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Background: Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic risk factor for Parkinson's disease (PD). While the corresponding pathogenic mechanisms remain largely unknown, LRRK2 has been implicated in the immune system.Objective: To assess whether LRRK2 mutations alter the sensitivity to a single peripheral inflammatory trigger, with ultimate impact on dopaminergic integrity, using a longitudinal imaging-based study design.Methods: Rats carrying LRRK2 p.G2019S and non-transgenic (NT) littermates were treated peripherally with lipopolysaccharide (LPS). They were monitored over 10 months with PET markers for neuroinflammation and dopaminergic integrity, and with behavioral testing. Tyrosine hydroxylase and CD68 expression were assessed postmortem, 12 months after LPS treatment, in the striatum and substantia nigra.Results: Longitudinal [C-11]PBR28 PET imaging revealed that LPS treatment caused inflammation in the brain, increasing over time, as compared to saline (corrected p = 0.008). LPS treated LRRK2 animals exhibited significantly increased neuroinflammation in the cortex and ventral-regions compared to saline treated animals (LRRK2 and NT) at 10 months post treatment, with the increase in [C-11] PBR28 binding from baseline averaging 0.128 +/- 0.045 g/mL. For LPS treated NT animals, the increase was not significant. CD68 immunohistochemistry data supported the imaging results, but without reaching statistical significance. No dopaminergic degeneration was observed.Conclusion: A single peripheral inflammatory trigger elicited long lasting, progressive neuroinflammation. A trend for an exacerbated inflammatory response in LRRK2 animals compared to NT controls was observed. Translationally, this implies that repeated exposure to inflammatory triggers may be needed for LRRK2 mutation carriers to develop active PD.

BACKGROUND The benefits of exercise in PD have been linked to enhanced dopamine (DA) transmission in the striatum. OBJECTIVE To examine differences in DA release, reward signaling, and clinical features between habitual exercisers and sedentary subjects with PD. METHODS Eight habitual exercisers and 9 sedentary subjects completed [11 C]raclopride PET scans before and after stationary cycling to determine exercise-induced release of endogenous DA in the dorsal striatum. Additionally, functional MRI assessed ventral striatum activation during reward anticipation. All participants completed motor (UPDRS III; finger tapping; and timed-up-and-go) and nonmotor (Beck Depression Inventory; Starkstein Apathy Scale) assessments. RESULTS [11 C]Raclopride analysis before and after stationary cycling demonstrated greater DA release in the caudate nuclei of habitual exercisers compared to sedentary subjects (P

Reward-related stimuli can potently influence behavior; for example, exposure to drug-paired cues can trigger drug use and relapse in people with addictions. Psychological mechanisms that generate such outcomes likely include cue-induced cravings and attentional biases. Recent animal data suggest another candidate mechanism: reward-paired cues can enhance risky decision making, yet whether this translates to humans is unknown. Here, we examined whether sensory reward-paired cues alter decision making under uncertainty and risk, as measured respectively by the Iowa Gambling Task and a two-choice lottery task. In the cued versions of both tasks, gain feedback was augmented with reward-concurrent audiovisual stimuli. Healthy human volunteers (53 males, 78 females) performed each task once, one with and the other without cues (cued Iowa Gambling Task/uncued Vancouver Gambling Task:n= 63; uncued Iowa Gambling Task/cued Vancouver Gambling Task:n= 68), with concurrent eye-tracking. Reward-paired cues did not affect choice on the Iowa Gambling Task. On the two-choice lottery task, the cued group displayed riskier choice and reduced sensitivity to probability information. The cued condition was associated with reduced eye fixations on probability information shown on the screen and greater pupil dilation related to decision and reward anticipation. This pupil effect was unrelated to the risk-promoting effects of cues: the degree of pupil dilation for risky versus risk-averse choices did not differ as a function of cues. Together, our data show that sensory reward cues can promote riskier decisions and have additional and distinct effects on arousal.SIGNIFICANCE STATEMENTAnimal data suggest that reward-paired cues can promote maladaptive reward-seeking by biasing cost-benefit decision making. Whether this finding translates to humans is unknown. We examined the effects of salient reward-paired audiovisual cues on decision making under risk and uncertainty in human volunteers. Cues had risk-promoting effects on a risky choice task and independently increased task-related arousal as measured by pupil dilation. By demonstrating risk-promoting effects of cues in human participants, our data identify a mechanism whereby cue reactivity could translate into maladaptive behavioral outcomes in people with addictions.

Background The objective of this study was to examine the effects of aerobic exercise on evoked dopamine release and activity of the ventral striatum using positron emission tomography and functional magnetic resonance imaging in Parkinson's disease (PD). Methods Thirty-five participants were randomly allocated to a 36-session aerobic exercise or control intervention. Each participant underwent an functional magnetic resonance imaging scan while playing a reward task before and after the intervention to determine the effect of exercise on the activity of the ventral striatum in anticipation of reward. A subset of participants (n = 25) completed [11 C] raclopride positron emission tomography scans to determine the effect of aerobic exercise on repetitive transcranial magnetic stimulation-evoked release of endogenous dopamine in the dorsal striatum. All participants completed motor (MDS-UPDRS part III, finger tapping, Timed-up-and-go) and nonmotor assessments (Starkstein Apathy Scale, Beck Depression Inventory, reaction time, Positive and Negative Affect Schedule, Trail Making Test [A and B], and Montreal Cognitive Assessment) before and after the interventions. Results The aerobic group exhibited increased activity in the ventral striatum during functional magnetic resonance imaging in anticipation of 75% probability of reward (P = 0.01). The aerobic group also demonstrated increased repetitive transcranial magnetic stimulation-evoked dopamine release in the caudate nucleus (P = 0.04) and increased baseline nondisplaceable binding potential in the posterior putamen of the less affected repetitive transcranial magnetic stimulation-stimulated hemisphere measured by position emission tomography (P = 0.03). Conclusions Aerobic exercise alters the responsivity of the ventral striatum, likely related to changes to the mesolimbic dopaminergic pathway, and increases evoked dopamine release in the caudate nucleus. This suggests that the therapeutic benefits of exercise are in part related to corticostriatal plasticity and enhanced dopamine release. © 2019 International Parkinson and Movement Disorder Society.

Background: As individuals age, they are more likely to experience increasing frailty and more frequent use of hospital services. First, we explored whether initiating home-based primary care in a frail homebound cohort, influenced hospital use. Second, we explored whether initiating regular home care support for personal care with usual primary care, in a second somewhat less frail cohort, influenced hospital use. Methods: This was a before-after retrospective cohort study of two frail populations in Vancouver, Canada using administrative data to assess the influence of two different services started in two different cohorts over the same time period. The participants were 246 recipients of integrated home-based primary care and 492 recipients of home care followed between July 1st, 2008 and June 30th, 2013 before and after starting their respective services. Individuals in each group were linked to their hospital emergency department visit and discharge abstract records. The main outcome measures were mean emergency department visit and hospital admission rates per 1000 patient days for 21 months before versus the period after receipt of services, and the adjusted incidence rate ratios (IRRs) on these outcomes post receipt of service. Results: Before versus after starting integrated home-based primary care, emergency department visit rates per 1000 patient days (95% confidence intervals) were 4.1 (3.8, 4.4) versus 3.7 (3.3, 4.1), and hospital admissions rates were 2.3 (2.1, 2.5) versus 2.2 (1.9, 2.5). Before versus after starting home care, emergency department visit rates per 1000 patient days (95% confidence intervals) were 3.0 (2.8, 3.2) versus 4.0 (3.7, 4.3) visits and hospital admissions rates were 1.3 (1.2, 1.4) versus 1.9 (1.7, 2.1). Home-based primary care IRRs were 0.91 (0.72, 1.15) and 0.99 (0.76, 1.27) and home care IRRs were 1.34 (1.15, 1.56) and 1.46 (1.22, 1.74) for emergency department visits and hospital admissions respectively. Conclusions: After enrollment in integrated home-based primary care, emergency department visit and hospital admission rates stabilized. After starting home care with usual primary care, emergency department visit and hospital admission rates continued to rise.

The benefits of exercise in PD have been linked to enhanced dopamine (DA) transmission in the striatum.To examine differences in DA release, reward signaling, and clinical features between habitual exercisers and sedentary subjects with PD.Eight habitual exercisers and 9 sedentary subjects completed [[Habitual exercise is associated with preservation of motor and nonmotor function, possibly mediated by increased DA release. This study formulates a foundation for prospective, randomized controlled studies. © 2018 International Parkinson and Movement Disorder Society.

Neuroinflammation in the aging rat brain was investigated using [11C]PBR28 microPET (positron emission tomography) imaging. Normal rats were studied alongside LRRK2 p.G2019S transgenic rats; this mutation increases the risk of Parkinson's disease in humans. Seventy [11C]PBR28 PET scans were acquired. Arterial blood sampling enabled tracer kinetic modeling and estimation of VT. In vitro autoradiography was also performed. PBR28 uptake increased with age, without differences between nontransgenic and transgenic rats. In 12 months of aging (4 to 16 months), standard uptake value (SUV) increased by 56% from 0.44 to 0.69 g/mL, whereas VT increased by 91% from 30 to 57 mL/cm3. Standard uptake value and VT were strongly correlated (r = 0.52, 95% confidence interval (CI) = 0.31 to 0.69, n = 37). The plasma free fraction, fp, was 0.21 ± 0.03 (mean ± standard deviation, n = 53). In vitro binding increased by 19% in 16 months of aging (4 to 20 months). The SUV was less variable across rats than VT; coefficients of variation were 13% ( n = 27) and 29% ( n = 12). The intraclass correlation coefficient for SUV was 0.53, but was effectively zero for VT. These data show that [11C]PBR28 brain uptake increases with age, implying increased microglial activation in the aged brain.

Summary Background Markers of neuroinflammation are increased in some patients with LRRK2 Parkinson's disease compared with individuals with idiopathic Parkinson's disease, suggesting possible differences in disease pathogenesis. Previous PET studies have suggested amplified dopamine turnover and preserved serotonergic innervation in LRRK2 mutation carriers. We postulated that patients with LRRK2 mutations might show abnormalities of central cholinergic activity, even before the diagnosis of Parkinson's disease. Methods Between June, 2009, and December, 2015, we recruited participants from four movement disorder clinics in Canada, Norway, and the USA. Patients with Parkinson's disease were diagnosed by movement disorder neurologists on the basis of the UK Parkinson's Disease Society Brain Bank criteria. LRRK2 carrier status was confirmed by bidirectional Sanger sequencing. We used the PET tracer N-11C-methyl-piperidin-4-yl propionate to scan for acetylcholinesterase activity. The primary outcome measure was rate of acetylcholinesterase hydrolysis, calculated using the striatal input method. We compared acetylcholinesterase hydrolysis rates between groups using ANCOVA, with adjustment for age based on the results of linear regression analysis. Findings We recruited 14 patients with LRRK2 Parkinson's disease, 16 LRRK2 mutation carriers without Parkinson's disease, eight patients with idiopathic Parkinson's disease, and 11 healthy controls. We noted significant between-group differences in rates of acetylcholinesterase hydrolysis in cortical regions (average cortex p=0·009, default mode network-related regions p=0·006, limbic network-related regions p=0·020) and the thalamus (p=0·008). LRRK2 mutation carriers without Parkinson's disease had increased acetylcholinesterase hydrolysis rates compared with healthy controls in the cortex (average cortex, p=0·046). Patients with LRRK2 Parkinson's disease had significantly higher acetylcholinesterase activity in some cortical regions (average cortex p=0·043, default mode network-related regions p=0·021) and the thalamus (thalamus p=0·004) compared with individuals with idiopathic disease. Acetylcholinesterase hydrolysis rates in healthy controls were correlated inversely with age. Interpretation LRRK2 mutations are associated with significantly increased cholinergic activity in the brain in mutation carriers without Parkinson's disease compared with healthy controls and in LRRK2 mutation carriers with Parkinson's disease compared with individuals with idiopathic disease. Changes in cholinergic activity might represent early and sustained attempts to compensate for LRRK2-related dysfunction, or alteration of acetylcholinesterase in non-neuronal cells. Funding Michael J Fox Foundation, National Institutes of Health, and Pacific Alzheimer Research Foundation.

Introduction We used positron emission tomography (PET) to assess dopaminergic and serotonergic terminal density in three subjects carrying a mutation in the DCT1 gene, two clinically affected with Perry syndrome. Methods All subjects had brain imaging using 18F-6-fluoro-l-dopa (FDOPA, dopamine synthesis and storage), (+)-11C-dihydrotetrabenazine (DTBZ, vesicular monoamine transporter type 2), and 11C-raclopride (RAC, dopamine D2/D3 receptors). One subject also underwent PET with 11C-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB, serotonin transporter). Results FDOPA-PET and DTBZ-PET in the affected individuals showed a reduction of striatal tracer uptake. Also, RAC-PET showed higher uptake in these area. DASB-PET showed significant uptake changes in left orbitofrontal cortex, bilateral anterior insula, left dorsolateral prefrontal cortex, left orbitofrontal cortex, left posterior cingulate cortex, left caudate, and left ventral striatum. Conclusions Our data showed evidence of both striatal dopaminergic and widespread cortical/subcortical serotonergic dysfunctions in individuals carrying a mutation in the DCTN1 gene. © 2014 International Parkinson and Movement Disorder Society

Rationale and Objectives To measure the impact of 1-year interventional fellowship training on fluoroscopic time and contrast media utilization in uterine artery embolization (UAE). Materials and Methods Retrospective single institution analysis of 323 consecutive UAEs performed by 12 interventional fellows using a standardized protocol. Fluoroscopy time and contrast media volume were recorded for each patient and correlated with stage of fellowship training. Preprocedure uterine volume (using MRI or ultrasound) was used as a measure of procedural complexity. Regression analysis was conducted per trainee factoring in duration of training, procedure number, supervising radiologist, uterine volume, and outcome variables of fluoroscopy time and contrast media volume. Results Median number of patients treated per trainee was 27 (range, 16-43) with mean fluoroscopic time 24.5 minutes (range, 4-90 min) and mean contrast volume 190 mL (range, 50-320 mL). Increasing uterine volume had no significant effect ( P > .05) on fluoroscopic time but significantly increased ( P 001) contrast media volume. Significant training effect was identified with decrease in fluoroscopic time ( P 001) and decrease in contrast volume ( P = . 02) over training. Over the course of a 1-year fellowship, these summed to a decrease of 12 minutes in UAE fluoroscopy time and 17 mL less contrast. Conclusion A significant ( P 05) training effect that is clinically relevant was demonstrated over the course of a yearlong interventional radiology fellowship program in performance of a standardized protocol for UAE. This data supports fellowship training as a basis for UAE credentialing and privileging.

RÉSUMÉCette étude a examiné comment la propriété des maisons de soins infirmiers porte sur les taux de transfert des services urgences (SU), comment les caractéristiques organisationnelles des installations sont réparties entre les groupes de propriété, et comment ces caractéristiques sont associées aux taux de transfert SU. L’échantillon comprenait une cohorte rétrospective de résidents des maisons de soins infirmiers dans la région de Vancouver Coastal Health (n = 13,140). Les taux de transferts SU ont été comparés entre les différents types de propriété des foyers de soins. Pour une analyse exploratoire, des données administratives ont ensuite été liées aux données provenant d’enquêtes auprès des caractéristiques organisationnelles des installations. Taux de transfert brut (SU transferts/100 ans résidents) étaient de 69, 70 et 51, respectivement, dans les installations à but lucratif, celles à but non-lucratif et les installations publiques. Avec des contrôles pour le sexe et l’age, la propriété publique a été associée aux taux de transfert SU inférieurs à ceux des installations à but lucratif et sans but lucratif. Les résultats ont aussi démontré un montant total plus élevé associé aux heures de soins directs infirmières par journée/résident, et la présence de personnel de Allied Health – qui sont présents de manière disproportionnée dans les installations de propriété publique – ont été associés aux taux de transfert inférieurs.

Summary Background People with Parkinson's disease can show premotor neurochemical changes in the dopaminergic and non-dopaminergic systems. Using PET, we assessed whether dopaminergic and serotonin transporter changes are similar in LRRK2 mutation carriers with Parkinson's disease and individuals with sporadic Parkinson's disease, and whether LRRK2 mutation carriers without motor symptoms show PET changes. Methods We did two cross-sectional PET studies at the Pacific Parkinson's Research Centre in Vancouver, BC, Canada. We included LRRK2 mutation carriers with or without manifest Parkinson's disease, people with sporadic Parkinson's disease, and age-matched healthy controls, all aged 18 years or older. People with Parkinson's disease were diagnosed by a neurologist with movement disorder training, in accordance with the UK Parkinson's Disease Society Brain Bank criteria. LRRK2 carrier status was confirmed by bidirectional Sanger sequencing. In the first study, LRRK2 mutation carriers with or without manifest Parkinson's disease who were referred for investigation between July, 1999, and January, 2012, were scanned with PET tracers for the membrane dopamine transporter, and dopamine synthesis and storage ( 18 F-6-fluoro-L-dopa; 18 F-FDOPA). We compared findings with those in people with sporadic Parkinson's disease and age-matched healthy controls. In the second study, distinct groups of LRRK2 mutation carriers, individuals with sporadic Parkinson's disease, and age-matched healthy controls seen from November, 2012, to May, 2016, were studied with tracers for the serotonin transporter and vesicular monoamine transporter 2 (VMAT2). Striatal dopamine transporter binding, VMAT2 binding, 18 F-FDOPA uptake, and serotonin transporter binding in multiple brain regions were compared by ANCOVA, adjusted for age. Findings Between January, 1997, and January, 2012, we obtained data for our first study from 40 LRRK2 mutation carriers, 63 individuals with sporadic Parkinson's disease, and 35 healthy controls. We identified significant group differences in striatal dopamine transporter binding (all age ranges in caudate and putamen, p 18 F-FDOPA uptake (in caudate: age ≤50 years, p=0·0002; all other age ranges, p LRRK2 mutation carriers with manifest Parkinson's disease (n=15) had reduced striatal dopamine transporter binding and 18 F-FDOPA uptake, comparable with amounts seen in individuals with sporadic Parkinson's disease of similar duration. LRRK2 mutation carriers without manifest Parkinson's disease (n=25) had greater 18 F-FDOPA uptake and dopamine transporter binding than did individuals with sporadic Parkinson's disease, with 18 F-FDOPA uptake comparable with controls and dopamine transporter binding lower than in controls. Between November, 2012, and May, 2016, we obtained data for our second study from 16 LRRK2 mutation carriers, 13 individuals with sporadic Parkinson's disease, and nine healthy controls. Nine LRRK2 mutation carriers without manifest Parkinson's disease had significantly elevated serotonin transporter binding in the hypothalamus (compared with controls, individuals with LRRK2 Parkinson's disease, and people with sporadic Parkinson's disease, p LRRK2 mutation carriers with manifest Parkinson's disease, p=0·01), after adjustment for age. Serotonin transporter binding in the cortex did not differ significantly between groups after age adjustment. Striatal VMAT2 binding was reduced in all individuals with manifest Parkinson's disease and reduced asymmetrically in one LRRK2 mutation carrier without manifest disease. Interpretation Dopaminergic and serotonergic changes progress in a similar fashion in LRRK2 mutation carriers with manifest Parkinson's disease and individuals with sporadic Parkinson's disease, but LRRK2 mutation carriers without manifest Parkinson's disease show increased serotonin transporter binding in the striatum, brainstem, and hypothalamus, possibly reflecting compensatory changes in serotonergic innervation preceding the motor onset of Parkinson's disease. Increased serotonergic innervation might contribute to clinical differences in LRRK2 Parkinson's disease, including the emergence of non-motor symptoms and, potentially, differences in the long-term response to levodopa. Funding Canada Research Chairs, Michael J Fox Foundation, National Institutes of Health, Pacific Alzheimer Research Foundation, Pacific Parkinson's Research Institute, National Research Council of Canada.

The BRCA2 gene is mutated in familial breast and ovarian cancer, and its product is implicated in DNA repair and transcriptional regulation. Here we identify a protein, EMSY, which binds BRCA2 within a region (exon 3) deleted in cancer. EMSY is capable of silencing the activation potential of BRCA2 exon 3, associates with chromatin regulators HP1β and BS69, and localizes to sites of repair following DNA damage. EMSY maps to chromosome 11q13.5, a region known to be involved in breast and ovarian cancer. We show that the EMSY gene is amplified almost exclusively in sporadic breast cancer (13%) and higher-grade ovarian cancer (17%). In addition, EMSY amplification is associated with worse survival, particularly in node-negative breast cancer, suggesting that it may be of prognostic value. The remarkable clinical overlap between sporadic EMSY amplification and familial BRCA2 deletion implicates a BRCA2 pathway in sporadic breast and ovarian cancer.

Asthma tends to be less well controlled among ethnic minority groups, and its prevalence in new immigrants increases significantly the longer they are in Canada; mainly due to their lack of familiarity with English and difficulty understanding information regarding the disease, health literacy, cultural issues, housing conditions, and lack of access to appropriate care services.To explore the effectiveness of different formats of culturally relevant information and its impact on asthma patients' self-management within the Punjabi, Mandarin, and Cantonese communities.Using a participatory approach, we developed and tested knowledge and community educational videos (with similar information, but used a different approach, i.e., scientific vs. colloquial) and a pictorial pamphlet. A total of 92 physician-diagnosed adult asthma patients (47 Chinese and 45 Punjabi) were assigned at random to three experimental groups (watched one or both videos) and one comparison group (read pictorial pamphlet) and participated in three in-person interviews and one telephone interview within a 9-month period. Patients received education on asthma self-management via videos and pamphlet and outcomes, including their knowledge of asthma triggers (environmental-related and behavioral-related triggers) and symptoms; inhaler use skills and patient-reported medication adherence were measured.Knowledge of asthma symptoms, inhaler use, and understanding of physician's instructions improved significantly from pretest to 3 months post-intervention follow-up among all participants.Participants performed significantly better at follow-up than they did at baseline assessment, with the most notable improvements observed in the group that watched both community and knowledge videos. The results suggest that short, simple, culturally, and linguistically appropriate interventions can promote knowledge gain about asthma and improve inhaler use that can be sustained over the short term. Such interventions that provide authentic learning materials that draw on patients' life experiences and sociocultural context can overcome certain limitations of conventional patient education approaches.

Objective: To investigate in vivo the impact of age on nigrostriatal dopamine dysfunction in Parkinson's disease (PD). Methods: PD patients (n = 78) and healthy control subjects (n = 35) underwent longitudinal positron emission tomography assessments using 3 presynaptic dopamine markers: (1) [11C](±)dihydrotetrabenazine (DTBZ), to estimate the density of the vesicular monoamine transporter type 2; (2) [11C]d-threo-methylphenidate, to estimate the density of the plasma membrane dopamine transporter; and (3) 6-[18F]-fluoro-L-dopa, to estimate the activity of the enzyme dopa-decarboxylase. Results: The study comprised 438 PD scans and 241 control scans (679 scans in total). At symptom onset, the loss of putamen DTBZ binding was substantially greater in younger compared to older PD patients (p = 0.015). Remarkably, however, the rate of progression of DTBZ binding loss was significantly slower in younger patients (p< 0.05). The estimated presymptomatic phase of the disease spanned more than 2 decades in younger patients, compared to 1 decade in older patients. Interpretation: Our results suggest that, compared to older patients, younger PD patients progress more slowly and are able to endure more damage to the dopaminergic system before the first motor symptoms appear. These observations suggest that younger PD patients have more efficient compensatory mechanisms. Ann Neurol 2011

Increase in dopamine (DA) turnover was found to occur early in symptomatic Parkinson's disease (PD) and to be functionally related to the dopamine transporter (DAT). The objectives of this study were to examine changes in DA turnover in the asymptomatic PD phase; to compare them with changes in other dopaminergic markers, and to investigate a possible relationship between DAT and DA turnover. Eight subjects from families at increased risk of PD due to LRRK2 mutation were investigated. Positron emission tomography imaging was performed with: ¹⁸F-fluorodopa to determine the effective DA distribution volume (EDV), the inverse of DA turnover, and the DA uptake rate K(occ), a marker of DA synthesis and storage; ¹¹C-methylphenidate (MP, a DAT marker) and ¹¹C-dihydrotetrabenazine (DTBZ, a VMAT2 marker) to estimate the binding potentials BP(ND_MP) and BP(ND_DTBZ). On average, EDV showed the largest reduction from age-matched control values (42%) followed by BP(ND_MP) (23%) and BP(ND_DTBZ) (17%), whereas K(occ) remained in the normal range for all subjects. No correlation was found between EDV and any other marker. DA turnover was found to be elevated in asymptomatic mutation carriers at increased risk of PD. Such change was determined to be larger than and statistically independent from changes observed with the other markers. These results support a compensatory role of increased DA turnover in presymptomatic disease and indicate that at this stage, in contrast to the symptomatic PD phase, increased turnover is not related to DAT.

Since the initial results of the DATATOP study, considerable effort has been devoted over the past 20 years to test neuroprotective therapies for Parkinson's disease (PD). Two trials (CALM-PD-CIT and REAL-PET studies) used neuroimaging dopamine changes as a surrogate marker for PD progression, and concluded that pramipexole and ropinirole could have a neuroprotective effect compared to levodopa. However, it should be recognized that all the presynaptic dopamine markers currently available for SPECT and PET studies are potentially subject to regulatory changes. Consequently, the results of these two trials can also be interpreted in terms of drug-related differences in dopamine regulation. More recently, the delayed-start design was applied to test whether rasagiline could have a neuroprotective effect in PD (ADAGIO study). Unfortunately, a major limitation of the delayed-start design is that, whenever the active treatment has a symptomatic effect, the blinding can be broken. This can lead to unequally-distributed placebo responses during phase 2, and is also a potential source of raters' biases. None of the trials on neuroprotective therapies for PD has yet provided solid evidence for neuroprotection.

Measuring the outcomes of nutrition interventions in health promotion settings can be a challenge. Nutrition screening tools are often used to measure dietary patterns and nutrition intervention outcomes, but these tools may lack quantitative scoring methods. Using the SmartDiet questionnaire from Oslo, Norway, as a model, the SmartDiet Canadian Version questionnaire was developed to assess fiber and fat intake. The purpose of this study was to assess the reliability and validity of this new questionnaire. In 2007, 54 volunteer subjects (63% men, mean age 68.3+/-9.7 years) were recruited from the Cardiac Rehabilitation Program at Vancouver General Hospital, Vancouver, BC, Canada. Test-retest reliability was assessed by having subjects complete the questionnaire at recruitment and 1 month later. Intraclass correlation coefficients of reliability (ICC) for both fiber and fat intake were calculated. For fiber scores the ICC was 0.66 (95% confidence interval 0.48, 0.79) and for fat scores the intraclass correlation coefficient was 0.74 (95% confidence interval 0.59, 0.84). Validity was assessed by correlating the completed questionnaire at recruitment with a 3-day food diary. The daily fat and fiber scores from the questionnaire were correlated with the corresponding average daily fat and fiber scores from the 3-day food diary by means of the Spearman correlation coefficient. For fiber scores, Spearman rho was 0.53 (P0.001), and for fat scores it was 0.48 (P0.001). The SmartDiet Canadian Version questionnaire is a reliable and valid tool for assessing the daily fiber and fat intake of cardiac rehabilitation clients.

To determine the effect of optically induced blur on the visual field measured with high pass spatially filtered targets, 10 normal subjects had field examinations with 0 diopter + 1.00 diopter or + 2.00 diopter of overcorrection in the cyclopleged state. All subjects showed a significant loss of sensitivity when defocussed, but not with pupil dilation. Mean thresholds for the central field rose from 4.79 +/- 0.68 dB (Mean +/- SD) with the image focussed and pupil dilated, to 7.16 +/- 0.72 dB with two diopters of image blur (P less than 0.001). The effects of defocussing did not differ significantly between the central and peripheral parts of the field. The great influence of defocussing the image on sensitivity should be considered during clinical perimetry as the 2.37 dB decline shown would place the group's mean sensitivity below the fifth percentile for age corrected normals.

Background: The prevalence of childhood obesity is increasing at an alarming rate. Many local governments have enacted policies to increase physical activity in schools as a way to combat childhood obesity. We conducted a systematic review and meta-analysis to determine the effect of school-based physical activity interventions on body mass index (BMI) in children. Methods: We searched MEDLINE, EMBASE, CINAHL and the Cochrane Central Register of Controlled Trials up to September 2008. We also hand-searched relevant journals and article reference lists. We included randomized controlled trials and controlled clinical trials that had objective data for BMI from before and after the intervention, that involved school-based physical activity interventions and that lasted for a minimum of 6 months. Results: Of 398 potentially relevant articles that we identified, 18 studies involving 18 141 children met the inclusion criteria. The participants were primarily elementary school children. The study duration ranged from 6 months to 3 years. In 15 of these 18 studies, there was some type of co-intervention. Meta-analysis showed that BMI did not improve with physical activity interventions (weighted mean difference –0.05 kg/m 2 , 95% confidence interval –0.19 to 0.10). We found no consistent changes in other measures of body composition. Interpretation: School-based physical activity interventions did not improve BMI, although they had other beneficial health effects. Current population-based policies that mandate increased physical activity in schools are unlikely to have a significant effect on the increasing prevalence of childhood obesity.

Objective: Dyskinesias are common in Parkinson disease (PD). Prior investigations suggest that dopamine (DA) terminals compensate for abnormal DA transmission. We verified whether similar adaptations could be related to the development of treatment-related complications. Methods: Thirty-six patients with PD with motor fluctuations were assessed with PET using [ 11 C]- d-threo -methylphenidate (MP) and [ 11 C]-(±) dihydrotetrabenazine (DTBZ). The expression of DA transporter relative to DA nerve terminal density was estimated by determining the MP/DTBZ ratio. Age, treatment, and disease severity were also taken into account in the evaluation of our data. Results: Twenty-seven of the 36 patients had dyskinesias. Nine individuals had motor fluctuations without dyskinesia. The two patient groups were comparable in terms of age, disease duration and severity, medication, and striatal MP and DTBZ binding potentials. The MP/DTBZ ratio in the caudate was not different between groups (nondyskinesia 1.54 ± 0.36, dyskinesia 1.39 ± 0.28; mean ± SD, p = 0.23). Putaminal MP/DTBZ was decreased in individuals with dyskinesia (1.18 ± 0.24), compared to those who had motor fluctuations without dyskinesia (1.52 ± 0.24, p = 0.019). The relationship between putaminal MP/DTBZ ratio and the presence of dyskinesias was not altered after correcting for age, treatment, and measures of disease severity. Conclusions: This investigation supports the role of presynaptic alterations in the appearance of dyskinesias. Dopamine (DA) transporter downregulation may minimize symptoms by contributing to increased synaptic DA levels in early Parkinson disease, but at the expense of leading to increased extracellular DA catabolism and oscillating levels of DA. Such oscillations might ultimately facilitate the appearance of dyskinesias. BP = binding potential; COMTi = catechol-O-methyl transferase inhibitors; CR = controlled release; DA = dopamine; DAT = DA transporter; DTBZ = [ 11 C]-(±) dihydrotetrabenazine; DVR = distribution volume; MF = motor fluctuation; MP = [ 11 C]- d-threo -methylphenidate; PD = Parkinson disease; ROI = region of interest; UPDRS = Unified Parkinson’s Disease Rating Scale.

The objective of this pilot project was to determine whether engaging critical care unit staff in designing and implementing enhancements to the practice environment would positively impact the clinical environment and staff outcomes. The project used a one-group pre-post test design and a participatory action process. Significant changes in the practice environment were observed in the priority areas identified by the unit staff. Results indicated that team collaboration and respectful work relationships improved following interventions.

Objective To determine the sensitivity of positron emission tomography with11C-labeled dihydrotetrabenazine (DTBZ) to the nigrostriatal changes associated with early, untreated Parkinson's disease (PD), and to determine the correlation between any regionally reduced DTBZ binding and the major motor features of PD. Methods Untreated patients with early PD (n = 27) and age-matched control subjects (n = 33) underwent DTBZ/positron emission tomography scanning to measure binding to the presynaptic type 2 vesicular monoamine transporter site in dopaminergic neurons in basal ganglia regions. Clinical symptoms were rated with the Unified Parkinson's Disease Rating Scale. Results Mean striatal DTBZ binding values in the patient group were decreased as compared with control subjects (p < 0.001) in all regions examined. The difference between patients and control subjects was most marked in the midputamen, where only one patient had DTBZ binding within 3 standard deviations of the control mean. Bradykinesia and rigidity scores correlated with DTBZ binding in the contralateral midputamen region, particularly for the clinically least affected limbs. Tremor scores showed no significant correlation. Interpretation Reduced striatal binding of DTBZ is associated with early PD. Tremor appears to be only partially related to presynaptic dopaminergic function and may have a mechanism differing from that of symptoms such as bradykinesia. The method appears to be most sensitive in mildly affected individuals with a possible “floor” effect that may limit the degree of additional change occurring once more severe clinical symptoms are evident. Ann Neurol 2008

BACKGROUND: Obstructive sleep apnea-hypopnea (OSAH) is a common disorder characterized by recurrent collapse of the upper airway during sleep. Patients experience a reduced quality of life and an increased risk of motor vehicle crashes (MVCs). Continuous positive airway pressure (CPAP), which is the first-line therapy for OSAH, improves sleepiness, vigilance and quality of life.OBJECTIVE: To assess the cost-effectiveness of CPAP therapy versus no treatment for OSAH patients who are drivers.METHODS: A Markov decision analytical model with a five-year time horizon was used. The study population consisted of male and female patients, between 30 and 59 years of age, who were newly diagnosed with moderate to severe OSAH. The model evaluated the cost-effectiveness of CPAP therapy in reducing rates of MVCs and improving quality of life. Utility values were obtained from previously published studies. Rates of MVCs under the CPAP and no CPAP scenarios were calculated from Insurance Corporation of British Columbia data and a systematic review of published studies. MVCs, equipment and physician costs were obtained from the British Columbia Medical Association, published cost-of-illness studies and the price lists of established vendors of CPAP equipment in British Columbia. Findings were examined from the perspectives of a third-party payer and society.RESULTS: From the third-party payer perspective, CPAP therapy was more effective but more costly than no CPAP (incremental cost-effectiveness ratio [ICER] of $3,626 per quality-adjusted life year). From the societal perspective, the ICER was similar ($2,979 per quality-adjusted life year). The ICER was most dependent on preference elicitation method used to obtain utility values, varying almost sixfold under alternative assumptions from the base-case analysis.CONCLUSION: After considering costs and impact on quality of life, as well as the risk of MVCs in individuals with OSAH, CPAP therapy for OSAH patients is a highly efficient use of health care resources. Provincial governments who do not provide funding for CPAP therapy should reconsider.

Objectives To assess reproducibility of core laboratory performance and impact on sample size calculations. Background Little information exists about overall reproducibility of core laboratories in contradistinction to performance of individual technicians. Also, qualitative parameters are being adjudicated increasingly as either primary or secondary end-points. The comparative impact of using diverse indexes on sample sizes has not been previously reported. Methods We compared initial and repeat assessments of five quantitative parameters [e.g., minimum lumen diameter (MLD), ejection fraction (EF), etc.] and six qualitative parameters [e.g., TIMI myocardial perfusion grade (TMPG) or thrombus grade (TTG), etc.], as performed by differing technicians and separated by a year or more. Sample sizes were calculated from these results. TMPG and TTG were also adjudicated by a second core laboratory. Results MLD and EF were the most reproducible, yielding the smallest sample size calculations, whereas percent diameter stenosis and centerline wall motion require substantially larger trials. Of the qualitative parameters, all except TIMI flow grade gave reproducibility characteristics yielding sample sizes of many 100’s of patients. Reproducibility of TMPG and TTG was only moderately good both within and between core laboratories, underscoring an intrinsic difficulty in assessing these. Conclusions Core laboratories can be shown to provide reproducibility performance that is comparable to performance commonly ascribed to individual technicians. The differences in reproducibility yield huge differences in sample size when comparing quantitative and qualitative parameters. TMPG and TTG are intrinsically difficult to assess and conclusions based on these parameters should arise only from very large trials.

Background: Abnormal varus-valgus alignment is a risk factor for patellofemoral osteoarthritis, but tibiofemoral alignment alone does not explain compartmental patellofemoral osteoarthritis progression. Other mechanical factors, such as patellar kinematics, probably play a role in the initiation and progression of the disease. The objective of this study was to determine which three-dimensional patellar kinematic parameters (patellar flexion, spin, and tilt and patellar proximal, lateral, and anterior translation) are associated with varus and valgus alignment in subjects with osteoarthritis. Methods: Ten individuals with knee osteoarthritis and varus (five subjects) or valgus (five subjects) knee alignment underwent assessment of three-dimensional patellar kinematics. We used a validated magnetic resonance imaging-based method to measure three-dimensional patellar kinematics in knee flexion while the subjects pushed against a pedal with constant load (80 N). A linear random-effects model was used to test the null hypothesis that there was no difference in the relationship between tibiofemoral flexion and patellar kinematics between the varus and valgus groups. Results: Patellar spin was significantly different between groups (p = 0.0096), with the varus group having 2° of constant internal spin and the valgus group having 4.5° of constant external spin. In the varus group, the patellae tracked with a constant medial tilt of 9.6° with flexion, which was significantly different (p = 0.0056) from the increasing medial tilt (at a rate of 1.8° per 10° of increasing knee flexion) in the valgus group. The patellae of the valgus group were 7.5° more extended (p = 0.0093) and positioned 8.8 mm more proximally (p = 0.0155) than the varus group through the range of flexion that was studied. The pattern of anterior translation differed between the groups (p = 0.0011). Conclusions: Our results suggest that authors of future large-scale studies of the relationships between knee mechanics and patellofemoral osteoarthritis should not rely solely on measurements of tibiofemoral alignment and should assess three-dimensional patellar kinematics directly. Clinical Relevance: Direct measurements of patellar kinematics should be used to investigate links between patellofemoral joint mechanics and the development of patellofemoral osteoarthritis.

Patients with untreated obstructive sleep apnea hypopnea (OSAH) are predisposed to developing hypertension, and therapy with continuous positive airway pressure (CPAP) may reduce blood pressure (BP). The purpose of this study was to assess the impact of CPAP therapy on BP in patients with OSAH. We performed a comprehensive literature search up to July 2006 [Medline, PubMed, EMBASE, Cochrane Database of Systematic Reviews (CDSR), Cochrane controlled trials register (CCTR), and Database of Abstract and Reviews of Effect (DARE)] to identify clinical studies and systemic reviews that examined the impact of CPAP on BP. Studies were included if they (1) were randomized controlled trials with an appropriate control group, (2) included systolic and diastolic BP measurements before and after CPAP/control in patients with OSAH, and (3) contained adequate data to perform a meta-analysis. To calculate pooled results, studies were weighted by inverse variances, with either a fixed or a random effects model used depending on the presence of heterogeneity (assessed with Q test). Ten studies met our inclusion criteria (587 patients): three studies were crossover (149 patients) and seven were parallel in design. Seven studies (421 patients) used 24-h ambulatory BP and three used one-time measurements. Two studies were of patients with heart failure (41 patients). Overall, the effects of CPAP were modest and not statistically significant; CPAP (compared to control) reduced systolic BP (SBP) by 1.38 mmHg (95% CI: 3.6 to -0.88, p = 0.23) and diastolic BP (DBP) by 1.52 mmHg (CI: 3.1 to -0.07; p = 0.06). Six of the trials studied more severe OSAH (mean AHI > 30/h, 313 patients); in these six trials, CPAP reduced SBP by 3.03 mmHg (CI 6.7 to -0.61; p = 0.10) and DBP by 2.03 mmHg (CI: 4.1 to -0.002; p = 0.05). There was a trend for SBP reduction to be associated with CPAP compliance. In unselected patients with sleep apnea, CPAP has very modest effects on BP. However, we cannot exclude the possibility that certain subgroups of patients may have more robust responses-this may include patients with more severe OSAH or difficult-to-control hypertension. Future randomized controlled trials in this area should potentially concentrate on these subgroups of patients.

To develop a method for quantitating coronary angiographic abnormalities of segmental size and shape (tapering) in comparison to gender- and segment-specific, population derived, normal values.In the absence of obvious focal stenoses, remodeling renders the angiogram insensitive to the presence of atherosclerosis and invalidates use of a "normal reference segment" for calculation of percent diameter stenosis.Equations were created for detection of size/shape abnormalities of coronary angiographic segments. After validation using intravascular ultrasound (IVUS), the equations were applied to a cohort of segments judged to be completely normal by a panel of highly experienced, core laboratory technicians; and a cohort of patients judged by an experienced interventionalist to have completely normal coronaries.In patients assessed by core technicians, 53% (162/303) of males, 39% (209/538) of normal segments in males, 60% (56/94) of females, and 40% (81/205) of normal segments in females had quantifiable abnormalities. In patients with normal coronaries as judged by an experienced interventionalist, 100% of males (n = 14) and females (n = 19), 37% (67/182) of segments in males and 43% (105/247) of segments in females had abnormalities. The left main segment was most commonly abnormal.We propose a set of equations validated using IVUS and based on gender- and segment-specific normal values for coronary angiographic size and shape that markedly improves the sensitivity of the coronary angiogram for detection of abnormalities. The method should replace the unfounded practice of labeling coronary angiograms as "normal" based solely on the failure to detect focal stenoses.

Introduction. Following the investigation of the mother's preceding pregnancies on fetal development and postnatal survival of the neonate, we turned our attention to an earlier period, that is the interval separating the onset of the current pregnancy from the end of the preceding one. The objectives of this study is to investigate the variations of interpregnancy interval length associated to the mother's preceding pregnancies. Methods. A population of 7773 neonates, alive at the time of hospital discharge, were divided into cohorts according to the current neonate's sex and number and sex of the mother's preceding pregnancies. Interpregnancy interval average of each cohort of same neonate's sex and mother's parity, but different configuration of preceding pregnancies, were measured and compared. Results. A positive association was found between mother's preceding pregnancies and length of interpregnancy interval when current pregnancy and preceding pregnancy were of the same sex, and a negative association when they were of opposite sex. Discussion. Interpregnancy interval length follows a pattern regarding the gravida's preceding pregnancy similar to the other early life indicators pattern, birth weight, placenta weight, gestation length and neonatal survival. Our results confirm and complete an immunological explanation of the indicators variations associated to the gravida's preceding pregnancy.

Introduction. A number of epidemiological studies on various diseases have drawn attention to relationships between fetal life events, as measured by health indicators and pathological events later in life. This accounts for the renewed interest in fetal health indicators. The objective of this retrospective study is to investigate the relationship between the sex of conceptuses of the mother’s preceding pregnancies and the gestation length of the current pregnancy. Methods. A population of 7773 neonates were divided into cohorts, according to the sex of the current neonate and number and sex of the mother’s preceding pregnancies. Average gestation lengths for each cohort were measured and compared between different configurations of preceding pregnancies. Results. There a positive association between the length of gestation of the neonate and its mother’s preceding pregnancies of same sex as its own. Gestation length increases with the number of conceptuses of same sex among the preceding pregnancies. Likewise, there is a negative association between the length of gestation of the neonate and its mother’s preceding pregnancies of opposite sex to its own. Gestation length decreases with the number of conceptuses of opposite sex among the preceding pregnancies. Discussion. The results of our study are compatible with the immunological hypothesis, based on the sex-linked concepto-gravidic antigenic dissimilarity, proposed to explain the association between preceding pregnancy and fetal development. The influence of the preceding pregnancy is significant enough to be taken into account for effective management of current pregnancies as well as for efficient clinical trial analysis.

Background: Neuroinflammation contributes to the pathogenesis of Alzheimer’s disease (AD). Increased pro-inflammatory cytokine levels have been reported in the brain and cerebro-spinal fluid of individuals affected by this neurodegenerative disorder. These same cytokines, including interleukin -1, interleukin-6 and tumor necrosis factor-α, are also believed to be involved in thermoregulation. Furthermore, their effects are thought to be mediated through the induction of cyclooxygenases resulting in increased production of inflammatory prostaglandins. Such increases have been observed in AD brains. We hypothesized that these increased levels of inflammatory mediators could lead to an increase in core body temperature in AD patients. Objective: To determine whether clinical signs of AD are accompanied by an increase in core body temperature. Methods: Analysis of the scientific literature identified six studies that used continuous rectal measurements of core body temperature in AD and control patients. Meta-analysis was performed on these published data. Results: Meta-analysis showed that the mean core body temperature in AD patients was significantly increased by 0.10°C when compared to healthy elderly subjects. The two-sided p value was 0.0355, and the 95% confidence interval was 0.0068–0.1950. The severity of AD pathology did not appear to contribute significantly (p = 0.235) to the heterogeneity in the core body temperature among different groups of AD patients. Conclusion: The significant increase in core body temperature in AD patients could be a direct consequence of local inflammatory reactions in the brain. Although the changes observed are probably too small to be of any diagnostic value, these observations lend further support to the neuroinflammatory hypothesis of AD pathology.

Aim. This paper reports a review of the literature on the association between critical care nurse staffing levels and patient mortality. Background. Statistically significant inverse associations between levels of nurse staffing and hospital mortality have not been consistently found in the literature. Critical care settings are ideal to address this relationship due to high patient acuity and mortality, high intensity of the nursing care required, and availability of individual risk adjustment methods. Methods. Major electronic databases were searched, including MEDLINE, EMBASE, and the Cumulative Index of Nursing and Allied Health Literature. The search terms included critical/intensive care, quality of health care, mortality/hospital mortality, personnel staffing and scheduling, and nursing staff (hospital). Only papers published in English were included. The original search was conducted in 2002 and updated in 2005. Results. Nine studies were selected from 251 references screened. All nine were observational. Six were conducted in the United States of America, one in Austria, one in Brazil, and one in Scotland. The unadjusted risk ratio of nurse staffing (high vs. low) on hospital mortality were combined meta-analytically (five studies). The pooled estimate was 0·65 (95% confidence interval 0·47–0·91). However, after adjusting for various covariates within each study, the individually reported associations between high nurse staffing and low hospital mortality became non-significant in all but one study. Conclusion. The impact of nurse staffing levels on patients’ hospital mortality in critical care settings was not evident in the reviewed studies. Methodological challenges that might have impeded correct assessment of the association include measurement problems in exposure status and confounding factors, often uncontrolled. The lack of association also indicates that hospital mortality may not be sensitive enough to detect the consequences of low nurse staffing levels in critical care settings.

Treatment-related motor complications in Parkinson's disease have been previously linked to disease-induced pre-synaptic alterations: dopaminergic denervation and changes in dopamine (DA) release patterns. The occurrence of such complications is also known to be partly dependent on the age of disease onset, occurring more frequently in patients with disease onset at a younger age. Using positron emission tomography (PET) and 4-h-long 18F-fluorodopa (FD) scans we have investigated in vivo an age dependence of disease-induced changes in DA turnover as a possible contributing factor to the age-related differences in treatment-related motor complications. We evaluated the relative changes in DA turnover (measured by its direct inverse, effective DA distribution volume--EDV) and DA synthesis and vesicular storage capacity (quantified by the plasma input uptake rate constant Ki) in Parkinson's disease patients as a function of age (n = 27, age range 38-79 years). After correcting for disease severity, a significant negative correlation was found between age and magnitude of disease-induced decrease in EDV and in Ki in the putamen (P < 0.001, P = 0.02, respectively). However, the difference between the disease-induced decrease in EDV and that in Ki also exhibited an age dependence (P < 0.001), indicating a relatively higher disease-induced increase in DA turnover (inverse of EDV) compared with the decrease in DA synthesis and storage rate in patients of younger age compared with older patients. This finding implies that DA turnover in younger-onset patients undergoes a relatively greater alteration and thus likely contributes to a greater imbalance between DA synthesis, storage and release, which could lead to larger swings in synaptic DA levels. It has indeed been suggested on theoretical grounds that such imbalance may contribute to the greater propensity for motor fluctuations. These results provide one possible explanation for the age-dependent occurrence of complications and support the existence of a pre-synaptic contribution to the occurrence of motor complications.

BACKGROUND: Computed tomography (CT) scans are used extensively to investigate chest disease because of their cross-sectional perspective and superior contrast resolution compared with chest radiographs. These advantages lead to a more accurate imaging assessment of thoracic disease. The actual use and evaluation of the clinical impact of thoracic CT has not been assessed since scanners became widely available.OBJECTIVE: To identify patterns of utilization, waiting times and the impact of CT scan results on clinical diagnoses.DESIGN: A before and after survey of physicians who had ordered thoracic CT scans.SETTING: Vancouver General Hospital – a tertiary care teaching centre in Vancouver, British Columbia.SUBJECTS: Physicians who had ordered CT scans.INTERVENTION: Physicians completed a standard questionnaire before and after the CT scan result was available.MEASUREMENTS: Changes in the clinical diagnosis, estimates of the probabilities for the diagnosis both before and after the CT scan, and waiting times.RESULTS: Four hundred fifty-four thoracic CT cases had completed questionnaires, of whom 80% were outpatients. A change in diagnosis was made in 48% of cases (25% with a normal CT scan and 23% with CT scan findings that indicated a different diagnosis). The largest change in probability scores for the clinical diagnosis before and after the CT scan was 43.9% for normal scans, while it was 36.3% for a different diagnosis and 26.3% for the same diagnosis. High-priority scans were associated with decreased waiting time (−7.89 days for each unit increase in priority).CONCLUSIONS: The CT scan results were associated with a change in diagnosis in 48% of cases. Normal scans constituted 25% of the total and had the greatest impact scores. Waiting times were highly correlated with increased urgency of the presenting problem.

Context Despite the investigation of multiple therapeutic options, idiopathic pulmonary fibrosis (IPF) remains a devastating, progressively fatal disease. Much interest has focused on the use of interferon (IFN)-γ1b therapy, but the efficacy of this treatment has not been proven. Objective To determine whether IFN treatment reduces mortality in patients with IPF. Design A metaanalysis of randomized controlled trials evaluating the use of IFN-γ1b as treatment for IPF. Main outcome measure Mortality in patients treated with IFN-γ1b was compared to mortality in patients treated with control therapies. Results A total of three studies involving 390 patients was included in the analysis. IFN-γ1b therapy was associated with reduced mortality (hazard ratio [HR], 0.418; 95% confidence interval [CI], 0.253 to 0.690; p = 0.0003). A comparison of mortality at different time points revealed that IFN-γ1b therapy was associated with significantly reduced mortality at 1 year (0.0861; 95% CI, 0.0244 to 0.1478; p = 0.0063), 18 months (0.1682; 95% CI, 0.1065 to 0.2299; p Conclusion When the results of multiple studies are combined in a metaanalysis, IFN-γ1b therapy is associated with reduced mortality.

The most widely used system for grading of endometrial carcinoma is the International Federation of Gynecology and Obstetrics (FIGO) grading system. This grading system requires evaluation of histologic features that are difficult to assess reproducibly. Two hundred and two cases of endometrial carcinoma, treated by hysterectomy, were retrieved from the archives of Vancouver General Hospital (1983-1998). For each tumor, the architectural pattern, nuclear grade, and mitotic index were assessed. The tumor architectural pattern, nuclear grade, and mitotic index were significant predictors of patient outcome (P0.0001 for each, by univariate analysis). There were no prognostic differences between patients having predominantly solid versus papillary tumors, or tumors with mild versus moderate nuclear atypia. The tumors were then classified into high and low grade based on assessment of these three features. The presence of at least two criteria of these three: 1) predominantly papillary or solid growth pattern, 2) mitotic indexor =6/10 high power fields, or 3) severe nuclear atypia, resulted in a tumor being considered high grade. Low-grade tumors satisfied at most one of those criteria. The proposed grading system was found to be an independent predictor of patient outcome when patient survival was adjusted for FIGO stage, patient age, and tumor cell type. It also had more prognostic power than other grading systems tested when it was applied to all tumors, regardless of their cell type; however, the FIGO grading system was superior for prognostication when only carcinomas of endometrioid type were considered. With the FIGO grading system, no significant difference in survival was observed between patients with grade 1 and grade 2 tumors. Combining FIGO grades 1 and 2 results in a binary system (grades 1 and 2 vs. grade 3) that was the most prognostically significant grading system tested, with the additional advantages of being highly reproducible and familiar to practicing pathologists.

Recent evidence indicates that the placebo effect in Parkinson's disease is mediated by the release of dopamine in the dorsal striatum. Interestingly, there is also placebo-induced dopamine release in the ventral striatum, which establishes a connection between the placebo effect and reward mechanisms. Specifically, we propose that placebo responses are related to the activation of the reward circuitry. Here, the clinical benefit induced by placebos represents the reward. The magnitude of the placebo effect likely depends on the a priori probability of clinical benefit. This notion has profound implications in the design of clinical trials and placebo investigations.

To compare the effectiveness of auto-titrating continuous positive airway pressure (APAP) versus conventional continuous positive airway pressure (CPAP) in reducing the apnea-hypopnea index (AHI), reducing the mean airway pressure, improving subjective sleepiness, and improving treatment adherence in patients with obstructive sleep apnea (OSA).Meta-analysis and metaregression of published randomized trials comparing APAP to CPAP.N/A.N/A.N/A.We identified 9 randomized trials studying a total of 282 patients. Compared to CPAP, there was no significant advantage of APAP in reducing AHI or sleepiness (pooled APAP-CPAP posttreatment AHI and Epworth Sleepiness Scale score = -0.20 events per hour, 95% confidence interval:[-0.74,0.35], and -0.56 [-1.4,0.3] respectively). The use of APAP reduced the mean applied pressure across the night by 2.2 cm water [1.9,2.5] compared to CPAP. Adherence with therapy was not substantially improved with APAP; pooled estimate of improvement was 0.20 hours per night ([-0.16,0.57], P = .28) using a random-effects model.Compared to standard CPAP, APAP is associated with a reduction in mean pressure. However, APAP and standard CPAP were similar in adherence and their ability to eliminate respiratory events and to improve subjective sleepiness. Given that APAP is more costly than standard CPAP, APAP should not be considered first-line chronic therapy in all patients with OSA. However, APAP may be useful in other situations (eg, home titrations, detection of mouth leak) or in certain subgroups of patients with OSA. Identifying circumstances in which APAP is a definite improvement over CPAP in terms of costs or effects should be the focus of future studies.

ObjectivesThe goal of this study was to determine the relative prognostic importance of noninvasive measures of endothelial function and atheroma burden in patients with coronary artery disease (CAD).BackgroundDirect measurement of atherosclerosis by carotid ultrasound and endothelial function assessment by brachial artery flow-mediated dilation (FMD) have both been shown to predict vascular events. The combined prognostic utility of carotid ultrasound and FMD relative to traditional risk markers and cardiovascular fitness has not been evaluated.MethodsA total of 152 patients with CAD underwent metabolic testing, exercise stress tests, carotid ultrasound, and endothelial function measurements.ResultsPatients were followed for 34 ± 10 months during which 22 vascular events occurred. Peak FMD (p = 0.012) and FMD/nitroglycerin-mediated dilation (NMD) ratio (p = 0.008) were lower in subjects with events. Univariate analysis with Cox proportional hazards modeling identified plaque area (p = 0.0047), total area (p = 0.0085), peak FMD (p = 0.01), FMD/NMD ratio (p = 0.008), stress test workload (p = 0.027), long-acting nitroglycerin (NTG) (p = 0.0071), and calcium blockers (p = 0.0057) as predictors of adverse events. Multivariate analysis showed that FMD/NMD ratio (p < 0.0001), carotid plaque area (p = 0.06), and NTG (p = 0.005) were independent predictors. Based on median values, subjects were divided into high and low “plaque burden” groups and into high and low FMD/NMD subgroups. Patients with high FMD/NMD had low event rates irrespective of the degree of carotid atheroma. Patients with low FMD/NMD and high “plaque burden” had the highest event rate (p < 0.05).ConclusionsThe structural and functional status of the vasculature are independent predictors of coronary events as shown by noninvasive measurement of endothelial function and carotid atheroma burden in patients with CAD. Preserved endothelial function attenuates the risk of future events associated with a high plaque burden.

We have previously designed and validated a 10-item bilingual questionnaire, the Parkinson's Impact Scale (PIMS), as a disease-specific instrument to measure the impact of Parkinson's disease (PD) on the quality of life of patients with PD. In this paper we extend the psychometric assessment of PIMS to a new set of patients, in the context of a cross-over trial by Hoffman-La Roche Ltd, comparing two doses of tolcapone in 116 PD patients who had developed wearing off effect on levodopa. Using data from this trial, we evaluate PIMS' test-retest reliability, construct validity, sensitivity and responsiveness to change. Validation is carried out by correlating the PIMS scores with corresponding UPDRS subscales and with the Schwab and England scale. We show that PIMS has excellent psychometric properties, and can therefore be used not only in clinical trials but also to identify quickly potential problems in major subjective areas of PD patients' lives, in order to refer them effectively to appropriate providers of assistance.

We examined the clinical features of familial (n = 26) and sporadic (n = 52) Parkinson's disease (PD) in patients presenting over the age of 40 years. Familial PD cases were tested for alpha-synuclein or parkin mutations as appropriate. No mutations were found in any of the families investigated. We found no between-group differences in the age at onset of PD, the pattern or severity of parkinsonian features, the dose of antiparkinsonian medications or treatment related complications. Cases of familial and sporadic PD in our cohort of patients display similar clinical features. This may suggest similar etiologies for both familial and sporadic PD.

Objective : To estimate the prevalence of Parkinson's disease (PD) in British Columbia utilizing the prescription database of the College of Pharmacists. Methods : Patients receiving anti-parkinsonian drug (anti-PD) prescriptions between 1996 and 1998 were stratified by year, age, gender, drug use category, and geographic location. The numbers of patients on levodopa alone, or levodopa and/or other anti-PD drugs were adjusted using published data which gave estimates of the proportion of undiagnosed patients with PD, the proportion of those treated for parkinsonism with definite PD, the proportion of patients with PD not being treated with anti-PD medications, and the proportion of patients treated with anti-PD medications who have PD. Use of the anti-PD drug bromocriptine for other purposes in women under 50 years of age was also considered. Results : The estimated prevalences of PD based on all anti-PD medications used were 109, 121, and 125 per 100,000 population in 1996, 1997, and 1998, respectively. Estimated prevalences of PD based on levodopa use were 126, 134, and 144, respectively. The prevalence in both prescription groups increased with age. The male to female ratio of prevalence ranged from 1.16 to 1.21. Conclusions : Using a large, accurate database, it is possible to estimate the prevalence of PD in a large population, though the assumptions built into the estimate remain to be validated in the subject population.

Recent evidence suggests that the placebo effect is mediated by the dopaminergic reward mechanisms in the human brain and that it is related to the expectation of clinical benefit. On the basis of this theory, we propose some criteria for the proper investigation of the placebo effect, and review the evidence for a placebo effect in Parkinson's disease, depression, pain, and other neurological disorders. We also discuss the evidence for the use of placebos in long-term substitution programmes for the treatment of drug addiction.

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