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Socioeconomic inequalities in the exposome have been found to be complex and highly context-specific, but studies have not been conducted in large population-wide cohorts from multiple countries. This study aims to examine the external exposome, encompassing individual and environmental factors influencing health over the life course, and to perform dimension reduction to derive interpretable characterization of the external exposome for multicountry epidemiological studies. Analyzing data from over 25 million individuals across seven European countries including 12 administrative and traditional cohorts, we utilized domain-specific principal component analysis (PCA) to define the external exposome, focusing on air pollution, the built environment, and air temperature. We conducted linear regression to estimate the association between individual- and area-level socioeconomic position and each domain of the external exposome. Consistent exposure patterns were observed within countries, indicating the representativeness of traditional cohorts for air pollution and the built environment. However, cohorts with limited geographical coverage and Southern European countries displayed lower temperature variability, especially in the cold season, compared to Northern European countries and cohorts including a wide range of urban and rural areas. The individual- and area-level socioeconomic determinants (i.e., education, income, and unemployment rate) of the urban exposome exhibited significant variability across the European region, with area-level indicators showing stronger associations than individual variables. While the PCA approach facilitated common interpretations of the external exposome for air pollution and the built environment, it was less effective for air temperature. The diverse socioeconomic determinants suggest regional variations in environmental health inequities, emphasizing the need for targeted interventions across European countries.

Background: Many studies reported associations between long-term exposure to environmental factors and mortality; however, little is known on the combined effects of these factors and health. We aimed to evaluate the association between external exposome and all-cause mortality in large administrative and traditional adult cohorts in Europe., Methods: Data from six administrative cohorts (Catalonia, Greece, Rome, Sweden, Switzerland and the Netherlands, totaling 27,913,545 subjects) and three traditional adult cohorts (CEANS-Sweden, EPIC-NL-the Netherlands, KORA-Germany, totaling 57,653 participants) were included. Multiple exposures were assigned at the residential addresses, and were divided into three a priori defined domains: (1) air pollution [fine particulate matter (PM 2.5 ), nitrogen dioxide (NO₂), black carbon (BC) and warm-season Ozone (warm-O 3 )]; (2) land/built environment (Normalized Difference Vegetation Index-NDVI, impervious surfaces, and distance to water); (3) air temperature (cold- and warm-season mean and standard deviation). Each domain was synthesized through Principal Component Analysis (PCA), with the aim of explaining at least 80% of its variability. Cox proportional-hazards regression models were applied and the total risk of the external exposome was estimated through the Cumulative Risk Index (CRI). The estimates were adjusted for individual- and area-level covariates., Results: More than 205 million person-years at risk and more than 3.2 million deaths were analyzed. In single-component models, IQR increases of the first principal component of the air pollution domain were associated with higher mortality [HRs ranging from 1.011 (95% CI: 1.005-1.018) for the Rome cohort to 1.076 (1.071-1.081) for the Swedish cohort]. In contrast, lower levels of the first principal component of the land/built environment domain, pointing to reduced vegetation and higher percentage of impervious surfaces, were associated with higher risks. Finally, the CRI of external exposome increased mortality for almost all cohorts. The associations found in the traditional adult cohorts were generally consistent with the results from the administrative ones, albeit without reaching statistical significance., Discussion: Various components of the external exposome, analyzed individually or in combination, were associated with increased mortality across European cohorts. This sets the stage for future research on the connections between various exposure patterns and human health, aiding in the planning of healthier cities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Nobile, Dimakopoulou, Åström, Coloma, Dadvand, de Bont, de Hoogh, Ibi, Katsouyanni, Ljungman, Melén, Nieuwenhuijsen, Pickford, Sommar, Tonne, Vermeulen, Vienneau, Vlaanderen, Wolf, Samoli and Stafoggia.)

Introduction: Scientific evidence supports dermoscopy as an essential tool in dermatological diagnosis., Objectives: The objective is to know the factors that influence its use in Chilean dermatologists., Methods: Analytical cross-sectional study. An adapted version of the survey was submitted from the pan-European study by Forsea et al to members of the Chilean Society of Dermatology, between September and December 2020. Analysis using descriptive statistics and multivariate analysis with ordinal logistic regression looking for factors associated with greater use of., Results: One hundred and ninety-eight responses, mean age 46.3 years and 14.6 years on average practicing as dermatologists. 61.6% trained in dermoscopy during their residency. 98% use a dermatoscope. More than 80% consider dermoscopy useful for the diagnosis of melanomas, follow-up of melanocytic lesions, and diagnosis of pigmented and non-pigmented tumors. Between 50% and 70% consider it useful for monitoring non-melanocytic lesions, nail and hair pathologies. Greater confidence when evaluating pigmented and non-pigmented tumors and capillary pathology. Adjusting for age, sex, confidence, and education, participation in teaching was associated with greater use of dermoscopy in non-pigmented and pigmented tumors, and capillary pathology., Conclusions: Percentage of participation in the survey and training in dermoscopy higher than in the reference study, recognizing the usefulness of dermoscopy for the diagnosis and follow-up of tumor pathologies. Participating in teaching is a strong independent factor that is associated with a greater use of dermoscopy in Chile. Dermoscopy is positioned as a tool widely used by Chilean dermatologists in their daily practice.

Background: We evaluated the independent and joint effects of air pollution, land/built environment characteristics, and ambient temperature on all-cause mortality as part of the EXPANSE project., Methods: We collected data from six administrative cohorts covering Catalonia, Greece, the Netherlands, Rome, Sweden, and Switzerland and three traditional cohorts in Sweden, the Netherlands, and Germany. Participants were linked to spatial exposure estimates derived from hybrid land use regression models and satellite data for: air pollution [fine particulate matter (PM 2.5 ), nitrogen dioxide (NO₂), black carbon (BC), warm season ozone (O 3 )], land/built environment [normalized difference vegetation index (NDVI), distance to water, impervious surfaces], and ambient temperature (the mean and standard deviation of warm and cool season temperature). We applied Cox proportional hazard models accounting for several cohort-specific individual and area-level variables. We evaluated the associations through single and multiexposure models, and interactions between exposures. The joint effects were estimated using the cumulative risk index (CRI). Cohort-specific hazard ratios (HR) were combined using random-effects meta-analyses., Results: We observed over 3.1 million deaths out of approximately 204 million person-years. In administrative cohorts, increased exposure to PM 2.5 , NO 2 , and BC was significantly associated with all-cause mortality (pooled HRs: 1.054, 1.033, and 1.032, respectively). We observed an adverse effect of increased impervious surface and mean season-specific temperature, and a protective effect of increased O 3 , NDVI, distance to water, and temperature variation on all-cause mortality. The effects of PM 2.5 were higher in areas with lower (10th percentile) compared to higher (90th percentile) NDVI levels [pooled HRs: 1.054 (95% confidence interval (CI) 1.030-1.079) vs. 1.038 (95% CI 0.964-1.118)]. A similar pattern was observed for NO 2 . The CRI of air pollutants (PM 2.5 or NO 2 ) plus NDVI and mean warm season temperature resulted in a stronger effect compared to single-exposure HRs: [PM 2.5 pooled HR: 1.061 (95% CI 1.021-1.102); NO 2 pooled HR: 1.041 (95% CI 1.025-1.057)]. Non-significant effects of similar patterns were observed in traditional cohorts., Discussion: The findings of our study not only support the independent effects of long-term exposure to air pollution and greenness, but also highlight the increased effect when interplaying with other environmental exposures., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer-review process and the final decision., (© 2024 Dimakopoulou, Nobile, de Bont, Wolf, Vienneau, Ibi, Coloma, Pickford, Åström, Sommar, Kasdagli, Souliotis, Tsolakidis, Tonne, Melén, Ljungman, de Hoogh, Vermeulen, Vlaanderen, Katsouyanni, Stafoggia and Samoli.)

Competing Interests: Competing interests:: None.

Background: Teledermatology was introduced in Chile to make up for the lack of dermatologists and improve the primary care system's ability to resolve problems. This strategy was implemented in the province of Palena in 2013, but outcomes were not analyzed and reported until now., Material and Methods: Descriptive, cross-sectional study with analysis of inter-rater agreement on diagnoses. All the teledermatology consultations made on behalf of patients in Ayacara, Chaitén, Futaleufú, and Palena from 2013 through 2017 were analyzed. Data were extracted from the MINSAL platform. The κ statistic was used to assess diagnostic agreement., Results: A total of 326 teledermatology consultations were made. The mean (SD) age of the patients was 35.8 (22.4) years. The majority (59.8%) were female. Palena generated the largest volume of cases (40.8%). The mean time until a teledermatology diagnosis was given was 12.6 (22.8) days. This response time decreased to 6.4 (5.2) days after a staff dermatologist from Hospital Puerto Montt joined the program (P=.0005). Diagnosis concordance between the general practitioner and the dermatologist was moderate (κ=0.5). Physical examination by the dermatologist at the hospital of reference (Puerto Montt) was necessary for 20.6% of the patients, and time until a definitive diagnosis for the patient took longer in such cases (25.7 [41.2] days) than for the cases that didn't need a physical evaluation at the Hospital of Puerto Montt (P<.0001)., Conclusions: Teledermatology provides a necessary diagnostic and therapeutic resource for general practitioners in isolated locations. Diagnostic agreement is moderate between the generalist and the specialist, similar to agreement in international studies but lower than agreement reported in other Chilean studies. The reduction in diagnostic response time after incorporation of a dermatologist on staff at the hospital of Puerto Montt was significant. The significant difference between the time for diagnosis under teledermatology and the delay when physical examination is required at the hospital of Puerto Montt identifies an aspect of care management to improve., (Copyright © 2019 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

The effect of the metal precursor (presence or absence of chlorine) on the preferential oxidation of CO in the presence of H2 over Pt/CeO2 catalysts has been studied. The catalysts are prepared using (Pt(NH3)4)(NO3)2 and H2PtCl6, as precursors, in order to ascertain the effect of the chlorine species on the chemical properties of the support and on the catalytic behavior of these systems in the PROX reaction. The results show that chloride species exert an important effect on the redox properties of the oxide support due to surface chlorination. Consequently, the chlorinated catalyst exhibits a poorer catalytic activity at low temperatures compared with the chlorine-free catalyst, and this is accompanied by a higher selectivity to CO2 even at high reaction temperatures. It is proposed that the CO oxidation mechanism follows different pathways on each catalyst., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To report two cases of penetrating keratoplasty using tissue from a donor who had undergone laser-assisted in situ keratomileusis (LASIK) surgery before its transplantation., Participants: Two patients who had penetrating keratoplasties and received donor corneas from eyes that had previous LASIK., Intervention: The two patients underwent corneal transplantation by two different surgeons who were unaware that the donor eyes had previous LASIK treatment., Results: Penetrating keratoplasty was completed without complication in both cases, although a separation of the corneal lamellae was noted during surgery in one of the cases. The two patients are doing well at 5.5 months postsurgery., Conclusion: With the increasing popularity of laser refractive surgery, eye banks should increase their awareness and refine screening techniques to rule out refractive surgery in the donor corneas. The long-term follow-up of those patients will reveal if surgical success was compromised by prior refractive surgery.

Purpose: The role of the inner wall of Schlemm's canal in determining aqueous outflow facility is poorly understood. To quantify the relationship between inner wall pore characteristics and aqueous outflow facility in human eyes, both control eyes and eyes in which facility had been pharmacologically increased by ethacrynic acid (ECA) infusion were studied., Methods: Outflow facility was measured in enucleated human eyes before and after delivery of 0.25 mM ECA (one eye of each of 6 pairs) or 2.5 mM ECA (one eye of each of 13 pairs). ECA, and vehicle in contralateral eyes, was delivered into Schlemm's canal by retroperfusion, thereby largely avoiding drug exposure to the trabecular meshwork. After facility measurement, eyes were fixed under conditions of either constant pressure (physiological intraocular pressure, 13 pairs) or "equal flow" (6 pairs) and were microdissected to expose the inner wall of Schlemm's canal. The density and diameter of intercellular and intracellular inner wall pores were measured using scanning electron microscopy., Results: Retroperfusion with 2.5 mM ECA increased facility by 73% (P < 0.001), whereas 0.25 mM ECA increased facility by 19% (not statistically significant). The density of intercellular pores in the inner wall of Schlemm's canal was increased by 520% in 2.5 mM ECA-retroperfused eyes (P < 0.00004), whereas intracellular pore density remained approximately constant. Large pores (size > or = 1.1 microm) were particularly enhanced in ECA retroperfused eyes. The net change in facility due to ECA was not correlated with changes in pore density or other inner wall pore statistics., Conclusions: Our data are most consistent with a model in which pores in the inner wall of Schlemm's canal indirectly influence facility. However, measured changes in facility due to changes in inner wall properties did not agree with quantitative predictions of the pore funneling theory, suggesting that changes in facility may instead be due to gel leakage from the extracellular spaces of the juxtacanalicular tissue. More definitive experiments are required to confirm this hypothesis.

Purpose: The influence of the inner wall of Schlemm's canal on aqueous outflow facility remains poorly understood. We examined the relationship between inner wall pore characteristics and outflow facility in living primate eyes in which facility had been pharmacologically increased by ethacrynic acid (ECA) infusion and in contralateral control eyes., Methods: Outflow facility (two-level constant pressure perfusion) was measured in eight pairs of living monkey eyes before and after administration of a bolus dose of either 0.125 mM ECA or vehicle. After exsanguination, eyes were fixed in situ under constant-pressure conditions (mean fixation pressure approximately 19 mm Hg). The density and diameter of inner wall pores and the number and area of platelet aggregates on the inner wall of Schlemm's canal were measured by scanning electron microscopy., Results: In ECA-treated eyes, outflow facility increased 63% (P < 0.0001), intracellular pore density decreased 46% (P = 0.0094), intracellular pore size increased 27% (P = 0.049), platelet aggregate density increased 158% (P < 0.0001), and area covered by platelets increased 210% (P = 0.012) relative to contralateral controls. Although the average density and size of intercellular pores were essentially unaffected by ECA, an increased density of large (> or = 1.90 microm) intercellular pores was seen in ECA-treated eyes. The density of intracellular pores increased with the duration of fixative perfusion. Other than a weak negative correlation between outflow facility and intracellular pore density in ECA-treated eyes (P = 0.052), facility was not correlated with inner wall pore features., Conclusions: Our data are most consistent with a scenario in which ECA promotes formation of large intercellular pores in the inner wall of Schlemm's canal, which are then masked by platelet aggregates. Masking of intercellular pores, combined with fixation-induced alteration of inner wall pore density, greatly complicates attempts to relate facility to inner wall structure and suggests that in vivo pore density is smaller than in fixed tissue. Additionally, facility-influencing effects of ECA on the juxtacanalicular tissue cannot be excluded.

Purpose: It has been reported that fixation conditions significantly influence the apparent pore density in the inner-wall endothelium of Schlemm's canal. In the present study, the manner in which fixation conditions affect the two subtypes of inner-wall pores, intracellular pores and intercellular (or border) pores, was investigated., Methods: Outflow facility was measured in enucleated human eyes. Eyes were fixed under constant flow" or constant pressure conditions, microdissected to expose the inner wall of Schlemm's canal, and prepared for scanning electron microscopy. The density and diameter of the two subtypes of pores in the inner wall were measured., Results: Intracellular pore density decreased with increasing postmortem time (P < 0.001) and increased with increasing volume of fixative passed through the outflow pathway (P < 0.001), whereas border pore density showed no dependence on these parameters (P > 0.25 and P > 0.15, respectively). Border pore density increased with increasing fixation pressure (P < 0.005), even though intracellular pore density showed no such dependence (P > 0.4). No correlation was found between outflow facility and the predictions of Poiseuille's law, Sampson's law, or the funneling theory for the hydraulic conductivity of the intracellular pores (P > 0.35) or the border pores (P > 0.1)., Conclusions: The intracellular and border pores form two morphologically and functionally distinct populations in the inner wall of Schlemm's canal. The dependence of intracellular pore density on postmortem time and on volume of fixative passed through the outflow pathway suggests that these pores are artifacts of tissue fixation or processing conditions. That border pores do not depend on such conditions and that their presence is correlative with perfusion pressure suggests that this population may be nonartifactual. New histologic techniques for examining the inner wall of Schlemm's canal are necessary to determine the in vivo state of inner-wall pores and how they influence outflow facility.

Purpose: A linear relationship between the density of pores in the inner wall of Schlemm's canal and aqueous outflow facility has been reported previously in a study in which investigators examined only eyes fixed at constant pressure, so that fixative flow rates differed from eye to eye. Because pores may form as a function of flow rate, the purpose in the current study was to verify the previous findings, using constant flow perfusions., Methods: Outflow facility was measured in enucleated human eyes. Eyes were fixed under either constant flow or constant pressure conditions, microdissected to expose the inner wall of Schlemm's canal, and prepared for scanning electron microscopy. The density and diameter of pores in the inner wall were measured., Results: Statistical analysis showed no correlation between outflow facility and either the density or the diameter of pores. Pore density decreased significantly during the hours after death. Examining only eyes for which experimentation was started within 20 hours of death, we found that pore density increased significantly with the volume of fixative that had been perfused through the outflow pathway., Conclusions: The correlation found by Allingham et al between outflow facility and pore density in the inner wall endothelium was not confirmed. However, the relationship between pore density and volume of fixative perfused is consistent with and may be responsible for the finding in the previous study. Because fixation conditions can influence the apparent pore density in the inner wall endothelium significantly, the conclusion reached previously, that pores contribute only 10% of the aqueous outflow resistance, may require reevaluation.

Purpose: To extend the retroperfusion technique to allow the delivery of drugs into Schlemm's canal in enucleated human eyes and to use this technique to gain insights into the function of the inner wall of Schlemm's canal., Methods: Using our previously developed retroperfusion technique, the anterior chamber of enucleated human eyes was held at a small negative pressure (-0.75 mm Hg), and fluid was allowed to flow retrograde from the limbal vessels, through the collector channels, and into Schlemm's canal. In this manner, the sulfhydryl agent N-ethyl maleimide (NEM) or the fixative agent glutaraldehyde was delivered to the inner wall of Schlemm's canal in normal and glaucomatous human eyes. Facility changes caused by retroperfusion were measured and correlated with histologic studies of the inner wall of Schlemm's canal., Results: Retroperfusion effectively delivers fluid from the scleral surface into the lumen of Schlemm's canal. Retroperfusion with vehicle alone does not alter facility or change outflow pathway morphology. Retroperfusion with NEM causes an approximately 35% facility increase and concomitant inner wall openings. Retroperfusion with glutaraldehyde in normal eyes and eyes with primary open-angle glaucoma causes a facility decrease of 53% and 64%, respectively, and localized fixation of the inner wall of Schlemm's canal. The magnitude of the facility changes caused by retroperfusion were similar to those seen using conventional forward perfusion of NEM and glutaraldehyde., Conclusions: Retroperfusion is a viable technique for the delivery of drugs or other agents into Schlemm's canal in enucleated human eyes. Retroperfusion-induced changes in outflow facility are correlated strongly with morphologically observed alterations in inner wall structure. The majority of outflow resistance is localized to the inner wall of Schlemm's canal or the immediately adjacent 10-microns region of the juxtacanalicular tissue in normal eyes and in eyes with primary open-angle glaucoma. Inner wall giant vacuoles and pores likely persist for sometime, even after fixation at zero or negative pressure.

The purpose of this study was to determine the mechanical response of the lamina cribrosa (LC) to elevated intraocular pressure (IOP) so as to identify possible mechanisms of optic nerve damage in early glaucoma. Ten pairs of normal human eyes were fixed after 24 hours' exposure to 50 mm Hg pressure (experimental eyes) or 5 mm Hg pressure (contralateral control eyes). Photomicrographs of the central region of the optic nerve head (ONH) were taken to examine the LC morphologically and to measure the dimensions of the LC. It was found that elevated IOP caused the LC to deflect posteriorly without affecting its thickness. The majority of the posterior displacement in the LC occurred near the periphery of the ONH. This shape change is consistent with a model of force distribution within the LC in which shear stresses are dominant; such stresses are maximal at the periphery and minimal at the centre of the ONH. These findings support a model in which mechanical forces, specifically shearing stresses within the peripheral lamina, play a direct role in the pathology of glaucomatous optic neuropathy.

We have examined the effect of cyclosporin A on transport processes (uptake, efflux, binding) of mitoxantrone in isolated rat liver cells. Accumulation and binding of mitoxantrone was rapid with or without cyclosporin A. The initial uptake was linear over a wide concentration range (1 to 1000 microM). For the first 100 s, the rate of uptake is constant. The uptake clearance ranged from 12.53 +/- 3.9 to 33.77 +/- 15.1 nl.min-cell-1 for different extracellular concentrations of mitoxantrone. Also cyclosporin A did not modified this coefficient. Initial binding of mitoxantrone to cell plasma membrane was estimated and it was modified by different extracellular concentrations of mitoxantrone but not by cyclosporin A. Respectively at 60 seconds it accounted to 79.6% and 81.6% of the total transport. Influx of mitoxantrone was not temperature sensitive. We next examined the efflux of mitoxantrone from cells that were preloaded with drug. Initial efflux was rapid for the first 5 minutes. Cyclosporin A slightly decrease this efflux (7%). The data suggest that the mechanism of uptake of mitoxantrone is passive diffusion and that cyclosporin A a p-glycoprotein 170 inhibitor agent has only a weak effect on efflux.

A human liver plasma membrane model for the evaluation of the specific binding and transport processes of drugs presenting high hepatic clearance such as vinca alkaloids was developed. Uptake of the two structural antitumor analogs, navelbine (NVB) and vincristine (VCR), which exhibit wide variabilities in their respective pharmacokinetic parameters and antitumor spectra, was investigated. The high yield, the enzymatic profile and the retention of physiologic transport capacities, as demonstrated by taurocholate uptake, revealed that this membrane preparation was well suited for studies of hepatic drug transport systems. For both drugs two distinct processes were observed: mainly membrane binding and transport. NVB was found to bind to the membrane vesicles more intensively than VCR, but the transport processes were almost identical. However only NVB uptake seems to involve Na(+)-dependent processes. These significant differences may be related to the respective lipophilicity of the drugs. The more lipophilic molecule (NVB) presents the highest uptake, which is presumably at the origin of its greatest distribution volume in vivo.

A high-performance liquid chromatography method which uses direct injection and a column-switching valve for determination of mitoxantrone in plasma is described. After addition of internal standard, plasma was deproteinized by adding 5-sulphosalicylic acid reagent. The supernatant was injected onto an enrichment precolumn flushed with washing solvent (methanol and water 5:95). Absorbed mitoxantrone was backflushed from the precolumn into an analytical column C18 Nucleosil 250 x 4 mm with a gradient elution (solvent A, ammonium formate buffer 1.6 M, pH 4.3; solvent B, acetonitrile and water 40:60; linear gradient from 45 to 55% of B for 30 min was programmed) at a flow rate of 1.3 mL/min. Detection was carried out at 665 nm. This method showed obvious advantages over conventional extraction procedures in terms of speed and facility of sample handling.

Sixteen adult patients with relapsed (7 patients) or refractory (9 patients) acute leukemia received mitoxantrone (10 mg/m2 per day for 3 days) and etoposide (200 mg/m2 per day for 3 days) with escalating dose of cyclosporin A (CsA) from a loading dose of 2 mg to 6.5 mg/kg per 2 h followed by 3 days continuous infusion of 5-15 mg/kg per day. The major toxicities were stomatitis and prolonged aplasia, occurring for 15 mg/kg per day of CsA. Transient conjugated hyperbilirubinemia occurred in all patients, and was CsA dose-dependent (r = 0.7). Adequate serum levels of CsA (> 1 microgram/ml) were obtained in 3/6 patients treated with 10 mg/kg per day and 4/4 patients with 15 mg/kg per day. The pharmacokinetic of mitoxantrone showed an unusual increase of carboxylic metabolites, parallel to CsA levels. We observed six responses (two complete and four partial remissions), and eight resistances. Two patients died at days 3 and 8 from sepsis. Before treatment, 7/16 patients tested for P-gp with C219 were positive (> 10% positive cells). 3/6 responders were P-gp-positive. At time of leukemic regrowth, cells expressing P-gp before therapy reverted to P-gp-negative cells.

Purpose: The goal of this study was to develop a new technique to deliver drugs or other agents to the lumen of the angular aqueous plexus/Schlemm's canal (AAP/SC) while bypassing the trabecular meshwork, thereby gaining insight into AAP/SC inner wall function., Methods: The anterior chamber is held at a small negative pressure and fluid is allowed to flow retrograde from the limbal vessels, through the collector channels, and into the AAP/SC ("retroperfusion"). Facility measurements are combined with histologic and tracer studies in bovine eyes., Results: (1) Retroperfusion with a saline solution does not alter facility or change outflow pathway morphology; (2) fluid is able to move retrograde from the scleral surface and enter the lumen of the AAP; and (3) retroperfusion with N-ethyl maleimide causes a dose-dependent increase in washout rate and concomitant inner wall breaks., Conclusions: It is hypothesized that the observed increase in washout is due to leakage of extracellular materials through breaks in the inner wall.

The pineal hormone, melatonin, enhanced the sodium-independent binding of [3H]-gamma-aminobutyric acid ([3H]GABA) and [3H]muscimol in the rat cerebral cortex in vitro. This effect was augmented by preincubation of synaptic membranes with melatonin but was abolished by preincubation with Triton X-100. Saturation binding studies using [3H]GABA (2.5 to 1000 nM) indicated that the melatonin-induced enhancement of binding is due to an increase in low-affinity GABAA binding sites. These findings suggest that the central effects of melatonin involve modulation of GABAergic function.

The possible interaction of melatonin with the GABAergic system at the receptor level was investigated. The effect of melatonin on the binding of the GABA agonist, [3H]muscimol, in crude synaptic membrane preparations was assayed. In fresh membrane preparations, melatonin increased [3H]muscimol binding in the rat striatum and frontal cortex. Treatment of membrane preparations with Triton X-100 appeared to abolish or depress the enhancing effect of melatonin. The use of Tris HCl as buffer appeared to be more effective than Tris-Citrate buffer suggesting a possible important ionic effect. The present findings suggest that melatonin is capable of enhancing [3H]muscimol binding in vitro, perhaps at the benzodiazepine-GABA-receptor-ionophore complex.

The effect of kainic and quinolinic acid on cortical cholinergic function was examined following injections of these agents into the nucleus basalis magnocellularis (nbm) or into the frontoparietal cortex. The release of cortical 3H-acetylcholine (3H-ACh), high affinity choline uptake (HACU) and acetylcholinesterase was measured 7 days following injections of saline (control), kainic acid (4.7 nmoles) and quinolinic acid (60, 150 and 300 nmoles) into the nbm. These cortical cholinergic parameters were also examined after injections of saline (control), kainic acid (9.4 nmoles) and quinolinic acid (300 nmoles) into the fronto-parietal cortex. The release of 3H-ACh, HACU and AChE was significantly reduced in animals injected with kainic or quinolinic acid into the nbm. Histological examination of stained sections showed a loss of cell bodies in the region of the nbm and the globus pallidus. The size of the lesion produced by quinolinic acid was proportional to the dose injected into the nbm. In animals injected with kainic acid or quinolinic acid into the cerebral cortex, the release of 3H-ACh, HACU and AChE was not significantly reduced when compared with control animals, although histological examination of stained cortical sections showed a marked loss of cortical neurons. The results show that quinolinic acid, an endogenous neuroexcitant, produces a deficit of cholinergic function similar to that described in the cortical tissue of patients with senile dementia of Alzheimer's type. The toxic effects of quinolinic acid on cortical cholinergic function are due to its action on cholinergic cell bodies in the nbm.(ABSTRACT TRUNCATED AT 250 WORDS)