Patients with knee osteoarthritis can be divided into subgroups based on tibiofemoral joint kinematics of gait - an exploratory and dynamic radiostereometric study.

OBJECTIVE: Patients with advanced knee osteoarthritis (KOA) frequently alter their gait patterns in an attempt to alleviate symptoms. Understanding the underlying pathomechanics and identifying KOA phenotypes are essential to improve treatments. We investigated kinematics in patients with KOA to identify subgroups of homogeneous knee joint kinematics. METHOD: A total of 66 patients with symptomatic KOA scheduled for total knee arthroplasty and 15 age-matched healthy volunteers with asymptomatic, non-arthritic knees were included. We used k-means clustering to divide patients into subgroups based on dynamic radiostereometry-assessed tibiofemoral joint kinematics. Clinical characteristics such as knee ligament lesions and KOA scores were graded by magnetic resonance imaging and radiographs, respectively. RESULTS: We identified four clusters that were supported by clinical characteristics. The flexion group (n = 20) consisted primarily of patients with medial KOA. The abduction group (n = 17) consisted primarily of patients with lateral KOA. The anterior draw group (n = 10) was composed of patients with medial KOA, some degree of anterior cruciate ligament lesion and the highest KOA score. The external rotation group (n = 19) primarily included patients with medial collateral and posterior cruciate ligament lesions. CONCLUSION: Based on tibiofemoral gait patterns, patients with advanced KOA can be divided into four subgroups with specific clinical characteristics and different KOA-affected compartments. The findings add to our understanding of how knee kinematics may affect the patient's development of different types of KOA. This may inspire improved and more patient-specific treatment strategies in the future.

Interaction of radiolabeled endotoxin molecules with human monocyte membranes.

Radiolabeled and biologically active endotoxin molecules were prepared, and their binding to monocyte plasma membranes was studied. The binding of 3H-endotoxin and 51Cr-lipid A to isolated membranes was found to be less specific and of lower apparent affinity than that observed using whole cells. Plasma membranes isolated from intact, viable 51Cr-lipid A-pretreated monocytes were found to contain a significant portion of the cell-associated 51Cr-lipid A following Percoll density gradient fractionation of post-nuclear homogenates. When monocytes were pretreated with 3H-endotoxin under the same experimental conditions, all of the label was recovered in the extracellular medium, and subcellular fractionation revealed no fractions which contained tritium. Taken together, our results suggest that specific and high affinity interactions between monocyte membranes and endotoxin molecules are likely to depend on plasma membrane structures which are assembled in intact monocytes but which are disrupted when plasma membranes are isolated from these cells.

Effect of bacterial endotoxin on the transmembrane electrical potential and plasma membrane fluidity of human monocytes.

In order to gain insight into the physical interaction between bacterial endotoxins and the surface of human monocytes, we investigated the effects of Salmonella typhi endotoxin and lipid A on two functional properties of the plasma membrane of these cells: (1) the transmembrane electrical potential and (2) the fluidity of the lipid bilayer. Using the fluorescent lipophilic cationic probe 3,3'-dipropylthiodicarbocyanine (di-S-C3(5] to monitor the transmembrane electrical potential, we found that neither endotoxin nor lipid A induced depolarization of the monocyte's plasma membrane or impeded its ability to undergo depolarization in response to phorbol myristate acetate. When the resting transmembrane potential of the monocyte was analyzed by exposing di-S-C3(5)-labeled cells suspended in media containing incremental concentrations of potassium ion (K+) to valinomycin, no difference between the response of control cells and cells pretreated with endotoxin was noted. We next examined the effect of endotoxin and lipid A on the fluidity of the monocyte's plasma membrane by monitoring the intensity of the fluorescence of 1,6-diphenyl-1,3,5-hexatriene. By quantifying the intensity of parallel and perpendicular polarized light emitted by this membrane-embedded probe between 8 and 56 degrees C, measurements of molecular anisotropy were used to identify temperature-dependent phase transitions within the hydrocarbon region of the plasma membrane and to estimate the relative microviscosity of the lipid bilayer before and after exposing the cells to endotoxin or lipid A. Although the temperature at which phase transitions occurred was the same in all experimental groups of cells, preincubation of monocytes with either endotoxin or lipid A appeared to increase both the apparent microviscosity of the cell membrane and the order of the lipid bilayer as reflected by a decrease in its flow-activation energy. Our data indicate that when endotoxin molecules contact the surface of the monocyte, the lipid A moiety appears to become incorporated into the plasma membrane, increasing the microviscosity of the lipid bilayer without significantly altering its ionic permeability. We therefore conclude that the metabolic activation of monocytes by endotoxin is not coupled to, or initiated by, membrane depolarization.

Pathophysiological mechanisms of estrogen effect on bone metabolism. Dose-response relationships in early postmenopausal women.

Dose-response relationships of estrogen (E) on indices of calcium balance and bone activity were studied in normal early postmenopausal women. Calcium balance was estimated by changes in forearm bone mineral content, measured by photon absorptiometry. Bone activity was estimated by serum alkaline phosphatases (S-aPh), indicating bone formation, and by fasting urinary excretion of hydroxyproline (U-HyPro) and calcium (U-Ca), indicating bone resorption. A total of 92 female volunteers were randomized to 12 months' treatment with placebo or one of three different doses (high, medium, or low) of natural estrogens (17 beta-estradiol and estriol, 4/2, 2/1, and 1/0.5 mg, respectively), sequentially combined with the same dose (1 mg) of norethisterone acetate for 10 of the 28 cycle days. The trial was completed by 79 women. Bone mineral content declined by 2% (P less than 0.001) in the placebo group, remained constant in the low hormone group and increased by 0.8% (P less than 0.05) and 1.5% (P less than 0.01), respectively, in the medium and high hormone groups. S-aPh decreased gradually and equally by 20-25% in the three hormone groups and U-HyPro and U-Ca decreased by 30-40% during 1-yr hormone treatment, irrespective of dose. The decrease in these three indices occurred practically without exceptions. Compared to the values found in 48 normal premenopausal women the untreated postmenopausal women had increased values of S-aPh (P less than 0.001), U-HyPro (P less than 0.01), and U-Ca (P less than 0.001), and no pretreatment values were below the normal premenopausal range. After treatment the mean values of S-aPh and U-HyPro were slightly lower than the premenopausal mean values (P less than 0.01). These data strongly support the major importance of E deficiency for early postmenopausal bone loss, which is prevented by even a small substitution dose of E.

Factors influencing nortriptyline steady-state kinetics: plasma and saliva levels.

Proportionality between dose and steady-state nortriptyline (NT) plasma levels was found both during initial treatment and after long-term treatment (years) within the NT Plasma level range of 20 to 296 ng/ml. There were day-to-day variations of 10% to 20% (coefficient of variation) but no systematic changes in plasma levels over time. A significant age variation in NT plasma levels was found in 116 patients. Patients over 70 yr of age (n = 23) had higher levels than other age groups (p < 0.001) dose corrected; p < 0.0001 dose and weight corrected). It was found that during episodes of acute inflammatory diseases NT steady-state plasma levels rose after a change in sedimentation rate. Our data show that the use of saliva rather than plasma in therapeutic drug level monitoring of NT cannot be recommended because the saliva/plasma ratio varied both intra- and interindividually by factors of from 2 to 4.

Cimetidine clearance and bioavailability in hepatic cirrhosis.

Nine patients with compensated alcoholic and nonalcoholic cirrhosis of the liver and 11 patients with peptic ulcer received 200 mg of cimetidine orally and intravenously. No differences were observed in cimetidine clearance between the group with peptic ulcer (556 +/- 44 ml/min, mean +/- SEM) and the group with cirrhosis (606 +/- 64 ml/min). The bioavailability of cimetidine was unchanged (84 +/- 4% and 97 +/- 7%). In the patients with cirrhosis, cimetidine clearance did not correlate with galactose elimination capacity or antipyrine clearance. Cimetidine clearance was related to creatinine clearance only when both groups were considered. A reduction of cimetidine dose in patients with compensated cirrhosis appears unwarranted.

Therapeutic advantages of monitoring plasma concentrations of perphenazine in clinical practice.

Two hundred and twenty-eight acute paranoid psychotic in-patients received continuous treatment with perphenazine for a period of at least 5 weeks, before blood samples were taken to determine perphenazine plasma levels and conclusions regarding therapeutic efficacy and motor side effects. Patients with plasma concentrations within the range of 2-6 nmol/l showed an excellent antipsychotic response, concomitantly with a low incidence of extrapyramidal side effects. However, patients with plasma levels below or above this range either demonstrated a poor therapeutic response or a high degree of side effects respectively. The results indicate that with increasing age significantly lower doses of perphenazine are required to ensure an optimal clinical response. No difference, however, was seen between sexes with regard to dose response.

Plasma concentrations of perphenazine and its sulphoxide metabolite during continuous oral treatment.

Plasma concentrations of perphenazine (PPZ) (Trilafon) and perphenazinesulphoxide (PPZSO) were estimated during a 2-week period in 16 patients receiving peroral PPZ treatment for various psychotic disorders. The results demonstrated that the average concentration of three plasma samples was a reasonably good expression of the steady-state plasma level despite a great fluctuation in the concentration from sample to sample. Increased doses in three of the patients resulted in disproportionate increases in the plasma levels. Neurological side effects were recorded and their relation to plasma concentrations are discussed.

Dose-response relationships of perphenazine in the treatment of acute psychoses.

A group of 26 acute psychotic patients received continuous oral treatment with perphenazine for a period of 5 weeks. Once-weekly blood samples were drawn for measurements of perphenazine levels and, simultaneously, the therapeutic outcome was registered. Another 26 acute psychotic patients received continuous oral treatment with perphenazine for a period of up to 4 weeks. A single blood sample was drawn and the perphenazine concentration was related to the appearance of extrapyramidal side effects. The following conclusions were made: (1) a high risk of provoking extrapyramidal side effects was associated with plasma levels of perphenazine above 3 nmol/l; (2) plasma levels below 2 nmol/l were associated with a poor therapeutic outcome; (3) a 'therapeutic window' between 2 and 3 nmol/l gives maximal therapeutic effect with a low risk of provoking extrapyramidal side effects.

Plasma levels of perphenazine (Trilafon) related to development of extrapyramidal side effects.

Thirteen acute psychotic patients received continuous oral treatment with perphenazine for a period of 8 weeks. Blood samples for quantification of perphenazine, perphenazine sulphoxide and prolactin were drawn twice weekly. Simultaneously, the therapeutic outcome and the degree of extrapyramidal side effects were recorded. The following conclusions were made: 1. In accordance with results achieved in one of our earlier investigations, a high risk of provoking extrapyramidal side effects was associated with plasma levels of perphenazine exceeding about 3 nmol/l. 2. An excellent therapeutic outcome was associated with plasma concentrations of perphenazine above 1.5 nmol/l. 3. Plasma concentrations of perphenazine and prolactin were poorly correlated to each other (R = 0.49). 4. A significant correlation (R = 0.85) was shown between the scores for the Brief Psychiatric Rating Scale and the Comprehensive Psychopathological Rating Scale.

Perphenazine decanoate and cis(z)-flupentixol decanoate in maintenance treatment of schizophrenic outpatients. Serum levels at the minimum effective dose.

Two groups of schizophrenic outpatients were treated with perphenazine decanoate (N = 20) and cis(z)-flupentixol decanoate (N = 24) respectively. Every 3 months the dose was gradually reduced until symptoms appeared that were suggestive of a prodromal phase of a psychotic episode. A slightly higher dose was then promptly reinstituted (the minimum effective dose). At each dose level, two blood samples were drawn for determination of serum concentration. The mean minimum effective dose of perphenazine decanoate was 99.3 mg/2 weeks (range 21.6-270.5), while the mean minimum effective dose of cis(z)-flupentixol decanoate was 60 mg/2 weeks (range 20-250). The corresponding mean serum level of perphenazine decanoate was 7.3 nmol/l (range 2.0-18.1) and of cis(z)-flupentixol decanoate 7.8 nmol/l (range 1.2-37.0). There was a significant correlation between the administered doses and the corresponding serum levels for both drugs (r = 0.87, P less than 0.01). A weak positive correlation was found between serum levels at the minimum effective dose and symptom intensity (BPRS total score) (r = 0.53, P less than 0.02) for perphenazine, but not cis(z)-flupentixol. No correlation was found between serum levels and side effects or length of neuroleptic treatment. It is concluded that the serum drug concentrations corresponding to the lowest effective dose are so variable that routine serum level monitoring may be of limited value in the long-term maintenance treatment of schizophrenia.

The practical significance of nortriptyline plasma control. A prospective evaluation under routine conditions in endogenous depression.

The problem of the advantage of using nortriptyline (NT) plasma level during treatment for endogenous depression has been approached. In an ordinary psychiatric department, 34 patients had their NT level checked the second week of treatment and their dosage subsequently adjusted, if it was outside the recommended therapeutic plasma range (50--150 ng/ml). A cautious dose policy led to low plasma levels followed by dose increase in about 40% of the patients. Only in a few patients was the plasma level above the upper limit. The general outcome, about 20% failures, was compatible with the best in literature. These and other results suggest that controlling the NT plasma concentration, aiming at a level of around 100 ng/ml, might offer a therapeutic advantage, but only if the department has established a therapeutic strategy that involves such a monitoring system. The therapeutic outcome was the same as or even better in the old-age group than that in patients under 65 years of age.

Plasma levels of zimelidine and norzimelidine in endogenous depression.

A new serotonin uptake inhibitor zimelidine was studied in 16 endogenously depressed inpatients, who received 150 mg/kg orally during 3--6 weeks in a phase II-type study. Plasma concentrations of zimelidine and its main metabolite norzimelidine were determined twice a week. Ten patients obtained a well-defined steady-state plasma level within 1--2 weeks, while three patients still had increasing concentrations of both substances or only norzimelidine within the investigation period. In two patients, biochemical affection of the liver could be demonstrated during the treatment; one associated with moderate clinical symptoms (dizziness and fever), the other without clinical symptoms. Both patients recovered upon cessation of the zimelidine treatment. In the former patient, very high concentrations of zimelidine at the time of hepatic symptoms were demonstrated, while the latter patient was within the average concentration range. Other adverse reactions were mild and few, particularly with respect to anticholinergic effects. With the applied, probably suboptimal, dosage the therapeutic response was only satisfactory in five cases.

Computer-assisted alignment of standard serial sections without use of artificial landmarks. A practical approach to the utilization of incomplete information in 3-D reconstruction of the hippocampal region.

An algorithm for the alignment of stained serial sections without the support of artificial landmarks is described. Four-hundred-thirty serial sections of the rabbit hippocampal region were digitized, and computer-based alignment was performed without use of artificial markers, resulting in a consistent matrix. Following proper filtration, artificial sections were cut through the matrix. In a second experiment every second image was deleted and reconstructed by interpolation with a minor loss of biological information. In a third experiment every second image was deleted and the rest of the images were 'disordered', realigned and the missing planes reconstructed by interpolation. Under these circumstances the matrix was reconstructed with some loss of information. These results may widen the limits of 3-dimensional (3-D) reconstruction, as routine histological preparations normally include only every second or every third section without artificial landmarks.

Computer-assisted three-dimensional reconstruction of the hippocampal region based on serial sections.

A large series of rabbit hippocampal Neo-Timm stained sections were manually aligned, digitized, and by a modified median filtration noise reduced and reconstructed into a three-dimensional object. From the presented simulated grey tone cuts of this object, the reader may assemble a rabbit hippocampal model, that spatially illustrates its anatomy.

The relationship between perphenazine plasma levels and clinical response in acute schizophrenia.

1. Twelve patients with schizophrenia according to RDC participated in a double-blind study, comparing two dose levels of perphenazine, 16 or 32 mg, during four weeks. 2. The patients were assessed with a subscale to CPRS and global scores, measuring improvement of regular intervals during four weeks. 3. Blood samples for assay of plasma perphenazine were collected once a week. 4. These results are in many respects in accordance with earlier published data with perphenazine, that is a good clinical response is achieved with a plasma concentration of perphenazine between 1-5 nmol/L. 5. No incidence of severe adverse symptoms were observed.

Effect of hylan on cartilage and chondrocyte cultures.

The protective role of hylan, a hyaluronan [hyaluronic acid (HA)] derivative, was studied in explanted bovine cartilage and isolated chondrocytes. Cartilage and chondrocytes were exposed to degradative enzymes (lysate from activated polymorphonuclear leukocytes), oxygen-derived free radicals (ODFR), conditioned media from mononuclear cells (MCCM), and interleukin-1 (IL-1), in the presence and absence of hylan. The effect of HA was also studied. In cartilage explants susceptibility to pertubation was evaluated in terms of 35S release and proteoglycan depletion and was compared to control cultures; high viscosity hylan was found to reduce 35S release in cartilage explants caused by degradative enzymes, ODFR, MCCM, and IL-1. The hylan effect was reversible and viscosity-dependent. In chondrocyte cultures, high viscosity hylan was effective in reducing cell injury caused by degradative enzymes and ODFR. The data suggest that the glycosaminoglycan hylan, as well as native HA, may mediate exposure to and/or response to stimuli associated with initiation of degenerative processes in cartilage tissues.

An easy procedure for in vivo estimation of protein binding and correction of elevated serum values induced by venous stasis.

Venous stasis augments the apparent concentrations of serum proteins. A theoretical mathematical model for the correction of serum protein-bound constituents is propounded and an easy procedure for such corrections described. It is suggested that the effect of venous stasis can also be utilized for in vivo estimation of the average protein binding. The hypotheses were tested in 19 epileptic patients. The results obtained by serum determinations of sodium, magnesium, calcium and phenytoin indicate the validity of the theories.

Matrix engineering.

Matrix engineering is a technology that utilizes hyaluronan (HA, hyaluronic acid) based matrices to control, direct or augment tissue regenerative processes. Hyaluronan and the concept of matrix engineering have become established tools in ophthalmic and orthopaedic medicine. The clinical indications for HA are limited by the physical properties and short residence time of the natural HA molecule. To expand and improve upon its current medical applications, a family of HA derivatives was prepared by chemical modification and cross-linking. Relative to the non-modified HA molecule, the hylan family of polymers provides more versatile physical forms, improved mechanical properties and an extended residence time. Hylan can also be used as a surface coating to improve blood compatibility. The chemical, physical and biological properties of hylans will be reviewed, focusing on the specific therapeutic indications they enable.

High serum enalaprilat in chronic renal failure.

BACKGROUND: Most angiotensin-converting enzyme (ACE) inhibitors and their metabolites are excreted renally and doses should hence be reduced in renal insufficiency. We studied whether the dosage of enalapril in daily clinical practice is associated with drug accumulation of enalaprilat in chronic renal failure. METHODS: Fifty nine out-patients with plasma creatinine >150 micromol/L and chronic antihypertensive treatment with enalapril were investigated, in a cross-sectional design. RESULTS: Median glomerular filtration rate (GFR) was 23(range 6-60) ml/minute/1.73 m2. The daily dose of enalapril was 10 (2.5-20) mg and the trough serum concentration of enalaprilat was 31.8 (<2.5-584.7)ng/ml. Ninety percent of the patients had higher serum concentrations of enalaprilat than has been reported in subjects with normal kidney function, and a marked elevation of serum enalaprilat was observed in patients with GFR <30 ml/minute. All but three patients had serum ACE activity below the reference range. The ACE genotype did not influence the results. Additional pharmacokinetic studies were done in nine patients in whom GFR was 23 (10-42)ml/minute/1.73 m2. The median clearance of enalaprilat was 28 (16-68) ml/minute and correlated linearly with GFR (r=0.86, p=0.003). Intra-subject day-to-day variation in trough concentrations was 19.7%. CONCLUSION: Patients with chronic renal failure given small or moderately high doses of enalapril may thus have markedly elevated levels of serum enalaprilat. Whether this affords extra renoprotection, or on the contrary may inappropriately impair renal function, is not known, and should be investigated in prospective, controlled studies.