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Biomedical subjects

N Tygstrup

Publications and source records attributed to N Tygstrup.

At least 73 records · Page 4Linked to original sources
PubMed1986

Differing attitudes of industry and academia towards controlled clinical trials.

A consensus conference was held in 1984 on controversial issues concerning controlled clinical trials. Thirty-six individuals working in academic institutions, forty-six in industry and twelve in regulatory authorities participated. Academics accepted and industrial representatives rejected the following: existing regulations cannot cope with the rate at which new treatments develop; drug companies may be reluctant to undertake surveillance programmes because sales will fall if adverse reactions are detected; novel remedies should not be promoted before extensive post-marketing surveillance; third parties should finance trials promising to reduce the costs of illness and trialists should be separated from sponsors in data analysis and interpretation, the investigator owning the data unless stated otherwise. Industrial representatives supported and academics rejected the following: government price control inhibits drug development and a multicentre trial can be justified simply by the wish to speed drug registration.

Attitude↗
PubMed1986

The effect of physiological temperature changes on the galactose elimination capacity of the isolated perfused pig liver.

The effect of temperature changes (36-40 degrees C) on the liver function was studied in the isolated perfused pig liver. When compared with control studies no effect was observed on lactate, glucose, bile flow, ATP and energy charge, and the recovery after the changes in temperature was complete. The only significant changes observed regarded the hepatic oxygen uptake and galactose elimination capacity. The increase of 1 degree C resulted in an increase in galactose elimination of 6%, corresponding to a Q10 of 1.98 (SEM 0.12) with an energy of activation of 48 kJ/mol (SEM 4.7). Oxygen uptake was linearly related to galactose elimination (1.75 mol for 1 mole change in galactose elimination). These results indicate that circulatory changes are unimportant within physiological temperature changes. It is concluded that temperature effects on galactose elimination are too small to warrant a correction when used as a clinical test of quantitative liver function.

Adenosine Diphosphate↗
PubMed1986

Cost-effectiveness of introducing a third-generation test for HBsAg in Danish blood donors.

Owing to the low incidence of hepatitis B in Denmark, screening of blood donors for HBsAg has mostly been done by immunoelectroosmophoresis (IEOP). The purpose of the present study was to carry out a cost-effectiveness analysis prior to the introduction of a third-generation test for HBsAg in Danish blood donors. The analysis was performed on data from a subsequent screening of 48 750 blood units by radioimmunoassay (RIA) 3 weeks after donation. The RIA-pos., IEOP-neg. blood donors identified in the study were evaluated by a follow-up examination, and the recipients of RIA-pos., IEOP-neg. blood units were monitored for up to 9 months as to the development of acute hepatitis B. The study shows that the estimated cost for each prevented case of transfusion-associated hepatitis B in Denmark is US$ 1100 when screening donors not previously tested by a third-generation technique, and US$ 240 000 when screening donors tested before by this technique.

Blood Donors↗
PubMed1986

Updating prognosis and therapeutic effect evaluation in cirrhosis with Cox's multiple regression model for time-dependent variables.

A multivariate Cox regression analysis with time-dependent variables has been performed on the data of 415 patients with cirrhosis included in a controlled clinical trial of 10-15 mg prednisone daily versus placebo. The analysis showed that a poor prognosis was associated with a low prothrombin index, marked ascites, GI bleeding, high age, high daily alcohol consumption, high bilirubin and alkaline phosphatase and low albumin values, little liver connective tissue inflammation, and poor nutritional status. Prothrombin index and ascites showed significant interaction with the treatment in such a manner that high prothrombin index and absence of ascites were associated with a beneficial effect of prednisone, whereas low prothrombin index and presence of ascites were associated with a harmful effect of prednisone treatment. The final model was validated in independent patients by comparing their actual survival with that predicted from the model, using a split-sample testing technique. The prognostic factors were combined with an index that can be used to update prognosis whenever changes occur in the clinical status of a patient during the course of the disease. The probability of surviving the next 3 or 6 months can be estimated from the prognostic index at any time during the course. The index may be of value for the correct timing of special therapeutic procedures such as liver transplantation.

Adult↗
PubMed1985

Screening of Danish blood donors for hepatitis B surface antigen using a third generation technique.

The profit to be gained by testing Danish blood donors for hepatitis B surface antigen (HBsAg) with a third generation technique instead of the currently used immunoelectrophoresis was investigated by additional screening of 48 750 blood units by radioimmunoassay three weeks after donation. Twenty nine units were positive for HBsAg on radioimmunoassay (0.059%). Only six of these were found by immunoelectrophoresis (0.012%). Most of the 23 donors positive on radioimmunoassay and negative on immunoelectrophoresis were healthy carriers of HBsAg (20) or had asymptomatic chronic liver disease (two). One donor had acute hepatitis B. Fifteen of the 23 blood units were transfused. The 15 recipients were monitored biochemically and serologically for up to nine months. One recipient developed fulminant hepatitis B, three developed acute hepatitis B, and one became a healthy carrier of HBsAg. All these patients had received blood from healthy carriers of HBsAg. Two recipients were immunised against HBsAg, and in one patient no seroconversion was observed. The remaining recipients died soon after transfusion or were protected by antibodies to HBsAg that had been present before the transfusion. Testing of Danish blood donors using a third generation technique identified a substantial number of donors positive for HBsAg overlooked by immunoelectrophoresis. Most of these donors were healthy carriers of HBsAg. Blood taken from such carriers is highly infectious when transfused, probably because of the large amount of material transmitted.

Blood Donors↗
PubMed1985

Beneficial effect of azathioprine and prediction of prognosis in primary biliary cirrhosis. Final results of an international trial.

The effect of azathioprine on survival of patients with primary biliary cirrhosis was studied prospectively in a multinational, double-blind, randomized clinical trial including 248 patients of whom 127 received azathioprine and 121 placebo. There were 57 deaths in the azathioprine group and 62 in the placebo group. The actual survival was slightly longer during azathioprine than during placebo treatment. Using Cox multiple regression analysis and adjusting for slight imbalance between the two treatment groups, the therapeutic effect of azathioprine was statistically significant (p = 0.01), with azathioprine reducing the risk of dying to 59% of that observed during placebo treatment (95% confidence interval 40%-90%) or improving survival time by 20 mo in the average patient. Furthermore, azathioprine slowed down progressing incapacitation. Side effects of azathioprine were relatively few. The analysis revealed that the following five variables independently implied poor prognosis: high serum bilirubin, old age, cirrhosis, low serum albumin, and central cholestasis. These factors were combined to a "prognostic index" for prediction of outcome in new patients. The index was validated on independent patient data. On the basis of these results we recommend azathioprine as a routine treatment of primary biliary cirrhosis.

Actuarial Analysis↗
PubMed1985

A therapeutic index that predicts the individual effects of prednisone in patients with cirrhosis.

Our aim was to construct an index that accurately predicts the degree of benefit or harm that prednisone therapy holds for patients with liver cirrhosis. The admission and survival data of 488 patients with cirrhosis who participated in a controlled clinical trial of prednisone in a dosage of 10-15 mg daily (251 patients) versus placebo (237 patients) and who were observed for up to 12 yr were analyzed using Cox's multiple regression model. Four variables each provided significant therapeutic information: antinuclear factor (p = 0.02) and large piecemeal necroses (p = 0.02) were associated with a beneficial effect, whereas ascites (p = 0.0004) and large regenerative nodules (p = 0.0007) were associated with a harmful effect of prednisone. From these four variables a therapeutic index was constructed. For a given patient the therapeutic index is a measure of how big the effect will be if prednisone is given. The gain in survival time obtained by administering prednisone according to the therapeutic index was estimated to be 349 yr, mainly confined to 217 patients with a significant positive (121) or negative (96) therapeutic index. The therapeutic index may prove useful for the optimal administration of prednisone treatment in new patients with cirrhosis.

Antibodies, Antinuclear↗
PubMed1985

Double blind controlled trial of d-penicillamine in patients with primary biliary cirrhosis.

One hundred and eighty nine patients with primary biliary cirrhosis were entered into a double blind, placebo controlled randomised trial starting in January 1978 to assess the therapeutic value of d-penicillamine 1200 mg daily. Eighteen of the 98 patients receiving d-penicillamine and 22 of the 91 placebo treated patients died during the study. Thirty six per cent of those on d-penicillamine and 8% of those on placebo were withdrawn from the study. No difference in overall survival was noted between the two groups of patients whether the results were analysed for the entire period of observation or only during the period in which the patients were receiving therapy. The mortality rate of those receiving d-penicillamine in histological stage I to II, however, was one third of that of the placebo group although this difference did not reach statistical significance. Using the occurrence rate ratio as the statistical method of analysis, no effect of d-penicillamine was noted on any clinical, biochemical or histological features examined, except the serum alanine aminotransferase activity which was greater in those on active treatment. In this trial we have been unable to establish any therapeutic benefit from the drug.

Clinical Trials as Topic↗
PubMed1985

Early features of primary biliary cirrhosis: an analysis of 85 patients.

A standardized clinical, laboratory, and histological assessment was carried out on 85 patients with primary biliary cirrhosis within 1 year of developing symptoms. Presenting symptoms included pruritus (n = 30), jaundice (n = 9), variceal bleeding (n = 6), ascites (n = 5), fatigue (n = 4), and abdominal pain (n = 4). Ten patients had symptoms not immediately suggestive of hepatic etiology and a further 17 were asymptomatic, the diagnosis being made fortuitously. Eighty four percent were not incapacitated and 52 were anicteric. Less than half were pigmented, 22% had xanthoma, and only 12% were deeply jaundiced. In contrast, all had significant laboratory abnormalities with alkaline phosphatase activity greater than 400 IU/L in 60% and IgM greater than 2.5 g/L in 75%. Mitochondrial antibody was detectable in 83% with a titer greater than 1:160 in 70%. Cirrhosis was present in 24 patients, nine of whom were anicteric and a further 11 had fibrosis or scarring.

Adult↗
PubMed1984

Kinetics of glucose metabolism in relation to insulin concentrations in patients with alcoholic cirrhosis and in healthy persons.

To characterize the insulin resistance in alcoholic cirrhosis we determined in vivo insulin-glucose disposal dose-response relationships in 6 patients with alcoholic cirrhosis of varying severity and in 6 control subjects, using the glucose-insulin clamp technique. Each subject was infused sequentially with insulin at rates of 0.5, 1.0, 2.0, and 10 mU/min X kg, each rate for 2 h. Euglycemia was maintained by a continuous servo-adjusted glucose infusion. The amount of glucose infused during the last 40 min of each 2-h period, corrected for accumulation in the glucose space, reflects overall net glucose metabolism. The dose-response curves demonstrated saturation kinetics. Lineweaver-Burk plots were consistently convex, rejecting a simple Michaelis-Menten relationship, but were linear when accommodated to allosterism with two active sites. The calculated affinity constant (i.e., the concentration of insulin leading to half-maximum glucose metabolism) of patients with cirrhosis was higher than that of normal controls (104 +/- 30 vs. 32 +/- 3 mU/L, mean +/- SD). In addition the maximum rate of glucose metabolism was significantly lower than that of normals (53 +/- 9 vs. 72 +/- 16 mumol/min X kg). We conclude that, in patients with alcoholic cirrhosis, insulin resistance is caused both by a marked decrease in sensitivity to insulin and a decreased maximum effect of insulin, indicating a combined receptor-postreceptor defect as the underlying cause.

Adult↗
PubMed1984

Prediction of fatality in fulminant hepatic failure.

Thirty-three consecutive patients admitted to the intensive care liver unit of Rigshospitalet with acute hepatic encephalopathy induced by viral hepatitis, drugs, or pregnancy were studied. All were treated with a standard anticoma regime. The 20 patients (61%) who died had a higher bilirubin level and lower total cholic acid conjugation and glycine cholic acid conjugation (p less than 0.05) than the surviving patients. Antipyrin clearance and galactose elimination capacity tended to be lower in the non-survival group than in the survival group (p = 0.09 and 0.11, respectively). Of single variables a bilirubin level of greater than 384 mumol/l gave the best prediction of non-survival (sensitivity, 0.80; specificity, 0.69; PVpos, 0.80; PVneg, 0.69; kappa, 0.49). However, a discriminant score based on combination of variables distinguished completely between non-survivors and survivors when validated by an unbiased method in which each patient is classified on the basis of the other patients' data. It is suggested that the discriminant score is used to select patients with very low probability of survival for liver transplantation or liver assistance procedures of unknown value.

Adult↗
PubMed1983

Splanchnic galactose uptake in patients with cirrhosis following single injection.

The galactose elimination capacity is used as a quantitative liver function test and is supposed to express the functioning liver cell mass. Clinical observations indicate, however, that the galactose elimination capacity overestimates functioning liver cell mass, and we therefore compare hepatic (splanchnic) and extrahepatic, extrarenal galactose elimination after a single injection of galactose in 23 patients with reduced liver function. The galactose elimination capacity was consistently greater than the hepatic (splanchnic) galactose elimination rate, estimated during liver vein catheterization. The difference was on the average 0.68 mmol min-1 (SD +/- 0.19, P less than 0.001) or about 40% of the galactose elimination capacity. If this difference, partly or fully, is due to extrahepatic extrarenal elimination, the clinical test for galactose elimination needs a correction (of the order of magnitude of 0.7 mmol min-1) to serve as an absolute measure of the hepatic functional capacity, but since the hepatic uptake rate may be underestimated following a single injection, the correction may be smaller.

Catheterization↗
PubMed1983

Splanchnic galactose uptake in patients with cirrhosis during continuous infusion.

The galactose elimination capacity (GEC) is considered a test of functional liver cell mass. The main uncertainties of the method are the effects of extrahepatic elimination and of uneven distribution in the body on the calculated maximal elimination rate of galactose. This has been evaluated by hepatic and renal venous catheterization during continuous infusion of galactose at two arterial concentration levels (mean 6.0 and 8.7 mmol l-1) in 10 patients with reduced liver function. Hepatic and renal blood flow were measured by constant infusions of Indocyanine Green and 131I Hippuran. Hepatic galactose elimination rate was identical (mean 1.36 and 1.32 mmol min-1, P greater than 0.4) at the two arterial concentration levels studied, indicating that hepatic galactose elimination rate was maximal (Vmax). The total body galactose elimination rate, calculated as amount infused during steady state, was 1.4 times greater than the hepatic elimination rate, calculated as arterio-hepatic venous concentration difference times hepatic blood flow. Within the experimental error, the extrahepatic (i.e. total minus hepatic) galactose elimination could be accounted for by renal elimination. The steady state studies show that the galactose elimination capacity, estimated from single injection, overestimates the hepatic Vmax by about 25%. The reason for this is probably mainly distribution phenomena and insufficient correction for urinary loss, but extrahepatic metabolism of galactose cannot be excluded.

Catheterization↗
PubMed1983

Heterogeneity of splanchnic vascular transit times in man.

A new method of quantifying the heterogeneity of transit times through vascular beds, free from corrections for effects of recirculation, is applied to data of splanchnic transit times in eight normal subjects and three patients with cirrhosis and end-to-side portocaval shunts, as obtained by Bradley's method. There is proportionality between the heterogeneity, expressed as standard deviation and the mean transit time in the eight normal subjects. The heterogeneity of plasma transit times is not appreciably larger than that of red blood cells, despite the larger volume of distribution of plasma. This may suggest that the large vessels contribute substantially to the dispersions of vascular transits in the entire splanchnic system. Pearson Type III distribution is proposed for the frequency function of the splanchnic transit times, and the power of the pre-exponential factor is deduced for plasma and for red blood cells. It is found that the initial splanchnic transits are dominated by plasma, this may be due to sequestration of red cells in the spleen. The heterogeneity of transit times in normals is not appreciably different from that in patients with cirrhosis and portocaval shunt, which suggests that the extra heterogeneity of the cirrhotic liver is of the same order as the heterogeneity of the normal extrahepatic splanchnic organs. The method may be a useful tool to describe heterogeneity of vascular transits in other organs.

Adolescent↗
PubMed1983

Main causes of death in cirrhosis.

The main causes of 436 deaths among 532 patients with cirrhosis followed up for up to 16 years constituted liver failure (24%), liver failure with gastrointestinal bleeding (13%), gastrointestinal bleeding (14%), primary liver cell carcinoma (4%), other liver-related causes (2%), infections (7%), cardiovascular diseases (22%), extrahepatic malignancies (9%), and other non-liver-related causes (5%). Totally, 57% died of liver-related causes. A high frequency of liver-related death was found among patients with a short observation time, high biochemical activity, pronounced change in liver architecture, ascites, and other signs of a poor prognosis at the time of diagnosis. The findings favoured the hypothesis that cirrhosis of the liver is a disease with an initial active and a subsequent inactive phase. Half of the patients were treated with prednisone, but this had no detectable influence on the distribution of causes of or on the frequency of single causes of death as infections or gastrointestinal bleeding. The group of patients responding favourably to prednisone treatment with regard to survival (non-alcoholic women without ascites) showed causes of death not different from those of the total material.

Bacterial Infections↗