Search

Summary Purpose To provide a narrative review of original articles on imaging of osteoarthritis (OA) published between January 1, 2020 and March 31, 2021, with a special focus on imaging of inflammation, imaging of bone, cartilage and bone-cartilage interactions, imaging of peri-articular tissues, imaging scoring methods for OA, and artificial intelligence (AI) applied to OA imaging. Methods The Embase, Pubmed, Medline, Cochrane databases were searched for original research articles in the English language on human, in-vivo, imaging of OA published between January 1, 2020 and March 31, 2021. Search terms related to osteoarthritis combined with all imaging modalities and artificial intelligence were applied. A selection of articles reporting on one of the focus topics was discussed further. Results The search resulted in 651 articles, of which 214 were deemed relevant to human OA imaging. Among the articles included, the knee joint (69%) and magnetic resonance imaging (MRI) (52%) were the predominant anatomical area and imaging modality studied. There were also a substantial number of papers (n=46) reporting on AI applications in the field of OA imaging. Conclusion Imaging continues to play an important role in the assessment of OA. Recent advances in OA imaging include quantitative, non-contrast, and hybrid imaging techniques for improved characterization of multiple tissue processes in OA. In addition, an increasing effort in AI techniques is undertaken to enhance OA imaging acquisition and analysis.

Summary: We developed and compared deep learning models to detect hip osteoarthritis on clinical CT. The CT-based summation images, CT-AP, that resemble X-ray radiographs can detect radiographic hip osteoarthritis and in the absence of large training data, a reliable deep learning model can be optimized by combining CT-AP and X-ray images. Introduction: In this study, we aimed to investigate the applicability of deep learning (DL) to assess radiographic hip osteoarthritis (rHOA) on computed tomography (CT). Methods: The study data consisted of 94 abdominopelvic clinical CTs and 5659 hip X-ray images collected from Cohort Hip and Cohort Knee (CHECK). The CT slices were sequentially summed to create radiograph-like 2-D images named CT-AP. X-ray and CT-AP images were classified as rHOA if they had osteoarthritic changes corresponding to Kellgren-Lawrence grade 2 or higher. The study data was split into 55% training, 30% validation, and 15% test sets. A pretrained ResNet18 was optimized for a classification task of rHOA vs. no-rHOA. Five models were trained using (1) X-rays, (2) downsampled X-rays, (3) combination of CT-AP and X-ray images, (4) combination of CT-AP and downsampled X-ray images, and (5) CT-AP images. Results: Amongst the five models, Model-3 and Model-5 performed best in detecting rHOA from the CT-AP images. Model-3 detected rHOA on the test set of CT-AP images with a balanced accuracy of 82.2% and was able to discriminate rHOA from no-rHOA with an area under the receiver operating characteristic curve (ROC AUC) of 0.93 [0.75–0.99]. Model-5 detected rHOA on the test set at a balanced accuracy of 82.2% and classified rHOA from no-rHOA with an ROC AUC of 0.89 [0.67–0.97]. Conclusion: CT-based summation images that resemble radiographs can be used to detect rHOA. In addition, in the absence of large training data, a reliable DL model can be optimized by combining CT-AP and X-ray images.

Osteoarthritis (OA) is among the top 10 burdensome diseases, with the knee the most affected joint. Magnetic resonance imaging (MRI) allows whole-knee assessment, making it ideally suited for imaging OA, considered a multitissue disease. Three-dimensional (3D) MRI enables the comprehensive assessment of OA, including quantitative morphometry of various joint tissues. Manual tissue segmentation on 3D MRI is challenging but may be overcome by advanced automated image analysis methods including artificial intelligence (AI). This review presents examples of the utility of 3D MRI for knee OA, focusing on the articular cartilage, bone, meniscus, synovium, and infrapatellar fat pad, and it highlights several applications of AI that facilitate segmentation, lesion detection, and disease classification.

We developed and compared deep learning models to detect hip osteoarthritis on clinical CT. The CT-based summation images, CT-AP, that resemble X-ray radiographs can detect radiographic hip osteoarthritis and in the absence of large training data, a reliable deep learning model can be optimized by combining CT-AP and X-ray images.In this study, we aimed to investigate the applicability of deep learning (DL) to assess radiographic hip osteoarthritis (rHOA) on computed tomography (CT).The study data consisted of 94 abdominopelvic clinical CTs and 5659 hip X-ray images collected from Cohort Hip and Cohort Knee (CHECK). The CT slices were sequentially summed to create radiograph-like 2-D images named CT-AP. X-ray and CT-AP images were classified as rHOA if they had osteoarthritic changes corresponding to Kellgren-Lawrence grade 2 or higher. The study data was split into 55% training, 30% validation, and 15% test sets. A pretrained ResNet18 was optimized for a classification task of rHOA vs. no-rHOA. Five models were trained using (1) X-rays, (2) downsampled X-rays, (3) combination of CT-AP and X-ray images, (4) combination of CT-AP and downsampled X-ray images, and (5) CT-AP images.Amongst the five models, Model-3 and Model-5 performed best in detecting rHOA from the CT-AP images. Model-3 detected rHOA on the test set of CT-AP images with a balanced accuracy of 82.2% and was able to discriminate rHOA from no-rHOA with an area under the receiver operating characteristic curve (ROC AUC) of 0.93 [0.75-0.99]. Model-5 detected rHOA on the test set at a balanced accuracy of 82.2% and classified rHOA from no-rHOA with an ROC AUC of 0.89 [0.67-0.97].CT-based summation images that resemble radiographs can be used to detect rHOA. In addition, in the absence of large training data, a reliable DL model can be optimized by combining CT-AP and X-ray images.

The incidence of low-energy acetabular fractures has increased. However, the structural factors for these fractures remain unclear. The objective of this study was to extract trabecular bone architecture and proximal femur geometry (PFG) measures from clinical computed tomography (CT) images to (1) identify possible structural risk factors of acetabular fractures, and (2) to discriminate fracture cases from controls using machine learning methods. CT images of 107 acetabular fracture subjects (25 females, 82 males) and 107 age-gender matched controls were examined. Three volumes of interest, one at the acetabulum and two at the femoral head, were extracted to calculate bone volume fraction (BV/TV), gray-level co-occurrence matrix and histogram of the gray values (GV). The PFG was defined by neck shaft angle and femoral neck axis length. Relationships between the variables were assessed by statistical mean comparisons and correlation analyses. Bayesian logistic regression and Elastic net machine learning models were implemented for classification. We found lower BV/TV at the femoral head (0.51 vs. 0.55, p = 0.012) and lower mean GV at both the acetabulum (98.81 vs. 115.33, p < 0.001) and femoral head (150.63 vs. 163.47, p = 0.005) of fracture subjects when compared to their matched controls. The trabeculae within the femoral heads of the acetabular fracture sides differed in structure, density and texture from the corresponding control sides of the fracture subjects. Moreover, the PFG and trabecular architectural variables, alone and in combination, were able to discriminate fracture cases from controls (area under the receiver operating characteristics curve 0.70 to 0.79). In conclusion, lower density in the acetabulum and femoral head with abnormal trabecular structure and texture at the femoral head, appear to be risk factors for low-energy acetabular fractures. Electronic supplementary material The online version of this article (10.1007/s10439-020-02563-4) contains supplementary material, which is available to authorized users.

Correction to: Jahangir, S., Mohammadi, A., Mononen, M.E. et al. Rapid X-Ray-Based 3-D Finite Element Modeling of Medial Knee Joint Cartilage Biomechanics During Walking. Ann Biomed Eng 50, 666–679 (2022). https://doi.org/10.1007/s10439-022-02941-0 Rinnakkaistallennettu versio / Self-archived version

IMPORTANCE Early exposure to complex dietary proteins may increase the risk of type 1 diabetes in children with genetic disease susceptibility. There are no intact proteins in extensively hydrolyzed formulas. OBJECTIVE To test the hypothesis that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of type 1 diabetes in young children. DESIGN, SETTING, AND PARTICIPANTS An international double-blind randomized clinical trial of 2159 infants with human leukocyte antigen-conferred disease susceptibility and a first-degree relative with type 1 diabetes recruited from May 2002 to January 2007 in 78 study centers in 15 countries; 1081 were randomized to be weaned to the extensively hydrolyzed casein formula and 1078 to a conventional formula. The follow-up of the participants ended on February 28, 2017. INTERVENTIONS The participants received either a casein hydrolysate or a conventional adapted cows milk formula supplemented with 20% of the casein hydrolysate. The minimum duration of study formula exposure was 60 days by 6 to 8 months of age. MAIN OUTCOMES AND MEASURES Primary outcome was type 1 diabetes diagnosed according to World Health Organization criteria. Secondary outcomes included age at diabetes diagnosis and safety (adverse events). RESULTS Among 2159 newborn infants (1021 female [47.3%]) who were randomized, 1744 (80.8%) completed the trial. The participants were observed for a median of 11.5 years (quartile [Q] 1-Q3, 10.2-12.8). The absolute risk of type 1 diabetes was 8.4% among those randomized to the casein hydrolysate (n = 91) vs 7.6% among those randomized to the conventional formula (n = 82) (difference, 0.8%[95% CI, -1.6% to 3.2%]). The hazard ratio for type 1 diabetes adjusted for human leukocyte antigen risk group, duration of breastfeeding, duration of study formula consumption, sex, and region while treating study center as a random effect was 1.1 (95% CI, 0.8 to 1.5; P = .46). The median age at diagnosis of type 1 diabetes was similar in the 2 groups (6.0 years [Q1-Q3, 3.1-8.9] vs 5.8 years [Q1-Q3, 2.6-9.1]; difference, 0.2 years [95% CI, -0.9 to 1.2]). Upper respiratory infections were the most common adverse event reported (frequency, 0.48 events/year in the hydrolysate group and 0.50 events/year in the control group). CONCLUSIONS AND RELEVANCE Among infants at risk for type 1 diabetes, weaning to a hydrolyzed formula compared with a conventional formula did not reduce the cumulative incidence of type 1 diabetes after median follow-up for 11.5 years. These findings do not support a need to revise the dietary recommendations for infants at risk for type 1 diabetes. Funding Agencies|Eunice Kennedy Shriver National Institute of Child Health and Development (NICHD); National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health [HD040364, HD042444, HD051997]; Canadian Institutes of Health Research; Commission of the European Communities [QLK1-2002-00372]; European Foundation for the Study of Diabates/JDRF/Novo Nordisk; Academy of Finland (Centre of Excellence in Molecular Systems Immunology and Physiology Research) [250114]; Dutch Diabetes Research Foundation; Finnish Diabetes Research Foundation; JDRF

Summary Objective Our aim was to investigate the relation between radiograph-based subchondral bone structure and cartilage composition assessed with delayed gadolinium enhanced magnetic resonance imaging of cartilage (dGEMRIC) and T 2 relaxation time. Design Ninety-three postmenopausal women (Kellgren–Lawrence grade 0: n = 13, 1: n = 26, 2: n = 54) were included. Radiograph-based bone structure was assessed using entropy of the Laplacian-based image ( E Lap ) and local binary patterns ( E LBP ), homogeneity indices of the local angles (HI Angles,mean , HI Angles,Perp , HI Angles,Paral ), and horizontal (FD Hor ) and vertical fractal dimensions (FD Ver ). Mean dGEMRIC index and T 2 relaxation time of tibial cartilage were calculated to estimate cartilage composition. Results HI Angles,mean ( r s = −0.22) and HI Angles,Paral ( r s = −0.24) in medial subchondral bone were related ( P E Lap ( r s = −0.23), FD Hor,0.34 mm ( r = 0.21) and FD Ver,0.68 mm ( r = 0.24) in medial subchondral bone were related ( P T 2 relaxation time values of the medial tibial cartilage. FD Hor at different scales in lateral subchondral bone were related ( P r = 0.29–0.41) and T 2 values of lateral tibial cartilage ( r = −0.28 to −0.36). FD Ver at larger scales were related ( P r = 0.24–0.25) and T 2 values of lateral tibial cartilage ( r = −0.21). HI Angles,Paral ( r = −0.25) and FD Ver,0.68 mm ( r s = 0.22) in the lateral tibial trabecular bone were related ( P Conclusion Our results support the presumption that several tissues are affected in the early osteoarthritis (OA). Furthermore, they indicate that the detailed analysis of radiographs may serve as a complementary imaging tool for OA studies.

Objectives To investigate whether subchondral bone structure from plain radiographs is different between subjects with and without articular cartilage damage or bone marrow lesions (BMLs). Methods Radiography-based bone structure was assessed from 80 subjects with different stages of knee osteoarthritis using entropy of Laplacian-based image (ELap) and local binary patterns (ELBP), homogeneity index of local angles (HIAngles,mean), and horizontal (FDHor) and vertical fractal dimensions (FDVer). Medial tibial articular cartilage damage and BMLs were scored using the magnetic resonance imaging osteoarthritis knee score. Level of statistical significance was set to p

Plain radiography is the most common modality to assess the stage of osteoarthritis. Our aims were to assess the relationship of radiography-based bone density and texture between radiographs with minimal and clinical post-processing, and to compare the differences in bone characteristics between controls and subjects with knee osteoarthritis or medial tibial bone marrow lesions (BMLs). Tibial bone density and texture was evaluated from radiographs with both minimal and clinical post-processing in 109 subjects with and without osteoarthritis. Bone texture was evaluated using fractal signature analysis. Significant correlations (p

Objective: To assess the ability of radiography-based bone texture variables in proximal femur and acetabulum to predict incident radiographic hip osteoarthritis (rHOA) over a 10 years period. Design: Pelvic radiographs from CHECK at baseline (987 hips) were analyzed for bone texture using fractal signature analysis (FSA) in proximal femur and acetabulum. Elastic net (machine learning) was used to predict the incidence of rHOA (including Kellgren–Lawrence grade (KL) ≥ 2 or total hip replacement (THR)), joint space narrowing score (JSN, range 0–3), and osteophyte score (OST, range 0–3) after 10 years. Performance of prediction models was assessed using the area under the receiver operating characteristic curve (ROC AUC). Results: Of the 987 hips without rHOA at baseline, 435 (44%) had rHOA at 10-year follow-up. Of the 667 hips with JSN grade 0 at baseline, 471 (71%) had JSN grade ≥ 1 at 10-year follow-up. Of the 613 hips with OST grade 0 at baseline, 526 (86%) had OST grade ≥ 1 at 10-year follow-up. AUCs for the models including age, gender, and body mass index (BMI) to predict incident rHOA, JSN, and OST were 0.59, 0.54, and 0.51, respectively. The inclusion of bone texture variables in the models improved the prediction of incident rHOA (ROC AUC 0.68 and 0.71 when baseline KL was also included in the model) and JSN (ROC AUC 0.62), but not incident OST (ROC AUC 0.52). Conclusion: Bone texture analysis provides additional information for predicting incident rHOA or THR over 10 years.

Plain radiography is the most common modality to assess the stage of osteoarthritis. Our aims were to assess the relationship of radiography-based bone density and texture between radiographs with minimal and clinical post-processing, and to compare the differences in bone characteristics between controls and subjects with knee osteoarthritis or medial tibial bone marrow lesions (BMLs). Tibial bone density and texture was evaluated from radiographs with both minimal and clinical post-processing in 109 subjects with and without osteoarthritis. Bone texture was evaluated using fractal signature analysis. Significant correlations (p

Knee osteoarthritis (OA) is the most common musculoskeletal disorder affecting all populations. One common knee OA symptom is instability; thus its assessment could allow diagnosing and following-up of the disease without using conventional imaging techniques, such as plain radiography or magnetic resonance imaging (MRI). Knee kinematic measurements using accelerometers could provide a low-cost and non-invasive option to quantify knee instability. The aim of this study was to assess the relationships between kinematic data, instability parameters derived from the imaging techniques, goniometer-based measurements, and radiological OA stage. The right knees of 66 females (44–67 years) were examined using MRI, plain radiography, and goniometer-based angle measurement. Kellgren–Lawrence (KL) grade and the joint line convergence angle (JLCA) were determined from the radiographs. Cartilage thickness and OA score (MOAKS) were derived from the MRI. A ratio between lateral and medial cartilage thicknesses was calculated from the average thickness of segmented cartilage over the weight bearing area (MRIratio). Accelerometers attached to thigh and shank were used to record kinematic signals during a one-leg-stand test. Power of the accelerometer signals along the anatomical longitudinal axis (Pacc) was used as a measure of knee instability. Finally, Spearman’s correlations between the acquired parameters and KL grade/MOAKS scores were calculated. Leave-one-out cross-validation and logistic regression were used to discriminate OA subjects (KL ≥ 2). All the instability parameters (Pacc, JLCA and MRIratio), except the goniometer angle, showed significant correlations with KL grading (rho = 0.32–0.64, p < 0.01) and MOAKS composite score (rho = 0.35–0.56, p < 0.01). Both Pacc and JLCA showed higher areas under the ROC curve to discriminate OA (AUC = 0.76 and AUC = 0.78) than MRIratio and goniometer angle (AUC = 0.55 and AUC = 0.56). Our results demonstrate the clinical potential of kinematic knee instability measurements using low-cost accelerometers. Such approach could become a potential new tool in OA diagnostics.

Osteoarthritis (OA) causes progressive degeneration of articular cartilage and pathological changes in subchondral bone, conventionally assessed volumetrically using micro-computed tomography (μCT) imaging in vitro. The local binary patterns (LBP) method has recently been suggested as a new alternative solution to perform analysis of local bone structures from μCT scans. In this study, a novel 3D LBP-based method to provide a new lead in bone microstructural analysis is proposed. In addition to the detailed description of the method, this solution is tested using µCT data of OA human trabecular bone samples, harvested from patients treated with total knee arthroplasty. The method was applied to correlate the distribution of orientations of local patterns with the severity of the disease. The local orientations of the bone fibers changed along the severity of OA, suggesting an adaptation of the bone to the disease. The structural parameters derived from the process were able to provide a new approach for the assessment of the disease, supporting the potential of this volumetric LBP-based method to assess trabecular bone changes.

To investigate the association of quantitative magnetic resonance imaging (qMRI) parameters with arthroscopic grading of cartilage degeneration. Arthroscopy of the knee is considered to be the gold standard of osteoarthritis diagnostics; however, it is operator-dependent and limited to the evaluation of the articular surface. qMRI provides information on the quality of articular cartilage and its changes even at early stages of a disease. qMRI techniques included T 1 relaxation time, T 2 relaxation time, and delayed gadolinium-enhanced MRI of cartilage mapping at 3 T in ten patients. Due to a lack of generally accepted semiquantitative scoring systems for evaluating severity of cartilage degeneration during arthroscopy, the International Cartilage Repair Society (ICRS) classification system was used to grade the severity of cartilage lesions. qMRI parameters were statistically compared to arthroscopic grading conducted with the ICRS classification system. qMRI parameters were not linearly related to arthroscopic grading. Spearman’s correlation coefficients between qMRI and arthroscopic grading were not significant. The relative differences in qMRI parameters of superficial and deep cartilage varied with degeneration, suggesting different macromolecular alterations in different cartilage zones. Results suggest that loss of cartilage and the quality of remaining tissue in the lesion site may not be directly associated with each other. The severity of cartilage degeneration may not be revealed solely by diagnostic arthroscopy, and thus, qMRI can have a role in the investigation of cartilage degeneration.

To investigate whether femoral neck fracture can be predicted retrospectively on the basis of clinical radiographs by using the combined analysis of bone geometry, textural analysis of trabecular bone, and bone mineral density (BMD).Formal ethics committee approval was obtained for the study, and all participants gave informed written consent. Pelvic radiographs and proximal femur BMD measurements were obtained in 53 women aged 79-82 years in 2006. By 2012, 10 of these patients had experienced a low-impact femoral neck fracture. A Laplacian-based semiautomatic custom algorithm was applied to the radiographs to calculate the texture parameters along the trabecular fibers in the lower neck area for all subjects. Intra- and interobserver reproducibility was calculated by using the root mean square average coefficient of variation to evaluate the robustness of the method.The best predictors of hip fracture were entropy (P = .007; reproducibility coefficient of variation1%), the neck-shaft angle (NSA) (P = .017), and the BMD (P = .13). For prediction of fracture, the area under the receiver operating characteristic curve was 0.753 for entropy, 0.608 for femoral neck BMD, and 0.698 for NSA. The area increased to 0.816 when entropy and NSA were combined and to 0.902 when entropy, NSA, and BMD were combined.Textural analysis of pelvic radiographs enables discrimination of patients at risk for femoral neck fracture, and our results show the potential of this conventional imaging method to yield better prediction than that achieved with dual-energy x-ray absorptiometry-based BMD. The combination of the entropy parameter with NSA and BMD can further enhance predictive accuracy.

Radiographic texture analysis has been developed lately to improve the assessment of bone architecture as a determinant of bone quality. We validate here an algorithm for the evaluation of trabecular homogeneity index (HI) in the proximal femur from hip radiographs, with a focus on the impact of the principal compressive system of the trabecular bone, and evaluate its correlation with femoral strength, bone mineral density (BMD), and volumetric trabecular structure parameters. A semiautomatic custom-made algorithm was applied to calculate the HI in the femoral neck and trochanteric areas from radiographs of 178 femoral bone specimens (mean age 79.3 ± 10.4 years). Corresponding neck region was selected in CT scans to calculate volumetric parameters of trabecular structure. The site-specific BMDs were assessed from dual-energy X-ray absorptiometry (DXA), and the femoral strength was experimentally tested in side-impact configuration. Regression analysis was performed between the HI and biomechanical femoral strength, BMD, and volumetric parameters. The correlation between HI and failure load was R2 = 0.50; this result was improved to R2 = 0.58 for cervical fractures alone. The discrimination of bones with high risk of fractures (load

Neuroradiological findings are presented of 19 patients with the northern epilepsy syndrome, a recessively inherited childhood epilepsy with associated mental deterioration. The first signs of cerebellar-brainstem atrophy already appeared in young adulthood, with atrophy tending to increase with age. Findings of cerebral atrophy were detected later: four of the seven patients under 30 years of age displayed central or cortical atrophy, while all 12 patients over 30 were affected. The degree of mental deterioration correlated well with the severity of cerebral atrophy. One half of the patients with either central or cortical atrophy were moderately to severely retarded, whereas all patients with both central and cortical atrophy were moderately to profoundly retarded.

Summary: Purpose: To study the prevalence and features of visual field constrictions (VFCs) associated with vigabatrin (VGB) in children. Methods: A systematic collection of all children with any history of VGB treatment in fifteen Finnish neuropediatric units was performed, and children were included after being able to cooperate reliably in repeated visual field tests by Goldmann kinetic perimetry. This inclusion criterion yielded 91 children (45 boys; 46 girls) between ages 5.6 and 17.9 years. Visual field extent

Northern epilepsy syndrome (NES, EPMR, progressive epilepsy with mental retardation, CLN8), an inherited childhood-onset epilepsy with mental retardation, has been recently characterized to belong to the family of neuronal ceroid lipofuscinoses (NCLs). In this study, four patients (ages 26-44 years) with NES and eight healthy controls underwent magnetic resonance imaging (MRI) and electrophysiological evaluation with somatosensory evoked magnetic field (SEF) studies. The findings in NES were compared with the known findings in juvenile NCL (JNCL, CLN3) and Finnish variant late infantile NCL (vLINCLFIN, CLN5) that manifest around the same age as NES. Also postmortem MRI was performed on one brain. On the MRIs, slight to moderate cerebellar atrophy was seen in all patients, whereas only two patients had slightly enlarged cerebral sulci. None of the MRIs demonstrated signal intensity abnormalities that are commonly seen in JNCL and vLINCLFIN and are considered to reflect the Wallerian degeneration after neuronal death. Generally SEFs in NES were within normal limits, indicating that the disease had not impaired the function of the neurons on the somatosensory pathway. In conclusion, MRI imaging and SEF findings suggest that the cerebral neuronal death and dysfunction in NES are minimal compared with JNCL and vLINCLFIN.

In search of the gene for progressive epilepsy with mental retardation (EPMR) we identified DLGAP2, the human homolog of the gene encoding the rat PSD-95/SAP90-associated protein-2 (Dlgap2). We extended the transcript in both the 5' and 3' directions and characterised the genomic structure of the approximately 10 kb gene. Sequence comparisons of human DLGAP2 cDNA sequences obtained from human testis and brain cDNA libraries with homologous rat genes suggest alternative splicing in the 5' end of the gene. The 5' coding sequence of the testis cDNA is complete, whereas based on homology with the rat gene 103 bp of coding sequence may still be missing in the 5' end of the DLGAP2 brain transcript. DLGAP2 was excluded as the gene responsible for EPMR.

Northern epilepsy is an autosomal recessive childhood onset epilepsy syndrome, clinically characterized by generalized tonic‐clonic seizures with onset at 5 to 10 years of age and subsequent slowly progressive mental deterioration. The patients may reach 50 or 60 years of age. A mutation responsible for the disease has recently been identified in a novel gene on chromosome 8p23, encoding a putative membrane protein with an unknown function. The present study, based on three autopsied patients, is the first neuropathological analysis of the disease, and showed intraneuronal accumulation of cytoplasmic autofluorescent granules. The granules were strongly stained by the Luxol fast blue, periodic acid‐Schiff, and Sudan black B methods in paraffin sections, and were immunoreactive for subunit c of the mitochondrial ATP synthase and sphingolipid activator proteins A and D. The intraneuronal storage was highly selective: the third layer of the isocortex and the hippocampal CA2, CA3, and CA4 sectors were severely affected, while other layers of the isocortex, the CA1 sector, and the cerebellar cortex were only minimally involved. The membrane‐bound storage cytosomes showed a curvilinear ultrastructure with admixture of some granular components. Western blotting and N‐terminal sequence analysis of purified storage material identified subunit c as the major component. These findings establish Northern epilepsy as a new form of neuronal ceroid‐lipofuscinosis with an exceptionally protracted course.

Progressive epilepsy with mental retardation (EPMR) is an autosomal recessive central nervous system disorder characterized by childhood onset epilepsy and subsequent mental retardation. The locus for EPMR has been mapped to human chromosome 8p23. We recently reported the construction of a YAC contig across the 4 centimorgan minimum genetic region that harbors the disease locus. We now report further delineation of the critical region to [The sequence data described in this paper have been submitted to the GenBank data library under accession nos. AF009188–AF009214.]

Arthroscopic ultrasound imaging enables quantitative evaluation of articular cartilage. However, the potential of this technique for evaluation of subchondral bone has not been investigated in vivo. In this study, we address this issue in clinical arthroscopy of the human knee (n = 11) by determining quantitative ultrasound (9 MHz) reflection and backscattering parameters for cartilage and subchondral bone. Furthermore, in each knee, seven anatomical sites were graded using the International Cartilage Repair Society (ICRS) system based on (i) conventional arthroscopy and (ii) ultrasound images acquired in arthroscopy with a miniature transducer. Ultrasound enabled visualization of articular cartilage and subchondral bone. ICRS grades based on ultrasound images were higher (p < 0.05) than those based on conventional arthroscopy. The higher ultrasound-based ICRS grades were expected as ultrasound reveals additional information on, for example, the relative depth of the lesion. In line with previous literature, ultrasound reflection and scattering in cartilage varied significantly (p < 0.05) along the ICRS scale. However, no significant correlation between ultrasound parameters and structure or density of subchondral bone could be demonstrated. To conclude, arthroscopic ultrasound imaging had a significant effect on clinical grading of cartilage, and it was found to provide quantitative information on cartilage. The lack of correlation between the ultrasound parameters and bone properties may be related to lesser bone change or excessive attenuation in overlying cartilage and insufficient power of the applied miniature transducer.

Radiographic texture analysis has been developed lately to improve the assessment of bone architecture as a determinant of bone quality. We validate here an algorithm for the evaluation of trabecular homogeneity index (HI) in the proximal femur from hip radiographs, with a focus on the impact of the principal compressive system of the trabecular bone, and evaluate its correlation with femoral strength, bone mineral density (BMD), and volumetric trabecular structure parameters. A semiautomatic custom-made algorithm was applied to calculate the HI in the femoral neck and trochanteric areas from radiographs of 178 femoral bone specimens (mean age 79.3 ± 10.4 years). Corresponding neck region was selected in CT scans to calculate volumetric parameters of trabecular structure. The site-specific BMDs were assessed from dual-energy X-ray absorptiometry (DXA), and the femoral strength was experimentally tested in side-impact configuration. Regression analysis was performed between the HI and biomechanical femoral strength, BMD, and volumetric parameters. The correlation between HI and failure load was R(2) = 0.50; this result was improved to R(2) = 0.58 for cervical fractures alone. The discrimination of bones with high risk of fractures (load3000 N) was similar for HI and BMD (AUC = 0.87). Regression analysis between the HIs versus site-specific BMDs yielded R(2) = 0.66 in neck area, R(2) = 0.60 in trochanteric area, and an overall of R(2) = 0.66 for the total hip. Neck HI and BMD correlated significantly with volumetric structure parameters. We present here a method to assess HI that can explain 50% of an experimental failure load and determines bones with high fracture risk with similar accuracy as BMD. The HI also had good correlation with DXA and computed tomography-derived data.

Traditional arthroscopic examination is subjective and poorly reproducible. Recently, we introduced an arthroscopic ultrasound method for quantitative diagnostics of cartilage lesions. Here we describe our investigation of the feasibility of ultrasound arthroscopy for simultaneous measurements of articular cartilage and subchondral bone. Human osteochondral samples (n = 13) were imaged using a clinical 9-MHz ultrasound system. Ultrasound reflection coefficients (R, IRC), the ultrasound roughness index (URI) and the apparent integrated backscattering coefficient (AIB) were determined for both tissues. Mechanical testing, histologic analyses and micro-scale computed tomography imaging were the reference methods. Ultrasound arthroscopies were conducted on two patients. The ultrasound reflection coefficient correlated with the Mankin score and Young's modulus of cartilage (|r|0.56, p0.05). Ultrasound parameters (R, IRC, AIB) for subchondral bone correlated with the bone surface/volume ratio (|r|0.70, p0.05) and trabecular thickness (|r|0.59, p0.05). Furthermore, R and subchondral bone mineral density were significantly correlated (|r|0.65, p0.05). Arthroscopic ultrasound examination provided diagnostically valuable information on cartilage and subchondral bone in vivo.

A new autosomal recessively inherited disease of the central nervous system involving childhood epilepsy and mental deterioration is described. Twenty three patients (11 males and 12 females) belonging to 11 families from northern Finland have been identified. A common ancestor has been found for nine families. The mean age of onset of epilepsy was 6.7 years (range 5-10 years) and the epilepsy was characterised by generalised tonic-clonic seizures increasing in frequency up to puberty. One third of the patients also had complex partial seizures during childhood. During young adulthood the epileptic activity began to decrease, but complete remission did not occur. Electroencephalography showed progressive slowing of the background activity with relatively scanty epileptiform activity. Out of four ictal recordings the paroxysmal activity was initiated focally in two cases. Clonazepam and sodium valproate had some antiepileptic effect, clonazepam being the more beneficial of the two. Mental development, which was originally normal, began to deteriorate two to five years after the onset of epilepsy, and the deterioration continued during adulthood in spite of good epilepsy control, leading to mental retardation by middle age. The pathogenesis of the disorder, called the Northern epilepsy syndrome, is unknown. Linkage analysis using DNA markers linked to the EPM1 gene for progressive myoclonus epilepsy of Unverricht-Lundborg type showed that the Northern epilepsy syndrome is not allelic to EPM1.

Lack of security and trust is considered the biggest barrier to the increase of business-to-consumer e-commerce. In this chapter the authors aim at gaining insights of how online vendor design and usability relate to people’s opinions of the trustworthiness of shopping online. Additionally, common concerns regarding trust and security are explored both theoretically, based on existing literature, and empirically in a pilot study. The results showed that the most common concern among the respondents is online payment. The respondents valued detailed information of the products, of the processing and delivery of orders. Also the familiarity of products and vendors and easy-to-use online stores were appreciated. In e-business, quality design and good usability of vendors’ websites can be seen as a means to diminish the customer’s potentially risky situation. From the customer’s viewpoint, in turn, these can be taken as the indicators of quality and the vendor’s competence which reduce uncertainty and predict trust in e-commerce environment.

The binding of autoimmune anticardiolipin antibodies to phospholipid has been shown to require a plasma cofactor, beta-2-glycoprotein 1 (β2-GPI). Antibodies against β2-GPI are associated with both venous and arterial thrombosis in adults and have been suggested as a new antiphospholipid syndrome marker. We present six children with cerebral thrombosis at the age of 0–12 months, who had IgG antibodies to β2-GPI (titers 26, 29, 31, 39, 101 and 109 SGU, when 20 SGU was the cut-off). In at least four patients, the conventional antiphospholipid markers (lupus anticoagulant and IgG and IgM anticardiolipin) were negative. All six children had normal results in the other routine thrombophilia assays (thrombin time, antithrombin, protein C, protein S, factor V Leiden mutation, prothrombin mutation). Conclusion: the anti-beta-2 glycoprotein 1 assay, requiring only 5 μl serum, may be a useful addition to antiphospholipid-antibody diagnostics in cases of paediatric stroke.

We describe the neurophysiological findings in the northern epilepsy syndrome (NES), an autosomal recessively inherited childhood onset epilepsy with associated mental deterioration. Sixty-five EEGs of 18 patients (10 females and 8 males) from the age of 5 years to 52 years were analyzed. EEG showed relatively slight changes at the outbreak of epilepsy at the mean age of 6.6 years (range 5-10 years). Slowing of the background activity to 6-7 Hz theta activity, abundant diffuse or intermittent theta and delta activity and disappearance of sleep-specific activity characterized the EEGs at puberty. The amount of diffuse delta and theta activity diminished in adulthood. Epileptiform findings were scanty. Spikes and sharp waves occurred in 43% of the recordings with varying localization, form and extent. Intermittent 2-4 Hz sharp and slow wave rhythm was seen in 32% of the recordings. Of the three ictal recordings, one showed a primarily generalized discharge pattern, while two were clearly asymmetric. Clonazepam was the most effective antiepileptic drug, and it also normalized the EEG when started in childhood or at the onset of puberty. Visual evoked potentials were abnormal in 44% and brainstem auditory evoked potentials in 35%. The neurophysiological findings suggest an extensive, probably multifocal degenerative brain process, which reaches its peak at puberty. Although the abnormal features of EEG often decreased in adulthood, the clinical course of NES showed slow progression throughout the lifetime.

Progressive epilepsy with mental retardation (EPMR) is an autosomal recessive disorder discovered recently from an isolated region in Finland. The disorder is characterized by normal early development, generalized tonic-clonic seizures with onset at 5-10 years of age, and progressive mental retardation beginning 2-5 years after the onset of seizures. We recently mapped the EPMR locus to a 7-cM region on chromosome 8p between markers AFM185xb2 and D8S262. A recombination detected with a new microsatellite marker AFMa054td9 narrows the region to 4 cM. A yeast artificial chromosome (YAC) contig containing 22 YACs was constructed across the disease gene region. The YAC contig is characterized by a collection of 19 YAC-end sequence-tag sites together with seven microsatellite markers. The entire YAC contig spans a minimum of 3 Mb. Moreover, the distal end of the contig contains a subtelomeric YAC yRM2205 that anchors the contig to the telomere. Construction of a YAC contig across the disease gene region is an essential step toward the isolation of the EPMR gene.

Summary: We describe the clinical course and treatment of 19 patients with the Northern epilepsy syndrome, an autosomal recessively inherited epilepsy with associated mental deterioration. The clinical course could be divided into three successive stages. The first stage continued from the onset of epilepsy until puberty. Seizures began at a mean age of 6.6 years and consisted predominantly of generalized tonic-clonic convulsions (GTC) and, transiently, also of complex partial seizures (CPS). Until puberty, seizure frequency increased in most patients from one attack in 1–2 months to one to two attacks weekly. Seizures did not respond to phenytoin (PHT) or carbamazepine (CBZ), were transiently controlled by valproate (VPA) and phenobarbital (PB), but were effectively treated only by clonazepam (CZP). Mental deterioration began 2–5 years after the onset of epilepsy and was most rapid before adulthood, a time when the seizures were also most frequent. The second stage is marked by fewer seizures, further mental deterioration, and less rapid progression. All patients were demented (I.Q.

A recently delineated childhood epilepsy has hitherto been observed only in a small geographic region in northern Finland, where, with the exception of one, both parents of all of the 11 sibships with affected individuals descend from one or two founding couples. The disease is characterized by generalized tonic-clonic seizures with onset at 5-10 years and progressive, severe mental retardation with onset 2-5 years after the first seizures. In this study the gene locus is assigned to the telomeric region of chromosome 8p by linkage. Analyses of recombinations place the locus in the 7-centimorgan interval between AFM185xb2 and D8S262 in which three markers, D8S504, D8S264, and AFM077yg5, show no recombinations with the phenotype. Haplotypes comprising alleles at the above five loci support the hypothesis of a single founding mutation for all affected chromosomes except the one belonging to the unrelated parent, who has a very different haplotype, suggesting another mutation or a very old ancestry of a single mutation. This study raises to three the number of heritable epilepsies whose gene loci have been mapped and provides a starting point for the cloning of the gene. It also suggests the possibility that the disease might not be limited to the northern Finnish population.

In Finland, 19 children, born 1964--1977, from 13 families, have been diagnosed as suffering from nonketotic hyperglycinemia (NKH). This gives an incidence for NKH in the Finnish population of 1:55,000 newborns. The majority of these children were born in the northern part of the country, where the incidence is 1:12,000. The geographical distribution of the birth-places of the grandparents also seems to point towards an enrichment of the gene in northern Finland. An autosomal recessive mode of inheritance for this disease seems probable, since the corrected proportion of affected siblings (Apert's a priori method) is 0.288. Abnormally high plasma glycine concentration and elevated glycine urinary excretion in the parents of the NKH-children suggest the existence of a minor metabolic defect in heterozygotes of this disease. Some of the healthy siblings of the NKH-patients also show similary elevated levels. However, a definite diagnosis of the NKH-heterozygote state cannot easily be made on the basis of these laboratory findings, as the levels in some individuals are very close to, or even overlap corresponding values in a normal material.

The neuronal ceroid lipofuscinoses (NCLs) are a genetically heterogeneous group of progressive neurodegenerative disorders characterized by the accumulation of autofluorescent lipopigment in various tissues1. Progressive epilepsy with mental retardation (EPMR, MIM 600143) was recently recognized as a new NCL subtype2 (CLN8). It is an autosomal recessive disorder characterized by onset of generalized seizures between 5 and 10 years, and subsequent progressive mental retardation3. Here we report the positional cloning of a novel gene, CLN8, which is mutated in EPMR. It encodes a putative transmembrane protein. EPMR patients were homozygous for a missense mutation (70C→G, R24G) that was not found in homozygosity in 433 controls. We also cloned the mouse Cln8 sequence. It displays 82% nucleotide identity with CLN8, conservation of the codon harbouring the human mutation and is localized to the same region as the motor neuron degeneration mouse, mnd, a naturally occurring mouse NCL (ref. 4). In mnd/mnd mice, we identified a homozygous 1-bp insertion (267-268insC, codon 90) predicting a frameshift and a truncated protein. Our data demonstrate that mutations in these orthologous genes underlie NCL phenotypes in human and mouse, and represent the first description of the molecular basis of a naturally occurring animal model for NCL.