Lysosomal enzyme delivery by ICAM-1-targeted nanocarriers bypassing glycosylation- and clathrin-dependent endocytosis.

Enzyme replacement therapy, a state-of-the-art treatment for many lysosomal storage disorders, relies on carbohydrate-mediated binding of recombinant enzymes to receptors that mediate lysosomal delivery via clathrin-dependent endocytosis. Suboptimal glycosylation of recombinant enzymes and deficiency of clathrin-mediated endocytosis in some lysosomal enzyme-deficient cells limit delivery and efficacy of enzyme replacement therapy for lysosomal disorders. We explored a novel delivery strategy utilizing nanocarriers targeted to a glycosylation- and clathrin-independent receptor, intercellular adhesion molecule (ICAM)-1, a glycoprotein expressed on diverse cell types, up-regulated and functionally involved in inflammation, a hallmark of many lysosomal disorders. We targeted recombinant human acid sphingomyelinase (ASM), deficient in types A and B Niemann-Pick disease, to ICAM-1 by loading this enzyme to nanocarriers coated with anti-ICAM. Anti-ICAM/ASM nanocarriers, but not control ASM or ASM nanocarriers, bound to ICAM-1-positive cells (activated endothelial cells and Niemann-Pick disease patient fibroblasts) via ICAM-1, in a glycosylation-independent manner. Anti-ICAM/ASM nanocarriers entered cells via CAM-mediated endocytosis, bypassing the clathrin-dependent pathway, and trafficked to lysosomes, where delivered ASM displayed stable activity and alleviated lysosomal lipid accumulation. Therefore, lysosomal enzyme targeting using nanocarriers targeted to ICAM-1 bypasses defunct pathways and may improve the efficacy of enzyme replacement therapy for lysosomal disorders, such as Niemann-Pick disease.     

Cognitive and MRI correlates of orthostatic hypotension in Parkinson’s disease

Orthostatic hypotension (OH) is a frequent nonmotor feature of Parkinson’s disease (PD), and its occurrence has been associated with cognitive impairment. The underlying mechanism could be mediated by development of cerebrovascular disease induced by chronic or episodic hypoperfusion, but the extent of brain vascular load in PD patients with OH has never been investigated. This study aimed to assess the relationship between OH and cognitive function in PD patients and to investigate the contribution of brain vascular lesions. Forty-eight PD patients underwent a tilt table test (TT) to assess supine and orthostatic blood pressure as well as an extensive neuropsychological evaluation to evaluate cognitive function. Brain magnetic resonance imaging was acquired in 44/48 patients and analyzed by a visual semiquantitative scale. Twenty-three patients presented OH at TT (13/23 were symptomatic), and 25 did not. There were no differences in motor severity or disease duration between patients with and without OH. In patients with OH we found significantly worse cognitive performance in specific tasks, such as sustained attention, visuospatial and verbal memory, compared with patients without OH. However, there were no differences in vascular burden between the two groups. Our study confirms that there is an association between OH and selective cognitive deficits in PD, but rebuts the hypothesis that this is underlined by the development of cerebrovascular disease.     

Development of an on-line course on medication administration

The study describes the development of an on-line course on medication administration. The World Wide Web Course Tools (WebCT) that was used is software that provides various tools for supervisors and access to a number of environments for students who have a password. The course material is presented in a series of websites which are sub-divided into eight illustrated topics concerning medication administration routes, in addition to questions for knowledge assessment. A sample of undergraduate students at the University of S?o Paulo at Ribeir?o Preto College of Nursing has positively evaluated the course. It is now intended to be included as curricular course in the undergraduate program as an additional resource for student learning.     

Lacosamide-Induced Valproic Acid Toxicity

Valproic acid is commonly used in the treatment of both focal and generalized epilepsies and is often well tolerated. There are many reported cases of hyperammonemic encephalopathy and other well-known side effects reported during use of valproic acid either alone or in combination with other antiepileptics. This case report demonstrates valproic acid toxicity in the presence of lacosamide, which has not previously been reported. Full recovery occurred after withdrawal of both valproic acid and lacosamide.     

Enumeration skills in Down syndrome

Individuals with Down syndrome (DS) exhibit various math difficulties which can be ascribed both to global intelligence level and/or to their atypical cognitive profile. In this light, it is crucial to investigate whether DS display deficits in basic numerical skills. In the present study, individuals with DS and two groups of typically developing (TD) children matched for mental and chronological age completed two delayed match-to-sample tasks in order to evaluate the functioning of visual enumeration skills. Children with DS showed a specific deficit in the discrimination of small numerosities (within the subitizing range) with respect to both mental and chronological age matched TD children. In contrast, the discrimination of larger numerosities, though lower than that of chronological age matched controls, was comparable to that of mental age matched controls. Finally, counting was less fluent but the understanding of cardinality seemed to be preserved in DS. These results suggest a deficit of the object tracking system underlying the parallel individuation of small numerosities and a typical – but developmentally delayed – acuity of the approximate number system for discrimination of larger numerosities.     

Impairment of simultaneous-spatial working memory in nonverbal (visuospatial) learning disability: A treatment case study

We report the case of B.A., an 11-year-old child with a nonverbal (visuospatial) learning disability (NLD). Detailed psychometric and neuropsychological assessment on visuospatial working memory (VSWM) revealed specific simultaneous-spatial working memory impairment. A treatment targeting simultaneous-spatial working memory was given to B.A. for seven sessions (over one month); this resulted in improvement of simultaneous-spatial working memory, with the benefit that the training was maintained after six months.

Discussion of clinical and theoretical implications is given, taking account of the distinctions that can be made between the different components of visuospatial working memory and different subtypes of NLD, thus allowing the tailoring of specific training to target the impaired VSWM component.