ABSTRACT
Recent data show that regulatory cells with transforming growth factor (TGF)-ß1-dependent activity are able to restore self-tolerance in overtly diabetic non-obese diabetic (NOD) mice. Thus, TGF-ß1 seems to have a relevant role in protection from autoimmune diabetes. Our aim was to investigate the possible significance of serum TGF-ß1 measurement in the natural history of diabetes in NOD mice, as well as in children positive for at least one islet-related antibody. Serum TGF-ß1 (both total and active) was measured by enzyme-linked immunosorbent assay at monthly intervals in 26 NOD mice during the spontaneous development of diabetes and, on a yearly basis, in nine siblings of patients with type 1 diabetes (T1D) with a follow-up of 4 years. Diabetes appeared between the 12th week of age and the end of the study period (36 weeks) in 17 mice. TGF-ß1 serum level variations occurred in the prediabetic period in both NOD mice and humans and diabetes diagnosis followed a continuing reduction of active TGF-ß1 (aTGF-ß1) serum levels. In mice, aTGF-ß1 serum levels measured at 4 weeks of age correlated positively with severity of insulitis, and negatively with percentage of insulin-positive cells. Our findings suggest that in NOD mice serum TGF-ß1 levels during the natural history of the diabetes reflect the course of islet inflammation. The measurement of aTGF-ß1 in islet-related antibody-positive subjects may provide insights into the natural history of prediabetic phase of T1D.
Subject(s)
Diabetes Mellitus, Type 1/diagnosis , Pancreas/pathology , Transforming Growth Factor beta1/blood , Adolescent , Animals , Autoantibodies/blood , Child , Child, Preschool , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/physiopathology , Disease Progression , Female , Follow-Up Studies , Humans , Inflammation , Male , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Pancreas/immunologyABSTRACT
The psychostimulant methylphenidate and the non-stimulant atomoxetine are two approved drugs for attention-deficit hyperactivity disorder (ADHD) therapy. The aim of this study was to investigate the long-term effects of prepuberal subchronic methylphenidate and atomoxetine on adult behaviour and the forebrain neurotransmitter and metabolite content of Naples High-Excitability (NHE) rats, a genetic model for the mesocortical variant of ADHD. Male NHE rats were given a daily intraperitoneal injection (1.0mg/kg) of methylphenidate, atomoxetine or vehicle from postnatal day 29 to 42. At postnatal day 70-75, rats were exposed to spatial novelty in the Làt and radial (Olton) mazes. Behavioural analysis for indices of horizontal, vertical, non-selective (NSA) and selective spatial attention (SSA) indicated that only methylphenidate significantly reduced horizontal activity to a different extent, i.e., 39 and 16% respectively. Moreover methylphenidate increased NSA as assessed by higher leaning duration. The high-performance liquid chromatography (HPLC) tissue content assessment of dopamine, norepinephrine, serotonin and relative metabolites in the prefrontal cortex (PFC), cortical motor area (MC), dorsal striatum (DS), ventral striatum (VS), hippocampus and mesencephalon indicated that methylphenidate decreased (i) dopamine, DOPAC, norepinephrine, MHPG, 5-HT and 5-HIAA in the PFC, (ii) dopamine, DOPAC, HVA, serotonin, 5-HIAA in the DS, (iii) dopamine, DOPAC, HVA and MHPG (but increased norepinephrine) in the VS and (iv) norepinephrine, MHPG, serotonin and 5-HIAA in the hippocampus. Atomoxetine increased dopamine and decreased MHPG in the PFC. Like methylphenidate, atomoxetine decreased dopamine, DOPAC, HVA, serotonin and 5-HIAA in the DS, but decreased MHPG in the VS. These results suggest that methylphenidate determined long-term effects on behavioural and neurochemical parameters, whereas atomoxetine affected only the latter.
Subject(s)
Adrenergic Uptake Inhibitors/pharmacology , Attention Deficit Disorder with Hyperactivity/drug therapy , Central Nervous System Stimulants/pharmacology , Methylphenidate/pharmacology , Propylamines/pharmacology , Prosencephalon/drug effects , Adrenergic Uptake Inhibitors/administration & dosage , Aging , Animals , Atomoxetine Hydrochloride , Attention/drug effects , Attention Deficit Disorder with Hyperactivity/metabolism , Central Nervous System Stimulants/administration & dosage , Disease Models, Animal , Dopamine/metabolism , Male , Maze Learning/drug effects , Methylphenidate/administration & dosage , Norepinephrine/metabolism , Propylamines/administration & dosage , Prosencephalon/metabolism , Random Allocation , Rats , Serotonin/metabolism , Time FactorsABSTRACT
This study examined the production of English /b/ and the perception of short-lag English /b d g/ tokens by four groups of bilinguals who differed according to their age of arrival (AOA) in Canada from Italy and amount of self-reported native language (L1) use. A clear difference emerged between early bilinguals (mean AOA= 8 years) and late bilinguals (mean AOA= 20 years). The late bilinguals showed a stronger L1 influence than the early bilinguals did on both the production and perception of English stops. In experiment 2, the late bilinguals produced a larger percentage of prevoiced English /b/ tokens than early bilinguals and native English (NE) speakers did. In experiment 3, the late bilinguals misidentified short-lag English /b d g/ tokens as /p t k/ more often than the early bilinguals and NE speakers did. Experiment 4 revealed that the frequencies with which the bilinguals prevoiced /b d g/ in Italian and English were correlated. The observed differences between the early and late bilinguals were attributed to differences in the quantity and quality of English phonetic input they had received, not to a greater likelihood by the early than late bilinguals to establish new phonetic categories for English /b d g/.
