Enhanced pitch sensitivity in individuals with autism: a signal detection analysis

Past research has shown a superiority of participants with high-functioning autism over comparison groups in memorizing picture-pitch associations and in detecting pitch changes in melodies. A subset of individuals with autism, known as "musical savants," is also known to possess absolute pitch. This superiority might be due to an abnormally high sensitivity to fine-grained pitch differences in sounds. To test this hypothesis, psychoacoustic tasks were devised so as to use a signal detection methodology. Participants were all musically untrained and were divided into a group of 12 high-functioning individuals with autism and a group of 12 normally developing individuals. Their task was to judge the pitch of pure tones in a "same-different" discrimination task and in a "high-low" categorization task. In both tasks, the obtained psychometric functions revealed higher pitch sensitivity for subjects with autism, with a more pronounced advantage over control participants in the categorization task. These findings confirm that pitch processing is enhanced in "high-functioning" autism. Superior performance in pitch discrimination and categorization extends previous findings of enhanced visual performance to the auditory domain. Thus, and as predicted by the enhanced perceptual functioning model for peaks of ability in autism (Mottron & Burack, 2001), autistic individuals outperform typically developing population in a variety of low-level perceptual tasks.     

Direction-selective motion blindness after unilateral posterior brain damage

Motion blindness (MB) is defined as the selective disturbance of visual motion perception despite intact perception of other features of the visual scene. MB is characterized by a pandirectional deficit of motion direction discrimination and is assumed to result from damage to the visual motion pathway, especially area MT/V5. However, the most characteristic feature of primate MT/V5 neurons is not their motion selectivity but their preference for one direction of motion (direction selectivity), which changes incrementally at neighbouring columns. In addition to this microscopic directional organization, studies in nonhuman and human primates suggest that single directions of motion are also coded at a more macroscopic level. We thus hypothesized that if MB in humans results from damage to direction-selective neurons in the visual motion pathway, posterior brain damage might cause MB which is direction selective, not pandirectional. The present study investigated motion direction discrimination in patients with posterior unilateral brain damage and determined separate psychophysical thresholds for the four cardinal directions. In addition, we analysed whether the direction of erroneous motion perception (i.e. the perception of right motion for upward motion) was random or showed a directional bias. We report three principal findings. First, motion direction discrimination was severely impaired in one or two directions while it was normal in the other directions. This constituted direction-selective MB. Second, MB was characterized not only by a quantitative direction-selective increase in psychophysical thresholds but also by a qualitative impairment of perceiving motion direction systematically in wrong directions. Both findings suggest that the cortical modules specialized for the perception of a single direction of motion might be larger than previously thought. Third, lesion analysis showed that unilateral damage, not only the human homologue of MT/V5 but also to parieto-occipital cortex, leads to MB.     

Increased sensitivity of a new assay for anti-thyroglobulin antibody detection in patients with autoimmune thyroid disease

OBJECTIVES: To verify the cut-off values and to determine the clinical sensitivity of antithyroglobulin (TgAb) determinations using our routine RIA and the new electrochemiluminescent Elecsys assay. DESIGN AND METHODS: We used the DYNOtest anti-Tgn manual RIA from BRAHMS and the new automated Elecsys electrochemiluminescent immunoassay from Roche Diagnostics. We analyzed 452 sera from the following subjects: 193 euthyroid controls, 163 with treated and untreated autoimmune thyroid diseases (AITD) (108 Graves' disease and 55 thyroiditis), 50 with differentiated thyroid carcinoma, 13 with nonautoimmune thyroid disease and 33 with type 1 diabetes mellitus. RESULTS: As expected, using the proposed thresholds (BRAHMS 60 kIU/L, Elecsys 115 kIU/L) approximately 6% of the control subjects were positive for TgAb with both methods. In AITD patients, the sensitivity of TgAb determination was significantly higher with the Elecsys assay (51.5%) than with the BRAHMS assay (39.3%). This difference was not observed in the other patient groups. CONCLUSION: The Elecsys assay can be preferred not only because it is automated and rapid, but also because of its better clinical performance in AITD patients.     

Susceptible MHC alleles,not background genes,select an autoimmune T cell reactivity

To detect and characterize autoreactive T cells in diabetes-prone NOD mice, we have developed a multimeric MHC reagent with high affinity for the BDC-2.5 T cell receptor, which is reactive against a pancreatic autoantigen. A distinct population of T cells is detected in NOD mice that recognizes the same MHC/peptide target. These T cells are positively selected in the thymus at a surprisingly high frequency and exported to the periphery. They are activated specifically in the pancreatic LNs, demonstrating an autoimmune specificity that recapitulates that of the BDC-2.5 cell. These phenomena are also observed in mouse lines that share with NOD the H-2g7 MHC haplotype but carry diabetes-resistance background genes. Thus, a susceptible haplotype at the MHC seems to be the only element required for the selection and emergence of autoreactive T cells, without requiring other diabetogenic loci from the NOD genome.     

Inhibition of adrenal cortical steroid formation by procaine is mediated by reduction of the cAMP-induced 3-hydroxy-3-methylglutaryl-coenzyme A reductase messenger ribonucleic acid levels

Elevated glucocorticoid levels are associated with many diseases, including age-related depression, hypertension, Alzheimer's disease, and acquired immunodeficiency syndrome. Cortisol-lowering agents could provide useful complementary therapy for these disorders. We examined the effect of procaine and procaine in a pharmaceutical formulation on adrenal cortical steroid formation. Procaine inhibited dibutyryl cyclic AMP (dbcAMP)-induced corticosteroid synthesis by murine Y1 and human H295R adrenal cells in a dose-dependent manner without affecting basal steroid formation. Treatment of rats with the procaine-based formulation reduced circulating corticosterone levels. This steroidogenesis-inhibiting activity of procaine was not observed in Leydig cells, suggesting that the effect was specific to adrenocortical cells. In search of the mechanism underlying this inhibitory effect on cAMP-induced corticosteroidogenesis, procaine was found to affect neither the cAMP-dependent protein kinase activity nor key proteins involved in cholesterol transport into mitochondria, cytochrome P450 side chain cleavage enzyme expression, and enzymatic activities associated with cholesterol metabolism to final steroid products. However, procaine reduced in a dose-dependent manner the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA) activity and the dbcAMP-induced HMG-CoA reductase mRNA levels by affecting mRNA stability. These data suggest that the inhibitory effect of procaine on cAMP-induced corticosteroid formation is due to the reduced synthesis of cholesterol. This modulatory effect of procaine on HMG-CoA reductase mRNA expression was also seen in dbcAMP-stimulated Hepa1-6 mouse liver hepatoma cells. Taken together, these results suggest that procaine may provide a pharmacological means for the control of hormone-induced HMG-CoA reductase mRNA expression and hypercortisolemia.     

Risks associated with the microbiological quality of bodies of fresh and marine water used for recreational purposes: summary estimates based on published epidemiological studies

The current European standards for microbiological quality of bathing water (i.e., all running or still fresh waters or parts thereof and/or sea water [with the exception of water intended for therapeutic purposes and water used in swimming pools]) were issued in 1976 and are currently undergoing revision. In this article, the authors propose parameters for select microorganism indicators to assist in the establishment of public-health-based objectives for fresh and marine water quality. A type-II meta-analysis of the results of 18 published epidemiological studies was implemented in an attempt to characterize the relationship(s) between concentrations of bacterial indicators and rates of acute gastrointestinal diseases among bathers who had used fresh or marine water for recreational purposes. The authors fit multiple linear-regression models, which allowed for random effects across studies, to derive dose-response curves. Several confounders and effect modifiers were controlled for in the analyses. Risks were then estimated for a hypothetical individual who would bathe 20 times/yr in water that contained a given concentration of microorganisms. For fresh-water-associated highly credible gastrointestinal illnesses, a level of 10 fecal coliforms/100 ml water yielded an attributable risk of 0.2 cases/1,000 person-years; a risk of 2 cases/1,000 person-years was found for fecal streptococci. The corresponding yearly attributable risks were 1 and 13 cases/1,000 person-years, respectively, for 100 bacteria/100 ml fresh water. Risks associated with fecal coliforms were found to be lower in marine water than in fresh water. Irrespective of the type of water examined, total coliforms were related only weakly with acute digestive morbidity. Developers of future bathing-water standards should state the level of risk deemed acceptable for public health. The authors of this study maintain that levels of fecal coliforms and fecal streptococci should be used as criteria for infectious risk management associated with bodies of marine and fresh water used for recreational purposes.     

Melanoma: role of ultraviolet radiation: from physiology to pathology

EPIDEMIOLOGIC DATA: The frequency of malignant melanoma, by far the most fatal skin cancer, has increased by a factor of approximately 15 in the past 60 years. The factors underlying this rapid increase are incompletely understood, although ultraviolet radiations are likely strongly implicated. Epidemiologic studies demonstrate the role of altered patterns of sun exposure, and overexposition to UVA radiation, as confirmed by experimental data on animal models. BIOLOGICAL ASPECTS: Melanin produced by melanocytes has a photoprotective function in the skin, whereas UVB-induced DNA damage enhance the repair capacity of these cells. However, this photoprotective effect is not induced by intense intermittent sun exposure. In addition, melanocytes demonstrate resistance to UVB-induced apoptosis and are thus at high risk for incorporating UV-induced mutations. MOLECULAR ASPECTS: Different mutations in susceptibility genes (CDKN2A, INK4), or in genes implicated in control of cell cycle or maintenance of cell integrity (DNA repair) are involved in initiation and promotion steps of melanocarcinogenesis. Moreover, tumor progression is stimulated by UVB through the activation of different target genes that are implicated in control of melanoma environment (immune surveillance, angiogenesis, growth factors...).     

Population pharmacokinetics of fluconazole given for secondary prevention of oropharyngeal candidiasis in HIV-positive patients

OBJECTIVES: To determine fluconazole population pharmacokinetics and explore the relationships between fluconazole average concentration and treatment effectiveness or microbiological resistance induction during a study aimed at evaluating the efficacy, tolerability and resistance induction after secondary prevention with fluconazole (150 mg weekly) versus placebo in human immunodeficiency virus-positive (HIV+) patients with oropharyngeal candidiasis. METHODS: Population pharmacokinetic parameters of fluconazole determined from 458 serum drug concentration measurements obtained over 37 months in 132 HIV + patients not receiving highly active antiretroviral therapy. Mean estimates and variabilities were generated using non-linear regression analysis. Logistic and linear regression analyses were used to explore the relationships between the estimated average concentration of fluconazole and candidiasis relapse or fungal resistance towards fluconazole. RESULTS: Fluconazole kinetics were best described by a one-compartment model with first-order oral absorp tion from the gastrointestinal tract. The pharmacokinetics were influenced only by body weight. No effect was observed for gender, age, height or lymphocyte CD4 counts. The mean apparent population clearance was 0.79 l/h, the volume of distribution 571 and the absorption constant (ka) 0.93 h(-1). Inter-occasion variability in clearance (45%) was large relative to intersubject variability (21%). Taking into account the average fluconazole concentration or the time above the minimal inhibitory concentrations did not clinically improve the prediction of the occurrence of oropharyngeal relapse or microbiological resistance. CONCLUSION: The relationship between fluconazole concentrations and preventive effectiveness was poor. Together with the rather large inter-occasion variability in fluconazole clearance, this suggests no role of therapeutic drug monitoring in optimising fluconazole treatment for secondary prevention.