The Microbleed Anatomical Rating Scale has good intrarater and interrater reliability for the presence of definite microbleeds in all brain locations when applied to different MRI sequences and levels of observer experience.

The relative importance of Lewy- and Alzheimer-type pathologies to dementia in Parkinson's disease remains unclear. We have examined the combined associations of α-synuclein, tau and amyloid-β accumulation in 56 pathologically confirmed Parkinson's disease cases, 29 of whom had developed dementia. Cortical and subcortical amyloid-β scores were obtained, while tau and α-synuclein pathologies were rated according to the respective Braak stages. Additionally, cortical Lewy body and Lewy neurite scores were determined and Lewy body densities were generated using morphometry. Non-parametric statistics, together with regression models, receiver-operating characteristic curves and survival analyses were applied. Cortical and striatal amyloid-β scores, Braak tau stages, cortical Lewy body, Lewy neurite scores and Lewy body densities, but not Braak α-synuclein stages, were all significantly greater in the Parkinson's disease-dementia group (P<0.05), with all the pathologies showing a significant positive correlation to each other (P<0.05). A combination of pathologies [area under the receiver-operating characteristic curve=0.95 (0.88-1.00); P<0.0001] was a better predictor of dementia than the severity of any single pathology. Additionally, cortical amyloid-β scores (r=-0.62; P=0.043) and Braak tau stages (r=-0.52; P=0.028), but not Lewy body scores (r=-0.25; P=0.41) or Braak α-synuclein stages (r=-0.44; P=0.13), significantly correlated with mini-mental state examination scores in the subset of cases with this information available within the last year of life (n=15). High cortical amyloid-β score (P=0.017) along with an older age at onset (P=0.001) were associated with a shorter time-to-dementia period. A combination of Lewy- and Alzheimer-type pathologies is a robust pathological correlate of dementia in Parkinson's disease, with quantitative and semi-quantitative assessment of Lewy pathology being more informative than Braak α-synuclein stages. Cortical amyloid-β and age at disease onset seem to determine the rate to dementia.

In this article, we describe a general framework for the analysis of correlated event histories, with an application to a study of partnership transitions and fertility among a cohort of British women. Using a multilevel, multistate competing-risks model, we examine the relationship between prior fertility outcomes (the presence and characteristics of children and current pregnancy) and the dissolution of marital and cohabiting unions and movements from cohabitation to marriage. Using a simultaneous-equations model, we model these partnership transitions jointly with fertility, allowing for correlation between the unobserved woman-level characteristics that affect each process. The analysis is based on the partnership and birth histories that were collected for the 1958 birth cohort (National Child Development Study) aged 16-42. The findings indicate that preschool children have a stabilizing effect on their parents 'partnership, whether married or cohabiting, but the effect is weaker for older children. There is also evidence that although pregnancy precipitates marriage among cohabitors, the odds of marriage decline to prepregnancy levels following a birth.

Gang members show inordinately high levels of psychiatric morbidity, placing a heavy burden on mental health services. Traumatization and fear of further violence, exceptionally prevalent in gang members, are associated with service use. Gang membership should be routinely assessed in individuals presenting to health care services in areas with high levels of violence and gang activity. Health care professionals may have an important role in promoting desistence from gang activity.

Conventional magnetic resonance imaging (cMRI) is often used to aid the diagnosis of progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), but its ability to predict the histopathological diagnosis has not been systematically studied. cMRI from 48 neuropathologically confirmed cases, including PSP (n = 22), MSA (n = 13), Parkinson's disease (PD) (n = 7), and corticobasal degeneration (n = 6), and controls (n = 9) were assessed blinded to clinical details and systematically rated for reported abnormalities. Clinical diagnosis and macroscopic postmortem findings were retrospectively assessed. Radiological assessment of MRI was correct in 16 of 22 (72.7%) PSP cases and 10 of 13 (76.9%) MSA cases with substantial interrater agreement (Cohen's kappa 0.708; P < .001); no PSP case was misclassified as MSA or vice versa. MRI was less sensitive but more specific than clinical diagnosis in PSP and both more sensitive and specific than clinical diagnosis in MSA. The "hummingbird" and "morning glory" signs were highly specific for PSP, and "the middle cerebellar peduncle sign" and "hot cross bun" for MSA, but sensitivity was lower (up to 68.4%) and characteristic findings may not be present even at autopsy. cMRI, clinical diagnosis, and macroscopic examination at postmortem have similar sensitivity and specificity in predicting a neuropathological diagnosis. We have validated specific radiological signs in pathologically confirmed PSP and MSA. However, the low sensitivity of these and macroscopic findings at autopsy suggest a need for imaging techniques sensitive to microstructural abnormalities without regional atrophy.

Objectives: MRI-based measurements used to diagnose progressive supranuclear palsy (PSP) typically lack pathologic verification and are not easy to use routinely. We aimed to develop in histologically proven disease a simple measure of the midbrain and pons on sagittal MRI to identify PSP.Methods: Measurements of the midbrain and pontine base on midsagittal T1-weighted MRI were performed in confirmed PSP (n 5 12), Parkinson disease (n 5 2), and multiple system atrophy (MSA) (n 5 7), and in controls (n 5 8). Using receiver operating characteristic curve analysis, cutoff values were applied to a clinically diagnosed cohort of 62 subjects that included PSP (n 5 21), Parkinson disease (n 5 10), MSA (n 5 10), and controls (n 5 21). Results:The mean midbrain measurement of 8.1 mm was reduced in PSP (p , 0.001) with reduction in the midbrain to pons ratio (PSP smaller than MSA; p , 0.001). In controls, the mean midbrain ratio was approximately two-thirds of the pontine base, in PSP it was ,52%, and in MSA the ratio was greater than two-thirds. A midbrain measurement of ,9.35 mm and ratio of 0.52 had 100% specificity for PSP. In the clinically defined group, 19 of 21 PSP cases (90.5%) had a midbrain measurement of ,9.35 mm. Conclusions:We have developed a simple and reliable measurement in pathologically confirmed disease based on the topography of atrophy in PSP with high sensitivity and specificity that may be a useful tool in the clinic. Neurodegenerative diseases presenting with parkinsonism including idiopathic Parkinson disease (PD), progressive supranuclear palsy (PSP), and multiple system atrophy (MSA) can be difficult to differentiate clinically particularly early in the disease course.1 Characteristic midbrain atrophy in PSP and pontine atrophy in MSA can be assessed on MRI 2 ; however, many magnetic resonance-based measurements proposed as diagnostic for PSP or MSA lack pathologic verification and are often not easy to apply routinely. [3][4][5][6][7][8][9] Our hypothesis was that simple measurements of the midbrain and pons (or their ratio) on midsagittal MRI would identify confirmed PSP and MSA.METHODS Standard protocol approvals, registrations, and patient consents. A pathologically confirmed cohort of PSP, PD, and MSA subjects (table 1) was selected from the Queen Square Brain Bank at UCL Institute of Neurology; brains were donated following ethically approved protocols under license from the Human Tissue Authority. A cohort of PSP, PD, MSA, and healthy subjects was prospectively recruited at the National Hospital for Neurology and Neurosurgery, as part of an ethically approved study with written informed consent.Participants and protocols. In the pathologically confirmed group, the diagnosis was determined using standard neuropathologic criteria. 10 In the clinically diagnosed group, participants fulfilled operational criteria 11-13 and were assessed with clinimetric scales including Hoehn and Yahr,

BACKGROUND: Osteosarcoma is the most common malignant bone tumor in children and young people. Efficacy of multiagent MAP (methotrexate, doxorubicin [Adriamycin], cisplatin) chemotherapy may be influenced by multiple cellular pathways. This pilot study aimed to investigate the association of 36 candidate genetic polymorphisms in MAP pathway genes with histological response, survival, and grade 3‐4 chemotherapy toxicity in osteosarcoma. METHODS: Blood samples were obtained from 60 patients who had completed MAP chemotherapy. All patients were manually genotyped for 5 polymorphisms. The remaining 31 polymorphisms were genotyped in 50 patients using the Illumina 610‐Quad microarray. Associations between candidate polymorphisms and histological response, progression‐free survival, and toxicity were estimated using Pearson chi‐square and Fisher exact tests, the Kaplan‐Meier method, the log‐rank test, and the Cox proportional hazards model. RESULTS: Poor histological response was increased in variants of ABCC2 c.24C>T (P = .011) and GSTP1 c.313A>G p.Ile105Val (P = .009), whereas MTHFD1 c.1958G>A p.Arg653Gln was protective (P = .03). Methotrexate toxicity was increased in variants of MTHFR c.1298A>C p.Glu429Ala (P = .038), ABCB1 c.3435T>C Ile145Ile (P = .027), and ABCC2 c.3563T>A p.Val1188Glu (P = .028). Variants of GSTP1 c.313A>G p.Ile105Val were at increased risk of myelosuppression (P = .024) and cardiac damage (P = .008). CONCLUSIONS: This pilot study represents the most comprehensive study to date examining the role of genetic polymorphisms in osteosarcoma. Although small and retrospective, it shows that several polymorphisms appear to significantly influence toxicity and clinical outcome. These deserve prospective validation in the hope of optimizing treatment for resistant disease and reducing the late effects burden. Cancer 2012. © 2011 American Cancer Society.

Following an episode of optic neuritis, thinning of the retinal nerve fibre layer, which indicates axonal loss, is observed using optical coherence tomography. The longitudinal course of the retinal changes has not been well characterized. We performed a serial optical coherence tomography study in patients presenting with optic neuritis in order to define the temporal evolution of retinal nerve fibre layer changes and to estimate sample sizes for proof-of-concept trials of neuroprotection using retinal nerve fibre layer loss as the outcome measure. Twenty-three patients (7 male, 16 female, mean age 31 years) with acute clinically isolated unilateral optic neuritis were recruited to undergo optical coherence tomography, visual assessments and visual evoked potentials at presentation (median 16 days from onset of visual loss) and after 3, 6, 12 and 18 months. Compared with the clinically unaffected fellow eye, the retinal nerve fibre layer thickness of the affected eye was significantly increased at presentation and significantly reduced at all later time points. The evolution of retinal nerve fibre layer changes in the affected eye fitted well with an exponential model, with thinning appearing a mean of 1.6 months from symptom onset and the rate of ongoing retinal nerve fibre layer loss decreasing thereafter. At presentation, increased retinal nerve fibre layer thickness was associated with impaired visual acuity and prolonged visual evoked potential latency. Visual function after 12 months was not related to the extent of acute retinal nerve fibre layer swelling but was significantly associated with the extent of concurrent retinal nerve fibre layer loss. Sample size calculations for placebo-controlled trials of acute neuroprotection indicated that the numbers needed after 6 months of follow up are smaller than those after 3 months and similar to those after 12 months of follow-up. Study power was greater when investigating differences between clinically unaffected and affected eyes rather than retinal nerve fibre layer thickness of the affected eye alone. Inflammation in the optic nerve and impaired axonal transport (implied by retinal nerve fibre layer swelling) are associated with visual dysfunction and demyelination (long visual evoked potential latency) during acute optic neuritis. Retinal nerve fibre layer thinning is usually evident within 3 months. Optical coherence tomography-measured retinal nerve fibre layer loss after 6 months is a suitable outcome measure for proof-of-concept trials of acute neuroprotection in optic neuritis.