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Biomedical subjects

M Hansen

Publications and source records attributed to M Hansen.

At least 109 records · Page 6Linked to original sources
PubMed1998

Pregnancy and epilepsy: a retrospective study of 151 pregnancies.

OBJECTIVE: We studied the course of pregnancy in women with epilepsy to identify possible risk factors which might complicate the epilepsies and pregnancy outcomes. MATERIAL AND METHODS: Data were collected retrospectively from the records of 151 pregnancies in 124 women with epilepsy from 1978-1992. Epilepsy variables were compared with that of non-pregnant women with epilepsy matched for age. Obstetric and neonatal variables were compared with those of all deliveries in the same unit from 1979-1992 (n=38,983). RESULTS: Pregnancy among patients with epilepsy was more likely to occur in women with relatively mild epilepsy. In 12% of the pregnancies, the women were untreated while 71% were on monotherapy. Twenty-one percent had increased seizure frequency during the pregnancy. Perinatal deaths among newborns of epileptic mothers (1.3%) was more frequent but not significantly increased compared to the background population of 0.5% (95% CI 0.2-4.7). A total of 5.3% had congenital malformations compared to 1.5% in the controls (95% CI 2.3-10.3). No neural tube defects were observed. Maternal treatment with phenytoin was significantly related to the occurrence of congenital malformations, P=0.04. CONCLUSIONS: Most women with epilepsy have an uncomplicated pregnancy and normal healthy offsprings. Maternal treatment with phenytoin might be associated with congenital malformations. No other risk factors could be identified.

Abnormalities, Drug-Induced↗
PubMed1998

BEAM+autologous stem cell transplantation in malignant lymphoma: 100 consecutive transplants in a single centre. Efficacy, toxicity and engraftment in relation to stem-cell source and previous treatment.

One hundred consecutive patients with malignant lymphoma treated with high-dose chemotherapy and autologous stem cell transplantation, followed at least 1 yr post-transplant, are reported, 68 with non-Hodgkin's lymphoma and 32 with Hodgkin's disease. At transplant, 23 patients were in first remission, 69 in later chemosensitive disease and 8 were chemotherapy resistant. Based on previous treatment and stem-cell source, the patients were subdivided into 3 cohorts: BMT1: bone-marrow harvest and transplant after > or =3 treatment regimens (38 patients); BMT2: bone marrow harvest and transplant after less than 3 treatment regimens (24 patients); PBSCT: peripheral-blood stem cell transplant (38 patients, 5 of these with CD34+ cell selected PBSC). The 4-yr survival and progression-free survival of all patients was 45 and 40%, respectively. Forty-one patients have died, 27 of lymphoma, evenly distributed in the cohorts. Fourteen treatment-related deaths occurred, 13 of these in the BMT1 cohort, significantly more than in the other cohorts (p=0.001). In univariate survival analysis cohort, age, disease status at transplant and number of previous treatment regimens were significant. In multivariate survival analysis cohort, age and sex were independently significant, women having a shorter survival. The patients transplanted with unselected PBSC had significantly shorter duration of pancytopenia and hospital stay than the otherwise comparable BMT2 patients, but their progression-free survival was identical. We confirm that high-dose therapy with autologous stem cell transplant from blood or bone marrow in not-too-heavily pretreated patients is a safe procedure but will cure only half the patients.

Adult↗
PubMed1998

Human immunodeficiency virus type 1 cDNA integration: new aromatic hydroxylated inhibitors and studies of the inhibition mechanism.

Integration of the human immunodeficiency virus type 1 (HIV-1) cDNA is a required step for viral replication. Integrase, the virus-encoded enzyme important for integration, has not yet been exploited as a target for clinically useful inhibitors. Here we report on the identification of new polyhydroxylated aromatic inhibitors of integrase including ellagic acid, purpurogallin, 4,8, 12-trioxatricornan, and hypericin, the last of which is known to inhibit viral replication. These compounds and others were characterized in assays with subviral preintegration complexes (PICs) isolated from HIV-1-infected cells. Hypericin was found to inhibit PIC assays, while the other compounds tested were inactive. Counterscreening of these and other integrase inhibitors against additional DNA-modifying enzymes revealed that none of the polyhydroxylated aromatic compounds are active against enzymes that do not require metals (methylases, a pox virus topoisomerase). However, all were cross-reactive with metal-requiring enzymes (restriction enzymes, a reverse transcriptase), implicating metal atoms in the inhibitory mechanism. In mechanistic studies, we localized binding of some inhibitors to the catalytic domain of integrase by assaying competition of binding by labeled nucleotides. These findings help elucidate the mechanism of action of the polyhydroxylated aromatic inhibitors and provide practical guidance for further inhibitor development.

Anthracenes↗
PubMed1998

DINAMO: a coupled sequence alignment editor/molecular graphics tool for interactive homology modeling of proteins.

Gaining functional information about a novel protein is a universal problem in biomedical research. With the explosive growth of the protein sequence and structural databases, it is becoming increasingly common for researchers to attempt to build a three-dimensional model of their protein of interest in order to gain information about its structure and interactions with other molecules. The two most reliable methods for predicting the structure of a protein are homology modeling, in which the novel sequence is modeled on the known three-dimensional structure of a related protein, and fold recognition (threading), where the sequence is scored against a library of fold models, and the highest scoring model is selected. The sequence alignment to a known structure can be ambiguous, and human intervention is often required to optimize the model. We describe an interactive model building and assessment tool in which a sequence alignment editor is dynamically coupled to a molecular graphics display. By means of a set of assessment tools, the user may optimize his or her alignment to satisfy the known heuristics of protein structure. Adjustments to the sequence alignment made by the user are reflected in the displayed model by color and other visual cues. For instance, residues are colored by hydrophobicity in both the three-dimensional model and in the sequence alignment. This aids the user in identifying undesirable buried polar residues. Several different evaluation metrics may be selected including residue conservation, residue properties, and visualization of predicted secondary structure. These characteristics may be mapped to the model both singly and in combination. DINAMO is a Java-based tool that may be run either over the web or installed locally. Its modular architecture also allows Java-literate users to add plug-ins of their own design.

Amino Acid Sequence↗
PubMed1998

Reversal of ethanol-induced testosterone suppression in peripubertal male rats by opiate blockade.

Teenage drinking is a major problem in the United States, as well as abroad. Besides psychosocial implications, ethanol (EtOH) has detrimental effects on the reproductive system. Clinical problems associated with reduced reproductive hormones include osteoporosis, decreased muscle function, anemia, altered immune function, prostate involution, and decreased reproductive abilities. Education coupled with strategies aimed at preventing these deleterious consequences even in the face of continued EtOH intake is extremely important. We have tested the possibility that naltrexone, a drug currently used in patients to decrease alcohol craving, might also prevent the fall in the male hormone, testosterone, caused by EtOH exposure. Rats aged 35 days old (prepubertal), 45 days old (midpubertal), and 55 days old (late pubertal) were injected (intraperitoneally) with either saline, EtOH, naltrexone, or EtOH plus naltrexone. In the two older age groups, EtOH significantly suppressed testosterone, which was prevented by administration of naltrexone. In the youngest animals, there was no treatment effect presumably due to low basal levels of testosterone. EtOH similarly reduced luteinizing hormone (LH), but this suppression was not prevented by naltrexone. There was no consistent effect of any treatment on hypothalamic concentration of pro-LH releasing hormone (RH) (LHRH), LHRH, or on steady-state levels of LHRH mRNA. We conclude that, as animals progress through puberty, EtOH suppresses LH and testosterone. The testosterone decline can be prevented by opiate blockade with naltrexone, an effect primarily seen at gonadal level. Thus, naltrexone, a drug already used clinically to reduce EtOH intake, also has protective physiological effects on the endocrine system.

Animals↗
PubMed1997

Structure-function studies of recombinant murine tripeptidyl-peptidase II: the extra domain which is subject to alternative splicing is involved in complex formation.

Tripeptidyl-peptidase II (TPP II) is an exopeptidase with a remarkably high native Mr (> 10(6)). Recently, an alternatively spliced, murine cDNA variant was identified which contains an additional 39 bp, encoding 13 amino acids in the C-terminal end of the protein. The two enzyme variants were expressed in human kidney 293 cells. Both types of subunit were found to form the active oligomers. In addition, subunits containing the extra 13 amino acids formed an even larger complex eluting in the void volume of a Sepharose CL-4B column. Thus, it appears that this sequence is important for aggregation of subunits.

Alternative Splicing↗
PubMed1997

Systemic delivery of human growth hormone or human factor IX in dogs by reintroduced genetically modified autologous bone marrow stromal cells.

Canine bone marrow stromal cells were expanded to numbers in excess of 10(9) cells from the initial 10-20 ml of marrow aspirates and transfected to express high levels of human growth hormone (hGH) in vitro. Ex vivo-modified marrow stromal cells were used in a gene therapy model system for the systemic delivery of transgene products in dogs. Adherent bone marrow stromal cell cultures, established and expanded from iliac crest marrow aspirates from each of 8 dogs, were transfected with a hGH gene plasmid expression vector and shown to express from 0.54-3.84 micrograms/10(6) cells per 24 hr hGH in vitro. The transfected plasmid vector does not possess a eukaryotic origin of replication nor does it possess sequences required for efficient integration into the host cell genome. As such, expression was expected to be transient. Transfected cells were autologously reintroduced into each dog by either infusion into a foreleg vein or directly into iliac crest marrow. In two cases, the stromal cells were cryopreserved following transfection, and subsequently thawed and infused. In one case, the expanded stromal cells were first cryopreserved, and then thawed, recultured, transfected, and infused. Reintroduced cell numbers ranged from 2.2 x 10(7) to 2.6 x 10(9), with total hGH expression capacities ranging from 62 to 1,400 micrograms/24 hr. Plasma of each of the dogs contained detectable hGH for a mean of 3.1 days (SD +/- 0.8 day) ranging from 2 to 5 days following reinfusion of cells. Peak plasma levels ranged from 0.10 to 1.76 ng/ml. Similar hGH expression values, based upon total expression capacity of the cells infused and dog body weight, were obtained for all dogs. Vector-modified stromal cells were detectable, by polymerase chain reaction (PCR) analysis, in the peripheral circulation following reinfusion in all 4 dogs analyzed. In 3 of the dogs, modified stromal cells were detected for 8.5-15 weeks. In addition, modified stromal cells were detected in iliac crest marrow of 2 dogs for 9 and 13 weeks, respectively, following reinfusion. In another experiment, cultured bone marrow stromal cells were transfected with a human factor IX (hFIX) plasmid vector. Modified cells (5.57 x 10(8)), with a total hFIX expression capacity of 281 micrograms/24 hr, were reinfused, resulting in detectable hFIX in plasma continuously for 9 days with a peak level of 8 ng/ml on day 1. These results demonstrate that the ex vivo bone marrow stromal cell system is a potentially powerful method by which to deliver secreted transgene product to the systemic circulation of large animals.

Animals↗
PubMed1997

Phase II trial of high-dose cisplatin plus ifosfamide as first-line followed by carboplatin as second-line treatment in epithelial ovarian carcinoma.

BACKGROUND: In a previous study of combined platinum and ifosfamide we found a pathologic complete response rate of 42%. The present study was to test whether the high response rate could be reproduced or even improved by combining high-dose cis-platinum and increased dose of ifosfamide. METHODS: Forty-two previously untreated ovarian cancer patients were included in the study. Cisplatin 50 mg/m2 and ifosfamide 2000 mg/m2 together with mesna 1200 mg/m2 were given daily, Day 1-3 every 4 weeks for six cycles, followed by second-look laparotomy. In the event of residual disease carboplatin was given every 4 weeks for a further six cycles. RESULTS: The pathologic complete response rate was 20% (8 of 41). Five of 26 patients achieved a further response on carboplatin. Hematologic and nonhematologic toxicity caused dose reduction in more than 90 and 50% of the patients, respectively. CONCLUSION: The results of this high-dose regimen equals those obtained with conventional, far less toxic, regimens. Only patients with potentially platinum-sensitive tumors achieved further response when crossed over to the analogue, which may indicate that prolonged treatment is better than increased dose. A randomized trial is still needed to assess the importance of dose intensity in ovarian cancer.

Adult↗
PubMed1997

Dose-finding study of oral metopimazine.

A few studies indicate a dose-response effect of the antiemetic metopimazine. The aim of this study was therefore to investigate the tolerability of increasing doses of metopimazine given orally every 4 h for eleven doses. The dose levels 20 mg, 30 mg, 40 mg, 50 mg and 60 mg were studied in 36 patients completing 46 cycles of chemotherapy. Serum concentrations of metopimazine and the acid metabolite AMPZ were measured by HPLC in 13 patients (15 cycles). The dose-limiting toxicity was moderate to severe dizziness caused by orthostatic hypotension as seen in 0, 0, 17%, 42% and 50% of patients at the respective dose levels. Other side effects were few and mild, and only a single possible extrapyramidal adverse event was observed in a patient at the 60-mg dose. High serum concentrations were not predictive for toxicity, as found on comparison of patients with and without symptoms, but in individual patients symptoms were seen at the time of Cmax. We found that metopimazine was safe with a dosage of 30 mg x 6. This dose is four times higher than that previously recommended for antiemetic use.

Administration, Oral↗
PubMed1997

Optimizing radiology in the new picture archiving and communication system environment.

Picture archiving and communications systems (PACS) have inescapably altered the face of radiology. Images are available to radiologists and clinicians alike, nearly instantaneously. For patient care management, service has improved, but without inclusion of input from radiologists. Effecting timely report availability requires reorganization of radiology. In a hospital-wide PACS environment, we undertook to render a preliminary report on all nonprocedural computed radiography examinations within 30 minutes in a teaching environment. Two periods of time in the same month were analyzed, one before reorganization and one after. Of 686 reports, 117 were examined with a statistical significance of alpha = .05 (95% confidence) and a power of 90%. Average times for examination acquisition to preliminary report availability on the PACS decreased from 5 hours to 31 minutes. Standard deviation in report generation times decreased from 8 hours to 30 minutes. This preliminary study suggests that business process reengineering can effect improvement in information flow within a teaching facility resulting in radiologists rejoining the patient care management team. Successes, pitfalls, and future requirements are discussed.

Efficiency, Organizational↗
PubMed1997

Single-dose pharmacokinetics of sublingual versus oral administration of micronized 17 beta-estradiol.

OBJECTIVE: To investigate the pharmacokinetic profiles of different doses of micronized 17 beta-estradiol administered by oral or sublingual routes. METHODS: Single doses of micronized 17 beta-estradiol were administered orally (1 mg, 0.5 mg) or sublingually (1 mg, 0.5 mg, 0.25 mg) to six postmenopausal women in a randomized clinical trial. We calculated pharmacokinetic parameters for estradiol (E2) and estrone (E1) of maximum serum concentration, time to maximum serum concentration, terminal half-life, area under the concentration curve, and oral clearance. Serum levels of E1 sulfate also were compared at 4, 12, and 24 hours after dosing. RESULTS: Sublingual administration resulted in rapid absorption with significantly higher E2 levels than did comparable oral dosing. Estrone levels did not vary with route of administration but correlated with the dosage administered. Estrone sulfate levels correlated with the dosage administered and also tended to be higher with sublingual administration. Sublingual administration resulted in a significantly lower E1 to E2 ratio during the 24 hours than did oral administration. CONCLUSION: Sublingual administration of micronized 17 beta-estradiol results in a rapid, burst-like absorption into the systemic circulation, yielding high E2 levels that fall rapidly over the first 6 hours.

Administration, Oral↗
PubMed1997

Short-term growth and collagen turnover in asthmatic adolescents treated with the inhaled glucocorticoid budesonide.

Short-term lower leg growth, the insulin-like growth factor axis, and collagen turnover were assessed in 16 adolescents with asthma during treatment with inhaled budesonide, 800 micrograms/d, from a pressurized metered dose inhaler with a volume spacer. The design was a randomized double blind, placebo-controlled two-period crossover trial with treatment periods of 4 weeks and a 1-week wash-out. Lower leg growth was assessed by knemometry. Serum levels of insulin-like growth factor-I, insulin-like growth factor-binding protein-3, and the following markers of collagen turnover were evaluated: Serum markers of type I collagen formation and degradation; the carboxy-terminal propeptide of type I procollagen and the carboxy terminal pyridinoline cross-linked telopeptide of type I procollagen (ICTP), the serum marker of type III collagen formation; the amino-terminal propeptide of type III procollagen (PIIINP) and the urinary concentrations of the type I collagen degradation products pyridinoline (PYD) and deoxypyridinoline (DPD) cross-links. Mean lower leg growth velocity was suppressed from 0.51 mm/week during placebo to 0.18 mm/week during budesonide treatment (p < 0.001). No statistically significant effects on insulin-like growth factor-1, insulin-like growth faster-binding protein-3, or carboxy-terminal propeptide of type I procollagen were observed. ICTP and PIIINP were reduced with 2.3 and 2.5 micrograms/liter (p < 0.001 and p < 0.001, respectively) during budesonide treatment, urinary concentrations of PYD and DPD with 32.9 nmol/mmol creatinine (p < 0.005) and 6.8 nmol/mmol creatinine (p < 0.005), respectively. Significant correlations between lower leg growth velocity and ICTP, PIIINP, PYD, and DPD during placebo (p < 0.01, p < 0.05, p < 0.01, and p < 0.01) and budesonide (p < 0.05, p < 0.05, p < 0.05, and p < 0.05) periods were found. Short term lower leg growth suppression in adolescents treated with inhaled budesonide, 800 micrograms/d, reflects suppression of type I and III collagen turnover.

Administration, Topical↗
PubMed1997

Effect of casein phosphopeptides on zinc and calcium absorption from bread meals.

Animal studies suggest that casein phosphopeptides (CPP), formed by proteolytic digestion of casein, have a positive effect on Ca availability. The aim of this study was to investigate the ability of CPP to improve Zn and Ca absorption from phytate-containing bread meals. Secondly, it was tested whether the Ca content of the meal influenced the effect of CPP on Zn absorption from a high-phytate meal. Zn and Ca absorption from single model meals was determined by extrinsic labeling with 65Zn and 47Ca and measurement of whole-body retention. Thirty-one healthy adults (19-30 y) divided into three groups received one of three meal types based on white-wheat rolls with different phytate and Ca content: A: low-phytate/high-Ca (n = 10), B: high-phytate/high-Ca (n = 10) and C: high-phytate/low-Ca (n = 11). Each individual received the same meal type at three different occasions with 0, 250 and 1000 mg CPP added. CPP had no effect on Zn absorption: A: 14.3 +/- 4.4% (mean +/- SD) (0 mg CPP), 16.7 +/- 6.6% (250 mg CPP) and 16.0 +/- 8.8% (1000 mg CPP); B: 7.0 +/- 1.6%, 7.7 +/- 3.0% and 8.0 +/- 2.6%; C: 7.7 +/- 2.5%, 7.0 +/- 2.3% and 6.5 +/- 1.6%, respectively. Addition of 1000 mg CPP reduced fractional Ca absorption from meal A: 33.8 +/- 7.1%, 30.5 +/- 6.3% and 25.9 +/- 8.7% (p < 0.05), whereas CPP had no effect in meal B: 29.3 +/- 8.3%, 27.0 +/- 7.4% and 27.6 +/- 11.0%. However, the absolute quantity of Ca absorbed was unaffected. In conclusion, Zn and Ca absorption from these meals were not significantly influenced by the addition of CPP, Ca addition could not explain the failure of CPP to improve Zn absorption.

Absorption↗
PubMed1997

RNA aptamers to the peptidyl transferase inhibitor chloramphenicol.

BACKGROUND: The problem of how macromolecules adopt specific shapes to recognize small molecules in their environment is readily addressed through in vitro selections (the SELEX protocol). RNA-antibiotic interactions are particularly attractive systems for study because they provide an opportunity to expand our understanding of molecular recognition by RNA and to facilitate ribosomal modeling. Specifically, the antibiotic chloramphenicol (Cam) naturally binds bacterial ribosomes in the 'peptidyl transferase loop' of 23S ribosomal RNA to inhibit peptide bond formation. RESULTS: We identified Cam-binding RNA molecules ('aptamers') from two independent initial random RNA populations. Boundary determinations, ribonuclease S1 sensitivity analyses and the activity of truncated minimal RNAs identified a structural motif that is shared by sequences from both selections. The pseudosymmetric motif consists of a highly conserved central helix of five to six base pairs flanked by A-rich bulges and additional helices. Addition of Cam prior to ribonuclease S1 protected nucleotides in the conserved cores from cleavage. Reselection from a pool of mutated variants of the minimal aptamer further refined the sequence requirements for binding. Finally, we used proton nuclear magnetic resonance (NMR) to establish a 1:1 RNA: Cam stoichiometry of the complex. Both the protection and NMR data both show that Cam stabilizes the active fold of this aptamer. CONCLUSIONS: There are many different RNA sequences that can bind Cam. The Cam aptamers that we examined have a well-defined secondary structure with a binding pocket that appears to be stabilized by Cam. This RNA motif superficially resembles the Cam-binding site in 23S rRNA, although further work is needed to establish the significance of these similarities.

Base Sequence↗