The identification of a hexanucleotide repeat expansion in the C9ORF72 gene as the cause of chromosome 9-linked frontotemporal dementia and motor neuron disease offers the opportunity for greater ...understanding of the relationship between these disorders and other clinical forms of frontotemporal lobar degeneration. In this study, we screened a cohort of 398 patients with frontotemporal dementia, progressive non-fluent aphasia, semantic dementia or mixture of these syndromes for mutations in the C9ORF72 gene. Motor neuron disease was present in 55 patients (14%). We identified 32 patients with C9ORF72 mutations, representing 8% of the cohort. The patients' clinical phenotype at presentation varied: nine patients had frontotemporal dementia with motor neuron disease, 19 had frontotemporal dementia alone, one had mixed semantic dementia with frontal features and three had progressive non-fluent aphasia. There was, as expected, a significant association between C9ORF72 mutations and presence of motor neuron disease. Nevertheless, 46 patients, including 22 familial, had motor neuron disease but no mutation in C9ORF72. Thirty-eight per cent of the patients with C9ORF72 mutations presented with psychosis, with a further 28% exhibiting paranoid, deluded or irrational thinking, whereas <4% of non-mutation bearers presented similarly. The presence of psychosis dramatically increased the odds that patients carried the mutation. Mutation bearers showed a low incidence of motor stereotypies, and relatively high incidence of complex repetitive behaviours, largely linked to patients' delusions. They also showed a lower incidence of acquired sweet food preference than patients without C9ORF72 mutations. Post-mortem pathology in five patients revealed transactive response DNA-binding protein 43 pathology, type A in one patient and type B in three. However, one patient had corticobasal degeneration pathology. The findings indicate that C9ORF72 mutations cause some but not all cases of frontotemporal dementia with motor neuron disease. Other mutations remain to be discovered. C9ORF72 mutations are associated with variable clinical presentations and pathology. Nevertheless, the findings highlight a powerful association between C9ORF72 mutations and psychosis and suggest that the behavioural characteristics of patients with C9ORF72 mutations are qualitatively distinct. Mutations in the C9ORF72 gene may be a major cause not only of frontotemporal dementia with motor neuron disease but also of late onset psychosis.
Highlights • tDCS and rehabilitation had small non-significant effect on upper extremity impairments. • Varied tDCS and rehabilitation programmes were identified in selected studies. • Future ...research needs to further analyse tDCS and therapy interventions in stroke.
Summary Background Community-led total sanitation (CLTS) uses participatory approaches to mobilise communities to build their own toilets and stop open defecation. Our aim was to undertake the first ...randomised trial of CLTS to assess its effect on child health in Koulikoro, Mali. Methods We did a cluster-randomised trial to assess a CLTS programme implemented by the Government of Mali. The study population included households in rural villages (clusters) from the Koulikoro district of Mali; every household had to have at least one child aged younger than 10 years. Villages were randomly assigned (1:1) with a computer-generated sequence by a study investigator to receive CLTS or no programme. Health outcomes included diarrhoea (primary outcome), height for age, weight for age, stunting, and underweight. Outcomes were measured 1·5 years after intervention delivery (2 years after enrolment) among children younger than 5 years. Participants were not masked to intervention assignment. The trial is registered with ClinicalTrials.gov , number NCT01900912. Findings We recruited participants between April 12, and June 23, 2011. We assigned 60 villages (2365 households) to receive the CLTS intervention and 61 villages (2167 households) to the control group. No differences were observed in terms of diarrhoeal prevalence among children in CLTS and control villages (706 22% of 3140 CLTS children vs 693 24% of 2872 control children; prevalence ratio PR 0·93, 95% CI 0·76–1·14). Access to private latrines was almost twice as high in intervention villages (1373 65% of 2120 vs 661 35% of 1911 households) and reported open defecation was reduced in female (198 9% of 2086 vs 608 33% of 1869 households) and in male (195 10% of 2004 vs 602 33% of 1813 households) adults. Children in CLTS villages were taller (0·18 increase in height-for-age Z score, 95% CI 0·03–0·32; 2415 children) and less likely to be stunted (35% vs 41%, PR 0·86, 95% CI 0·74–1·0) than children in control villages. 22% of children were underweight in CLTS compared with 26% in control villages (PR 0·88, 95% CI 0·71–1·08), and the difference in mean weight-for-age Z score was 0·09 (95% CI –0·04 to 0·22) between groups. In CLTS villages, younger children at enrolment (<2 years) showed greater improvements in height and weight than older children. Interpretation In villages that received a behavioural sanitation intervention with no monetary subsidies, diarrhoeal prevalence remained similar to control villages. However, access to toilets substantially increased and child growth improved, particularly in children <2 years. CLTS might have prevented growth faltering through pathways other than reducing diarrhoea. Funding Bill & Melinda Gates Foundation.
Introduction
Cell biological and genetic evidence implicate failures in degrading aggregating proteins, such as tau and TDP‐43, through the autophagy or lysosomal pathways in the pathogenesis of ...frontotemporal lobar degeneration (FTLD).
Methods
We investigated changes in the degradative pathways in 60 patients with different pathological or genetic forms of FTLD employing immunohistochemistry for marker proteins such as lysosomal‐associated membrane proteins 1 (LAMP‐1) and 2 (LAMP‐2), cathepsin D (CTSD) and microtubule‐associated protein 1 light chain 3 alpha (LC3A). Immunostained sections were qualitatively and semi‐quantitatively assessed for the appearance, distribution and intensity of staining in neurones of the dentate gyrus (DG) and CA4 region of the hippocampus, and the temporal cortex (Tcx).
Results
Lower levels of neuronal LAMP‐1 immunostaining were present in the DG and Tcx in FTLD‐tau compared to FTLD‐TDP. There was less LAMP‐1 immunostaining in FTLD‐tau with MAPT mutations, and FTLD‐tau with Pick bodies, compared to FTLD‐TDP types A and B, and less LAMP‐1 immunostaining in FTLD‐TDP type C than in FTLD‐TDP types A and B. There was greater LAMP‐1 immunostaining in GRN mutation which may reflect the underlying type A histology rather than mutation. There were no differences in neuronal LAMP‐2, CTSD, EEA‐1 or LC3A immunostaining between any of the five FTLD histological or four genetic groups, nor between FTLD‐TDP and FTLD‐tau.
Conclusions
The underlying pathological mechanism in FTLD‐tau may lie with a relative deficiency of lysosomes, or defective vesicular transport, whereas the failure to clear TDP‐43 aggregates may lie with lysosomal dysfunction rather than a lack of available lysosomes or degradative enzymes.
Study objective A 2-hour accelerated diagnostic pathway based on the Thrombolysis in Myocardial Infarction score, ECG, and troponin measures (ADAPT-ADP) increased early discharge of patients with ...suspected acute myocardial infarction presenting to the emergency department compared with standard care (from 11% to 19.3%). Observational studies suggest that an accelerated diagnostic pathway using the Emergency Department Assessment of Chest Pain Score (EDACS-ADP) may further increase this proportion. This trial tests for the existence and size of any beneficial effect of using the EDACS-ADP in routine clinical care. Methods This was a pragmatic randomized controlled trial of adults with suspected acute myocardial infarction, comparing the ADAPT-ADP and the EDACS-ADP. The primary outcome was the proportion of patients discharged to outpatient care within 6 hours of attendance, without subsequent major adverse cardiac event within 30 days. Results Five hundred fifty-eight patients were recruited, 279 in each arm. Sixty-six patients (11.8%) had a major adverse cardiac event within 30 days (ADAPT-ADP 29; EDACS-ADP 37); 11.1% more patients (95% confidence interval 2.8% to 19.4%) were identified as low risk in EDACS-ADP (41.6%) than in ADAPT-ADP (30.5%). No low-risk patients had a major adverse cardiac event within 30 days (0.0% 0.0% to 1.9%). There was no difference in the primary outcome of proportion discharged within 6 hours (EDACS-ADP 32.3%; ADAPT-ADP 34.4%; difference −2.1% −10.3% to 6.0%, P =.65). Conclusion There was no difference in the proportion of patients discharged early despite more patients being classified as low risk by the EDACS-ADP than the ADAPT-ADP. Both accelerated diagnostic pathways are effective strategies for chest pain assessment and resulted in an increased rate of early discharges compared with previously reported rates.
Frontotemporal lobar degeneration (FTLD) refers to a focal, non-Alzheimer form of cerebral degeneration that encompasses the distinct clinical syndromes of frontotemporal dementia (FTD), progressive ...non-fluent aphasia (PNFA) and semantic dementia. Some patients show tau-based pathological changes and in familial cases mutations have been identified in the microtubule-associated protein tau gene (MAPT) on chromosome 17q21. However, many cases are tau-negative, showing instead ubiquitin-immunoreactive (UBQ-ir) neuronal cytoplasmic inclusions and neurites, and in some familial cases UBQ-ir neuronal intranuclear inclusions of a lentiform appearance. Very recently, mutations have been identified in familial cases in the progranulin (PGRN) gene, also on chromosome 17q21. Clinical, pathological and molecular diversity within FTLD highlights the importance of careful examination of clinical-pathological-genetic relationships. This paper reports, for the first time, a clinico-pathological investigation of two FTLD families with PGRN mutations, and compares the clinical characteristics with those of patients studied in the department with MAPT mutations. The clinical profile associated with PGRN mutations constituted, in some patients, a prototypical picture of FTD and in others one of PNFA, both profiles occurring within the same family. Patients with PGRN mutations exhibited phonological deficits, whereas in patients with MAPT mutations language abnormalities, when present in addition to the prominent behavioural disorder, take the form of semantic disturbance. The findings provide compelling evidence for the link between FTD and PNFA, while raising the possibility of identifiable clinical differences between FTLD patients with MAPT and PGRN mutations.
Nearly 40% of mortality in the United States is linked to social and behavioral factors such as smoking, diet and sedentary lifestyle. Autonomous self-regulation of health-related behaviors is thus ...an important aspect of human behavior to assess. In 1997, the Behavior Change Consortium (BCC) was formed. Within the BCC, seven health behaviors, 18 theoretical models, five intervention settings and 26 mediating variables were studied across diverse populations. One of the measures included across settings and health behaviors was the Treatment Self-Regulation Questionnaire (TSRQ). The purpose of the present study was to examine the validity of the TSRQ across settings and health behaviors (tobacco, diet and exercise). The TSRQ is composed of subscales assessing different forms of motivation: amotivation, external, introjection, identification and integration. Data were obtained from four different sites and a total of 2731 participants completed the TSRQ. Invariance analyses support the validity of the TSRQ across all four sites and all three health behaviors. Overall, the internal consistency of each subscale was acceptable (most α values >0.73). The present study provides further evidence of the validity of the TSRQ and its usefulness as an assessment tool across various settings and for different health behaviors.
Objectives: To report a negative association between milk or dairy consumption and the metabolic syndrome and to examine associations within the Caerphilly cohort. Setting: A representative sample of ...men aged 45–59 years in Caerphilly, UK. Participants and data: Data on fasting blood glucose and plasma insulin, fasting plasma triglycerides and high-density lipoprotein cholesterol, body mass index, and blood pressure were used to define the metabolic syndrome in terms of levels of two or more variates within the top 10%. The clinical importance of the syndrome was assessed from 20-year incidence of diabetes, vascular events and deaths. The relationships between the syndrome and the consumption of milk and dairy products was examined using data from both a semiquantitative food frequence questionnaire, and from a 7-day weighed intake record which had been kept by a 1:3 subsample of the men. Main results: There were 2375 men without diabetes in the cohort. The prevalence of the metabolic syndrome was 15%. Men with the syndrome had significantly increased risks of a subsequent ischaemic heart disease event, death or diabetes. Negative relationships were shown between both the consumption of milk and dairy produce, and the syndrome. Adjusted odds ratio in men who regularly drank a pint of milk or more daily was 0.38 (0.18 to 0.78) and that for dairy food consumption was 0.44 (0.21 to 0.91). Milk intake showed no significant trend with incident diabetes. Conclusions: The consumption of milk and dairy products is associated with a markedly reduced prevalence of the metabolic syndrome, and these items therefore fit well into a healthy eating pattern.
We present ultraviolet, optical, and near-infrared observations of SN 2012ap, a broad-lined Type Ic supernova in the galaxy NGC1729 that produced a relativistic and rapidly decelerating outflow ...without a gamma-ray burst signature. Photometry and spectroscopy follow the flux evolution from -13 to +272 days past the B-band maximum of -17.4 + or - 0.5mag. The spectra are dominated by Fe II, OI, and Ca II absorption lines at ejecta velocities of v approximate 20,000 km ssup -1 that change slowly over time. Other spectral absorption lines are consistent with contributions from photo-spheric He I, and hydrogen may also be present at higher velocities. SN 2012ap joins SN2009bb as another exceptional supernova that shows evidence for a central engine capable of launching a non-negligible portion of ejecta to relativistic velocities without a coincident gamma-ray burst detection. The events support the notion that jet activity at various energy scales may be present in a wide range of supernovae.
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