Analysis of the data in this open-label study demonstrates the safety and potential efficacy of unilateral intraputaminal GDNF infusion. Unilateral administration of the protein resulted in significant, sustained bilateral effects.
Toxic effects of HIV-1 proteins contribute to altered function and decreased survival of select populations of neurons in HIV-1-infected brain. One such HIV-1 protein, Tat, can activate calcium release from IP 3 -sensitive intracellular pools, induce calcium in¯ux in neural cells, and, as a result, can increase neuronal cell death. Here, we provide evidence that Tat potentiates excitatory amino acid (glutamate and NMDA) triggered calcium¯ux, as well as glutamate-and staurosporine-mediated neurotoxicity. Calcium¯ux in cultured rat hippocampal neurons triggered by the transient application of glutamate or NMDA was facilitated by pre-exposure to Tat. Facilitation of glutamate-triggered calcium¯ux by Tat was prevented by inhibitors of ADP-ribosylation of G i /G o proteins (pertussis toxin), protein kinase C (H7 and bisindolymide), and IP 3 -mediated calcium release (xestospongin C), but was not prevented by an activator of G s (cholera toxin) or an inhibitor of protein kinase A (H89). Facilitation of NMDAtriggered calcium¯ux by Tat was reversed by inhibitors of tyrosine kinase (genestein and herbimycin A) and by an inhibitor of NMDA receptor function (zinc). Tat increased 32 P incorporation into NMDA receptor subunits NR2A and NR2B and this effect was blocked by genestein. Subtoxic concentrations of Tat combined with subtoxic concentrations of glutamate or staurosporine increased neuronal cell death signi®cantly. Together, these ®ndings suggest that NMDA receptors play an important role in Tat neurotoxicity and the mechanisms identi®ed may provide additional therapeutic targets for the treatment of HIV-1 associated dementia.
Navigate PD was an educational program established to supplement existing guidelines and provide recommendations on the management of Parkinson's disease (PD) refractory to oral/transdermal therapies. It involved 103 experts from 13 countries overseen by an International Steering Committee (ISC) of 13 movement disorder specialists. The ISC identified 71 clinical questions important for device-aided management of PD. Fifty-six experts responded to a web-based survey, rating 15 questions as 'critically important;' these were refined to 10 questions by the ISC to be addressed through available evidence and expert opinion. Draft guidance was presented at international/national meetings and revised based on feedback. Key take-home points are: • Patients requiring levodopa >5 times daily who have severe, troublesome 'off' periods (>1-2 h/day) despite optimal oral/transdermal levodopa or non-levodopa-based therapies should be referred for specialist assessment even if disease duration is <4 years. • Cognitive decline related to non-motor fluctuations is an indication for device-aided therapies. If cognitive impairment is mild, use deep brain stimulation (DBS) with caution. For patients who have cognitive impairment or dementia, intrajejunal levodopa infusion is considered as both therapeutic and palliative in some countries. Falls are linked to cognitive decline and are likely to become more frequent with device-aided therapies. • Insufficient control of motor complications (or drug-resistant tremor in the case of DBS) are indications for device-aided therapies. Levodopa-carbidopa intestinal gel infusions or subcutaneous apomorphine pump may be considered for patients aged >70 years who have mild or moderate cognitive impairment, severe depression or other contraindications to DBS.
This technique sensitively detects age-related motor performance decline in humans. There may be a critical period in late midlife when fine motor performance decline either begins or abruptly worsens.
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