Correlation of the Histological ICRS II Score and the 3D MOCART Score for the Analysis of Aged Osteochondral Regenerates in a Large Animal Model.

OBJECTIVE: Reliable outcome measures are essential to predict the success of cartilage repair techniques. Histology is probably the gold standard, but magnetic resonance imaging (MRI) has the potential to decrease the need for invasive histological biopsies. The 3D magnetic resonance observation of cartilage repair tissue (MOCART) score is a reliable yet elaborate tool. Moreover, literature is controversial concerning the correlation of histology and MRI. DESIGN: To test the applicability of the International Cartilage Regeneration and Joint Preservation Society (ICRS) II and MOCART 3D score for the evaluation of aged osteochondral regenerates in a large animal model, and to identify correlating histological and MRI parameters. Osteochondral defects in medial femoral condyles of n = 12 adult sheep were reconstructed with biodegradable bilayer implants. About 19.5 months postoperation, n = 10 joints were analyzed with MRI (3D MOCART score). Histological samples were analyzed using the ICRS II score; both pre- and post-training. The intraclass correlation coefficient, the inter-rater reliability, and the 95% confidence interval were calculated. Matching histological and MRI parameters were tested for correlation. RESULTS: We found a statistically significant correlation of all histological parameters. MRI parameters reflecting "overall" assessments had very strong inter-rater correlations. Statistically significant strong correlations were found for the MRI parameters defect filling, cartilage interface, bone interface, and surface. For defect overall (MRI) and overall assessment (ICRS II), we found a significant yet mild correlation. CONCLUSIONS: The ICRS II and the 3D MOCART score are applicable to aged osteochondral regenerates. Prior training on the scoring systems is essential. Select MRI and histological parameters correlate; however, the only statistically significant correlation was found for overall assessment.

Chondrogenic differentiation of bone marrow-derived mesenchymal stromal cells via biomimetic and bioactive poly-ε-caprolactone scaffolds.

The objective of this study was to develop a scaffold for mesenchymal stromal cell (MSC) recruitment, proliferation, and chondrogenic differentiation. The concept behind the design is to mimic the cartilage matrix and contain stimulatory agents that make continuous supply of inductive factors redundant. Nanofibrous (N: ~400 nm) and microfibrous (M: ~10 µm) poly-ε-caprolactone (PCL) scaffolds were combined with 1% high-molecular-weight sodium hyaluronate (NHA/MHA), 1% hyaluronan (HA) and 200 ng transforming growth factor-beta 1 (TGF-ß1; NTGF/MTGF), or 0.1% bovine serum albumin (N/M). Scaffolds were seeded with MSCs from bone marrow and cultured without growth factors in vitro. Cultures with chondrogenic medium supplemented with TGF-ß1 served as controls. Proliferation, migration, and release of TGF-ß1 were investigated. Cell differentiation was evaluated by polymerase chain reaction (PCR) and real-time PCR. NTGF and MTGF exhibited primarily an initial release of TGF-ß1. None of the factors released by the scaffolds recruited MSCs. The expression of aggrecan was dependent on the scaffold ultrastructure with nanofibers promoting increasing and microfibers decreasing expression levels. Composites containing HA demonstrated elevated seeding efficiency and lower type I collagen expression. Expression of type II collagen was dependent on continuous or late supply of TGF-ß1, which was not provided by our scaffold design. The initial release of TGF-ß1 induced an expression of type I collagen and osteogenic marker genes. In conclusion, nanofibrous PCL scaffolds with or without augmentation are suitable for chondrogenic initiation of MSCs. Initial release of HA is sufficient in terms of directing the implanted MSCs toward a chondrogenic end, whereas a late release of TGF-ß1 is preferred to foster type II and avoid type I collagen expression.

Idiothetic navigation in humans: estimation of path length.

When vision is excluded humans are still able to walk back to a starting point or to a previously seen target. This performance may be mediated by path integration, based on information about movement with respect to the ground or to inertial space, that is, on substratal or inertial idiothetic cues. We intend to unravel whether, and how accurately, these two inputs act and interact on the translatory component of this navigation performance. Subjects were asked 1) to reproduce a path they had walked, and 2) to indicate the location of a target they had seen before being blindfolded by (i) walking there, (ii) treading a motor-driven conveyor belt until they imagine they are there, and (iii) reporting, while being driven in a trolley, when they seem to pass the target. The estimation of path length turns out to vary as a function of walking velocity, step length, and step rate. The estimate becomes virtually veridical when subjects walk at their normal pace, but it overshoots at lower and undershoots at higher values of these variables. Veridicality at near normal speeds is also found with passive transport (iii), but with a reverse dependence on velocity. It is concluded that in these paradigms path control and perception are mediated by an open-loop performance of the underlying path integration system, calibrated in such a way as to yield veridical estimates during normal walking. Either inertial or substratal idiothetic information is sufficient for this performance. However, the quantitative relations found argue in favor of the hypothesis that substratal idiothetic information predominates when both are available. In spite of its limitations the capability shown here may serve as an essential constituent of navigation by path integration in humans.

Surface modification of extracorporeal circuits: is there really an impact on cerebral performance after cardiopulmonary bypass?

BACKGROUND: Pathophysiology of extracorporeal circulation is multifactorial, and the link between newly developed "biomaterials" and clinical outcome is not easy to illustrate. MATERIAL AND METHODS: We designed a randomized, double-blinded, prospective study in order to verify the impact of a new surface modification [SMAR(X)T] in combination with an optimized blood air interface, on the cerebral performance after cardiopulmonary bypass. 80 patients were randomly divided into two subgroups (SMAR(X)T vs. standard PVC control) and analyzed for the kinetic of cerebral ischemia markers neuronspecific enolase, protein S100 and neuropsychologically tested with the Mini-Mental-Status Test (MMST) before and after the operation. RESULTS: We could not show significant differences of protein S100 and neuron-specific enolase (NSE) levels between SMAR(X)T patients and the controls, but the incidence of neurological complications was exceptionally low. Although no statistically significant differences could be obtained for the MMST, the different pointloss between both groups trends toward a better cerebral performance in SMAR(X)T patients. CONCLUSION: The use of a biologically inert circuit in combination with an optimized perfusion management seems to be worthy of recommendation.

Triple-loop model of path control by head direction and place cells.

Arthropods as well as mammals are able to return straight home after a random search excursion under conditions that are designed to exclude all external cues. After a brief clarification of the terminology, two principal systems of information processing that can achieve this performance are introduced and analysed: Polar versus Cartesian path integration. The different demands and achievements of the two systems are confronted with neurophysiological findings on the functioning of the hippocampus, and with a recent comprehensive model of how the hippocampal place cells perform path integration. To connect the neurophysiological findings with the behavior of the animal, a new model is developed. It achieves three functionally diverse performances: maintenance and control of a compass direction, navigation by path integration, and formation of goals by connecting non-spatial features with their location. This is done by three interconnected feedback loops, set by a common reference variable. Their information-processing structure enables the animal not only to home but also to go straight from any stored goal to any other, without explicit representation of the distance between them, and without a topological arrangement of the store. The model explains behaviors not yet understood and predicts still undiscovered performances. Because it allows the isolation of orienting from storing functions yet also shows how they can be connected, the model may help to reconcile conflicting views on the function of the hippocampus.

The role of the otoliths in perception of the vertical and in path integration.

The role of the otoliths in essential performances of human orientation is analyzed. The following interactions of the otoliths are considered: 1. The otoliths cooperate with graviceptors in the trunk in the perception of body posture. The truncal graviceptors turn out to yield on average 60% of the total gain. 2. The otoliths cooperate with proprioceptors in the head-to-trunk coordinate transformation. However, under static conditions, proprioceptors in the legs, although effective in the control of posture, neither affect the perception of posture nor of the visual vertical. 3. In contrast to the perception of posture, the perception of the visual vertical (SVV) receives the necessary gravity information exclusively from the otoliths. However, their output appears to be affected by a central nervous component that tends to rotate the SVV into the z-axis of head and trunk. A theory of vectorial summation of this component, the "idiotropic vector," with the otolithic vector is able to explain the cause of the A- and E- effects, the increase of the variance of the SVV with the tilt angle, and the asymmetrical effect of rotatory visual flow. 4. Finally, it is shown that the otoliths, by the separation of the effects of tilt from those of translation, play an essential role in navigation by path integration.

Perception of spatial orientation in microgravity.

Experiments during space and parabolic flights have shown that human spatial orientation in microgravity differs to a significant extent from its performance on earth. Due to the missing reference of gravitational force, unusual perceptual phenomena are observed, from inversion illusions to errors of perceived motion and position with respect to the spacecraft. This article gives an overview of results collected from space missions and parabolic flight campaigns, and proposes new lines of research about the perceptual phenomena of spatial orientation in microgravity. It is shown that most of the disorientation phenomena can be explained by the existence of an internal estimate of the gravitational vertical. In microgravity it is still maintained, but incorrectly updated, and thus alters the processing of sensory information in the central nervous system. This in turn leads to the observed illusions, and probably also facilitates space motion sickness.

Origin and processing of postural information.

This contribution surveys the sources and the processing of spatial information about posture, that is, about the orientation of the body and its parts with respect to the vertical (whereas 'position' designates their orientation to each other). Postural information is, to a considerable extent, gained by sense organs in the head. Hence information gained by the mobile eyes and the pitched-up labyrinths is first transformed from a retinal and otolithic into a head-fixed frame of reference, then from head- to trunk-fixed coordinates, and, finally, from a trunk-fixed to an exocentric frame of reference. To that end the position of eyes and otoliths to the head, of the head to the trunk, and of the trunk to the rest of the world must be known, deduced by efference copies or measured by proprioceptors. It is shown that the perceived relation of the visual world to the vertical is exclusively determined by sense organs in the head, whereas body posture is also directly measured by recently discovered graviceptors in the human trunk. It appears that the proprioceptors mediate perception of position, but not, or only indirectly, of posture.

Shifts in blood volume alter the perception of posture.

Recent experiments have shown that somatic graviceptors exist in humans. Traditionally, extravestibular gravity information has been thought to originate from mechanoreceptors in the joints, muscles and skin. Experiments with normal, paraplegic and nephrectomized subjects revealed that the kidneys and the cardiovascular system are involved in providing truncal gravity information. The present study intends to determine the influence of shifts in body fluid, especially of the distribution of blood along the subjects' spinal (Z-) axis, on the perception of posture. To this end, the distribution of body fluids was altered by means of the technique of lower body negative and positive pressure (LBNP and LBPP). LBNP leads to venous pooling of blood in the legs, whereas LBPP prevents venous blood from pooling, increasing central volume. Changes in blood distribution were measured by segmental impedance cardiography for four body segments: the upper torso (thoracic cavity), lower torso (abdominal and pelvic region), thigh and calf. Seventeen healthy subjects (mean age: 27.3 years) participated in the experiment. They were positioned on the side (right-ear-down head position) on a tilt table which the subjects and the experimenter could tilt via remote control around an axis parallel to the subjects' visual (X-) axis. The experimenter set the initial tilt in total darkness to arbitrary angles while strictly alternating between head-up and head-down tilts. Subjects were then asked to rotate the board until they felt they were in a horizontal posture. Means and variances of eight pairs of settings were taken as a measure of the subjective horizontal posture (SHP). During LBNP (-30 mmHg), subjects perceived being tilted head-up, whereas LBPP (+30 mmHg) led them to feel tilted head-down. The results corroborate the hypothesis of an effect of the blood's mass on graviception and also indicate supplementary contributions of other visceral afferences.

Interaction of eye-, head-, and trunk-bound information in spatial perception and control.

This article reviews the author's investigations on the perception and control of spatial relations if the carriers of the relevant sense organs are mobile and controlled independently of each other. In the dragonfly, head rotation is controlled by the head's inertia, as well as by cervicocollic, optokinetic, and dorsal light reflexes and, in turn, controls trunk rotation by means of neck reflexes on the wings. In humans, invariance of head-referenced visual direction under eye-to-head rotation is attained by feedforward of an efference copy. In the pigeon, invariance of responses to trunk tilt under head-to-trunk rotation is, in flight, achieved by feedforward of head-to-trunk information yielded by neck receptors. But in standing or walking, this is accomplished by means of gravity sense organs in the trunk. Such organs are also shown to exist in the human trunk by means of experiments on a sled centrifuge. From tests with paraplegic and neuromectomized subjects, it is concluded that truncal graviception 1) is not influenced by mechanoreceptors in the legs, the skin, and between the vertebrae, but 2) is affected by at least two afferent inputs, one originating in the kidneys, another in the tissues that support the large blood vessels against the gravitational load. These conclusions are corroborated by experiments with bilaterally nephrectomized subjects and by means of positive air pressure to the legs, respectively. Recent results under application of positive and negative air pressure to the entire lower body indicate that yet another source of somatic graviception may exist, for example, one that exploits the hydrostatics of blood pressure or the inertia of the mass of the abdominal viscera.

Perception of spatial orientation in different g-levels.

NASA: Spatial orientation perception was examined in experiments on the MIR94 mission, during parabolic flight, and in ground control experiments. Space flight subjects were asked to remember their initial orientation, then turned and, with eyes closed, signal the ceiling direction. Ground-based control subjects were asked to indicate their original starting position while rotating on their backs. Results indicate a sensory conflict related to the vestibular system can lead to spatial disorientation.^ieng

The influence of otoliths and somatic graviceptors on angular velocity estimation.

In three psychophysical experiments subjects (Ss), blindfolded and earphoned with white noise, estimated their angular speed A) after brief acceleration to constant centric or eccentric rotation, and B) after deceleration to a full stop. Ss either indicated whenever they were rotated through 180 degrees, or manipulated the objective velocity such that the subjective one stayed constant. With Ss in an earth-vertical attitude, subjective speed declined exponentially with a time constant that depended on eccentricity in paradigm A, but not in B. The time constant depended linearly on the amount of the centrifugal force, but not on its direction. Thus, centrifugal force has an enhancing effect on perceived angular speed. The relevant sense organs were identified with Ss in a radial, earth-horizontal attitude. The enhancing effect was minimal when the axis of rotation was caudal of the otoliths, indicating an effect of graviceptors in the trunk. This effect, just as the effect of recently discovered truncal graviceptors on the perception of posture, turned out to depend on leg position: The minimum of the enhancing effect shifted from about 30 cm to about 60 cm caudal of the otoliths, when leg position changed from flexed to extended. It is concluded that the centrifugal force, measured by otoliths and truncal graviceptors, serves to provide information on angular velocity at eccentric rotation, at least as long as the output of the velocity storage is not yet zero.

Somatic graviception.

Psychophysical experiments show that the perception of posture is to a large degree affected by hitherto unknown graviceptors in the human trunk. By remote control subjects move themselves radially along their spinal axis over the horizontal platform of a rotating centrifuge until they feel horizontal. Normal subjects then set the centrifuge axis on average at 22-28 cm caudal of the meatus, neuromectomized subjects at 45-55 cm. Hence the mass centroid of these receptors should be situated near the last ribs. Evaluation of the residual faculties of paraplegic patients lead to the conclusion that somatic graviception is mediated by two distinctly localized inputs, the first entering the spinal cord at the 11th thoracic segment, and the second reaching the brain cranial of the 6th cervical segment, presumably via the N. phrenicus or the N. vagus. The effect of the first named input is abolished after bilateral nephrectomy. This proves that the kidneys affect gravity perception. But whether they function like statoliths or in another way cannot yet be decided. For the second input, however, the results show unequivocally that it yields gravity information through the inertia of a mass in the body. It is hypothesized that this mass may be that of the blood in the large vessels. This is corroborated by the effect of shifting blood craniad by means of positive pressure to the legs. It is inferred that the inertial forces are measured by mechanoreceptors in the structures that mechanically support the large vessels, rather than by baroreceptors.

Evidence of somatic graviception from new and classical investigations.

Recent psychophysical experiments have provided evidence of an influence of graviceptors in the human trunk on the perception of body posture that equals or even surpasses the contribution of the otoliths. A reinterpretation of classical results on mammals, notably of the Utrecht school, leads to the conclusion that somatic graviceptors also partake in controlling the posture of eyes, neck and limbs.

New diagnostic tests for the function of utricles, saccules and somatic graviceptors.

Clinical tests that allow us to discriminate between utricular, saccular and somatic effects on gravity perception and control are desirable but wanting. A new test battery is presented which combines four experimental paradigms based on the subjective horizontal body position (SHP), namely, a test on a tiltable board and on a sled centrifuge under varied leg position, with two paradigms based on the subjective visual vertical (SVV). It is shown by a combination of experiments and deductions, that, why, and how these tests can separate the effects of otoliths from those of somatic graviceptors, the effects of the utricles from those of the saccules, and the effects of the constituents of the somatic graviception from each other. The present study demonstrates the capabilities of the tests as well as their limitations.

Illusions of verticality in weightlessness.

In weightlessness most subjects feel themselves, and see the visual surroundings, in either an upright or an upside-down orientation although the gravitational force vector is missing. According to a theory of gravity perception, these illusions of positional and visual verticality are assumed to be caused by the force-independent z-axis bias of vestibular and somatic graviceptors. This hypothesis is tested by comparison of measurements of the joint bias in normal gravity with reports of probands in space flight. The expected correlations between the sign of the biases and the occurrence of the respective illusions appear in fact to exist, as well as a negative correlation to incidences of space sickness. If confirmed in a larger sample, the presumed dependency may eventually afford a predictive test of both phenomena.

Crucial effects of weightlessness on human orientation.

This contribution examines the consequences of two remarkable experiences of subjects in weightlessness, 1) the missing of sensations of trunk tilt and of the respective concomitant reflexes when the head is tilted with respect to the trunk, and 2) the persistence of a perception of "up" and "down," that is, of the polarity of the subjective vertical (SV) in the absence of, as well as in contradiction to, visual cues. The first disproves that the necessary head-to-trunk coordinate transformation be achieved by adding representations of the respective angles gained by utricles and neck receptors, but corroborates an extant model of cross-multiplication of utricular, saccular, and neck receptor components. The second indicates the existence of force-independent components in the determination of the SV. Although the number of subjects is still small and experimental conditions are not as homogeneous as desired, measurements and/or reports on the ground, in parabolic, and in space flight point to the decisive role of the saccular z-bias, that is, of a difference of the mean resting discharges of saccular units polarized in the rostrad and the caudad (+/- z-) direction.

Determinants of orientation in microgravity.

During two parabolic flight campaigns, one with the NASA-KC-135, the second with the ESA Caravelle, human spatial orientation in an altered gravitational environment was studied by measuring the subjective visual vertical (SVV) by means of a luminous line, and by asking the subjects to give a report, with eyes closed, about their orientation to apparent vertical. The inflight data are compared with baseline data measurements of the subjective horizontal body position (SHP) at normogravity (1g) and at 2g. Pertinent theoretical alternatives to modelling subjective static orientation are developed and compared to the data. It turns out that a good fit to the baseline results and a satisfactory prediction of the perceived orientation in microgravity can be obtained if the otolithic output is assumed to be normalized, but that of the somatic gravity sensors is not.

Somatic versus vestibular gravity reception in man.

In order to assess the effect of extravestibular gravity receptors on perception and control of body position against that of the otoliths, the subject (S) is exposed to gravitoinertial forces along the spinal (Z) axis on a tiltable board and on a sled centrifuge. It turns out that (1) both effects, on average, are equally strong, although with considerable variance between Ss; (2) the centroid of the mass(es) governing the somatic receptors lies near the centroid of the body; and (3) somatic gravity reception contains two distinctly different systems. Both appear unimpaired in paraplegic Ss with total bilateral sensory loss (TSL) from the 5th to the 1st lumbar spinal segment. One, the truncal system, is eliminated with TSL from the 11th thoracic segment upwards. Yet another is still functioning with TSL up to and including the 6th cervical segment, with the same effectiveness throughout this range. Hence it must be mediated by vagal or, less likely, sympathetic afference, that is, probably, by the influence of gravity on the cardiovascular system. That the afference of the truncal system appears to enter the cord at the last two thoracic segments supports earlier conjectures about a supererogatory static function of the kidneys. In fact, on the tiltable board, 7 bilaterally nephrectomized Ss behaved like paraplegics with TSL between T11 and C6, yet differed significantly in the predicted direction from the normal controls.