Validation of Visual Objective Biomarkers for Acute Concussion.

Objective: Despite an increase in the awareness and diagnosis of mild traumatic brain injury (mTBI), there remains a paucity of data examining the comparative efficacy of available assessments. This study aims to validate visual functions as potential biomarkers for mTBI. Methods: This case-control correlational design utilizes military personnel diagnosed with acute (≤72 h post-injury) mTBI (n = 100) and age-matched controls (n = 100) to examine the relative effectiveness of the pupillary light reflex (PLR), near point of convergence (NPC) break, King-Devick (KD) test time, and Convergence Insufficiency Symptom Survey (CISS) score to discriminate between participants with mTBI. Results: Three of the eight PLR parameters (i.e., average constriction velocity (ACV), average dilation velocity (ADV), and 75% re-dilation time; all p < 0.001) were affected in mTBI participants. Similarly, NPC break, KD test time, and CISS scores showed a statistically significant difference between groups (all p < 0.001). Area under the curve showed that ADV (0.82) and NPC (0.74) have the higher predictive values of all objective parameters. Conclusions: ADV, ACV, and NPC break are objective visual functions markedly affected in the acute mTBI group compared with controls; therefore, we proposed that they could be used as biomarkers for acute mTBI.

The consequence of spatial visual processing dysfunction caused by traumatic brain injury (TBI).

OBJECTIVE: A bi-modal visual processing model is supported by research to affect dysfunction following a traumatic brain injury (TBI). TBI causes dysfunction of visual processing affecting binocularity, spatial orientation, posture and balance. Research demonstrates that prescription of prisms influence the plasticity between spatial visual processing and motor-sensory systems improving visual processing and reducing symptoms following a TBI. RATIONALE: The rationale demonstrates that visual processing underlies the functional aspects of binocularity, balance and posture. The bi-modal visual process maintains plasticity for efficiency. Compromise causes Post Trauma Vision Syndrome (PTVS) and Visual Midline Shift Syndrome (VMSS). Rehabilitation through use of lenses, prisms and sectoral occlusion has inter-professional implications in rehabilitation affecting the plasticity of the bi-modal visual process, thereby improving binocularity, spatial orientation, posture and balance Main outcomes: This review provides an opportunity to create a new perspective of the consequences of TBI on visual processing and the symptoms that are often caused by trauma. It also serves to provide a perspective of visual processing dysfunction that has potential for developing new approaches of rehabilitation. CONCLUSIONS: Understanding vision as a bi-modal process facilitates a new perspective of visual processing and the potentials for rehabilitation following a concussion, brain injury or other neurological events.

Visual Dysfunctions at Different Stages after Blast and Non-blast Mild Traumatic Brain Injury.

PURPOSE: To assess the prevalence of visual dysfunctions and associated symptoms in war fighters at different stages after non-blast- or blast-induced mild traumatic brain injury (mTBI). METHODS: A comprehensive retrospective review of the electronic health records of 500 U.S. military personnel with a diagnosis of deployment-related mTBI who received eye care at the Landstuhl Regional Medical Center. For analysis, the data were grouped by mechanism of injury, and each group was further divided in three subgroups based on the number of days between injury and initial eye examination. RESULTS: The data showed a high frequency of visual symptoms and visual dysfunctions. However, the prevalence of visual symptoms and visual dysfunctions did not differ significantly between mechanism of injury and postinjury stage, except for eye pain and diplopia. Among visual symptoms, binocular dysfunctions were more common, including higher near vertical phoria, reduced negative fusional vergence break at near, receded near point of convergence, decreased stereoacuity, and reduced positive relative accommodation. CONCLUSIONS: The lack of difference in terms of visual sequelae between subgroups (blast vs. nonblast) suggests that research addressing the assessment and management of mTBI visual sequelae resulting from civilian nonblast events is relevant to military personnel where combat injury results primarily from a blast event.

Hearing Loss and Tinnitus in Military Personnel with Deployment-Related Mild Traumatic Brain Injury.

The objective of this study was to analyze differences in incidence and epidemiologic risk factors for significant threshold shift (STS) and tinnitus in deployed military personnel diagnosed with mild traumatic brain injury (mTBI) due to either a blast exposure or nonblast head injury. A retrospective longitudinal cohort study of electronic health records of 500 military personnel (456 met inclusion criteria) diagnosed with deployment-related mTBI was completed. Chi-square tests and STS incidence rates were calculated to assess differences between blast-exposed and nonblast groups; relative risks and adjusted odds ratios of developing STS or tinnitus were calculated for risk factors. Risk factors included such characteristics as mechanism of injury, age, race, military occupational specialty, concurrent diagnosis of posttraumatic stress disorder (PTSD), and nicotine use. Among blast-exposed and nonblast patients, 67% and 58%, respectively, developed STS, (P=.06); 59% and 40%, respectively, developed tinnitus (P<.001). Incidence of STS was 24% higher in the blast-exposed than nonblast group. Infantry service was associated with STS; Marine Corps service, PTSD, and zolpidem use were associated with tinnitus. Unprotected noise exposure was associated with both STS and tinnitus. This study highlights potential risk factors for STS and tinnitus among blast-exposed and nonblast mTBI patient groups.

Assessment of the King-Devick® (KD) test for screening acute mTBI/concussion in warfighters.

OBJECTIVES: The Department of Defense reported that 344,030 cases of traumatic brain injury (TBI) were clinically confirmed from 2000 to 2015, with mild TBI (mTBI) accounting for 82.3% of all cases. Unfortunately, warfighters with TBI are often identified only when moderate or severe head injuries have occurred, leaving more subtle mTBI cases undiagnosed. This study aims to identify and validate an eye-movement visual test for screening acute mTBI. METHODS: Two-hundred active duty military personnel were recruited to perform the King-Devick® (KD) test. Subjects were equally divided into two groups: those with diagnosed acute mTBI (≤72h) and age-matched controls. The KD test was administered twice for test-retest reliability, and the outcome measure was total cumulative time to complete each test. RESULTS: The mTBI group had approximately 36% mean slower performance time with significant differences between the groups (p<0.001) in both tests. There were significant differences between the two KD test administrations in each group, however, a strong correlation was observed between each test administration. CONCLUSIONS: Significant differences in KD test performance were seen between the acute mTBI and control groups. The results suggest the KD test can be utilized for screening acute mTBI. A validated and rapidly administered mTBI screening test with results that are easily interpreted by providers is essential in making return-to-duty decisions in the injured warfighter.

A Performance Comparison of Color Vision Tests for Military Screening.

BACKGROUND: Current color vision (CV) tests used for aviation screening in the U.S. Army only provide pass-fail results, and previous studies have shown variable sensitivity and specificity. The purpose of this study was to evaluate seven CV tests to determine an optimal CV test screener that potentially could be implemented by the U.S. Army. METHODS: There were 133 subjects [65 Color Vision Deficits (CVD), 68 Color Vision Normal (CVN)] who performed all of the tests in one setting. CVD and CVN determination was initially assessed with the Oculus anomaloscope. Each test was administered monocularly and according to the test protocol. The main outcome measures were test sensitivity, specificity, and administration time (automated tests). RESULTS: Three of the four Pseudoisochromatic Plate (PIP) tests had a sensitivity/specificity > 0.90 OD/OS, whereas the FALANT tests had a sensitivity/specificity > 0.80 OD/OS. The Cone Contrast Test (CCT) demonstrated sensitivity/specificity > 0.90 OD/OS, whereas the Color Assessment and Diagnosis (CAD) test demonstrated sensitivity/specificity > 0.85 OD/OS. Comparison with the anomaloscope ("gold standard") revealed no significant difference of sensitivity and specificity OD/OS with the CCT, Dvorine PIP, and PIPC tests. Finally, the CCT administration time was significantly faster than the CAD test. DISCUSSION: The current U.S. Army CV screening tests demonstrated good sensitivity and specificity, as did the automated tests. In addition, some current PIP tests (Dvorine, PIPC), and the CCT performed no worse statistically than the anomaloscope with regard to sensitivity/specificity. The CCT letter presentation is randomized and results would not be confounded by potential memorization, or fading, of book plates.

Assessment of an Alternative Army Aircrew Eyewear.

BACKGROUND: Currently, Army aircrews needing refractive correction are issued the HGU-4/P aviator spectacles. However, a recently published survey found dissatisfaction with the current spectacle frame. The Aircrew Flight Frame (AFF) has been used by the Air Force for over 14 yr, with the AFF-OP (Operational) style used the longest. The purpose of this study was to evaluate AFF-OP performance and compatibility among U.S. Army aircrew under operational conditions. METHODS: At 1-, 6-, and 12-wk intervals, 73 Army aircrew members wore the AFF-OP eyewear and completed a Likert scale survey. There were 14 outcome measures surveyed, with the main outcome measure being frame preference. RESULTS: The AFF-OP was preferred significantly more than the HGU-4/P spectacle. Overall, 94% of aircrew responses preferred the AFF-OP and the three highest subjective reasons for AFF-OP preference were: 1) comfort around the ears without helmet or headset; 2) comfort around the ears with helmet or headset; and 3) the effect on ear cup seal. There were no statistically significant differences in responses over the three surveyed time intervals. DISCUSSION: Army aviation aircrew preferred the AFF-OP over the current HGU-4/P spectacles. Two of the top three highest subjective reasons for AFF-OP preference coincided with two of the top three operational eyewear problems reported in the recently published survey. If Army aircrew do not wear their issued eyewear, they may purchase their own frame "out of pocket." However, this can lead to use of a frame that has not been tested for compatibility and may compromise performance of aircrew life support equipment.

Effects of repetitive low-level blast exposure on visual system and ocular structures.

UNLABELLED: The purpose of this study was to determine whether repetitive exposure to low-level blasts during military breacher training produces acute and cumulative damage to the ocular tissues or visual system. The effects of low-level blast exposure on high-contrast visual acuity, contrast sensitivity, oculomotor function, color vision, visual field (VF), pupillary light reflex, corneal endothelial cell density (ECD), macular thickness, retinal nerve fiber layer thickness, and cup-to-disc ratio were assessed using a battery of standard clinical ophthalmic tests administered 10 times over a 2-year period. Data from nine breacher instructors (Cadre) were compared with data from four breacher engineers (CONTROL). The Cadre group showed higher vertical deviation at near than the CONTROL group over time. The VF mean deviation on the left eye that tended to be worse in the Cadre group was worse throughout the study, suggesting a decrease in VF sensitivity (Cadre: -0.20 +/- 0.15 dB; CONTROL: 1.05 +/- 0.15 dB; p = 0.03). The Cadre group had a reduced ECD (right eye: Cadre 2,502 cells/mm(2) vs CONTROL 2,808 cells/mm(2), p = 0.05; left eye: Cadre 2,558 cells/mm(2) vs CONTROL 2,892 cells/mm(2), p = 0.04). These results suggest that even low-level primary blast has the potential to produce occult eye injury.

Case report: waardenburg syndrome.

PURPOSE: A case of Waardenburg syndrome type 1 is described and relevant literature is reviewed to raise awareness about this rare syndrome, including the classification of each subtype and the differentiating clinical manifestations. CASE REPORT: A 44-year-old African-American female presented for a routine evaluation with hearing loss, dystopia canthorum (W index = 2.74), and almost complete gray hair. In addition, she presented with heterochromia irides, different fundus pigmentation between eyes. The patient did not have any upper limbs defect, cranial skeletal abnormalities, or intestinal disorders. CONCLUSION: Facial abnormalities and a white forelock are prominent features difficult to overlook during a routine ophthalmological examination. A careful medical history in patients with suspected Waardenburg syndrome is important to accurately classify this rare condition and to identify potential systemic implications associated to each subtype. The associated systemic complications can be addressed and managed through referral to the appropriate subspecialties.

Visual field dysfunctions in warfighters during different stages following blast and nonblast mTBI.

OBJECTIVES: Traumatic brain injury (TBI) is the leading injury coming out of the past decades' two major military conflicts, with mild TBI (mTBI) being the most commonly diagnosed form. The aim of this study was to assess the frequency and types of visual field (VF) defects seen at different testing stages following nonblast and blast-induced mTBI. METHODS: A comprehensive retrospective review was performed on 500 electronic health records for military personnel sustaining an mTBI during deployment, of which 166 patients were tested with both confrontation VF and 30-2 Humphrey Matrix Frequency Doubling Technology (FDT) perimetry. RESULTS: Scatter defects (48%) were the most predominantly found deficits in both blast and nonblast mTBI injury mechanisms and over postinjury test time frames. Confrontation VF was shown to be a poor qualitative predictor of VF defect. A profound decrease in VF sensitivity was noted in comparison to previously reported FDT normative data. Finally, a significant trend of decreasing VF defects was seen over time, indicating the potential usage of FDT as a visual biomarker for monitoring mTBI recovery. CONCLUSIONS: The findings of this study highlight the importance of performing threshold perimeter testing in those who have suffered an mTBI or concussion-like event.

Cerebellar ischemia manifesting as vertical diplopia: a case study on skew deviation.

PURPOSE: Skew deviation mimics superior oblique palsy. Associated findings can include ocular torsion, head tilt, headache, and neurologic symptoms that may help localize the responsible intracranial lesion. Accurate diagnosis is essential in determining and treating the underlying cause. Imaging options will be reviewed. CASE REPORT: A 29-year-old white male presented to the emergency room with sudden onset vertical diplopia after self-neck manipulation. An ophthalmic evaluation led to the diagnosis of skew deviation. Diagnostic imaging revealed an infarct of the cerebellum likely secondary to a vertebral artery dissection. Besides neck manipulation, other possible contributing factors include smoking, elevated cholesterol, and elevated testosterone. Symptoms resolved within 24 hours and the patient was treated with aspirin and atorvastatin calcium. CONCLUSIONS: Skew deviation must be a consideration in patients with vertical diplopia, and ruled out before a superior oblique palsy diagnosis. Vertebral artery dissections are uncommon in the general population but can account for up to 25% of ischemic strokes in the young and middle-aged. Smoking, high cholesterol, and high testosterone are known risk factors of stroke. Research is inconclusive on spinal manipulation's relation to stroke. This report presents an example of neck manipulation directly preceding skew deviation secondary to stroke.

Proposed objective visual system biomarkers for mild traumatic brain injury.

The challenge and search for objectively based biomarkers to assess for the presence of concussion/mild traumatic brain injury is a high priority for the military establishment. We present a documented overview of specific test areas and related targeted, high-yield, objectively based parameters that may be potential "vision biomarkers" for the detection of concussion/mild traumatic brain injury based on results from our laboratory and others, with emphasis on oculomotor aspects. These findings have military relevance with respect to the initial diagnosis in the battlefield and in the far-forward medical facilities, pre-/postdeployment issues, pre-/postvisual rehabilitation evaluation, fitness-for-duty assessment, and establishment of a return-to-duty timeline.

Oculomotor neurorehabilitation for reading in mild traumatic brain injury (mTBI): an integrative approach.

BACKGROUND: Considering the extensive neural network of the oculomotor subsystems, traumatic brain injury (TBI) could affect oculomotor control and related reading dysfunction. OBJECTIVE: To evaluate comprehensively the effect of oculomotor-based vision rehabilitation (OBVR) in individuals with mTBI. METHODS: Twelve subjects with mTBI participated in a cross-over, interventional study involving oculomotor training (OMT) and sham training (ST). Each training was performed for 6 weeks, 2 sessions a week. During each training session, all three oculomotor subsystems (vergence/accommodation/version) were trained in a randomized order across sessions. All laboratory and clinical parameters were determined before and after OMT and ST. In addition, nearvision-related symptoms using the Convergence Insufficiency Symptom Survey (CISS) scale and subjective visual attention using the Visual Search and Attention Test (VSAT) were assessed. RESULTS: Following the OMT, over 80% of the abnormal parameters significantly improved. Reading rate, along with the amplitudes of vergence and accommodation, improved markedly. Saccadic eye movements demonstrated enhanced rhythmicity and accuracy. The improved reading-related oculomotor behavior was reflected in reduced symptoms and increased visual attention. None of the parameters changed with ST. CONCLUSIONS: OBVR had a strong positive effect on oculomotor control, reading rate, and overall reading ability. This oculomotor learning effect suggests considerable residual neuroplasticity following mTBI.

Military aircrew eyewear survey: operational issues.

BACKGROUND: Army aircrew are required to operate under stressful conditions within a degraded visual environment. To gain an understanding of current eyewear mission needs, we surveyed aircrew regarding operational issues associated with the current U.S. Army-issue aircrew eyewear. METHODS: An anonymous online survey was completed by 976 U.S. Army aircrew personnel recruited through an invitational e-mail. RESULTS: Of the respondents, 34% reported wearing corrective lenses. Nearly 50% of them reported dissatisfaction with the HGU-4/P Aviator spectacles. The leading problems reported were discomfort (15%), "hot spots" around the ears (13%), and break of the earcup seal (11%). Nearly 41% of the respondents wore multifocal lenses and, of those, 16% reported that the HGU-4/P's restricted field of view (FOV) adversely affected duty performance. Of those who wore Modified HGU-4/P Apache spectacles, 79% had an unacceptable FOV with the helmet display unit. A similar number of aircrew modified the Apache eyewear to increase the FOV. In addition, wind and dust created eye discomfort or affected the vision of 46% of all respondents when performing flight duties. Over 82% expressed the need for an improved aircrew spectacles and 73% desired aviation-compatible protective eyewear. DISCUSSION: The current Army HGU-4/P Aviator and the Modified HGU-4/P Apache spectacles have significant operational deficiencies and compatibility issues. Such deficiencies have led to poor wear compliance and unauthorized modification of the Army-issue Aviator eyewear, posing readiness and safety issues. The results of this survey formally identify the need for military combat eye protection that is compatible with flight systems.

Visual dysfunctions and symptoms during the subacute stage of blast-induced mild traumatic brain injury.

The purpose of the present study was to assess the occurrence of visual dysfunctions and associated symptoms in active duty warfighters during the subacute stage of blast-induced mild traumatic brain injury (mTBI). A comprehensive visual and oculomotor function evaluation was performed on 40 U.S. military personnel, 20 with blast-induced mTBI and 20 without. In addition, a comprehensive symptom questionnaire was used to assess the frequency of visual, vestibular, and neuropsychiatric-associated symptoms. The most common mTBI-induced visual dysfunctions were associated with near oculomotor deficits, particularly large exophoria, decreased fusion ranges, receded near point of convergence, defective pursuit and saccadic eye movements, decreased amplitude of accommodation, and monocular accommodative facility. These were associated with reduced reading speed and comprehension and an increased Convergence Insufficiency Symptom Survey score. Photosensitivity was a common visual dysfunction along with hearing, balance, and neuropsychiatric symptoms. The oculomotor testing for warfighters suspected of blast-induced mTBI should include, at a minimum, the assessment of near lateral and vertical phorias, positive fusional vergence, stereoacuity, near point of convergence, amplitude of accommodation, monocular accommodative facility, saccades, and pursuit eye movements. A reading test should be included in all routine exams as a functional assessment of the integration of oculomotor functions.

Effectiveness of computerized oculomotor vision screening in a military population: pilot study.

The prevalence of oculomotor dysfunctions associated with blast-induced mild traumatic brain injury (mTBI) in warfighters has increased as a consequence of recent conflicts. This study evaluated the effectiveness of computerized oculomotor vision screening (COVS) in a military population. Oculomotor functions were assessed with COVS and by conventional methods in 20 U.S. military personnel with and 20 without mTBI. The validity of COVS was determined by Pearson correlation and Bland-Altman method or the kappa coefficient. The repeatability of the COVS was assessed with the coefficient of repeatability or the kappa coefficient. The results showed that COVS had high sensitivity and specificity for screening near oculomotor functions. Overall, the COVS showed excellent validity and repeatability for assessing near lateral and vertical phorias, Worth 4 Dot, and fixation, as well as pursuit and saccadic eye movements. Despite the strong Pearson correlation, the Bland-Altman analysis identified minor to moderate discrepancies for both positive and negative fusional vergence and their associated recovery as well as for the monocular accommodative facility measurements. This study demonstrated that non-eye-care professionals may be able to use the COVS as a tool to efficiently screen oculomotor functions in a military population with or without mTBI.

Dependence of corneal epithelial cell proliferation on modulation of interactions between ERK1/2 and NKCC1.

Epidermal growth factor (EGF) receptor stimulation or protein kinase C (PKC) activation enhances corneal epithelial cell proliferation. This response is needed to maintain corneal transparency and vision. We clarify here in human corneal epithelial cells (HCEC) the cause and effect relationships between ERK1/2 and NKCC1 phosphorylation induced by EGF receptor or PKC activation. Furthermore, the roles are evaluated of NF-κB and ERK1/2 in mediating negative feedback control of ERK1/2 and NKCC1 phosphorylation through modulating DUSP1 and DUSP6 expression levels. Intracellular Ca(2+) rises induced by EGF elicited NKCC1 phosphorylation through ERK1/2 activation. Bumetanide suppressed EGF-induced NKCC1 phosphorylation, transient cell swelling and cell proliferation. This cause and effect relationship is similar to that induced by PKC stimulation. NKCC1 activation occurred through time-dependent increases in protein-protein interaction between ERK1/2 and NKCC1, which were proportional to EGF concentration. DUSP6 upregulation obviated EGF and PKC-induced NKCC1 phosphorylation. NF-κB inhibition by PDTC prolonged ERK1/2 activation through GSK-3 inactivation leading to declines in DUSP1 expression levels. These results show that EGF receptor and PKC activation induce increases in HCEC proliferation through ERK1/2 interaction with NKCC1. This response is modulated by changes in DUSP1- and DUSP6-mediated negative feedback control of ERK1/2-induced NKCC1 phosphorylation.

Dependence of EGF-induced increases in corneal epithelial proliferation and migration on GSK-3 inactivation.

PURPOSE: This study was designed to determine in human corneal epithelial cells (HCEC) whether the balance between epidermal growth factor (EGF)-induced increases in proliferation and migration is dependent on the duration and magnitude of extracellular signal-regulated kinase (Erk)1/2 activation. METHODS: Western blot analysis evaluated the phosphorylation status of Erk1/2 and phosphoinositide 3-kinase (PI3-K) along with cell cycle kinases, paxillin, and mitogen kinase protein phosphatase (MKP)-1. Proliferation and migration rates were determined by [(3)H]-thymidine incorporation and scratch wound healing assay, respectively. RESULTS: EGF induced increases in paxillin Ser-126 phosphorylation and cyclin D1 expression through transient Erk1/2 phosphorylation. However, preinhibition of glycogen synthase kinase (GSK)-3 activation with 20 microM SB415286 prolonged and augmented this Erk1/2 response to EGF but decreased cyclin D1 expression, whereas p27Kip1 levels rose. In turn, the mitogenic response fell, whereas paxillin phosphorylation occurred 45 minutes sooner than without SB415286. In contrast, blocking PI3-K activation with LY294002 (50 microM) eliminated EGF-induced GSK-3 inhibition and Erk1/2 phosphorylation as well as increases in proliferation and migration. SB415286 or U0126 (10 microM) suppression of Erk1/2 phosphorylation blocked EGF-induced MKP-1 phosphorylation. Inhibition of EGF-induced increases in proliferation and migration by LY294002 was associated with sustained MKP-1 phosphorylation induced by GSK-3. Prolonging MKP-1 phosphorylation by LY294002 increased p27Kip1, whereas cyclin D1 levels fell. CONCLUSIONS: GSK-3-induced MKP-1 phosphorylation mediates negative feedback control between EGF receptor-linked PI3-K and ERK signaling pathways. Inhibition of such control prolongs Erk1/2 activation and alters the balance between EGF-induced increases in proliferation and migration. Therefore, these responses to EGF can be modulated through altering the feedback between these two pathways.

Potassium-chloride cotransporter mediates cell cycle progression and proliferation of human corneal epithelial cells.

Epidermal growth factor (EGF)-induced proliferation of corneal epithelial cells contributes to its renewal, which maintains the protective and refractive properties of the cornea. This study characterized in human corneal epithelial cells (HCEC) the role of the potassium-chloride cotransporter (KCC) in mediating (1) EGF-induced mitogen-activated protein kinase (MAPK) pathway activation; (2) increases in cell cycle progression; and (3) proliferation. The KCC inhibitor [(dihydroindenyl)oxy] alkanoic acid (DIOA) and KCC activator N-ethylmaleimide (NEM), suppressed and enhanced EGF-induced p44/42MAPK activation, respectively. Such selective modulation was mirrored by corresponding changes in cell proliferation and shifts in cell cycle distribution. DIOA induced a 20% increase in G(0)/G(1)-phase cell population, whereas NEM induced a 22% increase in the proportion of cells in the G(2)/M-phase and accelerated the transition from G(0)/G(1)-phase to the S-phase. Associated with these changes, KCC1 content in a plasma membrane enriched fraction increased by 300%. Alterations in regulatory volume capacity were associated with corresponding changes in both KCC1 membrane content and activity. These results indicate that EGF-induced increases in KCC1 activity and content modulate cell volume changes required for (1) activation of the p44/42MAPK signaling pathway, (2) cell cycle progression, and (3) increases in cell proliferation.

Transient receptor potential vanilloid 1 activation induces inflammatory cytokine release in corneal epithelium through MAPK signaling.

In certain epithelial tissues, activation of transient receptor potential (TRP) vanilloid subtype 1 (TRPV1) by noxious stimuli induces pro-inflammatory cytokine release, which helps to mitigate the challenge. While the corneal epithelium elicits such responses to a variety of challenges, it remains unknown whether TRPV1 mediates pro-inflammatory cytokine secretion. Accordingly, we probed for TRPV1 expression and function in human (HCEC) and rabbit corneal epithelial cell (RCEC) lines, in their primary counterparts, and in human and mouse corneal epithelium in situ. Cell membrane and perinuclear TRPV1 expression was detected in all preparations and its identity verified by Western blot analysis. Capsaicin (CAP) (1-10 microM) increased nonselective cation channel whole cell currents (2.5-fold +/- 0.5-fold between -60 and 130 mV), resulting in calcium transients that were fully blocked by the TRPV1 antagonists capsazepine (CPZ) and ruthenium red, or removal of extracellular calcium. Another signaling event involved transient activation of global mitogen-activated protein kinase (MAPK) superfamily, which was followed by up to 3.3- and 9-fold increases in interleukins (IL)-6 and -8 release, respectively. Such increases in inflammatory mediators' release were suppressed by exposure to CPZ or MAPK inhibitors, or removal of Ca2+. Taken together, TRPV1 receptors may play a role in mediating corneal epithelial inflammatory mediator secretion and subsequent hyperalgesia.