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Biomedical subjects

H Pedersen

Publications and source records attributed to H Pedersen.

At least 37 records · Page 2Linked to original sources
PubMed1998

Osteochondritis dissecans of the femoral condyle treated with periosteal transplantation. Poor outcome in 14 patients followed for 6-9 years.

We evaluated 14 consecutive periosteal transplantations to treat osteochondritis dissecans lesions of the femoral condyle. 1 year postoperatively, 9 knees were pain-free, but with 6-9 years follow-up, only 2 knees were pain-free. Formation of hyaline-like cartilage, assessed in 12 knees, was documented in 1 patients and assessed as possible in 1 more, but in 10 patients the tissue formed in the defects was not or probably not hyaline cartilage. 6 knees had developed arthrosis.

Adolescent↗
PubMed1997

Protein-induced fit: the CRP activator protein changes sequence-specific DNA recognition by the CytR repressor, a highly flexible LacI member.

The CytR repressor and the cAMP receptor protein (CRP) bind cooperatively to several promoters in Escherichia coli to repress transcription initiation. The synergistic binding is mediated by protein-protein interactions between the two regulators. Here, in vitro selection experiments have been used to examine the DNA-binding characteristics of CytR, by itself and when co-binding with cAMP-CRP. We show that the optimal CytR-binding site consists of two octamer repeats, in direct or inverted orientation, and separated by 2 bp. However, when co-binding with cAMP-CRP, CytR instead recognizes inverted repeats separated by 10-13 bp, or direct repeats separated by 1 bp. The configurations of the latter set of operators correlate well with the configurations of natural CytR targets. Thus, cAMP-CRP induces conformational changes in CytR so that the repressor fits the natural targets. Most strikingly, CytR can adopt widely different conformations that are equally favored energetically for complex formation with cAMP-CRP. We propose that this structural adaptability is essential for CytR repression of promoters with diverse architectures. We discuss these novel concepts in the context of the CRP/CytR regulatory system, as well as the structural and functional implications for multiprotein-DNA complex formation in general.

Bacterial Proteins↗
PubMed1997

Early clinical investigation of sulofenur with a daily schedule in advanced solid tumours.

Sulofenur, a sulfonylurea, has demonstrated antitumour effect in preclinical studies. A phase I trial was initiated to study the clinical aspects. Sulofenur was given p.o. daily for a period of 28 days in 5-week courses. The initial dosage was 250 mg/m2 escalating to 700 mg/m2 daily with no dose modification for the individual patient at any given dose level; 38 patients with advanced solid malignant tumours were enrolled. Haemolytic anaemia was the main side effect. The toxicity was marked at dose levels of 600 and 700 mg/m2. Moderate methaemoglobinaemia also occurred. One case of reversible toxic hepatitis was observed. Generally was ALAT, and more moderately basic phosphatases, and LDH elevated. Tumour regression was not observed but one patient had stable disease throughout nine courses. The maximal detected plasma concentration of Sulofenur in this study was 348 x 10(-6) g/ml. In the present study the maximum tolerated dose (MTD) of Sulofenur was defined to 600 mg/m2. One conclusion from this study is that even at doses above that recommended for future studies-5-600 mg/m2-with this schedule, the suggested effective plasma level from preclinical studies could not be reached. The overall conclusion is that this schedule should not be recommended at all for future studies and the recommendation should be to try to find a schedule in which higher plasma levels can be achieved at a clinically tolerated dose.

Adult↗
PubMed1996

A flexible partnership: the CytR anti-activator and the cAMP-CRP activator protein, comrades in transcription control.

A vital point in gene regulation is control at the level of transcription initiation. Recent research has established that this regulation can involve sophisticated networks of interacting proteins that modulate the activity of the transcription machinery by DNA looping, direct protein-protein interactions or changing DNA topology in the promoter region. This Micro-Review focuses on our investigations of a relatively simple prokaryotic gene regulatory system, the Escherichia coli CytR regulon, which exhibits a number of these features. This work has opened the door to the molecular understanding of how a prokaryotic repressor can be correctly positioned at specific DNA sequences with the help of a global activator, and how the repressor subsequently inhibits factor-dependent transcription initiation.

Bacterial Proteins↗
PubMed1995

Enhanced D1 affinity in a series of piperazine ring substituted 1-piperazino-3-arylindans with potential atypical antipsychotic activity.

A study of the effect of aromatic substitution on D1 and D2 affinity in a series of previously reported trans-1-piperazino-3-phenylindans shows similar structure-activity relationships for the two receptor sites. 6-Substituted derivatives have affinity for both receptors, and 6-chloro-or 6-fluoro-substituted derivatives show preference for D1 receptors. D1 affinity and selectivity are significantly increased in a series of new piperazine ring substituted derivatives. Potent D1 and D2 antagonism in vivo are confined to derivatives with relatively small substituents in the 2-position of the piperazine ring (e.g. 2-methyl,2,2-dimethyl, 2-spirocyclobutyl or 2-spirocyclopentyl). Consequently, the effect of aromatic substitution is examined in a series of 1-(2,2-dimethylpiperazino)-3-arylindans. All these compounds except the 4-, 5-, 7- and 4'-chloro-substituted derivatives have potent D1 affinity (IC50's below 10 nM) and the majority of the compounds antagonize SK&F 38393-induced circling in 6-OHDA-lesioned rats with ED50 values about 1 mumol/kg. In vitro all compounds show preference for D1 receptors, but in vivo they are equally effective as D1 and D2 antagonists. The compounds have high affinity for 5-HT2 receptors and selected compounds show high affinity for alpha 1 adrenoceptors. Furthermore, a subgroup consisting of (-)-38, (-)-39, (-)-41, and (-)-54 does not induce catalepsy in rats. These compounds have the potential of being "atypical" antipsychotics and have consequently been selected for further studies. The non-receptor-blocking enantiomers are shown to be inhibitors of DA and NE uptake in accordance with previous observations in compounds unsubstituted in the piperazine ring. Two compounds, (+)-38 and (+)-40, block DA uptake with IC50 values below 10 nM. Finally, the observed structure-activity relationships are discussed in relation to previously published pharmacophore models for D2 and 5-HT2 receptors. It is concluded that the piperazine substituents might induce a different binding mode at the dopamine receptor sites, perhaps only at the D1 receptor site.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1995

Urokinase receptor in breast cancer tissue extracts. Enzyme-linked immunosorbent assay with a combination of mono- and polyclonal antibodies.

Urokinase plasminogen activator (uPA) is a proteolytic enzyme involved in degradation of the extracellular matrix during cancer invasion. The levels of uPA and its inhibitor PAI-1 in tumor extracts have previously been demonstrated to be of prognostic value in breast cancer as well as other types of cancer. We have previously characterized a specific cell surface receptor for uPA (uPAR) which strongly enhances the catalytic activity of uPA and is expressed during mammary cancer invasion. In order to quantitate uPAR in breast cancer tissue, we have now developed a sensitive enzyme-linked immunosorbent assay (ELISA), with polyclonal catching antibodies and three monoclonal detecting antibodies. The detection limit of the assay is approximately 0.16 fmol of uPAR in a volume of 100 microliters (1.6 pM). There is a linear relationship between signal and uPAR concentration up to at least 6.6 fmol per 100 microliters (66 pM). Both free uPAR and uPAR in complex with uPA is detected. The recovery of an internal uPAR standard in breast cancer tissue extracts is above 87%. The intra-assay and inter-assay variation coefficients are 7% and 13%. In order to find a suitable buffer for extraction of various components of the uPA-system from breast cancer tissue, we tested buffers which previously have been used for optimal extraction of estrogen receptor (A), uPA (B), and uPAR (C). Buffer A and B extracted approximately 30% and 50%, respectively, of the amount of uPAR extracted with buffer C.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Non-invasive impedance analysis: a new non-invasive test for graft surveillance.

Detection of failing grafts with early reoperation is clearly associated with better long-term patency than intervention after graft failure. Duplex ultrasonography is more accurate than ankle:brachial index for graft surveillance, but is expensive, time consuming and technically demanding. Non-invasive estimation of graft impedance is now possible. The present study was undertaken to evaluate the utility of non-invasive impedance in detecting the failing vein graft. Sixty-nine grafts in 51 patients were followed over a period of 12 months (April 1992-March 1993). High risk infrainguinal arterial vein bypass patients were entered into a graft surveillance program. Ankle:brachial index, non-invasive impedance and duplex ultrasonography were performed upon discharge, 1 month after surgery and then at 3-monthly intervals. Non-invasive impedance was measured using a mean Doppler flow signal obtained from both upper and lower ends of the graft paired with the mean pulse volume recording obtained from the distal arterial bed. The mean pulse volume recording and flow signals were digitized by discrete Fourier transform and an impedance index generated. An impedance index > or = 0.5 was considered abnormal. Impedance results were compared with ankle:brachial index, duplex ultrasonography and angiography when appropriate, and detected 28 failing and five failed grafts. Non-invasive impedance achieved a sensitivity of 91% and a specificity of 94%. Similarly, duplex ultrasonography was 91% sensitive and 97% specific, while ankle:brachial index was 58% sensitive and 94% specific. Non-invasive impedance is a simple, inexpensive and effective test which detects the failing graft and is an appropriate first-line alternative to duplex ultrasonography for postoperative graft surveillance.

Adult↗
PubMed1995

Gene-regulatory modules in Escherichia coli: nucleoprotein complexes formed by cAMP-CRP and CytR at the nupG promoter.

Repression by CytR depends on the formation of nucleoprotein complexes in which the CytR repressor and the cAMP-CRP activator complex bind co-operatively to the DNA. Transcription initiation from CytR-regulated promoters requires cAMP-CRP; therefore, the cAMP-CRP complex functions both as an activator and as a co-repressor in these promoters. Another interesting aspect of the CytR regulon is that each promoter appears to have individual features. Therefore, structural and functional rules governing the formation of repression and activation complexes in one promoter may not be valid for other promoters of the CytR regulon. Here we show that the Escherichia coli nupG gene contains one CytR- and four CRP-binding sites in the control region. Notably, the architecture of the CytR binding site is different from previously described targets. In addition, the CytR repressor triggers a DNA repositioning of a cAMP-CRP complex in the -35 region upon binding to its operator. Thus, formation of the repression and activation complexes at the nupG promoter involves different subsets of CRP-binding sites. These findings show that the bacterium uses positive and negative regulatory modules to differentially control the expression of CytR- and cAMP-CRP-regulated genes.

Bacterial Proteins↗
PubMed1995

Skin thickness in patients with osteoporosis and controls quantified by ultrasound A scan.

In order to study a possible association between skin thickness and osteoporosis, we measured skin thickness by A mode ultrasound scanning in 20 females with osteoporosis and 20 age- and sex-matched controls. Bone mineral content (BMC) of the lumbar spine and the forearm was measured by dual-photon absorptiometry. BMC of the lumbar spine was significantly reduced in the osteoporotic group as compared to controls (p < 0.002). No difference in skin thickness was found between osteoporotic patients and controls. A statistically significant correlation between skin thickness on the forearm and BMC of the forearm was found (p < 0.02), but was opposed by a lack of correlation between skin thickness and BMC of the lumbar spine. We found a correlation between skin thickness and body weight (p < 0.002), which to our knowledge had not been reported earlier.

Absorptiometry, Photon↗
PubMed1995

Metabolism of sertindole: identification of the metabolites in the rat and dog, and species comparison of liver microsomal metabolism.

1. The main exretion pathways of a novel antipsychotic drug, sertindole, in the rat and dog are faecal excretion via intestinal secretion and biliary excretion respectively. 2. Similar liver microsomal metabolic patterns were observed in the rat, monkey, and man, and Lu 30-131 (5-hydroxy-serindole) and Lu 30-148 (4-hydroxy-serindole) were the major metabolites, and Lu 25-073 (nor-sertindole) and Lu 28-092 (dehydro-sertindole) were minor ones. In the dog, however, Lu 31-096 (3'-fluoro-4'-hydroxy-sertindole) and Lu 30-148 (4-hydroxy-sertindole) were the major metabolites, and Lu 25-073 (nor-sertindole), Lu 28-092 (dehydro-sertindole), and Lu 30-131 (5-hydroxy-sertindole) were minor ones. These findings suggest that the metabolism of sertindole in man resembles those in the rat and monkey and is different from that in the dog. 3. Rat in vitro and in vivo liver metabolites, dog liver microsomal metabolites, and dog biliary metabolites were isolated and identified by liquid chromatography/mass spectrometry and/or 1H-nmr. 4. Two metabolites, Lu 31-096 (3'-fluoro-4'-hydroxy-sertindole) and Lu 31-154 (3'-fluoro-4'-hydroxy-dehydro-sertindole), were formed via the 'NIH shift' mechanism. 5. Sertindole is metabolized by hydroxylation at the 4- and 5-positions on the imidazolidinone ring, N-dealkylation, and an NIH shift at the fluorophenyl group. Further metabolism (dehydration, oxidation, hydroxylation, glucuronidation and sulphation) was also observed. 6. In the rat, oxidation at the imidazolidinone ring and N-dealkylation are the main metabolic reactions. On the other hand, in the dog, the NIH shift at the fluorophenyl group, followed by conjugation is the main metabolic pathway.

Animals↗
PubMed1994

Bioisosteres of arecoline: 1,2,3,6-tetrahydro-5-pyridyl-substituted and 3-piperidyl-substituted derivatives of tetrazoles and 1,2,3-triazoles. Synthesis and muscarinic activity.

A series of arecoline bioisosteres, where the ester group is replaced by a 1,2,3-triazole-4-yl or a tetrazole-5-yl group, was synthesized and evaluated in vitro for affinity and efficacy at muscarinic receptors and in vivo for cholinergic side effects. The corresponding piperidine derivatives were also studied. In the 1,2,3,6-tetrahydropyridyl-1,2,3-triazole series, only derivatives with 2-substituents in the 1,2,3-triazole ring exert muscarinic agonist activity. The same trend is seen in the corresponding tetrazole series, where only 2-substituted derivatives display muscarinic agonist activity. The methyl derivatives in both series are full agonists, whereas the derivatives with longer side chains are partial agonists. Introduction of methyl substituents in the 1,2,3,6-tetrahydropyridine ring generally lowers affinity considerably except for the 3-substituted derivatives, where some activity is retained. In both the 1,2,3-triazole and tetrazole series, derivatives without substituents at the basic nitrogen in the 1,2,3,6-tetrahydropyridine ring are unselective full agonists, whereas the methyl-substituted derivatives generally are more M1 selective compared to M2. Larger substituents than methyl abolish activity. The 4-(3-piperidyl)-1,2,3-triazole and 5-(3-piperidyl)-2H-tetrazole derivatives are generally less active than the corresponding 1,2,3,6-tetrahydropyridine derivatives, and only the 2-allyl- and 2-propargyl-1,2,3-triazole derivatives display activities comparable to the most active compounds in the 1,2,3,6-tetrahydropyridine series. The propargyl derivative is an unselective full agonist, and resolution did not reveal any stereoselectivity The allyl derivative is a partial agonist with some selectivity for the M1 receptor, and testing of the enantiomers showed that the (+)-enantiomer is an unselective partial agonist, whereas the (-)-enantiomer is a partial agonist with preference for the M1 receptor. Generally, the structure-activity relationships of the 1,2,3-triazole and tetrazole series are very similar, and two compounds, 2-ethyl-4-(1-methyl-1,2,3,6-tetrahydro-5-pyridyl)-1,2,3-triazole and 2-ethyl-5-(1-methyl-1,2,3,6-tetrahydro-5-pyridyl)-2H-tetrazole, are M1 agonists/M2 antagonists. Muscarinic compounds with this profile are of particular interest as drugs for the treatment of Alzheimer's disease.

Animals↗
PubMed1994

Prognostic impact of urokinase, urokinase receptor, and type 1 plasminogen activator inhibitor in squamous and large cell lung cancer tissue.

We have studied the prognostic value of urokinase-type plasminogen activator (uPA), uPA receptor (uPAR), and type 1 plasminogen activator inhibitor (PAI-1) in tumor extracts from 84 patients with squamous cell lung carcinoma and 38 patients with large cell lung carcinoma, measuring each molecule with sandwich enzyme-linked immunosorbent assays. High uPAR levels were significantly associated with short overall survival in patients with squamous cell lung carcinomas when the median value was used as a cutoff point (P = 0.038), while no statistically significant prognostic impact of uPA and PAI-1 levels was found in this group of patients. The combination of high uPAR and high PAI-1 levels did, however, have a particular significant association with short overall survival (P = 0.008). None of the 3 components was found to have a statistically significant prognostic impact in the group of 38 large cell lung cancer patients. There was a positive correlation between uPAR and PAI-1 levels in both groups and between uPA and uPAR levels in the large cell carcinoma patients. In a multivariate analysis, high uPAR was found to be an independent prognostic variable in squamous cell carcinoma patients, with a relative risk of 2.1 (95% confidence interval, 1.1-4.0) and tumor size the only other significant prognostic parameter. These data suggest that uPAR is an important prognostic factor in squamous cell lung carcinoma. In addition to the potential direct clinical usefulness, this information could be helpful in understanding the biology of this disease and developing new therapeutic approaches.

Aged↗
PubMed1994

The influence of body temperature on infarct volume and thrombolytic therapy in a rat embolic stroke model.

The effect of body temperature on cerebral infarcts and thrombolytic therapy was investigated in 91 rats embolized in the right carotid territory. Hypothermia of 32 degrees C for 2 h with preembolic onset (n = 15) or hyperthermia of 39 degrees C for 2 h with postembolic onset (n = 22) was compared to normothermic controls (n = 17). After 48 h of survival, neuropathological evaluation with measurement of infarct volume was performed. Median infarct volume in percent of affected hemisphere volume was 11% (9-21, quartiles) in rats treated with hypothermia alone, compared to 46% (14-59, quartiles) in normothermic controls (P = 0.04). Hyperthermia for 2 h increased median infarct volume to 65% (37-75, quartiles). There was a positive and significant correlation between infarct volume and body temperature (R = 0.53, P = 0.0002, n = 54). Mortality rate was significantly higher among rats treated with hyperthermia compared to normothermic controls (P = 0.005). A subset of 37 rats exposed to the same temperature regimen were treated with tissue plasminogen activator (20 mg/kg i.v. during 45 min) 2 h after embolization. Judged by posttreatment carotid angiography, hyperthermic rats (n = 11) had the best degree of recanalization (P = 0.03) compared to controls (n = 17), but median infarct volume in this group was (58% (27-67, quartiles)) significantly larger (P < 0.02) than normothermic (21% (15-39, quartiles), n = 14) and hypothermic (13% (7-31, quartiles), n = 12) rats treated with thrombolytic therapy. Thrombolytic therapy following 2 h of hypothermia, could not improve the effect of hypothermia alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Urokinase and plasminogen activator inhibitor type 1 in pulmonary adenocarcinoma.

The urokinase pathway of plasminogen activation is involved in proteolytic degradation of various tissues, including dissolution of the extracellular matrix and basement membranes during the process of cancer cell invasion. We have studied the prognostic value of urokinase-type plasminogen activator (uPA) and type-1 plasminogen activator inhibitor (PAI-1) in tumor extracts from 106 patients with adenocarcinoma of the lung. uPA and PAI-1 levels were determined by sandwich enzyme-linked immunosorbent assays. No correlation was found between uPA and PAI-1 (r = 0.23). High PAI-1 levels were significantly associated with short-duration overall survival (P = 0.017), while uPA levels showed no significant association with overall survival. Relating the levels of PAI-1 to other prognostic factors such as stage and age, no significant correlations were found. The prognostic impact of uPA and PAI-1 were investigated together with other prognostic factors in Cox multivariate analysis. PAI-1 was found to be an independent prognostic variable for survival, the relative risks being 1.5 (low versus medium PAI-1 values (95% confidence interval, 1.2-1.8) and 2.2 (low versus high (95% confidence interval, 1.8-2.6)). In patients with stage I disease (69 patients) high levels of PAI-1 were significantly associated with poor prognosis compared to low levels (P = 0.037). These data indicate that PAI-1 is a potentially important prognostic factor in pulmonary adenocarcinoma and may as such be used to select patients with low stage and poor prognosis for adjuvant therapy subsequent to complete surgical resection.

Adenocarcinoma↗
PubMed1994

Brain biopsy in AIDS. Diagnostic value and consequence.

Nineteen male patients with AIDS were investigated by biopsy of brain lesions. Six patients had progressive multiple leucoencephalopathy and no specific treatment was given. Toxoplasmosis (two patients), bacterial abscesses (two cases), viral encephalitis (two patients) and only gliosis (two cases) accounted for almost half of the cases. A fungal infection, a lymphoma and a sarcoma-like tumour were found in three patients. In two patients the biopsy was not diagnostic: one had only necrosis and one had normal findings. The biopsy findings gave reason for modifying the treatment in only three cases. The mean survival rate was relatively short, only 76 days with a range from 1 to 1041 days. Two patients were in a very bad clinical condition at the time of biopsy and one died of a haemorrhagic complication due to the biopsy. In ten cases an autopsy was carried out. In five cases there was agreement between the biopsy and autopsy findings. In the other five cases the autopsy findings differed widely. In our experience we can recommend cerebral biopsy in patients with AIDS only after treatment for toxoplasmosis and mainly to estimate the prognosis.

AIDS Dementia Complex↗