Non-invasive evaluation of nigrostriatal neuropathology in a proteasome inhibitor rodent model of Parkinson's disease

<p>Abstract</p> <p>Background</p> <p>Predominantly, magnetic resonance imaging (MRI) studies in animal models of Parkinson's disease (PD) have focused on alterations in T₂water ¹H relaxation or ¹H MR spectroscopy (MRS), whilst potential morphological changes and their relationship to histological or behavioural outcomes have not been appropriately addressed. Therefore, in this study we have utilised MRI to scan <it>in vivo </it>brains from rodents bearing a nigrostriatal lesion induced by intranigral injection of the proteasome inhibitor lactacystin.</p> <p>Results</p> <p>Lactacystin induced parkinsonian-like behaviour, characterised by impaired contralateral forelimb grip strength and increased contralateral circling in response to apomorphine. T₂-weighted MRI, 3-weeks post-lesion, revealed significant morphological changes in PD-relevant brain areas, including the striatum and ventral midbrain in addition to a decrease in T₂water ¹H relaxation in the substantia nigra (SN), but not the striatum. Post-mortem histological analyses revealed extensive dopaminergic neuronal degeneration and α-synuclein aggregation in the SN. However, extensive neuronal loss could also be observed in extra-nigral areas, suggesting non-specific toxicity of lactacystin. Iron accumulation could also be observed throughout the midbrain reflecting changes in T₂. Importantly, morphological, but not T₂relaxivity changes, were significantly associated with both behavioural and histological outcomes in this model.</p> <p>Conclusions</p> <p>A pattern of morphological changes in lactacystin-lesioned animals has been identified, as well as alterations in nigral T₂relaxivity. The significant relationship of morphological changes with behavioural and histological outcomes in this model raises the possibility that these may be useful non-invasive surrogate markers of nigrostriatal degeneration <it>in vivo</it>.</p

Risk of mortality in a cohort of patients newly diagnosed with chronic atrial fibrillation

OBJECTIVE: To estimate the mortality rate of patients newly diagnosed with chronic atrial fibrillation (AF) and compare it with the one in the general population. To evaluate the role of co-morbidity and other factors on the risk of dying among AF patients. METHODS: We used the General Practice Research Database in the UK to perform a retrospective cohort study. We followed a cohort of chronic AF patiens (N = 1,035) and an age and sex matched cohort of 5,000 subjects sampled from the general population. We used all deceased AF patients as cases (n = 234) and the remaining AF patients as controls to perform a nested case-control analysis. We estimated mortality risk associated with AF using Cox regression. We computed mortality relative risks using logistic regression among AF patients. RESULTS: During a mean follow-up of two years, 393 patients died in the general population cohort and 234 in the AF cohort. Adjusted relative risk of death in the cohort of AF was 2.5 (95%CI 2.1 – 3.0) compared to the general population. Among AF patients, mortality risk increased remarkably with advancing age. Smokers carried a relative risk of dying close to threefold. Ischaemic heart disease was the strongest clinical predictor of mortality with a RR of 3.0 (95% CI; 2.1–4.1). Current use of calcium channel blockers, warfarin and aspirin was associated with a decreased risk of mortality. CONCLUSIONS: Chronic AF is an important determinant of increased mortality. Major risk factors for mortality in the AF cohort were age, smoking and cardiovascular co-morbidity, in particular ischaemic heart disease

Risk of myocardial infarction and overall mortality in survivors of venous thromboembolism

<p>Abstract</p> <p>Background</p> <p>Venous thromboembolism (VTE) and thromboembolic arterial diseases are usually considered to be distinct entities, but there is evidence to suggest that these disorders may be linked. The aim of this study was to determine whether a diagnosis of VTE increases the long-term risk of myocardial infarction (MI).</p> <p>Methods</p> <p>The incidence rate (IR) and relative risk (RR) of MI in a cohort of patients with a diagnosis of VTE (n = 4890) compared with that of a control cohort without prior VTE (n = 43 382) were evaluated in the UK General Practice Research Database (GPRD). Death during follow-up was also determined. Patients were followed for up to 8 years (mean of 3 years).</p> <p>Results</p> <p>The IR of MI per 1000 person-years was 4.1 (95% CI: 3.1–5.3) for the VTE cohort and 3.5 (95% CI: 3.2–3.8) for the control cohort. The IR of MI was highest in the first year after the VTE episode, but overall differences between the two cohorts were not significant (RR of MI associated with VTE: 1.2; 95% CI: 0.9–1.6). The risk of death was higher in the VTE cohort than the control cohort, even after adjustment for cancer, heart failure and ischaemic heart disease (RR: 2.4; 95% CI: 2.2–2.6), particularly during the first year after VTE (RR: 3.8; 95% CI: 3.4–4.3).</p> <p>Conclusion</p> <p>A VTE episode does not significantly increase the risk of MI, but does increase the risk of death, particularly in the first year following VTE diagnosis.</p

Evolution of Extra-Nigral Damage Predicts Behavioural Deficits in a Rat Proteasome Inhibitor Model of Parkinson's Disease

Establishing the neurological basis of behavioural dysfunction is key to provide a better understanding of Parkinson's disease (PD) and facilitate development of effective novel therapies. For this, the relationships between longitudinal structural brain changes associated with motor behaviour were determined in a rat model of PD and validated by post-mortem immunohistochemistry. Rats bearing a nigrostriatal lesion induced by infusion of the proteasome inhibitor lactacystin into the left-medial forebrain bundle and saline-injected controls underwent magnetic resonance imaging (MRI) at baseline (prior to surgery) and 1, 3 and 5 weeks post-surgery with concomitant motor assessments consisting of forelimb grip strength, accelerating rotarod, and apormorphine-induced rotation. Lactacystin-injected rats developed early motor deficits alongside decreased ipsilateral cortical volumes, specifically thinning of the primary motor (M1) and somatosensory cortices and lateral ventricle hypertrophy (as determined by manual segmentation and deformation-based morphometry). Although sustained, motor dysfunction and nigrostriatal damage were maximal by 1 week post-surgery. Additional volume decreases in the ipsilateral ventral midbrain; corpus striatum and thalamus were only evident by week 3 and 5. Whilst cortical MRI volume changes best predicted the degree of motor impairment, post-mortem tyrosine hydroxylase immunoreactivity in the striatum was a better predictor of motor behaviour overall, with the notable exception of performance in the accelerating rotarod, in which, M1 cortical thickness remained the best predictor. These results highlight the importance of identifying extra-nigral regions of damage that impact on behavioural dysfunction from damage to the nigrostriatal system

Health-related quality of life of irritable bowel syndrome patients in different cultural settings

BACKGROUND: Persons with Irritable bowel syndrome (IBS) are seriously affected in their everyday life. The effect across different cultural settings of IBS on their quality of life has been little studied. The aim was to compare health-related quality of life (HRQOL) of individuals suffering from IBS in two different cultural settings; Crete, Greece and Linköping, Sweden. METHODS: This study is a sex and age-matched case-control study, with n = 30 Cretan IBS cases and n = 90 Swedish IBS cases and a Swedish control group (n = 300) randomly selected from the general population. Health-related quality of life, measured by SF-36 and demographics, life style indicators and co-morbidity, was measured. RESULTS: Cretan IBS cases reported lower HRQOL on most dimensions of SF-36 in comparison to the Swedish IBS cases. Significant differences were found for the dimensions mental health (p < 0.0001) and general health (p = 0.05) even after adjustments for educational level and co-morbidity. Women from Crete with IBS scored especially low on the dimensions general health (p = 0.009) and mental health (p < 0.0001) in comparison with Swedish women with IBS. The IBS cases, from both sites, reported significantly lower scores on all HRQOL dimensions in comparison with the Swedish control group. CONCLUSION: The results from this study tentatively support that the claim that similar individuals having the same disease, e.g. IBS, but living in different cultural environments could perceive their disease differently and that the disease might affect their everyday life and quality of life in a different way. The Cretan population, and especially women, are more seriously affected mentally by their disease than Swedish IBS cases. Coping with IBS in everyday life might be more problematic in the Cretan environment than in the Swedish setting

Discontinuation of low dose aspirin and risk of myocardial infarction: case-control study in UK primary care

Objectives To evaluate the risk of myocardial infarction and death from coronary heart disease after discontinuation of low dose aspirin in primary care patients with a history of cardiovascular events

Exploring diffrent design spaces - VR as a tool during building design

During the design process of a building different medias are often used to depict the design. Traditional media, especially 2D requires high spatial skill and cognitive demand on the designers. For inexperienced designers, this process can be demanding, be difficult and can cause potential biased designperceptions that are significantly different from the reality. However, studies have also shown that different media and representation facilitates different cognitive reasoning processes about the design. Immersive Virtual Reality (VR) is assumed to give another level of understanding and perception of design space from an egocentric perception than 2D plan drawings or bird-eye views, which have been argued to provide opportunities for better pattern and object recognition that is suitable when studying spatial organization in an allocentric reasoning process. This paper investigates, the different design medias and spatial space explorations further, by studying how students used the different representations and medias (e.g. sketches, 3d-models and VR) during their design process. By combining and using both of these two design space representations, (e.g. egocentric and allocentric) in the design process, it gives a possibility to achieve a more developed design outcome. The methods used in this study were observations and un-structured interviews during the design process and a follow up questionnaire at the end of the design project. The result show, by combining and using both VR and traditional design sketching tools that it is possible to support the two design space representations together and give the designer the possibilities to explore, understand, discuss and work with the design in a more elaborate way from both an egocentric and allocentric perspective. The paper also presents in what way VR can contribute to the Evidence Based Design (EBD) criteria and how the students used different design spaces representations for design and spatial reasoning about the healthcare design of the psychiatric facility they were designing

Impact of gastroesophageal reflux disease on daily life: the Systematic Investigation of Gastrointestinal Diseases in China (SILC) epidemiological study

<p>Abstract</p> <p>Background</p> <p>Gastroesophageal reflux disease imposes a significant burden of illness in Western populations. However, data on the impact of reflux symptoms on daily life in Asian populations are scarce. The current study aimed to evaluate the impact of GERD (defined on the basis of symptoms) on health-related quality-of-life (HRQoL) in individuals from five regions in China, as part of the Systematic Investigation of Gastrointestinal Diseases in China (SILC) study.</p> <p>Methods</p> <p>In total, 18 000 residents were randomly selected from across five regions of China and asked to complete a general information questionnaire and a Chinese version of the Reflux Disease Questionnaire (RDQ). A randomly selected subsample of one-fifth of subjects (20% from each region) completed Chinese versions of the 36-item self-administered (SF-36) questionnaire and Epworth Sleepiness Scale (ESS) questionnaire. Reflux symptoms were defined as the presence of heartburn and/or regurgitation. Symptom-defined GERD was diagnosed as mild heartburn and/or regurgitation ≥2 days per week, or moderate/severe heartburn and/or regurgitation ≥1 day a week, based on the Montreal Definition of GERD for population-based studies.</p> <p>Results</p> <p>The response rate was 89.4% for the total sample (16 091/18 000), and for the 20% subsample (3219/3600). Meaningful impairment was observed in all 8 SF-36 dimensions in participants with symptom-defined GERD, in 7 of the 8 SF-36 dimensions in participants with troublesome reflux symptoms, and in 6 of the 8 SF-36 dimensions in participants with reflux symptoms below the threshold for symptom-defined GERD. Meaningful daytime sleepiness was also observed in each of these groups. The proportion of individuals reporting troublesome symptoms increased as reflux symptom frequency and severity approached the threshold for symptom-defined GERD, and this was associated with concomitant decreases in all HRQoL measures. Troublesome symptoms were reported by 68.2% (75/110) of individuals with symptom-defined GERD.</p> <p>Conclusions</p> <p>GERD diagnosed using symptom/frequency criteria (recommended for population-based studies), or based on troublesome reflux symptoms (recommended for the clinic), is associated with significantly impaired HRQoL in Chinese individuals. However, patient groups identified using these definitions do not overlap completely, suggesting that they capture slightly different, though clinically relevant, GERD populations.</p

Predictors and prognosis of paroxysmal atrial fibrillation in general practice in the UK

BACKGROUND: Natural history of paroxysmal atrial fibrillation (AF) is not very well documented. Clinical experience suggests that paroxysmal AF could progress to chronic AF with estimates ranging between 15 and 30% over a period of 1–3 years. We performed an epidemiologic study to elucidate the natural history of paroxysmal AF, this study estimated its incidence in a general practice setting, identified associated factors and analyzed the progression into chronic AF as well as the mortality rate. METHODS: Using the UK General Practice Research Database (GPRD), we identified patients aged 40–89 years with a first-recorded episode of paroxysmal AF during 1996. Risk factors were assessed using 525 incident paroxysmal AF cases confirmed by the general practitioner (GP) and a random sample of controls. We follow-up paroxysmal AF patients and estimated their mortality rate and progression to chronic AF. RESULTS: The incidence of paroxysmal AF was 1.0 per 1,000 person-years. Major risk factors for paroxysmal AF were age and prior valvular heart disease, ischaemic heart disease, heart failure and hyperthyroidism. During a mean follow-up of 2.7 years, 70 of 418 paroxysmal AF patients with complete information progressed to chronic AF. Risk factors associated with progression were valvular heart disease (OR 2.7, 95% CI 1.2–6.0) and moderate to high alcohol consumption (OR 3.0, 95% CI 1.1–8.0). Paroxysmal AF patients did not carry an increased risk of mortality, compared to an age and sex matched sample of the general population. There was a suggestion of a small increased risk among patients progressing to chronic AF (RR 1.5, 96% CI 0.8–2.9). CONCLUSION: Paroxysmal AF is a common arrhythmia in the general practice setting, increasing with age and commonly associated with other heart diseases. It sometimes is the initial presentation and then progress to chronic AF. A history of valvular heart disease and alcohol consumption are associated with this progression