The human Mi-2/NuRD complex and gene regulation.

The Mi-2/nucleosome remodeling and deacetylase (NuRD) complex is an abundant deacetylase complex with a broad cellular and tissue distribution. It is unique in that it couples histone deacetylation and chromatin remodeling ATPase activities in the same complex. A decade of research has uncovered a number of interesting connections between Mi-2/NuRD and gene regulation. The subunit composition of the enzyme appears to vary with cell type and in response to physiologic signals within a tissue. Here, we review the known subunits of the complex, their connections to signaling networks, and their association with cancer. In addition, we propose a working model that integrates the known biochemical properties of the enzyme with emerging models on how chromatin structure and modification relate to gene activity.

A TMS coil positioning/holding system for MR image-guided TMS interleaved with fMRI.

OBJECTIVE: Transcranial magnetic stimulation (TMS) can be interleaved with fMRI to visualize regional brain activity in response to direct, non-invasive, cortical stimulation, making it a promising tool for studying brain function. A major practical difficulty is accurately positioning the TMS coil within the MRI scanner for stimulating a particular area of brain cortex. The objective of this work was to design and build a self-contained hardware/software system for MR-guided TMS coil positioning in interleaved TMS/fMRI studies. METHODS: A compact, manually operated, articulated TMS coil positioner/holder with 6 calibrated degrees of freedom was developed for use inside a cylindrical RF head coil, along with a software package for transforming between MR image coordinates, MR scanner space coordinates, and positioner/holder settings. RESULTS: Phantom calibration studies gave an accuracy for positioning within setups of dx=+/-1.9 mm, dy=+/-1.4 mm, dz=+/-0.8 mm and a precision for multiple setups of dx=+/-0.8 mm, dy=+/-0.1 mm, dz=+/-0.1 mm. CONCLUSIONS: This self-contained, integrated MR-guided TMS system for interleaved TMS/fMRI studies provides fast, accurate location of motor cortex stimulation sites traditionally located functionally, and a means of consistent, anatomy-based TMS coil positioning for stimulation of brain areas without overt response.

Vagus nerve stimulation therapy: a research update.

Over the past 5 years, and especially within the last year, there has been a rapid expansion of vagus nerve stimulation (VNS)-related preclinical research, as well as clinical studies in indications other than epilepsy. The research advances in understanding VNS are occurring in the midst of a blossoming of other forms of therapeutic brain stimulation, such as electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), and deep brain stimulation (DBS). In general, improved understanding of the neurobiological effects of VNS therapy as a function of the different use parameters (frequency, intensity, pulse width, duration, dose) is beginning to guide clinical use and help determine which diseases, in addition to epilepsy, VNS might treat.

Feasibility of vagus nerve stimulation-synchronized blood oxygenation level-dependent functional MRI.

RATIONALE AND OBJECTIVES: Left cervical vagus nerve stimulation (VNS) by use of an implanted neurocybernetic prosthesis (NCP) system is effective in treating epilepsy, with open data suggesting effectiveness in depression, yet the mechanisms of action are unknown. Our objective was to develop a methodology for performing VNS-synchronized functional magnetic resonance imaging (VNS-fMRI) and then to demonstrate its feasibility for studying VNS effects. METHODS: In nine patients implanted for treatment of intractable depression, a Macintosh computer was used to detect the signal from the implanted VNS stimulator and then to synchronize fMRI image acquisition with its regular firing. RESULTS: With our VNS-fMRI methodology, the blood oxygenation level-dependent response to VNS was shown in brain regions regulated by the vagus nerve: orbitofrontal and parieto-occipital cortex bilaterally, left temporal cortex, the hypothalamus, and the left amygdala. CONCLUSIONS: Vagus nerve stimulation pulses from an NCP system can be detected externally to determine its firing pattern, thus allowing VNS-fMRI studies of VNS-induced brain activity.

Estimation of right ventricular free-wall mass using two-dimensional echocardiography.

Echocardiographic methods based on geometric models have long been in use for estimating left ventricular mass, but there is currently no similar method for estimating right ventricular (RV) free-wall mass. We hypothesized that a one-quarter prolate ellipsoid model could be used with two-dimensional echocardiography to approximate RV mass. Over a 2-year period 39 patients who had both a complete cardiac magnetic resonance imaging (MRI) scan and an echocardiogram within 2 weeks of each other were retrospectively analyzed. MRI-derived RV mass was used as the standard for comparison. Echocardiographic RV mass was estimated using three equations based on the geometric model. Linear regression analysis was performed to determine the correction factors used in the final formulae. The formula with the lowest standard error of the estimate was then prospectively analyzed for accuracy using a separate group of 88 subjects. The most accurate echocardiographic equation derived was RV mass = 5.84 (apical four-chamber RV cavity planar area) (RV free-wall thickness) + 1. Compared to MRI-RV mass the correlation coefficient was 0.97 and the standard error of the estimate was 16.8%. The positive and negative predictive values for diagnosing RV hypertrophy were 95% and 88%, respectively. We conclude that RV free-wall mass can be estimated by two-dimensional echocardiography using a one-quarter prolate ellipsoid shell model.

A new framework for echocardiographic assessment of left ventricular mechanics: sensitivity to heart failure.

A recent report describes an approach to ventricular mechanics that employs mean end-systolic fiber stress and an exact mathematical strain index based on wall thickness referenced to myocardial mass. We used echocardiography and mean arterial pressures to determine the strain index and wall stress in (1) normal hearts from patients and swine, (2) swine with pacing-induced congestive heart failure, and (3) patients with dilated cardiomyopathy. Pigs were also studied under afterload variation with phenylephrine. Paired values of stress and strain index from control hearts (both swine and human) were tightly clustered. Values from animals and patients with congestive heart failure deviated from this cluster. Excellent separation (sensitivity 83%, specificity 94%) was displayed between control and paced pigs, despite confounding effects of varying afterload. We conclude that these variables display little change over a large range of normal cardiac mass, but deviate from this range during heart failure.

Constraints on cardiac hypertrophy imposed by myocardial viscosity.

Laplace's law constrains how thin the ventricular wall may be without experiencing excessive stress. The present study investigated constraints, imposed by myocardial viscosity (resistance to internal rearrangement), on how thick the wall may be. The ventricle was modeled as a contracting, spherical shell. The analysis demonstrated that viscosity generates stress and energy dissipation with inverse fourth- and eighth-power dependence, respectively, on distance from the cavity center. This result derives from the combination of squared dependence of viscous forces on shearing velocity gradients and the greater shear rearrangement required for inner layers of a contracting sphere. These predictions are based solely on geometry and fundamentals of viscosity and are independent of material properties, cytoskeletal structure, and internal structural forces. Calculated values of energy and force required to overcome viscosity were clearly large enough to affect the extent of thickening of the left ventricle. It is concluded that load-independent viscous resistance to contraction is an important factor in cardiac mechanics, especially of the thickened ventricles of concentric hypertrophy.

Vagus nerve stimulation: a new form of therapeutic brain stimulation.

Although the vagus nerve has traditionally been considered to perform efferent functions, in reality it performs significant afferent functions as well, carrying information from the body, head, and neck to the brain. Preliminary studies examining this afferent activity led to the theory that vagus nerve stimulation (VNS) could successfully control seizure activity in persons who are refractory to antiepileptic medications. Unlike other forms of brain stimulation, VNS is unable to directly stimulate multiple discrete areas of the brain; however, through several pathways, it is able to relay sensory information to higher brain regions. An implantable VNS device known as the VNSTM NeuroCybernetic Prosthesis (NCP) System has been used in approximately 9,000 epilepsy patients in Europe and the United States since 1994. The implant has reduced seizure frequency by an average of 25% to 30%, with minimal side effects. Studies underway are also showing some degree of success in the management of treatment-refractory depression. The future efficacy of the implantable system in other disorders may depend on whether the implant can be more precisely focused to affect different brain regions. Research in this area is underway.

Wall thickness referenced to myocardial volume: a new noninvasive framework for cardiac mechanics.

Dimensional variables measured for study of left ventricular mechanics are subject to errors arising from difficulty in determining zero-stress dimensions for use as a reference. Based on a method validated for measurements within individuals, we have devised an approach that facilitates comparison between individuals while minimizing random scatter. We define an exact mathematical index of strain, ln(h(0)/h), using wall thickness (h) referenced to extrapolated wall thickness at zero-luminal volume (h(0)). Noninvasive data from rabbits, pigs, and humans all yielded highly similar myocardial stress, ln(h(0)/h), and work values. The stress-ln(h(0)/h) relationship during afterload variation was constant among individual pigs with a twofold variation in ventricular mass. Stress-ln(h(0)/h) data from our analysis displayed lower scatter than either pressure-volume data normalized to myocardial mass or stress-ln(h(0)/h) data referenced to end-diastolic dimensions. A Frank-Starling-like curve with high correlation (r(2) = 0.96) was constructed from single points from different pigs, suggesting a low level of size and intersubject scatter. This method offers high precision for noninvasive characterization of ventricular and myocardial mechanics and for comparisons between subjects and between species.

Right ventricular volumes revisited: a simple model and simple formula for echocardiographic determination.

Our objective was to establish a crescentic model of the right ventricle as the basis of a reported 2/3 (Area)(Length) empirical formula for volume. This formula has been investigated by others without cognizance of its connection to a clear geometric model. The particular model, an ellipsoidal shell or difference of ellipsoids, has been investigated by several groups by using different volume formulas. Accordingly, we obtained echocardiographic images in 2 orthogonal planes from 7 patients and 4 volunteers. Specified area and length measurements from these images were used to calculate right ventricular volumes. These volumes were compared with values determined through multislice, magnetic resonance imaging with summation of lumen areas, a widely accepted standard. Obtained high correlations compared favorably with those of previous investigators who used equivalent but less well understood methods. We conclude that the ellipsoidal shell model of the right ventricle provides a simple area-length formula for the determination of lumen volume with echocardiography.

Incidence of femoral vein occlusion after catheter ablation in children: evaluation with magnetic resonance angiography.

Catheter ablation in children requires placement of multiple large femoral venous sheaths and catheters. Magnetic resonance angiography (MRA) was used to evaluate the effect of indwelling lines on femoral venous blood flow. Between October 1993 and February 1994 a total of 17 patients scheduled for catheter ablation underwent venous MRA. Two-dimensional time-of-flight MRA was performed 12-70 hours after catheterization on all patients. All patients received intravenous heparin during the procedure and had aspirin therapy instituted after ablation. Eighteen catheter ablations and MRA studies were performed on the 17 patients (one patient underwent repeat ablation). There were 7 females and 10 males, with a mean age of 14.8 +/- 4.2 years (range 8-21 years). Patients had three venous sheaths inserted in the left femoral vein (5F, 6F, and 7F with external diameters measuring 1.7, 2.0, and 2.3 mm, respectively) and one sheath in the right femoral vein (7F). Four patients (22%) had altered venous flow (two complete obstructions and two partial obstructions) following catheterization. None of these patients experienced symptoms or complications. It was concluded that there is an increased incidence (22%) of venous obstruction following catheter ablation, but there are no related complications. Venous MRA provides a rapid, noninvasive method for evaluating venous flow abnormalities and possibly detects patients at risk for complications.

Relationship between PVA and myocardial oxygen consumption can be derived from thermodynamics.

The pressure-volume area (PVA) has been shown to be an excellent, linear index of myocardial oxygen consumption. The thermodynamic basis for this result, however, has not been elucidated. The present study was undertaken to determine what information could be gained from analyzing the cardiac pressure-volume (P-V) cycle as an approximation to some "ideal" thermodynamic cycle operating under the constraints imposed by cardiovascular anatomy and physiology. The myocardium was approximated as a linear, chemically driven elastance in accordance with the time-varying elastance model. Analysis provided descriptions of a Carnot cycle for myocardium and a suboptimal ideal cycle, including isovolumic phases. Further analysis of the ideal cycle indicated that the end-systolic P-V relationship (ESPVR) is an approximation to the adiabatic P-V trajectory that primarily determines total energy consumption. Analysis also indicated possible explanations of current results that seem to be at odds with the time-varying elastance model. These results suggest that thermodynamic cycle analysis may provide a useful analytic tool for investigation of the cardiac cycle.

Right ventricular volume estimation using an ellipsoidal shell model and single-plane magnetic resonance imaging.

RATIONALE AND OBJECTIVES: To investigate whether accurate right ventricular volumes could be obtained using an ellipsoidal shell model with magnetic resonance (MR) image measurements from a single imaging plane. METHODS: An initial retrospective patient study included 10 patients with congenital cardiac defects who had undergone same-day or next-day radiographic contrast ventriculography. An expanded study included MR scans of a total of 29 patients with congenital cardiac defects. Magnetic resonance scans of 10 healthy volunteers were also included in part of the study. Right ventricular volumes were calculated from (1) model-based calculations using single-plane cine MR imaging, and (2) multislice calculations based on contrast angiography. RESULTS: Regression of angiography-based volumes against MR-based volumes showed high correlation (r = 0.97, see = 12.5 mL) and slope near unity. Regression of right against left stroke volumes, both calculated from MR data, showed excellent correlation (r = 0.90, see = 11.6 ml) and slope near unity. CONCLUSIONS: The ellipsoidal shell model can be used to reliably estimate right ventricular volume using single-plane MR images.

Right ventricular volume estimation with an ellipsoidal shell model and two-plane magnetic resonance imaging.

In patients with congenital and other heart disease, measurement of right ventricular (RV) volumes would be as useful as left ventricular (LV) volume measurement has been for diseases of the LV. Model-based techniques have had limited success. Simpson's rule (multislice) techniques require lengthy data collection and reduction. We investigated a technique for volume estimation with a new but simple geometric model. A retrospective patient study compared RV volumes from model-based calculations with dual-plane cine magnetic resonance (MR) imaging and multislice calculations with biplane cineangiography. Linear regression showed high correlation (r = 0.98, standard error of the estimate = 11.8 ml) between the two techniques, with a slope near unity. Comparison of calculated right and left stroke volumes also showed an excellent correlation (r = 0.93, standard error of the estimate = 10.4 ml) and a slope near unity. It is concluded that the ellipsoidal shell model can be used to estimate RV volume reliably and practically with dual-plane MR imaging.

An ellipsoidal shell model for volume estimation of the right ventricle from magnetic resonance images.

RATIONALE AND OBJECTIVES: I developed a volume estimation technique for the crescentic volume of the right ventricle (RV) of the heart. A geometric model was desired to avoid the lengthy data collection and reduction required by Simpson's rule. METHODS: An ellipsoidal shell model was developed that requires only simple mathematics and that resembles the RV shape. RV cast volumes were obtained by water displacement and Simpson's rule and model-based calculations using magnetic resonance (MR) imaging. RESULTS: Model-based estimates correlated well with water displacement volumes (r = 0.924), with a slope not significantly different from unity. Simpson's rule results showed a higher correlation (r = 0.994), but it required longer acquisition and processing. Geometric irregularity in the RV shape required no modification in mathematics. CONCLUSION: The model provides reliable RV volume estimates from two MR image planes. The mathematics provides a simple approach to a relatively complex, crescentic shape. Short times for data acquisition and analysis suggest the potential for time savings during routine clinical measurements.

Desktop publishing and medical imaging: paper as hardcopy medium for digital images.

Desktop-publishing software and hardware has progressed to the point that many widely used word-processing programs are capable of printing high-quality digital images with many shades of gray from black to white. Accordingly, it should be relatively easy to print digital medical images on paper for reports, instructional materials, and in research notes. Components were assembled that were necessary for extracting image data from medical imaging devices and converting the data to a form usable by word-processing software. A system incorporating these components was implemented in a medical setting and has been operating for 18 months. The use of this system by medical staff has been monitored.

Cloning and nucleotide sequence of the Vibrio proteolyticus aminopeptidase gene.

The gene encoding the Vibrio proteolyticus aminopeptidase was cloned and sequenced and its amino acid sequence was deduced. The gene encodes a 54 kDa protein, larger than the previously reported size of 30 kDa for the purified aminopeptidase. Sequence alignments revealed a 43-45% homology with two other Vibrio sp. extracellular proteinases.

Myocardial stiffness derived from end-systolic wall stress and logarithm of reciprocal of wall thickness. Contractility index independent of ventricular size.

The slope of the end-systolic pressure-volume relation (ESPVR) is useful in assessing acute changes in contractile state. However, a limitation of ESPVR is that its slope decreases progressively as ventricular size increases without this change necessarily indicating a change in contractile state. In this respect, an index of contractile function that is independent of ventricular size would have an obvious advantage. The exponential constant (k) of the end-systolic relation between wall stress (sigma) and the natural logarithm of the reciprocal of wall thickness [ln(1/H)], sigma = Cekln(1/H), corresponds to the stiffness constant of the myocardium (kSM), a contractile index that should be independent of ventricular size and geometry. To examine the size independence of kSM, we studied left ventricular kSM during beta-blockade (to stabilize inotropic state) in 25 normal dogs with greatly differing ventricular sizes whose end-diastolic volumes ranged from 14 to 82 ml. The kSM was nearly constant (3.6 +/- 0.4) over this wide range of end-diastolic volumes and thus was independent of end-diastolic volume. Conversely, ESPVR, also obtained during beta-blockade, was closely and negatively correlated to end-diastolic volume (r = 0.92). To test the ability of kSM to measure changes in contractile state, we altered contractile state pharmacologically. The kSM increased from 3.7 +/- 0.5 to 4.8 +/- 0.8 (p less than 0.01) with infusion of dobutamine (after reversal of beta-blockade) and decreased to 3.1 +/- 0.3 (p less than 0.05) with inhalation of isoflurane, a negative inotrope, during beta-blockade (p less than 0.05). We conclude that kSM is independent of ventricular size and is sensitive to changes in inotropic state. As such, it should be useful as an index of contractile function.