Endothelium-specific replacement of the connexin43 coding region by a lacZ reporter gene

The murine gap junction protein connexin43 (Cx43) is expressed in blood vessels, with vastly different contribution by endothelial and smooth muscle cells. We have used the Cre recombinase under control of TIE2 transcriptional elements to inactivate a floxed Cx43 gene specifically in endothelial cells. Cre-mediated deletion led to replacement of the Cx43 coding region by a lacZ reporter gene. This allowed us to monitor the extent of deletion and to visualize the endothelial expression pattern of Cx43. We found widespread endothelial expression of the Cx43 gene during embryonic development, which became restricted largely to capillaries and small vessels in all adult organs examined. Mice lacking Cx43 in endothelium did not exhibit altered blood pressure, in contrast to mice deficient in Cx40. Our results show that lacZ activation after deletion of the target gene allows us to determine the extent of cell type-specific deletion after phenotypical investigation of the same animal.

Meta-analysis: chondroitin for osteoarthritis of the knee or hip

BACKGROUND: Previous meta-analyses described moderate to large benefits of chondroitin in patients with osteoarthritis. However, recent large-scale trials did not find evidence of an effect. PURPOSE: To determine the effects of chondroitin on pain in patients with osteoarthritis. DATA SOURCES: The authors searched the Cochrane Central Register of Controlled Trials (1970 to 2006), MEDLINE (1966 to 2006), EMBASE (1980 to 2006), CINAHL (1970 to 2006), and conference proceedings; checked reference lists; and contacted authors. The last update of searches was performed on 30 November 2006. STUDY SELECTION: Studies were included if they were randomized or quasi-randomized, controlled trials that compared chondroitin with placebo or with no treatment in patients with osteoarthritis of the knee or hip. There were no language restrictions. DATA EXTRACTION: The authors extracted data in duplicate. Effect sizes were calculated from the differences in means of pain-related outcomes between treatment and control groups at the end of the trial, divided by the pooled SD. Trials were combined by using random-effects meta-analysis. DATA SYNTHESIS: 20 trials (3846 patients) contributed to the meta-analysis, which revealed a high degree of heterogeneity among the trials (I2 = 92%). Small trials, trials with unclear concealment of allocation, and trials that were not analyzed according to the intention-to-treat principle showed larger effects in favor of chondroitin than did the remaining trials. When the authors restricted the analysis to the 3 trials with large sample sizes and an intention-to-treat analysis, 40% of patients were included. This resulted in an effect size of -0.03 (95% CI, -0.13 to 0.07; I2 = 0%) and corresponded to a difference of 0.6 mm on a 10-cm visual analogue scale. A meta-analysis of 12 trials showed a pooled relative risk of 0.99 (CI, 0.76 to 1.31) for any adverse event. LIMITATIONS: For 9 trials, the authors had to use approximations to calculate effect sizes. Trial quality was generally low, heterogeneity among the trials made initial interpretation of results difficult, and exploring sources of heterogeneity in meta-regression and stratified analyses may be unreliable. CONCLUSIONS: Large-scale, methodologically sound trials indicate that the symptomatic benefit of chondroitin is minimal or nonexistent. Use of chondroitin in routine clinical practice should therefore be discouraged.

Replacement of histidine in position 105 in the alpha(5) subunit by cysteine stimulates zolpidem sensitivity of alpha(5)beta(2)gamma(2) GABA(A) receptors

Zolpidem is a positive allosteric modulator of GABA(A) receptors with sensitivity to subunit composition. While it acts with high affinity and efficacy at GABA(A) receptors containing the alpha(1) subunit, it has a lower affinity to GABA(A) receptors containing alpha(2), alpha(3), or alpha(5) subunits and has a very weak efficacy at receptors containing the alpha(5) subunit. Here, we show that replacing histidine in position 105 in the alpha(5) subunit by cysteine strongly stimulates the effect of zolpidem in receptors containing the alpha(5) subunit. The side chain volume of the amino acid residue in this position does not correlate with the modulation by zolpidem. Interestingly, serine is not able to promote the potentiation by zolpidem. The homologous residues to alpha(5)H105 in alpha(1), alpha(2), and alpha(3) are well-known determinants of the action of classical benzodiazepines. Other studies have shown that replacement of these histidines alpha(1)H101, alpha(2)H101, and alpha(3)H126 by arginine, as naturally present in alpha(4) and alpha(6), leads to benzodiazepine insensitivity of these receptors. Thus, the nature of the amino acid residue in this position is not only crucial for the action of classical benzodiazepines but in alpha(5) containing receptors also for the action of zolpidem.

Accuracy considerations in navigated cup placement for total hip arthroplasty

Computer assisted orthopaedic surgery (CAOS) technology has recently been introduced to overcome problems resulting from acetabular component malpositioning in total hip arthroplasty. Available navigation modules can conceptually be categorized as computer tomography (CT) based, fluoroscopy based, or image-free. The current study presents a comprehensive accuracy analysis on the computer assisted placement accuracy of acetabular cups. It combines analyses using mathematical approaches, in vitro testing environments, and an in vivo clinical trial. A hybrid navigation approach combining image-free with fluoroscopic technology was chosen as the best compromise to CT-based systems. It introduces pointer-based digitization for easily assessable points and bi-planar fluoroscopy for deep-seated landmarks. From the in vitro data maximum deviations were found to be 3.6 degrees for inclination and 3.8 degrees for anteversion relative to a pre-defined test position. The maximum difference between intraoperatively calculated cup inclination and anteversion with the postoperatively measured position was 4 degrees and 5 degrees, respectively. These data coincide with worst cases scenario predictions applying a statistical simulation model. The proper use of navigation technology can reduce variability of cup placement well within the surgical safe zone. Surgeons have to concentrate on a variety of error sources during the procedure, which may explain the reported strong learning curves for CAOS technologies.

Atherogenic lipoprotein phenotype and low-density lipoprotein size and subclasses in patients with growth hormone deficiency before and after short-term replacement therapy

Patients with growth hormone deficiency (GHD) have increased cardiovascular risk and may show elevated triglyceride and reduced high density lipoprotein (HDL) cholesterol concentrations, two lipid abnormalities usually accompanied by increased small dense LDL in the 'atherogenic lipoprotein phenotype' (ALP). In the present study, we directly investigated (1) whether hypopituitary patients with GHD have increased small dense LDL; (2) whether growth hormone replacement therapy (GHRT) beneficially impact on such particles; (3) the prevalence of ALP in GHD and GHRT patients.

Aortic root replacement does not affect outcome and quality of life

BACKGROUND: Different studies have analyzed the potential impact of the underlying pathologic process and the use of deep hypothermic circulatory arrest on outcome and quality of life after surgery on the thoracic aorta. The aim of this study is to analyze the impact of different surgical procedures on outcome and quality of life. METHODS: Between June 2001 and December 2003, 244 patients underwent surgery for various diseases of the ascending aorta with or without involvement of the aortic valve or root. They were divided according to the operative procedure: 76 patients (31.2%) underwent isolated replacement of the ascending aorta, 42 patients (17.2%) received separate aortic valve replacement and supracoronary replacement of the ascending aorta, 86 patients (35.2%) received a mechanical composite graft, and 40 patients (16.4%) received a biologic composite graft. All in-hospital data were assessed, and a follow-up was performed in all survivors after 26.6 +/- 8.8 months, focusing on outcome and quality of life (SF-36). RESULTS: Overall in-hospital mortality was 6.1%, and late mortality was 5.7%, with no significant difference between groups. Independent of the surgical technique and the extent of surgery, there was no difference in quality of life between the surgical collective and an age-matched and sex-matched standard population. CONCLUSIONS: Operations of the ascending aorta and aortic valve are very safe, with low in-hospital mortality and favorable midterm outcome regarding late mortality and morbidity. Quality of life after operations of the ascending aorta and aortic valve is equal to a standard population and is not affected by the surgical procedure. Liberal use of aortic root replacement is therefore justified to radically treat the diseased aortic segment.

Pathomorphologic alterations predict presence or absence of hip osteoarthrosis

Abnormal morphology of the hip has been associated with primary osteoarthrosis. We evaluated the morphology of 464 consecutive hips contralateral to hips treated by THA. We excluded all hips with known diagnoses leading to secondary osteoarthritis and all hips with advanced arthrosis to eliminate the effect of arthritic remodeling on the morphologic measurements. Of the remaining 119 hips, 25 were in patients aged 60 years or older who had no or mild arthrosis (Tönnis Grade 0 or 1) and 94 hips had Tönnis Grade 2 osteoarthrosis. We quantified morphologic parameters on plain radiographs and CT images and simulated range of motion using virtual bone models from the CT data. The nonarthritic hips had fewer pathomorphologic findings. High alpha angles and high lateral center edge angles were strongly associated with the presence of arthritis; decreased internal and external rotation in 90 degrees flexion showed lesser correlation. The data confirm previous observations that abnormal hip morphology predates arthrosis and is not secondary to the osteoarthritic process. Hips at risk for developing arthrosis resulting from pathomorphologic changes may potentially be identified at the cessation of growth, long before the development of osteoarthrosis.

Computed tomography-based surgical navigation for hip arthroplasty

Component malpositioning and postoperative leg length discrepancy are the most common technical problems associated with total hip arthroplasty (THA). Surgical navigation offers the potential to reduce the incidence of these problems. We reviewed 317 patients (344 hips) that underwent THA using computed tomography-based surgical navigation, including 112 THAs using a simplified method of measuring leg length. Guided by the navigation system, cups were placed in 40.8 degrees +/- 2 degrees of operative abduction (range, 35 degrees -50 degrees) and 30.8 degrees +/- 3.2 degrees (range, 19 degrees -43 degrees) of operative anteversion. We subsequently measured radiographic abduction on plain anteroposterior pelvic radiographs and calculated abduction and anteversion. Radiographically, 97.1 % of the cups were in the safe zone for abduction and 92.4% for anteversion. The mean incision length was less than 8 cm for 327 of the 344 hips. Leg length change measured intraoperatively was 6.6 +/- 4.1 mm (range, -2-22), similar to measurements from the pre- and postoperative magnification-corrected radiographs. Computer assistance during THA increased the consistency of component positioning and allowed reliable measurement of leg length change during surgery.

Hip2Norm: an object-oriented cross-platform program for 3D analysis of hip joint morphology using 2D pelvic radiographs

We developed an object-oriented cross-platform program to perform three-dimensional (3D) analysis of hip joint morphology using two-dimensional (2D) anteroposterior (AP) pelvic radiographs. Landmarks extracted from 2D AP pelvic radiographs and optionally an additional lateral pelvic X-ray were combined with a cone beam projection model to reconstruct 3D hip joints. Since individual pelvic orientation can vary considerably, a method for standardizing pelvic orientation was implemented to determine the absolute tilt/rotation. The evaluation of anatomically morphologic differences was achieved by reconstructing the projected acetabular rim and the measured hip parameters as if obtained in a standardized neutral orientation. The program had been successfully used to interactively objectify acetabular version in hips with femoro-acetabular impingement or developmental dysplasia. Hip(2)Norm is written in object-oriented programming language C++ using cross-platform software Qt (TrollTech, Oslo, Norway) for graphical user interface (GUI) and is transportable to any platform.

Minimum ten year results of total hip arthroplasty with the acetabular reinforcement ring in avascular osteonecrosis

Total hip arthroplasty (THA) still carries a higher failure rate in patients with avascular necrosis of the femoral head (AVN) than in a similar patient population with THA for other reasons. This is particularly true for the acetabular component. One of the major factors accounting for this is the compromised acetabular bone quality with structural defects subsequent to collapsing of the femoral head in high-grade AVN. In this study we implanted an acetabular reinforcement ring with hook (ARRH), which had been used successfully for other indications with acetabular bone stock deficiency, in 32 consecutive THA's in 29 patients with AVN. Five patients died during the observation period of causes unrelated to the surgery, one patient was lost to follow-up and one patient could not be followed up due to chronic illness, leaving 25 hips (23 patients) with a minimum follow-up of ten years (mean: 11.8; range: 10-15). The mean Merle d'Aubigne score increased significantly from 7.7 preoperatively to 16.6 postoperatively (p < 0.001). One revision was performed for aseptic stem loosening. Of the unrevised hips, one acetabular component was classified as definitively loose. The cumulative 12-year survivorship for THA with ARRH in AVN was 95.2% (confidence interval: 86.1-100%) for both components, 100% for the cup and 95.2% for the stem (86.1-100%).

Hip arthroscopy after previous surgical hip dislocation for femoroacetabular impingement

PURPOSE: The purpose of this study was to examine whether arthroscopic adhesiolysis can relieve symptoms of patients with persistent pain after open surgical hip dislocation for femoroacetabular impingement syndrome without osseous or cartilaginous alterations. METHODS: This study comprised 16 consecutive patients (6 men and 10 women; mean age, 33.5 years [range, 19 to 60 years]) with persistent pain without osseous or cartilaginous alterations after surgical hip dislocation for the treatment of femoroacetabular impingement. At index surgery, all patients had osteochondroplasty of the head-neck junction and resection of the acetabular rim with reattachment of the labrum in 9 cases. All patients had preoperative magnetic resonance imaging-arthrogram and were treated with arthroscopy of the hip. RESULTS: At arthroscopy, all reattached labra were stable. In the cases without preservation of the labrum at the index operation, the joint capsule was attached at the level of the acetabular rim and synovitis was noticed. All patients had adhesions between the neck of the femur and joint capsule or between the labrum and capsule. In 3 patients the arthroscopic procedure was technically limited by massive thickening of the capsule. Overall, 81% of patients (13/16) showed less pain or were pain-free. The Merle d'Aubigné score improved from 13 points preoperatively to 16 points at the last follow-up. CONCLUSIONS: Persistent pain after surgical dislocation of the hip without evidence of cartilaginous and osseous alterations could result from intra-articular adhesions. Hip arthroscopy after previous surgery can be demanding because of scarring. If the adhesions can be released, good results can be achieved. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Influence of preoperative functional status on outcome after total hip arthroplasty

BACKGROUND: International registries with large, heterogeneous patient populations provide excellent research opportunities for studying factors that influence treatment outcomes after total hip arthroplasty. In the present study, we used a European multinational database to investigate whether there is an association between three functional variables (preoperative pain, mobility, and motion) and functional outcome. METHODS: We performed a retrospective cohort study on preoperative and follow-up clinical data that were prospectively entered into the International Documentation and Evaluation System European hip registry between 1967 and 2002. The inclusion criteria for this study were an age of more than twenty years, an underlying diagnosis of osteoarthritis, and a Charnley class-A functional designation at the time of surgery. A total of 12,925 patients (13,766 total hip arthroplasties) who met these criteria were entered into the analysis. Three functional variables (pain, mobility, and motion) that were assessed preoperatively were evaluated postoperatively at various follow-up examinations for a maximum of ten years. RESULTS: Six thousand four hundred and one patients could walk longer than ten minutes preoperatively; of these, 57.1% had a walking capacity of more than sixty minutes at the time of the most recent follow-up. In comparison, 6896 patients had a preoperative walking capacity of less than ten minutes and only 38.9% of these patients could walk more than sixty minutes at the time of the most recent follow-up. The difference was significant (p < 0.01). Similarly, 10,375 patients had a preoperative hip flexion range of >70 degrees ; of these, 74.7% had a flexion range of >90 degrees at the time of the most recent follow-up. In comparison, 2793 patients had a preoperative hip flexion range of <70 degrees and only 62.6% of these patients had a flexion range of >90 degrees at the time of the most recent follow-up. The difference was also significant (p < 0.01). Lasting, complete, or almost complete pain relief was achieved by >80% of the patients following total hip arthroplasty regardless of their preoperative categorization of pain. CONCLUSIONS: Patients with poor preoperative walking capacity and hip flexion are less likely to achieve an optimal outcome with regard to walking and motion. In contrast, there is no correlation between the preoperative pain level and pain alleviation, which is generally good and long-lasting after total hip arthroplasty.