bluuebunny/crossref_metadata_2025 huggingface dataset:
Paracrine Regulation of Matrix Metalloproteinase Expression in Endometriosis
Authors: SHARPE‐TIMMS KATHY L. , COX KATHRYN E.
Published: July 2009

Abstract: Following retrograde menstruation, shed endometrial tissue fragments attach to and invade the peritoneal surface to form established endometriotic lesions. With disease progression, the biochemically active lesions undergo remodeling and become fibrotic. Matrix metalloproteinase enzymes (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) play a significant role in normal endometrial remodeling during menses. Anomalous expression of MMPs and TIMPs has been identified in endometriotic lesions as compared to their highly regulated expression in eutopic endometrium. The paracrine mechanisms regulating misexpression of MMPs and TIMPs by endometriotic lesions are, however, not well defined. Misexpression of the MMPs and TIMPs may be due to innate anomalies in the eutopic endometrium from women with endometriosis, in the resident immune cells and peritoneal cells that juxtapose the ectopic endometrium, and/or numerous substances present in peritoneal fluid of women with endometriosis. The majority of MMPs are under strict transcriptional regulation. Steroid hormones and cytokines appear to act on the MMP promoter, either independently or in consort, to provide both positive and negative regulation of these genes. Misregulated expression of MMPs and TIMPs is associated with a more aggressive phenotype and a cascade of events facilitating peritoneal extracellular matrix degradation and establishment or remodeling of endometriotic lesions. The mechanisms by which MMP and TIMP expression are misregulated warrant further investigation as such information may provide insight into novel therapeutic modalities for endometriosis.
Regulation and Modulation of Abnormal Immune Responses in Endometriosis
Authors: SIDELL NEIL , HAN SHOU WEI , PARTHASARATHY SAMPATH
Published: July 2009

Abstract: There is ample evidence demonstrating that endometriosis is accompanied by inflammatory reactions in the peritoneum, resulting in abnormal levels of a variety of cytokines and chemokines in the peritoneal fluid. Among the immunological parameters that have been shown to be altered in the peritoneal cavity of women with endometriosis, an increase in the number of activated nonadherent macrophages that show reduced surface expression of scavenger receptors has been observed. The cause‐and‐effect relationship between aberrant peritoneal macrophage activity and endometriosis is still unknown. We have demonstrated that steroid hormone receptor agonists and antagonists [e.g., retinoids, antiglucocorticoids, ligands to peroxisome proliferator activated receptors (PPARs)] can regulate macrophage functions in ways that could either suppress or stimulate the growth of ectopic endometrial lesions. Our studies include a number of relevant findings: (1) RU486, acting as an antioxidant, can suppress activation of NFκB, a nuclear transcription factor that affects the expression of several inflammatory genes such as those for MCP‐1, GM‐CSF, CSF‐1, and various adhesion molecules; (2) IL‐6 secretion from a variety of cell types including endometrial cells is inhibited by retinoic acid; and (3) retinoids and PPARγ ligands can upregulate the expression of scavenger receptors in cells of the monocyte/macrophage lineage. These observations, combined with the possibility that macrophage activity may play a fundamental role in endometriosis, suggest that pharmacologic manipulation of macrophage function may provide a novel mechanism for treating this disease.
Macrophages, Oxidation, and Endometriosis
Authors: SANTANAM NALINI , MURPHY ANA A. , PARTHASARATHY SAMPATH
Published: July 2009

Abstract: Retrograde menstruation has been suggested to be the cause for the presence of endometrial cells in the peritoneal cavity. However, little is known about the events that lead to the adhesion and growth of these cells that ultimately result in endometriosis, considering the fact that the disease occurs only in certain women despite the common occurrence of retrograde menstruation in most women. We postulate that, in normal women, the endometrial cells and tissue that arrive in the peritoneal cavity during menstruation are effectively removed by macrophages that are chemoattracted and become resident tissue macrophages in the peritoneal cavity. In contrast, the peritoneal macrophages in women with endometriosis are nonadherent and ineffectively scavenged, resulting in the sustained presence and growth of the endometrial cells. We also postulate that the peritoneal fluid is not a passive reservoir of the factors secreted by cells of the peritoneum, but actively promotes endometriosis. The peritoneal fluid is rich in lipoproteins, particularly low‐density lipoprotein, which generates oxidized lipid components in a macrophage‐rich inflammatory milieu. The oxidants exacerbate the growth of endometriosis by inducing chemoattractants such as MCP‐1 and endometrial cell growth‐promoting activity. We provide evidence for the presence of oxidative milieu in the peritoneal cavity of women with endometriosis, the nonscavenging properties of macrophages that are nonadherent, and the synergistic interaction between macrophages, oxidative stress, and the endometrial cells. For example, the peritoneal fluid lipoproteins of subjects with endometriosis have increased the propensity to undergo oxidation as compared with plasma lipoproteins, and the subjects also have increased titer of autoantibodies to oxidatively modified proteins. If the oxidative proinflammatory nature of the peritoneal fluid is an important mediator of endometriosis growth, anti‐inflammatory agents and antioxidants might afford protection against endometriosis.
Implantation Defects in Infertile Women with Endometriosis
Authors: LESSEY BRUCE A.
Published: July 2009

Abstract: The endometrium undergoes characteristic histologic changes during the menstrual cycle as it prepares for embryo implantation. Historic and current data suggest the presence of a defined period of maximal uterine receptivity during the mid‐secretory phase occurring between days 7 and 10 postovulation. In recent years, we and others have sought to define biochemical markers of receptivity that might be used to better understand this time of endometrial differentiation. Based on the work with cell adhesion molecules, we have discovered three different integrins that are only coexpressed during this time in the cycle when embryos will successfully implant. By studying the regulation of one of these, the αvβ3 integrin, and its extracellular matrix ligand, osteopontin (OPN), we have defined two separate regulatory pathways that may regulate endometrial receptivity. While αvβ3 expression appears to be stimulated by EGF or heparin‐binding EGF, osteopontin is stimulated by progesterone. We now believe the former pathway is a paracrine‐mediated signal, while the latter is a direct effect of progesterone on the estrogen‐primed endometrial epithelium. In women with endometriosis, it appears that αvβ3 expression is reduced, while OPN expression is unaffected. Interestingly, binding of OPN to the surface epithelium appears quite limited when αvβ3 expression is lacking. Such evidence continues to reinforce the notion that endometrium from some women with endometriosis is dysfunctional and may account for the reduction in cycle fecundity noted in this group of patients.
Conventional Medical Therapies for Endometriosis
Authors: RICE VALERIE MONTGOMERY
Published: July 2009

Abstract: Endometriosis is a common gynecologic disorder that affects approximately 14% of all women and 30% to 50% of infertile women. Since the most common symptoms of endometriosis—progressive dysmenorrhea, dyspareunia, chronic pelvic pain, and infertility—are also symptoms of multiple disorders, a diagnosis of endometriosis can be elusive and confirmed only by visualization, that is, laparoscopy. Endometriosis is often treated surgically upon diagnosis; however, the rate of recurrence is high, suggesting that a combination of therapeutic approaches might provide better outcomes than any one option alone. The most widely utilized hormonal treatments for endometriosis are GnRH agonists and oral contraceptives; agents indicated by the Food and Drug Administration include GnRH agonists and the androgen, danazol. The majority of evidence in support of medical therapy for endometriosis is largely observational, with the exception of studies of GnRH agonists, danazol, and a few progestins. Conventional treatment approaches for the medical management of endometriosis focus on suspected endometriosis, following a diagnosis of endometriosis, following surgical treatment of endometriosis, long‐term management, and retreatment. Although major advances have been made in the treatment of endometriosis in recent decades, lack of randomized clinical trials evaluating the use of agents such as oral contraceptives alone or as add‐back therapy for GnRH agonists, or those that examine combined medical and surgical treatments, has hampered the ability of physicians to provide the broadest range of medical therapies for this disorder. Future trials addressing these issues are warranted.
Research Aspects of Endometriosis Surgery
Authors: MARTIN DAN C.
Published: July 2009

Abstract: This paper asks various questions regarding endometriosis surgery. These address the research issues of the necessity of treatment, surgical technique, terminology, the definition of the rectovaginal septum, standards for research, and the impact of RBRVS/RDG.
Selective Progesterone Receptor Modulators (SPRMs)
Authors: CHWALISZ KRISTOF , GARG RAMESH , BRENNER ROBERT M. , SCHUBERT GERD , ELGER WALTER
Published: July 2009

Abstract: Endometriosis, the presence of endometrial tissue outside the uterus, is a progressive, estrogen‐dependent disease and occurs nearly exclusively in menstruating women of reproductive age. Pain syndrome, however, represents the major clinical problem of this disease, manifested as dysmenorrhea, pelvic pain, lower abdominal pain, and dyspareunia. The manifestation of the disease, that is, the pain syndrome, rather than the disease itself currently represents the major indication for both the medical and surgical therapies of endometriosis. The major drawbacks of current medical therapies of endometriosis are sometimes severe side effects. In this review, selective progesterone receptor modulators (SPRMs, mesoprogestins) as a potential therapeutic concept in endometriosis are discussed. Due to endometrial selectivity and favorable pharmacological profile, SPRMs may have advantages over the current medical treatments of this disease. Other emerging therapeutic approaches for this disease are also mentioned.
A Personal Introduction to Eye Movements
Authors: DAROFF ROBERT B.
Published: July 2009

Abstract: The presentations at this meeting demonstrate that the control of eye movements is probably the best understood motor system from the level of genes and molecules to the neural orchestration of complex behaviors. Here I review my early involvement in this field, with personal impressions of how our current concepts developed and the individuals who shaped them.
Extraocular Muscle: Cellular Adaptations for a Diverse Functional Repertoire
Authors: PORTER JOHN D.
Published: July 2009

Abstract: Oculomotor control systems are considerably more complex and diverse than are spinal skeletomotor systems. Moreover, individual skeletal muscles are frequently functional role‐specific, while all extraocular muscles operate across a very wide dynamic range. We contend that the novel phenotype of the extraocular muscles is a direct consequence of the functional demands imposed upon this muscle group by the central eye movement controllers. This review highlights five basic themes of extraocular muscle biology that set them apart from more typical skeletal muscles, specifically, the (a) novel innervation pattern, (b) heterogeneity in contractile proteins, (c) structural and functional compartmentalization of the rectus and oblique muscles, (d) diversity of extraocular muscle fiber types, and (e) relationship between the novel muscle phenotype and the differential response of these muscles in neuromuscular and endocrine disease. Finally, new data from broad genome‐wide profiling studies are reviewed, with global gene expression patterns lending substantial support to the notion that the extraocular muscles are fundamentally different from traditional skeletal muscle. This novel eye muscle phenotype represents an adaptation that exploits the full range of variability in skeletal muscle to meet the needs of visuomotor systems.
The Orbital Pulley System: A Revolution in Concepts of Orbital Anatomy
Authors: DEMER JOSEPH L.
Published: July 2009

Abstract:Magnetic resonance imaging (MRI) now enables precise visualization of the mechanical state of the living human orbit. Resulting insights have motivated histological re‐examination of human and simian orbits, providing abundant consistent evidence for theactive pulley hypothesis, a re‐formulation of ocular motor physiology. Each extraocular muscle (EOM) consists of a global layer (GL) contiguous with the tendon and inserting on the eyeball, and a similar‐sized orbital layer (OL) inserting on a connective tissue ring forming the EOMpulley. The pulley controls the EOM path and serves as the EOM's functional origin. Activity of the OL positions the pulley along each rectus EOM to assure that its pulling direction shifts by half the change in ocular orientation, the half‐angle behavior characteristic of a linear ocular motor plant. Half‐angle behavior is equivalent to Listing's law of ocular torsion, and makes 3‐D ocular rotations effectively commutative. Pulleys are configured to maintain oblique EOM paths orthogonal to half‐angle behavior, and violate Listing's law during the vestibulo‐ocular reflex. Rectus pulley positions shift during convergence, facilitating stereopsis.

Innervations, fiber types, and metabolism of the OL and GL differ, consistent with the elastic loading of the former, and viscous loading of the latter. Disorders of the location and stability of rectus pulleys are associated with predictable patterns of incomitant strabismus that may mimic cranial nerve palsies. Surgical interventions improve defective pulley function. Understanding of ocular motor control requires characterization of the behavior of the EOM pulleys as well as knowledge of angular eye orientation.
Differential Susceptibility of the Ocular Motor System to Disease
Authors: KAMINSKI HENRY J. , RICHMONDS CHELLIAH R. , KUSNER LINDA L. , MITSUMOTO HIROSHI
Published: July 2009

Abstract: This review summarizes an alternative approach to the understanding of neuromuscular disease. By contrasting disease susceptibility of extraocular muscle and ocular motor neurons, it is hoped that unique insights into disease mechanisms may be identified. Disorder of eye movements leads to dramatic symptoms for patients and the ocular motor system is relatively limited in its ability to compensate rapidly for such disruptions. However, more profound reasons exist as to why myasthenia gravis compromises neuromuscular transmission at ocular muscle synapses as well as why Graves' ophthalmopathy exists. In contrast, muscular dystrophies spare the eye muscles while devastating all other skeletal muscles; the same is true for motor neuron diseases. It is hoped that this review will encourage others to view the world of neuromuscular diseases as delineated into those that spare the ocular motor system and those that do not.
Studies of the Role of the Paramedian Pontine Reticular Formation in the Control of Head‐Restrained and Head‐Unrestrained Gaze Shifts
Authors: SPARKS DAVID L. , BARTON ELLEN J. , GANDHI NEERAJ J. , NELSON JON
Published: July 2009

Abstract: Results of three experiments related to the role of the paramedian pontine reticular formation (PPRF) in the control of gaze are described. (1) Chronic unit recording methods, used to study the on‐directions of short‐lead burst neurons in head‐restrained monkeys, and (2) reversible inactivation techniques confirmed the traditional view of the importance of PPRF in the control of horizontal eye movements. Reversible inactivation of neurons in the vicinity of identified short‐lead burst neurons produced dramatic reductions in the speed of saccades to horizontal target displacements. The reductions in velocity were largely compensated for by an increase in saccade duration. Only minor, if any, effects were observed upon the velocity, duration, and amplitude of saccades to upward target displacements. (3) Microstimulation was applied to omnipause neurons to gate activity of excitatory burst neurons that discharge during coordinated eye‐head movements. The microstimulation failed to noticeably slow (prevent) head movements when stimulation was applied during (prior to onset of) gaze shifts, suggesting that signals relayed to motoneurons innervating the neck muscles are not inhibited by the omnipause neurons. In other words, the desired gaze signal is parsed into eye and head pathways upstream of the excitatory burst neurons.
Contribution of the Superior Colliculus and the Mesencephalic Reticular Formation to Gaze Control
Authors: WAITZMAN DAVID M. , PATHMANATHAN JAY , PRESNELL RACHEL , AYERS AMANDA , DePALMA STACY
Published: July 2009

Abstract: Converging lines of evidence support a role for the intermediate and deep layers of the superior colliculus (SC) and the mesencephalic reticular formation (MRF) in the control of combined head and eye movements (i.e., gaze). Recent microstimulation, single‐cell recording, and lesion experiments are reviewed in which monkeys are free to move their heads. Cells in the SC discharge in advance of combined head and eye movements and most likely provide a gaze error signal to downstream structures. In contrast, the neurons in the MRF are of at least two types. Eye cells have features that are similar to neurons in the rostral portion of the SC, but fire before the onset of horizontal eye movments. A second group of MRF neurons begin to fire after the onset of the gaze shift and are most closely associated with movements of the head. The peak discharge of these late‐onset MRF neurons occurs near the peak head velocity. Stimulation in the rostral SC generates eye movements with fixed amplitude and direction. A similar response is noted after stimulation of the more dorsal portion of the caudal MRF. Stimulation in the caudal portion of the SC produces combined head and eye movements of fixed amplitude. Electrical activation of the more ventral portions of the caudal MRF generates goal‐directed and centering eye movements. Temporary inactivation of the SC with the GABA agonist muscimol generated hypometria and curved trajectories of contralateral eye movements. Inactivation of the caudal MRF produced contralateral hypermetria and ipsilateral hypometria of saccades. Release of the monkey's head demonstrated a profound contralateral head tilt. Taken together, these data suggest that the gaze signal generated in the SC is filtered by neurons in the MRF to generate a feedback signal of eye motor error. The head signal found in the MRF could cancel a portion of the gaze signal coming from the SC in the form of head velocity feedback.
Neural Discharge in the Superior Colliculus during Target Search Paradigms
Authors: KELLER EDWARD L. , McPEEK ROBERT M.
Published: July 2009

Abstract: Neural studies of oculomotor function in the past have been conducted with the use of very simple visual stimuli. More recently there has been a new emphasis on using more natural stimuli to extend our knowledge of oculomotor organization. Visual search paradigms are an example of the use of these more natural visual surrounds. In search a subject must locate and saccade to a target that appears simultaneously with an array of distractors. When monkeys are used in this paradigm, it is possible to record from neurons located in various central structures in the brain while the initial visual response, subsequent discrimination processes and final saccadic movement unfold. In the present study we used an array of four visual stimuli, and the target was distinguished by its odd color from three distractors of uniform color. Location of the target within the array and its color were randomly selected on each trial. Neurons located in the deeper layers of the superior colliculus (SC) were recorded by standard methods in blocks of search trials.

We found several new features in the discharge of SC neurons using this search paradigm that have not previously been reported in studies using single‐target visual displays. (1) In contrast to the “winner take all” behavior previously reported for the SC, we found evidence of concurrent processing of alternative movement vectors. When incorrect movements were made to distractor locations, this concurrent activity was associated with significantly shorter intersaccadic intervals. (2) The discharge profile of the visual response in many units was modified by the appearance of a second prominent peak which followed the initial phasic visual response, but which was clearly differentiated from a third burst in activity associated with a saccade into the cell's response field. In some neurons, the activity in this second peak was discriminatory for the impending saccade vector. That is, it was larger when the target appeared in the response field of the cell than when it contained a distractor. This target selection signal was thus distinct from the burst normally associated with saccades into the movement fields of SC neurons. (3) Some saccades in search had a curved trajectory bowing toward the location of a distractor. These saccades were accompanied by an elevated discharge of neurons coding that distractor.
Cerebellar Influences on Saccade Plasticity
Authors: ROBINSON F. R. , FUCHS A. F. , NOTO C. T.
Published: July 2009

Abstract: Inaccurate saccades adapt to become more accurate. In this experiment the role of cerebellar output to the oculomotor system in adapting saccade size was investigated. We measured saccade adaptation after temporary inactivation of saccade‐related neurons in the caudal part of the fastigial nucleus which projects to the oculomotor brain stem. We located caudal fastigial nucleus neurons with single unit recording and injected 0.1% muscimol among them. Two monkeys received bilateral injections and two monkeys unilateral injections. Unilateral injections made ipsiversive saccades hypermetric (gains >1.5) and contraversive saccades hypometric (gains ∼0.6). Bilateral injections made both leftward and rightward saccades hypermetric (gains >1.5). During unilateral inactivation neither ipsiversive nor contraversive saccade size adapted after ∼1,000 saccades. During bilateral inactivation, adaptation was either small or very slow. Most intact monkeys completely adapt after ∼1,000 saccades to similar dysmetrias produced by intrasaccadic target displacement. After the monkeys receiving bilateral injections made >1,000 saccades in each horizontal direction, we placed them in the dark so that the muscimol dissipated without the monkeys receiving visual feedback about its saccade gain. After the dark period, 20‐degree saccades were adapted to be 12% smaller, and 4‐degree saccades to be 7% smaller. We expect this difference in adaptation because during caudal fastigial nucleus inactivation, monkeys made many large overshooting saccades and few small overshooting saccades. We conclude from these results that: (1) caudal fastigial nucleus activity is important in adapting dysmetric saccades; and (2) bilateral caudal fastigial nucleus inactivation impairs the relay of adapted signals to the oculomotor system, but it does not stop all adaptation from occurring.
Distributed Model of Collicular and Cerebellar Function during Saccades
Authors: OPTICAN LANCE M. , QUAIA CHRISTIAN
Published: July 2009

Abstract: How does the brain tell the eye where to go? Classical models of rapid eye movements are lumped control systems that compute analogs of physical signals such as desired eye displacement, instantaneous error, and motor drive. Components of these lumped models do not correspond well with anatomical and physiological data. We have developed a more brain‐like, distributed model (called a neuromimetic model), in which the superior colliculus (SC) and cerebellum (CB) play novel roles, using information about the desired target and the movement context to generate saccades. It suggests that the SC is neither sensory nor motor; rather it encodes the desired sensory consequence of the saccade in retinotopic coordinates. It also suggests a non‐computational scheme for motor control by the cerebellum, based on context learning and a novel spatial mechanism, the pilot map. The CB learns to use contextual information to initialize the pilot signal that will guide the saccade to its goal. The CB monitors feedback information to steer and stop the saccade, and thus replaces the classical notion of a displacement integrator. One consequence of this model is that no desired eye movement signal is encoded explicitly in the brain; rather it is distributed across activity in both the SC and CB. Another is that the transformation from spatially coded sensory information to temporally coded motor information is implicit in the velocity feedback loop around the CB. No explicit spatial‐to‐temporal transformation with a normalization step is needed.
The Cerebellar Contribution to Eye Movements Based upon Lesions
Authors: ZEE DAVID S. , WALKER MARK F. , RAMAT STEFANO
Published: July 2009

Abstract: The study of human cerebellar patients and monkeys with experimental cerebellar lesions has taught us much about the role of the cerebellum in normal ocular motor control. Here we emphasize recent findings that point to a role for the cerebellum in (1) the control of the three‐dimensional axis about which the eye rotates in response to visual and vestibular stimuli, and (2) the generation of the translational VOR. Findings in cerebellar patients include abnormalities of eye torsion during attempted fixation that suggest a cerebellar role in the control of torsion so that Listing's law is obeyed. Abnormal torsion during vertical pursuit suggests that central processing of information for smooth pursuit may be based upon a phylogenetically old, semicircular canal coordinate scheme. Inappropriate and disconjugate vertical and torsional eye movements (“cross‐coupling”) occur during brief, high‐acceleration rotations of the head. This suggests a role for the cerebellum in the binocular control of the rotation axis of the VOR. Finally, abnormalities of the modulation of the translational VOR with near viewing in cerebellar patients, but with sparing of the very initial 25‐30 msec of response, suggests an important role for the cerebellum in the translational VOR.
Spatial Orientation of Caloric Nystagmus
Authors: ARAI YASUKO , YAKUSHIN SERGEI B. , DAI MINGJIA , KUNIN MIKHAIL , RAPHAN THEODORE , SUZUKI JUN‐ICHI , COHEN BERNARD
Published: July 2009

Abstract: The spatial orientation of the slow‐phase eye velocity of caloric nystagmus was investigated in cynomolgus monkeys after all six semicircular canals had been plugged. Normal animals generate responses that have dominant convective components produced by movement of the endolymph in the lateral canal toward or away from gravity. As a result, the direction of horizontal slow‐phase velocity induced by cold‐water irrigation changes direction with changes in head position with regard to gravity. Plugging produced a dense overgrowth of bone that blocked the flow of endolymph, but the end organs were intact. Robust caloric nystagmus was elicited after recovery, but the horizontal (yaw) component was now always toward the stimulated (ipsilateral) side, regardless of head position re gravity. The induced caloric nystagmus had strong spatial orientation properties after canal plugging. With animals upright, the three‐dimensional velocity vector of the caloric nystagmus was close to the yaw axis with small vertical and roll components. Roll components became stronger in supine and prone positions and vertical components were enhanced in the right‐ and left‐side down positions. In each instance, the addition of the roll and vertical components moved the velocity vector of the nystagmus closer to the spatial vertical. Modeling supported the postulate that the caloric nystagmus after canal plugging is influenced by three factors: (1) a reduction in neural activity in the ampullary nerves on the stimulated side due to cooling of the nerves; (2) contraction of the endolymph in the closed space between the cupula and the plug due to cooling, which resulted in deflection of the cupula and hair cells toward the plug (ampullofugal deflection); and (3) alignment of eye velocity to gravity due to the orientation properties of velocity storage. Although convection is the most prominent factor in producing caloric responses in the normal state, our results suggest that alteration of nerve activity due to thermal effects, endolymph contraction or expansion, and velocity storage are also likely to contribute to the total response.
Visual‐Vestibular and Visuovisual Cortical Interaction
Authors: BRANDT THOMAS , GLASAUER STEFAN , STEPHAN THOMAS , BENSE SANDRA , YOUSRY TAREK A. , DEUTSCHLÄNDER ANGELA , DIETERICH MARIANNE
Published: July 2009

Abstract: PET and fMRI studies have revealed that excitation of the vestibular system by caloric or galvanic stimulation not only activates the parietoinsular vestibular cortex but also bilaterally deactivates the occipital visual cortex. Likewise, visual motion stimulation not only activates the visual cortex but also deactivates the parietoinsular vestibular cortex. These findings are functionally consistent with the hypothesis of an inhibitory reciprocal visual‐vestibular interaction for spatial orientation and motion perception. Transcallosal visuovisual interaction between the two hemispheres was found by using half‐field visual motion stimulation: activation of motion‐sensitive areas hMT/V5 and deactivations of the primary visual cortex contralateral to the stimulated hemisphere. The functional significance of these inter‐ and intra‐sensory interactions could be that they (A) allow a shift of the sensorial weight between two incongruent sensory inputs and (B) ensure a correspondence of the two hemispheres during evaluation of contradictory motion stimulation of the right and left hemifields. In terms of mathematical modeling, these findings may reflect the concepts of a sensory conflict mechanism or a mismatch between expected and actual sensory input.
Neural Mechanisms for the Control of Vergence Eye Movements
Authors: GAMLIN PAUL D.R.
Published: July 2009

Abstract: Our recent studies in non‐human primates have identified and characterized cerebro‐ponto‐cerebellar pathways involved in the control of vergence eye movements. Specifically, within the deep cerebellar nuclei and nucleus reticularis tegmenti pontis, we have identified neurons that are related to either the near response (convergence and increased ocular accommodation) or the far response (divergence and decreased ocular accommodation). In addition, within the prearcuate region (area 8a), we have characterized neurons related not only to either the far response or the near response, but also to the sensorimotor transformations underlying these eye movements. Because the vergence‐related prearcuate region abuts the frontal eye fields, we suggest that the extent of the frontal eye fields be expanded to include this region. We further suggest that with inclusion of this vergence‐related region, the frontal eye fields are important for all voluntary eye movements.
Neural Basis of Disjunctive Eye Movements
Authors: KING W. M. , ZHOU WU
Published: July 2009

Abstract: New evidence has challenged a widely accepted interpretation of Hering's law of equal innervation, which states that disjunctive saccades are produced by the linear addition of conjugate and vergence innervation commands produced by independent oculomotor subsystems. We hypothesize, instead, that saccades are produced by a monocular premotor control network. A model, based on this hypothesis and consistent with known brain‐stem anatomy, simulates realistic disjunctive saccades including initial and late slow vergence movements.
Population Coding in Cortical Area MST
Authors: TAKEMURA A. , KAWANO K. , QUAIA C. , MILES F. A.
Published: July 2009

Abstract: Disparity steps applied to large patterns elicit vergence eye movements at ultrashort latencies. Disparity tuning curves, describing the dependence of the amplitude of the initial vergence responses on the amplitude of the disparity steps, resemble the derivative of a gaussian and indicate that appropriate servo‐like behavior occurs only with small disparity steps (<1 degree). Lesion data from monkeys suggest that these vergence responses are mediated, at least in part, by neurons in the medial superior temporal area of the cerebral cortex, and we here review a recent study of the associated single unit activity in that area. Few medial superior temporal neurons have disparity tuning curves whose shapes resemble the tuning curve for vergence. Yet, when the disparity tuning curves for all of the disparity‐sensitive cells recorded from a given monkey are summed together, they match the tuning curves for the vergence responses of that monkey very closely, even reproducing that animal's idiosyncracies. When all of the spike trains elicited by a given disparity step are summed together to give an average discharge profile for the whole population of recorded cells, many are noisy, but others that are less so match the temporal profile of the motor response, vergence velocity, quite well. We conclude that the discharges of the disparity‐sensitive cells in the medial superior temporal area each represent only a very limited aspect of the sensory stimulus (and/or associated motor response?), but when pooled together, they provide a complete description of the vergence velocity motor response: population coding.
Otolith Function: Basis for Modern Testing
Authors: PAIGE GARY D.
Published: July 2009

Abstract: The major challenge in developing a robust test of otolith function, particularly with regard to linear vestibulo‐ocular reflex (LVOR) and perceptual measures, is to find a way in which graded lesions are reflected in graded response properties and abnormalities. The ability of the vestibulo‐ocular reflex (VOR) to compensate and adapt to dysfunction and pathology presents formidable challenges for registering localizing clinical findings, whether in the angular vestibulo‐ocular reflex (AVOR), the LVOR, or both. Based on a variety of considerations, various forms of eccentric rotation seem to provide the most convenient, and potentially the most useful, means to generate motion profiles from which otolith function can be directly assessed. Both translational and tilt responses can be recorded depending on the stimulus profile. The near‐centric version is particularly enticing because of the ability to study one labyrinth at a time, much like calorics. In that case and in others in which the tilt‐LVOR is prominent, measures of the perceived visual vertical are useful and by all accounts similar to ocular torsion. The latter does hold the important advantage of being an objective measure, requiring no intervention on the part of the patient. The translational‐LVOR can be derived from eccentric rotation responses with the head displaced forward as well as backward, while viewing near targets in hopes of generating a large addition or subtraction (even inversion) of an otherwise AVOR‐driven reflex. These considerations provide an impetus to pursue improved methods of quantifying otolith function in a clinical population. The sobering caveat is that the diagnosis of total unilateral vestibular loss presents little challenge either clinically or by classic testing (e.g., calorics), and yet most of our efforts in developing quantifiable measures of dysfunction over the years have yielded results that are modest and hardly compelling.
Genetics of Familial Episodic Vertigo and Ataxia
Authors: BALOH ROBERT W. , JEN JOANNA C.
Published: July 2009

Abstract: The familial episodic ataxias are prototypical inherited channelopathies that result in episodes of vertigo and ataxia triggered by stress and exercise. Episodic ataxia type 1 (EA‐1) is caused by missense mutations in the potassium channel gene KCNA1, whereas episodic ataxia type 2 (EA‐2) is caused by missense and nonsense mutations in the calcium channel gene CACNA1A. These ion channels are crucial for both central and peripheral neurotransmission. Within the last few years, the genetic mechanisms underlying these relatively rare familial episodic ataxia syndromes have been worked out. They provide a model for understanding the mechanisms of more common recurrent vertigo and ataxia syndromes, particularly those associated with migraine. Migraine affects as many as 15‐20% of the general population, and it has been estimated that about 25% of patients with migraine experience spontaneous attacks of vertigo and ataxia. We identified 24 families with migraine and benign recurrent vertigo inherited in an autosomal dominant fashion. These families have numerous features in common with EA‐1 and EA‐2 (particularly EA‐2), suggesting that benign recurrent vertigo may be an inherited channelopathy. An ion channel mutation shared by brain and inner ear could explain the combined central and peripheral features of the syndrome.
Animal Models for Visual Deprivation‐Induced Strabismus and Nystagmus
Authors: TUSA RONALD J. , MUSTARI MICHAEL J. , DAS VALLABH E. , BOOTHE RONALD G.
Published: July 2009

Abstract: The development of gaze‐stabilizing systems depends on normal vision during infancy. Monkeys reared with binocular lid suture (BLS) for the first 25‐40 days of life have strabismus, optokinetic nystagmus deficits, latent nystagmus, and decreased binocular cells in the visual cortex and nucleus of the optic tract. When BLS is extended to 55 days, pendular and congenital nystagmus also occurs. Eyelids in infant monkeys are hairless and thin, but BLS still degrades sensory fusion, motion, and form perception. To determine to what extent these visual properties are critical in the development of normal gaze stabilization, we examined infant monkeys reared with one opaque contact lens over one eye, alternated to the fellow eye every other day (AMO); and monkeys reared in a 3‐Hz strobe environment. Monkeys reared with AMO develop strabismus, but have normal optokinetic nystagmus and no spontaneous nystagmus. Area 17 is monocular, but the medial temporal area and the nucleus of the optic tract are binocular. Monkeys reared in strobe light develop pendular nystagmus but not strabismus. We were puzzled by the results of the AMO monkeys until we examined infant monkeys with BLS that were prevented from seeing form through the lids. This was done by leaving the tarsal plate intact behind the eyelid. They developed similar to the AMO monkeys. These results suggest that disruption of sensory fusion during infancy (BLS, AMO) causes strabismus. If strabismus occurs while the monkeys have some form vision from each eye (BLS without tarsal plate), then the nucleus of the optic tract becomes monocular, which causes optokinetic nystagmus deficits and latent nystagmus. Infant monkeys reared without visual motion develop pendular nystagmus.
Wine Phenolics
Authors: WATERHOUSE ANDREW L.
Published: July 2009

Abstract: Wine contains many phenolic substances, most of which originate in the grape berry. The phenolics have a number of important functions in wine, affecting the tastes of bitterness and astringency, especially in red wine. Second, the color of red wine is caused by phenolics. Third, the phenolics are the key wine preservative and the basis of long aging. Lastly, since phenolics oxidize readily, they are the component that suffers owing to oxidation and the substance that turns brown in wine (and other foods) when exposed to air. Wine phenolics include the non‐flavonoids: hydroxycinnamates, hydroxybenzoates and the stilbenes; plus the flavonoids: flavan‐3‐ols, the flavonols, and the anthocyanins. While polymeric condensed tannins and pigmented tannins constitute the majority of wine phenolics, their large size precludes absorption and thus they are not likely to have many health effects (except, perhaps, in the gut). The total amount of phenols found in a glass of red wine is on the order of 200 mg versus about 40 mg in a glass of white wine.
Chemistry of the Antioxidant Effect of Polyphenols
Authors: BORS WOLF , MICHEL CHRISTA
Published: July 2009

Abstract: Most plant‐derived polyphenols exhibit strong antioxidant potentials, established by various assay procedures. With pulse radiolysis experiments, absolute scavenging rate constants can be obtained with a variety of oxidizing radicals which allow further structure‐activity correlations and, combined with EPR spectroscopy, detailed insight into the mechanisms governing these antioxidant reactions. The most striking difference occurs between regular flavonoids and both condensed and hydrolyzable tannins. The tannins are considered superior antioxidants as their eventual oxidation may lead to oligomerization via phenolic coupling and enlargement of the number of reactive sites, a reaction which has never been observed with the flavonoids themselves.
Vasodilating Procyanidins Derived from Grape Seeds
Authors: FITZPATRICK DAVID F. , BING BETTYE , MAGGI DAVID A. , FLEMING RICHARD C. , O'MALLEY REBECCA M.
Published: July 2009

Abstract: We have shown in previous work that extracts of grape seeds (GSE) and skins, grape juice, and many red wines exhibit endothelium‐dependent relaxing (EDR) activity in vitro. This EDR activity involves endothelial nitric oxide (NO) release and subsequent increase in cyclic GMP levels in the vascular smooth muscle cells. The NO/cyclic GMP pathway is known to be involved in many cardiovascular‐protective roles. The current study focuses on the isolation and identification of EDR‐active compounds (procyanidins) from GSE. Crushed Concord grape seeds were extracted with methanol and the extract was separated into seven fractions (A‐G) on a Toyopearl TSK‐HW‐40 column. EDR‐active fractions (D‐G) were further separated into 25 individual compound peaks by HPLC, 16 of which were EDR active (threshold for relaxation ranged between less than 0.5 μg/mL and greater than 4 μg/mL). Procyanidin identification was accomplished by electrospray‐ion trap mass spectrometry (ES‐ITMS), MS/MS, and by tannase treatment and acid thiolysis, followed by HPLC and ES‐ITMS of the products. Activity of isolated procyanidins tended to increase with degree of polymerization, epicatechin content, and with galloylation. These EDR‐active compounds (many of which also possess antioxidant activity), individually or in the form of wines, juices, or nutritional supplements, may be useful in preventing or treating cardiovascular diseases.
Cardiovascular Protection by Alcohol and Polyphenols
Authors: PARKS DALE A. , BOOYSE FRANCOIS M.
Published: July 2009

Abstract: Cardiovascular disease, and in particular coronary heart disease (CHD), remains the leading cause of death in both men and women in the United States. Much epidemiologic evidence indicates that alcoholic beverages, and in particular red wine, results in a reduction in cardiovascular risk factors and decreases mortality; however, the mechanisms of this cardiovascular protection remains elusive. This review discusses evidence to suggest that •NO plays a critical role in cardiovascular protection and that nitric oxide synthase (NOS) is the responsible cardioprotective protein (see Bolli et al. 1998. Basic Res. Cardiol. 93:325‐338).
Cardioprotection with Alcohol
Authors: SATO MOTOAKI , MAULIK NILANJANA , DAS DIPAK K.
Published: July 2009

Abstract: Both epidemiological and experimental studies indicate that mild‐to‐moderate alcohol consumption is associated with a reduced incidence of mortality and morbidity from coronary heart disease. The consumption of wine, particularly red wine, imparts a greater benefit in the prevention of coronary heart disease than the consumption of other alcoholic beverages. The cardioprotective effects of red wine have been attributed to several polyphenolic antioxidants including resveratrol and proanthocyanidins. The results of our study documented that the polyphenolic antioxidants present in red wine, for example, resveratrol and proanthocyanidins, provide cardioprotection by their ability to function as in vivo antioxidants while its alcoholic component or alcohol by itself imparts cardioprotection by adapting the hearts to oxidative stress. Moderate alcohol consumption induced significant amount of oxidative stress to the hearts which was then translated into the induction of the expression of several cardioprotective oxidative stress‐inducible proteins including heat shock protein (HSP) 70. Feeding the rats with red wine extract or its polyphenolic antioxidants as well as alcohol resulted in the improvement of postischemic ventricular function. Additionally, both wine and alcohol triggered a signal transduction cascade by reducing proapoptotic transcription factors and genes such as JNK‐1 and c‐Jun thereby potentiating an anti‐death signal. This resulted in the reduction of myocardial infarct size and cardiomyocyte apoptosis. The results, thus, indicate that although both wine and alcohol alone reduce myocardial ischemic reperfusion injury, the mechanisms of cardioprotection differ from each other.
Wine Flavonoids Protect against LDL Oxidation and Atherosclerosis
Authors: AVIRAM MICHAEL , FUHRMAN BIANCA
Published: July 2009

Abstract:We have previously shown that consumption of red wine, but not of white wine, by healthy volunteers, resulted in the enrichment of their plasma LDL with flavonoid antioxidants such as quercetin, the potent free radicals scavenger flavanol, which binds to the LDL via a glycosidic ether bond. This phenomenon was associated with a significant three‐fold reduction in copper ion‐induced LDL oxidation. The ineffectiveness of flavonoid‐poor white wine could be overcome by grape's skin contact for 18 hours in the presence of alcohol, which extracts grape's skin flavonoids. Recently, we observed that the high antioxidant potency of Israeli red wine could be related to an increased content of flavonols, which are very potent antioxidants and their biosynthesis is stimulated by sunlight exposure. To find out the effect (and mechanisms) of red wine consumption on atherosclerosis, we used the apo E deficient (E0) mice. In these mice, red wine consumption for two months resulted in a 40% decrement in basal LDL oxidation, a similar decrement in LDL oxidizability and aggregation, a 35% reduction in lesion size, and a marked attenuation in the number and morphology of lesion's macrophage foam cells. Red wine consumption resulted in accumulation of flavonoids in the mouse macrophages and these cells oxidized LDL and took up LDL about 40% less than macrophages from placebo‐treated mice. Finally, the activity of serum paraoxonase (which can hydrolyze specific lipid peroxides in oxidized LDL and in atherosclerotic lesions) was significantly increased following consumption of red wine by E0mice. Red wine consumption thus acts against the accumulation of oxidized LDL in lesions as a first line of defense (by a direct inhibition of LDL oxidation), and as a second line of defense (by paraoxonase elevation and removal of atherogenic lesion's and lipoprotein's oxidized lipids).