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Introduction: Examination with CT and image registration is a new technique that we have previously used to assess 3D segmental motions in the lumbar spine in a phantom. Current multi-slice computed tomography (CT) offers highly accurate spatial volume resolution without significant distortion and modern CT scanners makes it possible to reduce the radiation dose to the patients. Our aim was to assess segmental movement in the lumbar spine with the aforementioned method in healthy subjects and also to determine rotation accuracy on phantom vertebrae., Material and Method: The subjects were examined in flexion-extension using low dose CT. Eleven healthy, asymptomatic subjects participated in the current study. The subjects were placed on a custom made jig which could provoke the lumbar spine into flexion or extension. CT examination in flexion and extension was performed. The image analysis was performed using a 3D volume fusion tool, registering one of the vertebrae, and then measuring Euler angles and distances in the registered volumes., Results: The mean 3D facet joint translation at L4-L5 was in the right facet joint 6.1 mm (3.1-8.3), left facet joint 6.9 mm (4.9-9.9), at L5-S1: right facet joint 4.5 mm (1.4-6.9), and for the left facet joint 4.8 mm (2.0-7.7). In subjects the mean angles at the L4-L5 level were: in the sagittal plane 14.3°, coronal plane 0.9° (-0.6 to 2.8), and in the transverse plane 0.6° (-0.4 to 1.5), in the L5-S1 level the rotation was in sagittal plane 10.2° (2.4-16.1), coronal plane 0° (-1.2 to 1.2), and in the transverse plane 0.2° (-0.7 to 0.3). Repeated analysis for 3D facet joint movement was on average 5 mm with a standard error of mean of 0.6 mm and repeatability of 1.8 mm (CI 95%). For segmental rotation in the sagittal plane the mean rotation was 11.5° and standard error of mean 1°. The repeatability for rotation was 2.8° (CI 95%). The accuracy for rotation in the phantom was in the sagittal plane 0.7°, coronal plane 1°, and 0.7 in the transverse plane., Conclusion: This method to assess movement in the lumbar spine is a truly 3D method with a high precision giving both visual and numerical output. We believe that this method for measuring spine movement is useful both in research and in clinical settings.

Background: Cervical total disc replacement (CTDR) is an alternative to anterior fusion. Therefore, it is desirable to have an accurate in vivo measurement of prosthetic kinematics and assessment of implant stability relative to the adjacent vertebrae., Purpose: To devise an in vivo CT-based method to analyze the kinematics of cervical total disc replacements (CTDR), specifically of two prosthetic components between two CT scans obtained under different conditions., Material and Methods: Nine patients with CTDR were scanned in flexion and extension of the cervical spine using a clinical CT scanner with a routine low-dose protocol. The flexion and extension CT volume data were spatially registered, and the prosthetic kinematics of two prosthetic components, an upper and a lower, was calculated and expressed in Euler angles and orthogonal linear translations relative to the upper component. For accuracy analysis, a cervical spine model incorporating the same disc replacement as used in the patients was also scanned and processed in the same manner., Results: Analysis of both the model and patients showed good repeatability, i.e. within 2 standard deviations of the mean using the 95% limits of agreement with no overlapping confidence intervals. The accuracy analysis showed that the median error was close to zero., Conclusion: The mobility of the cervical spine after total disc replacement can be effectively measured in vivo using CT. This method requires an appropriate patient positioning and scan parameters to achieve suitable image quality.

Colorectal cancer (CRC) is one of the most common and deadly forms of cancer. Despite improved treatment modalities, post-operative recurrence and metastasis remain the major problems for extending patient survival after surgery. This highlights the need to search for biomarkers for prognostication and treatment stratification of colorectal cancer patients. In this study, we applied the SYBR-green quantitative PCR-based array approach to screen for differentially expressed miRNAs between patients with short (<50 months, range 10-33 months) and long survival (≥ 50 months, range 50-152 months). The selected candidate prognostic miRNAs were validated in a cohort of 50 CRC patients by TaqMan quantitative PCR. We found that high expression of miR-185 and low expression of miR-133b were correlated with poor survival (p=0.001 and 0.028, respectively) and metastasis (p=0.007 and 0.036, respectively) in colorectal cancer. Our findings suggest the potential prognostic values of these miRNAs for predicting clinical outcome after surgery.

There have been many attempts to evaluate the shape, volume, and contour of breasts both before and after operation. To evaluate and compare results objectively in a reproducible, low-cost way is difficult. The aim of this study was to compare three-dimensional techniques with traditional methods in evaluating the volume and shape of breasts. Twelve patients with breast cancer were evaluated, 6 patients preoperatively and 6 patients postoperatively, using plastic cups, thermoplastic casts, magnetic resonance imaging (MRI), and three-dimensional imaging techniques. Thermoplastic casts and plastic cups measured better accordance with the volume of the operated breast than either the three-dimensional technique or MRI, which resulted in significantly higher values. The three-dimensional technique offered a new possibility to evaluate the shape of breasts objectively.

Background: We evaluated the accuracy and repeatability of a 3D method for polyethylene acetabular cup wear measurements using computed tomography (CT). We propose that the method be used for clinical in vivo assessment of wear in acetabular cups., Material and Methods: Ultra-high molecular weight polyethylene cups with a titanium mesh molded on the outside were subjected to wear using a hip simulator. Before and after wear, they were (1) imaged with a CT scanner using a phantom model device, (2) measured using a coordinate measurement machine (CMM), and (3) weighed. CMM was used as the reference method for measurement of femoral head penetration into the cup and for comparison with CT, and gravimetric measurements were used as a reference for both CT and CMM. Femoral head penetration and wear vector angle were studied. The head diameters were also measured with both CMM and CT. The repeatability of the method proposed was evaluated with two repeated measurements using different positions of the phantom in the CT scanner., Results: The accuracy of the 3D CT method for evaluation of linear wear was 0.51 mm and the repeatability was 0.39 mm. Repeatability for wear vector angle was 17°., Interpretation: This study of metal-meshed hip-simulated acetabular cups shows that CT has the capacity for reliable measurement of linear wear of acetabular cups at a clinically relevant level of accuracy.

The prognostic value of gene abnormalities in colorectal cancer is unclear, varies between investigators, and may be unreliable due to tumor heterogeneity. We analyzed tumors completely divided into biopsies to characterize the overall distribution of LOH at 5q, 17p, 18q, K-ras mutations, and methylation of the p16 and MGMT genes. Seventeen tumors (stage II-III) were completely divided into biopsy cubes from which DNA was sequentially analyzed. The results from fragment analysis for LOH at 5q, 17p, 18q, TGGE of the K-ras, and MSP for p16 and MGMT genes were used to characterize the occurrence of these aberrations. LOH at 18q, 17p, and LOH 5q were present in 17/17, 15/17, and 15/16 tumors, respectively. p16 and MGMT were methylated in 16/17 and 14/17, respectively. The frequency of these aberrations varied largely between tumors. K-ras-mutations, present in 8/17 tumors, were much more consistently distributed in mutated tumor. Methylation of p16 and MGMT and LOH at 18q, 17p, and 5q are present within the tumor mass in a large majority of CRC tumors and are of no or little prognostic value. K-ras mutations appear more homogeneously distributed. This has clinical relevance for biopsing to predict anti-EGFR response.

Kinematic analysis for in vivo assessment of elbow endoprostheses requires knowledge of the exact positions of motion axes relative to bony landmarks or the prosthesis. A prosthesis-based reference system is required for comparison between individuals and studies. The primary aim of this study was to further develop an earlier described algorithm for fusion of radiostereometric analysis (RSA) data and data obtained in 3D computed tomography (CT) for application to the elbow after total joint replacement. The secondary aim was to propose a method for marking of prostheses in 3D CT, enabling definition of a prosthesis-based reference system. Six patients with elbow endoprostheses were investigated. The fusion of data made it possible to visualize the motion axes in relation to the prostheses in the 3D CT volume. The differences between two repeated positioning repetitions of the longitudinal prosthesis axis were less than 0.6 degrees in the frontal and sagittal planes. Corresponding values for the transverse axis were less than 0.6 degrees in the frontal and less than 1.4 degrees (in four out of six less than 0.6 degrees ) in the horizontal plane. This study shows that by fusion of CT and RSA data it is possible to determine the accurate position of the flexion axes of the elbow joint after total joint replacement in vivo. The proposed method for implant marking and registration of reference axes enables comparison of prosthesis function between patients and studies., (2010 Elsevier Ltd. All rights reserved.)

Objective: In this study we explore the possibility of accurately and cost-effectively monitoring tibial deformation induced by Taylor Spatial Frames (TSFs), using time-separated computed tomography (CT) scans and a volume fusion technique to determine tibial rotation and translation., Materials and Methods: Serial CT examinations (designated CT-A and CT-B, separated by a time interval of several months) of two patients were investigated using a previously described and validated volume fusion technique, in which user-defined landmarks drive the 3D registration of the two CT volumes. Both patients had undergone dual osteotomies to correct for tibial length and rotational deformity. For each registration, 10 or more landmarks were selected, and the quality of the fused volume was assessed both quantitatively and via 2D and 3D visualization tools. First, the proximal frame segment and tibia in CT-A and CT-B were brought into alignment (registered) by selecting landmarks on the frame and/or tibia. In the resulting "fused" volume, the proximal frame segment and tibia from CT-A and CT-B were aligned, while the distal frame segment and tibia from CT-A and CT-B were likely not aligned as a result of tibial deformation or frame adjustment having occurred between the CT scans. Using the proximal fused volume, the distal frame segment and tibia were then registered by selecting landmarks on the frame and/or tibia. The difference between the centroids of the final distal landmarks was used to evaluate the lengthening of the tibia, and the Euler angles from the registration were used to evaluate the rotation., Results: Both the frame and bone could be effectively registered (based on visual interpretation). Movement between the proximal frame and proximal bone could be visualized in both cases. The spatial effect on the tibia could be both visually assessed and measured: 34 mm, 10 degrees in one case; 5 mm, 1 degrees in the other., Conclusion: This retrospective analysis of spatial correction of the tibia using Taylor Spatial Frames shows that CT offers an interesting potential means of quantitatively monitoring the patient's treatment. Compared with traditional techniques, modern CT scans in conjunction with image processing provide a high-resolution, spatially correct, and three-dimensional measurement system which can be used to quickly and easily assess the patient's treatment at low cost to the patient and hospital.

Background and Purpose: Considerable migration of the acetabular cup is required for diagnosis of loosening by conventional radiography. We have developed a new clinically applicable method for assessment of cup loosening using computed tomography (CT)., Patients and Methods: 10 patients scheduled for revision hip replacement due to suspected wear or loosening were scanned twice with CT under torsion loading of the prosthesis. Two independent examiners assessed each patient with respect to motion of the acetabular cup relative to the pelvis using CT volume registration. The CT measurements were compared to findings at revision surgery., Results: The method was applicable in 8 of the 10 patients. 1 patient had a severe tremor. In 1 patient, surgery revealed that the hip was ankylotic due to massive ectopic bone formation. This left 8 patients that could be evaluated. 4 cups were loose at surgery, and 3 of these cups could be seen to be mobile by CT. 4 cups that were stable on revision were accurately diagnosed as not being mobile by CT. Movements of less than 1 millimeter between bone and prosthesis could not be distinguished from errors in CT acquisition and volume registration. There was good agreement between the two observers., Interpretation: Movement of loose acetabular cups during torsion loading could be detected using CT volume registration. It was sensitive to cup movement in 3 out of 4 cases of loose cups. The method was specific and yielded no false positive results.

Background and Purpose: Polyethylene wear is an important cause of aseptic loosening in hip arthroplasty. Detection of significant wear usually happens late on, since available diagnostic techniques are either not sensitive enough or too complicated and expensive for routine use. This study evaluates a new approach for measurement of linear wear of metal-backed acetabular cups using CT as the intended clinically feasible method., Material and Methods: 8 retrieved uncemented metal-backed acetabular cups were scanned twice ex vivo using CT. The linear penetration depth of the femoral head into the cup was measured in the CT volumes using dedicated software. Landmark points were placed on the CT images of cup and head, and also on a reference plane in order to calculate the wear vector magnitude and angle to one of the axes. A coordinate-measuring machine was used to test the accuracy of the proposed CT method. For this purpose, the head diameters were also measured by both methods., Results: Accuracy of the CT method for linear wear measurements was 0.6 mm and wear vector angle was 27 degrees . No systematic difference was found between CT scans., Interpretation: This study on explanted acetabular cups shows that CT is capable of reliable measurement of linear wear in acetabular cups at a clinically relevant level of accuracy. It was also possible to use the method for assessment of direction of wear.

Objective: To validate a new non-invasive CT method for measuring segmental translations in lumbar spine in a phantom using plastic vertebrae with tantalum markers and human vertebrae., Material and Methods: One hundred and four CT volumes were acquired of a phantom incorporating three lumbar vertebrae. Lumbar segmental translation was simulated by altering the position of one vertebra in all three cardinal axes between acquisitions. The CT volumes were combined into 64 case pairs, simulating lumbar segmental movement of up to 3 mm between acquisitions. The relative movement between the vertebrae was evaluated visually and numerically using a volume fusion image post-processing tool. Results were correlated to direct measurements of the phantom., Results: On visual inspection, translation of at least 1 mm or more could be safely detected and correlated with separation between the vertebrae in three dimensions. There were no significant differences between plastic and human vertebrae. Numerically, the accuracy limit for all the CT measurements of the 3D segmental translations was 0.56 mm (median: 0.12; range: -0.76 to +0.49 mm). The accuracy for the sagittal axis was 0.45 mm (median: 0.10; range: -0.46 to +0.62 mm); the accuracy for the coronal axis was 0.46 mm (median: 0.09; range: -0.66 to +0.69 mm); and the accuracy for the axial axis was 0.45 mm (median: 0.05; range: -0.72 to + 0.62 mm). The repeatability, calculated over 10 cases, was 0.35 mm (median: 0.16; range: -0.26 to +0.30 mm)., Conclusion: The accuracy of this non-invasive method is better than that of current routine methods for detecting segmental movements. The method allows both visual and numerical evaluation of such movements. Further studies are needed to validate this method in patients.

Background: Diagnosis of loosening of total wrist implants is usually late using routine radiographs. Switching modality to computed tomography (CT) should aid in early diagnosis., Purpose: To propose and evaluate the accuracy of a new CT method for assessing loosening of the carpal component in total wrist arthroplasty., Material and Methods: A protocol encompassing volume registration of paired CT scans of patients with unexplained pain in a prosthetically replaced wrist (used in clinical routine) is presented. Scans are acquired as a dynamic examination under torsional load. Using volume registration, the carpal component of the prosthesis is brought into spatial alignment. After registration, prosthetic loosening is diagnosed by a shift in position of the bones relative to the prosthesis. This study is a preclinical validation of this method using a human cadaverous arm with a cemented total wrist implant and tantalum markers. Seven CT scans of the arm were acquired. The scans were combined into 21 pairs of CT volumes. The carpal component was registered in each scan pair, and the residual mismatch of the surrounding tantalum markers and bone was analyzed both visually and numerically., Results: The detection limit for prosthetic movement was less than 1 mm., Conclusion: The results of this study demonstrate that CT volume registration holds promise to improve detection of movement of the carpal component at an earlier stage than is obtainable with plain radiography.

Purpose: Recently a common variant of the TGFBR1 gene, TGFBR1*6A, has been proposed to act as a low-penetrance tumor susceptibility allele for colorectal cancer, but data from published studies with individually low statistical power are conflicting. To further evaluate the relationship between TGFBR1*6A and colorectal cancer risk, we have conducted a large case-control study and a meta-analysis of previously published studies., Experimental Design: A total of 1,042 colorectal cancer cases and 856 population controls were genotyped for the TGFBR1*6A polymorphism. Previously published case-control studies of the relationship between TGFBR1*6A and colorectal cancer were identified, and a meta-analysis was conducted., Results: We found no evidence that homozygosity, heterozygosity or carrier status for the TGFBR1*6A allele confers an increased risk of colorectal cancer; respective odds ratios (OR) were 1.05 [95% confidence interval (95% CI), 0.83-1.32], 0.82 (95% CI, 0.34-1.99), and 0.92 (95% CI, 0.74-1.15), respectively. A meta-analysis of our case-control study and seven other studies that provided data on 2,627 colorectal cancer cases and 3,387 controls also yielded no evidence that possession of the TGFBR1*6A allele is associated with an elevated risk of colorectal cancer; pooled estimate of the OR were 1.20 (95% CI, 0.64-2.24) for homozygosity, 1.11 (95% CI, 0.96-1.29) for heterozygosity, and 1.13 (95% CI, 0.98-1.30) for carriers of TGFBR1*6A., Conclusion: Current data provide limited support for the hypothesis that sequence variation in TGFBR1 defined by the TGFBR1*6A allele confers an elevated risk of colorectal cancer.

Improvement of joint prostheses is dependent upon information concerning the biomechanical properties of the joint. Radiostereometric analysis (RSA) and electromagnetic techniques have been applied in previous cadaver and in vivo studies on the elbow joint to provide valuable information concerning joint motion axes. However, such information is limited to mathematically calculated positions of the axes according to an orthogonal coordinate system and is difficult to relate to individual skeletal anatomy. The aim of this study was to evaluate the in vivo application of a new fusion method to provide three-dimensional (3D) visualization of flexion axes according to bony landmarks. In vivo RSA data of the elbow joint's flexion axes was combined with data obtained by 3D computed tomography (CT). Results were obtained from five healthy subjects after one was excluded due to an instable RSA marker. The median error between imported and transformed RSA marker coordinates and those obtained in the CT volume was 0.22 mm. Median maximal rotation error after transformation of the rigid RSA body to the CT volume was 0.003 degrees . Points of interception with a plane calculated in the RSA orthogonal coordinate system were imported into the CT volume, facilitating the 3D visualization of the flexion axes. This study demonstrates a successful fusion of RSA and CT data, without significant loss of RSA accuracy. The method could be used for relating individual motion axes to a 3D representation of relevant joint anatomy, thus providing important information for clinical applications such as the development of joint prostheses.

Background: The cell cycle checkpoint kinase 2 (CHEK2) 1100delC variant has recently been identified at high frequency in families with both breast and colorectal cancer, suggesting the possible role of this variant in colorectal cancer predisposition., Patients and Methods: To evaluate the role of CHEK2 ll00delC among Swedish colorectal cancer patients, the variant frequency was determined in 174 selected familial cases, 644 unselected cases and 760 controls, as well as in l8 families used in the genome-wide linkage analysis, where weak linkage was seen for the region harboring the CHEK2 gene., Results: CHEK2 l100delC was found in 1.15% of familial and in 0.93% of unselected cases, compared to 0.66% of controls, showing no significant difference between groups. One out of 45 familial cases with a family history of breast cancer was shown to be a carrier. The variant was not identified in the 18 families included in the linkage analysis., Conclusion: The CHEK2 1100delC was not significantly increased in Swedish colorectal cancer patients, however, in order to determine the role of the variant in colorectal cancer families with the history of breast cancer a larger sample size is needed.

Purpose: To validate a clinically useful method for measuring acetabular cup wear using computed tomography (CT)., Material and Methods: Eight uncemented acetabular cups were scanned twice ex vivo using CT. The linear penetration depth of the femoral component head into the cup and the thickness of the remaining polyethylene liner were measured in the CT volumes using dedicated software. Two independent examiners twice assessed each volume. The CT measurements were compared to direct measurements using a coordinate measuring device and micrometer measurements., Results: Accuracy of wear measurements expressed as penetration depth was +/-0.6 and +/- 1.0 mm for the two examiners, respectively, with no significant differences between examiners, trials, and CT scans. Accuracy of measurements of remaining polyethylene was +/- 1.3 and +/- 1.0 mm, respectively, for the two examiners. Systematic differences between examiners were found, but no significant differences between trials and CT scans. These differences were due to different interpretations of metal artifacts in the volumes., Conclusion: The proposed CT method for evaluating wear as head penetration depth allows for reliable wear detection at a clinically relevant level. Measurements of remaining polyethylene on CT volumes are not as reliable as wear measurements owing to metal artifacts.

Purpose: To validate an image post-processing method for re-orienting the pelvis in CT volumes to a standardized orientation in a model and in 10 patients., Material and Methods: Twenty-four CT volumes of a pelvic model and 10 pairs of postoperative total hip arthroplasty (THA) patient CT scans were rotated to a defined pelvic standard orientation and the rotation was recorded. For precision, a test-retest procedure was used. For accuracy, three exactly represented coordinate points were used. For clinical application, the standard orientation was used for calculating the direction of acetabular cup migration from a previous model study., Results: Precision of pelvic standard orientation, calculated as maximal directional error, was better than 1 degrees in the model study and better than 1.5 degrees in the patient study. Accuracy, expressed as angle between ideal and measured coordinate axes, was 0.1 degrees for x, y, z axes. No measurable systematic errors were found. When applied to acetabular cup migration in the model, standardization of pelvic orientation had no significant effect on the measurements., Conclusion: Reorienting the pelvis during image post-processing was shown to be accurate. It enables measurements relative to the pelvis and minimizes the dependency of patient positioning.

Free DNA in the circulation is increased five-to ten-fold in patients with solid tumours compared to healthy controls. A range of tumor-specific mutated DNA has been shown to be readily extractable and possible to analyse from plasma and serum in these patients. K-ras oncogene mutations are an early event in a subset of colorectal tumors and have been found in 30-60% of patients with colorectal carcinoma (CRC). The presence of tumor-derived k-ras gene mutations in the circulation has previously been described before surgery. The aim of this study was to characterize the presence of mutant k-ras in plasma in the short-term postoperative period after radical surgery of CRC patients, and further to characterize this in relation to relapse of the disease. Tumors and corresponding plasma pre- and postoperatively on day three after surgery were collected from 25 patients with CRC (Dukes' stage A-D). Biopsies for DNA extraction from the tumors were collected from the most invasive parts microscopically. After PCR amplification of the k-ras gene (codon 12 and 13), the presence of mutations was analysed by TGGE (temperature gradient gel electrophoresis). Twenty four/25 patients underwent putatively curative resections. Sixteen of the 25 patients (64%) expressed k-ras mutations in their tumor. Of these, 9 patients (56%) also had detectable k-ras mutations in preoperative plasma samples. On day three postoperatively, 8 of these patients persistently were found to have mutant k-ras in the plasma. This was not correlated with tumor stage. None of the 9 tumor mutation-negative cases expressed mutated k-ras in their plasma pre- or postoperatively. The results indicate that plasma mutant k-ras can be detected pre- and early postoperatively in all stages of colorectal neoplasia. No correlation between short-term postoperative persistence of mutant plasma-DNA and disease recurrence at follow-up was found. However, the use of k-ras as a marker during postoperative follow-up and as a possible tool for early detection of recurrent disease must be further characterized.

Background: It is difficult to assess the orientation of the acetabular component on routine radiographs. We present a method for determining the spatial orientation of the acetabular component after total hip arthroplasty (THA) using computed tomography., Patients and Methods: Two CT-scans, 10 min apart, were obtained from each of 10 patients after THA. Using locally developed software, two independent examiners measured the orientation of the acetabular component in relation to the pelvis. The measurements were repeated after one week. To be independent of the patient position during scanning, the method involved two steps. Firstly, a 3D volumetric image of the pelvis was brought into a standard pelvic orientation, then the orientation of the acetabular component was measured. The orientation of the acetabular component was expressed as operative anteversion and inclination relative to an internal pelvic reference coordinate system. To evaluate precision, we compared measurements across pairs of CT volumes between observers and trials., Results: Mean absolute interobserver angle error was 2.3 degrees for anteversion (range 0-6.6 degrees), and 1.1 degrees for inclination (range 0-4.6 degrees). For interobserver measurements, the precision, defined as one standard deviation, was 2.9 degrees for anteversion, and 1.5 degrees for inclination. A Student's t-test showed that the overall differences between the examiners, trials, and cases were not significant. Data were normally distributed and were not dependent on examiner or trial., Interpretation: We conclude that the implant angles of the acetabular component in relation to the pelvis could be detected repeatedly using CT, independently of patient positioning.

Objective: Growth hormone (GH) induces hepatic low-density lipoprotein (LDL) receptors and lowers plasma cholesterol. We characterized the influence of GH treatment on plasma LDL clearance in normal humans and investigated the relative role of LDL receptor (LDLR) activity and stimulation of bile acid synthesis in subjects with different LDLR expression., Methods and Results: Plasma clearance of autologous 125I-LDL was measured before and during 3 weeks of treatment with GH (0.1 IU/kg per day) in 9 healthy young males. Plasma LDL cholesterol was reduced by 13% and the fractional catabolic rate of LDL increased by 27%. More marked changes were seen in a patient with hypopituitarism substituted with GH (0.07 IU/kg per day) for 3 months. In a second study, GH dose-dependently reduced LDL cholesterol and increased Lp(a) levels in 3 groups of males: younger and elderly healthy subjects and heterozygous familial hypercholesterolemia (FH). No effect on bile acid synthesis measured by the plasma marker 7alpha-hydroxy-4-cholesten-3-one was observed. In an LDLR-deficient FH homozygote, LDL cholesterol was not affected by GH., Conclusions: GH treatment reduces plasma LDL cholesterol by inducing LDL clearance. In humans, LDLR expression is a prerequisite for this effect, whereas it is not related to stimulation of bile acid synthesis.

Purpose: To validate a CT method for detecting changes in acetabular cup orientation after THA., Material and Methods: 26 CT examinations were obtained from a pelvic model with an uncemented acetabular cup. The model position was altered between acquisitions, but the cup axis angle vis-à-vis the pelvis was maintained. Data sets were combined into 37 pairs, each containing a unique positioning error. The pelvi in different examinations were fused, creating transformed volumes. Landmarks corresponding to the cup before and after fusion were placed interactively by two independent examiners. The orientation of the acetabular axis was calculated for each volume and compared across volumes., Results: Before fusion the mean angle error between the acetabular axes was 4.17 degrees (SD +/- 1.95 degrees ). After fusion the mean angle error was 0.36 degrees (SD +/- 0.17). The 95% repeatability limits were below 0.7 degrees. There was no significant interobserver difference. Analysis of the cup landmarking pattern by condition numbers and individual landmark errors showed stability., Conclusion: Non-invasive fusion of CT volumes and a stable landmarking pattern for the acetabular cup outperforms routine plain radiography in detecting changes in the orientation of the acetabular axis over time. The method delivers both visual and numerical output and could be used in clinical practice.

Aims: Loss of heterozygosity (LOH) may vary almost randomly within a colorectal tumour due to the heterogeneous morphologic character of these tumours. Despite this, as a rule, single biopsies are the source of genetic material used in studies of markers important for prognosis, clinical behaviour of the disease, or susceptibility of specific tumours to different treatment modalities., Methods: To evaluate the importance of intratumoural variation for the results of analysis of LOH and point mutations in colorectal cancer and to determine the frequency of genetic alterations in different types of pre-neoplastic areas of the tumours, 36 consecutively operated patients with colorectal cancer were studied. After fixation, specimens were mounted on large slides containing the whole tumour. The specimens were sub classified into different areas defined as normal tissue, normal tissue closely adjacent the tumour mass, adenoma, dysplasia and invasive cancer cells. These areas were dissected and subjected to DNA extraction., Results: The extracted genomic DNA was studied for LOH at chromosome 5q, 17p, and 18q and for k-ras mutations. Overall, a correlation between the intratumoural degree of neoplastic progression and the frequency of LOH and k-ras mutations was seen. These correlations were significant (p<0.008) except for dysplasia/adenomatous tissue versus invasive cancer. Microsatellite instability was found in 9% of the tumours, all except one in invasive parts of the tumours., Conclusions: This study demonstrates a statistical correlation between intratumoural differences in neoplastic degree of dedifferentiation and genetic instability in terms of LOH and point mutations of the k-ras gene in colorectal carcinoma. The importance of a careful dissection in order to localise the region with the highest probability of genetic aberrations and multiple biopsing must not be neglected. The observation that the prevalence of k-ras mutations and LOH are correlated to the degree of dedifferentiation within a colorectal tumour is in line with the concept that selected cell clones are responsible for the neoplastic progression of the tumour.

Purpose: 3D detection of centerpoints of prosthetic cup and head after total hip arthroplasty (THA) using CT., Material and Methods: Two CT examinations, 10 min apart, were obtained from each of 10 patients after THA. Two independent examiners placed landmarks in images of the prosthetic cup and head. All landmarking was repeated after 1 week. Centerpoints were calculated and compared., Results: Within volumes, all measurements of centerpoints of cup and head fell, with a 95% confidence, within one CT-voxel of any other measurement of the same object. Across two volumes, the mean error of distance between center of cup and prosthetic head was 1.4 mm (SD 0.73). Intra- and interobserver 95% accuracy limit was below 2 mm within and below 3 mm across volumes. No difference between intra- and interobserver measurements occurred. A formula for converting finite sets of point landmarks in the radiolucent tread of the cup to a centerpoint was stable. The percent difference of the landmark distances from a calculated spherical surface was within one CT-voxel. This data was normally distributed and not dependent on observer or trial., Conclusion: The true 3D position of the centers of cup and prosthetic head can be detected using CT. Spatial relationship between the components can be analyzed visually and numerically.

Purpose: To develop a non-invasive method for detection of acetabular cup migration after total hip arthroplasty (THA) with a higher degree of accuracy than routine plain radiography., Material and Methods: Two CT examinations, 10 min apart, were obtained from each of 10 patients that had undergone THA. Using an in-house developed semiautomated program for volume merging, the pelves in the two examinations were fused and the acetabular cup was visually and numerically evaluated to test the method's accuracy in detecting migration., Results: In the visual evaluation of the best match a 1-mm translation of the cup was detectable. The numerical evaluation, comparing landmarks placed in the images of the acetabular cup and the head of the femur component in the two examinations, showed the mean difference in orientation of acetabular axes to be 2.5 degrees, the mean distance between centre of cup face to be 2.5 mm and the mean distance between centre of the head of the prosthetic femoral component to be 1 mm., Conclusion: This method has a significantly higher accuracy than routine plain radiography in detecting acetabular cup migration and could be used in clinical practice. It gives both a visual and a numerical correlate to migration.

To characterize the coordinate regulation of cholesterol metabolism in human liver, we simultaneously quantified mRNA levels of cholesterol 7alpha-hydroxylase (CYP7A1), 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), and low- density lipoprotein receptors (LDLRs) in liver biopsies from 76 patients undergoing cholecystectomy. The three transcript levels were not different between untreated gallstone and gallstone-free patients and not significantly altered by 10-d exclusion of dietary cholesterol. Treatment with chenodeoxycholic acid suppressed CYP7A1 and to a lesser extent HMGR mRNA levels. Cholestyramine treatment increased CYP7A1, but also HMGR and LDLR mRNA, and statins only increased HMGR mRNA. Resin + statin treatment increased all mRNA species. In untreated patients, the mRNA levels of HMGR and LDLR were more strongly correlated (r = +0.60) than those of CYP7A1 and HMGR (r = +0.49) or CYP7A1 and LDLR (r = +0.21). In the treated patients, in whom bile acid synthesis was suppressed or stimulated, mRNA levels of CYP7A1 and HMGR (r = +0.84) as well as CYP7A1 and LDLR (r = +0.62) were more strongly correlated than those of HMGR and LDLR (r = +0.59). The coordinate control of HMGR and LDLR mRNA levels reflects their common regulation by shared transcriptional activation. In contrast, following changes in bile acid flux through the liver, CYP7A1 gene expression becomes a strong modulator of hepatic cholesterol metabolism.

Background: In a small subgroup of patients with ulcerative colitis (UC) undergoing proctocolectomy and restorative ileal pouch-anal anastomosis (IPAA), a colonic-like pouch mucosa with severe and persistent villous atrophy (type C pattern) develops. Neoplastic transformation of the mucosa in the neorectum may occur in these patients. We hypothesized that genetic alterations associated with colorectal carcinoma (CRC) could be an early finding in this transformational process and thus potentially useful as clinical monitors in carcinoma risk assessment., Methods: In six patients with long-standing severe pouchitis and a type C-pattern mucosa, biopsies were obtained from five different locations of the pouches. DNA was PCR-amplified and analyzed by automated fragment analysis for loss of heterozygosity (LOH) at chromosome 5q14-22, 17p12-13, and 18q12-22. Point mutations of the K-ras and adenomatous polyposis coli (APC) genes were studied by sequencing., Results: The patients had varying degrees of dysplasia and one displayed DNA aneuploidy. Loss of heterozygosity at 5q15-22 was detected in three of five biopsies in one patient. This particular patient had no signs of dysplasia or DNA aneuploidy and a normal exon 15 sequence of the APC gene. No alterations of either the K-ras or the APC genes or LOH of 5q, 17p, or 18q were seen in any of the other patients., Conclusion: Dysplasia, aneuploidy, and LOH in 5q may all reflect different parts of an atrophic mucosa-dysplasia-carcinoma sequence, in line with current concepts of carcinogenesis for CRC in long-standing pouchitis. Further studies of histological and molecular events in IPAA patients with severe atrophy are warranted.

Background: Loss of heterozygosity (LOH) at 17p and 18q in colorectal carcinoma has been depicted as a potential prognostic marker for the disease. However, conclusions vary among reports, and evidence of clinically useful genetic prognostic markers is still lacking. As a rule, single biopsies are used. In this study, the authors hypothesized that an important cause of earlier contradictory results was the heterogeneity of colorectal neoplasms., Methods: In this study, DNA originating in each quadrant of tumors from 64 patients with colorectal carcinoma was analyzed. Microsatellite markers for chromosome 18q and 17p were amplified by polymerase chain reaction and automatically analyzed., Results: The authors found that, regardless of stage, LOH and non-LOH in both 17p and 18q varied among biopsies within the tumors in a random fashion. LOH in 18q was detected in all 4 quadrants in 22% and in 1 of 4, 2 of 4, or 3 of 4 quadrants in 56% of the tumors, whereas 22% of the tumors were homogeneously without LOH in 18q. LOH 17p was distributed similarly throughout the tumors and was present in 1 of 4, 2 of 4, or 3 of 4 of the quadrants in 44%. The authors also reexamined a subset of tumors by subdividing one biopsy from each into four. Analysis of the microsatellite markers then yielded identical results. No correlation between the degree of LOH status and patient survival was observed., Conclusions: LOH status within a colorectal tumor is extensively heterogeneous. However, it is more homologous on a lower macroscopic level. For relevant genetic analysis, multiple biopsies and DNA sampling preceded by careful morphologic examination must be standard in the preparation of DNA., (Copyright 2000 American Cancer Society.)

This study was undertaken to elucidate the specific effects of growth hormone (GH) on liver protein metabolism in humans during surgery. Otherwise healthy patients scheduled for elective laparoscopic cholecystectomy were randomized into controls (n = 9) or pretreatment with 12 units of GH for 1 day (GH 1, n = 9) or daily for 5 days (GH 5, n = 10). The fractional synthesis rate of liver proteins, as assessed by flooding with [2H5]phenylalanine, was higher in the GH 5 group (22.0 +/- 6.9%/day, mean +/- SD, P < 0.05) than in the control (16.1 +/- 3.1%/day) and GH 1 (16.5 +/- 5.5%/day) groups. During surgery, the fraction of polyribosomes in the liver, as assessed by ribosome analysis, decreased in the control group by approximately 12% (P < 0.01) but did not decrease in the GH-treated groups. In addition, the concentrations of the essential amino acids and aspartate in the liver decreased in response to GH treatment. In conclusion, GH pretreatment decreases hepatic free amino acid concentrations and preserves liver protein synthesis during surgery.

We investigated the acute (4-5 h) and short-term (5 days) effects of GH treatment on hepatic messenger RNA (mRNA) levels of the genes for the insulin-like growth factors (IGFs), insulin-like growth factor binding protein-1, -2, and -3 (IGFBPs), and the acid labile subunit (ALS), as well as serum levels of these proteins in humans. At the mRNA level, we observed an increase in IGF-1 transcription (+173%) following GH treatment in the acute group, which remained elevated in the short-term treatment group. IGFBP-2 mRNA decreased after short-term GH treatment, without changes in IGFBP-1 or -3 expression. The ALS transcript level increased after 5 days. In serum, we found increased levels of IGF-I and insulin, and decreased levels of IGF-II, in the short-term treatment group. IGFBP-1 decreased in both treatment groups, whereas IGFBP-2 was reduced after 5 days treatment. ALS increased in the short-term group. We observed increased IGFBP-3 serum levels after 5 days of GH treatment, likely due to increased formation of the ternary complex. Our results show that the metabolic effects by GH on the IGF axis are complex. In addition to a direct stimulation of IGF-I and ALS expression, GH inhibits IGFBP-1 serum levels and IGFBP-2 expression in an indirect manner, possibly facilitating enhanced IGF bioavailability to target tissues.

Growth hormone (GH) has an important role in the regulation of hepatic LDL receptor expression and plasma lipoprotein levels. This investigation was undertaken to evaluate if these effects of GH on hepatic LDL receptors are direct or mediated by insulin-like growth factor I (IGF-I). Two models were studied in which substitution with GH is important for the regulation of hepatic LDL receptors: hypophysectomized rats receiving high-dose ethynylestradiol or challenge with dietary cholesterol. The hypophysectomized rats were hormonally substituted by infusion with dexamethasone and L-thyroxine, and either GH or IGF-I. In both models, GH was essential for maintaining normal expression of LDL receptors. In contrast, despite fully normalized plasma levels, IGF-I did not support the expression of hepatic LDL receptors. Analysis of plasma lipoproteins revealed that substitution with GH, but not with IGF-I, reduced LDL and intermediate density lipoproteins. In addition, determination of hepatic mRNA levels for apo B-100 and apo B-48 indicated that GH may be more effective than IGF-I in the promotion of apo B mRNA editing. In conclusion, GH has specific effects on hepatic LDL receptor expression and plasma lipoprotein levels that are not mediated by IGF-I.

In response to treatment with growth hormone, serum levels of lipoprotein(a) increase, while those of LDL cholesterol decrease. To establish if increased levels of insulin-like growth factor-I may be of importance for these changes, we analyzed serum lipoprotein concentrations in 11 male patients with idiopathic osteoporosis who were treated with growth hormone (2 IU.m-2.d-1) or insulin-like growth factor-I (80 micrograms.kg-1.d-1) in a randomized, double-blind, cross-over study. LDL cholesterol was reduced by 0.7 mmol/L (P < .01) during growth hormone treatment but was not affected when the same patients received insulin-like growth factor-I. In contrast, mean lipoprotein(a) levels increased from 519 to 571 mg/L (P < .03) in response to growth hormone but were reduced from 538 to 478 mg/L (P < .04) during treatment with insulin-like growth factor-I. These results indicate that growth hormone exerts its effects on lipoprotein metabolism independent of insulin-like growth factor-I. Furthermore, the results suggest that treatment with insulin-like growth factor-I may reduce lipoprotein(a) levels.

Problem solving and critical thinking are important components of problem based learning (PBL). The driving forces are the students' interest, involvement and sense of responsibility. A curriculum comprising a combination of PBL and conventional instruction was introduced during the surgery course at Huddinge Hospital in the autumn term 1993. The results showed the level of knowledge attained by the students to be comparable with that attained under conventional instruction. The authors of the article conclude that good results can be obtained by introducing PBL in isolated sections of medical education within the framework of an otherwise traditional curriculum.

Operative liver biopsies were obtained from two male patients who developed gallstone disease during estrogen treatment of metastatic prostatic carcinoma. The heparin-sensitive binding of 125I-low-density lipoprotein (LDL) to liver homogenates (reflecting the expression of the LDL receptor) was determined, together with the activities of the rate-limiting enzymes in cholesterol synthesis [3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase], bile acid production (cholesterol 7 alpha-hydroxylase), and cholesterol esterification (acyl CoA:cholesterol acyl transferase). The results were related to data available in 18 patients (5 male, 13 female) who underwent cholecystectomy because of gallstone disease. The hepatic 125I-LDL-binding activity was increased threefold compared with five controls, and the activity of HMG-CoA reductase was increased twofold. There was no major difference in the activities of cholesterol 7 alpha-hydroxylase or acyl CoA:cholesterol acyl transferase. The concentration of free and total cholesterol in liver microsomes was approximately 30% lower in the estrogen-treated men than in 11 controls. The results indicate that estrogen at pharmacological doses stimulates hepatic LDL-receptor expression and HMG-CoA reductase activity in men. The increased LDL-receptor expression could in part explain the enhanced plasma clearance of injected 125I-LDL and hence the reduction in plasma LDL cholesterol previously shown to occur in estrogen-treated men.

GH appears to play an important role in mediating the increase in hepatic LDL receptor expression that occurs in response to pharmacological oestrogen treatment. Furthermore, in normal individuals there is evidence of an increased number of hepatic LDL receptors in response to GH, resulting in an accelerated elimination rate of the LDL particle and a subsequent lowering of LDL cholesterol. Further studies on lipoprotein metabolism in patients with GH deficiency, and also in patients with hypercholesterolaemia, would therefore be of interest.

This investigation was undertaken to determine the possible role of growth hormone (GH) in the hormonal regulation of hepatic low density lipoprotein (LDL) receptor expression. Treatment of normal rats with estrogen (ethynylestradiol, 5 mg/kg per day) increased the number of hepatic LDL receptors, and the LDL receptor mRNA levels were increased 2.4-fold. However, when hypophysectomized rats were treated with estrogen, the hepatic LDL receptor number and the mRNA levels only increased slightly. Treatment with GH was important to restore the induction of hepatic LDL receptors in hypophysectomized estrogen-treated rats. Further, the hypocholesterolemic effect of estrogen was abolished in hypophysectomized rats, and GH reversed this effect. To assess the effect of GH in humans, hepatic LDL receptor binding activity was determined in liver biopsy specimens from gallstone patients pretreated with GH (12 international units/day) prior to operation. GH administration induced hepatic LDL receptors approximately 2-fold, and this was accompanied by a 25% decrease in serum cholesterol. The LDL receptor stimulation caused by GH treatment was of similar magnitude as that observed upon 3 weeks of treatment with an established hypolipidemic drug (pravastatin or simvastatin). The data show that GH has an important role in the regulation of hepatic LDL receptors and suggest that GH secretion may be important for the control of plasma LDL levels in humans.

Cluster headache is considered a clinically distinct entity with no underlying gross pathology. However, in rare cases this kind of headache may be mimicked by an arteriovenous malformation. A 49-year-old male is described who had severe bouts of unilateral headache resembling those of cluster headache. The usual accompanying autonomic manifestations were minor and the headache attacks were prolonged. Treatment with ergotamine tartrate and pizotifen failed. A large ipsilateral arteriovenous malformation was diagnosed. Prospectively, true clustering of the headache attacks could not be documented.

Four hundred and fourteen carotid reconstructions performed on 352 patients during the years 1971-82 were analysed retrospectively. Fifty-eight percent of the patients were operated on because of hemispheric transient ischaemic attacks (TIA). Twenty-eight percent had suffered a stroke before surgery. The overall combined mortality and morbidity was 7.7%. The procedure mortality was 2.9% with a slightly higher mortality i.e. 5.9% in the stroke group although not significantly higher than among non-stroke patients with a mortality of 1.4%. Patients of more than 70-years had a significantly higher operative mortality (11.1%) than the rest of the patients (1.7%). Non-fatal strokes occurred in 20 patients (4.8%). No correlation was found with the degree of stenosis of the contralateral artery.

Computed tomography (CT) has been reported to show normal findings in 13-52% of patients with cerebrovascular diseases. Among factors deciding the diagnostic accuracy are the size and location of the lesion, the time elapsed from onset to examination, the use of contrast enhancement and the type of CT scanner used. To further elucidate these aspects, we designed the present study including 300 consecutive patients, all investigated by CT with a 160 x 160 matrix and cerebrospinal fluid spectrophotometry (CSF-SPE). CT indicated a specific diagnosis in 52.7%. In the majority of the remaining cases, additional subclassification was possible by CSF-SPE, emphasizing the complementary information obtained by combined examinations. CT was also found to be a useful tool for reliable prognostic prediction, irrespective of the initial clinical course.

The prevalence of ulceration in the carotid bifurcation, as judged from high-resolution 2-D ultrasound scanning and angiography, was compared with the findings at carotid endarterectomy in patients with TIA or stroke. The surgeons registered ulceration in 26 of the 29 treated carotid arteries. Angiography and ultrasonography identified ulceration in 9 and 19, respectively, of the same arteries, indicating that high-resolution 2-D ultrasound scanning is superior to angiography in the diagnosis of carotid ulceration. All arteries with tight stenosis (diameter reduction greater than or equal to 75%), but only two of four with less than 30% stenosis were ulcerated.

The diagnostic accuracy of 5 MHz continuous-wave (C-W) Doppler with spectral analysis for detecting carotid bifurcation disease was evaluated. In a first phase of the study, normal confidence intervals for peak frequency data and spectrum width were established and Doppler spectrum abnormalities were separated into three types (spectral broadening with preserved window, spectral broadening without window, sequence of abnormalities including inverted Doppler spectrum). In a second phase the diagnostic accuracy of these variables was tested on 86 carotid arteries as independently compared with angiography. Whereas both peak frequency data and spectrum distribution findings were invariably abnormal in stenoses greater than or equal to 60%, spectrum distribution findings were more accurate in 30-59% stenosis. Using spectrum distribution criteria, sensitivity and specificity for stenosis greater than or equal to 30% were 94.6% and 90.7% respectively. All variables were insensitive for stenoses less than 30% lumen diameter reduction.

The advantage of Tc-99m HM-PAO, a newly introduced compound for brain perfusion imaging, is illustrated in three patients with suspicion of brain death. With Tc-99m HM-PAO, the carotid flow study is not essential, as it is in the Tc-99m pertechnetate carotid angiogram; planar images are equally useful; and there is no need for SPECT images. For the diagnosis of brain death, Tc-99m HM-PAO can be injected in the intensive care unit and planar images can be obtained at a later time using a mobile camera or whenever the patient can be moved to the nuclear medicine department.

Attenuation profiles across the petrous bone covering the whole internal auditory meatus (IAM) were constructed from the printouts obtained by computed tomography (CT) with narrow collimation performed on 12 patients with 13 acoustic neuromas. In healthy patients the attenuation profiles of right and left petrous bone were very similar in shape. The attenuation values of the individual pixels in the pixel columns of the printout located at the site of the porus and the IAM reflected the demineralization of the petrous bone and the widening of the porus and the IAM caused by the acoustic neuroma. A widening deep in the meatus was demonstrated in a patient with an intracanalicular tumor, and therefore it seems possible to make this diagnosis by CT scanning combined with the construction of attenuation profiles across the petrous bone. In the presence of unilateral acoustic neuroma there was a significant and characteristic difference in shape between the attenuation profiles of the two sides with generally lower attenuation values on the tumor side together with signs of widening of the porus and the IAM. In cases of bilateral acoustic neuroma comparison of the attenuation profiles can be made with mean attenuation curves obtained from scanning normal petrous bones. The prevailing physical limitations for demonstrating a narrow bony canal like the IAM with CT was experimentally analyzed using bone-simulating plastic material.

This study presents the results from a follow-up after 414 carotid reconstructions performed on 352 patients during the years 1971-82. At the end of the follow-up period 267 patients were alive (75.8%) and 253 patients remained asymptomatic. The median follow-up time was 35 months (6 months-12 years). Patients with coronary artery disease (CAD) had a significantly lower survival than patients without signs of CAD. Coronary artery disease was significantly more frequent among patients with bilateral carotid lesions compared to patients with unilateral lesions. The actuarial stroke frequency, operative morbidity included, on the operated side was 2.5%/year. However, from 6 months postoperatively up to 8 years the stroke frequency was 1%/year. In the stroke frequencies all neurological deficits of more than 24 h duration are accounted for. Although there was a trend toward higher stroke rates among older patients there were no significant differences between age groups. Assuming a 10% stroke frequency during the first year after a TIA and a 6% annual stroke rate thereafter our results would cross even such a natural course curve at 18 months.

The immunohistochemical expression of insulin-like growth factor I (IGF-I; somatomedin C) was investigated in hindlimb skeletal muscle of rats during postnatal development. IGF-I immunoreactivity could be demonstrated in satellite fibres and myotubes 1, 2 and 3 days after birth, while no IGF-I immunoreactivity could be demonstrated in the more mature primary fibres. Five days after birth only scattered cells showed IGF-I immunoreactivity and 10 days after birth no specific IGF-I immunoreactivity could be demonstrated in muscle cells, i.e. the adult pattern was established. It is concluded that IGF-I immunoreactivity is expressed during a limited period of postnatal skeletal muscle maturation in rats. IGF-I is probably synthesized by IGF-I immunoreactive muscle cells and contributes to the differentiation/maturation process by autocrine and/or paracrine mechanisms.

The changes of the enhancement of the lesion with time after intravenous administration of contrast medium were measured with computed tomography (CT) in 23 cases of acoustic neuroma. The pattern of high initial enhancement followed by a fairly rapid decrease is confirmed. A more rigorous study of the enhancement pattern using a mathematical description of the enhancement curve of the tumor as well as a measurement of the individual blood enhancement curve is discussed.