Registration of dynamic CT image sequences is a crucial preprocessing step for clinical evaluation of multiple physiological determinants in the heart such as global and regional myocardial perfusion. In this work, we present a deformable deep learning-based image registration method for quantitative myocardial perfusion CT examinations, which in contrast to previous approaches, takes into account some unique challenges such as low image quality with less accurate anatomical landmarks, dynamic changes of contrast agent concentration in the heart chambers and tissue, and misalignment caused by cardiac stress, respiration, and patient motion. The introduced method uses a recursive cascade network with a ventricle segmentation module, and a novel loss function that accounts for local contrast changes over time. It was trained and validated on a dataset of n = 118 patients with known or suspected coronary artery disease and/or aortic valve insufficiency. Our results demonstrate that the proposed method is capable of registering dynamic cardiac perfusion sequences by reducing local tissue displacements of the left ventricle (LV), whereas contrast changes do not affect the registration and image quality, in particular the absolute CT (HU) values of the entire CT sequence. In addition, the deep learning-based approach presented reveals a short processing time of a few seconds compared to conventional image registration methods, demonstrating its application potential for quantitative CT myocardial perfusion measurements in daily clinical routine.

Background: Hemodynamic alterations in Fontan patients (FP) are associated with hemostatic dysbalance and Fontan-associated liver disease. Studies of other hepatopathologies indicate an interplay between cholestasis, tissue factor (TF), and von Willebrand factor (VWF). Hence, we hypothesized a relationship between the accumulation of bile acids (BA) and these hemostatic factors in FP. Methods: We included 34 FP (Phenprocoumon n = 15, acetylsalicylic acid (ASA) n = 16). BA were assessed by mass spectrometry. TF activity and VWF antigen (VWF:Ag) were determined by chromogenic assays. VWF collagen-binding activity (VWF:CB) was assessed via ELISA. Results: Cholestasis was observed in 6/34 FP (total BA ≥ 10 µM). BA levels and TF activity did not correlate (p = 0.724). Cholestatic FP had lower platelet counts (p = 0.013) from which 5/6 FP were not treated with ASA. VWF:Ag levels were increased in 9/34 FP and significantly lower in FP receiving ASA (p = 0.044). Acquired von Willebrand syndrome (AVWS) was observed in 10/34-FP, with a higher incidence in cholestatic FP (4/6) (p = 0.048). Conclusions: Cholestasis is unexpectedly infrequent in FP and seems to be less frequent under ASA therapy. Therefore, ASA may reduce the risk of advanced liver fibrosis. FP should be screened for AVWS to avoid bleeding events, especially in cholestatic states.

In the global debate about the use of Natural Language Processing (NLP)-based tools such as ChatGPT in healthcare decisions, the question of their use as regulatory-approved Software as Medical Device (SaMD) has not yet been sufficiently clarified. Currently, this discussion is conducted with an astonishing euphoria about countless clinical applications, including their opportunities, but also their pitfalls with potential errors in clinical use.1-5 Although the FDA and international regulatory authorities have already issued initial guideline documents for the development and approval of machine learning (ML)/artificial intelligence (AI)-based tools as SaMD, a mandatory regulatory process for NLP-based tools has not yet been fully clarified. ChatGPT therefore plays a special role in these considerations. In the United States, an FDA discussion paper from 2019 gives first ideas how to deliver safe and effective AI-based software functionality for the total product lifecycle.6 A recent guidance document for clinical decision support software (September 2022) further clarifies the FDA's position on what qualifies as a regulable medical device, particularly with respect to AI-driven clinical decision support tools.7 In March 2023, the FDA has published guidance on their algorithmic change control policy which discusses how it evaluates algorithms that are periodically updated, which is particularly relevant for NLP-based tools such as ChatGPT. In Europe, the medical device regulations (EU Regulations 2017/745 and 2017/746) are a major update to the way medical devices are regulated. According to the MDCG 2019-11 guidance document, the gap in SaMD classification has been closed so far.8 A Product Watch Report of the European Commission from July 2020 provides an additional update on this topic, discussing AI, ML and statistical tools for risk estimation or decision support.9 The very recently published AI Act (June 2023), a proposed European law on artificial intelligence, will have far-reaching consequences on medical device regulation in Europe in the near future. The International Medical Device Regulators Forum (IMDRF)/Software as a Medical Device Working Group to harmonize the regulatory requirements published a possible risk categorization framework for SaMD in 2014, and a follow-up document with more detailed information on ML/AI-based software in 2022.10 The IMDRF and FDA recommendations allow for clearer identification of risk categories based on the ‘intended use’ for healthcare decisions in different medical situations or conditions (diagnosis, prognosis, prevention or treatment). Currently, ChatGPT (Figure 1) is not intended by OpenAI for clinical use based on its terms of use (see https://openai.com/policies/terms-of-use), which clearly states that users should review its output for accuracy, that they make no warranties with respect to services, and that they have limited liability for any damages caused by its use. However, if the intended use of NLP-based tools, beyond ChatGPT, for clinical purposes falls within the definition of an AI/ML-based SaMD, regulatory approval is required. In contrast to ‘locked’ software algorithms with fixed functions, for example, a classifier for clinical decision support, an ‘adaptive, continuous learning’ (non-locked) algorithm changes its behavior. Because the standard medical device regulatory process is currently not designed for adaptive AI/ML technologies, additional efforts are needed by the regulators, although these algorithms have the potential to adapt and optimize software performance, in part in real-time, to continuously improve patient health outcomes. Inherent changes to the algorithm are typically made and verified through a well-defined and automated process to improve algorithm performance based on analysis and interpretation of new data.9 For clinical purposes, the data need to be evidence-based and scientifically proven. This is basically the concept of ChatGPT, but more complicated. ChatGPT is not actually an algorithm but merely refers to the user interface. GPT-3.5-turbo and GPT-4 are underlying algorithms that drive ChatGPT. Whether the weights for GPT-3.5-turbo and GPT-4 have not been updated since its release is not publicly known (no official confirmation by OpenAI). It can be speculated that the underlying language model has not been updated with new training data ( cf. the ChatGPT references back to September 2021), but the prompting, the structure of the model, and the chat component may have been updated. The fact that these models produce different output in response to the same prompt is actually due to its use of sampling in the output (see Figure 1). Especially this fact makes it difficult to simply modify ChatGPT (if intended by OpenAI) for regulatory approval as a SaMD in its current architecture. However, this need not apply to the architectures of other NLP-based tools. The intended use of an NLP-based SaMD to support clinical decisions, for example for the diagnosis and prognosis of the Marfan syndrome, a multisystemic disorder, could be as follows: ‘The NLP-based software supports diagnostic and prognostic decision-making in patients with suspected Marfan syndrome (ICD-10 code: Q87.4), taking into account qualitative and quantitative information on the symptomatology of the cardiac, skeletal, ocular, skin, and pulmonary systems, as well as the genetic profile’. ‘An 8-years old patient carries an FBN1 mutation variant of c.3217G > T. Currently, only mild symptoms in the skeletal system are observed. Is aortic dilatation or dissection expected during the next 5 years?' The problem with ChatGPT is that the model produces different output (variations) in response to the same prompt, so regulatory approval of medical software based on a ChatGPT architecture remains a challenge and will require major efforts to make such NLP-tools available for clinical use. This behavior has significant implications for the relevant medical software certification requirements, including the IEC 62304 standard for the software life cycle processes, especially the development and maintenance process, usability engineering (IEC 62366), risk management (ISO 14971), the clinical evaluation to demonstrate clinical validity, among other requirements for which regulators are encouraged to define new or modified processes. Beyond the euphoric discussion within the international medical community, there is a high urgency for a regulated use of NLP-based tools to protect physicians and patients from potential errors and harms. All stakeholders—software developers, scientists, ethicists, healthcare professionals and healthcare providers, patient initiatives, regulators and governmental agencies—are called upon to raise public awareness of this important and urgent issue by taking the first binding steps. The authors declare that they have no conflict of interest.

For cardiac defibrillator testing and design purposes, the range and limits of the human TTI is of high interest. Potential influencing factors regarding the electronic configurations, the electrode/tissue interface and patient characteristics were identified and analyzed. A literature survey based on 71 selected articles was used to review and assess human TTI and the influencing factors found. The human TTI extended from 12 to 212 Ω in the literature selected. Excluding outliers and pediatric measurements, the mean TTI recordings ranged from 51 to 112 Ω with an average TTI of 76.7 Ω under normal distribution. The wide range of human impedance can be attributed to 12 different influencing factors, including shock waveforms and protocols, coupling devices, electrode size and pressure, electrode position, patient age, gender, body dimensions, respiration and lung volume, blood hemoglobin saturation and different pathologies. The coupling device, electrode size and electrode pressure have the greatest influence on TTI.

Patients with Marfan syndrome (MFS) have an increased risk of aortic aneurysm formation, dissection and development of a subtle cardiomyopathy. We analyzed amino acid and lipid metabolic pathways in MFS patients, seeking biomarker patterns as potential monitoring tools of cardiovascular risk with deterioration of myocardial function. We assessed myocardial function in 24 adult MFS patients and compared traditional laboratory values and mass spectrometry-based amino acid, phospholipid and acylcarnitine metabolomes in patients with those in healthy controls. Analytes for which values differed between patients and controls were subjected to regression analysis. A high proportion of patients had signs of impaired diastolic function and elevated serum levels of NT-proBNP. Patients had lower serum levels of taurine, histidine and PCaeC42:3 than controls. The evidence of diastolic dysfunction, aortic root dimensions and history of aortic root surgery correlated with NT-proBNP and taurine levels. Alterations in serum levels of metabolism derived analytes link MFS pathophysiology with inflammation, oxidative stress and incipient cardiomyopathy.

Background Mucopolysaccharidoses (MPS) are monogenic metabolic disorders that significantly affect the skeleton. Eleven enzyme defects in the lysosomal degradation of glycosaminoglycans (GAGs) have been assigned to the known MPS subtypes (I–IX). Arylsulfatase K (ARSK) is a recently characterised lysosomal hydrolase involved in GAG degradation that removes the 2-O-sulfate group from 2-sulfoglucuronate. Knockout of Arsk in mice was consistent with mild storage pathology, but no human phenotype has yet been described. Methods In this study, we report four affected individuals of two unrelated consanguineous families with homozygous variants c.250C>T, p.(Arg84Cys) and c.560T>A, p.(Leu187Ter) in ARSK, respectively. Functional consequences of the two ARSK variants were assessed by mutation-specific ARSK constructs derived by site-directed mutagenesis, which were ectopically expressed in HT1080 cells. Urinary GAG excretion was analysed by dimethylene blue and electrophoresis, as well as liquid chromatography/mass spectrometry (LC-MS)/MS analysis. Results The phenotypes of the affected individuals include MPS features, such as short stature, coarse facial features and dysostosis multiplex. Reverse phenotyping in two of the four individuals revealed additional cardiac and ophthalmological abnormalities. Mild elevation of dermatan sulfate was detected in the two subjects investigated by LC-MS/MS. Human HT1080 cells expressing the ARSK-Leu187Ter construct exhibited absent protein levels by western blot, and cells with the ARSK-Arg84Cys construct showed markedly reduced enzyme activity in an ARSK-specific enzymatic assay against 2-O-sulfoglucuronate-containing disaccharides as analysed by C18-reversed-phase chromatography followed by MS. Conclusion Our work provides a detailed clinical and molecular characterisation of a novel subtype of mucopolysaccharidosis, which we suggest to designate subtype X.

BackgroundMacitentan, a dual endothelin receptor antagonist (ERA), was approved in 2014 for the treatment of adults with idiopathic pulmonary arterial hypertension (PAH). Once-per-day dosing and low potential hepatic toxicity make macitentan an appealing therapeutic option for children with PAH, but reports on its use in pediatric patients are still lacking.MethodsProspective observational study of 18 children [10 male; median age: 8.5, minimum (min.): 0.6, maximum (max.): 16.8 years] with pulmonary hypertension (PH). Four of these 18 patients were treatment-naïve and started on a de novo macitentan therapy. The remaining 14/18 children were already on a PH-targeted pharmacotherapy (sildenafil or bosentan as monotherapy or in combination). Nine children who were on bosentan were switched to macitentan. We analyzed the 6-minute walking distance (6MWD), NYHA functional class (FC)/modified ROSS score, invasive hemodynamics, echocardiographic variables and the biomarker N-terminal pro-brain natriuretic peptide (NT-proBNP).ResultsThe median follow up was 6 months (min.: 0.5, max.: 30). Macitentan treatment was associated with improvement of invasive hemodynamics, e.g., the ratio of mean pulmonary arterial pressure/mean systemic arterial pressure decreased from a median of 62% (min.: 30%, max.: 87%) to 49% (min.: 30%, max.: 69%), P<0.05; pulmonary vascular resistance index (PVRi) decreased from a median of 7.6 (min.: 3.3, max.: 11.5) to 4.8 Wood units × m2 body surface area (min.: 2.5, max.: 10), P<0.05. The tricuspid annular plane systolic excursion (TAPSE) increased from a median of 1.4 (min.: 0.8, max.: 2.8) to 1.9 (min.: 0.8, max.: 2.7) cm, (P<0.05). NT-proBNP values decreased from a median of 272 (min.: 27, max.: 2,010) to 229 (min.: 23, max.: 814) pg/mL under macitentan therapy (P<0.05). The 6MWD and NYHA FC/modified ROSS score did not change significantly.ConclusionsThis is the first prospective study of macitentan pharmacotherapy in infants and children with PH <12 years of age. Except in one patient, macitentan treatment was well tolerated and was associated with improvements in invasive hemodynamics, longitudinal systolic RV function (TAPSE) and serum NT-proBNP values.

The use of different cardiac imaging modalities such as MRI, CT or ultrasound enables the visualization and interpretation of altered morphological structures and function of the heart. In recent years, there has been an increasing interest in AI and deep learning that take into account spatial and temporal information in medical image analysis. In particular, deep learning tools using temporal information in image processing have not yet found their way into daily clinical practice, despite its presumed high diagnostic and prognostic value. This review aims to synthesize the most relevant deep learning methods and discuss their clinical usability in dynamic cardiac imaging using for example the complete spatiotemporal image information of the heart cycle. Selected articles were categorized according to the following indicators: clinical applications, quality of datasets, preprocessing and annotation, learning methods and training strategy, and test performance. Clinical usability was evaluated based on these criteria by classifying the selected papers into (i) clinical level, (ii) robust candidate and (iii) proof of concept applications. Interestingly, not a single one of the reviewed papers was classified as a "clinical level" study. Almost 39% of the articles achieved a "robust candidate" and as many as 61% a "proof of concept" status. In summary, deep learning in spatiotemporal cardiac imaging is still strongly research-oriented and its implementation in clinical application still requires considerable efforts. Challenges that need to be addressed are the quality of datasets together with clinical verification and validation of the performance achieved by the used method.

s of the 26th European Workshop on Neonatology September 2–5, 2018 Cappadocia, Turkey Thyroxin Threshold Linked to Impaired Outcome in Preterm Infants: A Retrospective Cohort Study Jean Michel Hascoet1, Stephanie Coquelet1, Helene Deforge2 1Department of Neonatology, Regional Maternity, CHRU Nancy, France 2EA3450DevAH, University of Lorraine, France Introduction: It remains controversial whether transient hypothyroxinemia of prematurity infl uences shortand long-term outcomes. Thus, we aimed to defi ne a thyroxin threshold associated with neonatal clinical impairment and outcome at 3 years of age. Methods: We retrospectively analyzed medical records of infants born at a gestational age (GA) of < 29 weeks. A thyroxin threshold value was defi ned by ROC curve analysis in a cohort of infants born from 10/2008–12/2012, and validated in a second cohort of infants born from 01/2014– 12/2016 in our institution. Results: Our analysis included 460 patients (mean GA, 26.7 ± 1.3 weeks; mean birth weight, 935 ± 206 g). Thyroxin (FT4) measurements were available for 196/274 infants from the early time period, among whom 35 exhibited neonatal clinical impairment. ROC curve analysis indicated an FT4 threshold of 10 pmol/L, with a sensitivity of 85.7%, and a specifi city of 49.1%. FT4 measurements were available for 176/186 infants from the second time period: neonatal clinical impairment occurred in 20/78 infants with FT4 ≤ 10 pmol/L versus 3/98 with FT4 > 10 pmol/L (P <.001). Three-year follow-up data were available for 147/196 eligible infants. Poor outcome occurred in 65% (58/89) with FT4 ≤ 10 pmol/L versus 34% (20/58) with FT4 > 10 pmol/L (OR, 3.555; 95% CI, 1.774–7.128; P <.001). Conclusion: We defi ned and validated a FT4 threshold of 10 pmol/L as a signifi cant risk factor for neonatal clinical impairment, and a good predictor of poor outcome at 3 years of age.

Metabolic biomarkers may play an important role in the diagnosis, prognostication and assessment of response to pharmacological therapy in complex diseases. The process of discovering new metabolic biomarkers is a non-trivial task which involves a number of bioanalytical processing steps coupled with a computational approach for the search, prioritization and verification of new biomarker candidates. Kinetic analysis provides an additional dimension of complexity in time-series data, allowing for a more precise interpretation of biomarker dynamics in terms of molecular interaction and pathway modulation. A novel network-based computational strategy for the discovery of putative dynamic biomarker candidates is presented, enabling the identification and verification of unexpected metabolic signatures in complex diseases such as myocardial infarction. The novelty of the proposed method lies in combining metabolic time-series data into a superimposed graph representation, highlighting the strength of the underlying kinetic interaction of preselected analytes. Using this approach, we were able to confirm known metabolic signatures and also identify new candidates such as carnosine and glycocholic acid, and pathways that have been previously associated with cardiovascular or related diseases. This computational strategy may serve as a complementary tool for the discovery of dynamic metabolic or proteomic biomarkers in the field of clinical medicine.

Die bildgebende Diagnostik spielt in der Betreuung von Patienten mit genetischen Aortenerkrankungen wie dem Marfan-Syndrom, dem vaskulären Ehlers-Danlos-Syndrom oder dem Loeys-Dietz-Syndrom sowohl bei Diagnose der genetischen Aortenerkrankung im stabilen Stadium als auch bei der Notfalldiagnostik akuter Aortensyndrome eine essenzielle Rolle. Die bildgebenden Modalitäten zur elektiven Diagnostik und Akutdiagnostik umfassen die transthorale Echokardiographe, die transösophageale Echokardiographie, die CT mit CT-Angiographie und die Magnetresonanztomographie (MRI) mit MR-Angiographie (MRA).

Cardiovascular disease is the leading cause of death worldwide. Evidence points towards an unfavorable cardiovascular risk profile of former preterm infants in adolescence and adulthood. The aim of this study was to determine whether cardiovascular risk predictors are detectable in former very preterm infants at a preschool age. Five- to seven-year-old children born at <32 weeks' gestational age were included in the study. Same-aged children born at term served as controls. Basic data of study participants were collected by means of follow-up databases and standardized questionnaires. At study visit, anthropometric data, blood pressure readings and aortic intima-media thickness were assessed. Blood samples were obtained after an overnight fast. In comparison to children born at term, former preterm infants had higher systolic and diastolic blood pressure readings (odds ratio [95% confidence interval] per 1-SD higher blood pressure level 3.2 [2.0-5.0], p<0.001 and 1.6 [1.1-1.2], p = 0.008), fasting glucose levels (OR [95% CI] 5.2 [2.7-10.1], p<0.001), homeostasis model assessment index (OR [95% CI] 1.6 [1.0-2.6], p = 0.036), and cholesterol levels (OR [95% CI] 2.1 [1.3-3.4], p = 0.002). Systolic prehypertension (23.7% vs. 2.2%; OR [95% CI] 13.8 [3.1-60.9], p = 0.001), elevated glucose levels (28.6% vs. 5.9%; OR [95% CI] 6.4 [1.4-28.8], p = 0.016), and hypercholesterolemia (77.4% vs. 52.9%; OR [95% CI] 3.0 [1.3-7.1], p = 0.010) were significantly more prevalent in the preterm group. As former very preterm infants display an unfavorable cardiovascular risk profile already at a preschool age, implementation of routine cardiovascular follow-up programs might be warranted.

Objective— Preterm birth predisposes children to the development of cardiovascular diseases in adulthood. The aim of this study was to characterize elastic properties of the aorta at preschool age and test the hypothesis that prematurity is associated with decreased aortic distensibility and increased stiffness, both of which are predictors of increased cardiovascular risk. Approach and Results— In an observational study of 76 five- to seven-year-old children born at a gestational age <32 weeks and 79 term-born controls, elastic parameters of the ascending and descending abdominal aorta were determined noninvasively by means of M mode echocardiographic tracings and calculated using computerized wall contour analysis. Compared with children born at term, the preterm group showed significantly reduced distensibility and increased stiffness of the descending abdominal aorta. These results remained significant under multivariable adjustment for birth weight z score, maternal smoking in pregnancy, maternal education, family history of cardiovascular disease, breastfeeding, childhood nutrition, and current body mass index z score (multivariable odds ratios and 95% confidence intervals 5.1, 1.7–15.9; P =0.005 and 2.8, 1.0–7.9; P =0.046, respectively). Further adjustment for intravenous lipid therapy attenuated the strength of association. Elastic properties of the ascending aorta did not differ between the 2 study groups. Conclusions— Children born preterm are characterized by decreased elastic properties of the descending abdominal aorta potentially attributable to impaired viscoelastic properties of and lipid damage to the aorta. Clinical follow-up of preterm infants with a focus on aortic elastic properties may be useful for tailoring early prevention programs and counteracting cardiovascular risk in adulthood.

The search and validation of novel disease biomarkers requires the complementary power of professional study planning and execution, modern profiling technologies and related bioinformatics tools for data analysis and interpretation. Biomarkers have considerable impact on the care of patients and are urgently needed for advancing diagnostics, prognostics and treatment of disease. This survey article highlights emerging bioinformatics methods for biomarker discovery in clinical metabolomics, focusing on the problem of data preprocessing and consolidation, the data-driven search, verification, prioritization and biological interpretation of putative metabolic candidate biomarkers in disease. In particular, data mining tools suitable for the application to omic data gathered from most frequently-used type of experimental designs, such as case-control or longitudinal biomarker cohort studies, are reviewed and case examples of selected discovery steps are delineated in more detail. This review demonstrates that clinical bioinformatics has evolved into an essential element of biomarker discovery, translating new innovations and successes in profiling technologies and bioinformatics to clinical application.

Abnormal elastic properties of the ascending aorta in patients with coarctation of the aorta (CoA) are already present in neonates before and after successful repair. To prove the midterm outcome for vascular pathology, a cohort of 15 patients was prospectively reevaluated. In this study, 15 patients after neonatal CoA repair (study group) and 15 healthy normal children (control group) were examined (mean age, 3.0 +/- 1.0 years). The aortic wall stiffness index and distensibility were calculated using ascending and abdominal aortic M-mode diameters and noninvasive estimation of pulse pressure. The study group was compared with the control group and with its own previously obtained pre- and postoperative measurements. After a mean follow-up period of 2.9 +/- 0.9 years, the elastic properties of the ascending aorta remained impaired in the study group compared with the control group (distensibility: 62 +/- 28 vs 94 +/- 34; p = 0.01; stiffness index: 4.4 +/- 1.9 vs 2.7 +/- 1.0; p = 0.008). At follow-up evaluation, the elasticity of the ascending aorta in the study group showed no change from the initial neonatal findings (distensibility: 63 +/- 24 vs 62 +/- 28; p = 0.82; stiffness index: 4.0 +/- 1.6 vs 4.4 +/- 1.9; p = 0.65). In both groups, descending aortic elasticity increased during the follow-up period. Our data suggest that the diminished elastic properties of the prestenotic arteries remain unchanged years after successful CoA repair. Comparisons with the neonatal data showed no evidence for remodeling of the ascending aorta in this group.

We improved, evaluated, and used Sanger sequencing for quantification of single nucleotide polymorphism (SNTP) variants in transcripts and gDNA samples. This improved assay resulted in highly reproducible relax five allele frequencies (e.g., for a heterozygous gDNA 50.0 +/- 1.4%, and for a missense mutation-bearing transcript 46.9 +/- 3.7%) with a lower detection limit of 3-9%. It provided excellent accuracy and linear correlation between expected and observed relative allele frequencies. This sequencing assay, which can also be used for the quantification of copy number variations (CNVs), methylations, mosaicisms, and DNA pools, enabled us to analyze transcripts of the FBN1 gene in fibroblasts and blood samples of patients with suspected Marfan syndrome not only qualitatively but also quantitatively. We report a total of 18 novel and 19 known FBN1 sequence variants leading to a premature termination codon (PTC), 26 of which we analyzed by quantitative sequencing both at gDNA and cDNA levels. The relative amounts of PTC-containing FBN1 transcripts in fresh and PAXgene-stabilized blood samples were significantly higher (33.0 +/- 3.9% to 80.0 +/- 7.2%) than those detected in affected fibroblasts with inhibition of nonsense-mediated mRNA decay (NMD) (11.0 +/- 2.1% to 25.0 +/- 1.8%), whereas in fibroblasts without NMD inhibition no mutant alleles Could be detected. These results provide evidence for incomplete NMD in leukocytes and have particular importance for RNA-based analyses not only in FBN1 but also in other genes. Hum Mutat 30:1355-1364, 2009. (C) 2009 Wiley-Liss, Inc.

Objective: To investigate electrophysiological and functional signs of myocardial damage in patients with propionic acidemia (PA), an inborn error of metabolism caused by deficiency of propionyl CoA carboxylase (PCC).Study design: in an observational longitudinal study 10 patients with PA (6 boys and 4 girls) ranging between 2.5 and 20.2 (median 9.0) years of age at last follow-up were investigated over a period of up to 20 (mean 7.4) years using 12-lead electrocardiograms (ECGs), 24-hour continuous ECG recordings, bicycle exercise testings, and echocardiography with special focus on repolarization abnormalities such as corrected QT interval (QTc) prolongation, ventricular dysrhythmias, and left ventricular systolic function.Results: QTc interval was prolonged (> 440 ms) in 70% of patients beyond infanthood. Continuous ECG recordings revealed rhythm disturbances in 20% of patients. M-mode echocardiographic left ventricular function was reduced (fractional shortening [FS] < 30%) in 40%. One patient showed signs of dilated cardiomyopathy.Conclusions: The majority of patients with PA (even in clinically stable situations) have disturbances in cardiac electrophysiology that can contribute to cardiac complications. Possible mechanisms include effects of toxic metabolites or deprivation of essential substrates. To avoid life-threatening complications, we recommend regular cardiological evaluations in this group of patients.

UNLABELLED:The clinical diagnosis of Marfan syndrome in childhood is difficult, because symptoms may not have developed to their full expression until adulthood. The Ghent nosology for the diagnosis of Marfan syndrome classifies dural ectasia as a major diagnostic criterion. More than two thirds of adult patients with Marfan syndrome show dural ectasia, while the frequency in childhood is unknown. This prospective multicenter observational patient-control study was performed to identify pathologic changes of the lumbosacral spine in young patients with Marfan syndrome.DESIGN:Prospective clinical trial, multicentric, cross-sectional.SETTING:MRI of the lumbosacral spine.PATIENTS:Twenty patients with proven Marfan syndrome, 20 patients suspicious for Marfan syndrome and 38 healthy controls.OUTCOME MEASURES:Vertebral body diameter (VBD) from L1 to S1, dural sac diameter (DSD) from L1 to S1, dural sac ratio (DSR), qualitative assessment of the lumbosacral spine.RESULTS:DSD and VBD in different age groups were higher in patients with proven or suspected Marfan syndrome than in healthy controls (DSD: L1, 6-8 years, P < 0.05). VBD related to body height showed a similar growth related increase in patients with proven or suspected Marfan syndrome and controls. DSD related to body height was elevated in patients with proven or suspected Marfan syndrome at different levels of the lumbar spine. DSD at levels L1, L5, and S1, and DSR at levels L5 and S1 of patients with proven Marfan syndrome were significantly higher (P < 0.05) than in controls.CONCLUSION:Even during childhood pathologic changes inside the lumbosacral spine of patients with Marfan syndrome can be observed. Dural ectasia, which occurs at different levels of the lumbar spine, can be detected at levels L5 and S1 in up to 40% of patients with Marfan syndrome.