Review of pimecrolimus cream 1% in children for the treatment of mild to moderate atopic dermatitis.
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Child↗
Biomedical subjects
Bernard Cohen
Publications and source records attributed to Bernard Cohen.
Isolation of Trichophyton violaceum and Trichophyton soudanense in Baltimore, Maryland.
Tinea capitis is of public health importance because of its transmissibility. Trichophyton violaceum and Trichophyton soudanense, which are common causes of tinea capitis in parts of Africa and West Asia, have only rarely been reported to cause dermatophytoses in the United States. We identified 24 patients with 25 positive cultures for T. violaceum or T. soudanense that were processed in a single hospital laboratory in Baltimore, Maryland, between 1 January 2000 and 30 June 2006. Most patients for whom clinical information was available had tinea capitis. There was a marked increase in the isolation of these organisms between the period from 2000 to 2002 and the period from 2003 to 2006, possibly associated with changes in immigration to the Baltimore metropolitan area. The changing epidemiology of this transmissible fungal infection not only is of public health interest as an example of the introduction of a "new" pathogen to an area where it traditionally was not endemic but also is of clinical and microbiological importance given reports suggesting an increasing incidence of tinea capitis in some areas and increasing clinical failure rates of current therapies.
Antifungal Agents↗
Dynamics of quadrupedal locomotion of monkeys: implications for central control.
We characterized the three-dimensional kinematics and dynamics of quadrupedal gait of young adult rhesus and cynomolgus monkeys while they walked with diagonal and lateral gaits at 0.4-1.0 m/s on a treadmill. Rigid bodies on the wrist, ankle, and back were monitored by an optical motion detection system (Optotrak). Kinematic data could be normalized using characteristic stride length, reducing variance due to different gait styles, to emphasize common characteristics of swing and stance parameters among animals. Mean swing phase durations fell as walking speed increased, but the swing phase durations increased at each walking velocity as a linear function of increases in amplitude, thereby following a main sequence relationship. The phase plane trajectories of the swing phases, i.e., plots of the relation of the rising and falling limb velocity to limb position in the sagittal (X-Z) plane, had unique dynamic characteristics. Trajectories were separable at each walking velocity and increases in swing amplitude were linearly related to peak swing velocities, thus comprising main sequences. We infer that the swing phase dynamics are set by central neural mechanisms at the onset of the swing phases according to the intended amplitude, which in turn is based on the walking velocity in the stance phases. From the many dynamic similarities between swing phases and rapid eye movements, we further suggest that the swing phases may be generated by neural mechanisms similar to those that produce saccades and quick phases of nystagmus from a signal related to sensed or desired walking velocity.
Animals↗
Modeling gravity-dependent plasticity of the angular vestibuloocular reflex with a physiologically based neural network.
A neural network model was developed to explain the gravity-dependent properties of gain adaptation of the angular vestibuloocular reflex (aVOR). Gain changes are maximal at the head orientation where the gain is adapted and decrease as the head is tilted away from that position and can be described by the sum of gravity-independent and gravity-dependent components. The adaptation process was modeled by modifying the weights and bias values of a three-dimensional physiologically based neural network of canal-otolith-convergent neurons that drive the aVOR. Model parameters were trained using experimental vertical aVOR gain values. The learning rule aimed to reduce the error between eye velocities obtained from experimental gain values and model output in the position of adaptation. Although the model was trained only at specific head positions, the model predicted the experimental data at all head positions in three dimensions. Altering the relative learning rates of the weights and bias improved the model-data fits. Model predictions in three dimensions compared favorably with those of a double-sinusoid function, which is a fit that minimized the mean square error at every head position and served as the standard by which we compared the model predictions. The model supports the hypothesis that gravity-dependent adaptation of the aVOR is realized in three dimensions by a direct otolith input to canal-otolith neurons, whose canal sensitivities are adapted by the visual-vestibular mismatch. The adaptation is tuned by how the weights from otolith input to the canal-otolith-convergent neurons are adapted for a given head orientation.
Adaptation, Physiological↗
Three-dimensional kinematics and dynamics of the foot during walking: a model of central control mechanisms.
The foot is a critical interface between the body and supporting surface during walking, but there is no coherent framework on which to model the dynamics of the stance and swing phases. To establish this framework, we studied the rotational and translational dynamics of foot movement in three dimensions with a motion detection system (OPTOTRAK), while subjects walked on a treadmill. Positions, velocities, and durations were normalized to leg-length and gravity. Foot position and rotation at toe-off were closely related to walking velocity. Foot pitch at toe clearance increased with walking velocity, but the medial-lateral and vertical toe positions were unaltered. Phase-plane trajectories along the fore-aft direction, i.e., plots of toe velocity versus position, were circular during the swing phases, with radii proportional to walking velocity. Peak forward, lateral, and upward velocities were linearly related to corresponding excursions, forming main sequences. A second order model predicted the changes in toe position and velocity, and the approximately hyperbolic decrements in duration as a function of walking velocity. The model indicates that the foot is controlled in an overdamped manner during the stance phase and as a feedback-controlled undamped pendulum during the swing. The data and model suggest that the state of the foot at toe-off, set by walking velocity during the stance phase, determines the dynamics of the swing phase. Thus, in addition to determining locomotion kinematics, walking velocity plays a critical role in determining the phase-plane trajectories and main sequence relationships of foot movements during the swing phases.
Adult↗
Could more effective use of kidneys recovered from older deceased donors result in more kidney transplants for older patients?
In the face of a severe shortage of kidneys from deceased organ donors that limits access to transplantation for many patients, about one of every seven kidneys (more than 1,500 each year) recovered from deceased donors in the United States are not transplanted. Eurotransplant, which coordinates organ distribution for six countries and a population of about 118 million, discards only one of every 20 kidneys procured for transplantation. We compared kidney procurement, transplants, and discards between January 2000 and June 2003 in the United States and in the Eurotransplant region using the Organ Procurement and Transplantation Network/United Network for Organ Sharing and Eurotransplant databases to examine differences that might account for this wide disparity.
Aged↗
Inner ear troubles: the roar in the forest?
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Animals↗
Effects of baclofen on the angular vestibulo-ocular reflex.
The purpose of this study was to determine the effect of baclofen, a GABA(B) agonist on the angular vestibulo-ocular reflex (aVOR). Model studies have shown that the aVOR comprises a "direct" pathway, which determines its high frequency gain g (1), and an indirect "velocity storage" pathway, which determines its low frequency characteristics. Velocity storage can be characterized by an integrator with a dominant time constant, T (VOR), and a gain g (0) that couples afferent information from the semicircular canals to the integrator. Baclofen preferentially shortens the velocity storage time constant in monkeys, but its effect on T (VOR), g (0), and g (1) in humans is unknown. Six subjects were tested after administration of a placebo or of 10, 20, or 30 mg of baclofen in a double-blind design. The aVOR was elicited in darkness with steps of rotation at 138 degrees /s, and g (1), g (0), and T (VOR) were determined from model fits of the slow phase velocity of the per- and post-rotatory nystagmus. Baclofen significantly reduced both T (VOR) and g (0) at dosages of 20 and 30 mg, but had no effect on g (1). Small reductions in g (0) were associated with large reductions in vestibular output. Thus, baclofen does not affect the direct aVOR pathway in humans, but controls the low frequency aVOR in two ways: it limits the input to velocity storage and modulates its time constant. We speculate that pre-synaptic GABA(B) terminals in the vestibular nuclei are responsible for the control of the afferent input to velocity storage through g (0), while the post-synaptic GABA(B) terminals are responsible for altering the duration of activity that reflects the time constant. The lack of effect of baclofen on the aVOR gain suggests that only GABA(A) receptors are utilized in the direct aVOR pathway.
Adult↗
Eye velocity asymmetry, ocular orientation, and convergence induced by angular rotation in the rabbit.
We studied ocular asymmetries and orienting responses induced by angular rotation in rabbits with binocular video recordings. Slow phase velocities were significantly larger in the eye moving temporonasally than nasotemporally. The eyes also converged and pitched down during rotation, which increased and refocused binocular overlap in the visual fields. Eye position also shifted into the slow phase direction. Vergence and pitch outlasted the induced nystagmus, suggesting that they were generated by a separate vestibulo-oculomotor subsystem(s). Thus, mechanisms in the rabbit increase compensatory eye velocity in the eye that leads into the direction of rotation and enhance binocular vision.
Animals↗
Electrical activation of the human vestibulo-sympathetic reflex.
Muscle sympathetic nerve activity (MSNA) is modulated on a beat-to-beat basis by the baroreflex. Vestibular input from the otolith organs also modulates MSNA, but characteristics of the vestibulo-sympathetic reflex (VSR) are largely unknown. The purpose of this study was to elicit the VSR with electrical stimulation to estimate its latency in generating MSNA. The vestibular nerves of seven subjects were stimulated across the mastoids with short trains of high frequency, constant current pulses. Pulse trains were delivered every fourth heartbeat at delays of 300-700 ms after the R wave of the electrocardiogram. Vestibular nerve stimulation given 500 ms after the R wave significantly increased baroreflex-driven MSNA, as well as the diastolic blood pressure threshold at which bursts of MSNA occurred. These changes were specific to beats in which vestibular stimulation was applied. Electrical stimulation across the shoulders provided a control condition. When trans-shoulder trials were subtracted from trials with vestibular nerve stimulation, eliminating the background baroreflex-driven sympathetic activity, there was a sharp increase in MSNA beginning 660 ms after the vestibular nerve stimulus and lasting for about 60 ms. The increase in the MSNA produced by vestibular nerve stimulation, and the associated increase in the diastolic blood pressure threshold at which the baroreflex-driven bursts occurred, provide evidence for the presence of a short-latency VSR in humans that is likely to be important for the maintenance of blood pressure during rapid changes in head and body position with respect to gravity.
Adult↗
Spatial properties of central vestibular neurons.
We studied the spatial characteristics of 45 vestibular-only (VO) and 12 vestibular-plus-saccade (VPS) neurons in two cynomolgus monkeys using angular rotation and static tilt. The purpose was to determine the contribution of canal and otolith-related inputs to central vestibular neurons whose activity is associated with the central velocity storage integrator. Lateral canal-related neurons responded maximally during vertical axis rotation when the head was tilted 25 +/- 6 and 22 +/- 3 degrees forward relative to the axis of rotation in the two animals, and vertical canal-related neurons responded maximally with the head tilted back 63+/- 5 and 57 +/- 7 degrees . The origin of the vertical canal-related input was verified by rotation about a spatial horizontal axis. Thirty-one percent of cells received input in a single canal plane. Sixty-seven percent of canal-related cells received otolith input, 31% of vertical canal neurons had lateral canal input, and 43% of lateral canal neurons had vertical canal input. Twenty percent of neurons had convergent input from the lateral canals, the vertical canals, and the otolith organs. Some VO and VPS cells had spatial-temporal convergent (STC) properties; more of these cells had STC properties at lower frequencies of rotation. Thus VO and VPS neurons associated with velocity storage receive a broad range of convergent inputs from each portion of the vestibular labyrinth. This convergence could provide the basis for gravity-dependent eye velocity orientation induced through velocity storage.
Acceleration↗
Spatial properties of central vestibular neurons of monkeys after bilateral lateral canal nerve section.
Thirty-seven neurons were recorded in the superior vestibular nucleus (SVN) of two cynomolgus monkeys 1-2 yr after bilateral lateral canal nerve section to test whether the central neurons had spatially adapted for the loss of lateral canal input. The absence of lateral canal function was verified with eye movement recordings. The relation of unit activity to the vertical canals was determined by oscillating the animals about a horizontal axis with the head in various orientations relative to the axis of rotation. Animals were also oscillated about a vertical axis while upright or tilted in pitch. In the second test, the vertical canals are maximally activated when the animals are tilted back about -50 degrees from the spatial upright and the lateral canals when the animals are tilted forward about 30 degrees . We reasoned that if central compensation occurred, the head orientation at which the response of the vertical canal-related neurons was maximal should be shifted toward the plane of the lateral canals. No lateral canal-related units were found after nerve section, and vertical canal-related units were found only in SVN not in the rostral medial vestibular nucleus. SVN canal-related units were maximally activated when the head was tilted back at -47 +/- 17 and -50 +/- 12 degrees (means +/- SD) in the two animals, close to the predicted orientation of the vertical canals. This indicated that spatial adaptation of vertical canal-related vestibular neurons had not occurred. There were substantial neck and/or otolith-related inputs activating the vertical canal-related neurons in the nerve-sectioned animals, which could have contributed to oculomotor compensation after nerve section.
Action Potentials↗
Orienting eye movements and nystagmus produced by translation while rotating (TWR).
Sinusoidal translation while rotating at constant angular velocity about a vertical axis (translation while rotating, TWR) produces centripetal and translational accelerations along the direction of translation and an orthogonal Coriolis acceleration due to the translation in the rotating frame. Thus, a Coriolis acceleration is produced along the bitemporal axis when oscillating along the naso-occipital axis, and along the naso-occipital axis when oscillating along the bitemporal axis. Together, these components generate an elliptically rotating acceleration vector that revolves around the head in the direction of rotation at the frequency of oscillation. Here we studied the orienting and compensatory responses of rabbits during TWR. Combinations of centripetal and translational accelerations were held constant at 0.5 g, and oscillation frequencies were varied from 0.01-0.33 Hz. The amplitude of the Coriolis acceleration increased with the frequency of translation. Naso-occipital translation caused vergence and pitch at all frequencies and roll at higher frequencies, and bitemporal translation produced roll at all frequencies and vergence and pitch at higher frequencies. The sensitivity of each ocular orienting component to linear acceleration was comparable across the different oscillation frequencies. TWR also induced continuous yaw nystagmus with slow phase velocity in the direction of rotation of the acceleration vector. Thresholds for appearance of nystagmus were 0.05 Hz, corresponding to a Coriolis acceleration of 0.06 g. Mean slow phase velocity for a rotating linear acceleration vector produced by 0.5 g along the translation axis and 0.34 g of Coriolis acceleration along the orthogonal axis were approximately 9 degrees /s. Eye velocities during TWR were similar to those generated by off-vertical axis rotation (OVAR), but were opposite in direction with regard to head rotation, following the direction of the rotating acceleration vector in both paradigms. Both are produced by activation of velocity storage in the vestibular system. One important difference between TWR and OVAR is that the head is always upright with regard to gravity during TWR. We speculate that the brain may use these low amplitude rotating linear accelerations to generate eye velocities that help to orient gaze when making turns during normal locomotion.
Acceleration↗
Spatial distribution of gravity-dependent gain changes in the vestibuloocular reflex.
This study determined whether dependence of angular vestibuloocular reflex (aVOR) gain adaptation on gravity is a fundamental property in three dimensions. Horizontal aVOR gains were adaptively increased or decreased in two cynomolgus monkeys in upright, side down, prone, and supine positions, and aVOR gains were tested in darkness by yaw rotation with the head in a wide variety of orientations. Horizontal aVOR gain changes peaked at the head position in which the adaptation took place and gradually decreased as the head moved away from this position in any direction. The gain changes were plotted as a function of head tilt and fit with a sinusoid plus a bias to obtain the gravity-dependent (amplitude) and gravity-independent (bias) components. Peak-to-peak gravity-dependent gain changes in planes containing the position of adaptation and the magnitude of the gravity-independent components were both approximately 25%. We assumed that gain changes over three-dimensional space could be described by a sinusoid the amplitude of which also varied sinusoidally. Using gain changes obtained from the head position in which the gains were adapted, a three-dimensional surface was generated that was qualitatively similar to a surface obtained from the experimental data. This extends previous findings on vertical aVOR gain adaptation in one plane and introduces a conceptual framework for understanding plasticity in three dimensions: aVOR gain changes are composed of two components, one of which depends on head position relative to gravity. It is likely that this gravitational dependence optimizes the stability of retinal images during movement in three-dimensional space.
Adaptation, Physiological↗
Spatial orientation of optokinetic nystagmus and ocular pursuit during orbital space flight.
On Earth, eye velocity of horizontal optokinetic nystagmus (OKN) orients to gravito-inertial acceleration (GIA), the sum of linear accelerations acting on the head and body. We determined whether adaptation to micro-gravity altered this orientation and whether ocular pursuit exhibited similar properties. Eye movements of four astronauts were recorded with three-dimensional video-oculography. Optokinetic stimuli were stripes moving horizontally, vertically, and obliquely at 30 degrees/s. Ocular pursuit was produced by a spot moving horizontally or vertically at 20 degrees/s. Subjects were either stationary or were centrifuged during OKN with 1 or 0.5 g of interaural or dorsoventral centripetal linear acceleration. Average eye position during OKN (the beating field) moved into the quick-phase direction by 10 degrees during lateral and upward field movement in all conditions. The beating field did not shift up during downward OKN on Earth, but there was a strong upward movement of the beating field (9 degrees) during downward OKN in the absence of gravity; this likely represents an adaptation to the lack of a vertical 1-g bias in-flight. The horizontal OKN velocity axis tilted 9 degrees in the roll plane toward the GIA during interaural centrifugation, both on Earth and in space. During oblique OKN, the velocity vector tilted towards the GIA in the roll plane when there was a disparity between the direction of stripe motion and the GIA, but not when the two were aligned. In contrast, dorsoventral acceleration tilted the horizontal OKN velocity vector 6 degrees in pitch away from the GIA. Roll tilts of the horizontal OKN velocity vector toward the GIA during interaural centrifugation are consistent with the orientation properties of velocity storage, but pitch tilts away from the GIA when centrifuged while supine are not. We speculate that visual suppression during OKN may have caused the velocity vector to tilt away from the GIA during dorsoventral centrifugation. Vertical OKN and ocular pursuit did not exhibit orientation toward the GIA in any condition. Static full-body roll tilts and centrifugation generating an equivalent interaural acceleration produced the same tilts in the horizontal OKN velocity before and after flight. Thus, the magnitude of tilt in OKN velocity was dependent on the magnitude of interaural linear acceleration, rather than the tilt of the GIA with regard to the head. These results favor a 'filter' model of spatial orientation in which orienting eye movements are proportional to the magnitude of low frequency interaural linear acceleration, rather than models that postulate an internal representation of gravity as the basis for spatial orientation.
Acceleration↗
Vestibular experiments in space.
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Animals↗
The role of gravity in adaptation of the vertical angular vestibulo-ocular reflex.
The gain of the vertical angular vestibulo-ocular reflex (aVOR) was adapted in side-down and prone positions in two monkeys and tested in four planes: left-/right-side down; forward/backward; and two intermediate planes that lie approximately in the planes of the vertical semicircular canal pairs, left anterior/right posterior (LA/RP) and right anterior/left posterior (RA/LP). Gain changes, expressed as a percent of preadapted values, were plotted as a function of head orientation in the planes of tilt, and fitted with sinusoids to obtain the gravity-dependent (amplitude) and gravity-independent (bias) components of adaptation. Gravity-dependent gain changes were always maximal when tested in a plane that included the head orientation in which the aVOR gain had been adapted. Changes were minimal when the head was tilted in a plane orthogonal to the plane of adaptation, and were smaller but still significant when tested in the two intermediate planes. Gravity-independent VOR gain changes were uniform over all planes of head tilt. Thus, the gravity-dependent and gravity-independent components could be separated experimentally. The aVOR gain changes from the head tilts in different directions were utilized to reconstruct the gain changes in three dimensions. They formed a continuous surface, which peaked in and around the position of adaptation. These studies support the postulate that gain adaptation has both gravity-independent and gravity-dependent components, and further show that these gain changes have a three-dimensional structure. These results are similar to those in humans, indicating that the gravity-dependent adaptation of the aVOR is likely to be a common phenomenon across species.
Acclimatization↗
Instantaneous rotation axes during active head movements.
Rotation axes were calculated during active head movements using a motion analysis system. The mean rotation axis for 1 Hz head pitch when seated was posterior (6 mm) and inferior (21 mm) to the interaural axis, shifting 16 mm downwards when standing. During seated 2 Hz head pitch the rotation axis was close to the interaural axis, shifting downwards 15 mm when standing. This downward shift suggests that cervical vertebrae were recruited during head pitch with the trunk unsupported. The proximity of the pitch axis to the otoliths implies minimal otolith activation during small-amplitude, high-frequency pitch rotations, such as those encountered during locomotion. The mean rotation axis for 1 Hz yaw rotation was located slightly posterior (10 mm) to the interaural axis at the midpoint between the vestibular labyrinths when both seated and standing. In addition, the orientation of the plane of yaw rotation relative to the stereotaxic horizontal plane (pitched 5 degrees nose-down) was essentially fixed in head coordinates, regardless of the pitch orientation of the head, suggesting that yaw movements occur about an axis restricted by the mechanical structure of the atlanto-axial joint. The results demonstrate that the instantaneous rotation axes technique overcomes the inherent instability of the helical-axis representation for small head movements.
Adult↗