The effect of motivation on movement: a study of bradykinesia in Parkinson's disease.

Bradykinesia is a cardinal feature of Parkinson's disease (PD). Despite its disabling impact, the precise cause of this symptom remains elusive. Recent thinking suggests that bradykinesia may be more than simply a manifestation of motor slowness, and may in part reflect a specific deficit in the operation of motivational vigour in the striatum. In this paper we test the hypothesis that movement time in PD can be modulated by the specific nature of the motivational salience of possible action-outcomes

Microbial contamination of domiciliary nebulisers and clinical implications in chronic obstructive pulmonary disease.

BACKGROUND AND PURPOSE: Domiciliary nebulisers are widely used in chronic obstructive pulmonary disease (COPD) but nebuliser cleaning practice has not been assessed in patients with COPD who are often elderly and may have severe disease and multiple comorbidities. We aimed to evaluate microbial contamination of home nebulisers used by patients with COPD. METHODS: Random microbiological assessment of domiciliary nebulisers was undertaken together with an enquiry into cleaning practices. We also examined the effectiveness of the trust-wide cleaning instructions in eradicating isolated microorganisms in a laboratory setting. RESULTS: The mean age of patients in this study was 71 (range 40-93) years, and in 68% of patients a large number of significant comorbidities were present. Forty-four nebuliser sets were obtained and 73% were contaminated with microorganisms at >100 colony forming units/plate. Potentially pathogenic bacteria colonised 13 of the 44 nebulisers (30%) and organisms isolated included Pseudomonas aeroginosa, Staphylococcus aureus, multidrug resistant Serratia marcesans, Escherichia coli and multiresistant Klebsiella spp, Enterobacteriaceae and fungus Fusarium oxysporum. Washing of nebuliser masks, chambers and mouthpieces achieved complete eradication of Gram-positive bacterial and fungal flora. Gram-negative organisms were incompletely eradicated, which may be attributed to the presence of biofilms. We also found that in patients with pathogenic organisms cultured on the nebuliser sets, there was a higher probability of occurrence of a COPD exacerbation with a mean number of exacerbations of 3.3 (SD=1) per year in the group in whom pathogens were isolated compared with 1.7 (SD=1.2) exacerbations per year in those whose sets grew non-pathogenic flora (p=0.02). CONCLUSIONS: Nebulisers contaminated with microorganisms are potential reservoirs delivering serious pathogens to the lung. Relationships between nebuliser contamination, clinical infection and exacerbations require further examination, but is a potential concern in elderly patients with COPD with comorbidities who fail to effectively maintain reasonable standards of nebuliser cleanliness

Dopamine, Salience, and Response Set Shifting in Prefrontal Cortex.

Dopamine is implicated in multiple functions, including motor execution, action learning for hedonically salient outcomes, maintenance, and switching of behavioral response set. Here, we used a novel within-subject psychopharmacological and combined functional neuroimaging paradigm, investigating the interaction between hedonic salience, dopamine, and response set shifting, distinct from effects on action learning or motor execution. We asked whether behavioral performance in response set shifting depends on the hedonic salience of reversal cues, by presenting these as null (neutral) or salient (monetary loss) outcomes. We observed marked effects of reversal cue salience on set-switching, with more efficient reversals following salient loss outcomes. l-Dopa degraded this discrimination, leading to inappropriate perseveration. Generic activation in thalamus, insula, and striatum preceded response set switches, with an opposite pattern in ventromedial prefrontal cortex (vmPFC). However, the behavioral effect of hedonic salience was reflected in differential vmPFC deactivation following salient relative to null reversal cues. l-Dopa reversed this pattern in vmPFC, suggesting that its behavioral effects are due to disruption of the stability and switching of firing patterns in prefrontal cortex. Our findings provide a potential neurobiological explanation for paradoxical phenomena, including maintenance of behavioral set despite negative outcomes, seen in impulse control disorders in Parkinson's disease

Functional immune characterization of HIV-associated non-small-cell lung cancer.

Dear Editor, In the combined anti-retroviral therapy (cART) era, non-small cell lung cancer (NSCLC) is a highly incident cause of morbidity and mortality in people living with HIV (PLHIV)[1]. The immune-pathogenesis of NSCLC and HIV infection both rely on programmed-death 1 (PD-1) receptor-ligand interaction as a mechanism to induce T-cell exhaustion. To date, PLHIV have been excluded from clinical trials of immune-checkpoint inhibitors (ICPI), on the presumption that anti-tumour immunity might be compromised by HIV infection. To verify this, we evaluated the clinico-pathologic significance of PD-ligands expression in a consecutive series of 221 archival NSCLC samples, 24 of which were HIV-associated (Table S1)

The Interaction of N-Acylhomoserine Lactone Quorum Sensing Signaling Molecules with Biological Membranes: Implications for Inter-Kingdom Signaling

The long chain N-acylhomoserine lactone (AHL) quorum sensing signal molecules released by Pseudomonas aeruginosa have long been known to elicit immunomodulatory effects through a process termed inter-kingdom signaling. However, to date very little is known regarding the exact mechanism of action of these compounds on their eukaryotic targets.The use of the membrane dipole fluorescent sensor di-8-ANEPPS to characterise the interactions of AHL quorum sensing signal molecules, N-(3-oxotetradecanoyl)-L-homoserine lactone (3-oxo-C14-HSL), N-(3-oxododecanoyl)homoserine-L-lactone (3-oxo-C12-HSL) and N-(3-oxodecanoyl) homoserine-L-lactone (3-oxo-C10 HSL) produced by Pseudomonas aeruginosa with model and cellular membranes is reported. The interactions of these AHLs with artificial membranes reveal that each of the compounds is capable of membrane interaction in the micromolar concentration range causing significant modulation of the membrane dipole potential. These interactions fit simple hyperbolic binding models with membrane affinity increasing with acyl chain length. Similar results were obtained with T-lymphocytes providing the evidence that AHLs are capable of direct interaction with the plasma membrane. 3-oxo-C12-HSL interacts with lymphocytes via a cooperative binding model therefore implying the existence of an AHL membrane receptor. The role of cholesterol in the interactions of AHLs with membranes, the significance of modulating cellular dipole potential for receptor conformation and the implications for immune modulation are discussed.Our observations support previous findings that increasing AHL lipophilicity increases the immunomodulatory activity of these quorum compounds, while providing evidence to suggest membrane interaction plays an important role in quorum sensing and implies a role for membrane microdomains in this process. Finally, our results suggest the existence of a eukaryotic membrane-located system that acts as an AHL receptor

Temporal variability in shell mound formation at Albatross Bay, northern Australia

We report the results of 212 radiocarbon determinations from the archaeological excavation of 70 shell mound deposits in the Wathayn region of Albatross Bay, Australia. This is an intensive study of a closely co-located group of mounds within a geographically restricted area in a wider region where many more shell mounds have been reported. Valves from the bivalve Tegillarcca granosa were dated. The dates obtained are used to calculate rates of accumulation for the shell mound deposits. These demonstrate highly variable rates of accumulation both within and between mounds. We assess these results in relation to likely mechanisms of shell deposition and show that rates of deposition are affected by time-dependent processes both during the accumulation of shell deposits and during their subsequent deformation. This complicates the interpretation of the rates at which shell mound deposits appear to have accumulated. At Wathayn, there is little temporal or spatial consistency in the rates at which mounds accumulated. Comparisons between the Wathayn results and those obtained from shell deposits elsewhere, both in the wider Albatross Bay region and worldwide, suggest the need for caution when deriving behavioural inferences from shell mound deposition rates, and the need for more comprehensive sampling of individual mounds and groups of mounds

Small- bowel mucosal changes and antibody responses after low- and moderate-dose gluten challenge in celiac disease

<p>Abstract</p> <p>Background</p> <p>Due to the restrictive nature of a gluten-free diet, celiac patients are looking for alternative therapies. While drug-development programs include gluten challenges, knowledge regarding the duration of gluten challenge and gluten dosage is insufficient.</p> <p>We challenged adult celiac patients with gluten with a view to assessing the amount needed to cause some small-bowel mucosal deterioration.</p> <p>Methods</p> <p>Twenty-five celiac disease adults were challenged with low (1-3 g) or moderate (3-5g) doses of gluten daily for 12 weeks. Symptoms, small-bowel morphology, densities of CD3+ intraepithelial lymphocytes (IELs) and celiac serology were determined.</p> <p>Results</p> <p>Both moderate and low amounts of gluten induced small-bowel morphological damage in 67% of celiac patients. Moderate gluten doses also triggered mucosal inflammation and more gastrointestinal symptoms leading to premature withdrawals in seven cases. In 22% of those who developed significant small- intestinal damage, symptoms remained absent. Celiac antibodies seroconverted in 43% of the patients.</p> <p>Conclusions</p> <p>Low amounts of gluten can also cause significant mucosal deterioration in the majority of the patients. As there are always some celiac disease patients who will not respond within these conditions, sample sizes must be sufficiently large to attain to statistical power in analysis.</p

Dear British criminology: Where has all the race and racism gone?

In this article we use Emirbayer and Desmond’s institutional reflexivity framework to critically examine the production of racial knowledge in British criminology. Identifying weakness, neglect and marginalization in theorizing race and racism, we focus principally on the disciplinary unconscious element of their three-tier framework, identifying and interrogating aspects of criminology’s ‘obligatory problematics’, ‘habits of thought’ and ‘position-taking’ as well as its institutional structure and social relations that combine to render the discipline ‘institutionally white’. We also consider, briefly, aspects of criminology’s relationship to race, racism and whiteness in the USA. The final part of the article makes the case for British criminology to engage in telling and narrating racisms, urging it to understand the complexities of race in our subject matter, avoid its reduction to class and inequality, and to pay particular attention to reflexivity, history, sociology and language, turning to face race with postcolonial tools and resolve