Chronic Dyrk1 Inhibition Delays the Onset of AD-Like Pathology in 3xTg-AD Mice.

There is a critical need for new treatment approaches that can slow or prevent the progression of Alzheimer's disease (AD). Targets that act simultaneously on multiple relevant pathways could have significant therapeutic potential. Dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1a) phosphorylates both amyloid precursor protein (APP) and tau. Dyrk1a is upregulated in post-mortem brains of AD patients, and such elevated expression is associated with cognitive deficits. We previously demonstrated that small molecule inhibition of Dyrk1 is well-tolerated and reduces amyloid plaques and pathological forms of tau in 3xTg-AD mice if administered after formation of these pathologies. However, while insoluble forms of hyperphosphorylated tau were reduced by Dyrk1 inhibition, overt neurofibrillary tangle (NFT) pathology remained unchanged. Herein, we specifically test the hypothesis that inhibition of Dyrk1 prior to NFT formation will delay the onset of pathology. 3xTg-AD mice were treated chronically, beginning at 6 months of age, prior to NFT pathology. Mice were dosed daily for either 3 or 6 months and amyloid and tau pathology were assessed. We show that chronic Dyrk1 inhibition reduces insoluble forms of amyloid beta peptides (Aß) and hyper-phosphorylated tau long-term and that these reductions are associated with dramatic delay in the onset of both amyloid plaques and NFTs. In addition, we show that DYR219, a potent and selective small molecule Dyrk1 inhibitor, induces degradation of Dyrk1a protein, likely contributing to the efficacy of this small molecule approach in vivo. Collectively, these results suggest that therapeutic strategies targeting tau phosphorylation will show the greatest effect if administered very early in the pathogenesis of AD.

p62 improves AD-like pathology by increasing autophagy.

The multifunctional protein p62 is associated with neuropathological inclusions in several neurodegenerative disorders, including frontotemporal lobar degeneration, amyotrophic lateral sclerosis and Alzheimer's disease (AD). Strong evidence shows that in AD, p62 immunoreactivity is associated with neurofibrillary tangles and is involved in tau degradation. However, it remains to be determined whether p62 also plays a role in regulating amyloid-ß (Aß) aggregation and degradation. Using a gene therapy approach, here we show that increasing brain p62 expression rescues cognitive deficits in APP/PS1 mice, a widely used animal model of AD. The cognitive improvement was associated with a decrease in Aß levels and plaque load. Using complementary genetic and pharmacologic approaches, we found that the p62-mediated changes in Aß were due to an increase in autophagy. To this end, we showed that removing the LC3-interacting region of p62, which facilitates p62-mediated selective autophagy, or blocking autophagy with a pharmacological inhibitor, was sufficient to prevent the decrease in Aß. Overall, we believe these data provide the first direct in vivo evidence showing that p62 regulates Aß turnover.

Identification of learning-induced changes in protein networks in the hippocampi of a mouse model of Alzheimer's disease.

Memory loss is the most profound clinical manifestation in Alzheimer's disease (AD); however, the molecular mechanisms underlying these deficits are poorly understood. Identification of the molecular pathways involved in the onset of cognitive deficits may lead to the identification of key events in the pathogenesis of AD. Using isobaric tags for relative and absolute quantitation (iTRAQ) and proteomic methods, here we identified learning-induced changes in the hippocampal proteome of non-transgenic (NonTg) and 3 × Tg-AD mice, a widely used animal model of AD. We found that expression of 192 proteins was differentially regulated by learning in NonTg mice. Notably, of these 192 proteins, only 28 were also differentially regulated by learning in 3 × Tg-AD mice, whereas the levels of 164 proteins were uniquely changed in NonTg mice but not in 3 × Tg-AD mice. These data suggest that during learning, 3 × Tg-AD mice fail to differentially regulate 164 proteins. Gene ontology and protein interaction analyses indicated that these proteins were overrepresented in RNA processing, specifically RNA transport, splicing and mRNA translation initiation pathways. These findings suggest that mRNA-processing events that take place during learning and memory are significantly altered in 3 × Tg-AD mice.

Dentate gyrus expression of nestin-immunoreactivity in patients with drug-resistant temporal lobe epilepsy and hippocampal sclerosis.

PURPOSE: Granule cells pathology in dentate gyrus, have received considerable attention in terms of understanding the pathophysiology of temporal lobe epilepsy with hippocampal sclerosis. The aim of this study was to determine the nestin (an intermediate filament protein expressed by newly formed cells), immunoreactivity (IR) in granular cells layers of hippocampal tissue extirpated during epilepsy surgical procedure, in patients with drug-resistant epilepsy. METHODS: Hippocampal sections of 16 patients with hippocampal sclerosis and drug-resistant temporal lobe epilepsy were processed using immunoperoxidase with antibody to nestin. Archival material from 8 normal post-mortem hippocampus, were simultaneously processed. Reactive area for nestin-IR, the total number of positive nestin cells per field (20×), and the MGV (mean gray value) was determined by computerized image analysis (ImageJ), and compared between groups. Student's t test was used for statistical analysis. RESULTS: Nestin-IR cells were found in granule cells layers of both controls and patients. Larger reactive somas (p < 0.01) were found in epileptic's sections but a significant reduction in the total number of nestin-IR cells per field and in the MGV was found in granular cells layers of patients with hippocampal sclerosis (p < 0.01). CONCLUSION: Reduced expression of nestin-IR in granular cells layers of epileptic's dentate gyrus may reflect changes in dentate gyrus neuroplasticity associated to chronic temporal epilepsy with hippocampal sclerosis. Further studies are required to determine the clinical implications on memory an emotional alterations such as depression.

[Psychological features of body integrity identity disorder (BIID): personality traits, interpersonal aspects, coping mechanisms regarding stress and conflicts, body perception]. / Psychische Merkmale von Body Integrity Identity Disorder (BIID): Persönlichkeitseigenschaften, Interpersonale Aspekte, Copingmechanismen bei Stress und Konflikten, Körpererleben.

BACKGROUND: In BIID a disorder of body identity, concerned subjects desire an amputation of a healthy limb. So far, no psychiatric comorbidity was found in the few studies on BIID-subjects. PATIENTS AND METHODS: This study explored clinical symptoms, personality characteristics, interpersonal aspects and coping strategies in 15 BIID persons. Psychometric testing on the topics (1) clinical symptoms, (2) personality and interpersonal aspects, (3) coping strategies, (4) attitudes towards the body were used and statistically evaluated with the T-test for one sample. RESULTS: Some psychopathologies such as depression, anxiety and obsessive-compulsive disorders (OCD) could be excluded although an increased tendency of depressiveness was found. BIID subjects showed specific personality and interpersonal characteristics: high agreeableness, autonomy, autarky and restrained behaviour towards others. Stress and conflicts are managed by self-control and self-affirmation. Their subjective physical attractiveness was low. CONCLUSION: BIID persons do not exhibit psychopathological characteristics (such as anxiety, depression or OCD), but do show specifics in personality, relationships and coping mechanisms. In the future, further personality traits and personality disorders should be investigated to shed more light on the categorisation and treatment of BIID.

[Quality of life for adolescents with vocal cord dysfunction]. / Lebensqualität bei jugendlichen mit vocal cord dysfunction.

BACKGROUND: Vocal cord dysfunction (VCD) is a functional breathing disorder. A psychosomatic aetiology has been discussed and associations with depression, anxiety disorders, and social stress have been reported. We have undertaken a screening of behavioural and emotional problems in adolescent patients using standardised questionnaires. METHODS: Thirty-one patients (8 - 16 years) with the clinical suspicion of VCD were investigated using the Youth-Self-Report (YSR/11 - 18) and for the assessment of the parents we used the analoguous Child-Behaviour-Checklist (CBCL/6 - 18). YSR and CBCL contain two sub-areas: (a) competence scales that measure the child's participation in activities, social skills and school achievements and (b) items that contain subscales for emotional problems such as depressive and anxiety symptoms, conduct problems such as oppositional defiant problems and aggressive behaviour, social problems and physical complaints. RESULTS: On average, the features of VCD patients were not significantly different from those of the reference population. But we did observe tendencies of psychological problems (YSR 16.7 %, CBCL 20 %) compared with the standard (2 %) in the syndrome scales of both questionnaires Adolescents reported particularly more internalising disorders such as social retreat, physical complaint and anxiety and depressive symptoms. The parents reported more often "physical complaints" (13.3 %) and "aggressive behaviour" (10 %). CONCLUSIONS: We found tendencies of psychological strain, mainly social retreat, physical complaints and anxiety and depressive symptoms. Further investigations should focus on those emotional problems as well as on psychosomatically caused physical problems. Personality and psychological stress of the parents should be included in the investigation in order to evaluate the reports of the parents on higher aggressive behaviour and enhanced physical problems of their children in relation to their own psychological strain. We suggest family therapies, family counselling, or parental coaching as a therapeutic approach.

Malformations of cortical development and epilepsy in adult patients.

OBJECTIVE: To describe clinical features of epilepsy secondary to Malformation of Cortical Development (MCD) in a series of adult patients. MATERIALS AND METHODS: We searched our database for all cases with confirmed epilepsy and MCD and included in the study only those with complete data. Mean age, sex, age at seizure onset (ASO), seizure types, abnormal neurological exam (ANE), mental retardation, family history, gestational or perinatal insults (G-PI), interictal EEG and response to treatment were analyzed. Cases were classified into the 3 main groups (G) according to the Barkovich classification (BC) and then compared: (G1) "malformations due to abnormal cell proliferation", (G2) "malformations due to abnormal migration" and (G3) "malformations due to abnormal cortical organization". RESULTS: We identified 152 (5.06%) patients with MCD from a total of 3000 with epilepsy. In total, 138 patients with complete medical data were included in this study. The mean age of patients was 36.2 years, 52.2% were female, the mean ASO was 12.3 years, 5.1% of cases had a positive family history and 21% had G-PI. An ANE was observed in 21% and mental retardation in 31.9%. Most of the patients (84.8%) had refractory epilepsy. The distribution of cases according to the BC was: 51.4% in G1, 28.9% in G2 and 19.6% in G3. Comparing the 3 groups, we found that an ANE was statistically more frequent in G3 and was present in 70.4% of cases. CONCLUSION: Our series of adult patients with epilepsy and MCD suggests that MCD are identified as commonly in a developing country as in previous "first world" series. Neurological deficits were more common in the subgroup of patients with polymicrogyria and schizencephaly (BC Group 3).

Análisis de los trastornos psicóticos en pacientes con epilepsia parcial refractaria, diagnóstico psiquiátrico y características clínicas / Analysis of psychotic disorders in patients with refractory partial epilepsy, psychiatric diagnoses and clinical aspects

Introducción. La asociación entre trastornos psicóticos y epilepsia ha sido motivo de controversias. Actualmente se describen en la literatura diferentes subtipos de trastornos psicóticos en los pacientes con epilepsia de acuerdo con la relación temporal con las crisis: las psicosis postictales (PPI), interictales (PII) y bimodales (PB).Objetivos. Determinar las características clínicas de pacientes con epilepsia parcial refractaria y psicosis y compararlos hallazgos con un grupo control de pacientes con epilepsia parcial refractaria sin psicosis. Métodos. Se estudiaron 57 pacientes con epilepsia parcial refractaria y trastornos psicóticos (GP) y 56 pacientes con epilepsia parcial refractaria sin psicosis (GnP) de acuerdo con los criterios del DSM-IV. En todos los pacientes se realizó una evaluación neurológica completa, estudios neurofisiológicos, neuroimágenes y evaluaciones psiquiátricas DSM-IV y SCID-I. Las variables clínicas, demográficas y psiquiátricas fueron comparadas entre los pacientes GP y GnP.Resultados. En el GP 15 pacientes (26%) cumplían criterios para PPI, 29 pacientes (51 %) para PII y 13 pacientes(23 %) para PB. Encontramos una duración más prolongada de la epilepsia y una mayor incidencia de esclerosis hipocámpica bilateral en los pacientes GP. Los pacientes de GP presentaron un mayor tiempo de evolución de la epilepsia y una mayor incidencia de esclerosis hipocámpica bilateral (p < 0,05).No se observaron diferencias entre los distintos subtipos de psicosis. Conclusiones. El mayor tiempo de evolución de las crisis epilépticas y la presencia de una esclerosis hipocámpica bilateral podrían incrementar el riesgo de desarrollar psicosis en pacientes con epilepsia parcial refractaria (AU)

Introduction. The association between psychotic disorders and epilepsy has been controversial. Different subtypes of psychotic disorders in epilepsy patients have been described according to temporal relationship with seizures-postictal (PIP), interictal (IIP) and bimodal (BP) psychoses are described in literature. Objectives. Determine clinical characteristics of patients with refractory partial epilepsy and psychoses and compare the results with a control group of patients with refractory partial epilepsy without psychoses. Methods. A total of 57 patients with refractory partial epilepsy and psychotic disorders (psychotic group [PG]) and 56 patients with refractory partial epilepsy and without psychoses (control group, CG) were evaluated according to DSM-IV criteria and SCID-I. All patients underwent complete neurological, neuroimaging, neuropsychological, and psychiatric assessment. Clinical, demographic and neuroimaging data were compared between patients in CG and PG. Results. In PG 15 patients (26%) had criteria for PIP,29 patients (51 %) for IIP and 13 patients (23 %) for BP. Epilepsy time duration and bilateral hippocampal sclerosis were significantly more frequent in patients with psichosis.PG patients had a longer evolution time of epilepsy and greater frequency of bilateral hippocampal sclerosis (p < 0.05). No differences were found between psychoses subtypes. Conclusions. Longer evolution of seizures and the presence of bilateral hippocampal sclerosis may increase propensity to develop psychoses in patients with refractory partial epilepsy (AU)

[Analysis of psychotic disorders in patients with refractory partial epilepsy, psychiatric diagnoses and clinical aspects]. / Análisis de los trastornos psicóticos en pacientes con epilepsia parcialrefractaria, diagnóstico psiquiátrico y características clínicas.

INTRODUCTION: The association between psychotic disorders and epilepsy has been controversial. Different subtypes of psychotic disorders in epilepsy patients have been described according to temporal relationship with seizures-postictal (PIP), interictal (IIP) and bimodal (BP) psychoses are described in literature. OBJECTIVES: Determine clinical characteristics of patients with refractory partial epilepsy and psychoses and compare the results with a control group of patients with refractory partial epilepsy without psychoses. METHODS: A total of 57 patients with refractory partial epilepsy and psychotic disorders (psychotic group [PG]) and 56 patients with refractory partial epilepsy and without psychoses (control group, CG) were evaluated according to DSM-IV criteria and SCID-I. All patients underwent complete neurological, neuroimaging, neuropsychological, and psychiatric assessment. Clinical, demographic and neuroimaging data were compared between patients in CG and PG. RESULTS: In PG 15 patients (26 %) had criteria for PIP, 29 patients (51%) for IIP and 13 patients (23%) for BP. Epilepsy time duration and bilateral hippocampal sclerosis were significantly more frequent in patients with psichosis. PG patients had a longer evolution time of epilepsy and greater frequency of bilateral hippocampal sclerosis (p < 0.05). No differences were found between psychoses subtypes. CONCLUSIONS: Longer evolution of seizures and the presence of bilateral hippocampal sclerosis may increase propensity to develop psychoses in patients with refractory partial epilepsy.

Modeling behavioral and neuronal symptoms of Alzheimer's disease in mice: a role for intraneuronal amyloid.

The amyloid Abeta-peptide (Abeta) is suspected to play a critical role in the cascade leading to AD as the pathogen that causes neuronal and synaptic dysfunction and, eventually, cell death. Therefore, it has been the subject of a huge number of clinical and basic research studies on this disease. Abeta is typically found aggregated in extracellular amyloid plaques that occur in specific brain regions enriched in nAChRs in Alzheimer's disease (AD) and Down syndrome (DS) brains. Advances in the genetics of its familiar and sporadic forms, together with those in gene transfer technology, have provided valuable animal models that complement the traditional cholinergic approaches, although modeling the neuronal and behavioral deficits of AD in these models has been challenging. More recently, emerging evidence indicates that intraneuronal accumulation of Abeta may also contribute to the cascade of neurodegenerative events and strongly suggest that it is an early, pathological biomarker for the onset of AD and associated cognitive and other behavioral deficits. The present review covers these studies in humans, in in vitro and in transgenic models, also providing more evidence that adult 3xTg-AD mice harboring PS1M146V, APPSwe, tauP301L transgenes, and mimicking many critical hallmarks of AD, show cognitive deficits and other behavioral alterations at ages when overt neuropathology is not yet observed, but when intraneuronal Abeta, synaptic and cholinergic deficits can already be described.

Clinical-electroencephalogram patterns at seizure onset in patients with hippocampal sclerosis.

OBJECTIVE: The purpose of this study is to identify specific clinical-electroencephalogram (EEG) patterns at seizure onset in patients with hippocampal sclerosis (HS). METHODS: Sixty-six ictal video-EEG recordings corresponding to 26 patients with HS have been reviewed, focusing on the EEG features found during the first 30 ictal s. The EEG activity has been classified into the following groups: (A) according to spatial distribution: type 1: temporal electrodes on one side; type 2: temporal and adjacent frontal electrodes on one side; and type 3: non-lateralizing electrographic activity; and (B) according to morphology; subtype (a): regular 5-9 Hz rhythmic activity (RA); subtype (b): low-voltage rapid activity, followed by a 5-9 Hz RA; and subtype (c): irregular EEG sharp waves. We analyzed the clinical symptoms sequence and established the relationship with the ictal EEG patterns. RESULTS: Considering spatial distribution and morphology, the most frequent ictal EEG patterns were type 1 (57%), type 2 (37%), and subtype (a): 62%; subtype (b): 27%; and subtype (c): 11%. The sequence of clinical symptoms observed was: aura-->behavioral arrest-->oro-alimentary automatisms-->unilateral hand automatisms. All seizures with aura and including two or more symptoms of the clinical sequence (65%) were associated with a 1a, 1b, 2a or 2b EEG pattern. CONCLUSIONS: The identification of a specific clinical-EEG pattern provides a useful tool for the epileptogenic zone localization in non-invasive pre-surgical assessment of patients with hippocampal sclerosis. SIGNIFICANCE: The identification of a specific clinical-EEG pattern associated to neuroimaging findings and neuropsychological testing allows indicating surgery for the treatment of epilepsy in patients with hippocampal sclerosis, without performing any further complementary studies.

Spike-and-wave complexes and seizure exacerbation caused by carbamazepine.

The purpose of this research is to analyse patients in whom carbamazepine (CBZ) therapy adversely affected electroencephalogram (EEG) recordings leading to seizure exacerbation and to identify risk factors for these events. From a total number of 2191 patients (p.) included in the Municipal Epilepsy Center (MEC) database, 77 patients with spike-and-wave (SW) discharges while on CBZ treatment have been selected. Patient population was divided in two groups: (i) patients who were already receiving CBZ at the time of their first visit to the MEC; and (ii) patients to whom CBZ was prescribed during follow-up at the MEC. CBZ was discontinued in all patients with confirmed evidence of an increase in seizure frequency, or with no improvement of epilepsy. During follow-up, EEG findings as well as all clinical changes were duly recorded. Group 1: Carbamazepine was discontinued in 17 patients (p.) as a result of paradoxical reactions. This condition occurs when an antiepileptic drug (AED) appears to exacerbate a type of seizure against which it is usually effective, or when it leads to the onset of new types of seizures. Three p. were withdrawn because of inappropriate drug selection. Group 2: CBZ was discontinued in six patients (p.) as a result of paradoxical reactions. The paradoxical reaction was more frequent in patients with frontal epilepsy and generalized SW discharges on the EEG (P=0.09) and patients with benign rolandic epilepsy (BRE) with diffuse interictal sharp and slow-wave discharges. In both groups, clinical and electrical changes returned to their initial status upon CBZ withdrawal. On the basis of this study, it may be concluded that EEGs might eventually help to screen high-risk patients. If EEG recordings become substantially worse, with more frequent and longer generalized SW bursts after initiation of CBZ therapy, patients should be carefully monitored in order to detect any sign of clinical impairment.

Clinical features and prognosis of nonepileptic seizures in a developing country.

PURPOSE: To determine the predictive value of clinical features and medical history in patients with nonepileptic seizures (NESs). METHODS: One hundred sixty-one consecutive ictal video-EEGs were reviewed, and 17 patients with 41 NESs identified. NES diagnosis was defined as paroxysmal behavioral changes suggestive of epileptic seizures recorded during video-EEC without any electrographic ictal activity. Clinical features, age, sex, coexisting epilepsy, associated psychiatric disorder, social and economic factors, delay in reaching the diagnosis of NES, previous treatment, and correlation with outcome on follow-up were examined. RESULTS: The study population included 70% female patients with a mean age of 33 years. Mean duration of NESs before diagnosis was 9 years. Forty-one percent had coexisting epilepsy. The most frequent NES clinical features were tonic-clonic mimicking movements and fear/anxiety/hyperventilation. The most common psychiatric diagnosis was conversion disorder and dependent and borderline personality disorder. Seventy-three percent of patients with pure NESs received antiepileptic drugs (AEDs), and 63.5% of this group received new AEDs. Fifty-nine percent of the patients received psychological/psychiatric therapy. At follow-up, 23.5% were free of NESs. CONCLUSIONS: All seizure-free patients had two good prognostic factors: having an independent lifestyle and the acceptance of the nonepileptic nature of the episodes. Video-EEG monitoring continues to be the diagnostic method to ensure accurate seizure classification. Establishing adequate health care programs to facilitate access to new technology in public hospitals as well as the implementation of continuous education programs for general practitioners and neurologists could eventually improve the diagnosis and treatment of patients with NESs.

[Magnetic resonance and clinical and electroencephalographical localization in focal epilepsy]. / Resonancia magnética y localización clínica y electroencefalográfica en la epilepsia focal.

Magnetic Resonance Imaging (MRI) is the method of choice to search for epileptogenic lesions. We correlated MRI findings with the epileptogenic zone (EZ) depicted by clinical and electroencephalographic (EEG) data. We studied 400 clinical records of patients who had been submitted to MRI studies and we analyzed, retrospectively, their ictal semiology, EEG characteristics and response to treatment. They were classified into 3 groups: A) temporal lobe epilepsy, B) frontal lobe epilepsy and C) parieto-occipital epilepsy. We included 155 patients: Group A) 68 cases (43.9%), 28 men (41.1%), mean age 32 +/- 11 years old, abnormal IMR in 44 (64.7%), refractory to treatment 48 (70.5%). Group B) 68 cases (43.9%), 38 men (55.8%), mean age 30 +/- 15 years old, abnormal IMR in 26 (38.2%), refractory to treatment 30 (44.1%). Group C) 19 cases (12.2%), 13 men (68.4%), mean age 27 +/- 11 years old, abnormal IMR in 11 (57.8%), refractory to treatment 12 (63.1%). Results showed that there were higher possibilities of detecting lesions which correlate with EZ in temporal than in frontal or parieto-occipital lobes epilepsy. The chances to find abnormalities on the MRI were 5 times higher in refractory patients than in those who were non-refractory.

Resonancia magnética y localización clínica y electroencefalográfica en la epilepsia focal. / [Magnetic resonance and clinical and electroencephalographical localization in focal epilepsy]

Magnetic Resonance Imaging (MRI) is the method of choice to search for epileptogenic lesions. We correlated MRI findings with the epileptogenic zone (EZ) depicted by clinical and electroencephalographic (EEG) data. We studied 400 clinical records of patients who had been submitted to MRI studies and we analyzed, retrospectively, their ictal semiology, EEG characteristics and response to treatment. They were classified into 3 groups: A) temporal lobe epilepsy, B) frontal lobe epilepsy and C) parieto-occipital epilepsy. We included 155 patients: Group A) 68 cases (43.9

), 28 men (41.1

), mean age 32 +/- 11 years old, abnormal IMR in 44 (64.7

), refractory to treatment 48 (70.5

). Group B) 68 cases (43.9

), 38 men (55.8

), mean age 30 +/- 15 years old, abnormal IMR in 26 (38.2

), refractory to treatment 30 (44.1

). Group C) 19 cases (12.2

), 13 men (68.4

), mean age 27 +/- 11 years old, abnormal IMR in 11 (57.8

), refractory to treatment 12 (63.1

). Results showed that there were higher possibilities of detecting lesions which correlate with EZ in temporal than in frontal or parieto-occipital lobes epilepsy. The chances to find abnormalities on the MRI were 5 times higher in refractory patients than in those who were non-refractory.

Texture segregation in chromatic element-arrangement patterns.

An element-arrangement pattern is composed of two types of elements arranged differently in different regions of a pattern. Rapid texture segregation depends on spontaneously discriminating the difference in the arrangement of the elements. Five experiments investigated the perceived segregation of patterns composed of two types of squares arranged in vertical stripes in the top and bottom regions and in a checkerboard arrangement in the middle region. The squares were either equal in luminance and different in hue or equal in hue and different in luminance. The rated similarities of the two hues in a pattern failed to predict perceived segregation. For a given background luminance, the perceived segregation was predicted by the square-root of the sum of the squares of the differences in the outputs of the L - M + S and L + M - S opponent channels, where L, M, and S were the cone contrasts of the long-, medium-, and short-wavelength receptors. The perceived similarity of the two hues in a pattern was not affected by the background luminance but was a function of cone excitations instead. For patterns differing in hue and equal in luminance, perceived segregation was an inverse function of the background luminance. A white background decreased the perceived segregation, but a black background did not. The effect of background luminance was not on the discrimination of the individual hues. The two hues making up a texture pattern were clearly distinguishable on a white background. A white background interfered with the discrimination of the vertical and diagonal columns of squares that distinguished the texture regions. For patterns differing in luminance and equal in hue, black and white backgrounds decreased the perceived segregation. The results indicate that adapting to an achromatic luminance distant from the luminance of the squares increased the Weber threshold for discriminating luminance differences, but did not increase the Weber threshold for discriminating hue differences. The experiments also revealed that luminance was the primary factor affecting perceived segregation and that perceived brightness is secondary. The results are consistent with the hypothesis that perceived segregation in element-arrangement patterns is primarily a function of the differences in the outputs of relatively early filtering mechanisms that encode pattern differences prior to the specification of the element shapes and their properties.

Genetic susceptibility to experimental autoimmune uveoretinitis in the rat is associated with an elevated Th1 response.

This study examines whether genetic susceptibility vs genetic resistance to experimental autoimmune uveoretinitis (EAU) are connected to a predisposition to mount a Th1-dominated (IFN-gamma high, IL-4 low) vs a Th2-dominated (IL-4 high, lFN-gamma low) response. Lewis rats developed disease with high incidence after immunization with the uveitogenic peptide R16, whereas F344 rats were resistant. Primed lymph node cells from both strains proliferated in culture in response to R16. However, while the Lewis cultures transferred EAU to syngeneic recipients, those of F344 did not. The Lewis cultures produced substantially more IFN-gamma mRNA and protein in response to R16, than did those of F344. Both strains made low levels of IL-10 mRNA and IL-4 mRNA. Unlike the primary cultures, long-term (R16-specific) T cell lines derived from each of the strains transferred EAU equally well to their respective recipients, and produced similar, high levels of IFN-gamma mRNA and protein. Treatment of F344 with Bordetella pertussis toxin concurrently with immunization abrogated its resistance, enhanced Ag-specific IFN-gamma production in culture, and yielded a primed cell population capable of transferring EAU. Conversely, immunization of Lewis rats with R16 in IFA induced little or no disease; the primed cells produced minimal amounts of IFN-gamma and did not transfer EAU. However, addition of IL-12 into the culture resulted in a highly pathogenic, IFN-gamma-producing cell population. We conclude that genetic susceptibility to ocular autoimmunity in this model is connected to an elevated Th1 response. Genetic resistance, however, does not seem to involve an elevated Th2 response, but rather an inhibited development of Th1-like effector cells.