Diagnostics and treatment delay in primary central nervous system lymphoma: What the neurosurgeon should know.

PURPOSE: The gold standard for diagnostics in primary central nervous system lymphoma (PCNSL) is histopathological diagnosis after stereotactic biopsy. Yet, PCNSL has a multidisciplinary diagnostic work up, which associated with diagnostic delay and could result in treatment delay. This article offers recommendations to neurosurgeons involved in clinical decision-making regarding (novel) diagnostics and care for patients with PCNSL with the aim to improve uniformity and timeliness of the diagnostic process for patients with PCNSL. METHODS: We present a mini review to discuss the role of stereotactic biopsy in the context of novel developments in diagnostics for PCNSL, as well as the role for cytoreductive surgery. RESULTS: Cerebrospinal fluid-based diagnostics are supplementary and cannot replace stereotactic biopsy-based diagnostics. CONCLUSION: Histopathological diagnosis after stereotactic biopsy of the brain remains the gold standard for diagnosis. Additional diagnostics should not be a cause of diagnostic delay. There is currently no sufficient evidence supporting cytoreductive surgery in PCNSL, with recent studies showing contradictive data and suboptimal study designs.

Genetic mutations and phenotype characteristics in peripheral vascular malformations: A systematic review.

Vascular malformations (VMs) are clinically diverse with regard to the vessel type, anatomical location, tissue involvement and size. Consequently, symptoms and disease impact differ significantly. Diverse causative mutations in more and more genes are discovered and play a major role in the development of VMs. However, the relationship between the underlying causative mutations and the highly variable phenotype of VMs is not yet fully understood. In this systematic review, we aimed to provide an overview of known causative mutations in genes in VMs and discuss associations between the causative mutations and clinical phenotypes. PubMed and EMBASE libraries were systematically searched on November 9th, 2022 for randomized controlled trials and observational studies reporting causative mutations in at least five patients with peripheral venous, lymphatic, arteriovenous and combined malformations. Study quality was assessed with the Newcastle-Ottawa Scale. Data were extracted on patient and VM characteristics, molecular sequencing method and results of molecular analysis. In total, 5667 articles were found of which 69 studies were included, reporting molecular analysis in a total of 4261 patients and 1686 (40%) patients with peripheral VMs a causative mutation was detected. In conclusion, this systematic review provides a comprehensive overview of causative germline and somatic mutations in various genes and associated phenotypes in peripheral VMs. With these findings, we attempt to better understand how the underlying causative mutations in various genes contribute to the highly variable clinical characteristics of VMs. Our study shows that some causative mutations lead to a uniform phenotype, while other causal variants lead to more varying phenotypes. By contrast, distinct causative mutations may lead to similar phenotypes and result in almost indistinguishable VMs. VMs are currently classified based on clinical and histopathology features, however, the findings of this systematic review suggest a larger role for genotype in current diagnostics and classification.

The association between medication use and gait in adults with intellectual disabilities.

BACKGROUND: Adults with intellectual disabilities (ID) often have polypharmacy and often use antipsychotics. Both polypharmacy and antipsychotics have a negative effect on gait in the general population, but this has not been studied in adults with ID. These negative effects may add to pre-existing gait disturbances in adults with ID and increase the risk for adverse health outcomes in this population. Therefore, the aim of this study is to investigate the difference in gait parameters between adults with ID with and without polypharmacy and between adults with ID using and not using antipsychotics. METHOD: The gait parameters of 31 participants were collected with the GAITRite walkway, a pressure sensitive walkway measuring spatial and temporal gait parameters, in addition to information about personal characteristics, prescribed medication and presence of polypharmacy. RESULTS: After adjustment for sex and body mass index, participants with polypharmacy had a significantly shorter step length [polypharmacy B (SE) = -0.079 (0.034), P = 0.03], shorter stride length [polypharmacy B (SE) = -0.157 (0.069), P = 0.03] and longer double support time [polypharmacy B (SE) = 0.0004 (0.0001), P = 0.047]. Participants using antipsychotics had a significantly longer double support time [antipsychotic use B (SE) = 0.0003 (0.0002), P = 0.019]. CONCLUSION: This study showed for the first time that both polypharmacy and using antipsychotics are associated with gait in adults with ID. The differences seem to resemble a more cautious gait. Further investigation with larger study samples, additional medication types and dosages are needed to acquire more insight in this important topic.

Development, behaviour and sensory processing in Marshall-Smith syndrome and Malan syndrome: phenotype comparison in two related syndromes.

BACKGROUND: Ultrarare Marshall-Smith and Malan syndromes, caused by changes of the gene nuclear factor I X (NFIX), are characterised by intellectual disability (ID) and behavioural problems, although questions remain. Here, development and behaviour are studied and compared in a cross-sectional study, and results are presented with genetic findings. METHODS: Behavioural phenotypes are compared of eight individuals with Marshall-Smith syndrome (three male individuals) and seven with Malan syndrome (four male individuals). Long-term follow-up assessment of cognition and adaptive behaviour was possible in three individuals with Marshall-Smith syndrome. RESULTS: Marshall-Smith syndrome individuals have more severe ID, less adaptive behaviour, more impaired speech and less reciprocal interaction compared with individuals with Malan syndrome. Sensory processing difficulties occur in both syndromes. Follow-up measurement of cognition and adaptive behaviour in Marshall-Smith syndrome shows different individual learning curves over time. CONCLUSIONS: Results show significant between and within syndrome variability. Different NFIX variants underlie distinct clinical phenotypes leading to separate entities. Cognitive, adaptive and sensory impairments are common in both syndromes and increase the risk of challenging behaviour. This study highlights the value of considering behaviour within developmental and environmental context. To improve quality of life, adaptations to environment and treatment are suggested to create a better person-environment fit.

[​Biomechanics of new implants for HTO]. / Biomechanik neuer Implantate für die HTO.

Biomechanical characteristics of 5 tibial osteotomy plates for the treatment of medial knee joint osteoarthritis were examined. Fourth-generation tibial bone composites underwent a medial open-wedge high tibial osteotomy, using TomoFix™ standard, PEEKPower®, ContourLock®, TomoFix™ small stature plates, and iBalance® implants. Static compression load to failure and load-controlled cyclic fatigue failure tests were performed. All plates had sufficient stability up to 2400 N in the static compression load to failure tests. Screw breakage in the iBalance® group and opposite cortex fractures in all constructs occurred at lower loading conditions. The highest fatigue strength in terms of maximal load and number of cycles performed prior to failure was observed for the ContourLock® group followed by the iBalance® implants, the TomoFix™ standard and small stature plates. PEEKPower® had the lowest fatigue strength. All plates showed sufficient stability under static loading. Compared to the TomoFix™ and the PEEKPower® plates, the ContourLock® plate and iBalance® implant showed a higher mechanical fatigue strength during cyclic fatigue testing, suggesting that both mechanical static and fatigue strength increase with a wider proximal T­shaped plate design together with diverging proximal screws. Mechanical strength of the bone-implant constructs decreases with a narrow T­shaped proximal end design and converging proximal screws (TomoFix™) or a short vertical plate design (PEEKPower®). Published results indicate high fusion rates and good clinical results with the TomoFix™ plate, which is contrary to our findings. A certain amount of interfragmentary motion rather than high mechanical strength and stiffness seem to be important for bone healing which is outside the scope of this paper.

Glioblastoma-derived extracellular vesicles modify the phenotype of monocytic cells.

Glioblastoma multiforme (GBM) is the most common primary brain tumor and is without exception lethal. GBMs modify the immune system, which contributes to the aggressive nature of the disease. Particularly, cells of the monocytic lineage, including monocytes, macrophages and microglia, are affected. We investigated the influence of GBM-derived extracellular vesicles (EVs) on the phenotype of monocytic cells. Proteomic profiling showed GBM EVs to be enriched with proteins functioning in extracellular matrix interaction and leukocyte migration. GBM EVs appeared to skew the differentiation of peripheral blood-derived monocytes to alternatively activated/M2-type macrophages. This was observed for EVs from an established cell line, as well as for EVs from primary cultures of GBM stem-like cells (GSCs). Unlike EVs of non-GBM origin, GBM EVs induced modified expression of cell surface proteins, modified cytokine secretion (e.g., an increase in vascular endothelial growth factor and IL-6) and increased phagocytic capacity of the macrophages. Most pronounced effects were observed upon incubation with EVs from mesenchymal GSCs. GSC EVs also affected primary human microglia, resulting in increased expression of Membrane type 1-matrix metalloproteinase, a marker for GBM microglia and functioning as tumor-supportive factor. In conclusion, GBM-derived EVs can modify cells of the monocytic lineage, which acquire characteristics that resemble the tumor-supportive phenotypes observed in patients.

X-linked congenital ptosis and associated intellectual disability, short stature, microcephaly, cleft palate, digital and genital abnormalities define novel Xq25q26 duplication syndrome.

Submicroscopic duplications along the long arm of the X-chromosome with known phenotypic consequences are relatively rare events. The clinical features resulting from such duplications are various, though they often include intellectual disability, microcephaly, short stature, hypotonia, hypogonadism and feeding difficulties. Female carriers are often phenotypically normal or show a similar but milder phenotype, as in most cases the X-chromosome harbouring the duplication is subject to inactivation. Xq28, which includes MECP2 is the major locus for submicroscopic X-chromosome duplications, whereas duplications in Xq25 and Xq26 have been reported in only a few cases. Using genome-wide array platforms we identified overlapping interstitial Xq25q26 duplications ranging from 0.2 to 4.76 Mb in eight unrelated families with in total five affected males and seven affected females. All affected males shared a common phenotype with intrauterine- and postnatal growth retardation and feeding difficulties in childhood. Three had microcephaly and two out of five suffered from epilepsy. In addition, three males had a distinct facial appearance with congenital bilateral ptosis and large protruding ears and two of them showed a cleft palate. The affected females had various clinical symptoms similar to that of the males with congenital bilateral ptosis in three families as most remarkable feature. Comparison of the gene content of the individual duplications with the respective phenotypes suggested three critical regions with candidate genes (AIFM1, RAB33A, GPC3 and IGSF1) for the common phenotypes, including candidate loci for congenital bilateral ptosis, small head circumference, short stature, genital and digital defects.

Patient-specific analysis of cartilage and labrum mechanics in human hips with acetabular dysplasia.

BACKGROUND: Acetabular dysplasia is a major predisposing factor for development of hip osteoarthritis (OA), and may result from alterations to chondrolabral loading. Subject-specific finite element (FE) modeling can be used to evaluate chondrolabral mechanics in the dysplastic hip, thereby providing insight into mechanics that precede OA. OBJECTIVE: To evaluate chondrolabral contact mechanics and congruency in dysplastic hips and normal hips using a validated approach to subject-specific FE modeling. METHODS: FE models of ten subjects with normal acetabula and ten subjects with dysplasia were constructed using a previously validated protocol. Labrum load support, and labrum and acetabular cartilage contact stress and contact area were compared between groups. Local congruency was determined at the articular surface for two simulated activities. RESULTS: The labrum in dysplastic hips supported 2.8-4.0 times more of the load transferred across the joint than in normal hips. Dysplastic hips did not have significantly different congruency in the primary load-bearing regions than normal hips, but were less congruent in some unloaded regions. Normal hips had larger cartilage contact stress than dysplastic hips in the few regions that had significant differences. CONCLUSIONS: The labrum in dysplastic hips has a far more significant role in hip mechanics than it does in normal hips. The dysplastic hip is neither less congruent than the normal hip, nor subjected to elevated cartilage contact stresses. This study supports the concept of an outside-in pathogenesis of OA in dysplastic hips and that the labrum in dysplastic hips should be preserved during surgery.

Influence of the 20-week anomaly scan on prenatal diagnosis and management of fetal facial clefts.

OBJECTIVE: To investigate trends in prenatal diagnosis and termination of pregnancy rates in cases of fetal cleft lip with or without cleft palate (CL ± P), before and after the introduction in The Netherlands of the 20-week anomaly scan in 2007, and to assess the accuracy of this scan for the diagnosis of facial clefts. METHODS: This was a retrospective cohort study of consecutive cases of CL ± P diagnosed in 2001-2010 in the referral region of the Academic Medical Centre. Cases diagnosed prenatally were identified from the hospital's database. These data, grouped according to the periods before and after the introduction of the routine 20-week anomaly scan, were compared with data of all cases managed by the multidisciplinary cleft team, which services the same region, to identify cases of CL ± P that were not seen prenatally. RESULTS: We identified 123 cases of CL ± P diagnosed prenatally, of which 76% (93/123) were diagnosed before 24 weeks. In one case, the CL ± P was not confirmed after birth. There were 46 cases with associated structural anomalies and 76 isolated cases. The median gestational age at diagnosis decreased by 2 weeks after 2007 (P = 0.02). The proportion of isolated clefts detected prenatally increased significantly after 2007 (P < 0.0001), whereas the proportion of associated clefts remained stable over the years (P = 0.426). The overall detection rate of CL ± P increased from 43% before 2007 to 86% after 2007 (P < 0.0001), without an increase in terminations of pregnancy. CONCLUSION: Introduction of the routine fetal anomaly scan has decreased the gestational age at diagnosis of CL ± P and has increased the proportion diagnosed prenatally, without a significant change in the number of terminations of pregnancy.

Validation of a personalized ligament-constraining discrete element framework for computing ankle joint contact mechanics.

BACKGROUND AND OBJECTIVE: Computer simulations of joint contact mechanics have great merit to improve our current understanding of articular ankle pathology. Owed to its computational simplicity, discrete element analysis (DEA) is an encouraging alternative to finite element analysis (FEA). However, previous DEA models lack subject-specific anatomy and may oversimplify the biomechanics of the ankle. The objective of this study was to develop and validate a personalized DEA framework that permits movement of the fibula and incorporates personalized cartilage thickness as well as ligamentous constraints. METHODS: A linear and non-linear DEA framework, representing cartilage as compressive springs, was established, verified, and validated. Three-dimensional (3D) bony ankle models were constructed from cadaveric lower limb CT scans imaged during application of weight (85 kg) and/or torque (10 Nm). These 3D models were used to generate cartilage thickness and ligament insertion sites based on a previously validated statistical shape model. Ligaments were modelled as non-linear tension-only springs. Validation of contact stress prediction was performed using a simple, axially constrained tibiotalar DEA model against an equivalent FEA model. Validation of ligamentous constraints compared the final position of the ankle mortise to that of the cadaver after application of torque and sequential ligament sectioning. Finally, a combined ligamentous-constraining DEA model was validated for predicted contact stress against an equivalent ligament-constraining FEA model. RESULTS: The linear and non-linear DEA model reproduced a mean articular contact stress within 0.36 MPa and 0.39 MPa of the FEA calculated stress, respectively. With respect to the ligamentous validation, the DEA ligament-balancing algorithm could reproduce the position of the distal fibula within the ankle mortise to within 0.97 mm of the experimental observed distal fibula. When combining the ligament-constraining and contact stress algorithm, DEA was able to reproduce a mean articular contact stress to within 0.50 MPa of the FEA calculated contact stress. CONCLUSION: The DEA framework presented herein offers a computationally efficient alternative to FEA for the prediction of contact stress in the ankle joint, manifesting its potential to enhance the mechanical understanding of articular ankle pathologies on both a patient-specific and population-wide level. The novelty of this model lies in its personalized nature, inclusion of the distal tibiofibular joint and the use of non-linear ligament balancing to maintain the physiological ankle joint articulation.

Static rotational and sagittal knee laxity measurements after reconstruction of the anterior cruciate ligament.

PURPOSE: The goal of the present study was to evaluate static anteroposterior and rotational knee laxity after ACL reconstructions with two noninvasive measurement devices by comparing the measured results of the operated with the contralateral healthy knees of the patients. METHODS: Fifty-two consecutive patients were reviewed after isolated single-bundle transtibial ACL reconstruction using a BPTB graft. At a mean follow-up of 27 months, sagittal AP laxity was tested using a noninvasive knee measurement system (Genourob) with an applied pressure of 67 N, 89 N and 134 N. Rotational laxity was measured using a noninvasive rotational knee laxity device (Rotameter) with an applied torque of 5, 8 and 10 Nm. The results were compared with the measurements of the patients' healthy contralateral knees. Tegner, Lysholm and IKDC score were used in order to evaluate the clinical outcome. RESULTS: Pivot shift was negative (33) or glide (16) in 49 patients with 12 of 16 (75%) patients having also a pivot glide on the healthy contralateral side; Lachman tests were negative in 50 cases. Subjective assessment of the IKDC score was classified according to category A in 44 patients, B in 5 patients and C in 3 patients. Mean Lysholm score was 94.5 ± 9.5, median Tegner score was 7 (3-9) preoperative and 6 (3-9) at follow-up (n.s.). Anteroposterior knee laxity measurements revealed mean side-to-side differences of 0.6-1.3 mm (P < 0.0001). Rotational laxity measurements revealed no statistical significant differences between the operated and the contralateral knee (n.s.). The measured differences in the entire rotational range varied from 0.2° to 1° depending on the applied torque. In those 3 patients with a positive pivot shift, differences in the entire rotational range of 4.5° at 5 N, 4.6° at 8 N and 4.1° at 10 N were found. CONCLUSION: Static knee laxity was quantified after ACL surgery using the introduced noninvasive measurement systems by comparing the measured results of the operated with the contralateral healthy knees. Significant differences were found in AP laxity although they were defined as clinically successful according to the IKDC classification. No significant differences were found in rotational knee laxity measurements. Therefore, the used noninvasive masurement devices might offer a high potential for objective quality control in knee ligament injuries and their treatment. LEVEL OF EVIDENCE: Retrospective case series, Level IV.

Genome-wide evaluation and discovery of vertebrate A-to-I RNA editing sites.

RNA editing by adenosine deamination, catalyzed by adenosine deaminases acting on RNA (ADAR), is a post-transcriptional modification that contributes to transcriptome and proteome diversity and is widespread in mammals. Here we administer a bioinformatics search strategy to the human and mouse genomes to explore the landscape of A-to-I RNA editing. In both organisms we find evidence for high excess of A/G-type discrepancies (inosine appears as a guanosine in cloned cDNA) at non-polymorphic, non-synonymous codon sites over other types of discrepancies, suggesting the existence of several thousand recoding editing sites in the human and mouse genomes. We experimentally validate recoding-type A-to-I RNA editing in a number of human genes with high scoring positions including the coatomer protein complex subunit alpha (COPA) as well as cyclin dependent kinase CDK13.

Mammalian RNA-dependent deaminases and edited mRNAs.

The past year has witnessed major progress in the field of mammalian nuclear RNA editing. Two new sequence-related RNA-dependent adenosine deaminases, distantly related to the previously characterized double-stranded RNA adenosine deaminase DRADA/dsRAD, have been molecularly characterized. One of these deaminases edits in vitro with precision for the molecular determinant that controls the Ca2+ permeability of fast synaptic glutamate-gated cation channels. This deaminase, like DRADA, is expressed in many tissues and the search is now on for more substrates of these RNA-editing enzymes. Moreover, the physiological role of the apolipoprotein B RNA editing enzyme APOBEC-1 has been investigated in genetically manipulated mice.

Enlarged nuchal translucency in chromosomally normal fetuses: strong association with orofacial clefts.

OBJECTIVES: The aim of this study was to investigate whether there is an association between enlarged nuchal translucency (NT) and orofacial clefts. METHODS: The pregnancy outcome of women who underwent an NT measurement between January 2000 and November 2008 was reviewed. All orofacial clefts detected prenatally and postnatally in karyotypically normal fetuses/infants were reviewed and a distinction was made between isolated defects and clefts as part of multiple congenital anomalies (associated). RESULTS: The cohort included 8638 fetuses. The NT was enlarged in 746 (8.6%). The karyotype was normal in 8347 fetuses, including 513 of the fetuses with an enlarged NT. Isolated or associated cleft lip, with or without cleft palate (CL/P), or cleft palate (CP) were diagnosed in 18 chromosomally normal fetuses (an incidence of 2.2 per 1000). In eight of these cases the NT was normal (8/7834; an incidence of 1.0 per 1000) and in the remaining 10 it was enlarged (10/513; an incidence of 19.5 per 1000). CL/P and CP were isolated or associated in three and seven of the chromosomally normal fetuses with an enlarged NT, respectively. Euploid fetuses with an enlarged NT had a relative risk for any clefts of 19 and a relative risk for isolated or associated clefts of 8 and 53, respectively (P < 0.001). CONCLUSIONS: Chromosomally normal fetuses with an enlarged NT have an increased risk of orofacial clefts. CL/P and CP are, in these fetuses, mostly associated findings, frequently part of a genetic syndrome. A detailed ultrasound examination with special attention given to the orofacial area is indicated in these fetuses.

Phenotype and genotype in 17 patients with Goltz-Gorlin syndrome.

BACKGROUND: Goltz-Gorlin syndrome or focal dermal hypoplasia is a highly variable, X-linked dominant syndrome with abnormalities of ectodermal and mesodermal origin. In 2007, mutations in the PORCN gene were found to be causative in Goltz-Gorlin syndrome. METHOD: A series of 17 patients with Goltz-Gorlin syndrome is reported on, and their phenotype and genotype are described. RESULTS: In 14 patients (13 females and one male), a PORCN mutation was found. Mutations included nonsense (n = 5), frameshift (n = 2), aberrant splicing (n = 2) and missense (n = 5) mutations. No genotype-phenotype correlation was found. All patients with the classical features of the syndrome had a detectable mutation. In three females with atypical signs, no mutation was found. The male patient had classical features and showed mosaicism for a PORCN nonsense mutation in fibroblasts. Two affected sisters had a mutation not detectable in their parents, supporting germline mosaicism. Their father had undergone radiation for testicular cancer in the past. Two classically affected females had three severely affected female fetuses which all had midline thoracic and abdominal wall defects, resembling the pentalogy of Cantrell and the limb-body wall complex. Thoracic and abdominal wall defects were also present in two surviving patients. PORCN mutations can possibly cause pentalogy of Cantrell and limb-body wall complexes as well. Therefore, particularly in cases with limb defects, it seems useful to search for these. CONCLUSIONS: PORCN mutations can be found in all classically affected cases of Goltz-Gorlin syndrome, including males. Somatic and germline mosaicism occur. There is no evident genotype-phenotype correlation.

Mechanical behaviour of standardized, endoskeleton-including hip spacers implanted into composite femurs.

Two-stage reconstruction using an antibiotic loaded cement spacer is the preferred treatment method of late hip joint infections. Hip spacers maintain stability of the joint and length of the limb during treatment period. However, as the material strength of bone cement (PMMA) is limited, spacer fractures led to serious complications in the past. This study investigated the load capacity of custom made hip spacers, developed at the 'Klinik für Orthopädie und Orthopädische Chirurgie' (Universitätsklinikum des Saarlandes, Homburg/Saar, Germany), and implanted into composite femurs. In a quasi-static test, non-reinforced spacers tolerated hip joint loads of about 3000 N, whereas reinforced spacers with titanium-grade-two endoskeletons doubled this load up to 6000 N. Even for cyclic loading, endoskeleton-including hip spacers tolerated loads of >4500 N with 500,000 load cycles. Thus, an endoskeleton-including spacer should provide a mobile and functional joint through the treatment course. A generated FE-model was used to determine the fracture stresses and allows for further sensitivity analysis.

Reliability testing of a new device to measure tibial rotation.

The purpose of this study was to evaluate the reliability of a new developed device to measure tibial rotation, the Rotameter. Thirty healthy subjects (15 males, 15 females, 24 years) were examined with the Rotameter measurement device. External and internal rotation was performed at an applied torque of 5, 10 and 15 Nm by two independent examiners in order to test the inter-observer reliability. The patients were measured again after a mean of 31 +/- 43 days by the same examiners to test the intra-observer reliability. Statistical analysis was performed using the intra-class correlation coefficient. The Pearson Correlation coefficient was used to compare the measurements of the left with the right side of the participants. In the measurements, a high inter- and intra-observer reliability was found at 5, 10 and 15 Nm of applied torque for the external rotation, internal rotation and the rotational range (internal + external rotation). Comparison of the left and the right knee of the same participant also revealed high correlations in the Pearson correlation coefficient at all applied torques. In conclusion, the Rotameter testing device for the measurement of tibial rotation showed a high inter-observer and intra-observer reliability. It is easy to perform and might be used in a wide field as a non-invasive instrument to objectively determine rotational stability and to investigate the restoration of the rotational stability after surgical procedures.

A non-invasive device to objectively measure tibial rotation: verification of the device.

The purpose of this study was the correlation of the results of a new measurement device for tibial rotation (Rotameter) in comparison with the measurements of a knee navigation system as standard method. In a biomechanical laboratory study, all soft tissues were removed from 20 human cadaveric knees leaving only the intact capsule and the bone. Specific tracers were bicortically fixed in the bone in order to measure tibial rotation using a knee navigation system. The knees were fixed to a custom-made inside-boot to rule out undesirable rotation of the reconstruction inside the Rotameter measurement device. Internal and external rotation values were measured at an applied torque of 5, 10 and 15 Nm. The different methods to evaluate tibial rotation were compared using the Pearson correlation coefficient. The correlations were deemed to be reliable if a value of >or=0.80 was achieved. At 5 Nm of applied torque, high correlations for the internal rotation, external rotation and the entire rotational range were found in the Pearson correlation coefficient between the Rotameter testing device in comparison with the knee navigation system as invasive reference method. These results were also confirmed at an applied torque of 10 and 15 Nm. In conclusion, the Rotameter testing device showed high correlations compared with the knee navigation system as an invasive standard method. It might be used as a non-invasive and easy alternative to investigate tibial rotation.

Genome-wide methylation profiling of Beckwith-Wiedemann syndrome patients without molecular confirmation after routine diagnostics.

Beckwith-Wiedemann syndrome (BWS) is caused due to the disturbance of imprinted genes at chromosome 11p15. The molecular confirmation of this syndrome is possible in approximately 85% of the cases, whereas in the remaining 15% of the cases, the underlying defect remains unclear. The goal of our research was to identify new epigenetic loci related to BWS. We studied a group of 25 patients clinically diagnosed with BWS but without molecular conformation after DNA diagnostics and performed a whole genome methylation analysis using the HumanMethylation450 Array (Illumina).We found hypermethylation throughout the methylome in two BWS patients. The hypermethylated sites in these patients overlapped and included both non-imprinted and imprinted regions. This finding was not previously described in any BWS-diagnosed patient.Furthermore, one BWS patient exhibited aberrant methylation in four maternally methylated regions-IGF1R, NHP2L1, L3MBTL, and ZDBF2-that overlapped with the differentially methylated regions found in BWS patients with multi-locus imprinting disturbance (MLID). This finding suggests that the BWS phenotype can result from MLID without detectable methylation defects in the primarily disease-associated loci (11p15). Another patient manifested small but significant aberrant methylation in disease-associated loci at 11p near H19, possibly confirming the diagnosis in this patient.

A genome-wide DNA methylation signature for SETD1B-related syndrome.

SETD1B is a component of a histone methyltransferase complex that specifically methylates Lys-4 of histone H3 (H3K4) and is responsible for the epigenetic control of chromatin structure and gene expression. De novo microdeletions encompassing this gene as well as de novo missense mutations were previously linked to syndromic intellectual disability (ID). Here, we identify a specific hypermethylation signature associated with loss of function mutations in the SETD1B gene which may be used as an epigenetic marker supporting the diagnosis of syndromic SETD1B-related diseases. We demonstrate the clinical utility of this unique epi-signature by reclassifying previously identified SETD1B VUS (variant of uncertain significance) in two patients.