Cyclosporine A Decreases Dryness-Induced Hyperexcitability of Corneal Cold-Sensitive Nerve Terminals.

Cyclosporine A (CsA) is used for the treatment of dry eye (DE) with good clinical results, improving tear secretion and decreasing subjective symptoms. These effects are attributed to the improved tear film dynamics, but there are no data on the effect of CsA on the abnormal sensory nerve activity characteristic in DE. Our purpose was to evaluate the CsA effect on the enhanced activity of corneal cold thermoreceptors in a tear-deficient DE animal model using in vitro extracellular recording of cold thermoreceptors nerve terminal impulses (NTIs) before and in the presence of CsA. NTI shape was also analyzed. Blinking frequency and tearing rate were also measured in awake animals before and after topical CsA. CsA increased the tearing and blinking of treated animals. CsA significantly decreased the peak response to cold of cold thermoreceptors. Neither their spontaneous NTIs discharge rate nor their cooling threshold were modified. CsA also seemed to reverse some of the changes in NTI shape induced by tear deficiency. These data suggest that, at least in part, the beneficial clinical effects of CsA in DE can be attributed to a direct effect on sensory nerve endings, although the precise mechanisms underlying this effect need further studies to be fully clarified.

Assessment of Visual Quality Improvement as a Result of Spectacle Personalization.

Personalized spectacles customized according to an individual's facial anatomy were developed to provide enhanced visual performance and overall comfort when compared to standard spectacles. In this comparative crossover trial, each subject was randomly assigned to wear either personalized spectacles or standard spectacles for two weeks and then tried the second pair for another two weeks. Visual acuity and reading speed were measured, and visual quality and comfort were assessed using specific questionnaires. The correlation of the wearing parameters with the subjects' satisfaction was calculated. According to our results, the subjects wearing personalized glasses reported significantly less experience of swaying and significantly higher overall satisfaction compared to those wearing the control spectacles. At the end of the study, 62% of subjects preferred the personalized spectacles, and visual quality was the primary reason for their spectacle preference followed by wearing comfort. The difference from the ideal cornea-vertex distance was significantly lower when wearing the personalized spectacles compared to the control frames. In addition, the absolute value of the difference from the ideal cornea-vertex distance was significantly correlated with patient satisfaction. These results suggest that personalized spectacles, customized according to an individual's facial anatomy for the ideal wearing parameters, result in both visual and comfort advantages for wearers.

Intraocular neutralizing antibodies against aflibercept in patients with age related macular degeneration.

PURPOSE: To detect immunoglobulins in aqueous humour of AMD patients after repeated administration of intravitreal aflibercept. PATIENTS AND METHODS: Twenty-one patients (age: 77.85 ± 9.21 years) previously treated with intravitreal aflibercept due to wet type age-related macular degeneration (AMD group) and 18 age-matched control subjects (age: 69.75 ± 12.67 years) were included in this study. Patients in the AMD group received a mean of 5 intravitreal injections (min: 1 max: 17) prior to the cataract surgery. Samples of aqueous humour (50 µl) were obtained by anterior chamber paracentesis as the first step of routine cataract surgery. The IgG content of the samples was analysed by an in-house developed ELISA system. RESULTS: A significant increase in nonspecific IgG levels in the AMD group was detected compared to the control group (13.37 ± 6.65 vs. 9.44 ± 6.55 µg/ml; p = 0.03). In 11 patients, intraocular anti-aflibercept immunoglobulins could be detected (0.05 ± 0.01 µg/ml) which was significantly higher than the limit of detection for anti-aflibercept (0.04 µg/ml; p = 0.001). No correlation was found between the number of injections or the type of CNV and the aqueous level of anti-aflibercept (r = 0.02; p = 0.95). CONCLUSION: According to our results, penetration of non-specific systemic antibodies through the impaired blood-retinal barrier is higher in patients with neovascular AMD than in subjects with an intact structural barrier. Evaluation of neutralizing antibodies to anti-VEGF agents in the aqueous humour can lead us to understanding tachyphylaxis and changes in intraocular immune mechanisms due to AMD.

Matrix Metalloproteinase-2 Impairs Homing of Intracoronary Delivered Mesenchymal Stem Cells in a Porcine Reperfused Myocardial Infarction: Comparison With Intramyocardial Cell Delivery.

BACKGROUND: Intracoronary (IC) injection of mesenchymal stem cells (MSCs) results in a prompt decrease of absolute myocardial blood flow (AMF) with late and incomplete recovery of myocardial tissue perfusion. Here, we investigated the effect of decreased AMF on oxidative stress marker matrix metalloproteinase-2 (MMP-2) and its influence on the fate and homing and paracrine character of MSCs after IC or intramyocardial cell delivery in a closed-chest reperfused myocardial infarction (MI) model in pigs. METHODS: Porcine MSCs were transiently transfected with Ad-Luc and Ad-green fluorescent protein (GFP). One week after MI, the GFP-Luc-MSCs were injected either IC (group IC, 11.00 ± 1.07 × 106) or intramyocardially (group IM, 9.88 ± 1.44 × 106). AMF was measured before, immediately after, and 24 h post GFP-Luc-MSC delivery. In vitro bioluminescence signal was used to identify tissue samples containing GFP-Luc-MSCs. Myocardial tissue MMP-2 and CXCR4 receptor expression (index of homing signal) were measured in bioluminescence positive and negative infarcted and border, and non-ischemic myocardial areas 1-day post cell transfer. At 7-day follow-up, myocardial homing (cadherin, CXCR4, and stromal derived factor-1alpha) and angiogenic [fibroblast growth factor 2 (FGF2) and VEGF] were quantified by ELISA of homogenized myocardial tissues from the bioluminescence positive and negative infarcted and border, and non-ischemic myocardium. Biodistribution of the implanted cells was quantified by using Luciferase assay and confirmed by fluorescence immunochemistry. Global left ventricular ejection fraction (LVEF) was measured at baseline and 1-month post cell therapy using magnet resonance image. RESULTS: AMF decreased immediately after IC cell delivery, while no change in tissue perfusion was found in the IM group (42.6 ± 11.7 vs. 56.9 ± 16.7 ml/min, p = 0.018). IC delivery led to a significant increase in myocardial MMP-2 64 kD expression (448 ± 88 vs. 315 ± 54 intensity × mm2, p = 0.021), and decreased expression of CXCR4 (592 ± 50 vs. 714 ± 54 pg/tissue/ml, p = 0.006), with significant exponential decay between MMP-2 and CXCR4 (r = 0.679, p < 0.001). FGF2 and VEGF of the bioluminescence infarcted and border zone of homogenized tissues were significantly elevated in the IM goups as compared to IC group. LVEF increase was significantly higher in IM group (0.8 ± 8.4 vs 5.3 ± 5.2%, p = 0.046) at the 1-month follow up. CONCLUSION: Intracoronary stem cell delivery decreased AMF, with consequent increase in myocardial expression of MMP-2 and reduced CXCR4 expression with lower level of myocardial homing and angiogenic factor release as compared to IM cell delivery.

[Ocular surface squamous neoplasia]. / Szemfelszíni laphám-neoplasia.

To summarize actual knowledge on epidemiology, etiology, pathology, clinical apparence and treatment of ocular surface squamous neoplasias. We summarize up-to-date literature on conjunctival intraepithelial neoplasia and invasive squamous cell carcinoma and present some own cases. Ocular surface squamous neoplasia is the most common malignant ocular surface tumor and the third most common ocular malignancy following malignant melanoma and lymphoma. In spite of its low malignant potential, in advanced stages it may reduce visual acuity significantly or even the eye globe has to be removed. In case of metastasis it may also be life-threatening. As local recurrences of ocular surface squamous neoplasias may occur, knowledge of intra- and postoperative adjuvant treatment options are indispensable and regular control examinations are necessary. Identification and adequate treatment of ocular surface squamous neoplasias are necessary in order to avoid its progression and to prevent recurrences. Orv Hetil. 2017; 158(51): 2011-2022.

[Impact of crosslinking on corneal epithelial healing]. / Crosslinking kezelés hatása a szaruhártya hámosodására.

INTRODUCTION AND AIM: To analyse the effect of crosslinking (CXL) on corneal epithelial healing. PATIENTS AND METHOD: 39 keratoconus patients following CXL and 11 patients following PRK were enrolled in this study. 21, 45 and 69 hours after CXL and 16, 37 and 61 hours following PRK slitlamp photographs were taken using fluorescein staining and the size of the epithelial defect and the time of epithelial closure was determined. As the observation time-points differed in both groups, the size of the epithelial defect following PRK was calculated for the time points used for analysis of CXL patients. These data were compared using chi-quadrat test. RESULTS: Following crosslinking, epithelial closure occured within 3, following PRK within 4 days. In the area of epithelial erosion 45 and 69 hours after CXL or PRK treatment statistically significant difference (p = 0.005 and p<0.001) was verified. CONCLUSION: Our results show beneficial effect of crosslinking on corneal epithelial healing. Orv. Hetil., 2017, 158(10), 376-379.

[Relationship between corneal surface temperature and air flow conditions during refractive laser eye surgery using three different excimer lasers]. / A szaruhártya felszíni homérséklete és légáramlási viszonyainak alakulása refraktív célú lézeres beavatkozás közben három különbözo típusú és ismétlési frekvenciájú excimer lézerberendezésnél.

INTRODUCTION: Thermal conditions during photorefractive keratectomy might be an important issue related to the corneal wound healing and long-term outcomes. AIM: Authors tried to find out the importance of temperature conditions during the treatment. METHOD: One eye of 90 patients has been included into the study. Photorefractive keratoctomy was applied with Carl Zeiss MEL 70, MEL 80 and Wavelight Allegretto excimer lasers. EBRO TLC 730 infrared thermometer was used for the measurement of surface temperature of the cornea before epithelial removal, as well as before and after the treatment. Average age of the patients was 25.5 ± 3 yr. Average myopic correction was -3.2 ± 0.8 Dpt. RESULTS: Statistically significant difference was found in temperature change between MEL 80 and the other two types of excimer laser devices. CONCLUSIONS: Different air flow conditions of the smoke removal system might have an influence on changes of the corneal temperature during treatment, but the refractive results were not influenced by this issue. Orv. Hetil., 2016, 157(43), 1717-1721.

Evaluation of the mechanical properties of the anterior lens capsule following femtosecond laser capsulotomy at different pulse energy settings.

PURPOSE: To evaluate and compare the mechanical properties of anterior capsule opening performed with femtosecond laser capsulotomy at different energy settings in ex vivo porcine anterior lens capsule specimens. METHODS: Twenty-five fresh porcine eyes per group were included in the study. Femtosecond laser capsulotomy was performed with three different pulse energy levels: 2 µJ (low energy group), 5 µJ (intermediate energy group), and 10 µJ (high energy group). The capsule openings were stretched with universal testing equipment until they ruptured. The morphologic profile of the cut capsule edges was evaluated using scanning electron microscopy. RESULTS: The high energy group had significantly lower rupture force (108 ± 14 mN) compared to the intermediate energy group (118 ± 10 mN) (P < .05) and low energy group (119 ± 11 mN) (P < .05), but the difference between the intermediate energy and low energy groups was not significant (P = .9479). The high energy group had significantly lower circumference stretching ratio (144% ± 3%) compared to the intermediate energy group (148% ± 3%) (P < .05) and low energy group (148% ± 3%) (P < .05), but the difference between the intermediate energy group and low energy group was not significant (P = .9985). Scanning electron microscopy images showed that the edge was only serrated with low and intermediate energy, but additional signs of collagen melting and denaturation were observed at high energy. CONCLUSIONS: Anterior capsule openings created at a high energy level were slightly weaker and less extensible than those created at low or intermediate levels, possibly due to the increased thermal effect of photo-disruption.

Evaluation of intereye corneal asymmetry in patients with keratoconus. A scheimpflug imaging study.

PURPOSE: To assess the correlation between keratoconus severity and intereye asymmetry of pachymetric data and posterior elevation values and to evaluate their combined accuracy in discriminating normal corneas from those with keratoconus. METHODS: This study included 97 patients: 65 subjects with bilateral normal corneas (NC) and 32 with keratoconus (KC). Central corneal thickness (CCT), thinnest corneal thickness (ThCT) and posterior elevation (PE) at the thinnest point of the cornea were measured in both eyes using Scheimpflug imaging. Intereye asymmetry and its correlation with keratoconus severity were calculated for each variable. The area under the receiver operating characteristic curve (AUROC) was used to compare predictive accuracy of different variables for keratoconus. RESULTS: In normal eyes, intereye differences were significantly lower compared with the keratoconus eyes (p<0.001, for CCT, ThCT and PE). There was a significant exponential correlation between disease severity and intereye asymmetry of steep keratometry (r2 = 0.55, p<0.001), CCT (r2 = 0.39, p<0.001), ThCT (r2 = 0.48, p<0.001) and PE (r2 = 0.64, p<0.001). After adjustment for keratoconus severity, asymmetry in thinnest pachymetry proved to be the best parameter to characterize intereye corneal asymmetry in keratoconus. This variable had high accuracy and significantly better discriminating ability (AUROC: 0.99) for KC than posterior elevation (AUROC: 0.96), ThCT (AUROC: 0.94) or CCT (AUROC: 0.92) alone. CONCLUSIONS: There is an increased intereye asymmetry in keratometry, pachymetry and posterior corneal elevation values in keratoconic patients compared to subjects with normal corneas. Keratoconus patients with more severe disease are also more asymmetric in their disease status which should be taken into account during clinical care.

Comparison of the mechanical properties of the anterior lens capsule following manual capsulorhexis and femtosecond laser capsulotomy.

PURPOSE: To evaluate and compare the mechanical properties of anterior capsule openings performed with the continuous curvilinear capsulorhexis (CCC) technique and femtosecond laser capsulotomy (FLC) in ex vivo porcine lens capsule specimens. METHODS: Fresh porcine eyes were included in the study (CCC group, n = 50; FLC group, n = 30). The capsule openings were stretched with universal testing equipment until they ruptured. The rupture force and circumference stretching ratio were evaluated. The morphologic profile of the cut capsule edges was evaluated using scanning electron microscopy (SEM). RESULTS: The average rupture force was higher in the CCC group (median: 155 mN; interquartile range [IQR]: 129 to 201 mN; range: 71 to 294 mN) than in the FLC group (median: 119 mN; IQR: 108 to 128 mN; range: 91 to 142 mN) (P < .01, Mann-Whitney U test). The average circumference stretching ratio in the CCC group was greater (median: 150%; IQR: 146% to 156%; range: 136% to 161%) than in the FLC group (median: 148%; IQR: 145% to 150%; range: 141% to 154%) (P = .0468, Mann-Whitney U test). When less than 71 mN, no capsular tear occurred in either group. When less than 91 mN, no capsular tear occurred in the FLC group, whereas at 91 mN, the probability of capsular tears was 9% for the CCC group. SEM examination found that the CCC group had smooth edges, whereas those of the FLC group were gently serrated. CONCLUSIONS: According to the current results in a porcine eye model, FLC had less average resistance to capsule tear than CCC, but the weakest openings were seen in the CCC group.

Analysis of planned and postoperatively measured flap thickness after LASIK using the LenSx multifunctional femtosecond laser system.

PURPOSE: To evaluate LASIK corneal flaps using a multifunctional femtosecond laser suitable for cataract and corneal surgery (LenSx; Alcon Laboratories, Inc., Aliso Viejo, CA) and to compare the planned and postoperatively measured flap thickness using an anterior segment optical coherence tomography device (AS-OCT). METHODS: Twenty patients (38 eyes) diagnosed as having myopia and myopic astigmatism were enrolled. LASlK was performed using the LenSx femtosecond laser for intracorneal flaps and the Wavelight Allegretto 400 excimer laser (Alcon Laboratories, Inc.) for intra- stromal photoablation. Desired flap thickness and diameter were 140.0 + 0.0 pm and 8.5 + 0.0 mm, respectively, whereas mean ablation depth and diameter of the excimer laser treatment were 67.9 ± 24.18 pm and 6.5 ± 0.08 mm, respectively. Entered data of the LenSx femtosecond laser were used to determine desired flap thickness, whereas AS-OCT (RTVue; Optovue, Inc., Fremont, CA) was used to measure flap thickness postoperatively. The Wilcoxon signed-rank test, dependent paired t test, and Friedman test were used for comparison of dependent and repeated measures. RESULTS: There was no statistically significant difference in the planned and postoperatively measured flap thickness (140.0 ± 0.0 vs 140.28 _ 8.0 pm; P = .4067). Interfaces of the flaps had even surfaces according to the images and calculations on the AS-OCT device (P = .058). CONCLUSIONS: Application of this multifunctional femtosecond laser performing LASIK proved to be a safe and effective method regarding predictability of flap thickness.

Aromatase and estrogen receptor beta expression in the rat olfactory bulb: Neuroestrogen action in the first relay station of the olfactory pathway?

The expression pattern of aromatase (ARO), the enzyme converting androgens to estrogens, was analyzed in the olfactory bulb of adult male rats and was compared with the distribution of estrogen receptor beta (ERbeta), the main estrogen receptor isoform expressed in this brain region. A strong ARO immunolabeling obtained with a specificity tested antibody was observed in juxtaglomerular neurons of the glomerular layer and a weaker immunoreaction was detected in the mitral cell layer of the main olfactory bulb, while the granule cell layer of the main olfactory bulb as well as all layers in the accessory olfactory bulb showed faint immunolabeling. Fluorescence double labeling experiments revealed that ARO detected in juxtaglomerular neurons of the main olfactory bulb colocalized with tyrosine hydroxylase (TH) and glutamic acid decarboxylase 67 (GAD67), while no colocalization between ARO and the calcium binding proteins calretinin (CR) and calbindin (CB) was observed. Furthermore, the TH immunoreactive neurons expressed metabotropic glutamate receptor 1 (mGluR1) too. ERß immunoreactivity, in contrast to ARO, was detected in all layers of both the main and accessory olfactory bulb. In the glomerular layer of the main olfactory bulb it was expressed in TH and GAD67 containing juxtaglomerular neurons, and it colocalized with CR, CB and even with glial fibrillary acidic protein too. Our morphological findings suggest that ARO expression is a novel feature of dopaminergic/GABAergic juxtaglomerular neurons in the adult rat main olfactory bulb, and raise the possibility that ARO activity may change in function of olfactory input via mGluR1. In situ estrogen production in the olfactory bulb in turn may modulate interglomerular circuits through ERbeta.

Changes of corneal topography indices after CXL in progressive keratoconus assessed by Scheimpflug camera.

PURPOSE: To evaluate the accuracy of Scheimpflug camera topography indices in detecting the therapeutic effect of corneal collagen cross-linking (CXL) on progressive keratoconus in the long term. METHODS: Fifty eyes of 25 patients with keratoconus were enrolled. CXL was performed in 25 eyes with progressive keratoconus (CXL group) and 25 fellow eyes with nonprogressive keratoconus served as controls. Thinnest corneal thickness, anterior keratometry (flat, steep), and keratoconus indices were measured with Scheimpflug camera before and 12 to 25 months after CXL. Regression analysis was used to evaluate the influence of corneal thickness and follow-up time on flattening effect of CXL. RESULTS: At baseline, steep keratometric values were significantly higher and thinnest corneal thickness values were lower in the CXL group (P = .027, .034), parallel with increased values of keratoconus indices: index of surface variance (P = .013), index of vertical asymmetry (P = .038), keratoconus index (P = .019), center keratoconus index (P = .039), index of height asymmetry (P = .037), index of height decentration (P = .0016), and radius minimum (P = .008). After adjustment for thinnest corneal thickness and follow-up time, CXL showed significant flattening effect expressed by changes in radius minimum (P < .001), index of surface variance (P = .03), keratoconus index (P = .006), center keratoconus index (P = .03), and index of height asymmetry (P = .026). Thinnest corneal thickness had significant influence on changes of index of surface variance (P = .049), index of vertical asymmetry (P = .01), and center keratoconus index (P = .03). Follow-up time showed no significant influence in any models (P > .05). CONCLUSIONS: Topographic indices indicate corneal flattening after CXL in the long term. Monitoring keratoconus index and index of height asymmetry should be the preferred choice in daily clinical practice because changes in values of these indices are independent from initial corneal thickness.

Wavefront properties of the anterior and posterior corneal surface after photorefractive keratectomy.

PURPOSE: The aim of this study was to evaluate the balance and changes of corneal higher order aberrations (HOAs) after photorefractive keratectomy (PRK). METHODS: Myopic and myopic-astigmatic patients (89 eyes of 48 patients) were enrolled in this study. A PRK was performed using an Asclepion Meditec MEL 80 G flying-spot excimer laser. The mean ablation depth and diameter were 76.78 µm (±19.40 µm) and 6.0 mm (±0.06 mm), respectively. Before and 1 year after the surgery, uncorrected and best spectacle-corrected visual acuities were determined. Wavefront aberrations of the anterior [root mean square (RMS)-HOA anterior], posterior (RMS-HOA posterior), and total cornea (RMS-HOA total) were measured using a Scheimpflug Camera. Linear piecewise regression analysis was used for correlations between the ablation depth and aberration of the anterior corneal surface. The follow-up time was 1 year. RESULTS: At baseline, RMS-HOA anterior proved to be significantly higher compared with RMS-HOA total (P < 0.001). After the PRK was performed, the RMS-HOA anterior (P < 0.001) and RMS-HOA total values (P < 0.001) increased significantly; however, RMS-HOA posterior values (P = 0.12) remained stable. Above an ablation depth of 76.78 µm, the RMS-HOA anterior increased 2.4-fold. Uncorrected and best spectacle-corrected visual acuities were 1.0 (20/20) in 95.5% and 98.8% of the patients 1 year postoperatively. CONCLUSIONS: Aberrations of the posterior corneal surface seem to compensate for wavefront alterations of the anterior cornea, decreasing the amount of wavefront error regarding the total cornea in myopic patients. PRK induced increased HOAs with respect to the anterior corneal surface; however, the posterior surface remained stable. The increase in the HOAs was measured to be significantly larger above 76.78 µm photoablation depth.

Complications of femtosecond laser-assisted cataract surgery.

PURPOSE: To analyze complications of femtosecond lasers used for cataract surgery. SETTING: Department of Ophthalmology Semmelweis University, Budapest, Hungary. DESIGN: Retrospective analysis. METHODS: Intraoperative complications of the first 100 femtosecond laser-assisted (Alcon-Lensx, Inc.) cataract surgeries were collected. Possible complications of femtosecond capsulotomies and their management were also assessed. RESULTS: The complications were as follows: suction break (2%), conjunctival redness or hemorrhage (34%), capsule tags and bridges (20%), anterior tear (4%), miosis (32%), and endothelial damage due to cut within the endothelial layer (3%). There were no cases of capsule blockage or posterior capsule tear. During the learning curve, there was no complication that would require vitrectomy. All complications occurred during the first 100 cases. CONCLUSIONS: Femtosecond laser cataract surgery had a learning curve during the first 100 cases. With cautious surgical technique, the complications can be avoided. The femtosecond laser-assisted method was efficient and safe for cataract surgery.

Femtosecond laser-assisted cataract surgery in management of phacomorphic glaucoma.

PURPOSE: To report the use of femtosecond laser-assisted cataract surgery in management of phacomorphic glaucoma. METHODS: An 89-year-old patient developed acute phacomorphic glaucoma in her right eye with elevated intraocular pressure (62 mm Hg), shallow anterior chamber, and mature cataract. After conservative antiglaucoma therapy and Nd:YAG iridotomy, femtosecond laser-assisted cataract surgery was performed. A Malyugin ring was implanted for mechanical pupil dilatation and a 4.8-mm capsulorrhexis and lens fragmentation was performed using a femtosecond laser system (Alcon LenSx Inc., Aliso Viejo, CA) followed by in-the-bag intraocular lens implantation. RESULTS: Intact 4.8-mm capsulorrhexis and successful lens fragmentation could be performed using femtosecond laser. After cataract surgery, the patient's visual acuity increased from hand motions to 0.4 (Snellen 4/10) and the intraocular pressure returned to normal range without antiglaucoma drop therapy. CONCLUSIONS: The results indicate that femtosecond laser can be successfully used in certain cases of phacomorphic glaucoma, even if mechanical pupil dilatation is needed.

Computer-aided structure analysis of an epimerized dehydroepiandrosterone derivative and its biological effect in a model of reactive gliosis.

The naturally occurring steroid dehydroepiandrosterone (DHEA) is reported to reduce glial fibrillary acidic protein (GFAP) overexpression in a model of reactive gliosis due to its conversion to estradiol by the enzyme aromatase. In the present study we examined the biological effect of a new epimerized derivative of DHEA, 16alpha-iodomethyl-13alpha-dehydroepiandrosterone derivative (16alpha-iodomethyl-13alpha-DHEAd, 16alpha-iodomethyl-13alpha-androst-5-en-3beta,17beta-diol), using the same model system, and compared the 3D structure of this molecule with that of DHEA and two steroidal type aromatase inhibitors, formestane and exemestane. The synthetic compound, in contrast to the reported effect of DHEA, was able to reduce GFAP overexpression only if the enzyme aromatase was inhibited. Data obtained from computational calculations fortified by X-ray crystallography revealed that contrary to the nearly planar sterane framework of DHEA, the synthetic derivative 16alpha-iodomethyl-13alpha-DHEAd has a bent sterane skeleton, resulting in a 3D structure that is similar to that of formestane or exemestane. Moreover, 16alpha-iodomethyl-13alpha-DHEAd resulted to be metabolically more stable than DHEA. The results suggest that epimerization of the sterane skeleton of DHEA inclines the plane of the D ring, leading to a significantly altered biological activity. The synthetic molecule has a DHEA-like effect on GFAP overexpression when the enzyme aromatase is inhibited and the naturally occurring DHEA is ineffective in this respect. On the other hand, based on their structural similarity it can be hypothesized that 16alpha-iodomethyl-13alpha-DHEAd applied alone might have a biological effect similar to that of formestane or exemestane.

Estradiol-induced synaptic remodeling of tyrosine hydroxylase immunopositive neurons in the rat arcuate nucleus.

Gonadal steroids induce synaptic plasticity in several areas of the adult nervous system. In the arcuate nucleus of adult female rats, 17beta-estradiol triggers synaptic remodeling, resulting in a decrease in the number of inhibitory synaptic inputs, an increase in the number of excitatory synapses, and an enhancement of the frequency of neuronal firing. In the present paper, we studied the specificity of hormonal effects by determining the changes in synaptic connectivity of tyrosine hydroxylase (TH) immunoreactive (IR) neurons in the arcuate nucleus. We combined pre-embedding TH and post-embedding gamma-aminobutyric acid (GABA) immunostaining, and performed unbiased stereological measurements in gonadectomized and 17beta-estradiol-treated rats. We conclude that the synaptic connectivity of the TH-IR neurons is different from the other, nonlabeled population, and the response to estradiol is not uniform. TH-IR (dopaminergic) arcuate neurons of both male and female rats have more GABAergic (inhibitory) axosomatic inputs than the nondopaminergic population. Our study shows that the effect of 17beta-estradiol is sex and cell specific in the sense that not all arcuate neurons are affected by the structural synaptic remodeling. In ovariectomized females hormone treatment decreased the numerical density of GABAergic axosomatic synapses on TH-IR, but not on nondopaminergic, neurons, whereas in orchidectomized males, 17beta-estradiol treatment increased inhibitory synapses onto nondopaminergic neurons but did not affect the number of inhibitory terminals onto TH-IR neurons. The hormone-induced plastic changes in synaptic connectivity of TH-IR neurons may serve as the morphological basis for the cyclical regulation of the anterior pituitary.