Cerebrotendinous xanthomatosis without neurological involvement.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessively inherited inborn error of metabolism. Neurological symptoms are considered to be a clinical hallmark of untreated adult patients. We describe a 'milder CTX phenotype', without neurological involvement. METHODS: We performed a retrospective patient file study in 79 genetically confirmed Dutch patients with CTX (55 patients aged ≥ 21 years) to study the clinical heterogeneity of CTX. We studied the frequency of adult patients with CTX without neurological involvement at diagnosis, in our Dutch cohort, and included a family from South Africa and patients from Italy, USA, Chile and Asia from the literature. RESULTS: In total, we describe 19 adult patients with CTX from 16 independent families, without neurological symptoms at diagnosis. A relatively small percentage (21%, n = 4) had a history of cataract. The majority, 84% (n = 16), presented with tendon xanthomas as the sole or predominant feature. The majority of patients showed increased plasma cholesterol levels. No correlation was found between this 'milder phenotype', the cholestanol levels and the CYP27A1 genotype. In addition, we describe three novel mutations in the CYP27A1 gene. CONCLUSIONS: This study shows the clinical heterogeneity of CTX, highlighting the existence of a 'milder phenotype', that is without neurological involvement at diagnosis. Adult patients with CTX may present with tendon xanthomas as the sole or predominant feature, mimicking familial hypercholesterolemia. It is important to realize that the absence of neurological symptoms does not rule out the development of future neurological symptoms. As CTX is a treatable disorder, early diagnosis and initiation of treatment when additional clinical signs occur is therefore essential.

Infarct-related chronic total coronary occlusion and the risk of ventricular tachyarrhythmic events in out-of-hospital cardiac arrest survivors.

INTRODUCTION: Chronic total coronary occlusion (CTO) has been identified as a risk factor for ventricular arrhythmias, especially a CTO in an infarct-related artery (IRA). This study aimed to evaluate the effect of an IRA-CTO on the occurrence of ventricular tachyarrhythmic events (VTEs) in out-of-hospital cardiac arrest survivors without ST-segment elevation. METHODS: We conducted a post hoc analysis of the COACT trial, a multicentre randomised controlled trial. Patients were included when they survived index hospitalisation after cardiac arrest and demonstrated coronary artery disease on coronary angiography. The primary endpoint was the occurrence of a VTE, defined as appropriate implantable cardioverter-defibrillator (ICD) therapy, sustained ventricular tachyarrhythmia or sudden cardiac death. RESULTS: A total of 163 patients from ten centres were included. Unrevascularised IRA-CTO in a main vessel was present in 43 patients (26%). Overall, 61% of the study population received an ICD for secondary prevention. During a follow-up of 1 year, 12 patients (7.4%) experienced at least one VTE. The cumulative incidence rate of VTEs was higher in patients with an IRA-CTO compared to patients without an IRA-CTO (17.4% vs 5.6%, log-rank p = 0.03). However, multivariable analysis only identified left ventricular ejection fraction < 35% as an independent factor associated with VTEs (adjusted hazard ratio 8.7, 95% confidence interval 2.2-35.4). A subanalysis focusing on CTO, with or without an infarct in the CTO territory, did not change the results. CONCLUSION: In out-of-hospital cardiac arrest survivors with coronary artery disease without ST-segment elevation, an IRA-CTO was not an independent factor associated with VTEs in the 1st year after the index event.

Hepatic steatosis does not cause insulin resistance in people with familial hypobetalipoproteinaemia.

AIMS/HYPOTHESIS: Hepatic steatosis is strongly associated with hepatic and whole-body insulin resistance. It has proved difficult to determine whether hepatic steatosis itself is a direct cause of insulin resistance. In patients with familial hypobetalipoproteinaemia (FHBL), hepatic steatosis is a direct consequence of impaired hepatic VLDL excretion, independently of metabolic derangements. Thus, patients with FHBL provide a unique opportunity to investigate the relation between increased liver fat and insulin sensitivity. METHODS: We included seven male participants with FHBL and seven healthy matched controls. Intrahepatic triacylglycerol content and intramyocellular lipid content were measured using localised proton magnetic resonance spectroscopy (¹H-MRS). A two-step hyperinsulinaemic-euglycaemic clamp, using stable isotopes, was assessed to determine hepatic and peripheral insulin sensitivity. RESULTS: ¹H-MRS showed moderate to severe hepatic steatosis in patients with FHBL. Basal endogenous glucose production (EGP) and glucose levels did not differ between the two groups, whereas insulin levels tended to be higher in patients compared with controls. Insulin-mediated suppression of EGP during lower dose insulin infusion and insulin-mediated peripheral glucose uptake during higher dose insulin infusion were comparable between FHBL participants and controls. Baseline fatty acids and lipolysis (glycerol turnover) at baseline and during the clamp did not differ between groups. CONCLUSIONS/INTERPRETATION: In spite of moderate to severe hepatic steatosis, people with FHBL do not display a reduction in hepatic or peripheral insulin sensitivity compared with healthy matched controls. These results indicate that hepatic steatosis per se is not a causal factor leading to insulin resistance. TRIAL REGISTRATION: ISRCTN35161775.

In vivo proton MR spectroscopy findings specific for adenylosuccinate lyase deficiency.

Adenylosuccinate lyase (ADSL) deficiency is an inherited metabolic disorder affecting predominantly the central nervous system. The disease is characterized by the accumulation of succinylaminoimidazolecarboxamide riboside and succinyladenosine (S-Ado) in tissue and body fluids. Three children presented with muscular hypotonia, psychomotor delay, behavioral abnormalities, and white matter changes on brain MRI. Two of them were affected by seizures. Screening for inborn errors of metabolism including in vitro high resolution proton MRS revealed an ADSL deficiency that was confirmed genetically in all cases. All patients were studied by in vivo proton MRS. In vitro high resolution proton MRS of patient cerebrospinal fluid showed singlet resonances at 8.27 and 8.29 ppm that correspond to accumulated S-Ado. In vivo proton MRS measurements also revealed a prominent signal at 8.3 ppm in gray and white matter brain regions of all patients. The resonance was undetectable in healthy human brain. In vivo proton MRS provides a conclusive finding in ADSL deficiency and represents a reliable noninvasive diagnostic tool for this neurometabolic disorder.

NMR structure of a classical pseudoknot: interplay of single- and double-stranded RNA.

Pseudoknot formation folds the 3' ends of many plant viral genomic RNAs into structures that resemble transfer RNA in global folding and in their reactivity to transfer RNA-specific proteins. The solution structure of the pseudoknotted T arm and acceptor arm of the transfer RNA-like structure of turnip yellow mosaic virus (TYMV) was determined by nuclear magnetic resonance (NMR) spectroscopy. The molecule is stabilized by the hairpin formed by the 5' end of the RNA, and by the intricate interactions related to the loops of the pseudoknot. Loop 1 spans the major groove of the helix with only two of its four nucleotides. Loop 2, which crosses the minor groove, interacts closely with its opposing helix, in particular through hydrogen bonds with a highly conserved adenine. The structure resulting from this interaction between the minor groove and single-stranded RNA at helical junctions displays internal mobility, which may be a general feature of RNA pseudoknots that regulates their interaction with proteins or other RNA molecules.

Conformational changes in oligo-nucleotides upon binding to a peptide representing the N-terminal region of a viral coat protein. An optical spectroscopy study.

Conformational changes of the oligonucleotides r(A)12, d(GC)5, and d(AT)5 upon binding to a pentacosapeptide representing the RNA-binding N-terminus of the coat protein of cowpea chlorotic mottle virus (CCMV) were studied by using absorption and circular dichroism spectroscopy. The peptide destabilizes the single-stranded structure of r(A)12 at pH 7.2, but disrupts the double-stranded structure of r(A)12 at pH 5.0. However, at pH 4.0, the peptide is not able to disrupt this double-stranded structure. The double-stranded structures of d(GC)5 and d(AT)5 with Watson-Crick base-pairing are stabilized upon binding to the peptide.

Conformation and mobility of the RNA-binding N-terminal part of the intact coat protein of cowpea chlorotic mottle virus. A two-dimensional proton nuclear magnetic resonance study.

Two-dimensional proton nuclear magnetic resonance (n.m.r.) experiments were performed on the coat protein of cowpea chlorotic mottle virus (molecular mass: 20.2 kDa) present as dimer (pH 7.5) or as capsid consisting of 180 protein monomers (pH 5.0). The spectra of both dimers and capsids showed resonances originating from the flexible N-terminal region of the protein. The complete resonance assignment of a synthetic pentacosapeptide representing this N terminus made it possible to interpret the spectra in detail. The capsid spectrum showed backbone amide proton resonances arising from the first eight residues having a flexible random coil conformation, and side-chain resonances arising from the first 25 N-terminal amino acids. The dimer spectrum showed also side-chain resonances of residues 26 to 33, which are flexible in the dimer but immobilized in the capsid. The n.m.r. experiments indicated that the conformation of the first 25 amino acids of the protein in dimers and capsids is comparable to the conformation of the synthetic peptide, which alternates among extended and helical conformations on the n.m.r. time-scale. It is suggested that the alpha-helical region, situated in the region between residues 10 and 20, binds to the RNA during assembly of the virus particle.

Echo-time independent signal modulations using PRESS sequences: a new approach to spectral editing of strongly coupled AB spin systems.

In clinical MR spectroscopy, double spin-echo point resolved spectroscopy (PRESS) sequences are routinely used for volume selection. For strongly coupled AB spin systems under PRESS excitation, the dependence of the signal on the echo time TE has been thoroughly investigated, whereas less attention has been paid to the signal modulation which occurs at constant TE with varying interpulse delays. A substantial TE-independent J modulation is here predicted from analytical solutions of the Liouville equation and density matrix simulations, and verified with experiments on citrate at 1.5 and 3T. It is also shown that this modulation effect could be exploited for editing of strongly coupled AB resonances or for removal of singlets in spectra-by means of difference spectroscopy-just using a standard PRESS sequence. The applicability in vivo of this new spectral editing approach is also demonstrated, with selective detection of citrate resonances in the human prostate. This novel approach has the advantages of being simple, and directly applicable on standard clinical MR scanners, provided that the exact behavior of the resonance is known.

The use of multivariate MR imaging intensities versus metabolic data from MR spectroscopic imaging for brain tumour classification.

This study investigated the value of information from both magnetic resonance imaging and magnetic resonance spectroscopic imaging (MRSI) to automated discrimination of brain tumours. The influence of imaging intensities and metabolic data was tested by comparing the use of MR spectra from MRSI, MR imaging intensities, peak integration values obtained from the MR spectra and a combination of the latter two. Three classification techniques were objectively compared: linear discriminant analysis, least squares support vector machines (LS-SVM) with a linear kernel as linear techniques and LS-SVM with radial basis function kernel as a nonlinear technique. Classifiers were evaluated over 100 stratified random splittings of the dataset into training and test sets. The area under the receiver operating characteristic (ROC) curve (AUC) was used as a global performance measure on test data. In general, all techniques obtained a high performance when using peak integration values with or without MR imaging intensities. For example for low- versus high-grade tumours, low- versus high-grade gliomas and gliomas versus meningiomas, the mean test AUC was higher than 0.91, 0.94, and 0.99, respectively, when both MR imaging intensities and peak integration values were used. The use of metabolic data from MRSI significantly improved automated classification of brain tumour types compared to the use of MR imaging intensities solely.

Automated correction of unwanted phase jumps in reference signals which corrupt MRSI spectra after eddy current correction.

A commonly applied step in the postprocessing of gradient localized proton MR spectroscopy, is correction for eddy current effects using the water signal as a reference. However, this method can degrade some of the metabolite signals, in particular if applied on proton MR spectroscopic imaging data. This artifact arises from the water reference signal in the presence of a second signal which resonates close to the main water resonance. The interference of both resonances will introduce jumps in the phase of the reference time domain signal. Using this phase for eddy current correction will result in a ringing artifact in the frequency domain of the metabolite signal over the whole frequency range. We propose a moving window correction algorithm, which screens the phase of reference signals and removes phase jumps in time domain caused by interference of signals from multiple spin systems. The phase jumps may be abrupt or gradually distributed over several time data points. Because the correction algorithm only corrects time data points which contain phase jumps, the phase is minimally disrupted. Furthermore, the algorithm is automated for large datasets, correcting only those water reference signals which are corrupted. After correction of the corrupted reference signals, normal eddy current correction may be performed. The algorithm is compared with a method which uses a low-pass filter and tested on simulated data as well as on in vivo proton spectroscopic imaging data from a healthy volunteer and from patients with a brain tumor.

Automatic correction for phase shifts, frequency shifts, and lineshape distortions across a series of single resonance lines in large spectral data sets.

A new model-free method is presented that automatically corrects for phase shifts, frequency shifts, and additional lineshape distortions of one single resonance peak across a series of in vivo NMR spectra. All separate phase and frequency variations are quickly and directly derived from the common lineshape in the data set using principal component analysis and linear regression. First, the new approach is evaluated on simulated data in order to quantitatively assess the phase and frequency shifts which can be removed by the proposed correction procedure. Subsequently, the value of the method is demonstrated on in vivo (31)P NMR spectra from skeletal muscle of the hind leg of the mouse focusing on the phosphocreatine resonance which is distorted by the experimental procedure. Phase shifts, frequency shifts, and lineshape distortions with respect to the common lineshape in the spectral data set could successfully be removed.

Classification of brain tumours using short echo time 1H MR spectra.

The purpose was to objectively compare the application of several techniques and the use of several input features for brain tumour classification using Magnetic Resonance Spectroscopy (MRS). Short echo time 1H MRS signals from patients with glioblastomas (n = 87), meningiomas (n = 57), metastases (n = 39), and astrocytomas grade II (n = 22) were provided by six centres in the European Union funded INTERPRET project. Linear discriminant analysis, least squares support vector machines (LS-SVM) with a linear kernel and LS-SVM with radial basis function kernel were applied and evaluated over 100 stratified random splittings of the dataset into training and test sets. The area under the receiver operating characteristic curve (AUC) was used to measure the performance of binary classifiers, while the percentage of correct classifications was used to evaluate the multiclass classifiers. The influence of several factors on the classification performance has been tested: L2- vs. water normalization, magnitude vs. real spectra and baseline correction. The effect of input feature reduction was also investigated by using only the selected frequency regions containing the most discriminatory information, and peak integrated values. Using L2-normalized complete spectra the automated binary classifiers reached a mean test AUC of more than 0.95, except for glioblastomas vs. metastases. Similar results were obtained for all classification techniques and input features except for water normalized spectra, where classification performance was lower. This indicates that data acquisition and processing can be simplified for classification purposes, excluding the need for separate water signal acquisition, baseline correction or phasing.

In vivo proton MR spectroscopy reveals altered metabolite content in malignant prostate tissue.

BACKGROUND: Recently the potential of magnetic resonance (MR) methods for non-invasive diagnosis and therapy evaluation of prostate cancer has improved substantially. In this study proton MR spectroscopy (1H MRS) was explored for the detection of cancer in the prostate. PATIENTS AND METHODS: Employing an endorectal probe localized 1H MRS and contrast enhanced MR imaging was performed on the prostate of healthy volunteers and of patients with benign prostatic hyperplasia (BPH) and/or prostate cancer (PCa). RESULTS: 1H MR spectra of the human prostate showed major signals for citrate, creatine and choline compounds. For cancer tissue the average citrate/choline signal ratio was significantly lower than for BPH and non-cancerous peripheral and central zone tissue, but individual ratios overlapped with ratios for normal central zone and BPH tissue. Low citrate/choline ratios in tumour tissue correspond with early MR contrast enhancement. CONCLUSIONS: 1H MRS has potential for non-invasive detection and follow-up of tumours in the prostate.

Brain tumor classification based on long echo proton MRS signals.

There has been a growing research interest in brain tumor classification based on proton magnetic resonance spectroscopy (1H MRS) signals. Four research centers within the EU funded INTERPRET project have acquired a significant number of long echo 1H MRS signals for brain tumor classification. In this paper, we present an objective comparison of several classification techniques applied to the discrimination of four types of brain tumors: meningiomas, glioblastomas, astrocytomas grade II and metastases. Linear and non-linear classifiers are compared: linear discriminant analysis (LDA), support vector machines (SVM) and least squares SVM (LS-SVM) with a linear kernel as linear techniques and LS-SVM with a radial basis function (RBF) kernel as a non-linear technique. Kernel-based methods can perform well in processing high dimensional data. This motivates the inclusion of SVM and LS-SVM in this study. The analysis includes optimal input variable selection, (hyper-) parameter estimation, followed by performance evaluation. The classification performance is evaluated over 200 stratified random samplings of the dataset into training and test sets. Receiver operating characteristic (ROC) curve analysis measures the performance of binary classification, while for multiclass classification, we consider the accuracy as performance measure. Based on the complete magnitude spectra, automated binary classifiers are able to reach an area under the ROC curve (AUC) of more than 0.9 except for the hard case glioblastomas versus metastases. Although, based on the available long echo 1H MRS data, we did not find any statistically significant difference between the performances of LDA and the kernel-based methods, the latter have the strength that no dimensionality reduction is required to obtain such a high performance.

Pronounced weight gain in insulin-treated patients with type 2 diabetes mellitus is associated with an unfavourable cardiometabolic risk profile.

Pronounced weight gain after start of insulin therapy in patients with type 2 diabetes mellitus (T2DM) may offset beneficial effects conferred by the improvement of glycaemic control. This hypothesis was tested by comparing the cardiometabolic risk profile of a group of type 2 diabetes patients with a marked increase in body weight ('gainers) after the start of insulin treatment and a similar group without any or only minimal weight gain ('non-gainers'). In a cross-sectional study, we compared two predefined groups of patients with T2DM who had been on insulin therapy for a mean of 4.0 years: 'gainers' vs 'non-gainers'. Cardiometabolic risk was assessed by measuring fat content and distribution (physical examination, bioelectrical impedance analysis, dual energy X-ray absorption, and magnetic resonance imaging), liver fat content (magnetic resonance spectroscopy), physical activity levels (Sensewear® armband) and plasma markers. Each subgroup consisted of 14 patients. Gainers had significantly more total body and trunk fat (especially subcutaneous fat) compared with no-gainers. Gainers had similar liver fat content, and slightly higher levels of fat hormones. Furthermore, gainers performed significantly less physical activity. Lastly, gainers had higher total cholesterol, low-density lipoprotein cholesterol, and alanine aminotransferase levels with similar cholesterol-lowering treatment. Patients with T2DM who show pronounced weight gain during insulin therapy have a less favourable cardiometabolic risk profile compared with patients who show no or minimal weight gain.

Methylsulfonylmethane (MSM) ingestion causes a significant resonance in proton magnetic resonance spectra of brain and cerebrospinal fluid.

The use of methylsulfonylmethane (MSM), available as an "over-the-counter" dietary supplement, led to the occurrence of an abnormal resonance at 3.15 ppm in the in vivo brain proton MR spectrum as well as the in vitro cerebrospinal fluid NMR study of a 4-year-old girl. The concentration of this compound amounted to 1.2 mmol/l in brain tissue and 1.7 mmol/l in cerebrospinal fluid. Our findings illustrate that ingestion of exogenous compounds, e.g., in medication, food or "innocent" supplements, may lead to abnormal resonances in spectroscopy studies that might be difficult to assign.

Intake of 13C-4 creatine enables simultaneous assessment of creatine and phosphocreatine pools in human skeletal muscle by 13C MR spectroscopy.

The feasibility of a novel method for the noninvasive and local assessment of creatine (Cr) and phosphocreatine (PCr) dynamics in human skeletal muscle based on (13)C magnetic resonance (MR) spectroscopy is presented. A high dose of Cr, labeled at the guanidino C-4 position with (13)C 11% enrichment, was administered orally to a human subject for 5 days. Using a surface coil, (13)C MR spectra of the lower leg were acquired on a 1.5T MR system at regular time intervals during and after Cr supplementation. An almost twofold increase in the intensities of the resolved PCr and Cr (13)C-4 signals was observed during this period. The slow decrease in these signals to normal values after supplementation reflects the slow daily turnover of Cr. The PCr/Cr ratio did not appear to change over the whole measurement period. During exercise of the leg, reversible changes in PCr and Cr signals were observed, reflecting conversion by the Cr kinase reaction.

Sensitivity-enhanced 13C MR spectroscopy of the human brain at 3 Tesla.

A new coil design for sensitivity-enhanced 13C MR spectroscopy (MRS) of the human brain is presented. The design includes a quadrature transmit/receive head coil optimized for 13C MR sensitivity. Loss-less blocking circuits inside the coil conductors allow this coil to be used inside a homogeneous circularly polarized 1H B1 field for 1H decoupled 13C MRS. A quadrature 1H birdcage coil optimized for minimal local RF heating makes broadband 1H decoupling in the entire human brain possible at 3 Tesla while remaining well within international safety guidelines for RF absorption. Apart from a substantial increase in sensitivity compared to conventional small linear coils, the quadrature 13C coil combined with the quadrature 1H birdcage coil allows efficient cross polarization (CP) in the brain, resulting in an additional 3.5-fold sensitivity improvement compared to direct 13C measurements without nuclear Overhauser enhancement (NOE) or polarization transfer. Combined with the gain in power efficiency, this setup allows broadband 1H to 13C CP over large areas of the brain. Clear 13C resonances from glutamate (Glu), glutamine (Gln), aspartate (Asp), lactate (Lac), and gamma-aminobutyrate (GABA) carbon spins in the human brain demonstrate the quality of 13C MR spectra obtained in vivo with this coil setup.