Impact of Air Pollution on the Ocular Surface and Tear Cytokine Levels: A Multicenter Prospective Cohort Study.

Purpose: To assess air pollution-induced changes on ocular surface and tear cytokine levels. Methods: As a prospective multicenter cohort study, 387 dry eye disease (DED) participants were recruited from five provinces in China and underwent measurements of ocular surface disease index (OSDI), Schirmer's I test (ST), tear meniscus height (TMH), tear film break-up time (TBUT), corneal fluorescein staining (CFS), meibomian gland (MG) function, and tear cytokines. The associations between ocular surface parameters and exposure to particulate matter (PM), ozone (O3), nitrogen dioxide (NO2), and sulfur dioxide (SO2) for 1 day, 1 week, and 1 month before the examination were analyzed in single- and multi-pollutant models adjusted for confounding factors. Results: In the multi-pollutant model, the OSDI score was positively correlated with PM with diameter ≤2.5 µm (PM2.5), O3, and SO2 exposure [PM2.5: ß (1 week/month) = 0.229 (95% confidence interval (CI): 0.035-0.424)/0.211 (95% CI: 0.160-0.583); O3: ß (1 day/week/month) = 0.403 (95% CI: 0.229-0.523)/0.471 (95% CI: 0.252-0.693)/0.468 (95% CI: 0.215-0.732); SO2: ß (1 day/week) = 0.437 (95% CI: 0.193-0.680)/0.470 (95% CI: 0.040-0.901)]. Tear secretion was negatively correlated with O3 and NO2 exposures but positively correlated with PM2.5 levels. Air pollutants were negatively correlated with TBUT and positively related with CFS score. Besides SO2, all other pollutants were associated with aggravated MG dysfunction (MG expression, secretion, and loss) and tear cytokines increasement, such as PM2.5 and interleukin-8 (IL-8) [ß (1 day) = 0.016 (95% CI: 0.003-0.029)], PM with diameter ≤10 µm (PM10) and IL-6 [ß (1 day) = 0.019 (95% CI: 0.006-0.033)], NO2 and IL-6 [ß (1 month) = 0.045 (95% CI: 0.018-0.072)], among others. The effects of air pollutants on DED symptoms/signs, MG functions and tear cytokines peaked within 1 week, 1 month, and 1 day, respectively. Conclusion: Increased PM2.5, O3, and SO2 exposures caused ocular discomfort and damage with tear film instability. PM10 exposure led to tear film instability and ocular injury. PM, O3, and NO2 exposures aggravated MG dysfunction and upregulated tear cytokine levels. Therefore, each air pollutant may influence DED via different mechanisms within different time windows.

The effects of short-term and long-term air pollution exposure on meibomian gland dysfunction.

We aim to assess the effects of different air pollutants on meibomian gland dysfunction (MGD). As a prospective multicenter study, 864 patients were recruited from four different regions (i.e., coal, oil, steel, and living). The oil region had a significantly lower temperature and higher O3 and SO2 concentrations than other regions. Notably, participants in oil region presented with more frequent and serious MGD signs and higher cytokine levels (median interleukin 6 [IL-6] in oil: 2.66, steel: 0.96, coal: 0.38, living: 0.56; IL-8 in oil: 117.52, steel: 46.94, coal: 26.89, living: 33; vascular endothelial growth factor [VEGF] in oil: 25.09, steel: 14.02, coal: 14.02, living: 28.47). The short-term fluctuations of cytokine levels were associated with the changes in gas levels (PM2.5 and IL-8: ß = 0.016 [0.004-0.029]; O3 and IL-6: ß = 0.576 [0.386-0.702]; O3 and IL-8: ß = 0.479 [0.369-0.890]; SO2 and VEGF: ß = 0.021 [0.001-0.047]). After long-term exposure, lid margin neovascularization (r = 0.402), meibomian gland (MG) expression (r = 0.377), MG secretion (r = 0.303), MG loss (r = 0.404), and tear meniscus height (r = - 0.345) were moderately correlated with air quality index (AQI). Individuals in oil region had more serious MGD signs and higher cytokine levels. MGD is susceptible to long-term exposure to high AQI.

Validation and comparison of the National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25) and the Visual Function Index-14 (VF-14) in patients with cataracts: a multicentre study.

PURPOSE: The present study aimed to investigate and compare the psychometric properties of the National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25) and the Visual Function Index-14 (VF-14) in a large sample of patients with cataracts. METHODS: A total of 1052 patients with bilateral age-related cataracts were recruited in the study. Patients with other comorbidities that severely impacted vision were excluded. Participants completed the two questionnaires in random order. Classical test theory and Rasch analyses were used to assess the psychometric properties of the questionnaires. RESULTS: Complete data were obtained from 899 patients. The mean overall index score on the NEI VFQ-25 was 76.1 ± 19.0, while that on the VF-14 was 46.5 ± 15.0. Cronbach's α-values for the NEI VFQ-25 and VF-14 were 0.89 and 0.95, respectively. Ceiling effects were observed on nine of the 12 subscales in the NEI VFQ-25. The correlation between total scores on the NEI VFQ-25 and VF-14 was moderate (r = 0.600; p < 0.001), and subscales of the NEI VFQ-25 were weakly or moderately correlated with the similar domains on the VF-14. Rasch analysis revealed ordered category thresholds and sufficient person separation for both instruments, while the two questionnaires had critical deficiencies in unidimensionality, targeting and differential item functioning. CONCLUSION: Neither the NEI VFQ-25 nor VF-14 is optimal for the assessment of vision-related quality of life in typical Chinese patients with cataracts. The potential deficiencies of the questionnaires should be taken into consideration prior to application of the instruments or interpretation of the results.

Activation and Blockade of Serotonin-4 Receptors in the Lateral Habenula Produce Antidepressant Effects in the Hemiparkinsonian Rat.

BACKGROUND: The 5-hydroxytryptamine (5-HT) neurotransmitter system and lateral habenula (LHb) are involved in the regulation of depression, while the mechanisms remain to be clarified. OBJECTIVES: The effects and possible mecha-nism underlying activation or blockade of 5-HT4 receptors (5-HT4Rs) in the LHb in depression were investigated by behavioral and neurochemical methods based on a Parkinson's disease (PD) rat model. METHOD: 6-Hydroxydopamine (6-OHDA) was injected unilaterally into the substantia nigra pars compacta to establish the PD rat model. The depressive-like behaviors were measured by the forced swimming test (FST) and sucrose preference test (SPT). The concentrations of dopamine (DA), noradrenaline (NA) and 5-HT in the related brain regions were measured by a neurochemical method. RESULTS: The 6-OHDA lesions increased the immobility time in the FST and decreased the sucrose consumption in the SPT, suggesting the induction of depressive-like behaviors. Intra-LHb injection of BIMU-8 (5-HT4R agonist) or GR113808 (5-HT4R antagonist) produced antidepressant effects in the lesioned rats. Intra-LHb injection of BIMU-8 significantly increased the DA levels in the medial prefrontal cortex (mPFC) and ventral hippocampus (vHip), increased the 5-HT level in the mPFC and decreased the NA level in the vHip only in the lesioned rats, while intra-LHb injection of GR113808 changed DA, NA and 5-HT levels in the mPFC, LHb and vHip in both sham and the lesioned rats. CONCLUSIONS: All these results suggest that activation or blockade of the LHb 5-HT4Rs produce antidepressant effects in the 6-OHDA-lesioned rats, which are related to the changes of monoamines in the limbic and limbic-related regions.

The Association between Socioeconomic Factors and Visual Function among Patients with Age-Related Cataracts.

BACKGROUND: With the development of the economy, socioeconomic factors, such as inequalities in the status of regional economies and the subsequent effects on health systems, have influenced the status of health. We explored the association between age-related cataracts and socioeconomic indicators, including the regional economy, health systems, and energy industries. METHODS: This was a prospective, multicenter, Chinese population-based, cross-sectional study. A total of 830 participants from seven centers were enrolled. Data on the best-corrected visual acuity (BCVA), Lens Opacities Classification System III (LOCS III) score, Visual Function Index-14 (VF-14) score, total and subscale scores of the 25-item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25), per capita disposable income (PCDI), medical resource-related indicators, and investments in the energy industry were obtained. Associations among these parameters were analyzed. RESULTS: The PCDI ranking was correlated with the VF-14 score (R = -0.426, P < 0.01), total score of NEI-VFQ-25 (r = -0.500, P < 0.01), and BCVA (r = 0.278, P < 0.01). The number of health agencies (r1 = 0.267, r2 = -0.303, r3 = -0.291,), practicing or assistant practicing doctors (r1 = -0.283, r2 = 0.427, r3 = 0.502,), registered nurses (r1 = -0.289, r2 = 0.409, r3 = 0.469, P < 0.01), and health technicians (r1 = -0.278, r2 = 0.426, r3 = 0.500, P < 0.01) per 10,000 of the population was each correlated with the BCVA, VF-14 score, and total score of NEI-VFQ-25, respectively. Health expenditure per capita was correlated with the VF-14 score (r = 0.287, P < 0.01) and total score of NEI-VFQ-25 (r = 0.459, P < 0.01). The LOCS III P score was correlated with investments in the energy industry (r = 0.485, P < 0.001). CONCLUSIONS: Patients in higher economic regions with greater medical resources show a greater demand to undergo cataract surgery at a better subjective and objective visual function. The energy industry has a significant effect on cataracts, especially the posterior subcapsular cataract, and thus more attention should be paid to people in regions with abundant energy industries.

Activation of calcium-impermeable GluR2-containing AMPA receptors in the lateral habenula produces antidepressant-like effects in a rodent model of Parkinson's disease.

Evidence indicates that depression is closely related to hyperactivity of the lateral habenula (LHb). However, it is not clear how activation and blockade of AMPA receptors (AMPARs) in the LHb affect depressive-like behaviors, particularly in Parkinson's disease-related depression. In this study, unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc) in rats induced depressive-like behaviors and led to hyperactivity of LHb neurons compared to SNc sham-lesioned rats. Interestingly, intra-LHb injection of AMPAR agonist (S)-AMPA produced antidepressant-like effects in the two groups of rats and antagonist NBQX induced depressive-like behaviors, although (S)-AMPA excited LHb neurons and NBQX inhibited these neurons. We further found that intra-LHb injection of (S)-AMPA excited dopaminergic neurons in the anterior ventral tegmental area (aVTA) and serotonergic neurons in the dorsal raphe nucleus (DRN), which increased release of DA and 5-HT in the medial prefrontal cortex (mPFC), while NBQX induced the opposite effects. Further, lesioning the GABAergic rostromedial tegmental nucleus did not alter the proportions of the responses of these neurons to AMPAR stimulation. Additionally, lesions of the SNc reduced the level of p-GluR2-S880 in the LHb, which can increase the surface expression of calcium-impermeable GluR2-containing AMPARs (CI-AMPARs). This change in SNc-lesioned rats enhanced effects of (S)-AMPA and NBQX on the behaviors, LHb neuronal firing and release of DA and 5-HT. Collectively, antidepressant-like effects produced by (S)-AMPA attribute to activation of LHb neurons expressing CI-AMPAR, which excites aVTA dopaminergic neurons and DRN serotonergic neurons via the direct projection, thereby increasing release of mPFC DA and 5-HT.

Activation and blockade of serotonin4 receptors in the lateral habenula improve working memory in unilateral 6-hydroxydopamine-lesioned Parkinson's rats.

Objective: The aim of the present study was to investigate the effects and mechanism of 6-hydroxydopamine (6-OHDA) lesions and serotonin 4 (5-HT4) receptors in the lateral habenula (LHb) on Parkinson's disease (PD) related working memory. Methods: The working memory was measured by the T-maze rewarded alternation test in sham rats and rats with unilateral 6-OHDA lesions of substantia nigra pars compacta (SNc). The concentrations of dopamine (DA), noradrenaline (NA) and 5-HT in the related brain regions were measured by neurochemistry.Results: The results showed that 6-OHDA lesions of the SNc induced working memory impairment. Intra-LHb injection of 5-HT4 receptor agonist BIMU-8 (2, 4 or 8 µg) and antagonist GR113808 (1, 3.3 or 10 µg) improved the working memory only in the lesioned rats. Intra-LHb injection of BIMU-8 (8 µg) significantly increased DA levels in the medial prefrontal cortex, dorsal hippocampus and amygdala in the lesioned rats but not in sham rats. BIMU-8 did not change NA and 5-HT levels in the related brain regions in both sham and lesioned rats. Intra-LHb injection of GR113808 (10 µg) changed DA, NA and 5-HT levels in related brain regions in both sham and the lesioned rats. In addition, the 5-HT4 receptor-positive neurons in the LHb increased significantly in the lesioned rats.Conclusion: These findings suggested that unilateral lesions of the SNc induced working memory impairment and up-regulation of 5-HT4 receptors in the LHb. Activation and blockade of LHb 5-HT4 receptors improved working memory, that were related to the change of monoamines levels. Abbreviation: 6-OHDA: 6-hydroxydopamine; serotonin:5-HT; LHb: lateral habenula; PD: Parkinson's disease; SNc: substantia nigra pars compacta; DA: dopamine; NA: noradrenaline.

Enhanced AMPA receptor-mediated excitatory transmission in the rodent rostromedial tegmental nucleus following lesion of the nigrostriatal pathway.

The GABAergic rostromedial tegmental nucleus (RMTg) has reciprocal connections with the dopaminergic ventral tegmental area and substantia nigra pars compacta (SNc), and is involved in inhibitory control of monoaminergic nuclei. At present, it is not clear whether unilateral 6-hydroxydopamine lesions of the SNc in rats affect AMPA receptor-mediated excitatory transmission in the RMTg. Here we found that lesions of the SNc in rats increased the firing rate of GABAergic neurons and the level of glutamate in the RMTg compared to sham-operated rats. Intra-RMTg injection of AMPA receptor agonist (S)-AMPA increased the firing rate of the GABAergic neurons in both sham-operated and the lesioned rats, while AMPA receptor antagonist NBQX decreased the firing rate of the neurons. Further, intra-RMTg injection of (S)-AMPA decreased the levels of dopamine and serotonin in the medial prefrontal cortex (mPFC) in the two groups of rats; conversely, NBQX increased the levels of dopamine and serotonin. Compared to sham-operated rats, the duration of (S)-AMPA and NBQX action on the firing rate of GABAergic neurons in the RMTg and release of doapmine and serotonin in the mPFC was prolonged in the lesioned rats. In addition, lesions of the SNc in rats increased protein expression of t-GluR1 and p-GluR1-S831 subunits compared to sham-operated rats. Therefore, these changes in the lesioned rats are associated with increased release of glutamate and up-regulated expression of GluR1 subunit-containing AMPA receptors in the RMTg, which suggest that degeneration of the nigrostriatal pathway enhances AMPA receptor-mediated excitatory transmission in the RMTg.

Serotonin6 Receptors in the Prelimbic Cortex are Involved in the Regulation of Anxiety-Like Behaviors in the Rat 6-Hydroxydopamine Parkinson's Disease Model.

The role of serotonin6 (5-HT6) receptors in the regulation of anxiety is poorly understood, particularly in Parkinson's disease-related anxiety. Here we examined whether 5-HT6 receptors in the prelimbic cortex (PrL) involve in the regulation of anxiety-like behaviors in sham-operated rats and rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle. The lesion induced anxiogenic responses as measured by the open-field and elevated-plus maze tests compared to sham-operated rats. Intra-PrL injection of 5-HT6 receptor agonist WAY208466 (0.5, 3 and 6 µg/ rat) decreased the percentage of time spent in the center area of the open field and percentages of open arm entries and open arm time in sham-operated rats, indicating the induction of anxiogenic responses, and injection of 5-HT6 receptor antagonist SB258585 (1, 2, and 4 µg/rat) showed anxiolytic effects. Interestingly, WAY208466, at the same doses, increased the percentage of time spent in the center area of the open-field and percentages of open arm entries and open arm time in the lesioned rats, indicating the induction of anxiolytic effects, and SB258585, at the same doses, produced anxiogenic responses. Collectively, our findings indicate that 5-HT6 receptors in the PrL are involved in the regulation of anxiety-like behaviors, which may attribute to changes in dopamine and noradrenaline levels in the limbic and limbic-related brain regions after activation and blockade of PrL 5-HT6 receptors.

Involvement of lateral habenula α1 subunit-containing GABAA receptor-mediated inhibitory transmission in the regulation of depression-related behaviors in experimental Parkinson's disease.

The lateral habenula (LHb) plays an important role in the regulation of depression. At present, it is not clear whether GABAA receptor-mediated inhibitory transmission in the LHb is involved in Parkinson's disease (PD)-associated depression. In this study, unilateral 6-hydroxydopamine lesions of the substantia nigra in rats induced depressive-like behaviors and led to hyperactivity of LHb neurons compared to sham-operated rats, which attribute to depletion of dopamine, and decreased synthesis and release of GABA and increased release of glutamate in the LHb. Intra-LHb injection of GABAA receptor agonist muscimol produced antidepressant-like effects, while the injection of GABAA receptor antagonist picrotoxin induced or increased the expression of depressive-like behaviors in sham-operated and the lesioned rats. However, the doses producing these behavioral effects in the lesioned rats were lower than those in sham-operated rats. Intra-LHb injection of muscimol decreased the firing rate of LHb neurons and increased the medial prefrontal cortex serotonin (5-HT) release; conversely, picrotoxin increased the firing rate of the neurons and decreased 5-HT release in two groups of rats. Compared to sham-operated rats, the duration of muscimol and picrotoxin action on the firing rate of the neurons and 5-HT release was prolonged in the lesioned rats. These changes in the lesioned rats were associated with up-regulation of the expression of α1 subunit-containing GABAA receptors and reduction of GABA release in the LHb. Collectively, our findings suggest that degeneration of the nigrostriatal pathway impairs GABAA receptor-mediated inhibitory transmission in the LHb, and the transmission is important for regulating PD-associated depression.