Isolating the impact of visual perception on dyslexics' reading ability

A large body of data suggests that phonological deficits play an important causal role in dyslexics' reading difficulties. The functional role of visual impairments is still highly debated. Many recent studies have shown clear visual deficits in large subgroups of dyslexics. However, the relationship between these deficits and visual routines required for reading is not clear. To assess the direct contribution of visual factors to dyslexics' slower and less accurate reading, we composed a task that was similar to single word reading in its basic visual characteristics, but had none of the other (phonological, morphological, semantic, etc.) aspects of reading. Young adult dyslexics, with average or above general cognitive abilities, and controls matched for age and cognitive skills participated in the study. We measured both SOA and contrast thresholds for identifying unfamiliar letters. Letters were chosen from an alphabet graphically similar to Hebrew and English (a subset of Georgian letters), but unfamiliar to the subjects. Effects of decreasing letter size, increasing letter crowding (by adding a flanker letter on each side) and adding white noise, were measured. Dyslexics performed as well as controls under all test conditions, and had similar effect sizes. We thus conclude that, despite the data showing that dyslexics have marked difficulties with single word reading, the cause of these difficulties is not a visual processing deficit.     

The immunomodulator AS101 induces growth arrest and apoptosis in multiple myeloma: association with the Akt/survivin pathway

Multiple Myeloma (MM) is a clonal B-cell malignancy affecting both the immune and the skeletal systems, and accounts for 10% of all hematological cancers. The immunomodulator ammonium trichloro (dioxoethylene-O,O') tellurate (AS101) is a non-toxic compound which has direct anti-tumoral properties in several tumor models. The present study examined the anti-tumoral activity of AS101 in MM by targeting the Akt/Survivin signaling pathway, crucial for survival. We showed that AS101 inhibites cell proliferation and colonies formation of MM cell lines, in a dose-dependent manner. AS101 induced G(2)/M growth arrest and increased both cyclin-dependent kinase inhibitor p21(waf1) protein levels and Cdk1 (p34(cdc2))-inhibitory phosphorylation. Longer incubation of MM cells with AS101 resulted in accumulation of apoptotic cell population and in increased caspase 9, 3 and 7 activities. We also showed that AS101 down-regulated Akt phosphorylation and decreased expression of the inhibitor of apoptosis, survivin. Since Akt and survivin are potentials targets for MM therapy, we suggest that AS101, currently being used in clinical studies, may have therapeutic implications in myeloma and other hematopoietic malignancies.     

An integrated in silico 3D model-driven discovery of a novel, potent, and selective amidosulfonamide 5-HT1A agonist (PRX-00023) for the treatment of anxiety and depression

We report the discovery of a novel, potent, and selective amidosulfonamide nonazapirone 5-HT1A agonist for the treatment of anxiety and depression, which is now in Phase III clinical trials for generalized anxiety disorder (GAD). The discovery of 20m (PRX-00023), N-{3-[4-(4-cyclohexylmethanesulfonylaminobutyl)piperazin-1-yl]phenyl}acetamide, and its backup compounds, followed a new paradigm, driving the entire discovery process with in silico methods and seamlessly integrating computational chemistry with medicinal chemistry, which led to a very rapid discovery timeline. The program reached clinical trials within less than 2 years from initiation, spending less than 6 months in lead optimization with only 31 compounds synthesized. In this paper we detail the entire discovery process, which started with modeling the 3D structure of 5-HT1A using the PREDICT methodology, and then performing in silico screening on that structure leading to the discovery of a 1 nM lead compound (8). The lead compound was optimized following a strategy devised based on in silico 3D models and realized through an in silico-driven optimization process, rapidly overcoming selectivity issues (affinity to 5-HT1A vs alpha1-adrenergic receptor) and potential cardiovascular issues (hERG binding), leading to a clinical compound. Finally we report key in vivo preclinical and Phase I clinical data for 20m tolerability, pharmacokinetics, and pharmacodynamics and show that these favorable results are a direct outcome of the properties that were ascribed to the compound during the rational structure-based discovery process. We believe that this is one of the first examples for a Phase III drug candidate that was discovered and optimized, from start to finish, using in silico model-based methods as the primary tool.     

hTERT-immortalized prostate epithelial and stromal-derived cells: an authentic in vitro model for differentiation and carcinogenesis

Prostate cancer is the most commonly diagnosed type of cancer in men, and there is no available cure for patients with advanced disease. In vitro model systems are urgently required to permit the study of human prostate cell differentiation and malignant transformation. Unfortunately, human prostate cells are particularly difficult to convert into continuously growing cultures. We report here the successful immortalization without viral oncogenes of prostate epithelial cells and, for the first time, prostate stromal cells. These cells exhibit a significant pattern of authentic prostate-specific features. In particular, the epithelial cell culture is able to differentiate into glandular buds that closely resemble the structures formed by primary prostate epithelial cells. The stromal cells have typical characteristics of prostate smooth muscle cells. These immortalized cultures may serve as a unique experimental platform to permit several research directions, including the study of cell-cell interactions in an authentic prostate microenvironment, prostate cell differentiation, and most significantly, the complex multistep process leading to prostate cell transformation.     

Sequential spatial frequency discrimination is consistently impaired among adult dyslexics

The degree and nature of dyslexics' difficulties in performing basic visual tasks have been debated for more than thirty years. We recently found that dyslexics' difficulties in detecting temporally modulated gratings are specific to conditions that require accurate comparisons between sequentially presented stimuli [Brain 124 (2001) 1381]. We now examine dyslexics' spatial frequency discrimination (rather than detection), under simultaneous (spatial forced choice) and sequential (temporal forced choice) presentations. Sequential presentation (at SOAs of 0.5, 0.75 and 2.25 s) yielded better discrimination thresholds among the majority of controls (around 0.5 c/ degrees reference), but not among dyslexics. Consequently, there was a (large and significant) group effect only for the sequential conditions. Within the same dyslexic group, performance on a sequential auditory task, two-tone frequency discrimination, was impaired in a smaller proportion of the participants. Taken together, our findings indicate that visual paradigms requiring sequential comparisons are difficult for the majority of dyslexic individuals, perhaps because deficits either in visual perception or in visual memory could both lead to difficulties on these paradigms.     

Ammonium trichloro(dioxoethylene-o,o')tellurate (AS101) sensitizes tumors to chemotherapy by inhibiting the tumor interleukin 10 autocrine loop

Cancer cells of different solid and hematopoietic tumors express growth factors in respective stages of tumor progression, which by autocrine and paracrine effects enable them to grow autonomously. Here we show that the murine B16 melanoma cell line and two human primary cultures of stomach adenocarcinoma and glioblastoma multiforme (GBM) constitutively secrete interleukin (IL)-10 in an autocrine/paracrine manner. This cytokine is essential for tumor cell proliferation because its neutralization decreases clonogenicity of malignant cells, whereas addition of recombinant IL-10 increases cell proliferation. The immunomodulator ammonium trichloro(dioxoethylene-o,o')tellurate (AS101) decreased cell proliferation by inhibiting IL-10. This activity was abrogated by exogenous addition of recombinant IL-10. IL-10 inhibition by AS101 results in dephosphorylation of Stat3, followed by reduced expression of Bcl-2. Moreover, these activities of AS101 are associated with sensitization of tumor cells to chemotherapeutic drugs, resulting in their increased apoptosis. More importantly, AS101 sensitizes the human aggressive GBM tumor to paclitaxel both in vitro and in vivo by virtue of IL-10 inhibition. AS101 sensitizes GBM cells to paclitaxel at concentrations that do not affect tumor cells. This sensitization can also be obtained by transfection of GBM cells with IL-10 antisense oligonucleotides. Sensitization of GBM tumors to paclitaxel (Taxol) in vivo was obtained by either AS101 or by implantation of antisense IL-10-transfected cells. The results indicate that the IL-10 autocrine/paracrine loop plays an important role in the resistance of certain tumors to chemotherapeutic drugs. Therefore, anti-IL-10 treatment modalities with compounds such as AS101, combined with chemotherapy, may be effective in the treatment of certain malignancies.     

Noncardiac chest pain and psychopathology in children and adolescents

OBJECTIVE: We sought to examine the prevalence of DSM-IV psychiatric disorders in children and adolescents with complaints of noncardiac chest pain (NCCP). METHOD: We assessed 27 youngsters (ages 8-17 years) referred to a pediatric cardiology practice with complaints of NCCP. Each child and a parent were interviewed using the Anxiety Disorders Interview Schedule for Children. RESULTS: Sixteen youngsters (59%) were diagnosed with a current DSM-IV disorder. Fifteen (56%) had a current anxiety disorder, nine of whom were diagnosed with panic disorder. One participant was diagnosed with a depressive disorder. CONCLUSION: Results of this preliminary study suggest that DSM-IV anxiety disorders may be common in youngsters with NCCP. No evidence was found for high prevalence of depression in this sample. Larger controlled studies are needed to determine the prevalence and impact of psychopathology in youngsters with NCCP.     

Cat-scratch disease-associated arthropathy

OBJECTIVE: To characterize the articular manifestations of cat-scratch disease (CSD) and to evaluate the long-term clinical outcome of those manifestations. METHODS: A community- and hospital-based surveillance study of CSD was conducted in Israel between 1991 and 2002. CSD was defined as present in a patient when a compatible clinical syndrome and a positive confirmatory finding of Bartonella henselae (by serology and/or polymerase chain reaction) were identified. CSD patients with arthropathy (arthritis/arthralgia) that limited or precluded usual activities of daily living constituted the study group. Patients were followed up until > or =6 weeks after resolution of symptoms, or if symptoms persisted, for >/=12 months. CSD patients without arthropathy served as controls. RESULTS: Among 841 CSD patients, 24 (2.9%) had rheumatoid factor-negative arthropathy that was often severe and disabling. Both univariate and multivariate analyses identified female sex (67% of arthropathy patients versus 40% of controls; relative risk [RR] 2.5, P = 0.047), age older than 20 years (100% of arthropathy patients versus 43% of controls; RR 4.9, P = 0.001), and erythema nodosum (21% of arthropathy patients versus 2% of controls; RR 7.9, P = 0.001) as variables significantly associated with arthropathy. Knee, wrist, ankle, and elbow joints were most frequently affected. Ten patients (42%) had severe arthropathy in the weight-bearing joints, which substantially limited their ability to walk, and 4 of these patients were hospitalized. All of the patients had regional lymphadenopathy, 37.5% had nocturnal joint pain, and 25% had morning stiffness. Nineteen patients (79.2%) recovered after a median duration of 6 weeks (range 1-24 weeks), whereas 5 patients (20.8%) developed chronic disease persisting 16-53 months (median 30 months) after the onset of arthropathy. CONCLUSION: This is the first comprehensive study of arthropathy in CSD. CSD-associated arthropathy is an uncommon syndrome affecting mostly young and middle-age women. It is often severe and disabling, and may take a chronic course.     

Increased sensitivity to nicotine-induced seizures in mice heterozygous for the L250T mutation in the alpha7 nicotinic acetylcholine receptor

alpha7 Nicotinic acetylcholine receptors (nAChRs) are sparsely distributed throughout the peripheral and central nervous systems. Several studies have suggested that central alpha7 nicotinic receptors may influence sensitivity to nicotine-induced seizures in mice. In order to investigate the effect of alpha7 nAChRs on seizure sensitivity, we tested heterozygous mice with a threonine for leucine substitution at position 250 (L250T) within the channel domain, which is known to increase current amplitude and decreases desensitization of the channel. We show that administration of low doses of nicotine to these mutant mice increased the sensitivity to nicotine-induced seizures and the mortality rate. EEG recordings showed high amplitude rhythmic activity during tonic-clonic seizures. Pretreatment with the alpha7 nicotinic receptor antagonist methyllycaconitine inhibited the seizures induced by nicotine. These findings further suggest an important role for alpha7 nAChRs in the nicotine-induced seizures model of epilepsy.