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Biomedical subjects

O Kristensen

Publications and source records attributed to O Kristensen.

At least 19 recordsLinked to original sources
PubMed1999

Structural changes in the transition state of protein folding: alternative interpretations of curved chevron plots.

The interpretation of folding rates is often rationalized within the context of transition state theory. This means that the reaction rate is linked to an activation barrier, the height of which is determined by the free energy difference between a ground state (the starting point) and an apparent transition state. Changes in the folding kinetics are thus caused by effects on either the ground state, the transition state, or both. However, structural changes of the transition state are rarely discussed in connection with experimental data, and kinetic anomalies are commonly ascribed to ground state effects alone, e.g., depletion or accumulation of structural intermediates upon addition of denaturant. In this study, we present kinetic data which are best described by transition state changes. We also show that ground state effects and transition state effects are in general difficult to distinguish kinetically. The analysis is based on the structurally homologous proteins U1A and S6. Both proteins display two-state behavior, but there is a marked difference in their kinetics. S6 exhibits a classical V-shaped chevron plot (log observed rate constant vs denaturant concentration), whereas U1A's chevron plot is symmetrically curved, like an inverted bell curve. However, S6 is readily mutated to display U1A-like kinetics. The seemingly drastic effects of these mutations are readily ascribed to transition state movements where large kinetic differences result from relatively small alterations of a common free energy profile and broad activation barriers.

Amino Acid Sequence↗
PubMed1999

Plasma total homocysteine response to oral doses of folic acid and pyridoxine hydrochloride (vitamin B6) in healthy individuals. Oral doses of vitamin B6 reduce concentrations of serum folate.

Plasma total homocysteine response was compared in four groups of healthy individuals given orally divided doses of vitamin supplementations for a duration of 5 weeks. The vitamin supplements; A, 0.3 mg folic acid; B, 120 mg vitamin B6; C, combination of 0.3 mg folic acid and 120 mg vitamin B6 or D, 0.6 mg folic acid reduced the concentrations of plasma total homocysteine 20, 17, 32 and 24%, respectively. However, the intergroup comparisons did not show a significant difference in the effects of vitamin supplements. Multivariate analysis with correction for differences in pre-supplement values indicated a significant effect of vitamin B6 supplementation on plasma total homocysteine and serum folate. Our data show that plasma total homocysteine concentrations are reduced with low to medium divided doses of folic acid alone or in combination with vitamin B6.

Administration, Oral↗
PubMed1998

A structural basis for transition-state stabilization in antibody-catalyzed hydrolysis: crystal structures of an abzyme at 1. 8 A resolution.

The three-dimensional structure of a catalytic antibody, 6D9, has been solved as a complex with a transition state analog. The structure was determined from two different crystal forms, and was refined at a resolution of 1.8 A. The antibody 6D9, which was induced by immunization with the phosphonate transition state analog 3, hydrolyzes a prodrug of chloramphenicol monoester 1 to generate the parent drug 2. The kinetic studies have shown that the antibody is catalytic by virtue of the theoretical relationship between the affinity for the transition state and the catalytic efficiency (kcat/kuncat=KS/KTSA). The crystal structure makes it possible to visualize the theoretical relationship. A side-chain (Nepsilon) of HisL27D is placed in a key position to make a hydrogen bond to the phosphonate oxygen of the transition state analog with a distance of 2.72 A, suggesting a hydrogen bond to the oxyanion developing in the transition state of the hydrolysis. There are no catalytic residues, other than the histidine, around the phosphonate moiety. In addition, in the antibody-hapten complex, the hapten bears a folded conformation and the two stacked aromatic rings are buried deep in the antigen-combining site through aromatic-aromatic interaction with TrpH100I and TyrH58. The conformation of the bound hapten suggests that the antibody binds the substrate to change the conformation of the ester moiety to a thermodynamically unstable E-form, thereby making it easy for the substrate to reach the transition-state during catalysis. These observations reveal that the catalytic mechanism is explained purely on the basis of the stabilization of the transition state. The refined high resolution structures reported here are envisaged to have an impact on the understanding of other hydrolytic antibodies, since their haptens share some unique features with the hapten used in this study.

Antibodies, Catalytic↗
PubMed1996

Isolation, crystallization and X-ray analysis of the quaternary complex of Phe-tRNA(Phe), EF-Tu, a GTP analog and kirromycin.

Kirromycin inhibits bacterial protein synthesis by acting on elongation factor Tu (EF-Tu). Complexes of the antibiotic, Phe-tRNA(Phe), the guanosine triphosphate analog GDPNP, and mesophilic (Escherichia coli), as well as thermophilic (Thermus thermophilus) EF-Tu were isolated. Crystallization was achieved at 4 degrees C, pH 6.4, using ammonium sulphate as precipitant. Crystallographic data were recorded at cryogenic temperature on crystals exposed to synchrotron radiation. Crystals of the thermophilic complex are based on a rhombohedral lattice with cell dimensions of 137.3 A, and angles of 54.0 degrees. Although related, these cell parameters are different from those found in the crystals of the recently solved structure of the ternary complex of Phe-tRNA(Phe), GDPNP, and Thermus aquaticus EF-Tu (Nissen, P., Kjeldgaard, M., Thirup, S., Polekhina, G., Reshetnikova, L., Clark, B.F. and Nyborg, J. (1995) Science 270, 1464-1472 [1]), possibly indicating some allosteric effect caused by kirromycin. Crystals of the mesophilic complex belong to the cubic space P432, with cell axis of 196.26 A. In both cases, the crystals contain one complex per asymmetric unit.

Guanosine Triphosphate↗
PubMed1996

Survivorship analysis of cemented total condylar knee arthroplasty. A long-term follow-up report on 348 cases.

Survivorship analysis was used in the evaluation of 348 consecutive primary total condylar knee arthroplasties (total knee arthroplasties) performed on 253 patients in a 27-month period, with a maximum follow-up period of 12 years. The diagnosis was osteoarthrosis in 184 cases and rheumatoid arthritis in 164 cases. Ten patients (10 total knee arthroplasties) were lost to follow-up evaluation. The endpoint was defined as prosthesis not in situ. The variables considered were age, sex, body mass index, and diagnosis. The overall cumulative survival rate was 92%. The survival rate of the osteoarthrosis group was significantly higher (97%) than that of the rheumatoid arthritis group (87%). None of the other variables affected survival rate significantly.

Aged↗
PubMed1996

Controlled trial of lamotrigine (Lamictal) for treatment-resistant partial seizures.

The antiepileptic effect of lamotrigine (Lamictal) was assessed in a double-blind, placebo-controlled, crossover trial in 56 adult patients with refractory partial seizures. Lamotrigine or placebo was added to the patients' existing antiepileptic drugs (AEDs). The dose of lamotrigine varied from 75 to 400 mg daily. Thirty-eight patients completed the trial and 7 withdrew because of adverse experiences. There was a statistically significant reduction in seizure counts on lamotrigine compared with placebo for total seizures (30.3% reduction, 95% CI 8.4%, 47.0%), complex partial seizures (29.2% reduction, 95% CI 3.8%, 47.9%) and secondary generalised seizures (37.9%, CI 18.9%, 52.4%). The analysis of total seizure days showed a similar significant reduction during lamotrigine treatment for the same seizure categories. There was no statistically significant difference in reporting of adverse events between lamotrigine and placebo except for dizziness which was reported more frequently on lamotrigine than on placebo. There were no differences in abnormal haematological or biochemical findings between lamotrigine and placebo, and lamotrigine had no effect on plasma concentrations of concomitant AEDs.

Adolescent↗
PubMed1996

Pseudoarthrosis between a patellar tendon ossicle and the tibial tuberosity in Osgood-Schlatter's disease.

We report a case of pseudoarthrosis between a patellar tendon ossicle and the tibial tuberosity. A man, 18 years of age, had persistent symptoms of Osgood-Schlatter's disease from the left knee for 3 years. Conservative treatment was without effect. Excision of the ossicle resulted in complete relief of symptoms. Histologic examination showed a pseudoarthrosis covered with cartilage and no sign of inflammation. Persistent symptoms of Osgood-Schlatter's disease for more than 2 years indicate exploration.

Adolescent↗
PubMed1996

Manubrium sterni stress fracture: an unusual complication of non-contact sport.

Tremendous force is usually required to cause sternal fractures. Normally this is caused either by a direct blow to the chest or by an indirect injury from hyperflexion of the torso. A case is presented of a fracture of the manubrium sterni in a young man as a complication of body building exercises-a non-contact sport. It appears that this has not been reported before.

Adult↗
PubMed1994

[Neuropathy in adult metachromatic leukodystrophy].

Metachromatic leukodystrophy is a rare autosomal recessive disorder with deficient arylsulphatase A activity. Different forms occur according to the age at onset of symptoms. Adult forms generally present with presenile dementia and/or psychiatric symptoms. We report a case of a 45-year-old woman, without a family history of neuropsychiatric disorders, presenting with complaints of numbness and weakness of the lower limbs. No intellectual or behavioral disturbances were clinically detectable. Electrophysiological investigation was compatible with severe demyelinating neuropathy in upper and lower limbs. MRI of the brain showed multiple white matter lesions. Adult metachromatic leukodystrophy was diagnosed on the basis of low leucocyte arylsulfatase-A-activity and accumulation of metachromatic material in the sural nerve. Pseudo-deficiency was excluded by DNA analysis. This case indicates that adult metachromatic leukodystrophy should be considered in patients with symptoms and signs resembling multiple sclerosis with peripheral neuropathy and in patients with neuropathy of unknown etiology.

Brain Diseases↗
PubMed1994

[Femoral shaft fractures in children. An epidemiologic study in the Greater Arhus].

In a well-defined community, 144 cases of femoral shaft fracture in children (< 15 years old) were registered over a ten-year period. The cases were analysed epidemiologically. The variables taken into consideration were age, sex, aetiology of the fracture, and yearly and seasonal changes of the incidence rates of the fracture. The boy/girl ratio was found to be 2.8:1. The incidence rate was 28 per 100,000 child-years. Young children (< three years) had the highest incidence rates. The most common aetiology was traffic trauma (43.1%), fall trauma (41.7%) coming next. Falling off bicycles contributed with 41.9%, direct trauma with 3.5%, and jamming with 5.6%. An incidence peak was found in the summer months April through August. Involvement of children in traffic accidents and the number of femoral shaft fractures due to traffic trauma fell significantly over the ten-year period.

Adolescent↗
PubMed1994

Inter-observer variation in the evaluation of neurological signs: patient-related factors.

The influence of patient-related factors on inter-observer variability in the evaluation of neurological signs was investigated. Two hundred and two consecutive unselected inpatients were examined by two senior neurologists who were unaware of the neurological case history. Eight signs were evaluated: anisocoria, jerky eye movements, facial palsy, difference in elbow extension force, abnormal finger-nose test, Barré sign, difference in knee jerk, and extensor plantar reflex. Agreement rates were calculated in order to compare the inter-observer variability with reference to the patients' sex, age, mode of admission, and diagnosis at discharge. Observed agreement rates for the eight examined signs only sporadically showed statistically significant differences between the chosen patient-related factors. In general, inter-observer variation does not appear to be influenced by the sex, age, mode of admission or diagnosis at discharge of the patients.

Adolescent↗
PubMed1994

Interobserver variation in the evaluation of neurological signs: observer dependent factors.

Interobserver variation among four observers in evaluation of eight selected neurological signs was investigated. MATERIAL & METHODS--Two hundred and two consecutive unselected inpatients were examined by two senior neurologists and two trainees, all without knowledge of the neurological case history. The signs examined were: anisocoria, jerky eye movements, facial palsy, elbow extension force, finger-nose test, Barré sign, knee jerk, and extensor plantar reflex. Observed agreement rates and kappa coefficients were calculated in order to compare the interobserver variability among neurologists and trainees, and to evaluate differences in the interobserver variability between signs. RESULTS--Observed agreement rates varied from 0.80 to 0.95 for neurologists and from 0.65 to 0.98 for trainees. For neurologists kappa coefficients ranged from 0.40 to 0.67 and for trainees from 0.22 to 0.81. The neurologists had higher kappa values than the trainees in 5 signs, but this difference was only statistically significant for jerky eye movements. For the individual signs the observed agreement rates were between 0.50 and 0.93 for all four examiners combined, and overall kappa values varied from 0.32 to 0.71 with highest agreement for facial palsy and lowest for knee jerk. CONCLUSION--The magnitude of the interobserver and intersign variation indicates that the interpretation of the neurological signs tested, without knowledge of the case history, should be done with some caution.

Adolescent↗
PubMed1993

Therapeutic experiences with 947 epileptic out-patients in oxcarbazepine treatment.

Efficacy and tolerability of the new antiepileptic drug oxcarbazepine, was evaluated in a retrospective multicentre study. The records of all 947 epilepsy patients treated with oxcarbazepine in the eight participating centres from 1981 through 1990 were examined. The median daily dose of oxcarbazepine was 30 mg/kg in children, 18 mg/kg in adults, and 15 mg/kg in elderly patients, given b.i.d. or t.i.d. The mean plasma levels of the main active metabolite of oxcarbazepine was 88, 79, and 68 mumol/l in children, adults, and elderly, respectively. In patients shifted to oxcarbazepine treatment, seizure frequency was unchanged in 51-66%, 32-48% had a decrease, and 1-10% an increase in seizure frequency, considering the individual seizure types separately. Adverse events were reported in one third of patients, most frequently affecting the CNS (dizziness: 6%; sedation: 6%; fatigue: 6%). Rash was reported in 6% of patients, half of these patients had previously had an allergic reaction to carbamazepine. Hyponatremia was found in about a quarter of the patients from whom data were available. No congenital malformations were seen in nine live-born, first trimester oxcarbazepine-exposed children.

Adolescent↗