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Biomedical subjects

T Rasmussen

Publications and source records attributed to T Rasmussen.

At least 19 recordsLinked to original sources
PubMed2001

Identification of two tetranuclear FeS clusters on the ferredoxin-type subunit of NADH:ubiquinone oxidoreductase (complex I).

The proton-translocating NADH:ubiquinone oxidoreductase of respiratory chains (complex I) contains one flavin mononucleotide and five EPR-detectable iron-sulfur clusters as redox groups. Because of the number of conserved motifs typical for binding iron-sulfur clusters and the high content of iron and acid-labile sulfide of complex I preparations, it is predicted that complex I contains additional clusters which have not yet been detected by EPR spectroscopy. To search for such clusters, we used a combination of UV/vis and EPR spectroscopy to study complex I from Neurospora crassa and Escherichia coli adjusted to distinct redox states. We detected a UV/vis redox difference spectrum characterized by negative absorbances at 325 and 425 nm that could not be assigned to the known redox groups. Redox titration was used to determine the pH-independent midpoint potential to be -270 mV, being associated with the transfer of two electrons. Comparison with UV/vis difference spectra obtained from complex I fragments and related enzymes showed that this group is localized on subunit Nuo21.3c of the N. crassa or NuoI of the E. coli complex I, respectively. This subunit (the bovine TYKY) belongs to a family of 8Fe-ferredoxins which contain two tetranuclear iron-sulfur clusters as redox groups. We detected EPR signals in a fragment of complex I which we attribute to the novel FeS clusters of complex I.

Animals↗
PubMed2001

The muscarinic receptor agonist BuTAC, a novel potential antipsychotic, does not impair learning and memory in mouse passive avoidance.

(5R,6R)-6-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane) (BuTAC) is a novel, selective muscarinic receptor ligand with partial agonist mode of action at muscarinic M2 and M4 and antagonist mode of action at M1, M3 and M5 receptor subtypes in cloned cell lines. BuTAC exhibits functional dopamine receptor antagonism despite its lack of affinity for dopamine receptors, and parasympathomimetic effects in mice are produced only at doses well beyond the doses exhibiting the antipsychotic-like effects. In the present study we investigated the effects of BuTAC and the antipsychotic compounds clozapine, sertindole and olanzapine using one trial passive avoidance with mice as a model of learning and memory. Pharmacologically relevant doses of BuTAC and reference antipsychotics were identified, based on inhibition of apomorphine-induced climbing in mice as an assay measuring antidopaminergic potency. When ratios between the minimum effective dose (MED) for impairment of retention in passive avoidance and the MED for inhibition of apomorphine-induced climbing were calculated, BuTAC displayed a high ratio of >10, compared with clozapine (0.3), sertindole (3) and olanzapine (3). These data suggest that BuTAC is a potential novel antipsychotic which may have favourable effects on aspects of learning and memory.

Animals↗
PubMed2001

Regional immune responses with stage-specific antigen recognition profiles develop in lymph nodes of pigs following Ascaris suum larval migration.

The early life-cycle of the pig round worm, Ascaris suum, involves well-defined larval development in the liver, lungs and finally the small intestine. Distinct regional immune responses to larval antigens of A. suum were observed in the draining lymph nodes of immunized and challenged pigs during larval migration. This was reflected in a transient enlargement of the stimulated lymph nodes, due to increases in numbers of B cells and CD4 T cells, and the production of A. suum-specific antibody by antibody secreting cell (ASC) cultures. Larval antigen recognition pattern of antibodies in serum, bile and draining lymph node ASC culture supernatant (ASC-probes) was examined by immunoblotting. This revealed distinct organ-specific recognition patterns of larval-specific antigens by the draining lymph nodes at different times after challenge. In particular, an early larval 42 kDa antigen was recognized specifically by ASC-probes of the liver lymph nodes at 7 but not 14 days postchallenge (pc) which was not detected in other lymph nodes, serum or bile of the same pig. Similarly, a late larval antigen of 34 kDa was uniquely detected by lung and jejunal ASC-probes at 14 days pc. These observations demonstrate how development of distinct regional immune responses in tissues with different antigen stimulation can be monitored with ASC-probes and flow cytometry.

Animals↗
PubMed2000

Frequency and kinetics of polyclonal and clonal B cells in the peripheral blood of patients being treated for multiple myeloma.

Recent studies concerning the numbers of circulating clonal B cells in patients with multiple myeloma (MM) have reported conflicting data regarding the exact level and phenotype of clonal B cells and their response to treatment. In this report we document that the peripheral blood tumor burden at presentation was reduced by induction therapy to a low level, regardless of the initial tumor burden. However, the residual clonal compartment persisted before and after transplant. The level of clonal cells showed no correlation with CD19(+) cell levels. In a single patient with MM, high numbers of phenotypically aberrant clonal cells with altered CD19 expression were identified. (Blood. 2000;96:4357-4359)

Antigens, CD19↗
PubMed2000

Sturge-Weber syndrome: indications and results of surgery in 20 patients.

OBJECTIVE: To discuss the indications and timing for resective surgery in patients with Sturge-Weber syndrome (SWS) and medication-resistant epilepsy. BACKGROUND: SWS that causes epilepsy severe enough to merit surgery is rare. Because of the variable natural history of the disease, it is difficult to establish clear-cut indications for surgery and prospective studies are not feasible. Attitudes of clinicians and surgeons remain variable. METHODS: The authors assessed the presurgical epilepsy profile, criteria for surgery, monitoring techniques, and the postoperative outcome of epilepsy in all patients with SWS consecutively admitted between 1972 and 1990 to two referral centers (Paris and Montreal) and underwent surgery for intractable seizures. RESULTS: All 20 patients had a minimal postoperative follow-up of 4 years and all but one are still followed by one of the authors. One patient had a callosotomy, five underwent hemispherectomy, and 14 had cortical resection. Despite variability in the age at onset of seizures (range: 2 months to 12 years), age at operation (range: 8 months to 34 years) and surgical methods, almost all patients benefited from surgery. Visually guided complete resection of the pial angioma and underlying cortex, whenever possible, seemed sufficient; results were no better with intraoperative corticography. In children with previous hemiparesis, hemispherectomy proved particularly effective: all five became seizure free. None of the patients showed any aggravation of cognitive impairment following surgery; none of those who were operated on early presented with severe mental retardation, and 13 of 20 became seizure free. CONCLUSION: Although the natural history of SWS is imperfectly known, increasing duration of seizures and of postictal deficits, increase in atrophy or of calcified lesions or both, are indicative of its progressive nature. Despite the expected heterogeneity that renders formal comparison of the various approaches difficult, the current study provides new evidence to support early surgery in patients with SWS and drug-resistant epilepsy. The authors' results suggest that lesionectomy is a good approach, provided that the pial angioma is unilateral and the resection can be complete.

Child↗
PubMed2000

Nicotine inhaler and nicotine patch as a combination therapy for smoking cessation: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Nicotine replacement therapy is an effective treatment for nicotine-dependent smokers. However, cessation rates are modest, and preliminary studies suggest that combination therapy may be superior. We compared the efficacy of the nicotine inhaler plus nicotine patch vs nicotine inhaler plus placebo patch for smoking cessation. METHODS: A double-blind, randomized, placebo-controlled trial was conducted in 400 subjects who had smoked 10 or more cigarettes per day for 3 years or longer. Group 1 (n = 200) received the nicotine inhaler plus nicotine patch (delivering 15 mg of nicotine per 16 hours) for 6 weeks, then inhaler plus placebo patch for 6 weeks, then inhaler alone for 14 weeks. Group 2 (n = 200) received the nicotine inhaler plus placebo patch for 12 weeks, then inhaler for 14 weeks. Inhaler was used at a rate of 6 to 12 cartridges per day ad libitum for 3 months and then tapered off. Main outcome measures were complete abstinence (self-reported) and expired carbon dioxide concentration less than 10 ppm. RESULTS: Group 1 vs group 2 complete abstinence rates were 60.5% and 47.5% at 6 weeks (P =.009), 42.0% and 31.0% at 12 weeks (P =.02), 25.0% and 22.5% at 6 months (P =.56), and 19.5% and 14.0% at 12 months (P =. 14). One-year survival analysis showed a significant association between abstinence and treatment with nicotine inhaler plus nicotine patch (P =.04). Mean nicotine substitution at week 6 was 60.1% (group 1) and 24.6% (group 2) (P<.001). At 12 months, the frequency of respiratory symptoms in abstinent subjects fell significantly and lung function showed a trend toward improvement. The most common adverse events were throat irritation (inhaler) and itching (patch). CONCLUSIONS: Treatment with the nicotine inhaler plus nicotine patch resulted in significantly higher cessation rates than inhaler plus placebo patch.

Administration, Inhalation↗
PubMed2000

Determination of the of rate cross slip of screw dislocations

The rate for cross slip of screw dislocations during annihilation of screw dipoles in copper is determined by molecular dynamics simulations. The temperature dependence of the rate is seen to obey an Arrhenius behavior in the investigated temperature range: 225-375 K. The activation energy and the effective attempt frequency can therefore be extracted from the simulations. The transition state energy for the annihilation process is calculated by identifying the transition state using the nudged elastic band path technique. The two activation energies agree very well, indicating that transition state theory is applicable for this type of process.

Journal Article↗
PubMed2000

The catalytic center in nitrous oxide reductase, CuZ, is a copper-sulfide cluster.

The crystal structure of nitrous oxide reductase, the enzyme catalyzing the final step of bacterial denitrification in which nitrous oxide is reduced to dinitrogen, exhibits a novel catalytic site, called Cu(Z). This comprises a cluster of four copper ions bound by seven histidines and three other ligands modeled in the X-ray structure as OH(-) or H(2)O. However, elemental analyses and resonance Raman spectroscopy of isotopically labeled enzyme conclusively demonstrate that Cu(Z) has one acid-labile sulfur ligand. Thus, nitrous oxide reductase contains the first reported biological copper-sulfide cluster.

Acids↗
PubMed2000

Muscarinic receptor agonists decrease cocaine self-administration rates in drug-naive mice.

(5R,6R)-6-(3-Propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[ 3.2.1]octane (PTAC) is a selective muscarinic receptor ligand. The compound exhibits high affinity for central muscarinic receptors with partial agonist mode of action at muscarinic M(2) and M(4) and antagonist mode of action at muscarinic M(1), M(3) and M(5) receptor subtypes. The compound was earlier reported to exhibit functional dopamine receptor antagonism in rodents despite its lack of affinity for dopamine receptors. In the present study, we report that PTAC, as well as the muscarinic receptor agonists pilocarpine and oxotremorine, dose-dependently decreased rates of intravenous self-administration (fixed ratio 1) of the indirect dopamine receptor agonist cocaine in drug naive mice. Similar decreases in cocaine self-administration rates were obtained with the dopamine receptor antagonists olanzapine, clozapine, risperidone, fluphenazine and haloperidol. These findings suggest that compounds with partial muscarinic receptor agonist mode of action may be used in the medical treatment of cocaine abuse.

Animals↗
PubMed2000

Characterization of two novel redox groups in the respiratory NADH:ubiquinone oxidoreductase (complex I).

The proton-pumping NADH:ubiquinone oxidoreductase is the first of the respiratory chain complexes in many bacteria and mitochondria of most eukaryotes. The bacterial complex consists of 14 different subunits. Seven peripheral subunits bear all known redox groups of complex I, namely one FMN and five EPR-detectable iron-sulfur (FeS) clusters. The remaining seven subunits are hydrophobic proteins predicted to fold into 54 alpha-helices across the membrane. Little is known about their function, but they are most likely involved in proton translocation. The mitochondrial complex contains in addition to the homologues of these 14 subunits at least 29 additional proteins that do not directly participate in electron transfer and proton translocation. A novel redox group has been detected in the Neurospora crassa complex, in an amphipathic fragment of the Escherichia coli complex I and in a related hydrogenase and ferredoxin by means of UV/Vis spectroscopy. This group is made up by the two tetranuclear FeS clusters located on NuoI (the bovine TYKY) which have not been detected by EPR spectroscopy yet. Furthermore, we present evidence for the existence of a novel redox group located in the membrane arm of the complex. Partly reduced complex I equilibrated to a redox potential of -150 mV gives a UV/Vis redox difference spectrum that cannot be attributed to the known cofactors. Electrochemical titration of this absorption reveals a midpoint potential of -80 mV. This group is believed to transfer electrons from the high potential FeS cluster to ubiquinone.

Electrochemistry↗
PubMed2000

CD68+/CD83+/CD1a- dendritic cell subsets from patients with multiple myeloma are not infected with human herpesvirus 8.

Recently, a subset of dendritic cells with the phenotype CD68+/CD83+/CD1a-, present in patients with multiple myeloma (MM), was reported to be infected with human herpesvirus 8 (HHV-8). Therefore we wished to clarify whether HHV-8 infection might be related to the pathogenesis of MM. In an attempt to identify HHV-8 infected cells in patients with MM, long-term bone marrow cultures from 8 MM patients and dendritic cell cultures from 11 MM patients were established. In addition, fresh bone marrow aspirates from 10 MM and 10 patients with monoclonal gammopathy of undetermined significance (MGUS) were included in the study. All samples were analysed by a sensitive semi-nested PCR assay and were found to be consistently PCR negative. Phenotyping of day 7 dendritic cell cultures demonstrated the presence of a sufficient number of CD68+/CD1a- and CD83+/CD1a- cells. However, to exclude the presence of infrequent HHV-8 infected cells, the CD68+/CD1a- subset from 3 dendritic cell cultures was sorted in numbers of 105 for each PCR test, and again a negative PCR result was observed. This study documents that the CD68+/CD83+/CD1a- dendritic cells in patients with MM are not generally infected with HHV-8 and, as a consequence, it is unlikely that HHV-8 plays a role in the pathogenesis of MM.

Antigens, CD↗
PubMed2000

Quantitation of minimal residual disease in multiple myeloma using an allele-specific real-time PCR assay.

OBJECTIVE: To develop a real-time PCR method, based on the 5'nuclease TaqMan technology, for quantitation of clonal cells in multiple myeloma (MM). MATERIALS AND METHODS: The real-time quantitative PCR method incorporates both an allele-specific oligonucleotides (ASO) primer and an ASO dual-labeled fluorogenic probe (ASO TaqMan probe). The ASO primer and probe corresponded to the complementary determining region 3 (CDR3) of the rearranged immunoglobulin heavy chain gene (IgH). With the use of a sequence detector, PCR product accumulation was measured through the ASO TaqMan probe. The real-time PCR method was compared with flow cytometric quantitation of myeloma plasma cells. RESULTS: The application of the real-time quantitative ASO IgH PCR method is illustrated by a sequential analysis of minimal residual disease (MRD) in bone marrow (BM) samples from myeloma patients undergoing peripheral blood stem cell (PBSC) transplantation. The real-time PCR method was able to quantitate residual malignant cells in BM samples from patients who were considered to be in complete remission. Further, it was illustrated that a potential problem in determining tumor cell content in myeloma BM samples is the heterogeneous infiltration of the marrow. CONCLUSION: The application of the real-time PCR method provides a sensitive, highly specific, and reproducible quantitation of myeloma cells.

Adult↗
PubMed2000

Intravenous scopolamine is potently self-administered in drug-naive mice.

Scopolamine self-administration was investigated in an acute model using drug-naive mice. The mice could self-administer intravenous infusions contingent on nose poking and were tested in pairs using a contingent and a yoked control mouse. Upon nose poking of the contingent mouse, both mice received an intravenous infusion of either saline or scopolamine (fixed ratio 1). An inverted U-shaped unit dose-response curve was seen with the contingent mice. The unit dose at which nose poking of the contingent mice peaked (mean 375 per 30 min) was 0.1 mg/kg/infusion. Nose poking of yoked control mice also increased dose dependently, but it was significantly lower than that of the contingent mice. The apparent scopolamine-induced dose-dependent hyperactivity was, however, unlikely in itself to form the entire basis for the increase in nose poking of the contingent mice. The results demonstrate that scopolamine has acute and reinforcing properties in drug naive mice.

Analysis of Variance↗
PubMed2000

The clonal hierachy in multiple myeloma.

In this report we evaluated the number and phenotype of blood circulating B-cell subsets at different stages of differentiation in 26 patients with newly diagnosed multiple myeloma (MM). In all patients, plasma cells and/or plasma blasts could be identified by flow cytometry with a mean frequency of 1.20% and 0.07%, respectively. In 76.9% of the patients these cells showed aberrant expression mainly of CD56, CD28 and CD117, none of these markers were found on the earlier B-lymphocytes. Clonal B-cells preceding the plasma blast stage were identified by patient specific IgH RT-PCR on sorted B-cell subsets. The clonal cells included the less differentiated CD38+ CD19+ and CD38-/CD19+ subsets. illustrating that the clonal cells are part of an ongoing differentiation process. Further, the presence of CD38-/CD19+ cells with somatically mutated Cgamma transcripts identical to the tumor-specific Calpha transcript, shows that the clonal hierarchy in myeloma may include memory B-cells.

ADP-ribosyl Cyclase↗
PubMed2000

Randomised trial investigating effect of a novel nicotine delivery device (Eclipse) and a nicotine oral inhaler on smoking behaviour, nicotine and carbon monoxide exposure, and motivation to quit.

OBJECTIVE: To monitor the effect of a novel nicotine delivery device that may produce fewer carcinogens (Eclipse) on cigarette smoking, carbon monoxide and nicotine concentrations, and motivation to give up smoking. The smoker's own brand of cigarette and a nicotine replacement product (Nicotrol inhaler) were used as comparisons. DESIGN: After baseline data were recorded, smokers were randomised to either Eclipse or inhaler for two weeks and then switched to the other product for another two weeks. Thereafter a second baseline was obtained. SETTING AND PARTICIPANTS: Fifty smokers were included and data are reported for the 40 with complete data sets. The smokers were not trying to quit but were interested in trying a new product to reduce their risk. They visited a smoking clinic 10 times during the six week period of the trial. INTERVENTION: No counselling to aid reduction by Eclipse or inhaler was given. MAIN OUTCOME MEASURES: At each visit smoking status and carbon monoxide concentrations were recorded. In half of the visits withdrawal symptoms, attitudes towards smoking, heart rate, and blood nicotine concentrations were also recorded. RESULTS: Eclipse use decreased the number of cigarettes smoked per day (cpd) from 19.1 cpd at baseline to 2.1 cpd (p < 0.001), but increased carbon monoxide concentrations in parts per million (ppm) from 21.0 ppm to 33.0 ppm (p < 0.001). A similar decrease in cigarettes smoked per day was seen with the Nicotrol inhaler, from 19.1 cpd to 4.8 cpd (p < 0.001), but carbon monoxide decreased from 21.0 ppm to 12.7 ppm (p < 0.001). The blood nicotine concentration remained fairly stable with Eclipse, increasing slightly from 16.8 ng/ml to 18.0 ng/ml, while for the inhaler a significant drop was noted, from 16.8 ng/ml to 12. 2 ng/ml (p < 0.002). Craving and withdrawal did not increase with Eclipse. Few significant adverse events occurred with Eclipse. CONCLUSIONS: Eclipse can dramatically decrease cigarette consumption without causing withdrawal symptoms or decreases in nicotine concentrations or motivation to quit altogether. Unlike the inhaler, Eclipse produces an increase in carbon monoxide concentration. Thus Eclipse may not be a safer cigarette.

Administration, Inhalation↗
PubMed1999

A reductase/isomerase subunit of mitochondrial NADH:ubiquinone oxidoreductase (complex I) carries an NADPH and is involved in the biogenesis of the complex.

Respiratory chains of bacteria and mitochondria contain closely related forms of the proton-pumping NADH:ubiquinone oxidoreductase, or complex I. The bacterial complex I consists of 14 subunits, whereas the mitochondrial complex contains some 25 extra subunits in addition to the homologues of the bacterial subunits. One of these extra subunits with a molecular mass of 40 kDa belongs to a heterogeneous family of reductases/isomerases with a conserved nucleotide binding site. We deleted this subunit in Neurospora crassa by gene disruption. In the mutant nuo 40, a complex I lacking the 40 kDa subunit is assembled. The mutant complex I does not contain tightly bound NADPH present in wild-type complex I. This NADPH cofactor is not connected to the respiratory electron pathway of complex I. The mutant complex has normal NADH dehydrogenase activity and contains the redox groups known for wild-type complex I, one flavin mononucleotide and four iron-sulfur clusters detectable by electron paramagnetic resonance spectroscopy. In the mutant complex these groups are all readily reduced by NADH. However, the mutant complex is not capable of reducing ubiquinone. A recently described redox group identified in wild-type complex I by UV-visible spectroscopy is not detectable in the mutant complex. We propose that the reductase/isomerase subunit with its NADPH cofactor takes part in the biosynthesis of this new redox group.

Electron Spin Resonance Spectroscopy↗