Postsynaptic nigrostriatal dopamine receptors and their role in movement regulation

The article presents the hypothesis that nigrostriatal dopamine may regulate movement by modulation of tone and contraction in skeletal muscles through a concentration-dependent influence on the postsynaptic D1 and D2 receptors on the follow manner: nigrostriatal axons innervate both receptor types within the striatal locus somatotopically responsible for motor control in agonist/antagonist muscle pair around a given joint. D1 receptors interact with lower and D2 receptors with higher dopamine concentrations. Synaptic dopamine concentration increases immediately before movement starts. We hypothesize that increasing dopamine concentrations stimulate first the D1 receptors and reduce muscle tone in the antagonist muscle and than stimulate D2 receptors and induce contraction in the agonist muscle. The preceded muscle tone reduction in the antagonist muscle eases the efficient contraction of the agonist. Our hypothesis is applicable for an explanation of physiological movement regulation, different forms of movement pathology and therapeutic drug effects. Further, this hypothesis provides a theoretical basis for experimental investigation of dopaminergic motor control and development of new strategies for treatment of movement disorders

Selective Vulnerability in Striosomes and in the Nigrostriatal Dopaminergic Pathway After Methamphetamine Administration: Early Loss of TH in Striosomes After Methamphetamine

Methamphetamine (METH), a commonly abused psychostimulant, causes dopamine neurotoxicity in humans, rodents, and nonhuman primates. This study examined the selective neuroanatomical pattern of dopaminergic neurotoxicity induced by METH in the mouse striatum. We examined the effect of METH on tyrosine hydroxylase (TH) and dopamine transporter (DAT) immunoreactivity in the different compartments of the striatum and in the nucleus accumbens. The levels of dopamine and its metabolites, 3,4-dihidroxyphenylacetic acid and homovanillic acid, as well as serotonin (5-HT) and its metabolite, 5-hydroxyindolacetic acid, were also quantified in the striatum. Mice were given three injections of METH (4 mg/kg, i.p.) at 3 h intervals and sacrificed 7 days later. This repeated METH injection induced a hyperthermic response and a decrease in striatal concentrations of dopamine and its metabolites without affecting 5-HT concentrations. In addition, the drug caused a reduction in TH- and DAT-immunoreactivity when compared to saline-treated animals. Interestingly, there was a significantly greater loss of TH- and DAT-immunoreactivity in striosomes than in the matrix. The predominant loss of dopaminergic terminals in the striosomes occurred along the rostrocaudal axis of the striatum. In contrast, METH did not decrease TH- or DAT-immunoreactivity in the nucleus accumbens. These results provide the first evidence that compartments of the mouse striatum, striosomes and matrix, and mesolimbic and nigrostriatal pathways have different vulnerability to METH. This pattern is similar to that observed with other neurotoxins such as MPTP, the most widely used model of Parkinson’s disease, in early Huntington’s disease and hypoxic/ischemic injury, suggesting that these conditions might share mechanisms of neurotoxicity

Fulminant corticobasal degeneration: a distinct variant with predominant neuronal tau aggregates.

Corticobasal degeneration typically progresses gradually over 5-7 years from onset till death. Fulminant corticobasal degeneration cases with a rapidly progressive course were rarely reported (RP-CBD). This study aimed to investigate their neuropathological characteristics. Of the 124 autopsy-confirmed corticobasal degeneration cases collected from 14 centres, we identified 6 RP-CBD cases (4.8%) who died of advanced disease within 3 years of onset. These RP-CBD cases had different clinical phenotypes including rapid global cognitive decline (N = 2), corticobasal syndrome (N = 2) and Richardson's syndrome (N = 2). We also studied four corticobasal degeneration cases with an average disease duration of 3 years or less, who died of another unrelated illness (Intermediate-CBD). Finally, we selected 12 age-matched corticobasal degeneration cases out of a cohort of 110, who had a typical gradually progressive course and reached advanced clinical stage (End-stage-CBD). Quantitative analysis showed high overall tau burden (p = 0.2) and severe nigral cell loss (p = 0.47) in both the RP-CBD and End-stage-CBD groups consistent with advanced pathological changes, while the Intermediate-CBD group (mean disease duration = 3 years) had milder changes than End-stage-CBD (p < 0.05). These findings indicated that RP-CBD cases had already developed advanced pathological changes as those observed in End-stage-CBD cases (mean disease duration = 6.7 years), but within a significantly shorter duration (2.5 years; p < 0.001). Subgroup analysis was performed to investigate the cellular patterns of tau aggregates in the anterior frontal cortex and caudate by comparing neuronal-to-astrocytic plaque ratios between six RP-CBD cases, four Intermediate-CBD and 12 age-matched End-stage-CBD. Neuronal-to-astrocytic plaque ratios of Intermediate-CBD and End-stage-CBD, but not RP-CBD, positively correlated with disease duration in both the anterior frontal cortex and caudate (p = 0.02). In contrast to the predominance of astrocytic plaques we previously reported in preclinical asymptomatic corticobasal degeneration cases, neuronal tau aggregates predominated in RP-CBD exceeding those in Intermediate-CBD (anterior frontal cortex: p < 0.001, caudate: p = 0.001) and End-stage-CBD (anterior frontal cortex: p = 0.03, caudate: p = 0.01) as demonstrated by its higher neuronal-to-astrocytic plaque ratios in both anterior frontal cortex and caudate. We did not identify any difference in age at onset, any pathogenic tau mutation or concomitant pathologies that could have contributed to the rapid progression of these RP-CBD cases. Mild TDP-43 pathology was observed in three RP-CBD cases. All RP-CBD cases were men. The MAPT H2 haplotype, known to be protective, was identified in one RP-CBD case (17%) and 8 of the matched End-stage-CBD cases (67%). We conclude that RP-CBD is a distinct aggressive variant of corticobasal degeneration with characteristic neuropathological substrates resulting in a fulminant disease process as evident both clinically and pathologically. Biological factors such as genetic modifiers likely play a pivotal role in the RP-CBD variant and should be the subject of future research

Arbetsmiljöarbete och effekter en kunskapsöversikt

Work environment improvements and effects a literature review This report addresses the question 'Do work-environment improvements have any effects?' The aim was to produce a summary of knowledge that includes the methodological problems of measuring and evaluating effects, as well as literature reviews of effects from work environment improvement efforts on musculoskeletal health, health promotion, and economy. Results show that published literature reviews do not give unambiguous support for health benefits of interventions against musculoskeletal problems, when only studies using natural science criteria with experimental or quasi-experimental design are included. There are, on the other hand, many case studies in the so called 'grey' literature that report positive effects. Further, results show that health promotion interventions, and especially physical activity, have a positive effect on low back pain. Workplace interventions to increase physical activity are effective and lead to increased physical activity amongst employees. More studies are needed, however, at the organisational level. There is some support for the profitability of work-environment investments at the organisational level; even though there are few studies and methodological problems. The review also indicates that the financial benefits come mostly from quality and productivity improvements and, to a lesser extent from reductions in costs related to sickness absenteeism. While more recent literature reviews of the effects of health promotion interventions seem to show a stronger effect than older studies, comparisons of older versus more recent studies of interventions against musculoskeletal problems give a more ambiguous picture. Often, the focus of these reviews is on study design with less priority on the quality of the interventions themselves. Multifactorial interventions are particularly difficult to evaluate. At the same time, many studies and research reviews emphasise the need for multifactorial approaches as necessary for successful intervention. Inclusion criteria in literature reviews that only consider experimental designs in organisational interventions exclude studies with good interventions that can't be evaluated with traditional experimental methods. Difficulties in proving the effectiveness of interventions depends on views of what constitutes good scientific quality in the studies. This shows a need for a critical examination of the assumptions used for knowledge generation in this area. Conclusions are that work-environment improvement efforts have effects that are clear in some cases but are difficult to show in others. Effect evaluation poses large methodological challenges. These difficulties are considered to be an important cause of the lack of clear evidence, especially in the area of interventions against musculoskeletal problems. There is a need for new non-experimental research strategies that are suited to today's complex systems and an increased focus on practical, well conducted multifactorial interventions. Key words: Intervention, health promotion, ergonomics, economy, methodology, researchDetta arbete har inriktats mot frågeställningen om arbetsmiljöarbete har några effekter. Syftet har varit att göra en kunskapssammanställning som omfattar en beskrivning och problematisering av metodiken att mäta eller utvärdera effekter, samt litteraturöversikter om vad arbetsmiljöarbete har för belastningsergonomiska, hälsofrämjande och ekonomiska effekter. Resultaten visar att publicerade litteraturöversikter inte ger säkra belägg för att belastningsergonomiska interventioner har effekter på besvärsförekomst, i de fall enbart studier inkluderats utifrån naturvetenskapliga kriterier med krav på experimentell eller kvasi-experimentell metodik. Däremot finns ett flertal fallstudier och så kallad grå litteratur som i högre grad rapporterar positiva effekter. Vidare framgår det att hälsofrämjande interventioner, och speciellt fysisk aktivitet har en positiv effekt på ländryggsbesvär. Interventioner på arbetsplatser för att öka den fysiska aktiviteten är effektiva och ger en ökad fysisk aktivitet hos arbetstagarna. Fler studier behövs emellertid på organisationsnivå. Det finns visst belägg för att arbetsmiljösatsningar ofta är lönsamma på organisationsnivå, även om studierna är få och uppvisar metodbrister. Det finns flera indikationer på att lönsamheten i huvudsak härrör från produktivitets- och kvalitetsförbättringar, och i mindre grad från minskade frånvarokostnader. Nya litteraturöversikter om hälsofrämjande interventioner tycks uppvisa starkare effekter än gamla, medan jämförelser mellan äldre och nyare studier om belastningsergonomiska interventioner ger en mer mångtydig bild. Ofta ligger fokus på utvärderingsdesign, samtidigt som kvaliteten hos interventionens genomförande och utformning i sig inte ges samma prioritet. Interventioner med multifaktoriella insatser blir synnerligen svåra och komplexa att utvärdera, samtidigt som det i många studier och forskningsöversikter betonas att en förutsättning för framgång i förändringsarbetet är att man arbetar med en mångfald av insatser. Inklusionskriterier i litteraturöversikter som förutsätter experimentella upplägg i organisationsinterventioner selekterar bort studier med goda interventioner som inte kan utvärderas med traditionella metoder. Svårigheten att identifiera effekter av interventioner bedöms bero på synen om vad som utmärker god vetenskaplig kvalitet hos studier. Detta visar på behovet att närmare kritiskt granska förutsättningarna för kunskapsbildning inom området. Slutsatsen är att arbetsmiljöarbete i vissa fall har effekter men att det i andra fall är svårt att påvisa effekter. Effektutvärdering innebär stora metodologiska svårigheter. Dessa svårigheter bedöms vara en viktig orsak till bristen på underlag, speciellt inom det belastningsergonomiska området. Det finns ett stort behov av nya icke experimentella undersökningsstrategier som är anpassade till dagens komplexa system, såväl som ett behov av starkare fokus på praktiskt väl genomförda multifaktoriella interventioner

Widespread expression of Huntington's Disease gene (IT15) protein product

Huntington's Disease (HD) is caused by expansion of a CAG repeat within a putative open reading frame of a recently identified gene, IT15. We have examined the expression of the gene's protein product using antibodies developed against the N-terminus and an internal epitope. Both antisera recognize a 350 kDa protein, the predicted size, indicating that the CAG repeat is translated into polyglutamine. The HD protein product is widely expressed, most highly in neurons in the brain. There is no enrichment in the striatum, the site of greatest pathology in HD. Within neurons, the protein is diminished in nuclei and mitochondria and is present in the soluble cytoplasmic compartment, as well as loosely associated with membranes or cytoskeleton, in cell bodies, dendrites, and axons. It is concentrated in nerve terminals, including terminals within the caudate and putamen. Thus, the normal HD gene product may be involved in common intracellular functions, and possibly in regulation of nerve terminal function. The product of the expanded allele is expressed, consistent with a gain of function mechanism for HD at the protein level.link_to_subscribed_fulltex