Impact of Direct-Acting Antiviral Therapy on Liver Fibrosis Regression among People with Chronic HCV Infection: Results from a Real-Life Cohort in Patients Who Achieved Sustained Virological Response.

Background and Objectives: The global prevalence of chronic hepatitis C virus (HCV) infection is 0.8%, affecting around 58 million people worldwide. Treatment with DAAs reduces all-cause HCV mortality by 49-68%. This work aims to determine whether there is liver fibrosis regression (LFR) in patients who achieved Sustained Virological Response (SVR) after treatment with DAAs. Materials and Methods: An analytical, observational, single-center, and cohort study was carried out. The final sample consisted of 248 HCV-infected patients. All started treatment with DAAs between January 2015 and December 2017. Five measurements were performed to determine the fibrotic stage in patients (measured in kilopascals (kPa)) using transient elastography (FibroScan®, Echosens, The Netherlands). Results: Taking the baseline fibrotic stage as a reference, the distribution in subgroups was as follows: 77 F4 patients (31.0%); 55 F3 patients (22.2%); 53 F2 patients (21.4%); and 63 F0/F1 patients (25.4%). There were 40 patients (16.1%) with at least one HCV complication and 13 (5.2%) who developed hepatocellular carcinoma. The overall LFR rate was 77.8% (144 of 185 F2/F3/F4 patients, p = 0.01) at the end of the follow-up period. The highest mean FibroScan® values were observed in patients with: "male gender"; "metabolic syndrome"; "subtype 1a"; "NRP DAA"; "at least one HCV complication"; "death from HCV complications"; and "liver transplantation requirement". Conclusions: Treatment with DAAs achieved high rates of LFR and a decrease in mean FibroScan® values in all subgroups.

Viral RNA load in plasma is associated with critical illness and a dysregulated host response in COVID-19.

BACKGROUND: COVID-19 can course with respiratory and extrapulmonary disease. SARS-CoV-2 RNA is detected in respiratory samples but also in blood, stool and urine. Severe COVID-19 is characterized by a dysregulated host response to this virus. We studied whether viral RNAemia or viral RNA load in plasma is associated with severe COVID-19 and also to this dysregulated response. METHODS: A total of 250 patients with COVID-19 were recruited (50 outpatients, 100 hospitalized ward patients and 100 critically ill). Viral RNA detection and quantification in plasma was performed using droplet digital PCR, targeting the N1 and N2 regions of the SARS-CoV-2 nucleoprotein gene. The association between SARS-CoV-2 RNAemia and viral RNA load in plasma with severity was evaluated by multivariate logistic regression. Correlations between viral RNA load and biomarkers evidencing dysregulation of host response were evaluated by calculating the Spearman correlation coefficients. RESULTS: The frequency of viral RNAemia was higher in the critically ill patients (78%) compared to ward patients (27%) and outpatients (2%) (p < 0.001). Critical patients had higher viral RNA loads in plasma than non-critically ill patients, with non-survivors showing the highest values. When outpatients and ward patients were compared, viral RNAemia did not show significant associations in the multivariate analysis. In contrast, when ward patients were compared with ICU patients, both viral RNAemia and viral RNA load in plasma were associated with critical illness (OR [CI 95%], p): RNAemia (3.92 [1.183-12.968], 0.025), viral RNA load (N1) (1.962 [1.244-3.096], 0.004); viral RNA load (N2) (2.229 [1.382-3.595], 0.001). Viral RNA load in plasma correlated with higher levels of chemokines (CXCL10, CCL2), biomarkers indicative of a systemic inflammatory response (IL-6, CRP, ferritin), activation of NK cells (IL-15), endothelial dysfunction (VCAM-1, angiopoietin-2, ICAM-1), coagulation activation (D-Dimer and INR), tissue damage (LDH, GPT), neutrophil response (neutrophils counts, myeloperoxidase, GM-CSF) and immunodepression (PD-L1, IL-10, lymphopenia and monocytopenia). CONCLUSIONS: SARS-CoV-2 RNAemia and viral RNA load in plasma are associated with critical illness in COVID-19. Viral RNA load in plasma correlates with key signatures of dysregulated host responses, suggesting a major role of uncontrolled viral replication in the pathogenesis of this disease.

On the microscopic origin of the cryoprotective effect in lysine solutions.

The amino acid lysine has been shown to prevent water crystallization at low temperatures in saturated aqueous solutions [S. Cerveny and J. Swenson, Phys. Chem. Chem. Phys., 2014, 16, 22382-22390]. Here, we investigate two ratios of water and lysine (5.4 water molecules per lysine (saturated) and 11 water molecules per lysine) by means of the complementary use of computer simulations and neutron diffraction. By performing a detailed structural analysis we have been able to explain the anti-freeze properties of lysine by the strong hydrogen bond interactions of interstitial water molecules with lysine that prevent them from forming crystalline seeds. Additional water molecules beyond the 1 : 5.4 proportion are no longer tightly bonded to lysine and therefore are free to form crystals.

pH Impacts the Orientation of Antibody Adsorbed onto Gold Nanoparticles.

Novel detection strategies that exploit the unique properties of gold nanoparticles (AuNPs) hold great promise for the advancement of diagnostic testing. Fundamental to many of these nanoparticle-enabled techniques is the immobilization of antibodies onto the AuNP surface to afford selective binding to target species. Orientation and loading density of the immobilized antibodies govern Fab accessibility and are critical to the analytical performance. Here, we use pH to systematically control the surface charge distribution on an antibody and investigate the impact of protein charge on adsorption to AuNPs. Nanoparticle tracking analysis (NTA) is used to measure the adsorption dynamics of anti-horseradish peroxidase antibody (anti-HRP) onto AuNPs at different pHs. NTA enables in situ measurement of antibody adsorption on AuNP by measuring the increase in hydrodynamic diameter ( DH) of the AuNPs as a function of antibody concentration. The adsorption affinity, protein layer thickness, and binding cooperativity at each pH are extracted from the best fit of the adsorption isotherms to the Hill-modified Langmuir equation. Our data show a monolayer of antibody is formed at saturation at pHs 7.5, 8.0, and 8.5, and no difference in anti-HRP-AuNP binding constants is observed in this pH range ( Kd ∼11 nM). However, the increase in DH of the AuNPs with adsorbed protein at monolayer coverage is pH-dependent, measuring 13.2 ± 1.1 nm, 9.8 ± 1.0 nm, and 7.4 ± 0.6 nm for pHs 7.5, 8.0, and 8.5, respectively. Moreover, results of an enzyme-mediated assay reveal the antigen-binding capacity of the immobilized anti-HRP antibody is 33 ± 2%, 23 ± 7%, and 18 ± 2% when adsorbed at pHs 7.5, 8.0, and 8.5, respectively. Our data confirm that antibody charge can be altered with pH to modulate and optimize antibody orientation on AuNP. These studies describe our continued efforts to establish design criteria to prepare conjugates with maximum antigen-binding activity that will enhance the performance of biofunctional nanomaterials.

Antibodies Irreversibly Adsorb to Gold Nanoparticles and Resist Displacement by Common Blood Proteins.

Gold nanoparticles (AuNPs) functionalized with proteins to impart desirable surface properties have been developed for many nanobiotechnology applications. A strong interaction between the protein and nanoparticle is critical to the formation of a stable conjugate to realize the potential of these emerging technologies. In this work, we examine the robustness of a protein layer adsorbed onto gold nanoparticles while under the stress of a physiological environment that could potentially lead to protein exchange on the nanoparticle surface. The adsorption interaction of common blood plasma proteins (transferrin, human serum albumin, and fibrinogen) and anti-horseradish peroxidase antibody onto AuNPs is investigated by nanoparticle tracking analysis. Our data show that a monolayer of protein is formed at saturation for each protein, and the maximum size increase for the conjugate, relative to the AuNP core, correlates with the protein size. The binding affinity of each protein to the AuNP is extracted from a best fit of the adsorption isotherm to the Hill equation. The antibody displays the greatest affinity (Kd = 15.2 ± 0.8 nM) that is ∼20-65 times stronger than the affinity of the other plasma proteins. Antibody-AuNP conjugates were prepared, purified, and suspended in solutions of blood plasma proteins to evaluate the stability of the antibody layer. An enzyme-mediated assay confirms that the antibody-AuNP interaction is irreversible, and the adsorbed antibody resists displacement by the plasma proteins. This work provides insight into the capabilities and potential limitations of antibody-AuNP-enabled technologies in biological systems.

Calorimetric study of water's two glass transitions in the presence of LiCl.

A DSC study of dilute glassy LiCl aqueous solutions in the water-dominated regime provides direct evidence of a glass-to-liquid transition in expanded high density amorphous (eHDA)-type solutions. Similarly, low density amorphous ice (LDA) exhibits a glass transition prior to crystallization to ice Ic. Both glass transition temperatures are independent of the salt concentration, whereas the magnitude of the heat capacity increase differs. By contrast to pure water, the glass transition endpoint for LDA can be accessed in LiCl aqueous solutions above 0.01 mole fraction. Furthermore, we also reveal the endpoint for HDA's glass transition, solving the question on the width of both glass transitions. This suggests that both equilibrated HDL and LDL can be accessed in dilute LiCl solutions, supporting the liquid-liquid transition scenario to understand water's anomalies.

Relaxation Dynamics vs Crystallization Kinetics in the Amorphous State: The Case of Stiripentol.

With the aim of finding a correlation between the crystallization kinetics and the molecular dynamics of a substance that would allow prediction of its crystallization time as a function of temperature for a given α relaxation time, we have studied stiripentol, an anticonvulsant drug. Stiripentol has been characterized in its supercooled liquid, amorphous (glass), and crystalline states by the concurrent use of broadband dielectric spectroscopy (BDS), differential scanning calorimetry, X-ray diffraction, and optical microscopy. BDS was employed to study both the dipolar molecular dynamics and the kinetics of crystallization from the melt. Three different molecular relaxation dynamics were identified: an α relaxation corresponding to the collective reorientation of the molecules and associated with the glass transition (Tg = 246.2 ± 0.5 K), a Johari Goldstein ß relaxation that can be associated with the single-molecule precursor of the α process, and a γ relaxation arising from intramolecular motions. Isothermal crystallization of Stiripentol was studied by means of BDS well above the glass transition (between 273 and 293 K), and it was observed under optical microscope at ambient conditions. Stiripentol did not exhibit any sign of polymorphism at ambient pressure, and it recrystallized from the melt into its stable crystalline form. The crystallization kinetics did not obey the Avrami law. Stiripentol displayed a very low nucleation rate, and drops of liquid stiripentol were observed to crystallize completely from a single nucleus before the appearance of new nuclei, so that the crystallite grew according to the morphology of the liquid domains, a fact that might explain the lack of validity of the Avrami law. Possible correlations between the crystallization kinetics and the molecular dynamics have been analyzed, finding that the crystallization time has a sublinear dependence on the cooperative relaxation time, as is the case in other substances reported in the scientific literature. This could suggest a general correlation of these parameters, at least at temperatures above Tg. The low nucleation rate is an interesting feature in the quest of possible mechanisms that allow enhancing the physical stability of amorphous drugs.

On the structure of prilocaine in aqueous and amphiphilic solutions.

The solvation of prilocaine has been investigated in pure water and in an amphiphilic methanol/water solution using a combination of neutron diffraction with isotopic substitution augmented by Empirical Potential Structure Refinement (EPSR) simulations. This combination of techniques allows for details of the solvation structure on the atomic scale to be unravelled. The hydration of prilocaine is significantly altered relative to when this molecule is in pure water (as a hydrochloride salt) or in an amphiphilic environment (as a freebase compound). Interestingly, there is not a significant change in hydration around the amine group on prilocaine hydrochloride compared with prilocaine as a freebase. Despite this group being an ammonium group in water and an amine group in methanol/water solutions, the hydration of this motif remains largely intact. The changes in hydration between prilocaine as a free base and prilocaine·HCl instead appears to arise from a change in hydration around the aromatic ring and the amide group in the prilocaine molecule.

Increased blood draws for ultrasensitive ctDNA and CTCs detection in early breast cancer patients.

Early breast cancer patients often experience relapse due to residual disease after treatment. Liquid biopsy is a methodology capable of detecting tumor components in blood, but low concentrations at early stages pose challenges. To detect them, next-generation sequencing has promise but entails complex processes. Exploring larger blood volumes could overcome detection limitations. Herein, a total of 282 high-volume plasma and blood-cell samples were collected for dual ctDNA/CTCs detection using a single droplet-digital PCR assay per patient. ctDNA and/or CTCs were detected in 100% of pre-treatment samples. On the other hand, post-treatment positive samples exhibited a minimum variant allele frequency of 0.003% for ctDNA and minimum cell number of 0.069 CTCs/mL of blood, surpassing previous investigations. Accurate prediction of residual disease before surgery was achieved in patients without a complete pathological response. A model utilizing ctDNA dynamics achieved an area under the ROC curve of 0.92 for predicting response. We detected disease recurrence in blood in the three patients who experienced a relapse, anticipating clinical relapse by 34.61, 9.10, and 7.59 months. This methodology provides an easily implemented alternative for ultrasensitive residual disease detection in early breast cancer patients.

Assessment of the differences in pharmacokinetics and pharmacodynamics between four distinct formulations of triamcinolone acetonide.

PURPOSE: To compare the durability of Kenalog, Trivaris, Triesence, and compounding pharmacy preservative-free triamcinolone acetonide in pigmented rabbits with syneretic vitreous using direct visualization, pharmacodynamics, and pharmacokinetics. METHODS: Twenty-five Dutch-belted rabbits were used. Pharmacokinetic experiment: Rabbits were intravitreally injected with one of four 4-mg triamcinolone acetonide formulations. Wide-field imaging was serially performed to document residual drug mass. Pharmacodynamics experiment: Four triamcinolone acetonide groups and one control group received intravitreal recombinant human vascular endothelial growth factor 165 every 2 weeks and were followed with fluorescein angiography to assess vascular endothelial growth factor retinal vasculopathy as a measure of residual steroid effect. Particle size of the formulations was measured with Mastersizer 2000. RESULTS: Remaining triamcinolone acetonide mass after 19 weeks: 12,091 ± 2,512 pixels for the Kenalog group, 1,307.36 ± 695.57 for Trivaris, 5577 ± 1477 for Triesence, and 1,535 ± 329 for compounded preservative-free triamcinolone acetonide. Kenalog suppressed recombinant human vascular endothelial growth factor-induced retinopathy more effectively than the other triamcinolone acetonide groups at Week 39, the final time point assessed. Particle size (90th percentile) was 47 µm for Kenalog, 26 µm for Triesence, and 22 µm for both compounded preservative-free triamcinolone acetonide and Trivaris. CONCLUSION: Triamcinolone acetonide formulations do not have the same pharmacokinetics/pharmacodynamics. Kenalog has the longest vitreous visibility and durability. Particle size appears to correlate with efficacy and durability.

Outcomes of COVID-19 Among Hospitalized Patients With Non-dialysis CKD.

Background: Coronavirus disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome-Corona Virus 2 has generated significant impact on global health worldwide. COVID-19 can cause pneumonia and organ injury. Chronic kidney disease (CKD) has been associated with increased mortality in previous epidemics, but there is a paucity of data regarding actual risks for non-dialysis CKD patients with COVID-19. Methods: Multicenter, observational cohort study including 136 non-dialysis CKD patients and 136 age- and sex-matched controls that required hospitalization due to COVID-19. Patients with end-stage renal disease, a kidney transplant or without registered baseline glomerular filtration rate prior to COVID-19 infection were excluded. CKD and acute kidney injury (AKI) were defined according to KDIGO criteria. Results: CKD patients had higher white blood cell count and D-dimer and lower lymphocyte percentage. No differences were found regarding symptoms on admission. CKD was associated with higher rate of AKI (61 vs. 24.3%) and mortality (40.4 vs. 24.3%). Patients with AKI had the highest hazard for death (AKI/non-CKD HR:7.04, 95% CI:2.87-17.29; AKI/CKD HR:5.25, 95% CI: 2.29-12.02), followed by CKD subjects without AKI (HR:3.39, 95% CI:1.36-8.46). CKD status did not condition ICU admission or length of in-hospital stay. Conclusions: CKD patients that require hospitalization due to COVID-19 are exposed to higher risk of death and AKI.

Effects of Trypanosoma cruzi on the phenoloxidase and prophenoloxidase activity in the vector Meccus pallidipennis (Hemiptera: Reduviidae).

BACKGROUND: Triatomine insects are vectors of Trypanosoma cruzi, the causal agent of Chagas disease. The insect-parasite interaction has been studied in relation to the transmission and prevalence of this disease. For most triatomines, however, several crucial aspects of the insect immune response are still unknown. For example, only for Rhodnius prolixus and Triatoma infestans has the activity of phenoloxidase (PO) and its zymogen prophenoloxidase (proPO) been reported in relation to the hemolymph and anterior midgut (AM). The aim of this study was to gain insight into the immune response to T. cruzi infection of an important triatomine in Mexico, Meccus pallidipennis. METHODS: Parasites were quantified in the rectal contents of infected M. pallidipennis groups. We examined some key factors in disease transmission, including the systemic (hemolymph) and local (gut) immune response. RESULTS: Parasites were present in the rectal contents at 4 days post-infection (pi) and reached their maximum density on day 7 pi. At 7 and 9 days pi mainly metacyclic trypomastigotes occurred. Compared to the control, the infected insects exhibited diminished PO activity in the hemolymph on days 9, 16 and 20 pi, and in the AM only on day 9. Additionally, infected insects displayed lower proPO activity in the hemolymph on day 1, but greater activity in the AM on day 28. CONCLUSIONS: The parasite strain originating from M. pallidipennis rapidly colonized the rectum of nymphs of this triatomine and developed high numbers of metacyclic trypomastigotes. Neither the changes of concentrations of PO and proPO in the hemolymph nor in the AM correlated with the changes in the population of T. cruzi.

Genuine antiplasticizing effect of water on a glass-former drug.

Water is the most important plasticizer of biological and organic hydrophilic materials, which generally exhibit enhanced mechanical softness and molecular mobility upon hydration. The enhancement of the molecular dynamics upon mixing with water, which in glass-forming systems implies a lower glass transition temperature (T g ), is considered a universal result of hydration. In fact, even in the cases where hydration or humidification of an organic glass-forming sample result in stiffer mechanical properties, the molecular mobility of the sample almost always increases with increasing water content, and its T g decreases correspondingly. Here, we present an experimental report of a genuine antiplasticizing effect of water on the molecular dynamics of a small-molecule glass former. In detail, we show that addition of water to prilocaine, an active pharmaceutical ingredient, has the same effect as that of an applied pressure, namely, a decrease in mobility and an increase of T g . We assign the antiplasticizing effect to the formation of prilocaine-H 2 O dimers or complexes with enhanced hydrogen bonding interactions.

Evoked expression of the glutamate transporter GLT-1c in retinal ganglion cells in human glaucoma and in a rat model.

PURPOSE: Glaucoma is a common disease of the eye, a key characteristic consequence of which is the death of retinal ganglion cells. The cause of this loss is unknown, though glutamate-mediated toxicity has been implicated. Glutamate transporters are key regulators of glutamate; therefore, the purpose of the study was to determine whether unusual excitation is associated with unusual expression of one or more transporters. METHODS: The expression of a splice variant of the glutamate transporter GLT-1 (EAAT2) was examined in normal and glaucomatous retinas from humans and rats. RESULTS: In normal eyes of humans and rats, GLT-1c was expressed only in photoreceptors. In glaucoma, there was additional robust expression of GLT-1c in retinal ganglion cells, including occasional displaced ganglion cells. Conversely, cells such as displaced amacrine cells and amacrine cells were unlabeled. CONCLUSIONS: The induction of GLT-1c expression by retinal ganglion cells supports the notion that an anomaly or anomalies in glutamate homeostasis may be evident in glaucoma and that such anomalies selectively influence retinal ganglion cells. By analogy to in vitro experiments in which elevated glutamate levels induce expression of glutamate transporters, the authors hypothesize that expression of GLT-1c may represent an attempt by retinal ganglion cells to protect themselves against elevated levels of glutamate. Such anomalies in glutamate levels cannot be restricted to the ganglion cell layer, as this would not have affected displaced ganglion cells. GLT-1c may be a useful indicator of the extent of stress of the retinal ganglion cells and thus a tool for examining outcomes of potential therapeutic and experimental interventions.

Obstrucción intestinal alta secundaria a cálculo impactado en duodeno (síndrome de Bouveret) / Gastric outlet obstruction due to duodenal gallstone (Bouveret syndrome)

No disponible

Efficacy and safety of memantine treatment for reduction of changes associated with experimental glaucoma in monkey, I: Functional measures.

PURPOSE: To determine, using electrophysiological measures of visual system function, whether oral daily dosing of memantine is both safe and effective to reduce the injury associated with experimental glaucoma in primates. METHODS: Argon laser treatment of the anterior chamber angle was used to induce chronic ocular hypertension (COHT) in the right eye of 18 macaque monkeys. Nine animals were orally dosed daily with 4 mg/kg memantine while the other nine animals received an oral dose of vehicle only. Using both conventional and multifocal methods, recordings of the electroretinogram (ERG) were made at approximately 3, 5, and 16 months after elevation of the intraocular pressure (IOP). Recordings of the visually-evoked cortical potential (VECP) were also made at the 16-month time point. RESULTS: Chronic ocular hypertension was associated with a reduction in the amplitude of components of the multifocal ERG response and visually-evoked cortical potential. Memantine-treated animals suffered less amplitude reduction for these measures than did vehicle-treated animals, though this treatment effect on the ERG measures was observed only at the early time points (3 and 5 months post IOP elevation). Memantine treatment was not associated with an effect on either the kinetics or amplitude of ERG or VECP response measures obtained from the normotensive eyes. CONCLUSIONS: Systemic treatment with memantine, a compound which does not lower intraocular pressure, was both safe and effective for reduction of functional loss associated with experimental glaucoma.

Efficacy and safety of memantine treatment for reduction of changes associated with experimental glaucoma in monkey, II: Structural measures.

PURPOSE: To determine, using anatomic measurements, whether daily oral dosing with memantine is both safe and effective to reduce the injury associated with experimental glaucoma in primates. METHODS: Argon laser treatment of the anterior chamber angle was used to induce chronic ocular hypertension (COHT) in the right eyes of 18 macaque monkeys. Nine animals were daily orally dosed with 4 mg/kg memantine while the other nine animals received vehicle only. Measurements of intraocular pressure (IOP) from both eyes of all animals were made at regular intervals. Appearance of the optic nerve head, retinal vessels, and surrounding retina was documented with stereo fundus photographs obtained at multiple time points throughout the study. Measurements of optic nerve head topography were obtained from confocal laser scans made from animals with the highest IOPs at approximately 3, 5, and 10 months after elevation of IOP. At approximately 16 months after IOP elevation, animals were killed and histologic counts of cells in the retinal ganglion cell (RGC) layer were made. RESULTS: Histologic measurements showed that, for animals with moderate elevation of IOP, memantine treatment was associated with an enhanced survival of RGCs in the inferior retina. Measurements of optic nerve head topography showed less IOP-induced change in memantine-treated animals. This effect was seen in measurements of both the cup and the neuroretinal rim. A comparison of these same histologic and morphologic measurements in normotensive eyes from the two treatment groups showed that memantine treatment was not associated with any significant effects on these eyes. CONCLUSIONS: Histologic measurements of RGC survival as well as tomographic measurements of nerve head topography show that systemic treatment with memantine, a compound which does not lower intraocular pressure, is both safe and effective to reduce changes associated with experimental glaucoma.

Nitric oxide production and nitric oxide synthase expression in platelets from heroin abusers before and after ultrarapid detoxification.

Prolonged heroin abuse has been associated with neurotoxicity. Thus, the involvement of nitric oxide (NO) in heroin-induced dopaminergic neurotoxicity could be a reasonable explanation for heroin-induced changes in brain. Enzymatically derived NO has been implicated in numerous physiological and pathological processes in the brain. Whereas during development NO participates in growing and maturation processes, excess NO production in the adult in response to inflammation, injury, or trauma, participates in both cell death and repair. The expression and activity of the inducible isoform of NO synthase (iNOS) play a pivotal role in sustained and elevated NO release. Recent evidence suggests that neurons can respond to proinflammatory stimuli and take part in brain inflammation. The effect of heroin abuse on platelet NO production and on expression of iNOS in drug addicts submitted to an ultrarapid detoxification was studied. The NO production was estimated from the nitrite concentration, and nitric oxide synthase was determined by Western blotting analysis. Results showed no difference in nitrite content of resting platelets between heroin abuser and control groups. However, after platelet stimulation, heroin abusers showed significantly lower nitrite values. The Western blotting analysis reinforced these results. After ultrarapid detoxification, platelet nitrite production in heroin abusers showed no differences compared to control subjects. Our results suggest that heroin consumption decreases the iNOS synthase expression and platelet NO production. Detoxification treatment restores these changes.

Neuroprotective effect of memantine in different retinal injury models in rats.

PURPOSE: To evaluate the neuroprotective effect of memantine, an NMDA receptor channel blocker, in two retinal ganglion cell (RGC) injury models in rats. METHODS: Neuroprotective effect of memantine was tested in partial optic nerve injury and chronic ocular hypertensive models. In the optic nerve injury model, memantine (0.1 - 30 mg/kg) was injected intraperitoneally immediately after injury. Two weeks later, optic nerve function was determined by measuring compound action potential and surviving RGC was determined by retrograde labeling with dextran tetramethyl rhodamine. Chronic ocular hypertension was attained by laser photocoagulation of episcleral and limbal veins. Memantine (5 or 10 mg/kg) was administered continuously each day with an osmotic pump, either immediately after or 10 days after first laser photocoagulation, for 3 weeks, after which RGC survival was determined. RESULTS: Two weeks after partial optic nerve injury, there was approximately 80% reduction in RGC number. Memantine (5 mg/kg) caused a twofold increase in compound action potential amplitude and a 1.7-fold increase in survival of RGCs, respectively. In the chronic ocular hypertension model there was 37% decrease in RGCs after 3 weeks of elevated intraocular pressure. Memantine (10 mg/kg daily) reduced ganglion cell loss to 12% when applied immediately after first laser photocoagulation, and prevented any further loss when applied 10 days after first laser photocoagulation. CONCLUSION: The protective effect of memantine suggests that excessive stimulation of NMDA receptors by glutamate is involved in causing cell damage in these RGC injury models.