A NeuroD1 AAV-Based Gene Therapy for Functional Brain Repair after Ischemic Injury through In Vivo Astrocyte-to-Neuron Conversion.

Adult mammalian brains have largely lost neuroregeneration capability except for a few niches. Previous studies have converted glial cells into neurons, but the total number of neurons generated is limited and the therapeutic potential is unclear. Here, we demonstrate that NeuroD1-mediated in situ astrocyte-to-neuron conversion can regenerate a large number of functional new neurons after ischemic injury.

Properties and features of asymmetric partial devil's staircases deduced from piecewise linear maps.

A piecewise linear map with one discontinuity is used to link together iterated map properties with the shape of the ensuing staircases. In the main part of the paper, a three-segment map is treated, with a horizontal middle segment next to the discontinuity and the development of partial and asymmetric staircases is demonstrated. In particular, a possible hierarchy of partiality, connected with the ratio of the length of the horizontal segment to the discontinuity jump, is obtained.

Auditory cortex accesses phonological categories: an MEG mismatch study.

The studies presented here use an adapted oddball paradigm to show evidence that representations of discrete phonological categories are available to the human auditory cortex. Brain activity was recorded using a 37-channel biomagnetometer while eight subjects listened passively to synthetic speech sounds. In the phonological condition, which contrasted stimuli from an acoustic /dae/-/tae/ continuum, a magnetic mismatch field (MMF) was elicited in a sequence of stimuli in which phonological categories occurred in a many-to-one ratio, but no acoustic many-to-one ratio was present.

Modeling of diastole.

Modeling methods have been employed to further characterize the physical and physiologic processes of filling and diastolic function. They have led to more detailed understanding of the effect of alteration of physiologic parameters on the Doppler E-wave contour as well as pulmonary vein flow. Depending on the modeling approach, different aspects of the filling process have been considered from AV gradient and net compliance to atrial appendage function to the mechanical suction pump attribute of the heart.

Physiology of diastolic function and transmitral pressure-flow relations.

The study of diastolic function, in particular, the creative application of noninvasive modalities, such as echocardiography and MR imaging, requires an understanding and appreciation of the basic physiology of left ventricular filling dynamics. The physics and physiology of diastolic function and dysfunction is examined by relating the phasic patterns of transmitral flow to the properties of the cardiac chambers. Particular attention is paid to the equations governing the transmitral pressure-flow relations and the active and passive chamber properties that determine the flow patterns: Active relaxation, passive compliance, viscoelasticity, and elastic deformation.

Contraction-relaxation coupling: determination of the onset of diastole.

Left ventricular relaxation is dependent on afterload conditions during systole. An abrupt increase in afterload while the ventricle is actively contracting prolongs the duration of systole. An increase in afterload during ventricular relaxation shortens the duration of systole.

Concepts related to the study of diastolic function: a personal commentary.

The phasic character of the transmitral flow wave is determined by the AV pressure difference and the impedance of the mitral valve complex. The measured LV pressure is determined by the complex contributions from 4 sources: rate and extent of deactivation, passive myocardial properties, deformation due to shape change, and viscoelasticity. An understanding of the functional value of diastolic indices is helped by an understanding of the basic physiology.

UL-FS 49 (zatebradine) does not affect arterial baroreflex in conscious normal or aortic-constricted rats.

Heart-rate reduction is an important element of patient management during cardiac bypass surgery and in therapeutic measures for combating ischemia and relieving pain in patients with angina. UL-FS 49 is a novel bradycardic agent that purportedly acts solely on the sinoatrial node without potentially deleterious effects on arterial pressure and cardiac inotropism. However, little is known about influences of this agent on neuronal tissue and cardiovascular reflexes.

Left ventricular diastolic function of remodeled myocardium in dogs with pacing-induced heart failure.

In patients with heart failure, decreased contractility resulting in high end-diastolic pressures and a restrictive pattern of left ventricular filling produces a decrease in early diastolic filling, suggesting a stiff ventricle. This study investigated the elastic properties of the myocardium and left ventricular chamber and the ability of the heart to utilize elastic recoil to facilitate filling during pacing-induced heart failure in the anesthetized dog. Elastic properties of the myocardium were determined by analyzing the myocardial stress-strain relation.

Processing of vowels in supratemporal auditory cortex.

The auditory evoked neuromagnetic fields elicited by synthesized vowels of two different fundamental frequencies F0 were recorded in six subjects over the left and right temporal cortices using a 37-channel biomagnetometer. Single equivalent current dipole modeling of the fields elicited by all vowel types localized activity to a well-circumscribed area in supratemporal auditory cortex in both hemispheres. There were hemisphere asymmetries in the amplitude and latency of the M100 response.

A computer-controlled aortic and mitral valve occluder.

To study cardiac mechanics, it is important to study the beat-to-beat changes in the heart. Left ventricular diastolic filling properties are determined by a passive component and an active component due to ventricular relaxation that occur simultaneously. To separate the active and passive components of ventricular filling, we designed a computer-controlled mitral valve occluder that prevents left ventricular filling.

Task-induced asymmetry of the auditory evoked M100 neuromagnetic field elicited by speech sounds.

The auditory evoked neuromagnetic fields elicited by synthesized speech sounds (consonant-vowel syllables) were recorded in six subjects over the left and right temporal cortices using a 37-channel SQUID-based magnetometer. The latencies and amplitudes of the peaks of the M100 evoked responses were bilaterally symmetric for passively presented stimuli. In contrast, when subjects were asked to discriminate among the same syllabic stimuli, the amplitude of the M100 increased in the left and decreased in the right temporal cortices.

Time to dP/dtmax reflects both inotropic and chronotropic properties of cardiac contraction: a conscious dog study.

This study supports a mathematical model and previous findings indicating that td, the time from onset of contraction to dP/dtmax, reflects the time-dependent aspects of contraction and hence decreases with increasing contractility. Combined data from 20 conscious instrumented dogs create a highly significant inverse and linear td-HR (heart rate) relation. Both norepinephrine and isoproterenol decreased td values, but norepinephrine, in contrast to isoproterenol, decreased the heart rate by a reflex response.

Viscoelastic behavior of the isolated guinea pig left ventricle in diastole.

To determine left ventricular (LV) viscoelastic properties during acute volume changes, the relaxation of LV pressure (2-Fr, Millar) at steady LV volume after a known volume change was measured in 14 isolated guinea pig left ventricles arrested in diastole. The left ventricle was loaded and unloaded by manual injection and withdrawal of saline in 10 x 0.1-ml steps, controlling the steadiness of LV volume by measuring LV major and minor diameters (ultrasonic crystals).

Left ventricular diastolic suction with zero left atrial pressure in open-chest dogs.

We investigated left ventricular (LV) diastolic volume changes (suction inflows) with left atrial pressure (LAP) clamped to ambient pressure in six open-chest, anesthetized dogs. The left atrium was cannulated and connected to a servo pump, and LAP was clamped to a set point near 0 mmHg for four beats by withdrawing blood. LAP averaged 5.

Time to dP/dtmax, a preload-independent index of contractility: open-chest dog study.

A mathematical model of left ventricular pressure (LVP) during isovolumic contraction in the time domain shows the following predictions: 1) td, the time from onset of contraction to dP/dtmax and (dP/dt)/P, reflect only the time-dependent aspects of contraction, and are independent of preload; 2) dP/dtmax depends on both preload and the time-dependent aspects of contraction. To test preload independence we reduced filling volume (FV) by the method of ventricular volume clamps with a remote-controlled mitral valve in 7 anesthetized open-chest dogs. A decrease in FV of 80 +/- 15% produced a 29 +/- 12% (p < 0.

Determination of vascular impedance in the peripheral circulation by transcutaneous pulsed Doppler ultrasound.

Instantaneous blood flow velocity characteristics and vascular impedance spectra derived noninvasively by pulsed Doppler ultrasound and invasively by electromagnetic flow probe were compared in the canine common femoral artery to validate the pulsed Doppler technique for determination of vascular impedance in the peripheral circulation. Although Doppler ultrasonography is routinely performed to evaluate blood flow velocity patterns in the human peripheral circulation; the validity of this technique to derive peripheral vascular impedance has yet to be investigated. Simultaneous measurements of blood flow velocity were determined by both noninvasive pulsed Doppler ultrasound and surgically implanted electromagnetic flow probe in the common femoral artery of eight dogs and compared in both time and frequency domains.

Origin of regional pressure gradients in the left ventricle during early diastole.

Left ventricular (LV) pressure (P)-diameter, LVP-area, or LVP-volume relationships used to evaluate LV diastolic function assume uniform LV wall motion and constant LVP. Contrary to these assumptions, there are significant differences in ventricular dynamic geometry and in LV pressures measured simultaneously in different parts of the LV, particularly during early diastole. We instrumented six anesthetized open-chest dogs with three pairs of orthogonal ultrasonic crystals (anterior-posterior and septal-free wall minor axes, and base-apex major axis) and two micromanometers (in the apex and in the LV base).

Left atrial pressure-clamp servomechanism demonstrates LV suction in canine hearts with normal mitral valves.

A novel technique is presented to study suction of the in situ left ventricle in open-chest experimental animals without requiring cardiopulmonary bypass or disturbing the native mitral valvular apparatus. In 17 dogs, left ventricular pressure (LVP) and left atrial pressure (LAP) were measured, the left atrium was cannulated and connected to a servo pump, and LAP was controlled to a setpoint near 0 mmHg by withdrawing blood from the left atrium. Heart rate [103 +/- 17 (SD) min-1], peak pressure (100 +/- 13 mmHg), minimum pressure (1.

Modeling the transient response to volume perturbations in the beating heart by the difference equation method.

Discrete theoretical methods, compatible with the discrete features of the beating heart, are used together with experimental study to attain a quantitative understanding of the transient response to a volume perturbation and of sustained mechanical alternans (SMA) in the beating heart. This is done in three stages. In stage A, a first-order difference equation describes the stroke volume (SV) response due to the Frank-Starling mechanism.