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Biomedical subjects

M Rasmussen

Publications and source records attributed to M Rasmussen.

At least 19 recordsLinked to original sources
PubMed2001

HNPCC mutations in the human DNA mismatch repair gene hMLH1 influence assembly of hMutLalpha and hMLH1-hEXO1 complexes.

Hereditary nonpolyposis colorectal cancer (HNPCC) is a common inherited form of neoplasia caused by germline mutations in DNA mismatch repair (MMR) genes. MMR proteins have been reported to associate with several proteins, including the human exonuclease 1 (hEXO1). We report here novel HNPCC-hMLH1 mutant proteins (T117M, Q426X and 1813insA) in Danish HNPCC patients. We demonstrate that these mutant HNPCC-hMLH1 proteins are unable to form complexes with hEXO1 and hPMS2 in vivo. The results indicate that mutations found in HNPCC gene carriers disrupt hMLH1-hEXO1 complex formation and hMutLalpha heterodimer assembly essential for MMR activity.

Adaptor Proteins, Signal Transducing↗
PubMed2001

[Flexible sigmoidoscopy in Denmark. A questionnaire].

AIM: To assess the use of flexible sigmoidoscopy in Denmark in 1997. METHODS: A country wide questionnaire was mailed to all hospitals and specialists in surgery and gastroenterology. RESULTS: The response rate was 96%. Thirteen thousand one hundred and eighty-one flexible sigmoidoscopies were done. However, this number was much too small in order to examine all persons with colonic symptoms. Two severe complications were reported. CONCLUSIONS: A substantial extension of the flexible sigmoidoscopy service is needed to comply with the recommendations from the Danish National Board of Health to replace rigid proctoscopy with flexible sigmoidoscopy in the diagnostic strategy.

Abdominal Pain↗
PubMed2001

Origin of multiexponential T(2) relaxation in muscle myowater.

To obtain a further understanding of the nature of the multiexponential T(2) relaxation seen in muscle tissue water (myowater), relaxation measurements were carried out on whole, minced, and homogenized pork of three different qualities with regard to water-holding capacity (normal, red soft exudative, and dark firm dry). Whole, minced, and homogenized pork all resulted in multiexponential T(2) relaxation (three components) independently of the quality, even though microscopic studies on homogenized meat revealed considerable disruption of the macroscopic structure. This states that the relaxation behavior in meat cannot be explained by intra-/extracellular compartmentalization of the water as suggested in earlier studies. Subsequent studies of T(2) relaxation in either whole meat, where the structure integrity was changed by the introduction of dimethyl sulfoxide (membrane disruption) or urea (protein denaturation), or minced meat with added NaCl (inter-/intraprotein interactions) lead to the suggestion that in whole meat (i) the fastest relaxation component reflects water tightly associated with macromolecules, (ii) the intermediate relaxation component reflects water located within highly organized protein structures, for example, water in tertiary and/or quaternary protein structures and spatials with high myofibrillar protein densities including actin and myosin filament structures, and (iii) the slowest relaxation component reflects the extra-myofibrillar water containing the sarcoplasmatic protein fraction. Finally, relaxation patterns in heat-set gels of superprecipitated actomyosin and bovine serum albumin similar to that identified in whole meat support the proposed nature of T(2) relaxation in muscle myowater.

Animals↗
PubMed2001

Unique regulation of SclB - a novel collagen-like surface protein of Streptococcus pyogenes.

Slipped-strand mispairing at sites containing so-called coding repeats (CRs) can lead to phase variation of surface proteins in Gram-negative bacteria. This mechanism, believed to contribute to virulence, has so far not been identified in a Gram-positive bacterium. In the genome of the Gram-positive human pathogen Streptococcus pyogenes, we identified pentanucleotide CRs within a putative signal sequence of an open reading frame (ORF) encoding a novel collagen-like surface protein, denoted SclB. In 12 S. pyogenes strains, the number of CRs in the sclB gene varied from three to 19, rendering the start codon in frame with the downstream ORF in four strains and out of frame in eight strains. A protein reacting with anti-SclB antibodies could only be solubilized from three strains, all containing an intact sclB gene. Variations in the number of CRs were observed within strains of the same M serotype and occurred during growth of S. pyogenes in fresh human blood, but not in medium. The SclB protein has a hypervariable N-terminal part, a collagen-like central part and a typical cell wall sorting sequence containing the LPXTGX motif. SclB is related to the collagen-like SclA and is, like SclA, involved in the adhesion of S. pyogenes bacteria to human cells. However, the Mga protein, known to upregulate sclA and several additional genes encoding virulence factors of S. pyogenes, downregulates sclB transcription. This observation and the potential of SclB to phase vary by slipped-strand mispairing emphasize the unique regulation of this novel S. pyogenes surface protein.

Amino Acid Sequence↗
PubMed2001

Improved pattern for genome-based screening identifies novel cell wall-attached proteins in gram-positive bacteria.

With a large number of sequenced microbial genomes available, tools for identifying groups or classes of proteins have become increasingly important. Here we present an improved pattern for the identification of cell wall-attached proteins (CWPs), a group of proteins with diverse and important functions in gram-positive bacteria. This tripartite pattern is based on analysis of 65 previously described cell wall-attached proteins and takes into account the three principal requirements for cell wall sorting; a sortase target region (LPXTGX), a membrane-spanning region, and a charged stop-transfer tail. In five different genomes of gram-positive bacteria, the tripartite pattern identified a total of 35 putative CWPs, 19 of which were novel. The specificity and sensitivity of the tripartite pattern are higher than those of the classical pattern, which is based solely on the sortase target region. Several putative CWPs with atypical sortase target regions were identified. In the complete genome of the important human pathogen Streptococcus pyogenes, the tripartite pattern identified 14 putative CWPs. Seven of the putative S. pyogenes proteins were novel, and two of these were a 5' nucleotidase and a pullulanase. This study represents the first whole-genome screening for CWPs, and we conclude that the tripartite pattern is highly suitable for this purpose. Identification of CWPs using this pattern offers important possibilities in the study of the pathogenesis and physiology of gram-positive bacteria.

Amino Acid Sequence↗
PubMed2000

Identification of factors interacting with hMSH2 in the fetal liver utilizing the yeast two-hybrid system. In vivo interaction through the C-terminal domains of hEXO1 and hMSH2 and comparative expression analysis.

Mutations in DNA mismatch repair (MMR) genes have been shown to segregate with Hereditary Nonpolyposis Colorectal Cancer (HNPCC). However, because many HNPCC families fail to display mutations in known MMR genes, we argued that changes in other components of the MMR pathway may be responsible. The increasing number of proteins reported to interact in the MMR pathway suggests that larger complexes are formed, the composition of which may differ among cell types and tissues. In an attempt to identify tissue-specific MMR-associated factors, we employed the yeast two-hybrid system, using the human hMSH2 as bait and a human fetal liver library as prey. We demonstrate that hMSH2 interacts with a human 5'-3' exonuclease 1 (hEXO1/HEX1) and that this interaction is mediated through their C-terminal domains. The hMSH6 protein does not interact with hEXO1 in the two-hybrid system. Dot-blot analysis of multiple tissue RNA revealed that hMSH2 and hEXO1 are coexpressed at high levels in fetal liver as well as in adult testis and thymus. Northern blot analysis also revealed that hEXO1/HEX1 is highly expressed in several liver cancer cell lines as well as in colon and pancreas adenocarcinomas, but not in the corresponding non-neoplastic tissue.

14-3-3 Proteins↗
PubMed2000

The human cyclin B1 protein modulates sensitivity of DNA mismatch repair deficient prostate cancer cell lines to alkylating agents.

DNA damage caused by alkylating agents results in a G2 checkpoint arrest. DNA mismatch repair (MMR) deficient cells are resistant to killing by alkylating agents and are unable to arrest the cell cycle in G2 phase after alkylation damage. We investigated the response of two MMR-deficient prostate cancer cell lines DU145 and LNCaP to the alkylating agent MNNG. Our studies reveal that DU145 cancer cells are more sensitive to killing by MNNG than LNCaP. Investigation of the underlying reasons for lower resistance revealed that the DU145 cells contain low endogenous levels of cyclin B1. We provide direct evidence that the endogenous level of cyclin B1 modulates the sensitivity of MMR-deficient prostate cancer cells to alkylating agents.

Alkylating Agents↗
PubMed2000

Pulmonary function affects the quantification of rCBF by non-invasive xenon methods.

Estimates of regional cerebral blood flow (rCBF) by non-invasive xenon methods (133-xenon inhalation, xenon-enhanced computed tomography (Xe/CT) and 133-xenon iv injection) are frequently applied in the diagnosis and evaluation of patients suffering from diseases which cause disturbances in the cerebrovascular circulation. These methods all depend on an estimate of the arterial xenon concentration curve derived non-invasively from measurements of the end-tidal xenon concentration curve and used as brain input function in the Kety equation. We have studied the influence of impaired pulmonary gas exchange on the end-tidal and arterial xenon concentration curves in nine anaesthetized pigs by simultaneously measurements of both the end-tidal xenon and arterial xenon concentration curves. Computer simulations were performed to determine the deviations in the calculated rCBF values when using the end-tidal as compared to the arterial xenon concentration curve as brain input function. The results indicated that impairment of the pulmonary gas exchange caused a significant further 'delay' in the arterial xenon concentration curve in comparison to the end-tidal xenon concentration curve. The time constants of arterial curve delay were 11.9 s in the normal pulmonary group, 21 s in the right lung atelectasis group, and 19.7 s in the left pulmonary artery occlusion group. Accordingly, computer simulations indicated a statistically significant 'underestimation' of rCBF due to: (1) pulmonary gas exchange; (2) high or low levels of rCBF; (3) partition coefficient (lambda) of gray and white matter; and (4) xenon inhalation protocols. Our results indicate that quantitative measurements of rCBF by non-invasive xenon methods are markedly affected by deviations between the end-tidal and arterial xenon concentration curve, so that estimates of flow thresholds for infarction are problematic under conditions of impaired pulmonary gas exchange.

Animals↗
PubMed2000

Phospholipase C and D in the commitment to survival or death in the early lag phase of tetrahymena cultures.

We made three kinds of experiments in order to elucidate aspects of physiological mechanisms involved in a series of specific events leading to either cell death or survival in the lag phase of culture growth. We studied the fate of newly inoculated Tetrahymena cells in small droplets at 'high' (more than 1000 cells ml(-1)) and 'low' cell densities (less than 600 cells ml(-1)) in a nutrionally complete, synthetic nutrient medium. Confirming previous results we found that the cells in high-density cultures multiplied to final densities around 500,000 cells ml(-1) and that cells in low-density cultures died before multiplying. The appearance of the cells was recorded with a video camera at 20 frames per second for 6 h or until they died. The results indicated that the death process took place within milliseconds. We also studied the effects of U 73122, an inhibitor of the phosphatidylinositol-specific phospholipase C, on cell survival at low densities. At low inhibitor concentrations low-density cells were rescued from dying. At high inhibitor concentrations all cells died, and phosphatidylinositol - but not phosphatidylserine and phosphatidylcholine - saved them. The results indicate that the paths leading to either cell death or to cell proliferation separate within the first few minutes after subcultivation into a new medium, since the first cells in each culture died within 4-30 min after inoculation. Our results also indicate that some PLC activity was required for stimulation of phospholipase D, and that cell death during the early lag phase is caused by a shortage in phosphatidylinositol before the phospholipase D activity is upregulated. These experiments are shedding light on the lethal consequences of a cellular depletion of the important signalling compound phosphatidylinositol in an in vivo system, and may help to elucidate mechanisms behind the century-old fact that eukaryote cells die when inoculated at too low a cell density to survive.

Animals↗
PubMed2000

Are cells rescued from 'low density death' by co-operation between phospholipases C AND D?

Cells of the ciliate Tetrahymena thermophila die when transferred at low density to a lipid-free nutritionally complete medium. This death is prevented and they will start to proliferate if protein kinase C is activated and this activation is sustained. We propose that this takes place in two stages. Firstly, the phospholipase C pathway beginning with and specific for phosphatidylinositol leads to the formation of diacylglycerol and inositol tris -phosphate. Diacylglycerol activates protein kinase C, and inositol tris -phosphate via Ca(2+)phospholipase D (PLD). Secondly, the protein kinase C response can now be sustained by diacylglycerol produced by phospholipase D, using phosphatidylcholine and phosphatidylserine as substrates. Should this switching from PI-specific phospholipase C (PLC) to phospholipase D fail, then the cell will die in the course of milliseconds during the minutes following inoculation.

Animals↗
PubMed2000

Virtual temporal bone: creation and application of a new computer-based teaching tool.

The human temporal bone is a 3-dimensionally complex anatomic region with many unique qualities that make anatomic teaching and learning difficult. Current teaching tools have proved only partially adequate for the needs of the aspiring otologic surgeon in learning this anatomy. We used a variety of computerized image processing and reconstruction techniques to reconstruct an anatomically accurate 3-dimensional computer model of the human temporal bone from serial histologic sections. The model is viewed with a specialized visualization system that allows it to be manipulated easily in a stereoscopic virtual environment. The model may then be interactively studied from any viewpoint, greatly simplifying the task of conceptualizing and learning this anatomy. The system also provides for simultaneous computer networking that can bring distant participants into a single shared virtual teaching environment. Future directions of the project are discussed.

Computer Simulation↗
PubMed2000

High-dose rectal and oral acetaminophen in postoperative patients--serum and saliva concentrations.

BACKGROUND: The primary purpose of the study was to examine the absorption of acetaminophen by measuring serum and saliva concentrations produced by a standard postoperative acetaminophen dosing regimen and secondary to examine the correlation between saliva and serum concentrations of acetaminophen after rectal and oral dosing. METHODS: Twenty-four women, aged 18-60 years, scheduled for minor gynaecological laparoscopic surgery were studied. Patients received acetaminophen 2000 mg suppositories after surgery and oral doses of 1000 mg at 4 and 8 h postoperatively. Alfentanil was available via patient-controlled analgesia. Saliva and blood samples were collected postoperatively. RESULTS: At 1, 2, 3, and 4 h after rectal dosing the saliva concentrations (mean+/-SD) were 15.2+/-5.9 micromol/l, 33.7+/-12.5 micromol/l, 45.5+/-19.1 micromol/l, and 55.4+/-23.1 micromol/l, respectively. The serum concentrations at 2 and 4 h were 31.0+/-11.2 micromol/l and 54.8+/-23.8 micromol/l, respectively. Additional oral dosing resulted in saliva concentrations at 5, 8, and 9 h of 99.7+/-49.5 micromol/l, 106.9+/-31.7 micromol/l, and 139.3+/-55.4 micromol/l, respectively, with coincident serum concentrations of 100.1 +/- 50.2 micromol/l, 105.6+/-29.0 micromol/l, and 141.2+/-52.1 micromol/l. After rectal dosing the linear regression resulted in r2=0.96, P<0.001 and saliva/ serum-ratio=0.99. After additional oral dosing the outcome of linear regression was: r2=0.90, P<0.001 and saliva/serum-ratio= 1.00. CONCLUSION: The slow and ongoing absorption process resulting in no maximum concentration within 4 h after administration of 2000 mg acetaminophen suppositories makes this rectal regimen therapeutically irrational for treatment of postoperative pain. The significant ratio and linear correlation between saliva and serum concentrations of acetaminophen suggests that saliva could be used instead of blood to monitor acetaminophen administration in patients.

Absorption↗
PubMed2000

Tropisetron reduces postoperative vomiting in children undergoing tonsillectomy.

In this patient, parent and investigator blinded, randomized, placebo-controlled study, children undergoing tonsillectomy (mean age 6.4 years) received either intravenous placebo (n=36) or tropisetron 0.2 mg.kg-1 up to 5 mg (n=35) at induction of anaesthesia with halothane, nitrous oxide and oxygen. Morphine and paracetamol were given in theatre for postoperative pain. Episodes of vomiting were recorded during the first 24 h after surgery. Intravenous tropisetron was significantly (P<0.001, chi-squared) more effective than placebo in controlling the incidence and frequency of emesis during the first 24 h: vomiting was reduced from 89% to 46% and the mean number of vomits from 4.6 to 2.4. Minor side-effects occurred equally in both the placebo and active groups. Intravenous tropisetron is an effective and safe antiemetic for reducing postoperative vomiting in children undergoing tonsillectomy or adenotonsillectomy.

Anesthesia, Inhalation↗
PubMed2000

Tropisetron plus dexamethasone is more effective than tropisetron alone for the prevention of postoperative nausea and vomiting in children undergoing tonsillectomy.

The 5-HT3 antagonists are effective in reducing postoperative nausea and vomiting (PONV) associated with paediatric tonsillectomy. Although prophylactic tropisetron can reduce the incidence of PONV by half, the resulting level of over 40% is still unacceptably high. The aim of this study was to evaluate the effect of adding dexamethasone to tropisetron. In a blinded study, 59 children (mean age 6.1 years) were administered 0.1 mg.kg-1 up to 2 mg of tropisetron and 66 children (mean age 5.7 years) received the same dose of tropisetron plus 0.5 mg.kg-1 up to 8 mg of dexamethasone. Both drugs were given intravenously during induction of anaesthesia for tonsillectomy. During the inpatient stay of 24 h, the incidence of postoperative vomiting in the tropisetron alone group was 53% compared with 26% in the combination group (P=0.002, chi-squared). A significant reduction in nausea from 53% to 30% was also observed (P=0.02). Parents completed a daily diary for 5 days following discharge. Delayed vomiting occurred in 27% and 11% of the tropisetron and combination therapy groups, respectively (P=0.025) Sixteen percent and 9%, respectively, required medical attention (P=0.27). Tropisetron plus dexamethasone is more effective than tropisetron alone in reducing the incidence of PONV following paediatric tonsillectomy.

Adolescent↗
PubMed2000

Pharmacokinetics of rectal paracetamol after repeated dosing in children.

Twenty-three children (aged between 9 weeks and 11 yr) were given paracetamol suppositories 25 mg kg-1 every 6 h (maximum 5 days) after major surgery and serum and saliva concentrations were measured. There was a good correlation (r = 0.91, P < 0.05) between saliva and serum concentrations. A one-compartment linear model with first-order elimination and absorption and lag-time was fitted to the data (ADAPT II). At steady state, the mean (SD) concentration was 15.2 (6.8) mg litre-1. Mean (SD) time to reach 90% of the steady state concentration was 11.4 (8.6) h. Body weight, age and body surface area were well correlated (P < 0.05) with clearance and apparent volume of distribution. There was no evidence of accumulation leading to supratherapeutic concentrations during this dosing schedule for a mean of approximately 2-3 days.

Acetaminophen↗
PubMed2000

Knowledge and attitudes about vaginal birth after Caesarean section in Australian hospitals. VBAC Study Group. Vaginal Birth After Caesarean.

A survey of staff attitudes and knowledge about vaginal birth after Caesarean section (VBAC) was undertaken in Australian hospitals. There was a high response rate (67%), and over 900 responses were analysed. Generally, there was a high level of awareness about outcomes and the relative importance of many issues in considering VBAC. Registrars, consultants and midwives differed significantly in some aspects of their knowledge and attitudes to VBAC. There was also a wide range of opinion within each group. Approximately half (53%) of respondents believed patients should be actively encouraged to consider VBAC, whereas 47% felt it should be simply presented as an option.

Attitude of Health Personnel↗
PubMed2000

Vaginal birth after Caesarean section: an Australian multicentre study. VBAC Study Group.

Retrospective analysis of medical records and individual case review was undertaken at 11 major obstetric hospitals for a 5 year period from July 1992 to June 1997 to investigate rates of vaginal birth after Caesarean section (VBAC), the occurrences of uterine rupture, and the outcomes for mother and infant following rupture. Total deliveries were 234,015, of which 21,452 or 9.2% were associated with one or more previous Caesarean sections. Within this scar group, 5419 patients or 25.3% were delivered vaginally. There were 62 cases of significant uterine rupture with no maternal deaths. Perinatal mortality with rupture was 25% and serious maternal complications (usually hysterectomy) occurred in 25% of those with uterine rupture. In women attempting vaginal delivery after a previous lower segment Caesarean section, the uterine rupture rate was estimated at 0.3%, with 0.05% experiencing a perinatal death and 0.05% requiring a hysterectomy. Although VBAC rates in Australia remain lower than many overseas reported series, rates are increasing. While rupture continues to be associated with serious adverse outcomes, the incidence of rupture during trial of labour is low and appears to be associated with a better outcome than rupture of an unscarred uterus.

Australia↗