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Purpose: To examine the risks associated with the use of pilocarpine hydrochloride 1.25% ophthalmic solution prescribed for presbyopia. Methods: The adverse ocular events reported after the use of pilocarpine were compared with the symptoms experienced by a 62-year-old presbyopic man shortly after taking pilocarpine. Results: The patient reported symptoms soon after instilling pilocarpine, including eye pain, hazy vision, and floaters. An examination showed a horseshoe retinal tear, vitreous hemorrhage, and posterior vitreous detachment, for which the patient received extensive clinical and surgical management. Conclusions: This case highlights the need for comprehensive eye examinations and patient education about the warning signs of retinal tears or detachments before prescribing pilocarpine for presbyopia. Vigilance regarding the potential rare adverse effects of this new pilocarpine ophthalmic solution is warranted., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Background: Pilocarpine is commonly used after angle surgery for glaucoma despite a host of side effects and risks. We hypothesized that a pharmacological miosis during the first two months does not improve short- and long-term results of trabectome-mediated ab interno trabeculectomy. Methods: In this retrospective comparative 1-year case series, we compared 187 trabectome surgery eyes with (P+) or without (P-) 1% pilocarpine for two months. Primary outcome measures were the surgical success defined as intraocular pressure (IOP) ≤ 21 mmHg and decreased ≥ 20%, and no secondary glaucoma surgery. Secondary outcome measures were the number of glaucoma medications, complications, and IOP. Results: We categorized 86 (46%) eyes as P- and 101 (54%) eyes as P+. The mean age was 69.8±10.1 in P- and 70.5±9.4 in P+ (P=0.617) with equal gender distribution (P=0.38). The cumulative probability of qualified success at 12 months was 78.1% in the P- and 81% in the P+ (P=0.35). The IOP was decreased significantly from 20.2±6.8 mmHg at baseline to 15.0±4.8 mmHg at 12 months follow-up in P- (P=0.001) and 18.8±5.3 and 14.7±4.0, respectively (P=0.001). The medications decreased significantly from 1.4±1.2 in P- and 1.4±1.2 in P+ at baseline to 1.0±1.2 and 0.7±1.0, respectively (P=0.183). P- and P+ did not differ in IOP or medications (all P>0.05). In Multivariate Cox Regression models, the baseline IOP and central corneal thickness were associated with failure. Conclusions: Use of postoperative pilocarpine does not improve the efficacy of trabectome surgery.

In this study, we investigated antiepileptogenic and neuroprotective effects of the aqueous extract of Pergularia daemia roots (PDR) using in vivo and in vitro experimental models. In in vivo studies, status epilepticus caused by pilocarpine injection triggers epileptogenesis which evolves during about 1-2 weeks. After 2 h of status epilepticus, mice were treated during the epileptogenesis period for 7 days with sodium valproate and vitamin C (standards which demonstrated to alter epileptogenesis) or Pergularia daemia. The animals were then, 1 week after status epilepticus, challenged with acute pentylenetetrazole (PTZ) administration to test behaviorally the susceptibility to a convulsant agent of animals treated or not with the plan extract. Memory was assessed after PTZ administration in the elevated plus maze and T-maze paradigms at 24 and 48 h. Antioxidant and acetylcholinesterase activities were determined in the hippocampus after sacrifice, in vitro studies were conducted using embryonic rat primary cortical cultures exposed to L-glutamate. Cell survival rate was measured and apoptotic and necrotic cell death determined. The results showed that chronic oral administration of PDR significantly and dose-dependently increased the latency to myoclonic jerks, clonic seizures and generalized tonic-clonic seizures and the seizure score. In addition, PDR at all doses (from 4.9 to 49 mg/kg) significantly decreased the initial and retention transfer latencies in the elevated plus maze. Interestingly PDR at the same doses significantly increased the time spent and the number of entries in T-maze novel arm. PDR significantly increased the activities of acetylcholinesterase and antioxidant enzymes superoxide dismutase, catalase, and total glutathione and proteins, and decreased malondialdehyde level. Furthermore, PDR increased viability rate of primary cortical neurons after L-glutamate-induced excitotoxicity, in a dose dependent manner. Altogether these results suggest that PDR has antiepileptogenic and neuroprotective effects, which could be mediated by antioxidant and antiapoptotic activities. [ABSTRACT FROM AUTHOR]

Through studies with ligand binding to the acetylcholine binding protein (AChBP), we previously identified a series of 4,6-substituted 2-aminopyrimidines that associate with this soluble surrogate of the nicotinic acetylcholine receptor (nAChR) in a cooperative fashion, not seen for classical nicotinic agonists and antagonists. To examine receptor interactions of this structural family on ligand-gated ion channels, we employed HEK cells transfected with cDNAs encoding three requisite receptor subtypes: α7-nAChR, α4β2-nAChR, and a serotonin receptor (5-HT3AR), along with a fluorescent reporter. Initial screening of a series of over 50 newly characterized 2-aminopyrimidines with affinity for AChBP showed only two to be agonists on the α7-nAChR below 10 μM concentration. Their unique structural features were incorporated into design of a second subset of 2-aminopyrimidines yielding several congeners that elicited α7 activation with EC50 values of 70 nM and Kd values for AChBP in a similar range. Several compounds within this series exhibit specificity for the α7-nAChR, showing no activation or antagonism of α4β2-nAChR or 5-HT3AR at concentrations up to 10 μM, while others were weaker antagonists (or partial agonists) on these receptors. Analysis following cocrystallization of four ligand complexes with AChBP show binding at the subunit interface, but with an orientation or binding pose that differs from classical nicotinic agonists and antagonists and from the previously analyzed set of 2-aminopyrimidines that displayed distinct cooperative interactions with AChBP. Orientations of aromatic side chains of these complexes are distinctive, suggesting new modes of binding at the agonist-antagonist site and perhaps an allosteric action for heteromeric nAChRs. [ABSTRACT FROM AUTHOR]

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Background The parasympathetic nervous system (PNS), via neurotransmitter acetylcholine (ACh), modulates fibrogenesis in animal models. However, the role of ACh in human hepatic fibrogenesis is unclear. Aims We aimed to determine the fibrogenic responses of human hepatic stellate cells (hHSC) to ACh and the relevance of the PNS in hepatic fibrosis in patients with non-alcoholic steatohepatitis (NASH). Methods Primary hHSC were analyzed for synthesis of endogenous ACh and acetylcholinesterase and gene expression of choline acetyltransferase and muscarinic ACh receptors (mAChR). Cell proliferation and fibrogenic markers were analyzed in hHSC exposed to ACh, atropine, mecamylamine, methoctramine, and 4-diphenylacetoxy- N-methylpiperidine methiodide. mAChR expression was analyzed in human NASH scored for fibrosis. Results We observed that hHSC synthesize ACh and acetylcholinesterase and express choline acetyltransferase and M1-M5 mAChR. We also show that M2 was increased during NASH progression, while both M2 and M3 were found upregulated in activated hHSC. Furthermore, endogenous ACh is required for hHSC basal growth. Exogenous ACh resulted in hHSC hyperproliferation via mAChR and phosphoinositide 3-kinase and Mitogen-activated protein kinase kinase (MEK) signaling pathways, as well as increased fibrogenic markers. Conclusion We show that ACh regulates hHSC activation via M2 and M3 mAChR involving the phosphoinositide 3-kinase and MEK pathways in vitro. Finally, we provide evidence that the PNS may be involved in human NASH fibrosis. [ABSTRACT FROM AUTHOR]

Apolipoprotein E4 (apoE4) is the most prevalent genetic risk factor for Alzheimer's disease. We utilized apoE4-targeted replacement mice (approved by the Tel Aviv University Animal Care Committee) to investigate whether cholinergic dysfunction, which increases during aging and is a hallmark of Alzheimer's disease, is accentuated by apoE4. This revealed that levels of the pre-synaptic cholinergic marker, vesicular acetylcholine transporter in the hippocampus and the corresponding electrically evoked release of acetylcholine, are similar in 4-month-old apoE4 and apolipoprotein E3 (apoE3) mice. Both parameters decrease with age. This decrease is, however, significantly more pronounced in the apoE4 mice. The levels of cholinacetyltransferase (Ch AT), acetylcholinesterase ( AChE), and butyrylcholinesterase (BuChE) were similar in the hippocampus of young apoE4 and apoE3 mice and decreased during aging. For Ch AT, this decrease was similar in the apoE4 and apoE3 mice, whereas it was more pronounced in the apoE4 mice, regarding their corresponding AChE and BuChE levels. The level of muscarinic receptors was higher in the apoE4 than in the apoE3 mice at 4 months and increased to similar levels with age. However, the relative representation of the M1 receptor subtype decreased during aging in apoE4 mice. These results demonstrate impairment of the evoked release of acetylcholine in hippocampus by apoE4 in 12-month-old mice but not in 4-month-old mice. The levels of Ch AT and the extent of the M2 receptor-mediated autoregulation of ACh release were similar in the adult mice, suggesting that the apoE4-related inhibition of hippocampal ACh release in these mice is not driven by these parameters. [ABSTRACT FROM AUTHOR]

Acetylcholine (ACh) and ATP are rapidly acting neurotransmitters with a putative role in epileptic seizures. In the present study we investigated extracellular concentrations of both neurotransmitters in parallel by microdialysis in rat hippocampus. We found that infusion of neostigmine increases, while calcium-free perfusion and infusion of tetrodotoxin (TTX) decreases, ACh levels. Calcium-free perfusion also decreased ATP levels which were, however, not affected by neostigmine or TTX. During status epilepticus, ACh levels were increased threefold but returned to baseline after the termination of seizures by diazepam. ATP levels were unchanged during status epilepticus but a several-fold increase was seen when AOPCP, an inhibitor of 5′-endonucleotidase, was infused. The results demonstrate an increase of ATP levels during epileptic seizures which, however, was not of neuronal origin. [ABSTRACT FROM AUTHOR]

Structure modification of a lead compound (NSC13378) was accomplished in the present work by an in silico target-based design aimed at ligands acting on the nicotinic acetylcholine receptor (nAChR) for neurodegenerative diseases. A 187-compound focused library derived from the scaffold of the lead compound was screened against acetylcholine-binding proteins (AChBPs). Six compounds were identified and synthesized for binding and biological evaluations. Five compounds were found to bind with AChBPs. Among these compounds, QN1 and BZ1 showed the highest affinity binding with AChBP, with Kd values of 260 and 10 nM, respectively. Functional assays on isolated cell lines containing ligand-gated ion channels revealed that QN1 and BZ1 are α4β2-nAChR antagonists. QN1 and BZ1 significantly alleviated the memory impairment caused by the muscarinic cholinergic antagonist scopolamine (p < 0.05) in mice. Our findings demonstrate the potential of nAChR antagonists in drug development for cognitive impairments. [ABSTRACT FROM AUTHOR]

Myasthenia gravis (MG) is an autoimmune disease characterized by the formation of pathogenic autoantibodies mostly targeting the nicotinic acetylcholine receptor (AChR). The AChR is composed of two alpha subunits and one subunit of each beta, delta and gamma (fetal AChR), or epsilon (adult AChR), respectively. Serological diagnostics is commonly done by radioimmunoassay (RIA). Here we used an indirect immunofluorescence assay with MG patient sera on transiently transfected HEp-2 cells expressing selected components of the AChR. Our data show that already 12 out of 13 MG patient sera showed autoantibody binding to HEp-2 cells transfected to express the alpha subunit solely. Interestingly, 11 out of 13 patient sera reacted positive with cells transfected to reconstitute the complete fetal AChR, but only 6 out of 13 sera showed positive signals with cells expressing the components of adult AChR. Moreover, there was no strict correlation of the serum concentration required to obtain clear-cut fluorescence signals to the antibody titer as measured by RIA. It will be an interesting topic to further investigate if the optimal serum dilution for indirect immunofluorescence as well as the autoantibody binding preferences to defined AChR subunits and to the adult versus the fetal receptor variant could provide additional predictive value in MG diagnostics. [ABSTRACT FROM AUTHOR]

We designed, prepared and tested a set of structural analogs 1 – 4 as new hybrid compounds by incorporating, through a common alkyl chain of variable length, the pharmacophoric elements of N - n -alkyl nicotinium salts (non-α7 nicotinic acetylcholine receptors antagonists) and of 7-hydroxy-2-(aminomethyl)chromanes (dopaminergic D 2 receptor agonists). The target compounds, which were assayed in binding experiments and electrophysiological, functional and Erk1/2 activation tests, essentially combined the pharmacological profiles of their individual receptor ligands. Among the studied derivatives, hybrid 2 , one of the shortest homologs, in addition to the antagonist nicotinic profile similar to the other three congeners, behaved as a high affinity ligand at the investigated heteromeric nAChRs and as a low efficacy agonist at D 2 Rs. These bifunctional derivatives represent novel pharmacological tools in the study of nicotine addiction. [ABSTRACT FROM AUTHOR]

Glaucoma is a leading cause of visual morbidity throughout the world and is an age-related condition, the prevalence of which rises significantly with increasing age. Glaucoma, a condition affecting the optic nerve, has a variety of subtypes with multiple aetiological factors, the most important of which are intraocular pressure (IOP) and increasing age. Treatment by lowering of IOP is the only current method, for which there is evidence, by which the rate of progressive visual deterioration can be slowed or halted. Although there are surgical and laser treatments that are efficacious in lowering IOP, the most common manner in which patients with glaucoma control their IOP is with administration of daily topical ocular hypotensive drugs (eye drops). The variety of topical drugs utilised in the management of glaucoma all have the potential to have adverse effects and/or interactions with concomitant medications, many of which may be used for other age-related conditions. Adherence with appropriate medicines has a major effect on the outcome of medical conditions and this aspect applies to the management of glaucoma. There are certain specific issues that relate to the administration of topical agents, with respect to both adverse effects and adherence. Although many suspect poor adherence in elderly patients with glaucoma, relative to younger patients, adequate evidence for this is lacking. Furthermore, the manner by which adherence issues could be improved remains inadequately understood and poorly addressed. The aims of this article were to review, from a clinical perspective, the medical therapies currently used for glaucoma and discuss adherence issues with respect to the population of patients with glaucoma, who tend to be relatively elderly. [ABSTRACT FROM AUTHOR]

Alpha7 nicotinic acetylcholine receptors (nAChRs) have implications in the regulation of cognitive processes such as memory and attention and have been identified as a promising therapeutic target for the treatment of the cognitive deficits associated with schizophrenia and Alzheimer's disease (AD). Structure affinity relationship studies of the previously described α7 agonist SEN12333 ( 8 ), have resulted in the identification of compound 45 , a potent and selective agonist of the α7 nAChR with enhanced affinity and improved physicochemical properties over the parent compound (SEN12333, 8 ). [ABSTRACT FROM AUTHOR]

Background: Non-coding single nucleotide polymorphisms within the nicotinic acetylcholine receptor alpha 4 subunit gene (CHRNA4) are robustly associated with various neurological and behavioral phenotypes including schizophrenia, cognition and smoking. The most commonly associated polymorphisms are located in exon 5 and segregate as part of a haplotype. So far it is unknown if this haplotype is indeed functional, or if the observed associations are an indirect effect caused by linkage disequilibrium with not yet identified adjacent functional variants. We therefore analyzed the functional relevance of the exon 5 haplotype alleles. Results: Using voltage clamp experiments we were able to show that the CHRNA4 haplotype alleles differ with respect to their functional effects on receptor sensitivity including reversal of receptor sensitivity between low and high acetylcholine concentrations. The results indicate that underlying mechanisms might include differences in codon usage bias and changes in mRNA stability. Conclusions: Our data demonstrate that the complementary alleles of the CHRNA4 exon 5 haplotype are functionally relevant, and might therefore be causative for the above mentioned associations. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder involving impaired cholinergic neurotransmission and dysregulation of nicotinic acetylcholine receptors (nAChRs). Ly-6/neurotoxin (Lynx) proteins have been shown to modulate cognition and neural plasticity by binding to nAChR subtypes and modulating their function. Hence, changes in nAChR regulatory proteins such as Lynx proteins could underlie the dysregulation of nAChRs in AD. Using Western blotting, we detected bands corresponding to the Lynx proteins prostate stem cell antigen (PSCA) and Lypd6 in human cortex indicating that both proteins are present in the human brain. We further showed that PSCA forms stable complexes with the α4 nAChR subunit and decreases nicotine-induced extracellular-signal regulated kinase phosphorylation in PC12 cells. In addition, we analyzed protein levels of PSCA and Lypd6 in postmortem tissue of medial frontal gyrus from AD patients and found significantly increased PSCA levels (approximately 70%). In contrast, no changes in Lypd6 levels were detected. In concordance with our findings in AD patients, PSCA levels were increased in the frontal cortex of triple transgenic mice with an AD-like pathology harboring human transgenes that cause both age-dependent β-amyloidosis and tauopathy, whereas Tg2576 mice, which display β-amyloidosis only, had unchanged PSCA levels compared to wild-type animals. These findings identify PSCA as a nAChR-binding protein in the human brain that is affected in AD, suggesting that PSCA-nAChR interactions may be involved in the cognitive dysfunction observed in AD. [ABSTRACT FROM AUTHOR]

Objectives: To determine the clinical utility and performance characteristics of a laboratory-adapted flow cytometric method for the detection of acetylcholine receptor (AChR) modulating antibodies in myasthenia gravis (MG). Methods: Serum samples from 120 healthy donors and 100 patients with suspected MG were assessed for the ability to reduce surface AChR concentrations (antigenic modulation) in RD (TE671) or DB40 human muscle cell lines by flow cytometry. Reference ranges were established by receiver operating characteristic curve analysis, and results were then compared with those of the current radioimmunoassay (RIA). Results: Flow cytometric results from the RD cell line had an interpretive threshold of 46% modulation or greater and correlated best (98% sensitivity, 99% specificity) with those of the current RIA. Conclusions: The new flow cytometric method using the RD cell platform provided higher quality clinical results, a more robust and efficient assay format, a significant cost savings, and less environmental burden. [ABSTRACT FROM AUTHOR]

Primary objective: Conceptions of time in children having survived malignant cerebellar tumours (CT) and healthy children matched for chronological age (HCCA) were compared, knowing that the cerebellum has been involved in time perception. Methods and procedure: Study participants included 20 children with CT (13 boys) and 20 HCCA (10 boys) aged 6-12 years. All children with CT were at least 1 year after the end of treatment without relapse. A time questionnaire (TQ) exploring duration of daily activities, time units, planning and diachronic thinking was used, as well as a video animation (VA) displaying cyclic and linear time. Main outcomes and results: Children with CT obtained similar results as HCCA for time units, planning and diachronic thinking, but showed more difficulties than controls in estimating the duration of daily activities and understanding linear and cyclic time concepts (VA). Conclusions: These findings are not in favour of impaired time conceptions in children with CT and are probably linked to the specific life experience among children treated for a malignant pathology, rather than to the role of the cerebellum in time processing. [ABSTRACT FROM AUTHOR]

Abstract: An elevated aqueous humor protein level (aka flare) has always been considered to represent a pathological breakdown of the blood-aqueous barrier (BAB), regardless of the etiology. Recent studies in humans, using magnetic resonance imaging (MRI) to directly observe BAB kinetics in the posterior chamber of the human eye in-vivo, showed that pilocarpine-induced flare resulting from administration of a single drop of pilocarpine is not the result of breakdown of the BAB in the ciliary body. These MRI studies could not confirm whether pilocarpine caused an increase in iris vascular permeability. In the current studies we completed combined cell-flare meter and intravascular tracer studies, using intravenous horseradish peroxidase (HRP) in rabbits. One hour after receiving 3% pilocarpine in one eye, pupil size significantly decreased and aqueous flare significantly increased in pilocarpine-treated eyes. Light and electron microscopy demonstrated no leakage across either the iris vascular endothelium or the non-pigmented ciliary epithelium in either pilocarpine-treated or control eyes. One animal received HRP directly after pilocarpine to control for a transient increase in permeability before the peak flare response occurred. No leakage was found in the ciliary body or iris of this animal. Additional animals received topical pilocarpine in one eye but after 1 h they were sacrificed without tracer studies. Uveal tissues from these animals were used to assess the distribution of non-HRP protein in the ocular anterior segment and to assess the amount of elutable protein in the iris stromas of both treated and untreated eyes. Immunohistochemistry confirmed the presence of a reservoir of protein in the iris stroma. Analysis of elutable total protein from the iris stroma of pilocarpine-treated and control eyes showed significantly less total elutable protein in pilocarpine-treated eyes. Eyes with the greatest percent change in pupil size (i.e. the strongest miosis) correlated with lowest amounts of residual protein in the iris stroma. The tracer studies confirmed recent MRI studies in humans showing that the source of pilocarpine-induced flare is not disruption of the ciliary epithelial barrier. Extending this work, the current studies also showed no pilocarpine-induced leakage from the iris vasculature. The elutable protein experiments suggested that a primary source of pilocarpine-induced flare was extrusion of a portion of the reservoir of protein in the iris stroma. Taken together, these studies strongly suggest that not all clinically observable flare results from breakdown of the BAB. [Copyright &y& Elsevier]

Purpose: The aim of this work is to analyze the conformational changes in the acetylcholine receptor caused by channel opening and to investigate the electrostatic profile during ion translocation through the channel. Methods: A computational model of the human muscle-type acetylcholine receptor (AChR) was built and used to analyze channel structure and its interactions with different ions. Using the Torpedo AChR crystal structure as a homologous template, the 3D structure of the human muscle-type AChR was reconstructed. Results: This first model is optimized and an open structure of the channel is generated using Normal Mode Analysis in order to assess morphologic and energetic differences between open and closed structures. In addition, the issue of ion translocation is investigated in further detail. Results elucidate different aspects of the channel: channel gate structure, channel interactions with translocating ions, differences between muscle-type AChR and previous neuronal-type AChR models. Conclusions: The model constructed here is ideal for further computational studies on muscle-type AChR and its pathologic mutations. [ABSTRACT FROM AUTHOR]

The Alchornea triplinervia specie belongs to the Euphorbiaceae family, one of the main families of the Brazilian flora. In order to contribute to a better understanding of the specie, a counting of chromosome number and the microsporogenesis analysis of A. triplinervia were done. The inflorescences were collected in the municipalities of Paranavaí and Diamante do Norte, State of Paraná, Brazil, and the slides were prepared by squashing technique and staining with 1% acetic carmine. The analysis were performed using an optical microscope and showed a chromosome number for the specie equal to 2n=8x=72. Irregularities in the chromosome segregation process were the main meiotic abnormalities, presenting typical polyploid behavior. Other irregularities were observed; however, at low frequency without compromising the pollen grain formation of the analyzed plants. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to investigate the usefulness of a long-acting miotic (physostigmine) after phacoemulsification in preventing peripheral anterior synechiae (PAS), lens dislocation, and high postoperative intraocular pressure. Methods: This was a prospective randomized controlled trial of 400 patients (400 eyes) scheduled for phacoemulsification. Patients were randomly assigned either to receive a single application of physostigmine ointment directly after phacoemulsification or not. The main outcome measures were the change of intraocular pressure (IOP) before and after surgery, number of extra outpatient clinic visits within 4 weeks postoperatively, verbal rating pain scale (VRS), status of the angle by gonioscopy, and best corrected visual acuity (BCVA). Results: There was no significant difference in IOP and BCVA between both groups. There were more patients who reported a VRS score of more than 3 in the physostigmine group ( P=0.021). PAS or (anterior) lens dislocation was not observed. Conclusion: In eyes without co-morbidity, the routine use of physostigmine ointment has lost its rationale. [ABSTRACT FROM AUTHOR]

Background: Although evidence suggests that the prevalence of Parkinson’s disease (PD) is lower in smokers than in non-smokers, the mechanisms of nicotine-induced neuroprotection remain unclear. Stimulation of the α7 nicotinic acetylcholine receptor (α7-nAChR) seems to be a crucial mechanism underlying the anti-inflammatory potential of cholinergic agonists in immune cells, including astrocytes, and inhibition of astrocyte activation has been proposed as a novel strategy for the treatment of neurodegenerative disorders such as PD. The objective of the present study was to determine whether nicotine-induced neuroprotection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model occurs via α7-nAChR-mediated inhibition of astrocytes. Methods: Both in vivo (MPTP) and in vitro (1-methyl-4-phenylpyridinium ion (MPP+) and lipopolysaccharide (LPS)) models of PD were used to investigate the role(s) of and possible mechanism(s) by which α7-nAChRs protect against dopaminergic neuron loss. Multiple experimental approaches, including behavioral tests, immunochemistry, and stereology experiments, astrocyte cell cultures, reverse transcriptase PCR, laser scanning confocal microscopy, tumor necrosis factor (TNF)-α assays, and western blotting, were used to elucidate the mechanisms of the α7-nAChR-mediated neuroprotection. Results: Systemic administration of nicotine alleviated MPTP-induced behavioral symptoms, improved motor coordination, and protected against dopaminergic neuron loss and the activation of astrocytes and microglia in the substantia nigra. The protective effects of nicotine were abolished by administration of the α7-nAChR-selective antagonist methyllycaconitine (MLA). In primary cultured mouse astrocytes, pretreatment with nicotine suppressed MPP+-induced or LPS-induced astrocyte activation, as evidenced by both decreased production of TNF-α and inhibition of extracellular regulated kinase1/2 (Erk1/2) and p38 activation in astrocytes, and these effects were also reversed by MLA. Conclusion: Taken together, our results suggest that α7-nAChR-mediated inhibition of astrocyte activation is an important mechanism underlying the protective effects of nicotine. [ABSTRACT FROM AUTHOR]

Background: The aim was to determine the critical eccentricity at which two methods of elaborating peripheral wavefront measurements are significantly different and to characterise horizontal coma in healthy young adults. Methods: Peripheral aberrations were determined for 20 observers for central and eight peripheral gaze positions up to 20° using an IRX-3 aberrometer. In one subject, additional measurements up to 40° were obtained. Two definitions of stretching coefficients were compared. The raw empirical data were compared with theoretical modelling. Results: For both 3.5 mm and 6.0 mm pupils, no significant differences were observed between recalculated and non-recalculated elliptical pupils for both methods (p > 0.05) up to 20° eccentricity. For eccentricities greater than 20° and up to 40°, significant differences between circular and elliptical pupils at some eccentricities were apparent, which corresponded to theoretical models. Wide individual variations in horizontal coma across the peripheral field were observed. Conclusions: The data suggest that for eyes with average levels of aberrations, the elliptical transformation is of no practical importance for eccentricities up to 20°. In some cases the slope of horizontal coma was reversed compared with previous findings in normal eyes. [ABSTRACT FROM AUTHOR]

Abstract: Trifluralin is a herbicide capable of interfering in mitotic cell division due to either microtubule depolymerization or alteration in the concentration of calcium ions within the cell. The aim of this study was to investigate the effects of trifluralin in Allium cepa meristematic cells, evaluating the induction mechanisms of the chromosomal and nuclear aberrations. In this study, A. cepa root tips were submitted for 24h treatment to several concentrations of this herbicide and 48h recovery post-treatment. The results showed that some concentrations of trifluralin can lead to a mitotic index inhibition, besides inducing chromosomal and nuclear alterations throughout the mitotic cycle. Some of the alterations found seem to be resulting from the herbicide action in different phases and in more than one consecutive cell cycle. [Copyright &y& Elsevier]

Purpose: Exfoliation syndrome (XFS) is an age-related, generalized disorder of the extracellular matrix characterized by theproduction and progressive accumulation of a fibrillar extracellular material in many ocular tissues and is the mostcommon identifiable cause of open-angle glaucoma worldwide. Exfoliation syndrome plays an etiologic role in open-angle glaucoma, angle-closure glaucoma, cataract, and retinal vein occlusion. It is accompanied by an increase inserious complications at the time of cataract extraction, such as zonular dialysis, capsular rupture, and vitreous loss.It is associated systemically with an increasing number of vascular disorders, hearing loss, and Alzheimer's disease.Exfoliation syndrome appears to be a disease of elastic tissue microfibrils. Directed therapy simply means devisingspecific treatments for specific diseases. There was little incentive to attempt to distinguish between various open-angle glaucomas if the treatments were essentially the same. However, this view also prevented the application ofdirected therapy in those instances in which such was available and applicable. Pilocarpine has multiple beneficialactions in eyes with XFS. Not only does it lower IOP, but by increasing aqueous outflow, it should enable the trabecu-lar meshwork to clear more rapidly, and by limiting pupillary movement, should slow the progression of the disease.Theoretically, miotics should be the first line of treatment. Pilocarpine 2% q.h.s. can provide sufficient limitation ofpupillary mobility without causing these side effects. In 2007, two common single nucleotide polymorphisms in thecoding region of the lysyl oxidase-like 1 (LOXL1) gene located on chromosome 15 were specifically associated withXFS and XFG. LOXL1 is a member of the lysyl oxidase family of enzymes, which are essential for the formation,stabilization, maintenance, and remodelling of elastic fibers and prevent age-related loss of elasticity of tissues.LOXL1 protein is a major component of exfoliation deposits and appears to play a role in its accumulation and inconcomitant elastotic processes in intra- and extraocular tissues of XFS patients. This discovery should open the wayto new approaches and directions of therapy for this protean disorder. [ABSTRACT FROM AUTHOR]

O-isopropyl methylphosphonofluoridate, also known as sarin or GB, is a highly toxic organophosphorous compound that exerts its effect by inhibiting the enzyme acetylcholinesterase. While the effects of a single exposure to GB vapor are well characterized, the effects of multiple exposures to GB vapor are less clear. Previous studies in the rat and guinea pig have demonstrated that multiple exposures result in tolerance to the miotic effect of nerve agents. The aim of the present study was to examine potential mechanisms responsible for tolerance to the miotic effect of GB vapor that has been observed in the rat after multiple exposures. Multiple whole-body inhalation exposures to GB vapor were conducted in a dynamic airflow chamber. Exposures lasted 60 min and each of the three exposures occurred at 24-h intervals. The results of the present study demonstrate that the α-adrenergic antagonist phentolamine and the β-adrenergic receptor antagonist propranolol did not affect the development of tolerance to the miotic effect of GB vapor, suggesting that enhanced sympathetic tone to the eye is not responsible for the observed tolerance. Administration of atropine before the first exposure prevented the tolerance to the miotic effect of GB vapor after the third exposure, suggesting that the tolerance is the result of muscarinic receptor desensitization secondary to receptor stimulation. The present study extends the findings of previous studies to strengthen the hypothesis that the miotic tolerance observed in the rat upon repeated exposure to nerve agents is due to desensitization of muscarinic acetylcholine receptors located on the pupillary sphincter. [ABSTRACT FROM AUTHOR]

Purpose. A review of glaucoma and its treatment is presented. Summary. Glaucoma is a common eye disease that can cause irreversible blindness if left undiagnosed and untreated. Glaucoma is a leading cause of blindness in the United States and other industrialized countries. In most cases, the symptoms of early-stage glaucoma are minimal or nonexistent. There are several different types of glaucoma, and they have been classically divided into the categories of primary or secondary open-angle or angle-closure glaucoma. Secondary forms of glaucoma are caused by various ocular or systemic diseases. Every available treatment to prevent progressive glaucomatous optic neuropathy has potential adverse effects and involves a certain amount of risk and financial expense. Conventional first-line treatment of glaucoma usually begins with the use of a topical selective or nonselective β-blocker or a topical prostaglandin analog. Second-line drugs of choice include &agr;-agonists and topical carbonic anhydrase inhibitors. Parasympathomimetic agents, most commonly pilocarpine, are considered third-line treatment options. For patients who do not respond to antiglaucoma medications, laser trabeculoplasty and incisional surgery are further methods that can be used to lower intraocular pressure. The results of clinical trials have reaffirmed the utility of antiglaucoma medications in slowing the progression of the disease. Conclusion. Glaucoma is a common eye disease that is usually associated with an elevated intraocular pressure. Treatment options for patients with glaucoma include medications, laser therapy, and incisional surgery. The risks and benefits of each type of treatment must be carefully considered to maximize the treatment’s benefits while minimizing adverse effects. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy and side effects of oral pilocarpine for the treatment of ocular symptoms in patients with primary Sjögren's syndrome (SS).Methods: A 12 week, single centre, randomised controlled study was performed. Twenty nine patients were randomly assigned to receive oral pilocarpine (5 mg twice a day), 28 only artificial tears, and 28 inferior puncta occlusion. Patients receiving oral pilocarpine and those with inferior puncta occlusion also received artificial tears. Patients were evaluated at baseline and throughout the study for their subjective global assessment of dry eyes and for their objective assessment of dry eyes (Schirmer's-I test, rose bengal test, and imprint test).Results: Patients taking oral pilocarpine had significant improvement in subjective global assessment of dry eyes, as was evaluated by improvement of >55 mm on a visual analogue scale (VAS) for responses to the eye questionnaire, compared with patients treated with artificial tears (p<0.001) and those with inferior puncta occlusion (p<0.05). Furthermore, patients receiving oral pilocarpine also showed greater objective improvement, as measured by the rose bengal test (p<0.05), while Schirmer's-I test showed no differences between the treated groups. Commonly reported adverse events were headache, increased sweating, nausea, and vomiting in the pilocarpine group, while one patient in the inferior puncta occlusion group had blepharitis and was withdrawn from the study.Conclusion: 10 mg of pilocarpine daily given to patients with SS for 12 weeks had a beneficial effect on subjective eye symptoms, as evaluated by improvement >55 mm on a VAS. Additionally, an improvement of rose bengal staining was noted, but an increase in tear production, as measured by the Schirmer-I test, was not substantiated. [ABSTRACT FROM AUTHOR]