The role of vestibular evoked myogenic potentials in multiple sclerosis-related vertigo. A systematic review of the literature.

BACKGROUND: Vertigo is a common symptom of multiple sclerosis (MS) that can be caused by a central or peripheral involvement of the vestibular pathways. Magnetic Resonance Imaging (MRI) is commonly used to evaluate progression of MS but is not sensitive enough to detect small lesions. Vestibular evoked myogenic potentials (VEMPs) are commonly used to evaluate function of vestibular-cochlear pathways. The aim of this literature review is to evaluate the role of VEMPs in patients with MS-related vertigo as a tool to detect demyelinating lesions in the vestibular pathways of MS patients and to monitor MS progression. METHODS: Following the PRISMA guidelines, we performed a literature search with the following keywords: multiple sclerosis, vertigo, dizziness, equilibrium disorders, vestibular disorders, and VEMPs. Three different databases (PubMed, Scopus, and Google Scholar) were independently screened by two researchers. Publications in English, Italian, French, and Spanish were considered and reviewed by a native speaker. Details on patients' gender, age, and stage of MS, as well as VEMPs, MRI, and vertigo features (including their onset as a function of MS stage) were collected. Percentage and odds ratio were calculated. Spearman test was used to correlate vertigo, VEMPs, and MRI features. RESULTS: Thirty-five articles and 819 patients were included in the study. Nearly 37% of MS patients suffered from vertigo and 71% showed altered VEMPs. Central vestibular pathways were involved in the MS demyelination mostly in the early stage of the disease, while the peripheral vestibular system was mainly affected in late stage MS. A significant percentage (35.4%) of the patients with altered VEMPs showed normal MRI. CONCLUSIONS: Our results suggest that VEMPs may detect very small lesions in the vestibular pathways of MS patients; thus, they could have a role in the diagnosis of MS-related vertigo and in the monitoring of vertigo in MS patients as a tool additional to traditional MRI.

Pre-treatment with Melamil Tripto® induces sleep in children undergoing Auditory Brain Response (ABR) testing.

OBJECTIVES: Previous studies have shown that tryptophan and vitamin B6 used in conjunction with melatonin induce sleep more effectively than melatonin alone. This study aims at evaluating the efficacy of different dosages and timings of administration of a solution containing melatonin, tryptophan, and vitamin B6 for inducing sleep in children undergoing ABR testing. METHODS: 294 children scheduled for Auditory Brain Response (ABR) evaluation were administered a solution containing melatonin, tryptophan, and vitamin B6 to induce sleep before the exam. Two different administration timings (pre-treatment and single shot treatment) and three dosages (0.5 ml in pre-treatment, 1.5 ml in pre-treatment, and 3 ml in single shot) were tested. The following parameters were evaluated: time needed for the subject to fall asleep before ABR testing, subject sl'eep features during ABR testing (quality, stability, duration), recorded ABR quality (including presence of abnormalities in amplitude and latency), subject waking up modality, and time needed for the subject to wake up at the end of the ABR exam. RESULTS: Quality of ABR signals was similar across treatments, and subjects responded in a similar manner in terms of time needed to wake-up and wake-up modality. However, pretreatment with the 1.5 ml dose induced sleep faster than the two other dosages, and the length of the induced sleep was longer than that induced by pre-treatment with 0.5 ml. In general, the pre-treatment with 1.5 ml led to a shorter ABR exam, because reduces the time for inducing sleep, allows a long sleeping phase with a good quality, without variation in the wakening up times. CONCLUSIONS: Melamil Tripto® is an alternative to sedative drugs for inducing sleep in pediatric subjects undergoing ABR testing. A pre-medication with 1.5 ml of MT 1 week before ABR testing further improves the strength of the solution.

Sudden hearing loss as an early detector of multiple sclerosis: a systematic review.

OBJECTIVE: To evaluate whether Sudden Sensorineural Hearing Loss (S-SNHL) may be an early symptom of Multiple Sclerosis (MS). MATERIALS AND METHODS: A systematic review was conducted using the following keywords: "Multiple sclerosis, hearing loss, sudden hearing loss, vertigo, tinnitus, magnetic resonance imaging, otoacoustic emission, auditory brainstem responses, white matter lesions, sensorineural hearing loss, symptoms of MS and otolaryngology, nerve disease and MS". Only the articles that included results of at least one auditory test and MRI were considered. We evaluated the prevalence of SNHL in patients with MS, the presence of different forms of SNHL (S-SNHL and Progressive SNHL (P-SNHL)) and their correlation with the stage of MS, the results of electrophysiological tests, and the location (if any) of MS lesions as detected by white matter hyperintensities in the MRI. RESULTS: We reviewed a total of 47 articles, which included 29 case reports, 6 prospective studies, 6 cohort studies, 4 case-control studies, and 2 retrospective studies. 25% of patients suffered from SNHL. S-SNHL typically occurred in the early stage of the disease (92% of patients) and was the only presenting symptom in 43% of female subjects. Instead, P-SNHL occurred in the late stage of MS (88% of patients). Auditory Brainstem Responses (ABR) were abnormal in all MS patients with S-SNHL. When S-SNHL appeared during the early stage of the disease, MS lesions were found in the brain in 60% of patients and in the Internal Auditory Canal in 40% of patients. ABR remained abnormal after recovery. CONCLUSIONS: S-SNHL can be an early manifestation of MS and should always be considered in the differential diagnosis of this condition, especially in women. The pathophysiology can be explained by the involvement of microglia attacking the central and/or peripheral auditory pathways as indicated by WMHs.

Continued Sex-Differences in the Rate and Severity of Knee Injuries among Collegiate Soccer Players: The NCAA Injury Surveillance System, 2004-2009.

We extend previous analyses and examined sex-differences in the rate and severity of knee injuries among collegiate soccer players between 2004 and 2009. Data from the National Collegiate Athletic Association Injury Surveillance System (NCAA ISS) were used to calculate injury incidence density (ID) per 1 000 athletic exposures (AE). Multivariable regression modeling then tested the relation between sex and knee injury incidence and severity among all injured soccer players, while controlling for contact, setting, and division level, as well as for the interactions among these variables. The rate of knee injuries was 1.19 per 1 000 AEs in women and 0.91 per 1 000 AEs in men (RR=1.31, 95% Wald CI=[1.16, 1.47]). In the multivariable modeling, women continued to experience significantly higher odds of knee injury compared with men (aOR=1.44, 95% CI=[1.27,1.63]). Also, the adjusted odds of a knee injury that resulted in surgery remained higher in women compared with men (aOR=1.61 (1.00, 2.58), as well as the amount of time lost from participation (beta=0.129; p=0.05). Given the prominence of soccer play in the United States, continued efforts to evaluate and improve knee injury prevention practices and policies may be especially important for female players.

Transcranial direct current stimulation (tDCS) and robotic practice in chronic stroke: the dimension of timing.

BACKGROUND: Combining tDCS with robotic therapy is a new and promising form of neurorehabilitation after stroke, however the effectiveness of this approach is likely to be influenced by the relative timing of the brain stimulation and the therapy. OBJECTIVE: To measure the kinematic and neurophysiological effects of delivering tDCS before, during and after a single session of robotic motor practice (wrist extension). METHODS: We used a within-subjects repeated-measurement design in 12 chronic (>6 months) stroke survivors. Twenty minutes of anodal tDCS was delivered to the affected hemisphere before, during, or after a 20-minute session of robotic practice. Sham tDCS was also applied during motor practice. Robotic motor performance and corticomotor excitability, assessed through transcranial magnetic stimulation (TMS), were evaluated pre- and post-intervention. RESULTS: Movement speed was increased after motor training (sham tDCS) by ∼20%. Movement smoothness was improved when tDCS was delivered before motor practice (∼15%). TDCS delivered during practice did not offer any benefit, whereas it reduced speed when delivered after practice (∼10%). MEPs were present in ∼50% of patients at baseline; in these subjects motor practice increased corticomotor excitability to the trained muscle. CONCLUSIONS: In a cohort of stroke survivors, motor performance kinematics improved when tDCS was delivered prior to robotic training, but not when delivered during or after training. The temporal relationship between non-invasive brain stimulation and neurorehabilitation is important in determining the efficacy and outcome of this combined therapy.

Differential expression of HIF-1α in skin and mucosal wounds.

Despite accelerated epithelial closure, oral mucosal wounds exhibit lower levels of VEGF and a more refined angiogenic response than do skin wounds. The specific differences in angiogenesis suggest that skin and oral mucosal wounds may experience dissimilar levels of hypoxia and HIF-1α. Using a model of comparable wounds on murine dorsal skin and tongue, we determined levels of hypoxia and HIF-1α. Skin wounds were found to be significantly more hypoxic and had higher levels of HIF-1α than mucosal wounds. Furthermore, under stressed conditions, skin wounds, but not mucosal wounds, exhibited a further elevation of HIF-1α beyond that of non-stressed levels. To determine if manipulation of oxygen levels might equalize the repair response of each tissue, we exposed mice to hyperbaric oxygen treatment (HBOT) following wounding. HBOT did not significantly change HIF-1α or VEGF expression in either skin or mucosal wounds, nor did it alter wound bed vascularity. These studies suggest that skin wounds have higher levels of hypoxia than do mucosal wounds, along with a differential expression of HIF-1α. Interestingly, modulation of oxygen by HBOT does not ameliorate this difference. These results suggest that differential responses to hypoxia may underlie the distinctive wound-healing phenotypes seen in skin and oral mucosa.

Learning, not adaptation, characterizes stroke motor recovery: evidence from kinematic changes induced by robot-assisted therapy in trained and untrained task in the same workspace.

Both the American Heart Association and the VA/DoD endorse upper-extremity robot-mediated rehabilitation therapy for stroke care. However, we do not know yet how to optimize therapy for a particular patient's needs. Here, we explore whether we must train patients for each functional task that they must perform during their activities of daily living or alternatively capacitate patients to perform a class of tasks and have therapists assist them later in translating the observed gains into activities of daily living. The former implies that motor adaptation is a better model for motor recovery. The latter implies that motor learning (which allows for generalization) is a better model for motor recovery. We quantified trained and untrained movements performed by 158 recovering stroke patients via 13 metrics, including movement smoothness and submovements. Improvements were observed both in trained and untrained movements suggesting that generalization occurred. Our findings suggest that, as motor recovery progresses, an internal representation of the task is rebuilt by the brain in a process that better resembles motor learning than motor adaptation. Our findings highlight possible improvements for therapeutic algorithms design, suggesting sparse-activity-set training should suffice over exhaustive sets of task specific training.

EEG correlates of submovements.

Numerous studies on motor control in humans and primates have suggested that the Central Nervous System (CNS) generates and controls continuous movement via discrete, elementary units of movement or submovements. While most studies are based on analysis of kinematic data, investigations of neural correlates have been lacking. To fill this gap we recorded and analyzed kinematic and high-density electroencephalographic (64-channel EEG) data from three right-handed normal adults during a reaching task that required online movement corrections. Each kinematic submovement was accompanied by stereotyped scalp maps. Furthermore, the peaks of event-related potentials (ERP) recorded at electrode C1 (over contralateral motor cortex) were time-locked to kinematic submovement peaks. These results provide further evidence for the hypothesis that the CNS generates and controls continuous movement via discrete submovements. Applications include design of quantitative outcome metrics for motor disorders of neurological origin such as stroke and Parkinson's disease.

Factors affecting wound healing.

Wound healing, as a normal biological process in the human body, is achieved through four precisely and highly programmed phases: hemostasis, inflammation, proliferation, and remodeling. For a wound to heal successfully, all four phases must occur in the proper sequence and time frame. Many factors can interfere with one or more phases of this process, thus causing improper or impaired wound healing. This article reviews the recent literature on the most significant factors that affect cutaneous wound healing and the potential cellular and/or molecular mechanisms involved. The factors discussed include oxygenation, infection, age and sex hormones, stress, diabetes, obesity, medications, alcoholism, smoking, and nutrition. A better understanding of the influence of these factors on repair may lead to therapeutics that improve wound healing and resolve impaired wounds.

Discovery of a potent, metabolically stabilized resorcylic lactone as an anti-inflammatory lead.

With bioactivity-guided phenotype screenings, a potent anti-inflammatory compound f152A1 has been isolated, characterized and identified as the known natural product LL-Z1640-2. Metabolic instability precluded its use for the study on animal disease models. Via total synthesis, a potent, metabolically stabilized analog ER-803064 has been created; addition of the (S)-Me group at C4 onto f152A1 has resulted in a dramatic improvement on its metabolic stability, while preserving the anti-inflammatory activities.

Changing motor synergies in chronic stroke.

Synergies are thought to be the building blocks of vertebrate movements. The inability to execute synergies in properly timed and graded fashion precludes adequate functional motor performance. In humans with stroke, abnormal synergies are a sign of persistent neurological deficit and result in loss of independent joint control, which disrupts the kinematics of voluntary movements. This study aimed at characterizing training-related changes in synergies apparent from movement kinematics and, specifically, at assessing: 1) the extent to which they characterize recovery and 2) whether they follow a pattern of augmentation of existing abnormal synergies or, conversely, are characterized by a process of extinction of the abnormal synergies. We used a robotic therapy device to train and analyze paretic arm movements of 117 persons with chronic stroke. In a task for which they received no training, subjects were better able to draw circles by discharge. Comparison with performance at admission on kinematic robot-derived metrics showed that subjects were able to execute shoulder and elbow joint movements with significantly greater independence or, using the clinical description, with more isolated control. We argue that the changes we observed in the proposed metrics reflect changes in synergies. We show that they capture a significant portion of the recovery process, as measured by the clinical Fugl-Meyer scale. A process of "tuning" or augmentation of existing abnormal synergies, not extinction of the abnormal synergies, appears to underlie recovery.

Distinct patterns of angiogenesis in oral and skin wounds.

Clinical observation suggests that oral mucosal wounds heal faster than skin; however, little is known about the site-specific differences. Since fetal skin wounds heal rapidly, but are less vascular than adult wounds, we hypothesized that less robust wound angiogenesis might be observed in healing oral mucosa. This study investigated angiogenesis in equivalent-size oral and skin murine wounds. Change in wound bed vascularity was significantly lower in oral wounds than in skin. Also, vascular endothelial growth factor (VEGF) levels were less in oral than cutaneous wounds. Because keratinocytes are a prominent source of VEGF in wounds, we compared VEGF production by oral and epidermal keratinocytes in vitro. Significantly higher levels of VEGF protein and mRNA were observed in epidermal keratinocytes than in oral keratinocytes after 18 hrs of hypoxia. This study demonstrates distinct angiogenesis patterns in oral and skin wounds and intrinsic site-specific differences in VEGF production by keratinocytes.

Differential injury responses in oral mucosal and cutaneous wounds.

Oral mucosa heals faster than does skin, yet few studies have compared the repair at oral mucosal and cutaneous sites. To determine whether the privileged healing of oral injuries involves a differential inflammatory phase, we compared the inflammatory cell infiltrate and cytokine production in wounds of equivalent size in oral mucosa and skin. Significantly lower levels of macrophage, neutrophil, and T-cell infiltration were observed in oral vs. dermal wounds. RT-PCR analysis of inflammatory cytokine production demonstrated that oral wounds contained significantly less IL-6 and KC than did skin wounds. Similarly, the level of the pro-fibrotic cytokine TGF-b1 was lower in mucosal than in skin wounds. No significant differences between skin and mucosal wounds were observed for the expression of the anti-inflammatory cytokine IL-10 and the TGF-beta1 modulators, fibromodulin and LTBP-1. These findings demonstrate that diminished inflammation is a key feature of the privileged repair of oral mucosa.

Artificial neural network model of the mapping between electromyographic activation and trajectory patterns in free-arm movements.

Artificial neural networks (ANNs) have been used to identify the relationship between electromyographic (EMG) activity and arm kinematics during the execution of motor tasks. Although considerable work has been devoted to showing that ANNs perform this mapping, there has been little work to explore any relationship with physiological properties of the neuromuscular systems. A back-propagation through time (BPTT) ANN was used to map the EMG of five selected muscles (pectoralis major (PM), anterior deltoid (AD), posterior deltoid (PD), biceps brachii (BB) and triceps brachii (TB)) on arm kinematics in seven normal subjects performing three-dimensional unrestrained grasping movements. To investigate the physiological validity of the BPTT-ANN, inputs were artificially altered, and the predicted outputs were analysed. Results show that the BPTT-ANN performed the mapping correctly (root mean square (RMS) error between target and predicted outputs averaged across subject test sets was 0.092 +/- 0.015). Moreover, it provided insights into the roles of muscles in performing the movement (average indexes measuring the output alteration with respect to the target were 0.070 +/- 0.027, 0.356 +/- 0.172, 0.568 +/- 0.413, 0.510 +/- 0.268, 0.681 +/- 0.430 for PM, AD, PD, BB, TB, respectively, in the movement forward phase, and 0.077 +/- 0.015, 0.179 +/- 0.147, 0.291 +/- 0.247, 0.671 +/- 0.054, 0.232 +/- 0.097 in the return phase).

Importance of plasma leptin in predicting future weight gain in obese children: a two-and-a-half-year longitudinal study.

OBJECTIVE: To determine whether relatively low leptin levels predict changes in adiposity in prepubertal and pubertal obese children. RESEARCH METHODS AND PROCEDURES: In a biracial cohort of 68 obese children (33 male and 35 female; 46 Caucasians and 22 African-Americans, age range 7-18 y), we measured at baseline fasting insulin and leptin levels, height and weight and calculated body mass index (kg/m(2)) and expressed body mass index as (BMI) Z-score. After a 2.5-y follow-up, anthropometric measurements were repeated and changes in weight gain were calculated as changes in BMI Z-score. RESULTS: At baseline obese preadolescent boys and girls had similar age and BMI Z-score, fasting insulin and leptin levels. After an average follow-up of 2.5 y, mean weight change calculated by changes in BMI Z-score from baseline was similar in both groups. In obese adolescent boys and girls at baseline, no significant gender differences were observed for BMI Z-score and insulin levels. In contrast, plasma leptin levels were significantly higher in obese girls compared with obese adolescent boys. At follow-up, there was no significant difference in change in BMI Z-score between obese boys and girls. Multiple linear regression analysis revealed that high basal leptin levels were positively associated with greater changes in BMI Z-score only in girls (r(2)=0.18, P<0.02), after adjusting for basal BMI Z-score, Tanner stage, years of follow-up and basal insulin. High basal leptin levels in girls explained 18% of the weight gain. CONCLUSION: High leptin levels are associated with excessive future weight gain only in girls.

Physical activity in aging: changes in patterns and their relationship to health and function.

Sedentary behavior is an important risk factor for chronic disease morbidity and mortality in aging. However, there is a limited amount of information on the type and amount of activity needed to promote optimal health and function in older people. The purpose of this review is to describe the change in patterns of habitual physical activity in aging and the relationship of these changes to physical function and selected chronic diseases. We undertook a literature review of large population-based studies of physical activity in older people, and there is encouraging evidence that moderate levels of physical activity may provide protection from certain chronic diseases. Additionally, substantial health effects can be accrued independent of the fitness effects achieved through sustained vigorous activity. Thus, regular participation (i.e., 30 minutes/day on most days of the week) in activities of moderate intensity (such as walking, climbing stairs, biking, or yardwork/gardening), which increase accumulated daily energy expenditure and maintain muscular strength, but may not be of sufficient intensity for improving fitness, should be encouraged in older adults. Public policy should focus on ways of increasing volitional and lifestyle activity in older people, as well as on increasing the availability and accessibility of senior and community center programs for promoting physical activity throughout the life span.

Age-related alterations in the inflammatory response to dermal injury.

Previous studies have documented that the ability to heal wounds declines with age. Although many factors contribute to this age-associated deficit, one variable that has not been carefully examined is leukocyte recruitment and function in wounds. This investigation compares the inflammatory response in excisional wounds of young (age 8 wk) and aged (age 22 mo) mice. In the early inflammatory response, neutrophil content of wounds was similar for both aged and young mice. In contrast, macrophage levels were 56% higher in aged versus young mice (81 +/- 20 vs 52 +/- 13 cells per mm2). In the later inflammatory response, wounds of aged mice exhibited a delay in T cell infiltration, with maximum T cell levels at day 10 in aged mice versus day 7 in young mice. Despite this delay, the eventual peak concentration of T cells was 23% higher in the wounds of aged mice (152 +/- 11 cells per mm2 vs 124 +/- 21cells per mm2). The observed alterations in inflammatory cell content suggested that chemokine production might be altered with age. An elevation of monocyte chemoattractant protein (MCP-1) levels was observed in wounds of aged mice. RNase protection studies, however, revealed that the production of most chemokines, including MIP-2, MIP-1alpha, MIP-1beta, and eotaxin, tended to decline with age. Because optimal wound healing requires both appropriate macrophage infiltration and phagocytic activity, phagocytosis was examined. Compared to young mice, wound macrophages from aged mice exhibited a 37%-43% reduction in phagocytic capacity. Taken together, the data demonstrate age-related shifts in both macrophage and T cell infiltration into wounds, alterations in chemokine content, and a concurrent decline in wound macrophage phagocytic function. These alterations may contribute to the delayed repair response of aging.

Wound healing in MIP-1alpha(-/-) and MCP-1(-/-) mice.

A salient feature of normal wound healing is the development and resolution of an acute inflammatory response. Although much is known about the function of inflammatory cells within wounds, little is known about the chemotactic and activation signals that influence this response. As the CC chemokines macrophage inflammatory protein-1alpha (MIP-1alpha) and monocyte chemotactic protein-1 (MCP-1) are abundant in acute wounds, wound repair was examined in MIP-1alpha(-/-) and MCP-1(-/-) mice. Surprisingly, wound re-epithelialization, angiogenesis, and collagen synthesis in MIP-1alpha(-/-) mice was nearly identical to wild-type controls. In contrast, MCP-1(-/-) mice displayed significantly delayed wound re-epithelialization, with the greatest delay at day 3 after injury (28 +/- 5% versus 79 +/- 14% re-epithelialization, P < 0.005). Wound angiogenesis was also delayed in MCP-1(-/-) mice, with a 48% reduction in capillary density at day 5 after injury. Collagen synthesis was impeded as well, with the wounds of MCP-1(-/-) mice containing significantly less hydroxyproline than those of control mice (25 +/- 3 versus 50 +/- 8 microg/wound at day 5, P < 0.0001). No change in the number of wound macrophages was observed in MCP-1(-/-) mice, suggesting that monocyte recruitment into wounds is independent of this chemokine. The data suggest that MCP-1 plays a critical role in healing wounds, most likely by influencing the effector state of macrophages and other cell types.

Modulation of macrophage recruitment into wounds by monocyte chemoattractant protein-1.

Previous studies suggest that normal wound repair requires the regulated production of monocyte and macrophage chemoattractants. The current study examines the role of monocyte chemoattractant protein-1 (MCP-1) in coordinating monocyte recruitment into sites of injury. MCP-1 protein was detected in both incisional and excisional murine wounds, with a peak concentration occurring slightly before maximum macrophage infiltration. Compared to wounds treated with control antibody, wounds treated with a neutralizing monoclonal anti-MCP-1 antibody contained significantly fewer macrophages (8.2 +/- 0.9 vs. 14 +/- 1.7 macrophages per high power field, p < 0.05). Conversely, the addition of recombinant MCP-1 to wounds resulted in a substantial increase in the number of macrophages (107% to 124% increase over untreated wounds, p < 0.01). Because macrophages promote wound healing, the effect of recombinant MCP-1 on the wound healing process was examined. Incisional wounds (n = 12) were either left untreated or treated with vehicle alone, 5 ng recombinant MCP-1 in vehicle, or 50 ng recombinant MCP-1 in vehicle. Wound disruption strength was determined on days 7, 14, 21, and 28 for each group. Wounds treated with MCP-1 exhibited a slight increase in wound disruption strength at nearly all time points but this increase did not reach statistical significance. Addition of 100 ng of MCP-1 to excisional wounds did not have any significant effect on wound reepithelialization. Taken together, the results show that MCP-1 is produced within wounds at physiologic concentrations, and is an important positive regulator of macrophage recruitment into sites of injury. Addition of exogenous MCP-1 to wounds of normal mice yields only modest enhancement of the repair process.