Rescue of social behavior impairment by clozapine and alterations in the expression of neuronal receptors in a rat model of neurodevelopmental impairment induced by GRPR blockade.

We have previously shown that pharmacological blockade of the gastrin-releasing peptide receptor (GRPR) during the neonatal period in rats produces behavioral features of developmental neuropsychiatric disorders. Here, we show that social interaction deficits in this model are reversed by the atypical antipsychotic clozapine given in the adulthood. In addition, we analyzed the mRNA expression of three neuronal receptors potentially involved in the etiology of disorders of the autism spectrum. Rats were injected with the GRPR antagonist RC-3095 or saline (SAL) from postnatal days 1-10, and tested for social behavior and recognition memory in the adulthood. One hour prior to the behavioral testing, rats were given a systemic injection of clozapine or saline. The mRNA expression of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor, the epidermal growth factor receptor (EGFR), and GRPR was measured in the hippocampus and cortex of a separate set of rats given RC-3095 or SAL neonatally. Rats given neonatal RC-3095 showed decreased social interaction and impaired object recognition memory. Clozapine rescued the social interaction impairment. Neonatal treatment with RC-3095 also resulted in dose-dependent decreases in the expression of GRPR, NR1, and EGFR in the cortex, whereas all three receptor mRNAs were increased in the hippocampus in rats treated with the lower dose of RC-3095. The results contribute to further validate the novel rat model of neurodevelopmental disorders induced by GRPR blockade, and shows alterations in the expression of neuronal receptors in this model.

Emotional memory deficit and its psychophysiological correlate in family caregivers of patients with dementia.

This study examined the cortisol secretion pattern and declarative memory performance of dementia caregivers. An illustrated story paradigm memory task was used to evaluate the effects of emotional arousal on memory and assess the caregivers' cognitive compensation capacity. Younger (n=19) and elderly (n=24) noncaregivers and elderly caregivers (n=14) took part in 2 experiments to elucidate the effects of aging (experiment 1) and chronic stress (experiment 2) on memory performance and cortisol levels. Each group was divided in 2 subgroups: one that was exposed to an emotionally neutral story, and one that was exposed to a similar, but emotionally arousing story. Participants completed a multiple-choice questionnaire in the test session. Salivary cortisol samples were collected at 8:00 AM, 4:00 PM, and 10:00 PM, 1 day after memory testing. Experiment 1 showed that, despite an age-related memory deficit, arousal manipulation produced a similar effect in both age groups. Experiment 2 showed that, in addition to the characteristic memory decline of aging, elderly caregivers did not benefit from emotionally arousing material as their noncaregiver counterparts did. This impairment correlated with elevated nighttime cortisol levels, indicating a potential worsening impact of caregiver burden on age-related cognitive decline.

Subjective mild depressive symptoms are associated with abnormal diurnal cycle of salivary cortisol in older adults.

BACKGROUND: Alterations in cortisol secretion pattern seem to be involved in the associations between aging, depression, and cognitive decline. OBJECTIVE: The aim of this study was to mainly assess cortisol circadian profile in older adults with subjective depressive symptoms. METHODS: Salivary cortisol samples from healthy young (n = 22) and old adults (n = 22), and from older adults who self-reported depressive symptoms in Geriatric Depression Scale (n = 22) were collected at 7 AM, 4 PM, and 10 PM and were analyzed by radioimmunoassay. RESULTS: Older adults with depressive symptoms presented the characteristic cortisol circadian pattern, but they showed higher cortisol levels at 10 PM than healthy young and elderly controls. CONCLUSIONS: Our data suggest that mild depressive symptoms could be associated with a cortisol secretion pattern previously described as being predictive of cognitive decline.

mRNA expression of proteins involved in iron homeostasis in brain regions is altered by age and by iron overloading in the neonatal period.

Abnormally high levels of iron are observed in the brain of patients suffering from neurodegenerative disorders. The mechanisms involved in iron accumulation in neurodegenerative disorders remain poorly understood. In the present study we investigated the effects of aging and neonatal iron overload on the mRNA expression of proteins critically involved in controlling iron homeostasis. Wistar rat pups received a single daily dose of vehicle or iron (10 mg/kg of b.w. of Fe(2+)), at postnatal days 12-14. The expression of Transferrin Receptor (TfR), H-Ferritin, and IRP2 were analyzed by a semi-quantitative reverse transcriptase polymerase chain reaction assay in cortex, hippocampus and striatum of rats sacrificed at three different ages (15-day-old; 90-day-old and 2-year old rats). Results indicate that TfR, H-ferritin, and IRP2 mRNA expression was differentially affected by aging and by neonatal iron treatment in all three brain regions. These findings might have implications for the understanding of iron homeostasis misregulation associated with neurodegenerative disorders.

Contextual memory and encoding strategies in young and older adults with and without depressive symptoms.

OBJECTIVES: This study examines the role of depressive symptoms associated with age on contextual memory and how this association could impair the use of strategic instructions during encoding. METHOD: Young and older controls and older adults with depressive symptoms performed memory recognition tests for item and context. RESULTS: Memory results indicated that mild depressive symptoms did not aggravate the age-related contextual memory pattern, but interfered with the magnitude of the memory enhancement provided by specific encoding instructions when compared with young adults. These between-group differences in the use of memory strategies were eliminated with the inclusion of the performance on Wisconsin Card Sorting Test as a covariate. CONCLUSION: Mild depressive symptoms were associated with an impaired ability to use incidental memory strategies at encoding, suggesting the need for further investigation on the effects of non-clinical depressive symptomatology on cognitive decline in aging.

Noradrenergic activation of the basolateral amygdala modulates consolidation of object recognition memory.

Noradrenergic activation of the basolateral complex of the amygdala (BLA) modulates the consolidation of memory for many kinds of highly emotionally arousing training tasks. The present experiments investigated whether posttraining noradrenergic activation of the BLA is sufficient to enable memory consolidation of a low-arousing training experience. Sprague-Dawley rats received intra-BLA infusions of norepinephrine, the beta-adrenoceptor antagonist propranolol or saline immediately after either 3 or 10 min of object recognition training. Saline-infused controls exhibited poor 24-h retention when given 3 min of object recognition training and good retention when given 10 min of training. Norepinephrine administered after 3 min of object recognition training produced dose-dependent enhancement of 24-h object recognition memory whereas propranolol administered after 10 min of training produced dose-dependent impairment of memory. These findings provide evidence that posttraining noradrenergic activation of the BLA enhances memory of a low-arousing training experience that would otherwise not induce long-term memory. Thus, regardless of the degree of emotional arousal induced by an experience, noradrenergic activation of the BLA after the experience ensures that it will be better remembered.

CEFALIUM-INDUCED BILATERAL TRANSIENT MYOPIA, RETINAL FOLDS, AND FOCAL CHOROIDAL DELAY.

PURPOSE: To describe a case of acute bilateral transient myopia, retinal folds, and island of choroidal delay associated with oral administration of Cefalium, a medication commonly prescribed in Brazil for migraine that combines acetaminophen 500 mg, caffeine 40 mg, dihydroergotamine mesylate 1 mg, and metoclopramide hydrochloride 10 mg. METHODS: A 21-year-old woman with bilateral blurred vision 1 day after the use of Cefalium. The main outcomes measures were BCVA, ocular fundus, ocular coherence tomography, and angiography findings. RESULTS: The patient developed bilateral myopia, retinal folds, and focus choroidal delay 1 day after the administration of oral cefalium. Ocular fundus examination and ocular coherence tomography revealed retinal folds in the internal surface of the retina. Angiography showed focus areas of hypofluorescence in both eyes. Seven days after Cefalium was suspended, all clinical symptoms had resolved, with full recovery from the abnormal findings on ocular fundus, ocular coherence tomography, and angiography. CONCLUSION: This is the first report that identified and described bilateral transient myopia, retinal folds, and focus choroidal delay secondary the use of Cefalium.

Cumulative sum analysis score and phacoemulsification competency learning curve.

AIM: To use the cumulative sum analysis score (CUSUM) to construct objectively the learning curve of phacoemulsification competency. METHODS: Three second-year residents and an experienced consultant were monitored for a series of 70 phacoemulsification cases each and had their series analysed by CUSUM regarding posterior capsule rupture (PCR) and best-corrected visual acuity. The acceptable rate for PCR was <5% (lower limit h) and the unacceptable rate was >10% (upper limit h). The acceptable rate for best-corrected visual acuity worse than 20/40 was <10% (lower limit h) and the unacceptable rate was >20% (upper limit h). The area between lower limit h and upper limit h is called the decision interval. RESULTS: There was no statistically significant difference in the mean age, sex or cataract grades between groups. The first trainee achieved PCR CUSUM competency at his 22nd case. His best-corrected visual acuity CUSUM was in the decision interval from his third case and stayed there until the end, never reaching competency. The second trainee achieved PCR CUSUM competency at his 39th case. He could reach best-corrected visual acuity CUSUM competency at his 22nd case. The third trainee achieved PCR CUSUM competency at his 41st case. He reached best-corrected visual acuity CUSUM competency at his 14th case. CONCLUSION: The learning curve of competency in phacoemulsification is constructed by CUSUM and in average took 38 cases for each trainee to achieve it.

Fuchs endothelial corneal dystrophy: current perspectives.

Fuchs endothelial corneal dystrophy (FECD) is the most common corneal dystrophy and frequently results in vision loss. Hallmarks of the disease include loss of corneal endothelial cells and formation of excrescences of Descemet's membrane. Later stages involve all layers of the cornea. Impairment of endothelial barrier and pump function and cell death from oxidative and unfolded protein stress contribute to disease progression. The genetic basis of FECD includes numerous genes and chromosomal loci, although alterations in the transcription factor 4 gene are associated with the majority of cases. Definitive treatment of FECD is corneal transplantation. In this paper, we highlight advances that have been made in understanding FECD's clinical features, pathophysiology, and genetics. We also discuss recent advances in endothelial keratoplasty and potential future treatments.

Comparison of 20% sulfur hexafluoride with air for intraocular tamponade in Descemet membrane endothelial keratoplasty (DMEK).

PURPOSE:: To compare the effect of 20% sulfur hexafluoride (SF6) with that of air on graft detachment rates for intraocular tamponade in Descemet membrane endothelial keratoplasty (DMEK). METHODS:: Forty-two eyes of patients who underwent DMEK by a single surgeon (A.S.J.) at Wilmer Eye Institute between January 2012 and 2014 were identified; 21 received air for intraocular tamponade and the next consecutive 21 received SF6. The main outcome measure was the graft detachment rate; univariate and multivariate analyses were performed. RESULTS:: The graft detachment rate was 67% in the air group and 19% in the SF6 group (p<0.05). No complete graft detachments occurred, and all partial detachments underwent intervention with injection of intraocular air. The percentages of eyes with 20/25 or better vision were not different between the groups (67% vs. 71%). Univariate analysis showed significantly higher detachment rates with air tamponade (OR, 8.50; p<0.005) and larger donor graft size (OR, 14.96; p<0.05). Multivariate analysis with gas but not graft size included showed that gas was an independent statistically significant predictor of outcome (OR, 6.65; p<0.05). When graft size was included as a covariate, gas was no longer a statistically significant predictor of detachment but maintained OR of 7.81 (p=0.063) similar to the results of univariate and multivariate analyses without graft size. CONCLUSION:: In comparison with air, graft detachment rates for intraocular tamponade in DMEK were significantly reduced by 20% SF6.

Comparison of 20% sulfur hexafluoride with air for intraocular tamponade in Descemet membrane endothelial keratoplasty (DMEK) / Comparação de hexafluoreto de enxofre a 20% com ar para tamponamento intraocular na ceratoplastia endotelial de membrana Descemet (DMEK)

ABSTRACT Purpose: To compare the effect of 20% sulfur hexafluoride (SF6) with that of air on graft detachment rates for intraocular tamponade in Descemet membrane endothelial keratoplasty (DMEK). Methods: Forty-two eyes of patients who underwent DMEK by a single surgeon (A.S.J.) at Wilmer Eye Institute between January 2012 and 2014 were identified; 21 received air for intraocular tamponade and the next consecutive 21 received SF6. The main outcome measure was the graft detachment rate; univariate and multivariate analyses were performed. Results: The graft detachment rate was 67% in the air group and 19% in the SF6 group (p<0.05). No complete graft detachments occurred, and all partial detachments underwent intervention with injection of intraocular air. The percentages of eyes with 20/25 or better vision were not different between the groups (67% vs. 71%). Univariate analysis showed significantly higher detachment rates with air tamponade (OR, 8.50; p<0.005) and larger donor graft size (OR, 14.96; p<0.05). Multivariate analysis with gas but not graft size included showed that gas was an independent statistically significant predictor of outcome (OR, 6.65; p<0.05). When graft size was included as a covariate, gas was no longer a statistically significant predictor of detachment but maintained OR of 7.81 (p=0.063) similar to the results of univariate and multivariate analyses without graft size. Conclusion: In comparison with air, graft detachment rates for intraocular tamponade in DMEK were significantly reduced by 20% SF6.

RESUMO Objetivo: Comparar as taxas de descolamento do botão endotelial com o uso de gás hexafluoreto de enxofre a 20% (SF6) em relação ao ar para o tamponamento intraocular na ceratoplastia endotelial da membrana de Descemet (DMEK). Métodos: Quarenta e dois olhos foram operados com a técnica de DMEK por um único cirurgião (A.S.J.) no Wilmer Eye Institute entre janeiro de 2012 a 2014. Os primeiros 21 olhos receberam ar para o tamponamento intraocular após o enxerto do botão endotelial e os 21 olhos seguintes receberam SF6. O desfecho primário medido foi a taxa de descolamento do botão endotelial por análise univariada e multivariada. Resultados: A taxa de descolamento do botão endotelial foi de 67% no grupo que recebeu ar vs 19% no grupo que recebeu SF6 (p<0,05). Não houve nenhum descolamento total de botão e todos os parciais foram tratados com injeção de ar intraocular. Não houve diferença estatística significativa entre os grupos em relação a AV de 20/25 ou melhor (67% vs 71%). A análise univariada demonstrou maior taxa de descolamento com o tamponamento por ar intraocular (OR 8,50, p<0,005) e com botões doadores maiores (OR 14,96, p<0,05). Na análise multivariada, incluindo gás, mas não o tamanho do botão doador, o tipo de gás usado permaneceu sendo um fator preditivo independente e estatisticamente significativo para o desfecho primário, com OR de 6,65 (p<0,05). Porém, quando o tamanho do botão doador foi incluso como covariável, o gás perdeu a sua significância como preditor de descolamento, mantendo o OR de 7,81 (p=0,063), semelhante as análises univariada e multivariada excluindo o tamanho do botão doador. Conclusão: O uso de gás hexafluoreto de enxofre a 20% (SF6) para o tamponamento intraocular reduz a taxa de descolamento do botão endotelial quando comparado ao uso de ar no DMEK.

Early post-natal iron administration induces astroglial response in the brain of adult and aged rats.

This study was aimed to investigate neuropathological changes in adult and aged rats subjected to supplementary iron administration in a critical postnatal period to study the contribution of environmental risk factors to the pathogenesis of neurodegenerative disorders. Ten rats received a single daily oral administration of iron (10 mg/kg) between 12th and 14th post-natal days; nine rats received vehicle (sorbitol 5% in water) in the same period. Five iron-treated and three sorbitol-treated rats were killed at the age of 3 months while five iron-treated and six sorbitol-treated rats were killed at age of 24 months and their brains processed for immunohistochemistry. Increased astrocytosis, revealed by densitometry of GFAP-immunoreactive astrocytes, was found in aged (24 months) iron-treated rats in the substantia nigra and striatum and in the hippocampus of adult (3 months) iron-treated rats when compared to age-matching controls. Decreased densitometry of neurons, revealed by neuronal nucleus immunohistochemistry, was found in aged (24 months) iron-treated rats in substantia nigra and striatum when compared to age-matching controls. These findings suggest that transient dietary iron supplementation during the neonatal period is associated to cellular imprinting in the brain later in life.

Neonatal iron treatment increases apoptotic markers in hippocampal and cortical areas of adult rats.

Oxidative stress, cellular damage, and neuronal apoptosis are believed to underlie the progressive cognitive decline that accompanies natural aging and to be exacerbated in neurodegenerative diseases. Over the years, we have consistently demonstrated that iron neonatal treatment induces oxidative stress and memory deficits in adult rats, but the mechanisms underlying these effects remained undefined. The purpose of this study was to examine whether neonatal iron overload was associated with apoptotic cell death in adult and old rats. We analyzed Par-4 and caspase-3 immunoreactivity in specific brain areas including the hippocampus CA1, CA3 and dentate gyrus (DG), the adjacent cortex and the striatum in adult (3 months-old) and aged (24 months-old) rats from control (vehicle-treated) and neonatally iron-treated groups. Neonatal iron treatment consisted of a daily oral administration of 10 mg/kg of Fe(+2), for three consecutive days, from post-natal 12-14. Control aged animals showed increased levels of both markers when compared to untreated adult animals. When adults were compared, iron-treated animals presented significantly higher Par-4 and caspase-3 immunoreactivities in CA1, CA3 and cortex. In the DG, this effect was statistically significant only for Par-4. Interestingly, when control and iron-treated aged animals were compared, a significant decrease in both apoptotic markers was observed in the later groups in the same areas. These results may be interpreted as an acceleration of aging progressive damages caused by iron overload and may contribute to a better understanding of the damaging potential of iron accumulation to brain function and the resulting increased susceptibility to neurodegeneration.

Early life stress decreases hippocampal BDNF content and exacerbates recognition memory deficits induced by repeated D-amphetamine exposure.

Adverse experiences early in life may have profound influences on brain development, for example, determining alterations in response to psychostimulant drugs, an increased risk of developing a substance abuse disorder, and individual differences in the vulnerability to neuropsychiatric disorders later in life. Here, we investigated the effects of exposure to an early adverse life event, maternal deprivation, combined with repeated d-amphetamine (AMPH) administration in adulthood, on recognition memory and brain-derived neurotrophic factor (BDNF) levels in rats' brain and serum. Rats were exposed to one of the following maternal rearing conditions from postnatal days 1 to 14: non-deprived (ND) or deprived (D). In adulthood, both groups received injections of saline (SAL) or AMPH (2.0mg/kg, i.p.) for 7 days. In Experiment I (performed 24h after the last AMPH injection), AMPH induced long-term memory (LTM) impairments in ND and D groups. The D+AMPH group also presented short-term memory (STM) impairments, indicating that the effects of AMPH on memory were more pronounced when the animals where maternally deprived. The group exposed to D+SAL (SAL) showed only LTM impairments. In Experiment II (performed 8 days after the last injection), AMPH detrimental effects on memory persisted in ND and D groups. BDNF levels were decreased in the hippocampus of D+SAL rats. In conclusion, AMPH produces severe and persistent recognition memory impairments that were more pronounced when the animals were maternally deprived, suggesting that an early adverse life event may increase the vulnerability of cognitive function to exposure to a psychostimulant later in life.

Reversal of age-associated memory impairment by rosuvastatin in rats.

Increased levels of iron in brain regions have been reported in neurodegenerative disorders as well as in normal brain aging. We have previously demonstrated that neonatal iron loading induces cognitive impairment in adult rats. Here, we evaluate the effects of neonatal iron treatment on cognition in aged rats. We also investigated the effects of a late subchronic rosuvastatin treatment on iron- and age-induced cognitive deficits. Rats received vehicle or 10.0mg/kg Fe(2+) orally at postnatal days 12-14. When animals reached the age of 23 months, they received daily intraperitoneal injections of saline or rosuvastatin (0.2 or 2.0mg/kg) for 21 days. Twenty-four hours after the last injection, they were submitted to novel object recognition training. Retention test sessions were performed 1.5 and 24h after training, in order to assess short-term and long-term memory, respectively. Results indicated that aged animals that received iron in the neonatal period showed more severe memory deficits than vehicle-treated ones, suggesting that iron potentiates age-associated memory impairments. Rosuvastatin improved recognition memory deficits associated with iron loading and aging, providing evidence that statins may be considered for the treatment of age-associated cognitive decline.

Iron leads to memory impairment that is associated with a decrease in acetylcholinesterase pathways.

Increasing evidence indicates that excessive iron in selective regions of the brain may be involved in the etiology of neurodegenerative disorders. Accordingly, increased levels of iron have been described in brain regions of patients in Parkinson's and Alzheimer's diseases. We have characterized neonatal iron loading in rodents as a novel experimental model that mimics the brain iron accumulation observed in patients with neurodegenerative diseases and produces severe cognitive impairment in the adulthood. In the present study we have investigated the involvement of the cholinergic system on iron-induced memory impairment. The effects of a single administration of the acetylcholinesterase (AChE) inhibitor galantamine or the muscarinic receptor agonist oxotremorine on iron-induced memory deficits in rats were examined. Male Wistar rats received vehicle or iron (10.0 mg/kg) orally at postnatal days 12 to 14. At the age of 2-3 months, animals were trained in a novel object recognition task. Iron-treated rats showed long-term impairments in recognition memory. The impairing effect was reversed by systemic administration of galantamine (1 mg/kg) immediately after training. In addition, iron-treated rats that received oxotremorine (0.5 mg/kg) showed enhanced memory retention. Rats given iron showed a decreased AChE activity in the striatum when compared to controls. The results suggest that, at least in part, iron-induced cognitive deficits are related to a dysfunction of cholinergic neural transmission in the brain. These findings might have implications for the development of novel therapeutic strategies aimed at ameliorating cognitive decline associated with neurodegenerative disorders.

Síndrome do olho seco / Dry eye syndrome

A síndrome do olho seco é uma entidade muito comum na pratica medica e, por apresentar uma sintomalogia muito inespecífica, compartilhada por diversas outras doenças oculares, costuma ser subdiagnosticada. Atualmente, o termo olho seco é definido como “uma doença multifatorial do sistema lacrimal caracterizada por sintomas de desconforto, distúrbios visuais, com potencial dano à superfície ocular. É acompanhado de alteração de alterações na osmolaridade do filme lacrimal e inflamação da superfície ocular”.

Ceratocone: atualização / Keratoconus: update

Neste artigo de revisão discorremos sobre aspectos norteadores de uma doença relativamente freqüente das patologias oculares. Apresentamos aspectos essenciais sobre as teorias fisiopatológicas, aspectos clínicos, diagnósticos. Porem, nossos foco é apresentar uma atualização em relação ao tratamento, que tem evoluído muito nos últimos anos.