[Acute intermittent porphyria. Risk of secondary hypertension--needs follow-up!].
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Adult↗
Biomedical subjects
C Andersson
Publications and source records attributed to C Andersson.
Kinetic studies on rat liver microsomal glutathione transferase: consequences of activation.
Rat liver microsomal glutathione transferase is activated by sulfhydryl reagents and proteolysis. This property varies, however, depending on the combination, concentration and reactivity of the substrates. Thus, a multi-dimensional diagram can be envisioned in which the parameters affecting enzyme activity and activation are visualized. In principle activation could stem from an alteration in enzyme mechanism, transition-state complementarity, product release rate or pH-rate behaviour. These studies appear to rule out these possibilities and an alternate hypothesis is suggested based on the following experiments: (i) alternate substrate diagnosis of the kinetic mechanism of microsomal glutathione transferase indicates a random sequential mechanism. Non-activated and activated enzyme follow the same mechanism by these criteria. (ii) The microsomal glutathione transferase stabilizes a Meisenheimer complex between 1,3,5-trinitrobenzene and glutathione. The formation constants were similar for the unactivated and activated enzyme ((15 +/- 1).10(3) and (14 +/- 1).10(3) M-1, respectively, at pH 8). Inasmuch as the Meisenheimer complex resembles the transition state there is no evidence for an increased stabilization upon activation. (iii) The catalytic rate constant kcat does not vary with the viscosity in the assay medium. Thus, product release is not rate limiting for the unactivated and activated microsomal glutathione transferase (with saturating 1-chloro-2,4-dinitrobenzene and varying GSH). (iv) The pH dependence of the Kf-values for Meisenheimer complex formation exhibited pKa values close to 6 for both the activated and unactivated microsomal glutathione transferase. The pH profile of kcat (with saturating 1-chloro-2,4-dinitrobenzene and variable GSH concentrations) showed apparent pKa values of 5.7 +/- 0.5 and 6.3 +/- 0.4 for the unactivated and activated enzyme, respectively, indicative of a very similar requirement for deprotonation of the enzyme-GSH-1-chloro-2,4-dinitrobenzene complex. (v) Examination of the kinetic parameters (obtained with GSH as the variable substrate against increasingly reactive electrophilic substrates) in Hammett plots shows that the activation mechanism entails a more efficient utilization of GSH. It is suggested that a higher rate of formation of the glutathione thiolate anion occurs in the activated enzyme.
Amino Acid Sequence↗
Disparity in blood activation by two different heparin-coated cardiopulmonary bypass systems.
BACKGROUND: Several studies have indicated reduced "blood activation" in heparin-coated cardiopulmonary bypass systems. The present study compares the effect of two different heparin coatings on different blood activation indices. METHODS: Low-risk patients (n = 40) were randomized to coronary artery bypass grafting using cardiopulmonary bypass with surfaces coated entirely by either the Duraflo II heparin coat or the Carmeda Biological Active Surface, or with identical uncoated equipment. In all cases, a standard systemic heparin dosage was used. Complement activation (C3 activation products C3bc and C3a and formation of fluid phase terminal SC5b-9 complement complex), neutrophil activation (lactoferrin and myeloperoxidase), and lytic inhibitors (vitronectin and clusterin) were quantified during cardiopulmonary bypass and 6 hours postoperatively. RESULTS: Heparin coating by either method reduced the formation of terminal SC5b-9 complement complex and the release of lactoferrin and myeloperoxidase compared with uncoated systems. Lactoferrin and myeloperoxidase levels increased significantly during cardiopulmonary bypass in the Duraflo II group, whereas no significant increase was observed in the Carmeda Biological Active Surface group. The least formation of terminal SC5b-9 complement complex and neutrophil activation was observed with the Maxima Carmeda Biological Active Surface-coated equipment. The vitronectin and clusterin concentrations were significantly less reduced in the Duraflo II compared with the control group. This study underlines the importance of terminal SC5b-9 complement complex as a suitable marker in the evaluation of complement activation during cardiopulmonary bypass. CONCLUSIONS: Both heparin coatings reduce blood activation, probably more so with Carmeda Biological Active Surface than with Duraflo II.
Anticoagulants↗
Diagnosis of acute intermittent porphyria in northern Sweden: an evaluation of mutation analysis and biochemical methods.
OBJECTIVE: To validate the use of a recently observed guanine to adenine mutation in exon 10 in the porphobilinogen deaminase (PBGD) gene as a diagnostic marker of acute intermittent porphyria (AIP). To evaluate the efficiency of the traditional biochemical diagnostic methods. DESIGN: Matched and blinded case-control study (1:4). SETTING: A primary health care centre in Arjeplog, the National Porphyria Research Unit and a department of clinical genetics in Stockholm. SUBJECTS: A total of 48/49 (98%) patients over the age of 15 years living in Arjeplog with AIP, diagnosed according to standard clinical and biochemical criteria. For each AIP patient, four controls were matched for age, sex and geographical area and 164/196 (86%) participated. In the validity study, 35 patients were selected as indisputable AIP gene carriers, according to strict biochemical criteria, and 92 matched controls were selected with strict exclusion criteria. MAIN OUTCOME MEASURES: Validity, specificity and sensitivity of DNA diagnosis for this AIP mutation. Specificity and sensitivity of traditional biochemical methods. RESULTS: Validity study: the mutation was found in all 35 individuals classified as carriers of AIP. None of the 92 controls had the mutation. Evaluation study: all 48 AIP gene carriers, diagnosed by traditional methods, had the mutation, as had one of the control persons. In an inconclusive group of five persons with heredity for AIP, two had a positive DNA test. CONCLUSIONS: The PBGD mutation analysis was found to have full specificity and sensitivity and can be used as the sole diagnostic method in the family complex studied, representing the major AIP mutation in Sweden. The traditional diagnostic methods, used in optimal combinations, work in most cases, but they do not show high precision. However, they must be used when the specific mutation in the PBGD gene is not known.
Adolescent↗
Expression of proliferating cell nuclear antigen (PCNA) and Ki-67 in soft tissue sarcoma. Is prognostic significance histotype-specific?
Abnormal patterns of proliferation characterize the behavior of many tumors. Proliferating cell nuclear antigen (PCNA) and Ki-67 are two cell cycle antigens which are expressed in proliferative states. Our study examines the prognostic value of these cell-cycle antigens in soft tissue sarcoma (STS). Paraffin-embedded primary tumor tissues from 185 patients (1980-92) were stained with the anti-PCNA antibody PC-10; 182 of these were stained with the antibody MIB-1 for Ki-67. Using PCNA (< or = 50; > 50%) and Ki-67 (< or = 10; > 10%) indices, we examined and compared metastasis-free survival (MFS) in a mixed-histotype group, as well as after subdivision into MFH and non-MFH groups. Fifty-seven patients developed metastases. The median follow-up for survivors was 6 (2-13) years. In the mixed series, the 2-year MFS for a PCNA index < or = 50 was 76%, and for an index > 50 56%. Survival predicted by Ki-67 index was comparable. PCNA index (but not Ki-67) strongly correlated with the incidence of metastasis in MFH tumors and predicted 2-year MFS of 81 vs 48%. In contrast, Ki-67 index (but not PCNA) strongly correlated with metastasis in non-MFH tumors and predicted 2-year MFS survival of 90 vs 45%. No correlation existed between PCNA and Ki-67 indices in the mixed histotype, MFH or non-MFH groups. In combination, a high PCNA and Ki-67 index correlated with poor survival, a high PCNA and lower Ki-67 index (or vice versa) with an intermediate survival, and low PCNA and Ki-67 indices with the best survival. The pattern of PCNA and Ki-67 expression raises the possibility of histotype specificity.
Adult↗
Markers for vulnerability in acute porphyria. A hypothesis paper.
Previously symptomatic and permanently asymptomatic carriers of a gene mutation for acute intermittent porphyria as well as matched controls were screened with regard to a series of variables of possible relevance to the development of porphyric symptoms. The basis for the study was a concept of acute porphyria as a condition of a permanent system overload of oxidative stress, with long term effects on hepatic and renal tissue, and with instances of periodic overload of free radicals giving rise to acute neurologic involvement. Leukocyte concentrations of manganese, calcium, iron and zinc, as well as erythrocyte calcium differed between the groups, acute intermittent porphyria gene carriers, irrespective of previous porphyric illness, showing significantly higher levels than the controls. Manganese was found to be the most discriminative component of all the 78 variables investigated, accounting for about 98 per cent of the variance between the groups. An increment, by a factor of four, in cellular manganese is suggestive of an increase, in acute intermittent porphyria, of a manganese associated enzyme, e.g. glutamine synthetase, pyruvate carboxylase or mitochondrial superoxide dismutase. The best fit into the model considered is provided by a theory focused on superoxide dismutase, induced in response to superoxide anion radical produced from aminolaevulinic acid. In porphyria gene carriers seemingly resistant to porphyric manifestations, an increase in potentially prooxidant cellular iron is matched by a proportional increment in manganese, i.e. presumably by a corresponding mitochondrial superoxide dismutase induction. This mechanism is not operative in porphyric individuals prone to development of neuropsychiatric symptoms. In acute intermittent porphyria with a history of porphyric illness there is a positive correlation between erythrocyte manganese and serum folate and a negative correlation between leukocyte ferrochelatase activity and serum cobalamin concentration. This may mirror a role of the cobalamin-folate system in the acute porphyric process.
Adult↗
Immunocytochemical and ultrastructural characterization of type 1 astrocytes and 0-2A lineage cells in long-term co-cultures.
We examined cultures of purified type 1 astrocytes and mixed glial co-cultures containing type 1 astrocytes and 0-2A lineage cells in media containing fetal calf serum at 5 days in vitro (DIV), 12 DIV, and 30 DIV, using cell-specific immunocytochemical markers and electron microscopy. At all three time points and in both culture systems, the polygonal-shaped type 1 astrocytes were A2B5-, GFAP+, and GalC-(specific markers for 0-2A lineage cells, and mature astrocytes and oligodendrocytes, respectively). From 5 to 30 DIV, the type 1 astrocytes increased markedly in size and the appearance of the cytoskeleton changed dramatically, with the amount of glial filaments increasing and microtubules decreasing. At 5, 12, and 30 DIV, the 0-2A lineage cells were multipolar, A2B5 +, HNK-1 +, GFAP-, and GalC-. The 0-2 lineage cells could not be distinguished as either astrocytes or oligodendrocytes on the basis of immunocytochemical or ultrastructural characteristics. These cells had dense cytoplasm, very few intermediate filaments, and a large number of vacuoles and dense bodies. The general characteristics of the cultured astrocytes at 12 DIV and 30 DIV were similar to mature and aged astrocytes in vivo, respectively. These findings suggest that the culture environment in this study accelerated aging of type 1 astrocytes. 0-2A lineage cells, on the other hand, appeared unable to differentiate into either type 2 astrocytes or oligodendrocytes when cultured in the presence of both type 1 astrocytes and fetal calf serum.
Animals↗
Functional and structural membrane topology of rat liver microsomal glutathione transferase.
The membrane topology of rat liver microsomal glutathione transferase was investigated by comparing the tryptic cleavage products from intact and permeabilized microsomes. It was shown that lysine-4 of microsomal glutathione transferase is accessible at the luminal surface of the endoplasmic reticulum, whereas lysine-41 faces the cytosol. These positions are separated by a hydrophobic stretch of 25 amino acids (positions 11-35) which comprises the likely membrane-spanning region. Reaction of cysteine-49 of the microsomal glutathione transferase with the charged sulfhydryl reagent DTNB (2,2'-dithiobis(5-nitrobenzoic acid)) in intact microsomes further supports the cytosolic localization of this portion of the polypeptide chain. The role of two other potential membrane-spanning/associated segments in the C-terminal half of the polypeptide chain was examined by investigating the association of the protein to the membrane after trypsin cleavage at lysine-41. Activity measurements and Western blot analysis after washing with high concentrations of salt, as well as after phase separation in Triton X-114, indicate that this portion of the protein also binds to the membrane. It is also shown that cleavage of the purified protein at Lys-41 and subsequent separation of the fragments obtained yields a functional C-terminal polypeptide with the expected length for the product encompassing positions 42-154. The location of the active site of microsomal glutathione transferase was investigated using radiolabelled glutathione together with a second substrate. Since isolated rat liver microsomes do not take up glutathione or release the glutathione conjugate into the lumen, it can be concluded that the active site of rat liver microsomal glutathione transferase faces the cytosolic side of the endoplasmic reticulum.
Amino Acid Sequence↗
Prediction of outcome in multiple sclerosis based on multivariate models.
An incidence cohort of 308 multiple sclerosis patients was followed up repeatedly during at least 25 years of disease. In the patients with acute onset, multivariate survival analyses were performed and predictive models created. The endpoints DSS 6 and start of progressive disease were used. A number of variables were tested. The most important of these for prediction and therefore included in these models were: age at onset, sex, degree of remission after relapse, mono- or polyregional symptoms, type of affected nerve fibres, number of affected neurological systems. The relapse rate did not correlate with prognosis. In the predictive models, coefficients and risk ratios are provided that can be used for calculating the risk of progression and DSS 6 or to predict the median time for these endpoints in individual patients. It was also found that the risk of progression is not constant, but has a maximum a certain time after disease onset. For a patient with early onset, the risk is low in the beginning, but reaches a maximum level, which is several times higher, after about 15 years. The patient with a late onset has a much higher risk of endpoint immediately after onset, but reaches the maximum in a few years, and after that the risk decreases.
Acute Disease↗
Isolation of radiopure plasma and hepatic albumin in acute phase conditions.
It is essential to obtain biochemically and radioactively pure albumin in studies on albumin metabolism and kinetics in stress and nutrition related conditions. However, published work on albumin metabolism, in both animals and man with acute phase reactions has usually been based on inadequate chemical methods for isolation of homogeneous albumin free from acute phase proteins and other contaminants. Applications of conventional antibody precipitating techniques was usually either not sufficient to give radiopure albumin, or did not allow determination of the true specific radioactivity during in vivo experiments. Thus, the lack of applicable methods to achieve radiopure albumin from small plasma and tissue samples for subsequent analyses and determination of the true specific radioactivity in albumin initiated the present method development. The combination of HPLC ionchromatography (DEAE-sepharose), affinity chromatography (Blue sepharose CL-6B, Con A sepharose) and HPLC based size exclusion chromatography (Protein PAK 300 SW, Waters) was applied. By this procedure we obtained radiopure albumin from both plasma and hepatic samples from individual mice with acute phase response as confirmed by two-dimensional electrophoresis and immune precipitation.
Journal Article↗
Distribution of acidic and basic fibroblast growth factors in the mature, injured and developing rat nervous system.
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Animals↗
Enzymology of microsomal glutathione S-transferase.
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Animals↗
Structure elucidation of three triterpenoid saponins from Alphitonia zizyphoides using 2D NMR techniques.
High-field nmr experiments have been used to determine the structures of three new saponins, zizyphoisides C, D, and E [1-3], isolated from Alphitonia zizyphoides, a medicinal plant found in the Samoan rain forest. The saponins consist of the aglycone, jujubogenin, to which are attached three sugar units and an unsaturated side-chain. The three compounds are similar except for the location of an acetyl group on one of the sugar units.
Carbohydrate Sequence↗
Prescribing endodontic retreatment: towards a theory of dentist behaviour.
The large variations observed in dentists' management of periapical lesions in endodontically treated teeth suggest that disease concepts used in clinical practice should be investigated. In the present study it was hypothesized that dentists regard various periapical conditions as different stages on a health continuum. Variations could then be regarded as the result of the individuals selection of differing cut-off points for prescribing retreatment. The hypothesized decision-making model was tested using dental students in Amsterdam (Holland), Gothenburg (Sweden) and Pavia (Italy). The students were shown six simulated cases among which the quality of root filling seal and presence of post and crown were systematically varied. For each case, management of five periapical conditions was assessed. Five options were offered: no therapy, wait-and-see, nonsurgical retreatment, surgical retreatment, and extraction. For each examiner and case a 'retreatment preference score (RPS)' was established. The investigation showed large interindividual variations in RPS. A statistically significant higher mean RPS was seen among students in Pavia compared with students in Amsterdam and Gothenburg. Among all observers and cases it was found that if retreatment was proposed for a certain size of lesion, retreatment was subsequently selected for all larger lesions. The experiment gave evidence in support of the proposed hypothesis. The data also suggest that the choice of retreatment criterion is affected by values, costs of retreatment and technical quality of the original treatment.
Adult↗
Hypertension and renal disease in patients with acute intermittent porphyria.
OBJECTIVES: To assess the association between acute intermittent porphyria (AIP), hypertension and renal disease. DESIGN: A population-based matched case-control study (1:4) in 50 AIP patients (manifest/latent 25/25), a retrospective study of all individuals who died between the years 1978 and 1990 (2122 including 33 with AIP) and a group of eight patients with severe AIP. RESULTS: Hypertension was found in 56% of patients with manifest AIP, 33% of their controls (P = 0.041) and 16% of patients with latent AIP (P = 0.004). Renal disease was not more common in patients with AIP than in their controls. Three of the eight patients with severe recurrent AIP had impaired renal function, caused in one by systemic lupus erythematosus (SLE) nephritis. In the other two, no cause other than AIP could be found. In the mortality study, hypertension was registered in 68% of patients with manifest AIP compared to 21% of those with latent AIP (P = 0.008) but death from myocardial infarction and stroke was not more common. Uraemia was cited as the cause of death in 9.1% of AIP patients and 1.0% of those without AIP (P = 0.006). CONCLUSIONS: Hypertension is more common in patients with manifest AIP than in those with latent AIP or control subjects. Renal disease may be due to hypertension, to AIP or to SLE. AIP may predispose to other renal diseases.
Adolescent↗
Assessment of sensory block in epidural anaesthesia by electric stimulation.
The onset of sensory block in lumbar epidural anesthesia was investigated in 26 patients, aged 18 to 84 years, employing the loss of discrimination to cold and pinprick, as well as by determining threshold electric stimulation (threshold intensities). A standard dose of 2% mepivacaine with adrenaline, 5 micrograms.ml-1, (0.1 ml per cm body height) was given and the patients' ability to discriminate stimuli within dermatomes T8, T10, T12, L2, L4 and S1 was investigated at five min intervals for 30 min after injection. From the results of the study it is concluded that i) The interval to peak analgesic efficacy of the anaesthetic solution used is < 30 min when assessments are based on the patients' ability to discriminate cold or pinprick but > 30 min when determinations of threshold intensities are employed. ii) Cold discrimination is lost earlier than discrimination to pinprick and at lower threshold intensities. iii) Threshold intensities describe the time course of onset of sensory block more precisely than results of testing by cold or pinprick. iv) The onset of sensory block was found to be positively correlated to the age of patients in the following respects: a) Threshold intensities during early onset in all investigated dermatomes except L2. b) Intensity of block in T8, T10, and S1 at the end of the study period. c) Time to loss of discrimination to cold and pinprick in T12, L2 and S1, and d) Threshold intensities at loss of discrimination to cold and pinprick. We propose that determinations of threshold intensities offer distinct advantages over conventional testing by cold and pinprick discrimination, especially when detailed analyses of the sensory blocking effects of local anaesthetic drugs are being investigated.
Adolescent↗
Prognostic value of Ki-67 expression in 182 soft tissue sarcomas. Proliferation--a marker of metastasis?
Soft tissue sarcomas (STS) are characterized by deregulated proliferation. Ki-67 is a cell cycle antigen which may be elevated in proliferative states. We analysed Ki-67 expression in fixed and embedded tissues from STS in order to examine associations between proliferation, primary tumour characteristics, and metastasis. One hundred and eighty-two adult patients with trunk wall or extremity STS were treated at our institution between 1980 and 1992 (35 developed local recurrence and 56 developed metastases). Median follow-up time for survivors was 6 years (1-13). We used a semiquantitative score to the assess percentage of Ki-67-positive cells: < or = 10% (n = 86), > 10-25% (n = 57), > 25-50% (n = 30), > 50-75% (n = 7), > 75-100% (n = 2). Increasing Ki-67 expression correlated positively with tumour size, malignancy grade, necrosis, vascular invasion, S-phase fraction, and metastasis. A Ki-67 index Ki-D < or = 10% (n = 86) and > 10% (n = 96) defined two groups who had 84% and 56% 3-year metastasis-free survival (p = 0.0001), respectively. Tumours with Ki-D > 10 were typically large, high grade, necrotic, DNA aneuploid, and had intravascular invasion and a higher S-phase fraction. Ki-67 expression may be helpful in predicting survival of patients with soft tissue sarcomas.
Adult↗
Geographical distribution of TTR met30 carriers in northern Sweden: discrepancy between carrier frequency and prevalence rate.
The first Swedish case of familial amyloidotic polyneuropathy (FAP) was published in 1965. The same transthyretin (TTR met30) mutation as that seen in Japanese, Portuguese, and other populations was also found in Swedish FAP patients. More than 350 patients with clinical manifestations of FAP have been diagnosed in northern Sweden, most of them originating from the areas around Skellefteå and Piteå. The mean age of onset is 56 years, much later than in patients from Japan and Portugal. To estimate the frequency of the TTR met30 mutation in the counties of Västerbotten and Norrbotten, sera from 1276 persons aged 24 to 65 years, randomly sampled from a health programme (MONICA), were screened with the monoclonal antibody FD6. In 19 persons, 13 females and six males, a positive reaction was seen in an Elisa test using this antibody. DNA analysis confirmed the TTR met30 mutation and showed that 18 were heterozygous and one homozygous for this mutation. Other mutations were not looked for in this study. The mean TTR met30 carrier frequency in the area was 1.5% ranging from 0.0 to 8.3% in 23 subpopulations. There was a notable discrepancy between the regional distribution of the TTR met30 allele and the morbidity rate for FAP. The estimated number of TTR met30 gene carriers in a total population of 500,000 in the area is approximately 7500. The penetrance of the TTR met30 mutation shows considerable variation between families, and the overall diagnostic (predictive) value in this population is as low as around 2%.
Adult↗