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Biomedical subjects

J Werner

Publications and source records attributed to J Werner.

At least 109 records · Page 6Linked to original sources
PubMed1997

Pancreatic injury in rats induced by fatty acid ethyl ester, a nonoxidative metabolite of alcohol.

BACKGROUND & AIMS: The mechanism by which alcohol injures the pancreas remains unknown. Alcohol-intoxicated humans have high levels of fatty acid ethyl esters (FAEEs), nonoxidative products of ethanol metabolism, in blood, pancreas, and liver. The aims of this study were to determine whether FAEEs are toxic to the pancreas in vivo and, if so, to assess whether this injury is specific to the pancreas and to compare it to the injury observed in acute pancreatitis. METHODS: FAEEs were infused into Sprague-Dawley rats. Levels of FAEEs in plasma and pancreas were measured, and pancreatic injury was assessed during a 48-hour period for edema formation and ectopic trypsinogen activation and by light and electron microscopy. RESULTS: FAEEs induced highly significant increases in pancreatic edema, pancreatic trypsinogen activation, and vacuolization of acinar cells. These findings were specific to the pancreas and were not found in liver, lung, myocardium, skeletal muscle, or subcutaneous fat. CONCLUSIONS: FAEEs at concentrations found in human plasma produce a pancreatitis-like injury in rats, providing direct evidence that FAEEs can produce organ-specific toxicity. Thus, FAEEs may contribute to acute alcohol-induced damage to the pancreas.

Animals↗
PubMed1997

Differing roles of nitric oxide in the pathogenesis of acute edematous versus necrotizing pancreatitis.

BACKGROUND: Microcirculatory changes and leukocyte-endothelial interaction are both central to the pathogenesis of acute pancreatitis. We studied the effects of nitric oxide (NO) donors (intravenous or inhaled) and NO inhibitors, which affect each of these processes, on markers of experimental mild (edematous) and severe (necrotizing) pancreatitis in rats. METHODS: Mild pancreatitis was induced with intravenous cerulein (n = 100) and severe pancreatitis with intravenous cerulein and intraductal glycodeoxycholic acid (n = 100). Each group was randomly divided into five equal treatment subgroups: control, NO-synthase substrate L-arginine, NO donor sodium nitroprusside, NO-synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME), and NO-inhalation. After 6 hours edema was measured by a wet/dry weight ratio, and pancreatic injury was quantified by tissue levels of trypsinogen activation peptides (TAPs) and by histologic analysis of inflammation and necrosis. RESULTS: In mild pancreatitis (1) both NO donors reduced edema formation (p < 0.001) and also reduced intrapancreatic TAPs (p < 0.03); (2) L-NAME significantly increased tissue TAPs (p < 0.03); and (3) inhaled NO had no effect. In severe pancreatitis (1) both intravenous NO donors reduced edema formation (p < 0.005) and both markedly reduced intrapancreatic TAPs (p < 0.001); (2) L-NAME did not further increase the already high tissue TAPs; and (3) inhaled NO decreased tissue TAPs (p = 0.01). Evaluation of inflammation and necrosis by histologic scoring confirmed the reduction of pancreatic injury by NO donors and worsening with NO-synthase inhibitor. CONCLUSIONS: NO donors have a beneficial effect on edema formation in acute pancreatitis but confer more important protection against ectopic trypsinogen activation, which correlates with mortality, inflammation, and necrosis. Although direct microcirculatory action is likely, the salutary effect of inhaled NO in severe pancreatitis may suggest indirect action on circulating leukocytes, which are thought to potentiate tissue injury.

Amylases↗
PubMed1997

A rat model of pancreatic ductal adenocarcinoma: targeting chemical carcinogens.

BACKGROUND: Current experimental models of pancreatic cancer either fail to reproduce the ductal phenotype or cause simultaneous cancers in other organs also. To develop an animal of pancreatic cancer that accurately mimics the human condition, we restricted carcinogenic exposure to the pancreas and specifically targeted ductal epithelial cells. Three different carcinogens were either implanted directly into the pancreas or infused into the pancreatic duct, with or without near-total pancreatectomy (as a means of inducing pancreatic ductal cell proliferation). METHODS: Groups of male Sprague-Dawley rats were exposed to varying doses of dimethylbenzanthracine (DMBA), methynitronitrosoguanidine, or ethylnitronitrosoguanidine either through direct implantation into the pancreas or infusion into the pancreatic duct. Near-total pancreatectomy was added in all groups except two DMBA implantation groups. Surviving rats were killed at 3, 6, 9, or 12 months, and the pancreata were evaluated histologically. RESULTS: All three carcinogens caused pancreatic inflammation, ductal hyperplasia, atypia, and dysplasia beginning by 3 months and becoming more prominent at later time points. Only DMBA caused frequent invasive pancreatic ductal adenocarcinoma, which was first evident by 6 months. The prevalence of pancreatic cancer among DMBA-treated rats evaluated after 10 months was 39% (19 of 49). The addition of pancreatic resection did not enhance pancreatic cancer development. CONCLUSIONS: Of the strategies tested, only direct implantation of DMBA into the rat pancreas frequently produces pancreatic cancer histologically similar to human ductal adenocarcinoma. The development of hyperplastic, atypical, and dysplastic changes preceding and accompanying carcinomas suggests that these lesions are preneoplastic. This model recapitulates the progression from normal to neoplastic epithelium and is likely to be useful for the study of morphologic and molecular mechanisms underlying the early stages of pancreatic carcinogenesis and for the investigation of novel diagnostic and therapeutic techniques.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1997

Prevalence of activating K-ras mutations in the evolutionary stages of neoplasia in intraductal papillary mucinous tumors of the pancreas.

OBJECTIVE: The purpose of the study was to determine the prevalence of activating K-ras mutations in the pancreas of patients with intraductal papillary mucinous tumors (IPMT) and to analyze their relation to the degree of site-specific histopathologic abnormality. BACKGROUND: Intraductal papillary mucinous tumors of the pancreas have a biologic behavior that is significantly different from pancreatic ductal adenocarcinoma. Activating K-ras mutations, which may be important events in a multistage process of carcinogenesis, have been reported in IPMT. METHODS: Forty-six different histologic specimens (comprising normal pancreatic ducts, hyperplasia, low-grade dysplasia, high-grade dysplasia-carcinoma in situ, and carcinoma) from 16 patients with IPMT and 9 specimens from patients with pancreatic ductal adenocarcinomas were designated by a pathologist. Genomic DNA was extracted from paraffin-embedded tissue sections after microdissection. The K-ras gene was amplified by polymerase chain reaction and subjected to DNA sequencing. RESULTS: The K-ras mutations were detected in at least one specimen in 13 (81.2%) of 16 patients with IPMT. All mutations were found in codon 12. No codon 13 mutations were detected. The relative frequency of K-ras mutations in the different stages of IPMT was 16.7% in normal epithelium and papillary hyperplasia, 28.6% in low-grade dysplasia, and 57.1% in high-grade dysplasia-carcinoma in situ and invasive carcinoma. The K-ras mutations were detected in 6 (66%) of 9 pancreatic ductal adenocarcinomas. CONCLUSIONS: The K-ras codon 12 point mutations are as frequent in IPMT as in ductal adenocarcinoma. A stepwise increase in the frequency of codon 12 mutations correlated with the stage of neoplastic evolution to cancer. This finding is consistent with an important role of K-ras gene mutations in the transformation from normal epithelium to invasive carcinoma in the majority of patients with IPMT.

Carcinoma, Ductal, Breast↗
PubMed1997

Rapid in vivo hydrolysis of fatty acid ethyl esters, toxic nonoxidative ethanol metabolites.

Fatty acid ethyl esters (FAEE), esterification products of fatty acids and ethanol, are in use as fatty acid supplements, but they also have been implicated as toxic mediators of ethanol ingestion. We hypothesized that hydrolysis of orally ingested FAEE occurs in the gastrointestinal (GI) tract and in the blood to explain their apparent lack of toxicity. To study the in vivo inactivation of FAEE by hydrolysis to free fatty acids and ethanol, we assessed the hydrolysis of FAEE administered as an oil directly into the rat stomach and when injected within the core of low-density lipoprotein particles into the circulation of rats. Our studies demonstrate that FAEE are rapidly degraded to free fatty acids and ethanol in the GI tract at the level of the duodenum with limited hydrolysis in the stomach. In addition, FAEE are rapidly degraded in the circulation, with a half-life of only 58 s. Thus the degradation of FAEE in the GI tract and in the blood provides an explanation for the apparent lack of toxicity of orally ingested FAEE.

Administration, Oral↗
PubMed1997

Measuring treatment outcome by the Beck Depression Inventory.

The construct validity of the Beck Depression Inventory (BDI) in measuring treatment outcome is assessed in 103 psychiatric inpatients. In this context, construct validity means that the BDI measures the same construct in repeated measurement and that the change scores can be explained by treatment effects. In confirmatory factor analyses, only the first factor proved to be stable. In accordance with other studies, the sensitivity to therapeutic change in long-term intervals of several weeks could be confirmed. Significant changes in a short-term interval of 1 day in the non-endogenously depressed patients indicate an overreactivity of the BDI to change which cannot be explained by treatment effects or mood changes.

Adjustment Disorders↗
PubMed1997

Control of liquid cooling garments: technical control of mean skin temperature and its adjustments to exercise.

This paper describes an automatic control concept for liquid cooling garments. The concept consists of an own controller for mean skin temperature whose setpoint is either fixed or adjusted to the metabolic heat production by means of the heart rate signal. The controller for mean skin temperature included both a proportional and an integral signal path (PI-type), the latter being able to eliminate any load error within the control loop. This means that the actual skin temperature will always match the given setpoint irrespective of the amount and the origin of the heat gain at the body shell. Experiments were carried out to test the operation of the skin temperature controller. There the setpoint was fixed while metabolic heat production was changing. After a transient period with deviations, the load error was always eliminated by the skin temperature controller. With this result one can also imagine the controllers ability to compensate changing heat gains from the environment. Despite this behaviour, the amount of heat removal was not high enough to prevent sweating and warm discomfort during all exercise levels. Therefore we draw the conclusion that, in addition, the setpoint of the skin temperature should be adjusted to the metabolic rate/heat production. A convenient physiological signal that reflects the current level of metabolic rate is the heart rate signal. After being filtered the heart rate signal was used during some experiments to change the setpoint of the skin temperature controller. The reason for this filtering (lowpass, time constant = 10 min) was, firstly, the necessity of attenuating the consequences of short-term psychological effects on the heart rate and secondly, the avoidance of vasoconstriction due to too fast changes of the exercise/heart rate induced cooling rate. In the following experiments it became clear that the adjustment of the skin temperature setpoint to the exercise level was an improvement as there was less sweating and the subjects felt more comfortable.

Automation↗
PubMed1997

A dynamic model of the human/clothing/environment-system.

In this paper a dynamic model of the human/ clothing/environment-system is developed. The human body (controlled system) is subdivided into six segments consisting of the head, trunk, arms, hands, legs and feet. Each segment is further divided into the core, muscle, fat, and skin layer. The afferent signal of the controlling system is composed of the weighted temperatures measured by thermal receptors at sites distributed in the body. The difference between this signal and its threshold activates the thermoregulatory actions: vasomotor changes, metabolic heat production and sweat production. The model considers the competition between skin and muscle blood flow during exercise in hot environments because of limited cardiac capacity, as well as cold induced vasodilatation. Additionally a combined model of heat and mass transfer from the skin through clothing to the environment is developed and incorporated into the thermoregulatory model. The human/clothing model can be used to investigate the interaction between the human body, clothing and environment. The model is validated by comparing the simulation with experimental results under different conditions: heat, cold, exercise, clothing and transient phases. It turns out that the simulation is compatible with the experimental results. We conclude that the model can be applied in a broad range of environmental conditions. Application of the model is easy via a user-friendly interface i.e. a WINDOWS-shell.

Afferent Pathways↗
PubMed1996

Effects of subcutaneous glucagon-like peptide 1 (GLP-1 [7-36 amide]) in patients with NIDDM.

Intravenous glucagon-like peptide (GLP)-1 [7-36 amide] can normalize plasma glucose in non-insulin-dependent diabetic (NIDDM) patients. Since this is no form for routine therapeutic administration, effects of subcutaneous GLP-1 at a high dose (1.5 nmol/kg body weight) were examined. Three groups of 8, 9 and 7 patients (61 +/- 7, 61 +/- 9, 50 +/- 11 years; BMI 29.5 +/- 2.5, 26.1 +/- 2.3, 28.0 +/- 4.2 kg/m2; HbA1c 11.3 +/- 1.5, 9.9 +/- 1.0, 10.6 +/- 0.7%) were examined: after a single subcutaneous injection of 1.5 nmol/kg GLP [7-36 amide]; after repeated subcutaneous injections (0 and 120 min) in fasting patients; after a single, subcutaneous injection 30 min before a liquid test meal (amino acids 8%, and sucrose 50 g in 400 ml), all compared with a placebo. Glucose (glucose oxidase), insulin, C-peptide, GLP-1 and glucagon (specific immunoassays) were measured. Gastric emptying was assessed with the indicator-dilution method and phenol red. Repeated measures ANOVA was used for statistical analysis. GLP-1 injection led to a short-lived increment in GLP-1 concentrations (peak at 30-60 min, then return to basal levels after 90-120 min). Each GLP-1 injection stimulated insulin (insulin, C-peptide, p < 0.0001, respectively) and inhibited glucagon secretion (p < 0.0001). In fasting patients the repeated administration of GLP-1 normalized plasma glucose (5.8 +/- 0.4 mmol/l after 240 min vs 8.2 +/- 0.7 mmol/l after a single dose, p = 0.0065). With the meal, subcutaneous GLP-1 led to a complete cessation of gastric emptying for 30-45 min (p < 0.0001 statistically different from placebo) followed by emptying at a normal rate. As a consequence, integrated incremental glucose responses were reduced by 40% (p = 0.051). In conclusion, subcutaneous GLP-1 [7-36 amide] has similar effects in NIDDM patients as an intravenous infusion. Preparations with retarded release of GLP-1 would appear more suitable for therapeutic purposes because elevation of GLP-1 concentrations for 4 rather than 2 h (repeated doses) normalized fasting plasma glucose better. In the short term, there appears to be no tachyphylaxis, since insulin stimulation and glucagon suppression were similar upon repeated administrations of GLP-1 [7-36 amide]. It may be easier to influence fasting hyperglycaemia by GLP-1 than to reduce meal-related increments in glycaemia.

Adult↗
PubMed1996

Gastric emptying, glucose responses, and insulin secretion after a liquid test meal: effects of exogenous glucagon-like peptide-1 (GLP-1)-(7-36) amide in type 2 (noninsulin-dependent) diabetic patients.

The aim of the study was to investigate whether inhibition of gastric emptying of meals plays a role in the mechanism of the blood glucose-lowering action of glucagon-like peptide-1-(7-36) amide [GLP-1-(7-36) amide] in type 2 diabetes. Eight poorly controlled type 2 diabetic patients (age, 58 +/- 6 yr; body mass index, 30.0 +/- 5.2 kg/m2; hemoglobin A1c, 10.5 +/- 1.2%) were studied in the fasting state (plasma glucose, 11.1 +/- 1.1 mmol/L). A liquid meal of 400 mL containing 8% amino acids and 50 g sucrose (327 Kcal) was administered at time zero by a nasogastric tube. Gastric volume was determined by a dye dilution technique using phenol red. In randomized order, GLP-1-(7-36) amide (1.2 pmol/kg.min; Saxon Biochemicals) or placebo (0.9% NaCl with 1% human serum albumin) was infused between -30 and 240 min. In the control experiment, gastric emptying was completed within 120 min, and plasma glucose, insulin, C-peptide, GLP-1-(7-36) amide, and glucagon concentrations transiently increased. With exogenous GLP-1-(7-36) amide (plasma level, approximately 70 pmol/L), gastric volume remained constant over the period it was measured (120 min; P < 0.0001 vs. placebo), and plasma glucose fell to normal fasting values (5.4 +/- 0.7 mmol/L) within 3-4 h, whereas insulin was stimulated in most, but not all, patients, and glucagon remained at the basal level or was slightly suppressed. In conclusion, GLP-1-(7-36) amide inhibits gastric emptying in type 2 diabetic patients. Together with the stimulation of insulin and the inhibition of glucagon secretion, this effect probably contributes to the blood glucose-lowering action of GLP-1-(7-36) amide in type 2-diabetic patients when studied after meal ingestion. At the degree observed, inhibition of gastric emptying, however, must be overcome by tachyphylaxis, reduction in dose, or pharmacological interventions so as not to interfere with the therapeutic use of GLP-1-(7-36) amide in type 2 diabetic patients.

Aged↗
PubMed1996

Control of liquid cooling garments: technical control of body heat storage.

This paper describes a concept of how liquid cooling garments (LCG) can be automatically controlled by the objective physiological state. The technically controlled parameter was mean body temperature which was calculated from the measured rectal and mean skin temperature. This was motivated by the fact that mean body temperature is the basis for estimating body heat storage, a commonly used measure of thermal strain. Here the setpoint of mean body temperature was the individual value taken in a preceeding resting period and it was the task of the technical controller to keep the actual value of mean body temperature as close as possible to the setpoint. The most important tuning parameters of the controller were the weighting coefficients for rectal and mean skin temperature in the calculation for mean body temperature. The ratio of these two coefficients determined the degree of compensation for any rectal temperature shift by changing mean skin temperature. Test experiments were carried out (n = 5) in which the controller was able to clamp mean body temperature to the setpoint thereby preventing heat storage. Although exercise rate (75 W) was the same, sweating and warm discomfort occurred in some cases due to the individual rectal temperature rise. Another source of discomfort were delays or paradoxical time courses of rectal temperature at the start or end of exercise which were responsible for a delayed onset of cooling or heating. To avoid these effects, the oxygen consumption signal, which is very fast and directly correlated to the exercise rate, was added to the control loop. Each increase of this parameter above its resting level lowered suit temperature. As heat storage should not be completely rejected by this new signal pathway, the controller for mean body temperature still remained active. The repetition of the experiments showed that the load error in the control loop was smaller and the comfort level in transient phases higher. For a further improvement of this concept it is recommended that the weighting coefficients be tuned to the individual requirements.

Adult↗
PubMed1996

[Analysis of preconceived attitudes of medical personnel toward HIV positive and AIDS patients].

Attitudes of medical personnel towards HIV-positive-persons and AIDS-patients were investigated by means of 316 semi-structured interviews. Level of knowledge about AIDS exhibited no effect on the extent of prejudice. However, clear associations emerged between emotional variables and prejudice: the greater the fear of AIDS and/or homophobia, the greater the extent of prejudice. Medical personnel who characterized themselves as practicing-religious used relatively more prejudiced expressions, but were still ready to enter into social contact with AIDS patients. According to our results, continuing education programs cannot expect to reduce prejudice among medical professionals so long as they rely on assumption that increased factual knowledge about AIDS translates into attitudinal change.

Acquired Immunodeficiency Syndrome↗