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Neural Regeneration Research Aug 2017The cornea has unique features that make it a useful model for regenerative medicine studies. It is an avascular, transparent, densely innervated tissue and any... (Review)
Review
The cornea has unique features that make it a useful model for regenerative medicine studies. It is an avascular, transparent, densely innervated tissue and any pathological changes can be easily detected by slit lamp examination. Corneal sensitivity is provided by the ophthalmic branch of the trigeminal nerve that elicits protective reflexes such as blinking and tearing and exerts trophic support by releasing neuromediators and growth factors. Corneal nerves are easily evaluated for both function and morphology using standard instruments such as corneal esthesiometer and confocal microscope. All local and systemic conditions that are associated with damage of the trigeminal nerve cause the development of neurotrophic keratitis, a rare degenerative disease. Neurotrophic keratitis is characterized by impairment of corneal sensitivity associated with development of persistent epithelial defects that may progress to corneal ulcer, melting and perforation. Current neurotrophic keratitis treatments aim at supporting corneal healing and preventing progression of corneal damage. Novel compounds able to stimulate corneal nerve recovery are in advanced development stage. Among them, nerve growth factor eye drops showed to be safe and effective in stimulating corneal healing and improving corneal sensitivity in patients with neurotrophic keratitis. Neurotrophic keratitis represents an useful model to evaluate in clinical practice novel neuro-regenerative drugs.
PubMed: 28966630
DOI: 10.4103/1673-5374.213534 -
Investigative Ophthalmology & Visual... Aug 2023Aged C57BL/6J (B6) mice have increased levels of cathepsin S, and aged cathepsin S (Ctss-/-) knockout mice are resistant to age-related dry eye. This study investigated...
PURPOSE
Aged C57BL/6J (B6) mice have increased levels of cathepsin S, and aged cathepsin S (Ctss-/-) knockout mice are resistant to age-related dry eye. This study investigated the effects of cathepsin S inhibition on age-related dry eye disease.
METHODS
Female B6 mice aged 15.5 to 17 months were randomized to receive a medicated diet formulated by mixing the RO5461111 cathepsin S inhibitor or a standard diet for at least 12 weeks. Cornea mechanosensitivity was measured with a Cochet-Bonnet esthesiometer. Ocular draining lymph nodes and lacrimal glands (LGs) were excised and prepared for histology or assayed by flow cytometry to quantify infiltrating immune cells. The inflammatory foci (>50 cells) were counted under a 10× microscope lens and quantified using the focus score. Goblet cell density was investigated in periodic acid-Schiff stained sections. Ctss-/- mice were compared to age-matched wild-type mice.
RESULTS
Aged mice subjected to cathepsin S inhibition or Ctss-/- mice showed improved conjunctival goblet cell density and cornea mechanosensitivity. There was no change in total LG focus score in the diet or Ctss-/- mice, but there was a lower frequency of CD4+IFN-γ+ cell infiltration in the LGs. Furthermore, aged Ctss-/- LGs had an increase in T central memory, higher numbers of CD19+B220-, and fewer CD19+B220+ cells than wild-type LGs.
CONCLUSIONS
Our results indicate that therapies aimed at decreasing cathepsin S can ameliorate age-related dry eye disease with a highly beneficial impact on the ocular surface. Further studies are needed to investigate the role of cathepsin S during aging.
Topics: Animals; Female; Mice; Disease Models, Animal; Dry Eye Syndromes; Lacrimal Apparatus; Mice, Inbred C57BL; Mice, Knockout; Phenotype; Tears
PubMed: 37540176
DOI: 10.1167/iovs.64.11.7 -
Biomedical Engineering Online May 2016Laryngo-pharyngeal mechano-sensitivity (LPMS) is involved in dysphagia, sleep apnea, stroke, irritable larynx syndrome and cough hypersensitivity syndrome among other...
BACKGROUND
Laryngo-pharyngeal mechano-sensitivity (LPMS) is involved in dysphagia, sleep apnea, stroke, irritable larynx syndrome and cough hypersensitivity syndrome among other disorders. These conditions are associated with a wide range of airway reflex abnormalities. However, the current device for exploring LPMS is limited because it assesses only the laryngeal adductor reflex during fiber-optic endoscopic evaluations of swallowing and requires a high degree of expertise to obtain reliable results, introducing intrinsic expert variability and subjectivity.
METHODS
We designed, developed and validated a new air-pulse laryngo-pharyngeal endoscopic esthesiometer with a built-in laser range-finder (LPEER) based on the evaluation and control of air-pulse variability determinants and on intrinsic observer variability and subjectivity determinants of the distance, angle and site of stimulus impact. The LPEER was designed to be capable of delivering precise and accurate stimuli with a wide range of intensities that can explore most laryngo-pharyngeal reflexes.
RESULTS
We initially explored the potential factors affecting the reliability of LPMS tests and included these factors in a multiple linear regression model. The following factors significantly affected the precision and accuracy of the test (P < 0.001): the tube conducting the air-pulses, the supply pressure of the system, the duration of the air-pulses, and the distance and angle between the end of the tube conducting the air-pulses and the site of impact. To control all of these factors, an LPEER consisting of an air-pulse generator and an endoscopic laser range-finder was designed and manufactured. We assessed the precision and accuracy of the LPEER's stimulus and range-finder according to the coefficient of variation (CV) and by looking at the differences between the measured properties and the desired values, and we performed a pilot validation on ten human subjects. The air-pulses and range-finder exhibited good precision and accuracy (CV < 0.06), with differences between the desired and measured properties at <3 % and a range-finder measurement error of <1 mm. The tests in patients demonstrated obtainable and reproducible thresholds for the laryngeal adductor, cough and gag reflexes.
CONCLUSIONS
The new LPEER was capable of delivering precise and accurate stimuli for exploring laryngo-pharyngeal reflexes.
Topics: Aged; Aged, 80 and over; Air; Endoscopy; Equipment Design; Female; Humans; Larynx; Male; Middle Aged; Pharynx; Pressure; Reflex; Sensation
PubMed: 27160751
DOI: 10.1186/s12938-016-0166-1 -
BMJ Open Aug 2017Patients with obstructive sleep apnoea hypopnoea syndrome (OSA) might have varying degrees of laryngopharyngeal mechanical hyposensitivity that might impair the brain's... (Randomized Controlled Trial)
Randomized Controlled Trial
Accuracy and reliability of the sensory test performed using the laryngopharyngeal endoscopic esthesiometer and rangefinder in patients with suspected obstructive sleep apnoea hypopnoea: protocol for a prospective double-blinded, randomised, exploratory study.
INTRODUCTION
Patients with obstructive sleep apnoea hypopnoea syndrome (OSA) might have varying degrees of laryngopharyngeal mechanical hyposensitivity that might impair the brain's capacity to prevent airway collapse during sleep. However, this knowledge about sensory compromises in OSA comes from studies performed using methods with little evidence of their validity. Hence, the purpose of this study is to assess the reliability and accuracy of the measurement of laryngopharyngeal mechanosensitivity in patients with OSA using a recently developed laryngopharyngeal endoscopic esthesiometer and rangefinder (LPEER).
METHODS AND ANALYSIS
The study will be prospective and double blinded, with a randomised crossover assignment of raters performing the sensory tests. Subjects will be recruited from patients with suspected OSA referred for baseline polysomnography to a university hospital sleep laboratory. Intra-rater and inter-rater reliability will be evaluated using the Bland-Altman's limits of agreement plot, the intraclass correlation coefficient, and the Pearson or Spearman correlation coefficient, depending on the distribution of the variables. Diagnostic accuracy will be evaluated plotting ROC curves using standard baseline polysomnography as a reference. The sensory threshold values for patients with mild, moderate and severe OSA will be determined and compared using ANOVA or the Kruskal-Wallis test, depending on the distribution of the variables. The LPEER could be a new tool for evaluating and monitoring laryngopharyngeal sensory impairment in patients with OSA. If it is shown to be valid, it could help to increase our understanding of the pathophysiological mechanisms of this condition and potentially help in finding new therapeutic interventions for OSA.
ETHICS AND DISSEMINATION
The protocol has been approved by the Institutional Review Board of Fundacion Neumologica Colombiana. The results will be disseminated through conference presentations and peer-reviewed publication.
TRIAL REGISTRATION
This trial was registered at Clinical Trials Accuracy of the sensory test using the lLaryngopharyngeal endoscopic esthesiometer in obstructive sleep apnea. Protocol ID: 201611-22405. ClinicalTrials.gov ID: NCT03109171.
Topics: Colombia; Cross-Over Studies; Double-Blind Method; Endoscopy; Hospitals, University; Humans; Larynx; Pharynx; Polysomnography; Prospective Studies; ROC Curve; Reproducibility of Results; Research Design; Sensory Thresholds; Sleep Apnea, Obstructive
PubMed: 28827237
DOI: 10.1136/bmjopen-2016-015235 -
Ophthalmic Plastic and Reconstructive...Corneal neurotization is a fast-evolving surgical procedure for sensory reinnervation in neurotrophic keratopathy. After neurotization, prior reports document return of...
Corneal neurotization is a fast-evolving surgical procedure for sensory reinnervation in neurotrophic keratopathy. After neurotization, prior reports document return of corneal sensation on average 8 months after surgery with 38 mm of sensation gain measured via cochet bonnet esthesiometer testing. Here, the authors describe a dual nerve grafting approach via simultaneous parallel sural nerve grafts from both the supratrochelar and supraorbital nerves to the affected contralateral cornea with return of sensation by postoperative week 11.
Topics: Cornea; Corneal Diseases; Humans; Nerve Regeneration; Nerve Transfer; Transplantation, Autologous; Trigeminal Nerve Diseases
PubMed: 34652308
DOI: 10.1097/IOP.0000000000002064 -
PloS One 2020Ocular somatosensory-autonomic reflexes play critical roles in maintaining homeostasis of the eye. The purpose of this study was to investigate the pupil response to...
PURPOSE
Ocular somatosensory-autonomic reflexes play critical roles in maintaining homeostasis of the eye. The purpose of this study was to investigate the pupil response to nociceptive corneal stimuli.
METHODS
A Waterloo-Belmonte pneumatic esthesiometer was used to determine detection thresholds and randomly deliver mechanical and chemical stimuli from levels of detection threshold to twice the threshold in 50% steps to the central cornea of 15 healthy subjects. For each stimulus, imaging of the stimulated/unstimulated eye was performed using two modified/calibrated Logitech c920 digital cameras for 4 seconds each, pre/post stimulus capture. The data were processed with a custom segmentation algorithm to help identify the pupils and pupil diameter was measured using ImageJ software. Pupil dilation response differences between the ipsi- and contralateral eye was analyzed using dependent t-tests. The effect of stimulus intensity, modality and sex of subjects were analyzed using repeated measures.
RESULTS
In mechanical and chemical stimulation experiments, there was no difference in pupil responses between the stimulated eye and the unstimulated eye, (all dependent T-test p > 0.05). On average, pupil diameter increased from baseline as the corneal stimulus intensity increased. This happened regardless of whether mechanical or chemical stimulation occurred (ANOVA p < 0.05). At 200% threshold, pupil diameter was greater than at all stimulus intensities (Tukey HSD, all p < 0.05). Based on stimulus intensity, females had greater pupil diameters than males at levels of 150% threshold and 200% threshold (ANOVA p < 0.05, all Tukey HSD p < 0.05).
CONCLUSION
This study serves as a basis for the characterization of the local stimulus-response neural circuitry relating nociceptive stimuli to autonomic responses and in combination with our work on completely separate autonomic circuits of bulbar conjunctival vessel dilation and reflex tearing suggests that the monotonic measurements of redness, tearing and pupils provide accurate, separable responses that reflect painful stimulus intensity.
Topics: Adult; Carbon Dioxide; Cornea; Female; Humans; Male; Nociception; Physical Stimulation; Pupil; Reflex, Pupillary; Sensory Thresholds; Young Adult
PubMed: 31951635
DOI: 10.1371/journal.pone.0227771 -
Investigative Ophthalmology & Visual... Jun 2021The cornea is richly innervated by the trigeminal ganglion (TG) and its function supported by secretions from the adjacent lacrimal (LG) and meibomian glands (MG). In...
PURPOSE
The cornea is richly innervated by the trigeminal ganglion (TG) and its function supported by secretions from the adjacent lacrimal (LG) and meibomian glands (MG). In this study we examined how pigment epithelium-derived factor (PEDF) gene deletion affects the cornea structure and function.
METHODS
We used PEDF hemizygous and homozygous knockout mice to study effects of PEDF deficiency on corneal innervation assessed by beta tubulin staining, mRNA expression of trophic factors, and PEDF receptors by adjacent supporting glands, corneal sensitivity measured using a Cochet-Bonnet esthesiometer, and tear production using phenol red cotton thread wetting.
RESULTS
Loss of PEDF was accompanied by reduced corneal innervation and sensitivity, increased corneal surface injury and tear production, thinning of the corneal stroma and loss of stromal cells. PEDF mRNA was expressed in the cornea and its supporting tissues, the TG, LG, and MG. Deletion of one or both PEDF alleles resulted in decreased expression of essential trophic support in the TG, LG, and MG including nerve growth factor, brain-derived neurotrophic growth factor, and GDNF with significantly increased levels of NT-3 in the LG and decreased EGF expression in the cornea. Decreased transcription of the putative PEDF receptors, adipose triglyceride lipase, lipoprotein receptor-related protein 6, laminin receptor, PLXDC1, and PLXDC2 was also evident in the TG, LG and MG with the first three showing increased levels in corneas of the Pedf+/- and Pedf-/- mice compared to wildtype controls. Constitutive inactivation of ERK1/2 and Akt was pronounced in the TG and cornea, although their protein levels were dramatically increased in Pedf-/- mice.
CONCLUSIONS
This study highlights an essential role for PEDF in corneal structure and function and confirms the reported rescue of exogenous PEDF treatment in corneal pathologies. The pleiotropic effects of PEDF deletion on multiple trophic factors, receptors and signaling molecules are strong indications that PEDF is a key coordinator of molecular mechanisms that maintain corneal function and could be exploited in therapeutic options for several ocular surface diseases.
Topics: Animals; Cornea; Corneal Diseases; Corneal Injuries; Eye Proteins; Gene Deletion; Humans; Mice; Mice, Knockout; Nerve Growth Factors; Protease Inhibitors; Receptors, Neuropeptide; Serpins; Tears; Trigeminal Ganglion; Tubulin; Visual Perception
PubMed: 34132748
DOI: 10.1167/iovs.62.7.18 -
Research Square May 2023To analyze corneal sensitivity with a new noncontact and hand-held esthesiometer (Brill Engines, Spain) in patients with dry eye disease (DED) and patients on...
OBJECTIVES
To analyze corneal sensitivity with a new noncontact and hand-held esthesiometer (Brill Engines, Spain) in patients with dry eye disease (DED) and patients on hypotensive drops, and to compare it with healthy subjects.
METHODS
31 patients (57 eyes) with DED, 23 patients (46 eyes) with glaucoma and 21 healthy patients (33 eyes) were recruited. In all patients, corneal sensitivity was measured. Subsequently, a keratography test (Keratograph 5M, Oculus) was carried out to measure tear meniscus height (TMH), non-invasive break up time (NIBUT), bulbar redness (Jenvis scale) and corneal staining (CS, Oxford scale). Both corneal sensitivity and ocular surface parameters were compared between DED, glaucoma, and healthy subjects. Linear mixed models were constructed to utilize data from both eyes of patients. A 95% confidence level was considered statistically significant.
RESULTS
The mean age was 56.1±16.1 years in DED group, 69.5±11.7 years in the glaucoma group and 36.3±10.5 years in the control group. Adjusting for age and sex, esthesiometry was significantly worse in DED and glaucoma vs control group (p = 0.02 and p = 0.009, respectively). NIBUT was lower in DED and glaucoma patients (p < 0.001 and p = 0.001, respectively). Redness and CS values were higher in DED group (p = 0.04 and p = 0.001, respectively). TMH was lower in the glaucoma patients (p = 0.03).
CONCLUSIONS
Corneal sensitivity measured with a novel noncontact esthesiometer was reduced in DED and glaucoma patients compared to controls. In clinical practice, this esthesiometer could be an easy-to-use device to evaluate for patients with subclinical neurotrophic keratopathy.
PubMed: 37292809
DOI: 10.21203/rs.3.rs-2833826/v1 -
The Korean Journal of Pain Jan 2022Thrombospondin-4 (TSP4) upregulates in the spinal cord following peripheral nerve injury and contributes to the development of neuropathic pain (NP). We investigated the...
BACKGROUND
Thrombospondin-4 (TSP4) upregulates in the spinal cord following peripheral nerve injury and contributes to the development of neuropathic pain (NP). We investigated the effects of cyanocobalamin alone or in combination with morphine on pain and the relationship between these effects and spinal TSP4 expression in neuropathic rats.
METHODS
NP was induced by chronic constriction injury (CCI) of the sciatic nerve. Cyanocobalamin (5 and 10 mg/kg/day) was administered 15 days before CCI and then for 4 and 14 postoperative days. Morphine (2.5 and 5 mg/kg/day) was administered only post-CCI. Combination treatment included cyanocobalamin and morphine, 10 and 5 mg/kg/day, respectively. All drugs were administered intraperitoneally. Nociceptive thresholds were detected by esthesiometer, analgesia meter, and plantar test, and TSP4 expression was assessed by western blotting and fluorescence immunohistochemistry.
RESULTS
CCI decreased nociceptive thresholds in all tests and induced TSP4 expression on the 4th postoperative day. The decrease in nociceptive thresholds persisted except for the plantar test, and the increased TSP4 expression reversed on the 14th postoperative day. Cyanocobalamin and low-dose morphine alone did not produce any antinociceptive effects. High-dose morphine improved the decreased nociceptive thresholds in the esthesiometer when administered alone but combined with cyanocobalamin in all tests. Cyanocobalamin and morphine significantly induced TSP4 expression when administered alone in both doses for 4 or 14 days. However, this increase was less when the two drugs are combined.
CONCLUSIONS
The combination of cyanocobalamin and morphine is more effective in antinociception and partially decreased the induced TSP4 expression compared to the use of either drug alone.
PubMed: 34966013
DOI: 10.3344/kjp.2022.35.1.66