Biomedical subjects
Publications and source records attributed to E Christensen.
Lycopodium clavatum (LC) spores were found in two cases in transrectal ultrasound-guided core biopsies of the prostate. The source turned out to be the coating of the condoms used for protection of the ultrasound probe. To minimize confusion in analyzing the biopsies and to avoid granulomas of the prostate, LC spore-free condoms are available and are recommended for the biopsy procedure.
Two brothers with dystonia and slight MRI changes in the basal ganglia had normal urinary glutaric acid excretion, but slightly increased 3-hydroxyglutarate and conjugated glutarate excretions. Both siblings have high residual glutaryl-CoA dehydrogenase activity, and are compound heterozygotes for two mutations - R227P and V400M reported to be disease-causing in patients with glutaric aciduria type I.
BACKGROUND: Although low arterial oxygen tension (Po2) has been claimed to occur in one to two thirds of patients with cirrhosis, hypoxaemia appears to be rare in clinical practice. AIMS: To assess the frequency of arterial hypoxaemia in cirrhosis in relation to clinical and haemodynamic characteristics. PATIENTS: One hundred and forty two patients with cirrhosis without significant hepatic encephalopathy (grades 0-I) (41 patients in Child class A, 57 in class B, and 44 in class C) and 21 patients with hepatic encephalopathy. RESULTS: Mean Po2 in kPa was 11.3 in Child class A, 10.8 in class B, 10.6 in class C, and 10.6 in patients with encephalopathy (p < 0.05). The fraction of patients with Po2 below the lower normal limit of 9.6 kPa was 10%, 28%, 25%, and 43%, respectively in class A, B, C, and in patients with encephalopathy (p < 0.05). Oxygen saturation (So2) in these groups was respectively: 96%, 96%, 96%, and 93% (NS). So2 was below the lower limit of 92% in 0%, 9%, 7%, and 24% (p < 0.05). In patients without hepatic encephalopathy, a multivariate regression analysis revealed that independent determinants of a low Po2 were a high arterial carbon dioxide tension, a low systemic vascular resistance, and a low indocyanine green clearance (p < 0.0001). CONCLUSION: The prevalence of arterial hypoxaemia in cirrhosis is about 22% in patients without encephalopathy, but it varies from 10-40% depending on the degree of hepatic dysfunction. Arterial hypoxaemia in patients with cirrhosis of differing severity seems lower than previously reported, and patients with severe arterial hypoxaemia are rare.
BACKGROUND: An association between smoking and impaired wound healing has been reported in retrospective studies. The smoking status of a surgical patient may be confounded by social and medical parameters. We have evaluated the effect of smoking in a test wound in volunteers, with special reference to a reliable scientific match between smokers and nonsmokers. METHODS: In a prospective open study with blinded assessment, 19 smoking (20 cigarettes/day) and 18 nonsmoking healthy volunteers were matched with respect to baseline characteristics. The deposition of total protein and mature collagen (expressed as hydroxyproline) was assessed in an expanded polytetrafluoroethylene wound healing model implanted subcutaneously for 10 days. RESULTS: The nonsmokers had a 1.8 times higher median amount of hydroxyproline than the smokers (p < 0.01). The deposition of hydroxyproline was negatively correlated with the consumption of tobacco both before (r = -0.44; p < 0.01) and during the study (r = -0.48; p < 0.005). The impairment was specific for the production of collagenous proteins and not other proteins. CONCLUSIONS: The synthesis of subcutaneous collagen in smokers is specifically impeded, indicating an impaired wound-healing process. Because mature collagen is the main determinator of strength of an operative wound, the results support the view that patients should be advised to stop smoking before an operation.
A high-performance liquid chromatographic method has been developed for the analysis of the novel antiparasitic agent, licochalcone A (Lica), and three of its glucuronic acid conjugates in plasma and urine. The high-performance liquid chromatography assay was performed using gradient elution and UV detection at 360 nm. The proposed technique is selective, reliable and sensitive. The limits of quantification for Lica are 0.2 microg/ml in plasma and 0.14 microg/ml in urine, 1.2 microg/ml for the 4'-glucuronide in plasma and 1.4 microg/ml in urine, and 2.0 microg/ml for the 4-glucuronide in plasma and 3.2 microg/ml in urine. The reproducibility of the analytical method according to the statistical coefficients is 7% or below. The accuracy of the method is good, that is, the relative error is below 10%. The stability of Lica and its glucuronides in urine and plasma samples has been assessed during storage in the autosampler and freezer. The applicability of the assay for determining Lica and its intact glucuronide conjugates in biological fluids was shown using a single dose study in rat.
IGF-I is a single polypeptide chain with important anabolic and endocrine activities. The liver is the major source of IGF-I and its binding protein, IGFBP-3. Circulating concentrations of IGF-I and IGFBP-3 are decreased in patients with chronic liver disease and correlate with the severity. The aim of this study was to assess the additional prognostic value of IGF-I and IGFBP-3 in patients entered in a large multicentre study (EMALD). Three hundred and thirty-seven patients with alcoholic liver disease were studied in a randomised placebo-controlled trial of malotilate with a mean follow-up period of 569 days (range: 7-1544). A multivariate Cox regression analysis of pertinent clinical and biochemical variables revealed a significant independent prognostic value of years of alcohol intake, coagulation factors 2, 7, and 10, alkaline phosphatases, serum creatinine, and immunoglobulin M (IGM). When IGF-I or IGFBP-3 were added into this model, a Cox regression analysis showed that either had a significant independent prognostic value. As IGF-I and IGFBP-3 were closely correlated, they contained almost the same prognostic information. Inclusion of IGF-I gave these results: IGF-I (p < 0.03), alcohol intake (p < 0.02), coagulation factors 2, 7, and 10 (p < 0.01), creatinine (p < 0.001), and IgM (p < 0.01) contained independent prognostic information. Inclusion of IGFBP-3 gave these results: IGFBP-3 (p < 0.02), alcohol intake (p < 0.05), coagulation factor 2, 7, and 10 (p < 0.01), creatinine (p < 0.001), and IgM (p < 0.02) were independent predictors of survival. In conclusion IGF-I or IGFBP-3 provides important additional information on survival in patients with alcoholic liver disease.
BACKGROUND/AIMS: Low arterial blood pressure is recognised as a distinctive factor in the hyperdynamic circulation in cirrhosis. 24-hour monitoring of the blood pressure and heart rate has recently revealed a reduced circadian variation with relation to liver function. However, associations with other clinical and haemodynamic characteristics have not been investigated and the aim of the present study was to identify splanchnic and systemic determinants of the 24-h blood pressure and heart rate in cirrhosis. METHODS: The variables were measured by an automatic ambulant device for monitoring blood pressure and related to the results of an invasive haemodynamic investigation, including measurements of intra-arterial blood pressure (9.00-11.00 h) in 37 patients with cirrhosis. RESULTS: The 24-h blood pressures were significantly lower and the heart rate was significantly higher in patients with cirrhosis than in matched controls (p < 0.05-0.001). To identify determinants of 24-h or intra-arterial blood pressures and heart rate, pertinent variables were included in a multivariate regression model. This model revealed that independent determinants of a low 24-h arterial blood pressure were a high post-sinusoidal resistance, a low plasma volume, a short central circulation time, and the presence of ascites. In contrast, a low intra-arterial blood pressure was determined by a low serum sodium, a low haemoglobin, and a high cardiac output. Diuretic treatment did not influence this model. CONCLUSIONS: Although the 24-h blood pressure and the intra-arterial blood pressure were determined by different variables, the overall results indicate that abnormalities in both splanchnic and central haemodynamics and sodium-water retention are important in the pathophysiology of arterial hypotension in patients with portal hypertension.
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Twin brothers were born with clinical symptoms indicating that they were suffering from Zellweger syndrome. However, instead of a generalized peroxisomal dysfunction, only very long-chain fatty acids and the pristanic acid/phytanic acid ratio were elevated in plasma and decreased oxidation of very long-chain fatty acids and pristanic acid was the only impairment found in fibroblasts. The other peroxisomal parameters tested were normal, including normal oxidation of phytanic acid and normal activity of dihydroxyacetonephosphate acyltransferase in fibroblasts as well as normal plasma bile acids. Although the biochemical results point to a defect in peroxisomal beta-oxidation, the isolated finding of impaired oxidation of very long-chain fatty acids and pristanic acid has to our knowledge not been reported previously and is difficult to explain by a deficiency of a known peroxisomal beta-oxidation enzyme.
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1. Four glucuronic acid conjugates of licochalcone A (Lica), and their metabolites, have been synthesized using rabbit and pig liver microsomes and purified by preparative hplc. 2. The glucuronides were identified as E-Lica 4'-O-beta-glucuronide, E and Z-Lica 4-O-beta-glucuronide and a mono-glucuronide conjugate of a beta-hydroxylated Lica metabolite. The metabolites were identified by hplc-nmr (one and two-dimensional nmr) as well as hplc-ms. 3. At pH 8.5 Lica reacted with N-acetyl-L-cysteine giving the two epimeric conjugates, which were then isolated by preparative hplc and identified by one and two-dimensional nmr spectroscopic methods. 4. Only two glucuronic acid conjugates (E- and Z-Lica 4-O-beta-glucuronide) were found in the urine of rat after i.p. administration of a single dose of Lica.
BACKGROUND: Disorders of fatty acid metabolism are known to be responsible for cases of sudden and unexpected death in infancy. At least 14 disorders are known at present. 120 cases of sudden infant death syndrome (SIDS) had been examined for a prevalent mutation (G985) causing medium chain acyl CoA dehydrogenase deficiency, which is inherited in an autosomal recessive mode. No over-representation of either homozygous or heterozygous cases was found. AIMS: To investigate a broader spectrum of fatty acid oxidation disorders in a wider range of sudden deaths in infants and young children. METHODS: Seventy nine cases of unexpected death in infants and young children younger than 4 years old were examined for a minimum of nine fatty acid oxidation disorders, using the global [9, 10-3H] myristic acid oxidation assay in cultured fibroblasts from achilles tendon biopsies taken at postmortem examination. RESULTS: Three cases with fatty acid oxidation disorders and two carriers of the G985 mutation were found, all categorized as non-SIDS or borderline SIDS. The global assay used has the advantage of simplicity. CONCLUSIONS: These results indicate that disorders of fatty acid oxidation play a small but significant role in the cause of unexpected death in infants and young children, and that infants and children dying in this way should be regarded as high risk candidates for metabolic diseases.
OBJECTIVES: To further define the clinical spectrum of the disease for pediatric and metabolic specialists, and to suggest that the general pediatrician and pediatric neurologist consider succinic semialdehyde dehydrogenase (SSADH) deficiency in the differential diagnosis of patients with (idiopathic) mental retardation and emphasize the need for accurate, quantitative organic acid analysis in such patients. PATIENTS: The clinical features of 23 patients (20 families) with SSADH deficiency (4-hydroxybutyric acid-uria) are presented. The age at diagnosis ranged from 3 months to 25 years in the 11 male and 12 female patients; consanguinity was noted in 39% of families. OUTCOME MEASUREMENTS: The following abnormalities were observed (frequency in 23 patients): motor delay, including fine-motor skills, 78%; language delay, 78%; hypotonia, 74%; mental delay, 74%; seizures, 48%; decreased or absent reflexes, 39%; ataxia, 30%; behavioral problems, 30%; hyperkinesis, 30%; neonatal problems, 26%; and electroencephalographic abnormalities, 26%. Associated findings included psychoses, cranial magnetic resonance or computed tomographic abnormalities, and ocular problems in 22% or less of patients. Therapy with vigabatrin proved beneficial to varying degrees in 35% of the patients. Normal early development was noted in 30% of patients. CONCLUSIONS: Our data imply that two groups of patients with SSADH deficiency exist, differentiated by the course of early development. Our recommendation would be that accurate, quantitative organic acid analysis in an appropriate specialist laboratory be requested for any patients presenting with two or more features of mental, motor, or language delay and hypotonia of unknown cause. Such analyses are the only definitive way to diagnose SSADH deficiency; the diagnosis can be confirmed by determination of enzyme activity in white cells from whole blood. We think that increased use of organic acid determination will lead to increased diagnosis of SSADH deficiency and a more accurate representation of disease frequency. As additional patients are identified, we should have a better understanding of both the metabolic and clinical profiles of SSADH deficiency.
Differential diagnostic problems may occur in a patient with a cold, pale and swollen leg. Especially when the peripheral blood pressure is reduced, it is particularly difficult to distinguish cases caused by venous thrombosis from those caused by arterial embolism. Colour-Doppler ultra-sonography might be helpful for establishing the correct diagnosis. A case history is presented.
Insulinlike growth factor I (IGF-I) is a single-polypeptide chain with important anabolic and endocrine activities. The liver is the major source of IGF-I and its binding protein, IGFBP-3. Circulating concentrations of IGF-I and IGFBP-3 are decreased in patients with chronic liver disease and correlate with the severity. The aim of this study was to assess the additional prognostic value of IGF-I and IGFBP-3 in patients entered in a large multicenter study (EMALD). Three hundred thirty-seven patients with alcohol-induced liver disease were studied in a randomized placebo-controlled trial of malotilate with a mean follow-up period of 569 days (range, 7-1,544). A multivariate Cox regression analysis of pertinent clinical and biochemical variables showed a significant independent prognostic value of years of alcohol intake, coagulation factors 2, 7, and 10, alkaline phosphatases, serum creatinine, and immunoglobulin (Ig) M. When IGF-I or IGFBP-3 were added into this model, a Cox regression analysis showed that either had a significant independent prognostic value. Because IGF-I and IGFBP-3 were closely correlated, they contained almost the same prognostic information. Inclusion of IGF-I gave these results: IGF-I (P < .03), alcohol intake (P < .02), coagulation factors 2, 7, and 10 (P < .01), creatinine (P < .001), and IgM (P < .01) contained independent prognostic information. Inclusion of IGFBP-3 gave these results: IGFBP-3 (P < .02), alcohol intake (P < .05), coagulation factors 2, 7, 10 (P < .01), creatinine (P < .001), and IgM (P < .02) were independent predictors of survival. In conclusion, IGF-I or IGFBP-3 provide important additional information on survival in patients with alcohol-induced liver disease.
The issue of modelling the joint distribution of survival time and of prognostic variables measured periodically has recently become of interest in the AIDS literature but is of relevance in other applications. The focus of this paper is on clinical trials where follow-up measurements of potentially prognostic variables are often collected but not routinely used. These measurements can be used to study the biological evolution of the disease of interest; in particular the effect of an active treatment can be examined by comparing the time profiles of patients in the active and placebo group. It is proposed to use multilevel regression analysis to model the individual repeated observations as function of time and, possibly, treatment. To address the problem of informative drop-out--which may arise if deaths (or any other censoring events) are related to the unobserved values of the prognostic variables--we analyse sequentially overlapping portions of the follow-up information. An example arising from a randomized clinical trial for the treatment of primary biliary cirrhosis is examined in detail.
BACKGROUND/AIMS: Alpha interferon (IFN) is an established treatment of chronic hepatitis B. The effect has been shown to be dose related, recommended dose regimens being associated with a doubling of the spontaneous, baseline HBeAg to anti-HBe seroconversion rate. However, the efficacy of IFN treatment in relation to the dose of IFN actually received remains to be established. The aim of this study was to estimate the relative efficacy of IFN as a function of the cumulative IFN dose. In addition we determined if and when a patient returns to his baseline chance of seroconversion after stopping IFN therapy. MATERIALS AND METHODS: Individual patient data from 10 clinical controlled trials were available for the present analysis, in all, 746 patients, of whom 491 received IFN and 255 were untreated controls. The data were analyzed performing a time-dependent Cox regression analysis of the relative efficacy of IFN using the cumulative IFN dose administered up to any given time during the observation period and the time after termination of therapy as explanatory variables. RESULTS: In the proposed model, the chance of HBeAg disappearance for a treated patient relative to no therapy was estimated to 2.1 at a cumulative dose of 100 MU and leveled out at about 2.8 at a cumulative dose of 500 MU. The effect of IFN was shown to decay rapidly after discontinuation and after 3 months a patient could be considered to be back to his baseline chance of HBeAg disappearance. These findings show that IFN administered at a dose of 15-30 MU/week should be considered effective (relative efficacy approximately 2) already after 1-2 months of treatment. CONCLUSIONS: The present findings do not lend any support to the concept that IFN treatment becomes less effective when a certain total dose of IFN has been administered or that the treatment effect reaches beyond 3 months after stopping IFN.