ObjectiveGaucher disease (GD) is a lysosomal storage disease characterized by a deficiency of glucocerebrosidase. Although enzyme‐replacement and substrate‐reduction therapies are available, their efficacies in treating the neurological manifestations of GD are negligible. Pharmacological chaperone therapy is hypothesized to offer a new strategy for treating the neurological manifestations of this disease. Specifically, ambroxol, a commonly used expectorant, has been proposed as a candidate pharmacological chaperone. The purpose of this study was to evaluate the safety, tolerability, and neurological efficacy of ambroxol in patients with neuronopathic GD.MethodsThis open‐label pilot study included five patients who received high‐dose oral ambroxol in combination with enzyme replacement therapy. Safety was assessed by adverse event query, physical examination, electrocardiography, laboratory studies, and drug concentration. Biochemical efficacy was assessed through evidence of glucocerebrosidase activity in the lymphocytes and glucosylsphingosine levels in the cerebrospinal fluid. Neurological efficacy was evaluated using the Unified Myoclonus Rating Scale, Gross Motor Function Measure, Functional Independence Measure, seizure frequency, pupillary light reflex, horizontal saccadic latency, and electrophysiologic studies.ResultsHigh‐dose oral ambroxol had good safety and tolerability, significantly increased lymphocyte glucocerebrosidase activity, permeated the blood–brain barrier, and decreased glucosylsphingosine levels in the cerebrospinal fluid. Myoclonus, seizures, and pupillary light reflex dysfunction markedly improved in all patients. Relief from myoclonus led to impressive recovery of gross motor function in two patients, allowing them to walk again.InterpretationPharmacological chaperone therapy with high‐dose oral ambroxol shows promise in treating neuronopathic GD, necessitating further clinical trials.
Six experiments were conducted to examine the effect of knowledge of a target for overriding stimulus-driven interference in simple search tasks (Experiments 1-3) and compound search tasks (Experiments 4-6). In simple search when the target differed from nontargets in orientation, a singleton distractor that had an orientation equivalent to that of a target interfered with search for the target. When the singleton distractor was less salient than the target with respect to the target-defining feature, it still caused interference. Such within-dimensional, nonsaliency-based interference also occurred in compound search tasks. In contrast, no interference occurred when a singleton distractor was defined in cross-dimension in a simple search task. When a compound search task was used, the salient distractor interfered with the search for a less salient target. These results are discussed in terms of their applicability to existing models and the limitations of top-down penetrability of a feature processing stage.
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