ABSTRACT
Community-based studies are required to accurately describe the supportive services needed by people with multiple sclerosis (MS). Characteristics that influence (or result from) care-seeking may introduce bias into other types of studies. The Participation and Activity Limitation Survey (PALS) was a post-census survey conducted by Statistics Canada in association with a 2006 national census. The PALS collected data from a sample of 22,513 respondents having health-related impairments according to their census forms. The survey collected self-reported diagnostic data and obtained ratings for items assessing impairment as well as perceived met and unmet needs for care and support. It identified 245 individuals with MS, leading to an estimated (weighted) population prevalence of 0.2% (200 per 100,000). As expected, those with MS reported more-severe health problems than did those with other types of disability, particularly in the areas of mobility, dexterity, and cognition; they were also more likely to report having multiple caregivers. People with MS also reported more unmet health-care needs than did those with other forms of disability, particularly with respect to meal preparation, housework, shopping, and chores. Despite their more negative health status and greater reliance on caregivers, people with MS reported participation in society comparable to that of people without MS. Thus, people with MS report greater needs than do people with other forms of health-related disability and utilize supportive services more often. However, they also report higher levels of unmet needs. The substantial needs of people with MS are only partially addressed by existing services.
ABSTRACT
In this study, we investigated the effect of proteasomal inhibition on the induction of arylalkylamine-N-acetyltransferase (AA-NAT) enzyme in cultured rat pinealocytes, using two proteasome inhibitors, MG132 and clastolactacystin beta-lactone (c-lact). Addition of c-lact or MG132 3 h after norepinephrine (NE) stimulation produced a significant increase in AA-NAT protein level and enzyme activity. However, when the proteasome inhibitors were added before or together with NE, significant reductions of the NE-induced aa-nat mRNA, protein, and enzyme activity were observed. A similar inhibitory effect of MG132 on aa-nat transcription was observed when cells were stimulated by dibutyryl cAMP, indicating an effect distal to a post-cAMP step. The inhibitory effect of MG132 on adrenergic-induced aa-nat transcription was long lasting because it remained effective after 14 h of washout and appeared specific for aa-nat because the induction of another adrenergic-regulated gene, MAPK phosphatase-1, by NE was not affected. Time-profile studies revealed that the inhibitory effect of MG132 on NE-stimulated aa-nat induction was detected after 1 h, suggesting accumulation of a protein repressor as a possible mechanism of action. This possibility was also supported by the finding that the inhibitory effect of c-lact on NE-induced aa-nat induction was markedly reduced by cycloheximide, a protein synthesis inhibitor. Together, these results support an important role of proteasomal proteolysis in the adrenergic-mediated induction of aa-nat transcription through its effect on a protein repressor.
Subject(s)
Adrenergic alpha-Agonists/pharmacology , Arylalkylamine N-Acetyltransferase/biosynthesis , Norepinephrine/pharmacology , Peptide Hydrolases/metabolism , Pineal Gland/metabolism , Proteasome Endopeptidase Complex/metabolism , Animals , Arylalkylamine N-Acetyltransferase/antagonists & inhibitors , Arylalkylamine N-Acetyltransferase/genetics , Cells, Cultured , Cysteine Proteinase Inhibitors/pharmacology , Enzyme Induction/drug effects , Leupeptins/pharmacology , Male , Melatonin/antagonists & inhibitors , Melatonin/biosynthesis , Pineal Gland/cytology , Rats , Rats, Sprague-Dawley , Time Factors , Transcription, Genetic/drug effectsABSTRACT
The norepinephrine-driven increase in mitogen-activated protein kinase (MAPK) activity is part of the mechanism that regulates arylalkylamine N-acetyltransferase (AA-NAT) activity in the rat pineal gland. We now report a marked nocturnal increase in the expression of a MAPK phosphatase, MAP kinase phosphatase-1 (MKP-1), that was blocked by maintaining animals in constant light or treatment with propranolol. MKP-1 expression was regulated by norepinephrine acting through both alpha- and beta-adrenergic receptors. These results establish a nocturnal increase in pineal MKP-1 expression that is under the control of a photoneural system. Because substrates of MKP-1 can influence AA-NAT activity, our findings suggest the involvement of MKP-1 in the regulation of the nocturnal AA-NAT signal.
