Quantification of arterial flow using digital subtraction angiography.

PURPOSE: In this paper, a method for the estimation of arterial hemodynamic flow from x-ray video densitometry data is proposed and validated using an in vitro setup. METHODS: The method is based on the acquisition of three-dimensional rotational angiography and digital subtraction angiography sequences. A modest contrast injection rate (between 1 and 4 ml/s) leads to a contrast density that is modulated by the cardiac cycle, which can be measured in the x-ray signal. An optical flow based approach is used to estimate the blood flow velocities from the cyclic phases in the x-ray signal. RESULTS: The authors have validated this method in vitro, and present three clinical cases. The in vitro experiments compared the x-ray video densitometry results with the gold standard delivered by a flow meter. Linear correlation analysis and regression fitting showed that the ideal slope of 1 and intercept of 0 were contained within the 95 percentile confidence interval. The results show that a frame rate higher than 50 Hz allows measuring flows in the range of 2 ml/s to 6 ml/s within an accuracy of 5%. CONCLUSIONS: The in vitro and clinical results indicate that it is feasible to estimate blood flow in routine interventional procedures. The availability of an x-ray based method for quantitative flow estimation is particularly clinically useful for intra-cranial applications, where other methods, such as ultrasound Doppler, are not available.

α-Synuclein dimerization in erythrocytes of Gaucher disease patients: correlation with lipid abnormalities and oxidative stress.

Several observations suggest that disturbed homeostasis of α-Synuclein (α-Syn) may provide a link between Gaucher disease (GD) and Parkinson's disease (PD). We recently reported increased dimerization of α-Syn in the red blood cell (RBC) membrane of patients with GD. Several studies indicate a crucial relationship between lipids, oxidative stress and α-Syn status. Here we investigated the relationship between the observed increased dimerization of α-Syn in the cell membranes of RBCs, cells devoid of lysosomes and lacking lysosomal enzyme synthesis, and the lipid abnormalities and oxidative stress already described in GD. Correlation studies showed that in GD the α-Syn dimer/monomer ratio is positively correlated with the levels of glucosylceramide (GlcCer) and the glucosylceramide/ceramide (GlcCer/Cer) ratio and negatively with the levels of malonyldialdehyde (MDA) and plasmalogens. In conclusion, we have shown that the increased tendency of α-Syn to form dimers in the RBC membrane of patients with GD, is correlated with both the level of lipids, including GlcCer, the primary lipid abnormality in GD, and the increased oxidative stress observed in this disorder. The study of other tissues, and in particular brain, will be important in order to elucidate the significance of these findings regarding the link between GD and PD.

Dyscholesterolemia Protects Against Ischemia-Induced Ventricular Arrhythmias.

BACKGROUND: Hypercholesterolemia protects against ventricular fibrillation in patients with myocardial infarction. We hypothesize that hypercholesterolemia protects against ischemia-induced reentrant arrhythmias because of altered ion channel function. METHODS AND RESULTS: ECGs were measured in low-density lipoprotein receptor knockout (LDLr(-/-)), apolipoprotein A1 knockout (ApoA1(-/-)), and wild-type (WT) mice. Action potentials, calcium handling, and ion currents were recorded in ventricular myocytes. Gene expression was determined by quantitative polymerase chain reaction and Western blot. In isolated perfused hearts, regional ischemia was induced and arrhythmia inducibility was tested. Serum low-density lipoprotein (LDL) cholesterol was higher in LDLr(-/-) mice than in WT mice (2.6 versus 0.4 mmol/L), and high-density lipoprotein cholesterol was significantly lower in ApoA1(-/-) mice than in WT mice (0.3 versus 1.8 mmol/L). LDLr(-/-) and ApoA1(-/-) myocytes contained more cholesterol than WT (34.4±2.8 and 36.5±2.4 versus 25.5±0.4 µmol/g protein). The major potassium currents were not different in LDLr(-/-) and ApoA1(-/-) compared with WT mice. The L-type calcium current (I(Ca)), however, was larger in LDLr(-/-) and ApoA1(-/-) than in WT (12.1±0.7 and 12.8±0.8 versus 9.4±1.1 pA/pF). Calcium transient amplitude and fractional sarcoplasmic reticulum calcium release were larger and action potential and QTc duration longer in LDLr(-/-) and ApoA1(-/-) than in WT mice (action potential duration at 90% of repolarization: 102±4 and 106±3 versus 84±3.1 ms; QTc: 50.9±1.3 and 52.8±0.8 versus 43.5±1.2 ms). During ischemia, ventricular tachycardia/ventricular fibrillation inducibility was larger in WT than in LDLr(-/-) and ApoA1(-/-) hearts. Expression of sodium channel and Ca-handling genes were not significantly different between groups. CONCLUSIONS: Dyscholesterolemia is associated with action potential prolongation because of increased I(Ca) and reduces occurrence of reentrant arrhythmias during ischemia.

Therapeutic goals in the treatment of Gaucher disease.

Gaucher disease, the most common lysosomal storage disorder, is a heterogeneous multisystem condition. Patients with non-neuronopathic (type 1) Gaucher disease may suffer from hepatomegaly, splenomegaly, thrombocytopenia, bleeding tendencies, anemia, hypermetabolism, skeletal pathology, growth retardation, pulmonary disease, and decreased quality of life. Enzyme replacement therapy (ERT) with mannose-terminated glucocerebrosidase reverses or ameliorates many of the manifestations of type 1 Gaucher disease. However, the variable disease pattern and severity, and the uncertain manner of progression, render the decision to initiate ERT difficult. Thus, implementation of treatment and evaluation of the therapeutic response must be tailored to the individual patient. To obtain an evidence-based consensus on contemporary therapeutic goals, an international panel of physicians with extensive clinical experience in Gaucher disease met to review the extant literature on its treatment. The panel adopted an integrated system-based approach to arrive at a comprehensive guide to individualized management. Here we establish goals of treatment in Gaucher disease and propose a comprehensive schedule of monitoring of all relevant aspects to confirm the achievement, maintenance, and continuity of the therapeutic response.

Feasibility study of needle placement in percutaneous vertebroplasty: cone-beam computed tomography guidance versus conventional fluoroscopy.

OBJECTIVE: To investigate the accuracy, procedure time, fluoroscopy time, and dose area product (DAP) of needle placement during percutaneous vertebroplasty (PVP) using cone-beam computed tomography (CBCT) guidance versus fluoroscopy. MATERIALS AND METHODS: On 4 spine phantoms with 11 vertebrae (Th7-L5), 4 interventional radiologists (2 experienced with CBCT guidance and two inexperienced) punctured all vertebrae in a bipedicular fashion. Each side was randomization to either CBCT guidance or fluoroscopy. CBCT guidance is a sophisticated needle guidance technique using CBCT, navigation software, and real-time fluoroscopy. The placement of the needle had to be to a specific target point. After the procedure, CBCT was performed to determine the accuracy, procedure time, fluoroscopy time, and DAP. Analysis of the difference between methods and experience level was performed. RESULTS: Mean accuracy using CBCT guidance (2.61 mm) was significantly better compared with fluoroscopy (5.86 mm) (p < 0.0001). Procedure time was in favor of fluoroscopy (7.39 vs. 10.13 min; p = 0.001). Fluoroscopy time during CBCT guidance was lower, but this difference is not significant (71.3 vs. 95.8 s; p = 0.056). DAP values for CBCT guidance and fluoroscopy were 514 and 174 mGy cm(2), respectively (p < 0.0001). There was a significant difference in favor of experienced CBCT guidance users regarding accuracy for both methods, procedure time of CBCT guidance, and added DAP values for fluoroscopy. CONCLUSION: CBCT guidance allows users to perform PVP more accurately at the cost of higher patient dose and longer procedure time. Because procedural complications (e.g., cement leakage) are related to the accuracy of the needle placement, improvements in accuracy are clinically relevant. Training in CBCT guidance is essential to achieve greater accuracy and decrease procedure time/dose values.

MPI Cell Tracking: What Can We Learn from MRI?

Magnetic resonance imaging (MRI) cell tracking has become an important non-invasive technique to interrogate the fate of cells upon transplantation. At least 6 clinical trials have been published at the end of 2010, all of which have shown that real-time monitoring of the injection procedure, initial engraftment, and short-term biodistribution of cells is critical to further advance the field of cellular therapeutics. In MRI cell tracking, cells are loaded with superparamagnetic iron oxide (SPIO) particles that provide an MRI contrast effect through microscopic magnetic field disturbances and dephasing of protons. Magnetic particle imaging (MPI) has recently emerged as a potential cellular imaging technique that promises to have several advantages over MRI, primarily linear quantification of cells, a higher sensitivity, and "hot spot" tracer identification without confounding background signal. Although probably not fully optimized, SPIO particles that are currently used as MRI contrast agent can be employed as MPI tracer. Initial studies have shown that cells loaded with SPIO particles can give a detectable MPI signal, encouraging further development of MPI cell tracking.

Plasma level of the macrophage-derived soluble CD163 is increased and positively correlates with severity in Gaucher's disease.

Recently, soluble CD163 (sCD163) has been identified as a macrophage/monocyte-specific plasma protein and increased concentrations have been measured in patients with infection and myeloid leukaemia. In the present study we investigated the levels of sCD163 in patients with Gaucher's disease, an inherited lysosomal storage disorder characterised by hepato- and splenomegaly due to excessive accumulation of macrophages. The sCD163 plasma levels, median (25-75 percentiles), were far above the levels in normal subjects [7.1 mg/L (4.8-10.3) vs. 1.9 mg/L (1.5-2.4), P < 0.0001]. After initiation of enzyme supplementation therapy, the sCD163 levels were significantly reduced [4.7 mg/L (3.2-6.6), P = 0.0004]. sCD163 correlated with disease severity (rho = 0.43, P < 0.0061) and chitotriosidase activity (rho = 0.71, P > 0.0001). This study further establishes that sCD163 may be a valuable laboratory parameter in monitoring disease with increased macrophage activity.

Correlation of bone marrow response with hematological, biochemical, and visceral responses to enzyme replacement therapy of nonneuronopathic (type 1) Gaucher disease in 30 adult patients.

PURPOSE: This investigation correlates the marrow response with the degree of increase in hemoglobin (Hb) and platelet count (Plt); decrease in concentrations of plasma tartrate-resistant acid phosphatase, serum angiotensin-converting enzyme (ACE), serum ferritin, and plasma chitotriosidase; and decrease in liver and spleen size, measured by ultrasonography. METHODS: Thirty adult patients with nonneuronopathic (type 1) Gaucher disease (23% splenectomized) were followed for mean periods of 12 and 36 months. RESULTS: The series achieved highly significant mean responses in all hematological, biochemical, and visceral parameters over both observation periods; over a mean 36 months, 19 (63%) had a marrow response, 11 (37%) did not. Six of 7 splenectomized patients attained a marrow response. There were no significant differences between the marrow responders and nonresponders in age, sex, spleen status, Gaucher genotype distribution, mean baseline hematological or biochemical values or liver size, or mean follow-up. At a mean follow-up of 12 months, no significant differences yet were evident between marrow responders and nonresponders in seven of eight response parameters, but marrow responders had a significantly greater reduction in plasma chitotriosidase and a trend toward significantly greater reduction in serum ACE. At a mean follow-up of 36 months, marrow responders had a significantly greater mean increase in Plt and mean decrease in serum ferritin concentration and liver size than did marrow nonresponders; the trend toward greater ACE reduction in marrow responders deepened. However, chitotriosidase response now was equivalent in both subgroups. Marrow nonresponders had a significantly greater mean diminution in spleen size than did marrow responders, but the marrow nonresponders had significantly larger mean spleen size at baseline. Marrow nonresponders also had a greater mean increase in Hb than did marrow responders, but the difference was not significant. The two subgroups had equivalent mean reductions of plasma TRAP. CONCLUSIONS: The clinical relevance of qualitative MRI of the bone marrow in monitoring patients receiving ERT for nonneuronopathic Gaucher disease show that marrow nonresponders can derive considerable benefit from ERT across a variety of other response parameters and suggest an influence of spleen size on marrow response to ERT.

Design and synthesis of 2-acetamidomethyl derivatives of isofagomine as potential inhibitors of human lysosomal beta-hexosaminidases.

As part of a program towards the development of specific inhibitors of human lysosomal beta-hexosaminidase for use as chemical chaperones in therapy of G(M2) gangliosidosis related diseases, the synthesis of 2-acetamidomethyl derivatives of isofagomine has been undertaken. Key event in this synthesis is the conversion of a C-2 substituted gluconolactone derivative into the corresponding lactam, followed by reduction to the corresponding amine. The 1-N-imino-2 acetamidomethyl derivative 5 proved to be a rather selective inhibitor with a K(i) of 2.4 microM for homogenate of human spleen lysosomal beta-hexosaminidase.