Structure-function relationships of SDR hydroxysteroid dehydrogenases.
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17-Hydroxysteroid Dehydrogenases↗
Biomedical subjects
B Persson
Publications and source records attributed to B Persson.
The dopaminuric response to high salt diet in insulin-dependent diabetes mellitus and in family history of hypertension.
Alterations in the renal dopamine [DA] system have been suggested to contribute to the development of hypertension and diabetic nephropathy. To identify early abnormalities in renal handling of DA and sodium we challenged 16 normotensive patients with uncomplicated insulin-dependent diabetes (IDDM), 18 normotensive nondiabetic subjects with familial borderline hypertension, and 16 healthy controls, 14-29 years old, with a high-sodium diet (HSD). Systolic blood pressure was slightly higher in subjects with familial borderline hypertension than in the other groups on a normal sodium diet (NSD) (P < 0.05). Blood pressure and 24-h urinary measurements were performed on a NSD and after 3 days on a HSD. Twenty-four-hour urinary DA excretion was similar in all groups on NSD. A significant rise in DA excretion was noted after HSD in control subjects (P < 0.01), but not in subjects with a family history of hypertension or with IDDM. Urinary sodium excretion increased in all groups. A correlation between the change in DA and sodium/creatinine ratio after HSD was seen in healthy controls (r = 0.57, P = 0.02) but not in those with familial borderline hypertension (r = 0.18, P = 0.47) or with IDDM (r = 0.40, P = 0.15). A rise in systolic (but not diastolic) pressure was noted only in the IDDM group after HSD (P = 0.02). In conclusion, an impairment in the renal DA and sodium system can be detected early in IDDM and in individuals with familial hypertension. We speculate that this impairment may contribute to the development of hypertension and microvascular disease in both conditions.
Adolescent↗
Prediction of membrane protein topology utilizing multiple sequence alignments.
A technique for prediction of protein membrane topology (intra- and extracellular sidedness) has been developed. Membrane-spanning segments are first predicted using an algorithm based upon multiply aligned amino acid sequences. The compositional differences in the protein segments exposed at each side of the membrane are then investigated. The ratios are calculated for Asn, Asp, Gly, Phe, Pro, Trp, Tyr, and Val, mostly found on the extracellular side, and for Ala, Arg, Cys, and Lys, mostly occurring on the intracellular side. The consensus over these 12 residue distributions is used for sidedness prediction. The method was developed with a set of 42 protein families for which all but one were correctly predicted with the new algorithm. This represents an improvement over previous techniques. The new method, applied to a set of 12 membrane protein families different from the test set and with recently determined topologies, performed well, with 11 of 12 sidedness assignments agreeing with experimental results. The method has also been applied to several membrane protein families for which the topology has yet to be determined. An electronic prediction service is available at the E-mail address tmap@embl-heidelberg.de and on WWW via http://www.embl-heidelberg.de.
Amino Acid Sequence↗
Binding and inhibition of myeloperoxidase (MPO): a major function of ceruloplasmin?
Interactions between plasma proteins and MPO were studied. The protein fraction of normal plasma and serum was shown to exhibit an inhibitory effect on the peroxidase activity of MPO. Most of the inhibitory effect could be retained on an MPO-coupled affinity chromatography column. In particular, a protein with apparent mol. wt of 130 kD showed affinity for MPO. The protein was identified as ceruloplasmin by N-terminal amino acid sequencing and immunochemistry. During separation procedures the peroxidase inhibitory effect was limited to ceruloplasmin-containing fractions of plasma. Purified ceruloplasmin inhibited the peroxidase activity of MPO in a concentration-dependent manner, and exhibited selective binding to MPO-coated microtitre plates. This binding could be inhibited by MPO dissolved in buffer. Correspondingly the binding of MPO to ceruloplasmin-coated plates could be blocked by ceruloplasmin in solution, showing a physical interaction to occur between the two proteins under physiological conditions. We also found affinity to exist between MPO and C3 (and its C3d-containing fragments). However, C3 and C3 fragments did not inhibit the peroxidase reaction in vitro. We propose that ceruloplasmin takes part in the clearance and inactivation of MPO, in vivo. We also speculate that impaired inactivation of MPO may have a pathophysiological role in inflammatory diseases characterized by autoantibodies to MPO, such as rapidly progressive glomerulonephritis with P-ANCA (perinuclear anti-neutrophil cytoplasmic antibodies).
Ceruloplasmin↗
Growth environment and personality in adult migraineurs and their migraine-free siblings.
The aim of the study was to compare adult migraine discordant full siblings in terms of personality and psychosocial environment during childhood. The study, involving 30 sibling pairs and use of various personality instruments (Eysenck Personality Inventory [EPI], Color Word Test [CWT], Visual Aftereffects [VAE], Meta Contrast Technique [MCT], Cesarec-Marke Personality Schedule), showed the migraineurs scored significantly higher on neuroticism [EPI], also called emotional stress or trait anxiety; to be more sensitive (MCT); and to display signs of greater anxiety (VAE, CWT). Furthermore, migraineurs tended to report greater scarcity of friends during childhood and less verbal, as well as, nonverbal encouragement from their parents, than their migraine-free siblings. Neuroticism was found to correlate significantly with migraine, but not with headache frequency or severity in the migraine group. It is argued that, due to the high neuroticism of some migraineurs, psychotherapy should be considered as an alternative to other prophylactic treatments such as use of beta-adrenoceptor blockers, although the acute migraine onset should be pharmacologically treated.
Adult↗
Insulin sensitivity and insulin response in women with gestational diabetes mellitus.
Gestational diabetes mellitus (GDM) is associated with much increased risk of developing diabetes later on in life. Using the frequently sampled intravenous glucose tolerance test and the minimal model analyses we have therefore determined the early insulin response to glucose (EIR) and insulin sensitivity (Si), in women with GDM of different severity (n = 14) and in normal women (n = 10). During the last trimester of pregnancy. GDMs compared to controls had significantly lower EIR (p < 0.001) and Si (p < 0.01). The reduction in EIR was less marked in GDM patients treated with diet alone (n = 6) as compared to GMD patients (n = 8) who subsequently during pregnancy needed treatment also with insulin. The insulin treated GDM group only had higher fasting glucose level than controls (5.2 vs 4.2 mmol/l, p < 0.001). Both GDM subgroups had slightly elevated basal levels of FFA and 3-hydroxybutyrate. Si and EIR were inversely correlated in control women and their fasting glucose correlated both to EIR (r = 0.63, p < 0.05) and to Si (r = 0.59, p < 0.05). In the GDM subgroups Si and EIR were unrelated and there were no correlations between fasting glucose and Si or EIR. These results suggest that glucose intolerance in GDM patients in the last trimester of pregnancy is characterized by both an impaired insulin secretion and an increased resistance to insulin. The impairment of insulin secretion and action increases with the severity of hyperglycemia, and the relative insulin deficiency characterizing GDM patients is associated with a selected defect in insulin action mainly affecting gluco-regulation.
3-Hydroxybutyric Acid↗
Cordocentesis in IUGR fetuses.
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Acid-Base Equilibrium↗
Age governs gender-dependent islet cell autoreactivity and predicts the clinical course in childhood IDDM.
Most IDDM patients temporarily restore some of their beta-cell function following the initiation of insulin therapy. The aim of this study was to analyse the influence of age, gender, metabolic state at diagnosis and presence of autoantibodies (GAD65 antibodies and ICA) on the duration of the clinical partial remission. In total, 149 consecutively diagnosed IDDM children, 0-16 y old (70F, 79M, mean age 9.5 y) were studied. Partial remission was arbitrarily defined as the period when the insulin dose was below 0.5 U/BW 24 h-1 and HbA1c below 7.5%, and occurred in 119/149 patients with a duration between 1 and 38 months. Cox's regression analysis showed that the factors significantly associated with the duration of remission were age, gender, interaction between age and gender, ICA and a high initial HbA1c, whereas GAD65Ab had no influence. Young boys had the shortest remission period, while adolescent boys had the longest, as compared to young and adolescent girls. The ICA-negative patients (n = 42) had a longer remission period (median 9.7 months) than the ICA-positive children (n = 107; 5.0 months; p = 0.0001), regardless of GAD65Ab status. We speculate that the relative insulin resistance, which is more pronounced in pubertal girls than in boys, may be associated with a more rapid increase of exogenous insulin requirement. These findings are important when evaluating the effect of islet cell autoreactivity on the clinical course of IDDM in children.
Adolescent↗
Sub-clinical cerebral oedema does not occur regularly during treatment for diabetic ketoacidosis.
Fulminant cerebral oedema is an uncommon, fatal complication of diabetic ketoacidosis (DKA) in children. This study aimed to find out whether the sub-clinical compression of the brain ventricles found by an earlier study, is a general phenomenon during intravenous treatment for DKA. Four boys and four girls were examined. Blood glucose values ranged from 40 to 24.6 mmol/l, base excess -34.6 to -13.6 and capillary blood pH 6.89-7.22. The patients received fluids containing both glucose and electrolytes, and insulin intravenously. After about 10h, blood glucose was 8.7-21.8 mmol/l and base excess had decreased substantially (-9.5 to -2.9) in seven of the eight cases. Computerized tomography of the brain was then performed, and again after full recovery. Only two of the patients had an initial decrease in intercaudate distance, which exceeded the variability found in a reference group. Compression of the cerebral ventricles does not occur regularly during treatment for DKA.
Adolescent↗
Superantigen-based immunotherapy: a phase I trial of PNU-214565, a monoclonal antibody-staphylococcal enterotoxin A recombinant fusion protein, in advanced pancreatic and colorectal cancer.
PURPOSE: To establish the maximum-tolerated dose (MTD) and define the toxicities of a single-dose infusion of PNU-214565, a recombinant Escherichia coli-derived fusion protein of Staphylococcal enterotoxin A (SEA) and the Fab-fragment of the C242 monoclonal antibody in patients with advanced colorectal and pancreatic carcinomas. To investigate the capability of PNU-214565 to induce a superantigen (SAg) response resulting in cytokine production and tumor regression. PATIENTS AND METHODS: Twenty-one patients (age range, 39 to 76 years; median, 64; 12 men, nine women; 18 colorectal, three pancreatic cancers) were treated with a single 3-hour infusion of PNU-214565, with doses ranging from 0.01 to 1.5 ng/kg. All patients had prior chemotherapy and a good performance status Eastern Cooperative Oncology Group [ECOG] performance status [PS] = 0 [n = 10]; PS = 1 [n = 11]), 10 had prior radiation, and 18 had prior surgery. RESULTS: Fever and hypotension were the most common toxicities. Fever of any grade occurred in 16 of 21 patients (76%): four of 21 (19%) with grade 2 and two of 21 (9.5%) with grade 3. Hypotension of any grade occurred in 13 of 21 (62%): four of 21 with grade 2 and one of 21 (5%) with grade 3. Interleukin-2 (IL-2) and tumor necrosis factor alpha (TNF alpha) induction correlated with toxicity. In the two patients with grade 3 fever, peak IL-2 and TNF alpha levels were 2.9 IU/mL and 165 pg/mL, and 8.3 IU/mL and 245 pg/mL, respectively. Transient, > or = 50% decreases in circulating monocytes were observed in 17 of 21 patients as early as 0.5 hours (median time, 2 hours) from the start of infusion. Decreases (mean 33%) in circulating lymphocytes were observed in seven of 21 patients. All three patients with grade 3 toxicity were treated at the 0.5-ng/kg dose. The significance of baseline anti-SEA, human antimouse antibody (HAMA), CA242-soluble antigen levels, and T-cell receptor variable beta region (TCR V beta) subsets and histocompatibility leukocyte antigen-DR (HLA-DR) genotypes was assessed as possible predictors of toxicity. All toxicities were transient and easily managed. No grade 3 toxicity occurred at the higher dose levels. CONCLUSION: PNU-214565, a SAg-based tumor targeted therapy, is safe when given as a single 3-hour infusion at doses up to 1.5 ng/kg. The MTD for a single dose was not determined. The safety of a repeated dose schedule is currently under investigation, beginning with doses determined to be safe in this trial.
Adult↗
Predictors of renal morphological changes in the early stage of microalbuminuria in adolescents with IDDM.
OBJECTIVE: To evaluate the impact of glycemic control, blood pressure, lipid levels, glomerular filtration rate (GFR), age, and duration of IDDM on the degree of structural glomerular changes in the transitional stage of microalbuminuria. RESEARCH DESIGN AND METHODS: Fifteen adolescents (seven boys and eight girls) with > 5 years of duration of IDDM and with low-grade microalbuminuria (15-30 micrograms/min) participated. Seventeen living kidney donors served as healthy control subjects. Five-year mean HbA1c; 5-year mean systolic and diastolic blood pressure; GFR, cholesterol, and triglycerides 2-5 years before renal biopsy; age; and duration of IDDM were investigated and related to basement membrane thickness (BMT), mesangial and matrix volume fractions, and the overall glomerulopathy index [(BMT/10 + mat/glom, %) + matrix star volume]. RESULTS: BMT and the overall diabetic glomerulopathy were increased in diabetic patients as compared with control subjects (P < 0.001), whereas matrix volume fraction, but not mesangial volume fraction, tended to be increased (P = 0.11). In multivariate analysis, BMT was predicted by 5-year mean HbA1c, diabetes duration, and previous GFR (R2 = 0.71, P = 0.003). With matrix volume fraction as the dependent variable, BMT and diabetes duration were the only significant determinants (R2 = 0.63, P = 0.003). Diabetes duration, 5-year mean HbA1c, and GFR were the variables with an independent influence on the overall diabetic glomerulopathy index (R2 = 0.72, P = 0.003). Preceding blood pressure and lipid levels or age had no significant independent influence on these morphometric measures. CONCLUSIONS: In the very early stage of microalbuminuria in IDDM adolescents, a high percentage of the variation in BMT and overall severity of glomerulopathy is explained by prolonged hyperglycemia and diabetes duration. Previous glomerular hyperfiltration may also add to the prediction of these morphological changes.
Adolescent↗
Blood cadmium as an indicator of dose in a long-term follow-up of workers previously exposed to cadmium.
OBJECTIVES: This investigation attempted to follow the tubular function of 46 workers initially examined in 1984 and heavily exposed to cadmium from 1955 to 1978 and the occurrence of renal stones among these workers. Three different markers of tubular dysfunction were also studied, and blood cadmium was evaluated as an estimate of dose after the cessation of cadmium exposure. METHODS: Cadmium in blood (B-Cd) and urine (U-Cd) and the urinary excretion of beta 2-microglobulin (U-beta 2-microglobulin), protein HC (alpha 1-microglobulin) and N-Acetyl-beta-D-glucosaminidase (NAG) were determined. RESULTS: Although cadmium exposure ceased in 1978, 40% of the workers showed signs of tubular dysfunction both in 1984 and in 1993. The current B-Cd was the best dose indicator. Dose-response relationships were found for B-Cd and various tubular markers (U-beta 2-microglobulin, protein HC and NAG). Protein HC appeared to be the most sensitive, as well as an early, indicator of cadmium-induced tubular dysfunction. The levels of U-Cd had an average decrease of 48% for persons with a normal tubular function, 56% for those with slight tubular dysfunction, and 62% for workers with severe tubular damage. A history of renal stones was significantly more common for workers with high B-Cd levels. CONCLUSIONS: Cadmium-induced tubular dysfunction is irreversible and best assessed in an analysis of protein HC (alpha 1-microglobulin) in urine. B-Cd is the best dose estimate several years after the cessation of exposure, whereas U-Cd is less suitable for dose assessment in follow-up studies of persons with persistent tubular damage.
Acetylglucosaminidase↗
Alcohol dehydrogenase variability. Evolutionary and functional conclusions from characterization of further variants.
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Alcohol Dehydrogenase↗
Alcohol dehydrogenases.
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Alcohol Dehydrogenase↗
Oxidative modification of nicotinamide nucleotide transhydrogenase in submitochondrial particles: effect of endogenous ubiquinol.
The present paper describes the sensitivity of the mitochondrial nicotinamide nucleotide transhydrogenase (EC 1.6.1.1) to oxidative modification, and the effects of endogenous ubiquinol on this modification. A comparison is made between the effects of treatment with ADP-Fe3+ and ascorbate and with peroxynitrite, using kinetic, electrophoretic, and immunological analyses, together with lipid peroxidation measurements. The transhydrogenase was inactivated by both types of oxidative modification, but apparently through different mechanisms. Ubiquinol protected the enzyme against inactivation only when the modification was caused by ADP-Fe3+ and ascorbate treatment. Kinetic measurements revealed a threefold increase of the Km value of the enzyme for NADPH after exposure to ADP-Fe3+ and ascorbate, and a twofold increase of the Km values for both NADH and NADPH after exposure to peroxynitrite. NAD(H) exerted a protection against trans-hydrogenase inactivation when added to the preincubation in the case of peroxynitrite, but neither NAD(H) or NADP(H) protected in the case of ADP-Fe3+ and ascorbate. Using immunoblotting it was shown that the enzyme became both aggregated and fragmented, although to different extents, depending on the oxidative system used. Again, ubiquinol prevented these effects only in the case of ADP-Fe3+ and ascorbate treatment. Furthermore, there occurred a striking decrease in the 66-kDa trypsin fragment after exposure of the enzyme to ADP-Fe3+ and ascorbate, and of the 48-kDa trypsin fragment after exposure to peroxynitrite. It is concluded that the mitochondrial nicotinamide nucleotide transhydrogenase is sensitive to oxidative stress and that the mechanism underlying this can vary according to the challenge to which the enzyme is exposed. Endogenous ubiquinol may play a role in protecting the enzyme against agents perturbing the lipid phase of the membrane.
Adenosine Diphosphate↗
Arabidopsis formaldehyde dehydrogenase. Molecular properties of plant class III alcohol dehydrogenase provide further insights into the origins, structure and function of plant class p and liver class I alcohol dehydrogenases.
A glutathione-dependent formaldehyde dehydrogenase (class III alcohol dehydrogenase) has been characterized from Arabidopsis thaliana. This plant enzyme exhibits kinetic and molecular properties in common with the class III forms from mammals, with a K(m) for S-hydroxymethylglutathione of 1.4 microM, an anodic electrophoretic mobility (pI: 5.3-5.6) and a cross-reaction with anti-(rat class III alcohol dehydrogenase) antibodies. The enzyme structure, deduced from the cDNA sequence, fits into the complex system of alcohol dehydrogenases and shows that all life forms share the class III protein type. The corresponding mRNA is 1.4 kb and present in all plant organs; a single copy of the gene is found in the genome. The class III structural variability is different from that of the ethanol-active enzyme types in both vertebrates (class I) and plants (class P), although class P conserves more of the class III properties than class I does. Also the enzymatic properties differ between the two ethanol-active classes. Active-site variability and exchanges at essential residues (Leu/Gly57, Asp/Arg115) may explain the distinct kinetics. These patterns are consistent with two different metabolic roles for the ethanol-active enzymes, a more constant function, reduction of acetaldehyde during hypoxia, for class P, and a more variable function, the detoxication of alcohols and participation in metabolic conversions, for class I. A sequence motif, Pro-Xaa-Ile/Val-Xaa-Gly-His-Glu-Xaa-Xaa-Gly, common to all medium-chain alcohol dehydrogenases is defined.
Alcohol Dehydrogenase↗
Molecular modelling of human gastric alcohol dehydrogenase (class IV) and substrate docking: differences towards the classical liver enzyme (class I).
A three-dimensional model of the human class IV alcohol dehydrogenase has been calculated based upon the X-ray structure of the class I enzyme. As judged from the model, the substrate-binding site is wider than in class I, compatible with the differences in substrate specificities and the large difference in Km value for ethanol. Substrate docking performed for the class I structure and the class IV model show all-trans-retinol and 11-cis-retinol to bind better to the class IV enzyme. The calculations also indicate that 16-hydroxyhexadecanoic acid binds in a different manner for the two enzyme classes. A simulation of coenzyme-binding indicates that the adenine ring of the coenzyme might be differently bound in class IV than in class I, decreasing the interactions with Asp-223 which is compatible with the higher k(cat) values for class IV.
Alcohol Dehydrogenase↗
Lactate in cord blood and its relationship to pH and catecholamines in spontaneous vaginal deliveries.
The interrelationships between lactate and pH, nonadrenaline (NA), adrenaline (A) and dopamine (DA) were investigated in cord artery (CA) and vein (GV) blood at delivery. Sixty consecutive, spontaneous, vaginal deliveries with fetuses in cephalic presentation were assessed. Median gestational age at delivery was 40 weeks (range, 35-43). There were significant correlations between lactate and pH (P < 0.01), NA (P < 0.01), A (P < 0.05) and arterio-venous NA (P < 0.05) and DA differences (P < 0.01) in CA blood, while no variable correlated significantly to lactate in CV blood. The higher levels both of lactate and of catecholamines in CA blood are probably fetally derived. Dividing the material into high and low lactate subgroups (cut-off level, 75th percentile) showed a high lactate level to be associated with lower pH and higher catecholamine levels in CA blood, though the relationship was only statistically significant for pH. The levels both of catecholamines and of lactate were lower than those reported for cases of fetal distress, and reflect the lower level of fetal stress in the present series of normal deliveries. The low level of fetal stress and the differences in turnover rates between catecholamines and lactate might obscure their causal relationships, vis-a-vis fetal adaptation to extrauterine life during the course of parturition.
Delivery, Obstetric↗