined the possibility that AngII governs AT2 receptor expression in smooth muscle cells (SMC). A polyclonal antiserum, raised to a peptide corresponding to the AT2 receptor C-terminus, recognized a approximately 45-kDa protein after transfection of cos-7 cells with AT2 receptor cDNA. Detection of a approximately 65-kDa band in extracts of SMC indicated that the AT2 receptor was glycosylated. Treatment of SMCs with AngII increased AT2 receptor levels fourfold over 24 h. This response was abrogated by losartan, but not by PD123319, indicating AT1 receptor involvement. AngII-dependent increases in AT2 receptor levels were also prevented by LY294002, an inhibitor of phosphatidyinositol 3-kinase, but not by rapamycin. These results indicate AngII influences AT2 receptor expression through the AT1 receptor via a signaling pathway that includes PI3K.

Angiotensin II↗
PubMed1998

Expression and regulation of the insulin-like growth factor-1 receptor by growing and quiescent H4IIE hepatoma.

Recent evidence that insulin-like growth factor-1 (IGF-1) influences certain properties of H4IIE hepatoma cells independent of insulin led us to examine whether H4IIE cells express IGF-1 receptors. Competitive binding experiments demonstrated IGF-1, but not insulin or IGF-II, could compete with [125I]IGF-1. Chemical crosslinking detected a protein with an apparent mass of 175 kDa and its identity as the IGF-1 receptor alpha-subunit was confirmed by Western blotting. The apparent molecular mass of this protein decreased to 135 kDa following deglycosylation. Immunofluorescence microscopy verified that both insulin and IGF-1 receptors were present, although measurement of IGF-1 receptor quantity revealed they were less abundant than insulin receptors. Binding of IGF-1 was low in growing cells and higher in a quiescent cell population. Scatchard analysis confirmed that receptor density was increased in non-growing H4IIE cells while there was no apparent difference in receptor affinity. Western blot analysis and RT-PCR revealed that both protein and mRNA levels were elevated as cell growth ceased. Interestingly, addition of insulin to quiescent H4IIE cells, which stimulates cell proliferation, further increased IGF-1 receptor protein levels with a peak at 12-24 h. Distinct modes of regulating IGF-1 receptor expression are indicated.

Animals↗
PubMed1998

Non-invasive temperature imaging of muscles with magnetic resonance imaging using spin-echo sequences.

The application of spin-echo magnetic resonance imaging sequences on non-invasive temperature imaging for temperature mapping of human limbs is investigated. In an in vitro experiment performed on a meat sample, the equilibrium magnetisation P and the spin-lattice relaxation time T1 are calculated from the values for the repetition time TR and the signal intensities obtained by a spin-echo sequence at different tissue temperatures as measured by a fibre-optic probe. T1 is linearly correlated to the tissue temperature, and P is linearly correlated to the reciprocal value of the absolute temperature. Both effects, taken together, lead to a non-linear dependency of the signal intensity on temperature. Therefore a TR leading to maximum temperature dependency of the signal intensity is calculated and used in the further experiments. In the in vivo experiments, the lower legs of two volunteers are cooled from outside. Images are acquired with a spin-echo sequence (1.5 T, TR = 1200 ms, TE = 10 ms). A rise in signal intensity in the muscle with falling skin temperature is observed, particularly in more peripheral muscle layers. This study shows that spin-echo sequences can be used to monitor temperature changes and temperature differences in living muscle tissue.

Animals↗
PubMed1998

Technetium-99m-labeled white blood cells: a new method to define the local and systemic role of leukocytes in acute experimental pancreatitis.

OBJECTIVE: We developed a new method to quantitate leukocyte accumulation in tissues and used it to examine the time course and severity of acute experimental pancreatitis. BACKGROUND: Leukocyte activation and infiltration are believed to be critical steps in the progression from mild to severe pancreatitis and responsible for many of its systemic complications. METHODS: Pancreatitis of graded severity was induced in Sprague-Dawley rats with a combination of caerulein and controlled intraductal infusion. Technetium-99m (99mTc)-labeled leukocytes were quantified in pancreas, lung, liver, spleen, and kidney and compared with myeloperoxidase activity. The severity of pancreatitis was ascertained by wet/dry weight ratio, plasma amylase, and trypsinogen activation peptide in the pancreas. The time course of leukocyte accumulation was determined over 24 hours. RESULTS: Pancreatic leukocyte infiltration correlated well with tissue myeloperoxidase concentrations. In mild pancreatitis, leukocytes accumulated only in the pancreas. Moderate and severe pancreatitis were characterized by much greater leukocyte infiltration in the pancreas than in mild disease (p < 0.01), and increased 99mTc radioactivity was detectable in the lung as early as 3 hours. 99mTc radioactivity correlated directly with the three levels of pancreatitis. CONCLUSIONS: Mild pancreatitis is characterized by low-level leukocyte activation and accumulation in the pancreas without recruitment of other organs; marked leukocyte accumulation was found in the pancreas and in the lung in more severe grades of pancreatitis. These findings provide a basis for the pathophysiologic production of cytokines and oxygen free radicals, which potentiate organ injury in severe pancreatitis. This study validates a new tool to study local and systemic effects of leukocytes in pancreatitis as well as new therapeutic hypotheses.

Acute Disease↗
PubMed1998

The relative safety of MRI contrast agent in acute necrotizing pancreatitis.

OBJECTIVE: To validate the safety of gadolinium-diethylenetriamine pentaacetic acid (GD-DTPA) by measuring its effect on pancreatic capillary perfusion and acinar injury in acute pancreatitis. BACKGROUND: Contrast-enhanced computed tomography (CECT) is proposed as a gold standard for early evaluation of acute necrotizing pancreatitis. However, iodinated contrast media used for CECT have been shown in these circumstances to reduce pancreatic capillary flow and increase necrosis and mortality. Recent reports suggest that post-GD MRI provides images comparable to CECT in the assessment of severe acute pancreatitis. METHODS: Necrotizing pancreatitis was induced in 14 Wistar rats by intraductal glycodeoxycholic acid (10 mM/L) and intravenous caerulein (5 microg/kg/h) over 6 hours. Intravital microscopic quantitation of pancreatic capillary blood flow was performed using fluorescein isothiocyanate-labeled erythrocytes after induction of pancreatitis and 30 and 60 minutes after an intravenous bolus of either Ringer's solution or GD-DTPA (0.2 mL/kg). RESULTS: The two study groups were comparable with regard to mean arterial pressure, heart rate, arterial blood gases, hematocrit, amylase, lipase, and trypsinogen activation peptide production throughout the experiment. GD-DTPA did not reduce capillary flow (1.93 +/- 0.05 nL/capillary/min) compared to animals infused with Ringer's solution (1.90 +/- 0.06 nL/capillary/min). CONCLUSIONS: Intravenous injection of GD-DTPA does not further impair pancreatic microcirculation or increase acinar injury in acute necrotizing pancreatitis. Because of this advantage over CT contrast medium, further development of MRI as a staging tool in acute pancreatitis seems desirable.

Animals↗
PubMed1998

On the protective mechanisms of nitric oxide in acute pancreatitis.

BACKGROUND: Ectopic protease activation, microcirculatory changes, and leucocyte activation are the main events in the pathogenesis of acute pancreatitis. Nitric oxide (NO) is known to be a key mediator in the normal and inflamed pancreas. AIMS: To investigate the targets on which NO exerts its effect in caerulein induced pancreatitis. METHODS: Acute pancreatitis was induced in rats which additionally received either the NO synthase substrate, L-arginine; the NO donor, sodium nitroprusside; or the NO synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME). At six hours, pancreatic injury (oedema, leucocyte content, ectopic trypsinogen activation) was analysed and pancreatic oxygenation and perfusion were determined. A direct influence of NO on amylase secretion and trypsinogen activation was evaluated separately in vitro. RESULTS: Both NO donors reduced the grade of inflammation. L-NAME increased the severity of inflammation, while decreasing pancreatic tissue oxygenation. Although neither amylase secretion nor intracellular trypsinogen activation in caerulein stimulated pancreatic acini was influenced by either NO donors or inhibitors, both NO donors decreased intrapancreatic trypsinogen activation peptide (TAP) and pancreatic oedema in vivo, and L-NAME increased TAP. CONCLUSIONS: NO protects against injury caused by pancreatitis in the intact animal but has no discernible effect on isolated acini. It is likely that in pancreatitis NO acts indirectly via microcirculatory changes, including inhibition of leucocyte activation and preservation of capillary perfusion.

Acute Disease↗
PubMed1998

On the validity of the Beck Depression Inventory. A review.

The present review discusses validity aspects of the Beck Depression Inventory (BDI) on the basis of meta-analyses of studies on the psychometric properties. Shortcomings of the BDI are its high item difficulty, lack of representative norms, and thus doubtful objectivity of interpretation, controversial factorial validity, instability of scores over short time intervals (over the course of 1 day), and poor discriminant validity against anxiety. Advantages of the inventory are its high internal consistency, high content validity, validity in differentiating between depressed and nondepressed subjects, sensitivity to change, and international propagation. The present paper outlines agreements and contradictions between the various studies on the BDI and discusses the potential factors (composition of the subject sample, statistical procedures, point in time of measurement) accounting for the variance in their results. The Beck Depression Inventory (BDI) is world-wide among the most used self-rating scales for measuring depression. Since the test construction in 1961, the test has been employed in numerous (more than 2,000) empirical studies. The present review will only consider those investigations which are primarily concerned with the validity or the psychometric properties of the BDI. Since most studies are oriented along the criteria of the classical test theory, our review will discuss to what extent the BDI meets these criteria.

Depressive Disorder↗
PubMed1998

Lexipafant fails to improve survival in severe necrotizing pancreatitis in rats.

CONCLUSION: Lexipafant administration fails to improve survival or lessen the disease severity in two experimental models of severe acute pancreatitis. BACKGROUND: The potent platelet activating factor antagonist Lexipafant has been shown to attenuate the biochemical and histologic changes associated with some animal models of acute pancreatitis, suggesting an important role for this cytokine in its pathogenesis. However, a survival advantage following Lexipafant administration has not been demonstrated. This study evaluates the effect of this platelet activating antagonist on survival in rat models of necrotizing and fulminant hemorrhagic pancreatitis. METHODS: Sprague-Dawley rats underwent induction of either acute necrotizing (n = 40) or hemorrhagic pancreatitis (n = 36) with a time- and pressure-controlled bile duct infusion of 10 mM glycodeoxycholic acid (GDOC) or enterokinase 15 U/mL, in combination with supramaximal cerulein stimulation (5 micrograms/kg/h). Immediately after pancreatitis induction, rats were randomly divided into three groups and received Lexipafant (1 mg or 10 mg) or saline as a continuous intravenous infusion over 9 h. Twenty-four-hour survival rates were determined and severity of pancreatitis was assessed by pancreatic histology scores. RESULTS: The survival rates for GDOC treated rats were 55% (saline), 50% (1 mg Lexipafant) and 50% (10 mg Lexipafant). As expected, all rats induced with enterokinase and treated with saline died with hemorrhagic pancreatitis within 24 h. The same was true of those treated with high- and low-dose Lexipafant, and there was no difference in survival time. Histology scores did not differ between Lexipafant-treated and control rats in either GDOC or enterokinase rats.

Animals↗
PubMed1998

Noninvasive assessment of stiffness and failure load of human vertebrae from CT-data.

A calculational method based on noninvasively derived data for the assessment of the mechanical quality of individual vertebrae is presented. Dimensional data obtained from serial, segmented CT scans were used as the geometric input for a newly developed finite element model designed to calculate stiffness and failure load of these complex bone structures. Mechanical, structural data for cancellous bone was obtained by measurements of the compressive strength and failure load of actual vertebral specimens obtained at autopsy. The stiffness and failure load calculated by the newly developed finite element model were compared with the data obtained from mechanical measurements of vertebral specimens. A high correlation between measured and calculated failure load was found (r = 0.89, p < 0.001, n = 16). The correlation between the failure load and bone mineral density (BMD) was significant (r = 0.82, p < 0.001, n = 16). A similar correlation between calculated and measured stiffness (r = 0.81, p < 0.001, n = 15) was also found using the finite element model described herein. Thus the newly developed calculation methodology has been verified and can be used to predict the failure load and stiffness of osteoporotic vertebrae using data obtained non-invasively from CT scans.

Adult↗
PubMed1998

[Reduction of local and systemic complications of acute pancreatitis by monoclonal antibody to ICAM-1].

The prognosis of acute necrotizing pancreatitis is dependent on systemic complications. The endothelial adhesion molecule ICAM-1 mediates both leukocyte adhesion and migration. Expression of ICAM-1 was investigated at various time points in mild and severe necrotizing pancreatitis in the pancreas, lungs and intestine. A possible therapeutic effect of monoclonal antibodies against ICAM-1 was evaluated in severe necrotizing disease. The expression of ICAM-1 preceded the fulminant leukocyte Infiltration of the organs. In contrast to mild pancreatitis, ICAM-1 expression was increased at an earlier time point and systemically in severe necrotizing disease. Treatment with antibodies against ICAM-1 improved microcirculation and reduced local and systemic organ damage in severe pancreatitis.

Animals↗
PubMed1998

[Acute pancreatitis: reliable and prospective conservative therapy].

The management of acute pancreatitis is complex. Although numerous medical therapies have been proposed, few interventions have been shown to benefit patients with severe disease. Volume resuscitation, total parenteral nutrition and an adequate analgesia is the unspecific management of acute pancreatitis. Prophylactic antibiotic treatment should be performed in patients with necrotizing disease. Selective decontamination of the digestive tract has shown beneficial effects only in combination with systemic antibiotic therapy. ERCP and endoscopic sphincterotomy should be performed in severe gallstone pancreatitis. Somatostatin, protease inhibitors, hemofiltration and peritoneal lavage are some of the many medications now proven to be of no efficacy. Two clinical prospective trials are now under way to investigate the effects of two promising agents on the course of severe necrotizing pancreatitis: lexipafant, a platelet factor antagonist, and isovolemic hemodilution with dextran.

Clinical Trials as Topic↗