An evaluation of the potential drug interaction between warfarin and levothyroxine.

BACKGROUND: Drug interaction references report that initiation of levothyroxine potentiates the effects of warfarin, and recommend more frequent International Normalized Ratio (INR) monitoring, but the mechanism is not well understood. OBJECTIVE: To assess the impact of levothyroxine initiation on INR response. PATIENTS/METHODS: A retrospective, self-controlled study was performed on patients aged ≥ 18 years receiving chronic warfarin therapy who were started on levothyroxine between 1 January 2006 and 30 June 2013, and who were followed for 90 days prior to and after levothyroxine initiation. The included patients had at least one elevated thyroid-stimulating hormone laboratory value in the pre-period, continuous warfarin therapy for 100 days prior to levothyroxine initiation, no purchases of medications known to interact with warfarin, no procedures requiring warfarin interruption, and no bleeding or thromboembolic event during the study period. The primary outcome was a comparison of the warfarin dose/INR ratio recorded before the initiation of levothyroxine with the ratio recorded during the post-period after two consecutive INRs with no warfarin dose change. RESULTS: One hundred and two patients were included in the primary outcome. The mean warfarin dose/INR ratios in the pre-period and post-period were equivalent (P = 0.825). Although the mean warfarin dose was numerically lower in the post-period than in the pre-period, this difference did not reach statistical significance (P = 0.068). CONCLUSION: No difference in the mean warfarin dose/INR ratio before and after initiation of levothyroxine was detected. The results suggest that there is not a clinically significant interaction between warfarin and levothyroxine, and so additional monitoring may not be necessary.

Mechanical properties of Indonesian-made narrow dynamic compression plate.

Osteosynthesis plates are clinically used to fixate and position a fractured bone. They should have the ability to withstand cyclic loads produced by muscle contractions and total body weight. The very high demand for osteosynthesis plates in developing countries in general and in Indonesia in particular necessitates the utilisation of local products. In this paper, we investigated the mechanical properties, i.e. proportional limit and fatigue strength of Indonesian-made Narrow Dynamic Compression Plates (Narrow DCP) as one of the most frequently used osteosynthesis plates, in comparison to the European AO standard plate, and its relationship to geometry, micro structural features and surface defects of the plates. All Indonesian-made plates appeared to be weaker than the standard Narrow DCP because they consistently failed at lower stresses. Surface defects did not play a major role in this, although the polishing of the Indonesian Narrow DCP was found to be poor. The standard plate showed indications of cold deformation from the production process in contrast to the Indonesian plates, which might be the first reason for the differences in strength. This is confirmed by hardness measurements. A second reason could be the use of an inferior version of stainless steel. The Indonesian plates showed lower mechanical behaviour compared to the AO-plates. These findings could initiate the development of improved Indonesian manufactured DCP-plates with properties comparable to commonly used plates, such as the standard European AO-plates.

Surface properties of Indonesian-made narrow dynamic compression plates.

The enormous need of orthopaedic (surgical) implants such as osteosynthesis plates is difficult to be fulfilled in developing countries commonly rely on imported ones. One of the alternatives is utilization of local resources, but only after they have been proven safe to use, to overcome this problem. Surface properties are some of the determining factors of safety for those implants. We have succeeded in developing prototype of osteosynthesis plate and the results indicate that Indonesian-made plates need improvement with regards to the surface quality of physical characterization.

Evaluation of measures to decrease intra-operative bacterial contamination in orthopaedic implant surgery.

The aim of this study was to evaluate whether behavioural and systemic measures will decrease intra-operative contamination during total hip or knee replacements. The influence of these measures on subsequent prolonged wound discharge, superficial surgical site infection and deep periprosthetic infection was also investigated during an 18-month follow-up period. Four swabs were taken from instruments at the beginning and end of the procedure for 207 procedures. Removed bone material (acetabulum and femur in case of the hip joint; femur and tibia in case of the knee joint) was also tested for contamination. Initially, 70 operations performed under original control conditions were included, after which the first behavioural measure was introduced (i.e. better use of the plenum). Cultures were taken during 67 operations using better use of the plenum (Group 1), followed by disciplinary measures and the installation of a new laminar flow system. Seventy operations were monitored after this second intervention (Group 2). The control group showed intra-operative contamination in 32.9% (23/70) of cases, Group 1 showed contamination in 34.3% (23/67) of cases and Group 2 showed contamination in 8.6% (6/70) of cases. Prolonged wound discharge and superficial surgical site infection decreased significantly in Group 2, as did the incidence of deep periprosthetic infection; however, the latter did not reach statistical significance. This study shows that the combination of systemic and behavioural changes in an operating room significantly decreases the incidence of intra-operative bacterial contamination, subsequent prolonged wound discharge and superficial surgical site infection. After 18 months of follow-up, there was also a decrease in deep periprosthetic infection.

Review article: similarities and differences among delayed-release proton-pump inhibitor formulations.

Proton-pump inhibitors are acid-labile, and require an enteric coating to protect them from degradation in the stomach when given orally. However, this leads to delayed absorption and onset of action of the proton-pump inhibitor. This article aims to review the similarities and differences between the various formulations of delayed release proton-pump inhibitors. Delayed-release omeprazole and delayed-release lansoprazole have been suspended in sodium bicarbonate for tube administration; however, for omeprazole, absorption is further impaired and antisecretory effects are disappointing. Although such formulations may be more convenient for clinical use in certain patient groups, absorption of the proton-pump inhibitor is still influenced by residual enteric coating. There are few differences among the currently available delayed-release proton-pump inhibitors with respect to their pharmacodynamic effects during chronic administration. There are minor formulation-based pharmacokinetic differences among these agents, primarily reflected in their bioavailability following the first few doses. Differences in bioavailability may explain slight differences in the rate of onset of maximal antisecretory effect. However, minor pharmacodynamic and pharmacokinetic differences are not associated with meaningful differences in clinical outcomes.

Digital correction of magnification in pelvic x rays for preoperative planning of hip joint replacements: theoretical development and clinical results of a new protocol.

The introduction of digital radiological facilities leads to the necessity of digital preoperative planning, which is an essential part of joint replacement surgery. To avoid errors in the preparation and execution of hip surgery, reliable correction of the magnification of the projected hip is a prerequisite. So far, no validated method exists to accomplish this. We present validated geometrical models of the x-ray projection of spheres, relevant for the calibration procedure to correct for the radiographic magnification. With help of these models a new calibration protocol was developed. The validity and precision of this procedure was determined in clinical practice. Magnification factors could be predicted with a maximal margin of error of 1.5%. The new calibration protocol is valid and reliable. The clinical tests revealed that correction of magnification has a 95% margin of error of -3% to +3%. Future research might clarify if a strict calibration protocol, as presented in this study, results in more accurate preoperative planning of hip joint replacements.

Effect of pulsed ultrasound in combination with gentamicin on bacterial viability in biofilms on bone cements in vivo.

AIMS: The aim of this study is to investigate whether pulsed ultrasound (US) in combination with gentamicin yields a decreased viability of bacteria in biofilms on bone cements in vivo. METHODS AND RESULTS: Bacterial survival on bone cement in the presence and absence of ultrasound was compared in a rabbit model. Two bone cement samples with an Escherichia coli ATCC 10798 biofilm were implanted in a total of nine rabbits. In two groups bone cement discs loaded with gentamicin, freshly prepared and aged were used, and in one group unloaded bone cement discs in combination with systemically administered gentamicin. Pulsed ultrasound with a frequency of 28.48 kHz and a maximum acoustic intensity of 500 mW cm(-2) was applied continuously from 24 h till 72 h postsurgery on one of the two implanted discs. After euthanization and removal of the bacteria from the discs, the number of viable bacteria were quantified and skin samples were analysed for histopathological examination. Application of ultrasound, combined with gentamicin, reduced the viability of the biofilms in all three groups varying between 58 and 69% compared with the negative control. Histopathological examinations showed no skin lesions. CONCLUSIONS: Ultrasound resulted in a tendency of improved efficacy of gentamicin, either applied locally or systemically. Usage of ultrasound in this model proved to be safe. SIGNIFICANCE AND IMPACT OF THE STUDY: This study implies that ultrasound could improve the prevention of infection immediately after surgery, especially because the biomaterials, gentamicin and ultrasound used in this model are all in clinical usage, but not yet combined in clinical practice.

Bacterial survival in the interfacial gap in gentamicin-loaded acrylic bone cements.

Clinical experience indicates the beneficial effects of antibiotic-loaded bone cement. Although in vitro studies have shown the formation of a biofilm on its surface they have not considered the gap between the cement and the bone. We have investigated bacterial survival in that gap. Samples with gaps 200 microm wide were made of different bone cements. These were stored dry ('pre-elution') or submersed in phosphate-buffered saline to simulate the initial release of gentamicin ('post-elution'). The gaps were subsequently inoculated with bacteria, which had been isolated from infected orthopaedic prostheses and assessed for their sensitivity to gentamicin. Bacterial survival was measured 24 hours after inoculation. All the strains survived in plain cements. In the pre-elution gentamicin-loaded cements only the most gentamicin-resistant strain, CN5115, survived, but in post-elution samples more strains did so, depending on the cement tested. Although high concentrations of gentamicin were demonstrated in the gaps only the gentamicin-sensitive strains were killed. This could explain the increased prevalence of gentamicin-resistant infections which are seen clinically.

Adjusted transfusion triggers improve transfusion practice in orthopaedic surgery.

Although blood transfusion has never been safer, there remains concern about adverse effects. We designed guidelines, the 6-8-10-Flexinorm, based on the conditions which are relevant to the decision to transfuse. To evaluate these new guidelines, we performed a case-control study in patients undergoing elective primary total hip replacement. The study consisted of two parts. In the first part, physicians were strongly encouraged to use the new guidelines; in the second part, only registration took place. During the first and second part of the study, the use of packed red cells (PRC) in Hospital A (study hospital) decreased from 1.1 +/- 1.5 to 0.6 +/- 1.2 and 0.3 +/- 0.9 units, whereas in Hospital B (control), the use of PRC remained unchanged (1 +/- 1.5, 1 +/- 1.7 and 1 +/- 2 units). In the prestudy groups, 43% of the patients in Hospital A were transfused compared to 45% in Hospital B. In the first and second part of the study, 27%, respectively, 14% of the patients in Hospital A were transfused compared to 40% in both periods in Hospital B. The new guidelines lead to a reduction in the use of allogeneic blood and a decrease in the number of patients transfused.

Penetration of isoniazid, rifampicin and pyrazinamide in tuberculous pleural effusion and psoas abscess.

SETTING: Tuberculosis Centre, University Medical Centre, Groningen, The Netherlands. OBJECTIVES: To study intralesional concentrations of isoniazid (INH), rifampicin (RMP) and pyrazinamide (PZA) in tuberculous pleural effusions and psoas abscesses, and to compare these to reference serum values and minimal inhibitory concentration (MIC). DESIGN: Intralesional concentrations were measured 2 h after drug administration (six pleural effusions, 10 psoas abscesses). RESULTS: A wide range of concentrations was found for pleural effusions and psoas abscesses. Concentrations were below MIC values in none of 15 patients for INH, in two of 13 for RMP, and in eight of nine for PZA. The Cmax:MIC ratio was always >4 for INH, in four of 13 for RMP, and in none of nine for PZA. In 5/8 patients receiving all three drugs, both RMP and PZA had Cmax:MIC ratios <4, indicating sub-therapeutic drug levels. CONCLUSION: Penetration of INH was always sufficient, penetration of RMP mostly below the desired ratio, and for PZA on average 10 times too low. Five of eight patients on all three drugs had Cmax:MIC ratios <4. This indicates intralesional sub-therapeutic drug levels for RMP and PZA, and local monotherapy with INH. This could induce drug resistance. Drainage as additional therapy seems indicated.

[Medial unicompartmental knee prosthesis for patients with unicompartmental gonarthrosis]. / Mediale unicompartimentele knieprothese voor patiënten met unicompartimentele gonartrose.

The function and survival time of unicompartmental knee prostheses for patients with severe gonarthrosis have been improved the past few years by developments in their design, the instrumentarium and the surgical technique. A medial unicompartmental knee prosthesis may be indicated in patients with arthrosis of the medial tibiofemoral compartment. The prerequisites are an intact anterior cruciate ligament, an intact lateral compartment, a correctable varus axis and sufficient flexion in the knee. Contraindications are inflammatory arthropathies and a recent episode of septic arthritis. Relative contraindications are: old age, excess body weight, patellofemoral arthrosis and chondrocalcinosis. A unicompartmental knee prosthesis can be placed via a small parapatellar incision. The postoperative recovery is more rapid than following the classical open approach, while the knee function after 5 years is comparable. The knee function also seems better following a medial unicompartmental knee prosthesis than after valgusising tibial head osteotomy. The latter is still preferred for young active patients. Medial unicompartmental knee prostheses fail in 6-8% of patients. Revision to a total knee prosthesis is then the treatment of choice. In the long term, unicompartmental prostheses with a mobile bearing become loose less often than comparable prostheses with a fixed bearing.

[Three patients with hereditary multiple exostoses and malignant degeneration of an osteochondroma located in the pelvis]. / Drie patiënten met hereditaire multipele exostosen en maligne ontaarding van een bekkenosteochondroom.

In three male patients with hereditary multiple exostoses (HME), aged 50, 29 and 31 years, peripheral low-grade chondrosarcoma in the pelvic region led to swelling or pain. In the first patient, curative resection was not feasible because of the size and extension of the tumour. However, rapid tumour growth and unbearable pain necessitated a debulking procedure 16 months later. Histopathologic examination revealed a highly malignant dedifferentiated chondrosarcoma. The patient died two years after initial presentation as a result of local tumour growth. In the second patient, treatment consisted of wide resection of the tumour. Five years after the surgery the patient was free of disease. The third patient was initially treated by intralesional resection, followed by partial hemipelvectomy because of residual tumour. Thirteen months later, a local recurrence occurred that was treated by wide excision. Four years after the partial hemipelvectomy the patient was both pain-free and disease-free. Patients with HME are at increased risk for malignant degeneration of pelvic osteochondroma to chondrosarcoma. Periodic control of patients with pelvic osteochondromas is advised, preferably once every two years.

Increase of bone and joint tuberculosis in The Netherlands.

There has been an increase in the incidence of bone and joint tuberculosis (BJTB) in The Netherlands and we have carried out an epidemiological study in order to find an explanation for this increase. Data from 1993 to 2000 from The Netherlands Tuberculosis Register (NTR) were used. In 1993 there was a total of 52 patients with BJTB. This figure increased gradually to 80 in 1999 before decreasing to 61 in 2000. There was a total of 12447 patients with tuberculosis; BJTB was found in 532, accounting for 4.3% of all cases and 10.6% of all extrapulmonary cases. Localisation in the spine occurred in 56%. Certain immigrants, in particular from Somalia, were more likely to have BJTB than other immigrants or the native Dutch population. Increased age and female gender were associated with BJTB. Only 15% of BJTB patients also suffered from pulmonary tuberculosis. The usual long delay in the diagnosis of BJTB may be shortened if physicians are more aware of tuberculosis.

Backgrounds of antibiotic-loaded bone cement and prosthesis-related infection.

Antibiotic-loaded bone cement has been in use for over 30 years for the fixation of total joint arthroplasties, although its mechanism of action is still poorly understood. This review presents the backgrounds of bone cements, prosthesis-related infection and antibiotic-loaded bone cements. It is shown that antibiotic-loaded bone cement has a significant effect on bacteria, particularly in animal and clinical studies. However, recently, antimicrobial resistance among bacteria has been ascribed to the antibiotic-loaded bone cement. The unresolved issues both regarding the action of antibiotic-loaded bone cement and the nature of the antimicrobial resistance necessitate further research into the interaction of antibiotic-loaded bone cement and bacteria.

Long-term results of patellofemoral arthroplasty. A report of 56 arthroplasties with 17 years of follow-up.

We studied retrospectively the outcome of patellofemoral arthroplasty (PFA) using the Richards prosthesis in 51 patients (56 knees). Their mean age was 50 years (30 to 77). In 43 patients (45 knees), the American Knee Society score and the patients' subjective judgement were assessed. Excellent or good results were obtained in 86% of cases at a mean follow-up of 17 years (15 to 21). Because of ongoing tibiofemoral osteoarthritis, two patients required a high tibial osteotomy and ten PFAs were converted to a total knee arthroplasty after a mean of 15.6 years (10 to 21). The PFAs were stable during follow-up with a loosening rate of only 2%. We conclude that a patellofemoral prosthesis is a good treatment option with successful long-term results in middle-aged patients with radiologically documented, isolated, patellofemoral osteoarthritis.

Familial multiple epiphyseal dysplasia due to a matrilin-3 mutation: further delineation of the phenotype including 40 years follow-up.

In this study, we followed-up the family with bilateral hereditary micro-epiphyseal dysplasia (BHMED) originally described by Elsbach [1959: J Bone Joint Surg [Br] 41-B:514-523]. Clinical re-examination of all available family members resulted in further delineation of the clinical and radiological phenotype, which is distinct from common multiple epiphyseal dysplasia (MED). Linkage analysis excluded EDM1, EDM2, and EDM3 as candidate genes. Linkage and mutation analysis of matrilin-3 (MATN-3) revealed a new pathogenic mutation confirming that BHMED is indeed a distinct disease entity among MED and MED-like disorders.

The use of biodegradables in the treatment of osteochondritis dissecans of the knee: fiction or future?

The use of biodegradable fixation devices in the operative treatment of osteochondritis dissecans of the knee could avoid a second operation for removal of the hardware, but what are the disadvantages? Seven osteochondritis dissecans lesions, non-displaced in four adult knees and in one adolescent knee and displaced in two knees of adolescents, were treated by drilling and stabilisation with biodegradable pins, resulting in primary consolidation in the five non-displaced lesions and failure in the two detached lesions. However, two detached fragments in adults, primarily fixed with one metallic compression screw and three biodegradable pins both consolidated. In another adult patient, the fixation with two compression screws failed. A study of the available literature and the results of our limited experience seem to indicate that the primary operative treatment of choice of a non-detached osteochondritis dissecans lesion is drilling and fixation with biodegradable pins. However, if this regimen fails or in patients with a detached lesion, one metallic screw and a few additional biodegradable pins appear to constitute the best method of fixation. The use of biodegradable screws is still hazardous, because of the long degradation time and subsequent risk of erosion of the opposite cartilage and tissue reaction. Other resurfacing options are available for failures or fragmented or non-vital lesions.

[Radiologische Besonderheiten einer bilateral vererblichen Mikro-Epiphysendysplasie - deutliche Entität einer Skelettdysplasie]. / Radiological features of bilateral hereditary micro-epiphyseal dysplasia--a distinct entity in the skeletal dysplasias.

AIM: To prove that bilateral hereditary micro-epiphyseal dysplasia (BHMED), first described by Elsbach in 1959, is a distinct disorder radiologically as well as clinically, compared with multiple epiphyseal dysplasia (MED). MATERIAL AND METHODS: We used the data of the revised pedigree with 84 family members, performed a medical history, physical examination and made a radiological evaluation for defining a clinical and radiological phenotype of BHMED family members. We used blood samples for genetic analysis. RESULTS: Although there is a clear clinical picture of the dysplasia, the radiological signs are more reliable for making the diagnosis. Especially the typical deformity of the hip and knee joint are diagnostic for BHMED. By linkage analysis we excluded linkage with the three known MED-loci (EDM1, EDM2 and EDM3). CONCLUSION: BHMED is indeed an entity that is distinct from common multiple epiphyseal dysplasia (MED), clinically, as well as radiologically and genetically.