Publications by authors named "Milton R Alves"

10 Publications

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Codeine plus acetaminophen improve sleep quality, daily activity level, and food intake in the early postoperative period after photorefractive keratectomy: a secondary analysis.

Arq Bras Oftalmol 2021 Jan-Feb;84(1):45-50

Departamento de Oftalmologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.

Purpose: To determine whether codeine plus acetaminophen after photorefractive keratectomy (PRK) have beneficial effects on sleep quality, activity levels, and food intake, beyond their effect of pain relief.

Methods: We enrolled 40 patients (80 eyes) in this randomized, double-blind, paired-eye, placebo-controlled, add-on trial. Each eye was treated 2 weeks apart, and the patients were randomly allocated to receive either the placebo or the intervention (30 mg codeine and 500 mg acetaminophen) (4 times a day for 4 days). Outcomes were sleep quality, daily activity level, and food intake within 24-72 h post-photorefractive keratectomy, as measured by the McGill Pain Questionnaire.

Results: Sleep quality and daily activity level were inversely associated with pain scores within the first 48 h post-photorefractive keratectomy. During the intervention, patients were significantly more likely to score their sleep quality as good at 24 h (relative risk=2.5; 95% confidence interval 1.48-4.21, p<0.001) and 48 h compared to during placebo (relative risk=1.37; 95% confidence interval: 1.03-1.84, p=0.023). The probability of reporting good daily activity level at 24 and 72 hours post-photorefractive keratectomy was three times higher when patients received the intervention compared to the placebo (relative risk=3.0; 95% confidence interval: 1.49-6.15, p=0.006 and relative risk=1.31; 95% confidence interval: 1.02-1.67, p=0.021, respectively). No difference was observed in food intake.

Conclusion: The oral combination of codeine and acetaminophen significantly improves sleep quality and daily activity level within the first 24-72 h post-photorefractive keratectomy compared to a placebo.
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February 2021

Modulation of Oxidative Stress and Inflammation in the Aged Lacrimal Gland.

Am J Pathol 2021 02 4;191(2):294-308. Epub 2020 Nov 4.

Department of Ophthalmology, Baylor College of Medicine, Houston, Texas; Department of Ophthalmology, University of São Paulo, São Paulo, Brazil. Electronic address:

Inflammation and oxidative stress accompany aging. This study investigated the interplay between oxidative stress and inflammation in the lacrimal gland. C57BL/6 mice were used at 2 to 3, 12, and 24 months of age. Nuclear factor erythroid derived-2-related factor 2 (Nrf2) and corresponding wild-type mice were used at 2 to 3 and 12 to 13 months of age. A separate group of 15.5 to 17 months of age C57BL/6 mice received a diet containing an Nrf2 inducer (Oltipraz) for 8 weeks. Aged C57BL/6 lacrimal glands showed significantly greater lymphocytic infiltration, higher levels of MHC II, IFN-γ, IL-1β, TNF-α, and cathepsin S (Ctss) mRNA transcripts, and greater nitrotyrosine and 4-hydroxynonenal protein. Young Nrf2 mice showed an increase in IL-1β, IFN-γ, MHC II, and Ctss mRNA transcripts compared with young wild-type mice and greater age-related changes at 12 to 13 months of age. Oltipraz diet significantly decreased nitrotyrosine and 4-hydroxynonenal and decreased the expression of IL-1β and TNF-α mRNA transcripts, while decreasing the frequency of CD45CD4 cells in lacrimal glands and significantly increasing conjunctival goblet cell density compared with a standard diet. The findings provide novel insight into the development of chronic, low-grade inflammation and oxidative stress in age-related dry eye. New therapies targeting oxidative stress pathways will be valuable in treating age-related dry eye.
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February 2021

Glaucoma Management in Patients With Aniridia and Boston Type 1 Keratoprosthesis.

Am J Ophthalmol 2019 11 24;207:258-267. Epub 2019 Jun 24.

Department of Ophthalmology, University of Sao Paulo, Sao Paulo, Brazil.

Purpose: To assess outcomes and glaucoma management in eyes with aniridia following Boston type 1 Keratoprosthesis (KPro) implantation.

Design: Retrospective, interventional comparative case series.

Methods: The population included patients with aniridia and patients with other preoperative diagnoses (excluding Stevens-Johnson syndrome, mucous membrane pemphigoid, and congenital disorders) who underwent KPro implantation at Massachusetts Eye and Ear with at least 2 years of follow-up. One eye per patient was selected based on the longer follow-up time. The main outcome was intermediate and long-term outcomes related to glaucoma.

Results: The aniridia (n = 22) and comparison (n = 61) groups had similar preoperative visual acuity (VA, mean ± standard deviation, 1.86 ± 0.52 logMAR, P = .33) and follow-up time (65.6 ± 26.3 months, P = .25). Before KPro implantation, eyes with aniridia had more glaucoma (76.2%) and glaucoma surgery (57.1%) than comparison eyes (51.8%, P = .053; 23.2%, P = .005, respectively). More Ahmed valves were co-implanted with KPro in aniridia (47.6%) vs comparison eyes (17.9%, P = .008). At final follow-up, more aniridia eyes had glaucoma (90.5%) than comparison eyes (64.3%, P = .02), but the 2 groups had similar percentages of eyes with cup-to-disc ratio (CDR) >0.8 (23.8% vs. 30.4%, P = .57) or CDR progression of ≥0.2 (42.9% vs 44.6%, P = .89, respectively). None of the eyes with prophylactic tube implantation developed glaucoma. Eyes with and without aniridia did not differ in post-KPro VA improvement (72.7%, 72.1%, P = .96), and final VA (1.28 ± 0.79 logMAR, 1.23 ± 0.98 logMAR, P = .51).

Conclusion: Despite a higher glaucoma prevalence, eyes with aniridia achieved similar VA as comparison eyes with more than 5 years of mean follow-up time. Boston KPro offers satisfactory visual rehabilitation in aniridia when glaucoma is managed aggressively.
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November 2019

Age-related Autoimmune Changes in Lacrimal Glands.

Immune Netw 2019 Feb 27;19(1):e3. Epub 2019 Feb 27.

University of Sao Paulo, Sao Paulo, Brazil.

Aging is a complex process associated with dysregulation of the immune system and low levels of inflammation, often associated with the onset of many pathologies. The lacrimal gland (LG) plays a vital role in the maintenance of ocular physiology and changes related to aging directly affect eye diseases. The dysregulation of the immune system in aging leads to quantitative and qualitative changes in antibodies and cytokines. While there is a gradual decline of the immune system, there is an increase in autoimmunity, with a reciprocal pathway between low levels of inflammation and aging mechanisms. Elderly C57BL/6J mice spontaneously show LGs infiltration that is characterized by Th1 but not Th17 cells. The aging of the LG is related to functional alterations, reduced innervation and decreased secretory activities. Lymphocytic infiltration, destruction, and atrophy of glandular parenchyma, ductal dilatation, and secretion of inflammatory mediators modify the volume and composition of tears. Oxidative stress, the capacity to metabolize and eliminate toxic substances decreased in aging, is also associated with the reduction of LG functionality and the pathogenesis of autoimmune diseases. Although further studies are required for a better understanding of autoimmunity and aging of the LG, we described anatomic and immunology aspects that have been described so far.
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February 2019

Microvasculature of the Optic Nerve Head and Peripapillary Region in Patients With Primary Open-Angle Glaucoma.

J Glaucoma 2019 04;28(4):281-288

Department of Ophthalmology, Massachusetts Eye and Ear.

Purpose: To assess optic nerve head (ONH) and peripapillary microvasculature in primary open-angle glaucoma (POAG) of mild to moderate severity using swept-source optical coherence tomography angiography (OCTA).

Materials And Methods: In a cross-sectional study, swept-source OCTA images were analyzed for 1 eye from each of 30 POAG patients with glaucomatous Humphrey visual field loss and 16 controls. The anatomic boundary of ONH was manually delineated based on Bruch's membrane opening and large vessels were removed from en face angiography images to measure vessel density (VD) and the integrated OCTA by ratio analysis signal (IOS), suggestive of flow, in the ONH and peripapillary region. POAG subgroup analysis was performed based on a history of disc hemorrhage (DH) matched by visual field mean deviation (MD).

Results: POAG (mean MD±SD, -3.3±3.0 dB) and control groups had similar demographic characteristics and intraocular pressure on the day of imaging. Groups did not differ in superficial ONH VD or flow indicated by IOS (P≥0.28). POAG eyes showed significantly lower VD (39.4%±4.0%) and flow (38.8%±5.6%) in deep ONH, peripapillary VD (37.9%±2.9%) and flow (43.6%±4.0%) compared with control eyes (44.1%±5.1%, 44.7%±6.9%, 40.7%±1.7%, 47.8%±2.5%, respectively; P≤0.007 for all). In the subgroup analysis, POAG eyes with (n=14) and without DH (n=16) had similar measured OCTA parameters (P>0.99 for all).

Conclusions: The image processing methodology based on the anatomic boundary of ONH demonstrated compromised microvasculature in the deep ONH and peripapillary region in eyes with mild to moderate POAG, regardless of the history of DH.
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April 2019

Lacrimal Cytokines Assessment in Subjects Exposed to Different Levels of Ambient Air Pollution in a Large Metropolitan Area.

PLoS One 2015 20;10(11):e0143131. Epub 2015 Nov 20.

Laboratory for investigation in Ophthalmology (LIM-33), University of Sao Paulo Medical School, Sao Paulo, SP, Brazil.

Background: Air pollution is one of the most environmental health concerns in the world and has serious impact on human health, particularly in the mucous membranes of the respiratory tract and eyes. However, ocular hazardous effects to air pollutants are scarcely found in the literature.

Design: Panel study to evaluate the effect of different levels of ambient air pollution on lacrimal film cytokine levels of outdoor workers from a large metropolitan area.

Methods: Thirty healthy male workers, among them nineteen professionals who work on streets (taxi drivers and traffic controllers, high pollutants exposure, Group 1) and eleven workers of a Forest Institute (Group 2, lower pollutants exposure compared to group 1) were evaluated twice, 15 days apart. Exposure to ambient PM2.5 (particulate matter equal or smaller than 2.5 μm) was 24 hour individually collected and the collection of tears was performed to measure interleukins (IL) 2, 4, 5 and 10 and interferon gamma (IFN-γ) levels. Data from both groups were compared using Student's t test or Mann- Whitney test for cytokines. Individual PM2.5 levels were categorized in tertiles (lower, middle and upper) and compared using one-way ANOVA. Relationship between PM2.5 and cytokine levels was evaluated using generalized estimating equations (GEE).

Results: PM2.5 levels in the three categories differed significantly (lower: ≤22 μg/m3; middle: 23-37.5 μg/m3; upper: >37.5 μg/m3; p<0.001). The subjects from the two groups were distributed unevenly in the lower category (Group 1 = 8%; Group 2 = 92%), the middle category (Group 1 = 89%; Group 2 = 11%) and the upper category (Group 1 = 100%). A significant relationship was found between IL-5 and IL-10 and PM2.5 levels of the group 1, with an average decrease of 1.65 pg/mL of IL-5 level and of 0.78 pg/mL of IL-10 level in tear samples for each increment of 50 μg/m3 of PM2.5 (p = 0.01 and p = 0.003, respectively).

Conclusion: High levels of PM2.5 exposure is associated with decrease of IL-5 and IL-10 levels suggesting a possible modulatory action of ambient air pollution on ocular surface immune response.
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June 2016

Preoperative tranilast as adjunctive therapy to primary pterygium surgery with a 1-year follow-up.

Arq Bras Oftalmol 2015 Jan-Feb;78(1):1-5

Deparftment of Anatomy, Histology and Embryology, Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto, SP, Brazil.

Purpose: To determine the efficacy of tranilast as an adjunctive therapy in conjunctival autograft.

Methods: Twenty-nine patients were randomly allocated to the Tranilast Group (n=15) or the Control Group (n=14). The Tranilast Group received a subconjunctival injection of 0.5% tranilast 30 days prior to surgery. Conjunctival autograft was performed in both groups using fibrin sealant and 0.02% subconjunctival mitomycin C at the end of the surgery. After the resection of the pterygium, immunohistochemistry was performed with 100 cells to identify epithelial cells positive for transforming growth factor-β (TGF-β). Subjective symptoms were evaluated using a 5-point scale, and the recurrence rate was assessed.

Results: Both groups showed improvements in their symptoms and similar clinical results. Compared with the Control Group, the Tranilast Group failed to show a decreased recurrence rate (p=0.59). However, the number of epithelial cells expressing TGF-β was lower in the Tranilast Group (5 cells; 95% CI: 2.56-13.15; Control Group, 16 cells, 95% CI: 11.53-24.76; p=0.01). Minimal but reversible complications, including glaucoma secondary to corticosteroids and granuloma, occurred during the study.

Conclusion: Tranilast was effective in decreasing the number of pterygium epithelial cells expressing TGF-β.
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July 2015

Correlation between signs and symptoms of ocular surface dysfunction and tear osmolarity with ambient levels of air pollution in a large metropolitan area.

Cornea 2013 Apr;32(4):e11-5

Department of Ophthalmology, Laboratory for Investigation in Ophthalmology (LIM-33), University of São Paulo Medical School, São Paulo, Brazil.

Purpose: To evaluate the effect of high levels of environmental air pollution on tear osmolarity and its possible correlation with clinical signs and symptoms.

Methods: This was a panel study involving 71 taxi drivers and traffic controllers from São Paulo, Brazil. Mean individual levels of 24-hour exposure to nitrogen dioxide (NO2) and particulate matter smaller than 2.5 μm (PM2.5) were assessed on 4 different occasions. On the first and third visits, subjects were submitted to clinical evaluations including the administration of the Ocular Surface Disease Index questionnaire, slit-lamp examination, estimation of tear breakup time (BUT), the Schirmer test, and vital staining of the cornea and conjunctiva. On the second and fourth visits, tear samples were collected for osmolarity assays. Statistical analysis was performed using generalized estimating equations.

Results: Although the taxi drivers and traffic controllers in our sample were exposed to high levels of NO2 and PM2.5, few symptoms were reported on the Ocular Surface Disease Index questionnaire. BUT values were reduced, whereas vital staining and Schirmer test mean results were within normal limits, despite considerable variability. A significant and negative correlation was found between PM2.5 levels and tear film osmolarity levels (P < 0.05). An increase of 10 μg/m(3) in PM2.5 was associated with a 10.9 mOsm/kg decrease in tear osmolarity. There also was a negative correlation, although not statistically significant, between NO2 and tear osmolarity.

Conclusions: Exposure to air pollution reduces tear film stability and influences tear film osmolarity. Combining clinical examination with the assessment of tear osmolarity may help understand ocular surface response to high levels of air pollution.
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April 2013

Biomechanical corneal changes induced by different flap thickness created by femtosecond laser.

Clinics (Sao Paulo) 2011 ;66(6):1067-71

Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.

Objective: To evaluate the impact of the creation of corneal flaps at different thicknesses on the biomechanical properties of swine corneas.

Method: Twelve swine eyes were obtained to form two groups: 100 μm flap thickness and 300 μm flap thickness. Each eye was submitted to the following examinations: raster topography to investigate corneal curvature alterations, ocular response analyzer to investigate corneal hysteresis change, optical coherence tomography to measure central corneal and flap thickness and sonic wave propagation velocity as a measure of stiffness, before and immediately after flap creation. After flap amputation, surface wave velocity measurements were repeated.

Results: Measured flap thicknesses were statistically different for thin and thick flap groups, with an average of 108.5 + 6.9 and 307.8 + 11.5 μm respectively. Hysteresis and corneal resistance factor did not change significantly after flap creation in the thin flap group. With thicker flaps, both parameters decreased significantly from 8.0 +1.0 to 5.1 +1.5 mmHg and from 8.2 + 1.6 to 4.1 +2.5 mmHg respectively. Simulated keratometry values increased in the thick flap group (from 39.5 + 1 D to 45.9+1.2 D) after flap creation but not in the thin flap group (from 40.6 + 0.6 D to 41.4+ 1.0 D). Regarding surface wave velocity analysis, the surgical procedures induced statistically lower results in some positions.

Conclusion: In the experimental conditions established by this model, thicker flaps presented a greater biomechanical impact on the cornea.
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March 2012

Evaluation of a new system for obtaining donor lamellar grafts.

Cornea 2007 Feb;26(2):151-3

Eye Clinic Day Hospital, São Paulo University, São Paulo, Brazil.

Purpose: To evaluate the performance of a new system for obtaining corneal lamellar grafts of preset sizes. The system consists of the combination of an artificial anterior chamber (MALKS) and an automated microkeratotome (MASYK).

Methods: A prospective study was performed. Lamellar tissue was obtained with the microkeratotome from 40 human corneoscleral buttons mounted in the artificial anterior chamber. The instrument was set to cut lamellae with a center thickness of 350 microm and a diameter of 10 mm. A new cutting blade for the microkeratotome was used for every 8 cases. Thickness was measured by ultrasound pachymetry. The lamellar diameter was assessed with a micrometric caliper.

Results: The center thickness of the corneal lamellae ranged from 230 to 430 microm (mean, 322 +/- 48 microm; 95% confidence interval [CI], 307-337 microm). The diameter of the stromal ranged from 9.26 to 10.74 mm (mean, 10 +/- 0.27 mm; 95% CI, 9.9-10 mm). There were no cases of perforation or incomplete/irregular lamellae. The interface between the residual stroma and the lamellae was macroscopically smooth. The repetitive use of the same blade up to 8 times did not significantly change these results.

Conclusion: The MALKS and MASYK system showed good accuracy in obtaining lamellae of specific thickness and size taken from human corneoscleral buttons. It is a promising instrument for use in deep lamellar keratoplasty. The technique may be useful in obtaining precut lamellar donor tissue for distribution by eye banks.
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February 2007