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Indeed, orexin-A, a nonselective agonist for both orexin receptors (9), is low or undetectable in the cerebrospinal fluid of up to 95 of human cases of narcolepsy-cataplexy examined (15), and orexin mRNA and orexin-A immunoreactivity are drastically reduced in postmortem hypothalamic samples from narcoleptic-cataplectic humans (5, 7). Because of a strong association with certain HLA alleles, it has been speculated that narcolepsy-cataplexy may result from selective autoimmune degeneration of orexin neurons (16). These findings open up the possibility that replacement therapies based on administration of orexin receptor agonists might prove beneficial (1), a possibility not yet convincingly investigated in humans or animal models. *Department of Molecular Genetics and Howard Hughes Medical Institute, and Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9050; Department of Pharmacology, Institute of Basic Medical Sciences, University of Tsukuba, Ibaraki 305-8575, Japan; and Exploratory Research for Advanced Technology, Yanagisawa Orphan Receptor Project, Japan Science and Technology Agency, Tokyo 135-0064, Japan Hourly plots of sleep/wake states in transgenic and wild-type mice. Narcoleptic orexin/ataxin-3-transgenic mice as well as orexin/ataxin-3;CAG/orexin-double-transgenic mice exhibit hourly amounts of wakefulness and non-REM sleep that are similar to those of wild-type mice. In contrast, orexin/ataxin-3-transgenic mice exhibit significantly increased amounts of REM sleep during the dark phase (solid horizontal bars). Double-transgenic mice exhibit a specific rescue of this abnormality compared with wild-type mice. *, P < ; **, P < ; ***, P < compared with wild-type mice; and +, P < ; ++, P < ; +++, P < compared with orexin/ataxin-3;CAG/orexin-double-transgenic mice by ANOVA and Tukey's post hoc tests. Values are means SE. (n = 10 for wild-type mice, n = 6 for orexin/ataxin-3 mice, and n = 5 for CAG/orexin;orexin/ataxin-3-double-transgenic mice.)
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In this study, we examined whether symptoms of murine narcolepsy-cataplexy could be reversed either by ectopic production of orexin peptides from a prepro-orexin transgene or by pharmacological administrations of synthetic orexin-A. These interventions were evaluated by behavioral and electrophysiological criteria using orexin neuron-ablated orexin/ataxin-3-transgenic mice (8), an accepted biochemical and behavioral model of human narcolepsy-cataplexy. Immunohistochemical analysis of brains from transgenic mice. Anti-orexin-A immunostaining of coronal sections of brain tissue from wild-type, orexin/ataxin-3-hemizygous-transgenic-, CAG/orexin-hemizygous-transgenic-, and double-hemizygous-transgenic mice were performed as described (31). Note the punctate staining of native orexin-A-immunoreactive neurons clustered in the perifornical LH of wild-type mice (a and b) and the absence of orexin-A in the brains of orexin/ataxin-3-transgenic mice in which native orexinergic neurons have degenerated (c and d). CAG/orexin-transgenic mice have widespread, diffuse, ectopic production of orexin-A in addition to that observed in native neurons (e and f). In contrast, orexin/ataxin-3;CAG/orexin-double-transgenic mice exhibit only the ectopic pattern of orexin-A; native neurons are absent (g and h).
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As expected, orexin/ataxin-3 mice exhibited significantly higher
amounts of REM sleep than did wild-type controls during the dark
phase under baseline (vehicle-administered) conditions.
Critically, orexin-A effectively suppressed this elevation of REM
sleep in narcoleptic mice. Again, orexin-A was more effective at
suppressing REM sleep in narcoleptic mice than in wild-type
controls, regardless of the time of administration (Figs. ( and
7).
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After the cannulation of orexin/ataxin-3-transgenic animals for orexin administrations (see below), it was noted that cataplexy was not reliably elicited in some individuals, possibly due to stress associated with indwelling cannula, restraint, or injection procedures. Only animals consistently showing cataplectic attacks after vehicle administrations (5 of 16) were subjected to further analysis. Conclusion: Mountain biking is a growing cause of serious injuries. Young males are principally at risk and serious injuries result from intended activity and despite protective equipment. Injury prevention programs were developed to address these concerns. O certificado de Autocad é de curso livre de capacitação. O MEC só reconhece cursos de nível superior, como graduação e pós-graduação. Esse curso não é uma graduação, portanto não há regulamentação do MEC sobre ele. Saiba mais sobre o credenciamento no MEC CAG/orexin transgene prevents cataplectic behavioral arrests in orexin neuron-ablated mice. Cataplectic arrests are absent in orexin/ataxin-3;CAG/orexin-double-hemizygous-transgenic mice, compared with orexin/ataxin-3-hemizygous-transgenic littermates. The number of cataplectic arrests observed (a) and total time spent in cataplexy (b) in each mouse are shown for 3-h sessions.
Sleep/wake states in these mice are also illustrated by hourly plots of amounts of time spent in wakefulness, non-REM sleep, and REM sleep over 24 h (Fig. 4). Consistent with a previous description (8), orexin/ataxin-3 mice showed selective increases in amounts of REM sleep during the dark phase, compared with wild-type controls. Importantly, mice carrying both transgenes exhibited a normalization of REM sleep amounts during the dark phase with an additional tendency toward reduced amounts of REM sleep during the light phase as well. Overall, ectopic expression of the CAG/orexin transgene prevented the development of symptoms of narcolepsy-cataplexy, despite the postnatal ablation of endogenous orexin neurons, supporting a specific role for orexin peptides in preventing narcolepsy-cataplexy. Results: A total of 1,037 patients were identified as having bicycling-related injuries. Of these, 399 patients sustained 1,092 injuries while mountain biking. There was a threefold increase in the incidence of mountain biking injuries over a 10-year period. Young males were most commonly affected. Orthopedic injuries were most common (46.5) followed by head (12.2), spine (12), chest (10.3), facial (10.2), abdominal (5.4), genitourinary (2.2), and neck injuries (1). High operative rate was observed: 38 of injuries and 66 of patients required surgery. One patient died from his injuries. Injury prevention programs were developed and successfully engaged the target population. Existem 19 opções de cursos online e gratuitos do Senai que podem ser realizados pela internet. Os que são para iniciação profissional têm como requisito idade mínima de 12 anos. Já cada um dos módulos de especialização possui critérios específicos. Vale ressaltar maioria deles possui certificado de conclusão.