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T Clausen

Publications and source records attributed to T Clausen.

At least 37 records · Page 2Linked to original sources
PubMed2001

Excitation-induced Ca2+ influx and skeletal muscle cell damage.

Excessive exercise may lead to skeletal muscle cell damage with degradation of cellular components and leakage of intracellular enzymes. Calcium has repeatedly been proposed to be involved in these processes. Studies have shown that the resting level of cytoplasmic Ca2+ increases up to threefold during long-term low-frequency stimulation. We have shown that electrical stimulation produces a marked increase in Ca2+ uptake and Ca2+ content in rat skeletal muscle, both in vivo and in vitro. Continuous stimulation for 240 min at 1 Hz results in an increased release (18-fold) of lactate dehydrogenase (LDH) from extensor digitorum longus (EDL) muscle. This was associated with an increased total Ca2+ content (185%), was augmented at high [Ca2+]o and suppressed at low [Ca2+]o. The release of LDH may reflect partial loss of sarcolemmal integrity as a result of degradation of membrane components by Ca2+-activated enzymes (e.g. calpain or phospholipase A2). After cessation of stimulation the increased release of LDH continues for at least 120 min. This is associated with an up to sevenfold increase in 45Ca uptake. The increased permeability to Ca2+ may further activate calpain and phospholipase A2 and accelerate the loss of membrane integrity. Stimulation-induced uptake of Ca2+ and release of LDH is most pronounced in EDL (mainly composed of fast-twitch fibres at variance with soleus which is mainly composed of slow-twitch fibres). This may account for the observation that prolonged exercise leads to preferential damage to fast-twitch fibres. We hypothesize that excessive exercise may lead to an intracellular accumulation of Ca2+ and increased cytoplasmic Ca2+ causing activation of self-accelerating degradative pathways leading to muscle damage.

Animals↗
PubMed2001

High intake of energy, sucrose, and polyunsaturated fatty acids is associated with increased risk of preeclampsia.

OBJECTIVE: Preeclampsia is associated with high body mass index, insulin resistance, and hypertriglyceridemia. Our objective was to investigate prospectively whether diet in the first half of pregnancy is associated with the risk for preeclampsia. STUDY DESIGN: This prospective, population-based, cohort study of pregnant women investigated dietary intake early in the second trimester with a quantitative food frequency questionnaire. RESULTS: The questionnaire was completed by 3133 women (83%). Preeclampsia developed in 85 women. Adjusted odds ratio (95% CI) for preeclampsia was 3.7 (1.5-8.9) for energy intake of >3350 kcal/d compared with < or =2000 kcal/d. Adjusted odds ratio (95% CI) for preeclampsia was 3.6 (1.3-9.8) for sucrose intake (percent of total energy) of >25% compared with < or =8.5% and 2.6 (1.3-5.4) for polyunsaturated fatty acids intake (percent of total energy) of >7.5% compared with < or =5.2%. Other energy-providing nutrients were not associated with the risk for preeclampsia. CONCLUSION: The current study suggests that high intakes of energy, sucrose, and polyunsaturated fatty acids independently increase the risk for preeclampsia.

Adult↗
PubMed2001

The three-dimensional structure of cystathionine beta-lyase from Arabidopsis and its substrate specificity.

The pyridoxal 5'-phosphate-dependent enzyme cystathionine beta-lyase (CBL) catalyzes the penultimate step in the de novo biosynthesis of Met in microbes and plants. Absence of CBL in higher organisms makes it an important target for the development of antibiotics and herbicides. The three-dimensional structure of cystathionine beta-lyase from Arabidopsis was determined by Patterson search techniques, using the structure of tobacco (Nicotiana tabacum) cystathionine gamma-synthase as starting point. At a resolution of 2.3 A, the model was refined to a final crystallographic R-factor of 24.9%. The overall structure is very similar to other pyridoxal 5'-phosphate-dependent enzymes of the gamma-family. Exchange of a few critical residues within the active site causes the different substrate preferences between Escherichia coli and Arabidopsis CBL. Loss of interactions at the alpha-carboxyl site is the reason for the poorer substrate binding of Arabidopsis CBL. In addition, the binding pocket of Arabidopsis CBL is larger than that of E. coli CBL, explaining the similar binding of L-cystathionine and L-djenkolate in Arabidopsis CBL in contrast to E. coli CBL, where the substrate binding site is optimized for the natural substrate cystathionine.

Amino Acid Sequence↗
PubMed2001

Dyslipidemia in early second trimester is mainly a feature of women with early onset pre-eclampsia.

OBJECTIVE: To investigate whether hypertriglyceridemic dyslipidemia is a risk factor for either early or late onset pre-eclampsia. DESIGN: Prospective cohort study and nested case-control study. SETTING: Aker Hospital: a university hospital with all levels of obstetric care. PARTICIPANTS: 2,157 Caucasian pregnant women. METHODS: Blood samples were obtained from non-fasting subjects at 18 weeks of gestation. All samples were analysed for triglycerides, total-cholesterol, high density lipoproteins cholesterol and non-high density lipoproteins cholesterol. ApoB-100 were analysed in pre-eclamptic women and in 3:1 matched controls. The cohort data were analysed by multiple logistic regression and the case-control data by conditional logistic regression. MAIN OUTCOME MEASURES: Adjusted odds ratios of early and late onset pre-eclampsia according to early second trimester serum concentration levels of lipids and ApoB-100. RESULTS: Eighteen women developed early onset pre-eclampsia and 53 women developed late onset pre-eclampsia. In the cohort model, women with triglycerides above 2.4mmol/L had increased risk (OR 5. 1; 95% CI 1.1-23.1) of early onset pre-eclampsia compared with those with triglycerides levels < or = 1.5mmol/L. For women with high triglycerides: non-high density lipoproteins cholesterol ratios (>90 centile) the OR (95% CI) for early onset pre-eclampsia was 7.1 (2.3-22.0) compared with those with low ratios (< or = 50 centile). Similar associations were found in the case control model. We found no associations between plasma lipids and risk of late onset pre-eclampsia. CONCLUSIONS: Hypertriglyceridemic dyslipidemia before 20 weeks of gestation is associated with the risk of developing early but not late onset pre-eclampsia, giving support to the contention that these two variants of the disease are at least partly pathogenically different.

Adult↗
PubMed2001

Medical treatment and neuroprotection in traumatic brain injury.

The goal of this article is to give an overview about the established current treatment concepts of traumatic brain injury, as well as an outlook on possible future developments in pharmacological neuroprotection. Modern medical treatment modalities of traumatic brain injury (TBI), including the preclinical management of severely head-injured patients, are reviewed. Since an increased intracranial pressure represents the most common complication of severe traumatic brain injury, frequently associated with the development of secondary brain damage, special emphasis was given to an updated treatment algorithm for this important condition. New insight into the pathophysiology of severe traumatic brain injury, especially the realization that brain damage develops sequentially, initiated several new treatment approaches aiming at the interruption of pathophysiological mechanisms leading to secondary brain injury. A high number of pharmacological substances have been tested for their ability to ameliorate secondary damage after TBI, or are currently under clinical trial. Although no drug has achieved this goal so far, the most promising of these therapeutical approaches, glutamate receptor antagonists, calcium channel antagonists, free radical scavengers, and cyclosporin A will be discussed in this review. Although a "magical bullet" for the treatment of traumatic brain injury has not been developed yet, several of the currently investigated neuroprotective strategies seem to be encouraging. A promising future approach might be to evaluate treatment strategies that combine several pharmacological agents, and possibly other treatment modalities, such as mild hypothermia, "tailored" according to the special pathology of patient subgroups, or even to every single patient in order to achieve an improvement in outcome after TBI.

Brain Injuries↗
PubMed2001

Experiences with continuous intra-arterial blood gas monitoring.

Management of critically ill patients requires frequent arterial blood gas analyses for assessing the pulmonary situation and adjusting ventilator settings and circulatory therapeutic measures. Continuous arterial blood gas analysis is a real-time monitoring tool, which reliably detects the onset of adverse pulmonary effects. It gives rapid confirmation of ventilator setting changes and resuscitation and helps to ensure precise adjustment of therapy. In this study a newly available fiber optic sensor system has been employed for continuous intraarterial blood gas monitoring. The measurement performance was compared with a bench top blood gas analyzer. A prospective study was performed enrolling 20 patients undergoing surgery. A comparison between intermittent blood gas analyses (ABL Radiometer 610) and the results of continuous blood gas monitoring (Paratrend 7+, Agilent Technol.) was performed by simultaneous measurements. Statistical analysis in agreement with the method of "Bland and Altman" was employed. Two case reports are provided of patients with Acute Adult Respiratory Distress Syndrome and rapid changes in ventilator settings. Over a range of arterial oxygenation from 10 to 50 kPa the bias for pO2-measurement was 0.2 (limits of agreement 4), R2 = 0.9. If the arterial pO2 was higher than 50 kPa the bias was -7 (10) kPa. PCO2-measurement showed a bias of 0.25 (limits of agreement 0.45), R2 = 0.7. pH bias was -0.02 (limits of agreement 0.04), R2 = 0.7. The Paratrend 7+ sensor proved to be clinical feasible and showed an improved precision in terms of clinical situations with an arterial pO2 smaller than 50 kPa. However, the results are not much different regarding the findings with older systems consisting of hybrid technology combining optodes and electrochemical oxygen measurement. The advantages might be seen if the sensor is used for a period over several days in patients on ICU as demonstrated by the two case reports.

Adult↗
PubMed2000

The role of K+ channels in the force recovery elicited by Na+-K+ pump stimulation in Ba2+-paralysed rat skeletal muscle.

The present experiments were performed to assess the role of K+ channels in hormonal stimulation of the Na+-K+ pump and to determine the contribution of Na+-K+ pumps to the recovery of excitability and contractility in depolarized skeletal muscle. In soleus muscle, Ba2+ (0.02 and 1 mM) was found to inhibit 42K+ efflux and 42K+ influx. Both in the absence and the presence of Ba2+ (1 mM), salbutamol and calcitonin gene-related peptide (CGRP) induced a marked decrease in intracellular Na+ and stimulation of 42K+ uptake. In soleus muscles Ba2+ (0.1 and 1.0 mM) decreased twitch and tetanic force. Subsequent stimulation of the Na+-K+ pumps by salbutamol, CGRP or repeated electrical stimulation produced a highly significant restoration of force development, which was suppressed by ouabain, but not by glibenclamide. Also, in extensor digitorum longus muscles Ba2+ (0.1 mM) produced a considerable force decline, which was partly restored by salbutamol and CGRP. The area of compound action potentials (M-waves) elicited by indirect stimulation was decreased by Ba2+ (0.1 mM). This was associated with a concomitant decrease in tetanic force and depolarization. Salbutamol, CGRP or repeated electrical stimulation all elicited marked recovery of M-wave area, force and membrane potential. All recordings showed close correlations between these three parameters. The data add further support to the concept that due to its electrogenic nature and large transport capacity, the Na+-K+ pump is a rapid and efficient mechanism for the maintenance of excitability in skeletal muscle, acting independently of Ba2+- or ATP-sensitive K+ channel function.

Albuterol↗
PubMed2000

Effects of amylin and other peptide hormones on Na+-K+ transport and contractility in rat skeletal muscle.

1. In skeletal muscle, catecholamines and calcitonin gene-related peptide (CGRP) increase the content of cAMP, which mediates stimulation of the Na+-K+ pump. Amylin is structurally very similar to CGRP and also increases cAMP in muscle. 2. In isolated rat soleus and extensor digitorum longus muscle, amylin produced a rapid and marked decrease in intracellular Na+, which was maintained for several hours. In soleus, amylin was found to induce a 45 % stimulation of Na+ efflux, a 43 % increase in 86Rb influx and a rise in intracellular K+. All these effects were abolished by ouabain, indicating that amylin produces acute stimulation of the Na+-K+ pump. 3. In contrast, neither the closely related peptides islet amyloid polypeptide (IAPP) and adrenomedullin nor other peptide hormones (C peptide, neuropeptide Y or substance P) produced any detectable change in intracellular Na+ or K+ uptake in soleus. 4. When contractility in soleus was inhibited by increasing extracellular K+ to 12.5 mM, amylin (10-8 M) and insulin (0.7 x 10-8 M) both induced partial recovery of force. These effects were additive, and in combination the two hormones elicited 63 and 80 % recovery of tetanic and twitch force, respectively. Higher concentrations produced even larger increases, and all effects were blocked by ouabain. 5. In buffer containing 12.5 mM K+, dibutyryl cAMP induced 71 % force recovery, which was increased by theophylline. The results indicate that amylin (like catecholamines, cAMP, CGRP and insulin) stimulates the Na+-K+ pump and thereby improves the contractility of depolarized skeletal muscle cells. This adds further support to the concept that the Na+-K+ pump is important for the maintenance of excitability in skeletal muscle.

Adrenomedullin↗
PubMed2000

Crystal structure of cystalysin from Treponema denticola: a pyridoxal 5'-phosphate-dependent protein acting as a haemolytic enzyme.

Cystalysin is a C(beta)-S(gamma) lyase from the oral pathogen Treponema denticola catabolyzing L-cysteine to produce pyruvate, ammonia and H(2)S. With its ability to induce cell lysis, cystalysin represents a new class of pyridoxal 5'-phosphate (PLP)-dependent virulence factors. The crystal structure of cystalysin was solved at 1.9 A resolution and revealed a folding and quaternary arrangement similar to aminotransferases. Based on the active site architecture, a detailed catalytic mechanism is proposed for the catabolism of S-containing amino acid substrates yielding H(2)S and cysteine persulfide. Since no homologies were observed with known haemolysins the cytotoxicity of cystalysin is attributed to this chemical reaction. Analysis of the cystalysin-L-aminoethoxyvinylglycine (AVG) complex revealed a 'dead end' ketimine PLP derivative, resulting in a total loss of enzyme activity. Cystalysin represents an essential factor of adult periodontitis, therefore the structure of the cystalysin-AVG complex may provide the chemical basis for rational drug design.

Binding Sites↗
PubMed2000

Crystal structure of the cystine C-S lyase from Synechocystis: stabilization of cysteine persulfide for FeS cluster biosynthesis.

FeS clusters are versatile cofactors of a variety of proteins, but the mechanisms of their biosynthesis are still unknown. The cystine C-S lyase from Synechocystis has been identified as a participant in ferredoxin FeS cluster formation. Herein, we report on the crystal structure of the lyase and of a complex with the reaction products of cystine cleavage at 1.8- and 1.55-A resolution, respectively. The sulfur-containing product was unequivocally identified as cysteine persulfide. The reactive persulfide group is fixed by a hydrogen bond to His-114 in the center of a hydrophobic pocket and is thereby shielded from the solvent. Binding and stabilization of the cysteine persulfide represent an alternative to the generation of a protein-bound persulfide by NifS-like proteins and point to the general importance of persulfidic compounds for FeS cluster assembly.

Amino Acid Sequence↗
PubMed2000

Crystal structure of a NifS-like protein from Thermotoga maritima: implications for iron sulphur cluster assembly.

NifS-like proteins are ubiquitous, homodimeric, proteins which belong to the alpha-family of pyridoxal-5'-phoshate dependent enzymes. They are proposed to donate elementary sulphur, generated from cysteine, via a cysteinepersulphide intermediate during iron sulphur cluster biosynthesis, an important albeit not well understood process. Here, we report on the crystal structure of a NifS-like protein from the hyperthermophilic bacterium Thermotoga maritima (tmNifS) at 2.0 A resolution. The tmNifS is structured into two domains, the larger bearing the pyridoxal-5'-phosphate-binding active site, the smaller hosting the active site cysteine in the middle of a highly flexible loop, 12 amino acid residues in length. Once charged with sulphur the loop could possibly deliver S(0) directly to regions far remote from the protein. Based on the three-dimensional structures of the native as well as the substrate complexed form and on spectrophotometric results, a mechanism of sulphur activation is proposed. The His99, which stacks on top of the pyridoxal-5'-phosphate co-factor, is assigned a crucial role during the catalytic cycle by acting as an acid-base catalyst and is believed to have a pK(a) value depending on the co-factor redox state.

Allylglycine↗
PubMed2000

X-ray structure of MalY from Escherichia coli: a pyridoxal 5'-phosphate-dependent enzyme acting as a modulator in mal gene expression.

MalY represents a bifunctional pyridoxal 5'-phosphate-dependent enzyme acting as a beta-cystathionase and as a repressor of the maltose regulon. Here we present the crystal structures of wild-type and A221V mutant protein. Each subunit of the MalY dimer is composed of a large pyridoxal 5'-phosphate-binding domain and a small domain similar to aminotransferases. The structural alignment with related enzymes identifies residues that are generally responsible for beta-lyase activity and depicts a unique binding mode of the pyridoxal 5'-phosphate correlated with a larger, more flexible substrate-binding pocket. In a screen for MalY mutants with reduced mal repressor properties, mutations occurred in three clusters: I, 83-84; II, 181-189 and III, 215-221, which constitute a clearly distinguished region in the MalY crystal structure far away from the cofactor. The tertiary structure of one of these mutants (A221V) demonstrates that positional rearrangements are indeed restricted to regions I, II and III. Therefore, we propose that a direct protein-protein interaction with MalT, the central transcriptional activator of the maltose system, underlies MalY-dependent repression of the maltose system.

Bacterial Proteins↗
PubMed2000

[Methadone as an analgesic].

Methadone is a synthetic opioid agonist which has been available for more than 40 years. Although its main use has been in the maintenance therapy of opioid addicts, it has a number of unique characteristics including excellent analgesic effect, a high bioavailability, no known active metabolites, long duration of action during long-term treatment, high potency, and low cost. However, its use is limited by the complexity of the pharmacokinetics, with a risk of drug accumulation with toxic effects. Recent findings suggest that standard equianalgesic tables are unreliable, because methadone is much more potent when used for long-term treatment. Therefore methadone should be titrated carefully and increases in dosage should be performed every third or fourth day.

Analgesics, Opioid↗
PubMed2000

[Traditional surgery of inguinal hernia].

Inguinal hernia repair is associated with a variety of complications of which the recurrence rate is one of the most important. The aim of this study was to examine all patients one year after surgery for inguinal hernia in an outpatient clinic. 12 months after the operation patients were interviewed and physically examined. 172 hernias in 166 patients were repaired in 1996 in our outpatient unit. 17 surgeons used nine different techniques. Follow-up was achieved in 93.9% of patients alive. Ten recurrences were found (6.3%). Four of the patients were not aware of their recurrence. 11% of the patients still had discomfort or pain after twelve months, whereas 5.2% had not resumed full activity. Other complications occurred in more than 20% of the operations. A "free to do policy" in inguinal hernia repair results in high recurrence and complication rates even in the hands of experienced surgeons in our clinic. The present study shows that an interview as well as a physical examination are necessary in evaluating recurrences, postoperative complications, postoperative pain and time to full mobilisation. Without physical examination, the recurrence rate would have been underreported.

Adolescent↗
PubMed2000

Altered circulating levels of adhesion molecules at 18 weeks' gestation among women with eventual preeclampsia: indicators of disturbed placentation in absence of evidence of endothelial dysfunction?

OBJECTIVE: The purpose of this study was to investigate whether indications of activation of the maternal endothelium were present at 18 weeks' gestation in women in whom preeclampsia eventually developed. STUDY DESIGN: A total of 2190 blood samples were obtained at 18 weeks' gestation. Circulating levels of von Willebrand factor and soluble vascular adhesion molecule 1, soluble intercellular adhesion molecule 1, and E-selectin were assayed in 71 women with eventual preeclampsia and 71 control subjects. RESULTS: E-selectin and von Willebrand factor levels were similar between the 2 groups. Soluble vascular adhesion molecule 1 concentration was significantly lower in the women with eventual preeclampsia (median, 649.0 ng/mL vs 762.4 ng/mL; P <.001), whereas soluble intercellular adhesion molecule 1 concentration was significantly higher (median, 239.8 ng/mL vs 178.3 ng/mL; P <.001). CONCLUSION: We found no indications of endothelial activation at 18 weeks' gestation in women in whom preeclampsia later developed. However, decreased serum concentration of soluble vascular adhesion molecule 1 and increased serum concentration of soluble intercellular adhesion molecule 1 may reflect the disturbed placentation known to be associated with the development of preeclampsia.

Birth Weight↗
PubMed2000

A new mechanism for the control of a prokaryotic transcriptional regulator: antagonistic binding of positive and negative effectors.

MalT, the transcriptional activator of the Escherichia coli maltose regulon, self-associates, binds promoter DNA and activates initiation of transcription only in the presence of ATP and maltotriose, the inducer. In vivo studies have revealed that MalT action is negatively controlled by the MalY protein. Using a biochemical approach, we analyse here the mechanism whereby MalY represses MalT activity. We show that MalY inhibits transcription activation by MalT in a purified transcription system. In vitro, a constitutive MalT variant (which is partially active in the absence of maltotriose) is less sensitive than wild-type MalT to repression by MalY, as observed in vivo. We demonstrate that MalY forms a complex with MalT only in the absence of maltotriose and that, conversely, MalY inhibits maltotriose binding by MalT. Together, these results establish that MalY acts directly upon MalT without the help of any factor, and that MalY is a negative effector of MalT competing with the inducer for MalT binding.

Bacterial Proteins↗
PubMed2000

[Cerebral oxygen reactivity determination--a simple test with potential prognostic relevance].

UNLABELLED: Brain tissue oximetry (ptiO2) using flexible micro-polarographic electrodes is a loco-regional approach to monitor oxygen supply to the injured brain, after neuronal damage. In patients after severe head injury (SHI), disturbances of CBF and CO2 related vasoconstriction have been demonstrated. CO2 reactivity testing may assist to determine outcome in these patients. Not much information is available on the preservation of vasoreactivity to arterial hyperoxia after neuronal damage. Therefore, we studied the response of ptiO2 in 7 piglets and in 14 patients on day one after trauma to 100% FiO2 ventilation (O2rea) and analyzed the 3 month outcome using the Glasgow-Outcome-Score (GOS). In the animal study, we placed a Paratrend 7 (P7) sensor for ptiO2 measurements in the non injured frontal white matter. The animals were anesthetized and mechanically ventilated. FiO2 was increased from 30 (+/- 5)% to 100% over a period of 5 minutes. In patients, we placed the P7 probe in the frontal lobe. FiO2 was increased from 35 (+/- 5)% to 100% over a period of 6 hours. O2rea was tested by calculating the percentage change of ptiO2 during 100% FiO2 ventilation, compared to the baseline value of 35% FiO2. By analyzing the patient outcome, we were able to define two patient populations according to the GOS at three month (Group I: favorable outcome [GOS 0-2]; Group II: poor outcome [GOS 3-4]). For the non-injured brain tissue in animals were revealed an O2rea = 0.21 (+/- 0.12). PATIENTS: Group I: O2rea = 0.4 (+/- 0.16); Group II: 0.9 (+/- 0.6). Group I and II were statistical significant different (p < 0.05; unpaired t-test). Oxygen reactivity in severely head patients is a simple test with prognostic value using ptiO2 measurement. These results may be explained by the close relationship of CBF disturbances to oxygen vasoreactivity after traumatic brain injury. The O2rea in animals without neuronal damage is smaller than in patients after SHI. We speculate, the animal data could be considered as normal value of O2rea in non injured brain tissue.

Adolescent↗