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.

Switching patients from olanzapine or risperidone to a combination treatment using perphenazine plus buspirone: evaluation of antipsychotic efficacy and side-effects, including extrapyramidal effects and weight loss.

In this pilot study, we have investigated the effects of switching from olanzapine or risperidone treatment to low-dose perphenazine combined with buspirone in six schizophrenic patients who had experienced weight gain. We found no relapse as to psychotic symptoms measured by the CGI-S scale and no exacerbation of extrapyramidal side-effects as measured by the Simpson-Angus Scale. In addition, we observed a medium weight reduction of 10.5 kg (range 1-20 kg).

Pharmacological monitoring of azathioprine therapy.

BACKGROUND: Studies on azathioprine (Aza) treatment in Crohn disease have indicated a positive correlation between clinical remission and a concentration in erythrocytes of the metabolites 6-thioguanine nucleotides (E-6-TGN) above 230 pmol/8 x 10(8) RBC. A concentration of the methylated Aza metabolites (E-6-MMP) above 5000 pmol/8 x 10(8) RBC has been correlated to hepatotoxicity. Thiopurine methyltransferase (TPMT) is responsible for the formation of methylated metabolites and lower E-TGN levels, and TPMT genotyping has been proposed as guidance for dosage. In a cross-sectional study we investigated relationships between the clinical outcome and Aza dose, the TPMT genotype and the Aza metabolite levels among patients with Crohn disease. METHODS: TPMT genotype (PCR assay), azathioprine metabolite levels (HPLC analysis) and xanthine oxidase (XO) activity were determined once in 71 randomly selected Crohn patients on an unaltered Aza dose for at least 3 months. RESULTS: None of the doses of Aza, TPMT genotype, E-6-TGN-, E-6-MMP levels or XO activity were significantly related to disease activity (H-B score), (P = 0.18, P = 0.69, P = 0.90, P = 0.54, P = 0.29, respectively). Leucopenia and/or hepatotoxicity were not demonstrated in any patient. Four patients had a heterozygous TPMT genotype (6.1%; 95% CI: 1.68%-14.80%). The 4 TPMT heterozygous patients had higher E-6-TGN levels than did the 67 remaining patients (P = 0.008). CONCLUSIONS: To explore the applicability of TPMT genotyping, E-6-TGN and E-6-MMP levels for therapeutic drug monitoring, large prospective studies with patient entry at the start of Aza therapy are needed. Until the results of such studies are available, the dose adjustments of Aza should be guided primarily by clinical response and blood counts; metabolite level measurements can only be applied to identify therapeutic non-compliance.

Postoperative analgesia is not different after local vs systemic administration of meloxicam in patients undergoing inguinal hernia repair.

PURPOSE: To distinguish between local and systemic drug effects, we compared pain scores, analgesic consumption and plasma concentrations after local vs i.v. administration of meloxicam 7.5 mg in patients with inguinal hernia repair. METHODS: In a double-blind, randomized study 56 patients received either local or i.v. meloxicam 7.5 mg. Postoperative pain was assessed with a visual analogue scale (VAS) at rest, on mobilization, and on coughing, the need for supplementary analgesics (fentanyl i.v. and/or acetaminophen-codeine tablets) was recorded, and blood samples were drawn during 24 hr after meloxicam administration. RESULTS: No significant differences were found between groups with respect to pain scores, or in the consumption of supplementary analgesics. Following local application of meloxicam, the peak plasma concentration (C(max)) of 0.5 +/- 0.2 mg*L(-1) achieved after 1.8 +/- 0.5 hr was much lower than the C(max) of 2.5 +/- 0.9 mg*L(-1) achieved immediately after i.v. administration (P <0.05). Mean meloxicam plasma concentration after infiltration was significantly lower than after i.v. doses for the first three hours after administration (P <0.05). CONCLUSION: We showed no differences in pain scores and analgesic consumption between local and i.v. administration of meloxicam 7.5 mg during the first 24 hr after herniorrhaphy, while plasma concentration of meloxicam was lower after local administration. These results indicate a lack of difference in pain relief after concentrating meloxicam at the hernia wound or after achieving high blood levels rapidly (i.v.). Local administration of meloxicam may confer an advantage over systemic administration by eliciting lower incidences of systemic adverse effects.

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.

[Severe neonatal hyperparathyroidism in a family with familial hypocalciuric hypercalcemia]. / Neonatal svaer hyperparatyreoidisme i en familie med familiaer hypokalciurisk hyperkalcaemi.

Familial hypocalciuric hypocalcaemia (FHH) is a rare disorder, inherited in an autosomal dominant manner. It has earlier been believed that neonatal severe hyperparathyroidism (NSHPT) is the homozygous form of FHH, but in this case story we show that it is not always like that. We describe a girl who presents with a calcium metabolic disorder from birth. Genetic examination of the girl and her family shows a single abnormal allele in the calcium ion sensitive receptor. We discuss why some heterozygotic inactivating calcium receptor mutations cause NSHPT, while the majority of other mutations only cause mild, asymptomatic hypercalcaemia as in FHH.

Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism associated with mutations in the human Ca2+-sensing receptor gene in three Danish families.

We screened three unrelated Danish families with familial hypocalciuric hypercalcemia (FHH) for mutations in the Ca2+-sensing receptor (CASR) gene by polymerase chain reaction amplification and DNA sequencing of exons 2-7, which include the entire coding region of the gene. In one family the affected individuals have a T-->C mutation that changes the normal arginine at codon 220 to a tryptophan. In the other two FHH families, affected individuals have the same A-->G mutation, leading to conversion of the normal glycine at codon 552 to an arginine. These results confirm that FHH can be caused by non-conservative missense mutations in the CASR gene leading to abnormal calcium homeostasis. Both mutations are located in the amino-terminal extracellular domain of the receptor, which contains the binding site for extracellular Ca2+, the CASR's principal physiological agonist.

An analysis of seven different methods to diagnose Helicobacter pylori infections.

BACKGROUND: It has been debated which diagnostic test should be preferred for the diagnosis of Helicobacter pylori in patients with gastroduodenal diseases. METHODS: The H. pylori infection was diagnosed prospectively in 97 untreated patients. H. pylori was diagnosed by means of tests based on five different principles: 1) culture, 2) microscopy (HLO), 3) urease activity (urea breath test (UBT) and urease test on biopsy specimens (CLO test)), 4) DNA detection (polymerase chain reaction (PCR)), and 5) IgG antibody detection (enzyme-linked immunosorbent assay (EIA) and Western blotting (WB)). RESULTS: This study showed that two positive tests out of five tests, based on different principles, were most reliable for predicting the H. pylori infection. Most tests had specificities and predictive values for a negative result greater than 90%. The most important difference between the tests was the sensitivity and the predictive value for a positive result (PPV). WB, HLO, UBT, and PCR had sensitivities and PPV greater than 75%. CONCLUSIONS: The non-invasive tests UBT and WB are reliable, both alone and in combination, and they are recommended for the pre-endoscopic diagnosis of H. pylori. WB is recommended as a confirmative test for antibody detection by EIA. When patients have an upper endoscopy, we recommend taking biopsy specimens for culture and histology because of the additional information obtained about susceptibility, virulence determinants, and morphology, including the degree of inflammation.

Fluctuation of serum zuclopenthixol concentrations in patients treated with zuclopenthixol decanoate in viscoleo.

Zuclopenthixol serum concentrations were measured in 58 psychiatric patients referred for routine therapeutic drug monitoring (TDM). Patients were treated for prolonged time with zuclopenthixol decanoate in viscoleo in doses of 50-500 mg, administered intramuscularly at 14-day intervals. The serum concentration was determined at days 7 (C7) and 14 (C14) following injection. The mean ratio C7/C14 was 2.0 and was independent of the dosage given. In 14 patients, additional blood samples were drawn at day 3 (C3) following injection. The mean ratio C3/C14 of this group was 3.2. An almost log-linear decline of the serum concentration from day 3 to 14 appeared, which corresponds to an apparent half-life of zuclopenthixol in this dosage form of 7.4 days. The marked fluctuations of serum concentrations of zuclopenthixol from peak to trough levels in patients given fortnightly injections of the depot preparation indicate that shorter intervals between injections should be considered in many cases in order to diminish side effects.

Hylan gel biomaterial: dermal and immunologic compatibility.

Hylan, a hyaluronan derivative, was chemically cross-linked with divinyl sulfone to produce a water-insoluble gel. This gel was fragmented into a gel slurry and evaluated for particle size, biocompatibility, and residence times in selected tissues. Hylan gels used in this study are made up of pseudoplastic, deformable gel particles with greater elasticity (at all frequencies) and greater viscosity (shear rates, 0.01 sec-1) than the water soluble hylan polymer. Hylan gel was injected intradermally and subdermally in mice and was found to produce a minimal reaction at 24 h; thereafter (up to 7 weeks) there was no significant tissue reaction. Intradermal injection of [3H]-hylan gel in guinea pigs revealed a minimal tissue reaction after 1 week, and measurement of radioactivity in the tissue at 1, 2, and 4 weeks revealed only a slight decrease in the total amount of injected radioactivity. The immunogenic activity of hylan gel was evaluated in rabbits; unmodified hylan gel, degraded hylan gel, and hylan gel ovalbumin conjugate were used to immunize rabbits. No antibody production to any hylan gel sample was detected, although control rabbits immunized with ovalbumin developed titers > 400 of antiovalbumin antibodies by day 21, as measured by the passive cutaneous anaphylaxis assay (PCA). Last, serum from owl monkeys (Aotus trivirgatus) in which hylan gel had been placed intravitreally for up to 3 years contained no detectable anti-hylan gel antibodies (PCA assay). Skin tests on these monkeys were also negative.

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.

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.

Scintigraphic determination of gastrointestinal transit times. A comparison with breath hydrogen and radiologic methods.

A scintigraphic method for determination of gastrointestinal transit times was compared with the breath hydrogen test and a multiple-bolus, single-radiograph technique. A close temporal association was found between the caecal appearance of radioactivity and the onset of breath hydrogen excretion in eight healthy subjects. Neither mean small-intestinal nor mean orocaecal transit times of the radiolabelled marker were correlated with the magnitude of hydrogen peak, hydrogen peak time, or the area under hydrogen curve. No correlation was noted between whole-gut transit time of the radiolabelled marker and mean whole-gut transit time calculated from a 6-day administration of the radiopaque marker in 16 healthy subjects. The stool weight was inversely correlated with the mean colonic (r = -0.46, p = 0.009) and the mean whole-gut (r = -0.45, p = 0.011) transit times of the radiolabelled marker. In conclusion, inadequate delineation of the caecal region seems to be an unimportant drawback of the scintigraphic measurements, whereas day-to-day variation in gastrointestinal transit rates may influence the reliability of the assessments. Probably, quantitative transit data cannot be obtained from the breath hydrogen concentration profiles.

[Therapy control of perphenazine. 2. Clinical aspects]. / Terapistyring af perfenazinbehandling ved paranoide tilstande. 2. Kliniske aspekter.

Rational use of serum concentration monitoring of the neuroleptic, perphenazine, was evaluated in a prospective investigation. A total of 141 hospitalized patients with paranoid symptoms (excluding mania) requiring treatment were included during the investigation period (one year). Perphenazine was administered (fixed doses) orally (92 patients) and parenterally (depot, decanoate, 45 patients) in a six-week treatment period. Serum concentrations of perphenazine were monitored after 10-14 days oral treatment, on the 14th and 21st days after the commencement of depot treatment. The patients were steered on to the recommended therapeutic range for perphenazine (1.5-6 nmol), according to the serum level measured. Global clinical assessment was carried out by the departmental physicians. Therapy control of perphenazine by serum monitoring was an important supplement to the clinical evaluation of therapeutic effect. Fifteen (65%) out of 23 patients who were treated orally with insufficient therapeutic effect, showed non-compliance or elevated metabolism. On the basis of a single serum concentration measurements (12 hours values), it proved possible to steer the majority of patients onto the recommended therapeutic level. In this way, the individual patient reached optimal therapeutic effect with a minimum of side-effects.

Hylan gel composition for percutaneous embolization.

Viscoelastic, pseudoplastic, radiopaque injectable hylan gel for percutaneous embolization was developed and evaluated by in vitro and in vivo tests. The embolization gel is composed of cross-linked hylan (hyaluronan, hyaluronate), tantalum, microcrystalline cellulose, hexamethonium chloride, and thrombin. Upon delivery through small-lumen catheters to the appropriate vascular site, the gel induces formation of a solid blood/gel coagulum. Results from animal studies (rat aorta, rabbit auricular artery) demonstrate that formation of complete and long-lasting arterial blockage is readily achievable without complications due to blood flow, partial vessel obstruction, uncontrolled polymerization, or movement of the gel or its components (specifically thrombin and hexamethonium chloride) into the circulation. Microscopic evaluation indicates that arterial occlusion initially occurs as a result of the injected gel and formed fibrin; at 7 weeks and beyond, arteries are occluded by injected gel, inflammatory cells and fibrosis (scar tissue).

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.

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.