Breaking away from dopamine deficiency: an essential new direction for Parkinson's disease
ABSTRACT For the past 40 years Parkinson's disease (PD) has been intrinsically associated with dopamine (DA) deficiency of the nigrostriatal DA system. One of the fundamental strengths of this theoretical approach is based on a presumed relationship between the degree of DA deficiency and the severity of motor impairment in the disease and its models. However, detailed examination of a substantial number of exemplary preclinical and clinical studies reveals that any such interpretation is overoptimistic and suggests that DA deficiency may be merely an epiphenomenon of a larger process underlying this disorder. Such a conclusion is based on numerous examples of miscarriage of basic principles of good scientific practice including (i) failure to thoroughly examine the adverse effects of DA replacement, (ii) drawing of statistical inference without recognising excessive spread of measure thereby lessening the importance of outliers, (iii) confounding independent and dependent variables within the scientific paradigm, (iv) overlooking fundamental principles of modern pharmacology, (v) confusing correlation with causation in linking cause and effect and (vi) disinclination to incorporate conflicting findings thereby infringing the quintessential scientific principle of tertium quid. This review demonstrates the inherent risks and dangers in the incontrovertible defence of DA deficiency theory and serves to address the ethical problems that emerge from the clinical application of scientific findings. There is increasing interest in new directions for PD research by dimming down the current emphasis on the importance of DA deficiency and its replacement. This would provide genuine hope and a new direction for the sufferers of a most debilitating disease.
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ABSTRACT: Purpose: To systematically review the psychometric properties of outcome measures used in stroke self-management interventions (SMIs) to (1) inform researchers, clinicians and commissioners about the properties of the measures in use and (2) make recommendations for the future development of self-management measurement in stroke. Methods: Electronic databases, government websites, generic internet search engines and hand searches of reference lists. Abstracts were selected against inclusion criteria and retrieved for appraisal and systematically scored, using the COSMIN checklist. Results: Thirteen studies of stroke self-management originating from six countries were identified. Forty-three different measures (mean 5.08/study, SD 2.19) were adopted to evaluate self-SMIs. No studies measured self-management as a discreet concept. Six (46%) studies included untested measures. Eleven (85%) studies included at least one measure without reported reliability and validity in stroke populations. Conclusions: The use of outcome measures which are related, indirect or proxy indicators of self-management and that have questionable reliability and validity, contributes to an inability to sensitively evaluate the effectiveness of stroke self-SMIs. Further enquiry into how the concept of self-management in stroke operates, would help to clarify the nature and range of specific self-management activities to be targeted and aid the selection of existing appropriate measures or the development of new measures. [Box: see text].Disability and Rehabilitation 11/2012; DOI:10.3109/09638288.2012.737080 · 1.84 Impact Factor
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ABSTRACT: Mancozeb (manganese/zinc ethylene bis-dithiocarbamate) is an organometallic fungicide that has been associated with human neurotoxicity and neurodegeneration. In a high-throughput screen for modulators of KCNQ2 channel, a fundamental player modulating neuronal excitability, Mancozeb, was found to significantly potentiate KCNQ2 activity. Mancozeb was validated electrophysiologically as a KCNQ2 activator with an EC50 value of 0.92±0.23μM. Further examination showed that manganese but not zinc ethylene bis-dithiocarbamate is the active component for the positive modulation effects. In addition, the compounds are effective when the metal ions are substituted by iron but lack potentiation activity when the metal ions are substituted by sodium, signifying the importance of the metal ion. However, the iron (Fe(3+)) alone, organic ligands alone or the mixture of iron with the organic ligand did not show any potentiation effect, suggesting as the active ingredient is a specific complex rather than two separate additive or synergistic components. Our study suggests that potentiation on KCNQ2 potassium channels might be the possible mechanism of Mancozeb toxicity in the nervous system.Toxicology Letters 03/2013; 219(3). DOI:10.1016/j.toxlet.2013.03.020 · 3.36 Impact Factor
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ABSTRACT: The pedunculopontine nucleus (PPN) is a part of the mesencephalic locomotor region and is thought to be important for the initiation and maintenance of gait. Lesions of the PPN induce gait deficits, and the PPN has therefore emerged as a target for deep brain stimulation for the control of gait and postural disability. However, the role of the PPN in gait control is not understood. Using extracellular single-unit recordings in awake patients, we found that neurons in the PPN discharged as synchronous functional networks whose activity was phase locked to alpha oscillations. Neurons in the PPN responded to limb movement and imagined gait by dynamically changing network activity and decreasing alpha phase locking. Our results indicate that different synchronous networks are activated during initial motor planning and actual motion, and suggest that changes in gait initiation in Parkinson's disease may result from disrupted network activity in the PPN.Nature Neuroscience 02/2014; 17(3). DOI:10.1038/nn.3642 · 14.98 Impact Factor