877 research outputs found
Low Frequency of Loss and Heterozygosity At the Nevoid Basal Cell Carcinoma Locus and Other Selected Loci in Appendageal Tumors
Previous studies of loss of heterozygosity (LOH) have revealed distinct patterns of allelic loss in some skin tumors. In basal cell carcinomas (BCCs) loss of heterozygosity is virtually restricted to chromosome 9, whereas in squamous cell carcinomas (SCCs) and actinic keratoses loss is more widespread involving chromosomes 3, 9, 13, and 17. Because there are histological similarities between BCCs and some appendageal tumors, and because some lines of evidence suggest that BCCs are appendageal in origin, we carried out a limited allelotype in 41 appendageal tumors. The overall frequency of allelic loss was low (4 out of 247 informative loci; 1.6%). LOH was seen in a proliferating trichilemmal cyst (l7p), a sebaceous epithelioma (l7q), an eccrine porocarcinoma (17q), a trichoepithelioma (9q), and in two basal cell carcinomas showing eccrine or granular cell differentiation that were originally misdiagnosed (9q). The pattern of loss in this mixed group of appendageal tumors shows differences from both BCCs and SCCs, and further emphasizes the unique genetic profile and behavior of BCCs. The finding of 9q loss in BCCs with eccrine or granular cell differentiation shows that 9q loss occurs in different histological subtypes of BCCs
A Phase I and Pharmacologic Study of Weekly Gemcitabine in Combination with Infusional 5-fluorodeoxyuridine and Oral Calcium Leucovorin
Purpose: Since preclinical studies have shown more than additive cytotoxicity and DNA damage with the combination of gemcitabine and 5-fluoro-2ā²-deoxyuridine (FUDR), we studied this combination in a phase I trial. Methods: Gemcitabine alone was given in cycle 1 as a 24-h, 2-h or 1-h i.v. infusion weekly for 3 of 4 weeks; if tolerated, a 24-h i.v. infusion of FUDR was added with oral leucovorin. The cycle was aborted for grade 3 thrombocytopenia, grade 4 neutropenia, and grade 2 or worse nonhematologic toxicity. Results: During cycle 1, six of eight patients who received 150 or 100 mg/m2 over 24 h had dose-limiting neutropenia, thrombocytopenia, fatigue or mucositis. Six of seven patients treated with 1000 mg/m2 over 2 h required a gemcitabine dose reduction for cycle 2 (thrombocytopenia, neutropenia, fatigue). Of 25 assessable patients who received gemcitabine 1000 mg/m2 over 1 h, 7 did not complete cycle 1 due to thrombocytopenia (n = 6) or diarrhea (n = 1). Of 42 patients entered, 27 received at least one course of gemcitabine/FUDR (5-19.5 mg/m2 over 24 h) without appreciable toxicity. Due to a shortage of FUDR, the protocol was closed early. Gemcitabine plasma concentrations averaged 0.061 Ī¼M (24 h), 16.3 Ī¼M (2 h), and 31.9 Ī¼M (1 h). In 21 paired bone marrow mononuclear cell samples obtained before treatment and during FUDR infusion, thymidylate synthase ternary complex was only seen during FUDR infusion. Conclusions: Gemcitabine 100-150 mg/m2 over 24 h was poorly tolerated, whereas toxicity was acceptable with 800-1000 mg/m2 over 1 h. Inhibition of the target enzyme was demonstrated at all FUDR doses
Prefrontal GABA levels, hippocampal resting perfusion and the risk of psychosis
This article was originally published under NPGās License to Publish, but has now been made available under a [CC BY 4.0] license. The PDF and HTML versions of the paper have been modified accordingly.</p
Differences in trajectories of quality of life according to type of dementia: 6-year longitudinal findings from the IDEAL programme
Background: People with different types of dementia may have distinct symptoms and experiences that affect their quality of life. This study investigated whether quality of life varied across types of dementia and over time. Methods: The participants were 1555 people with mild-to-moderate dementia and 1327 carers from the IDEAL longitudinal cohort study, recruited from clinical services. As many as possible were followed for up to 6Ā years. Diagnoses included were Alzheimerās disease, vascular dementia, mixed Alzheimerās and vascular dementia, Parkinsonās disease dementia, dementia with Lewy bodies, and frontotemporal dementia. Self- and informant-rated versions of the Quality of Life in Alzheimerās Disease scaleĀ were used. A joint model, incorporating a mixed effects model with random effects and a survival model to account for dropout, was used to examine whether quality of life varied by dementia type at the time of diagnosis and how trajectories changed over time. Results: The strongest associations between dementia type and quality of life were seen around the time of diagnosis. For both self-ratings and informant ratings, people with Parkinsonās disease dementia or dementia with Lewy bodies had lower quality of life scores. Over time there was little change in self-rated scores across all dementia types (ā 0.15 points per year). Informant-rated scores declined over time (ā 1.63 points per year), with the greatest decline seen in ratings by informants for people with dementia with Lewy bodies (ā 2.18 points per year). Conclusions: Self-rated quality of life scores were relatively stable over time whilst informant ratings showed a steeper decline. People with Parkinsonās disease dementia or dementia with Lewy bodies report particularly low levels of quality of life, indicating the importance of greater attention to the needs of these groups
Health conditions in spousal caregivers of people with dementia and their relationships with stress, caregiving experiences, and social networks: longitudinal findings from the IDEAL programme
Objectives: Longitudinal evidence documenting health conditions in spousal caregivers of people with dementia and whether these influence caregiversā outcomes is scarce. This study explores type and number of health conditions over two years in caregivers of people with dementia and subgroups based on age, sex, education, hours of care, informant-rated functional ability, neuropsychiatric symptoms, cognition of the person with dementia, and length of diagnosis in the person with dementia. It also explores whether over time the number of health conditions is associated with caregiversā stress, positive experiences of caregiving, and social networks Methods: Longitudinal data from the IDEAL (Improving the experience of Dementia and Enhancing Active Life) cohort were used. Participants comprised spousal caregivers (n = 977) of people with dementia. Self-reported health conditions using the Charlson Comorbidity Index, stress, positive experiences of caregiving, and social network were assessed over two years. Mixed effect models were used Results: On average participants had 1.5 health conditions at baseline; increasing to 2.1 conditions over two years. More health conditions were reported by caregivers who were older, had no formal education, provided 10 + hours of care per day, and/or cared for a person with more neuropsychiatric symptoms at baseline. More baseline health conditions were associated with greater stress at baseline but not with stress over time
Caregivers' beliefs about dementia: findings from the IDEAL study
YesObjective: Informal caregivers of people with dementia develop
their own beliefs about the condition, referred to as Dementia
Representations (DRs), as they try to make sense of the changes
they are observing. The first aim of this study was to provide a
profile of the types of DRs held by caregivers. The second aim
was to examine the impact of caregiversā DRs on their well-being,
satisfaction with life (SwL) and caregiving stress.
Methods: Participants were 1264 informal caregivers of people in
the mild-to-moderate stages of dementia from time-point 1 of
the IDEAL cohort study.
Measures: DRs were measured using questionnaire items covering:
Identity, Cause, Control, and Timeline.
Results: Almost half (49.2%) of caregivers used a diagnostic term
to describe the personās condition, although 93.4% of caregivers
stated they were aware of the diagnosis. Higher well-being, SwL,
and lower caregiving stress were associated with the use of an
identity term relating to specific symptoms of dementia, attributing
the cause to ageing or not knowing the cause, and believing
the condition would stay the same. Lower well-being, SwL, and
higher caregiving stress were associated with believing there was
little that could be done to control the effects of the condition.
Conclusion: Healthcare professionals should assess and gain an
understanding of caregiversā DRs in order to provide more tailored
information and support.The IDEAL study is funded by the Economic and Social Research Council (UK) and the National Institute for Health Research (UK) through grant ES/L001853/2 āImproving the experience of dementia and enhancing active life: living well with dementiaā
Longitudinal trajectories of quality of life among people with mild-to-moderate dementia: a latent growth model approach with IDEAL cohort study data
Objectives We aimed to examine change over time in self-rated quality of life (QoL) in people with mild-to-moderate dementia and identify sub-groups with distinct QoL trajectories. Method We used data from people with mild-to-moderate dementia followed up at 12 and 24 months in the IDEAL cohort study (baseline n=1537). A latent growth model approach examined mean change over time in QoL, assessed with the QoL-AD scale, and investigated associations of baseline demographic, cognitive and psychological covariates with the intercept and slope of QoL. We employed growth mixture modelling to identify multiple growth trajectories. Results Overall mean QoL scores were stable and no associations with change over time were observed. Four classes of QoL trajectories were identified: two with higher baseline QoL scores, labelled Stable (74.9%) and Declining (7.6%), and two with lower baseline QoL scores, labelled Stable Lower (13.7%) and Improving (3.8%). The Declining class had higher baseline levels of depression and loneliness, and lower levels of self-esteem and optimism, than the Stable class. The Stable Lower class was characterised by disadvantage related to social structure, poor physical health, functional disability, and low psychological well-being. The Improving class was similar to the Stable Lower class but had lower cognitive test scores. Discussion Understanding individual trajectories can contribute to personalised care planning. Efforts to prevent decline in perceived QoL should primarily target psychological well-being. Efforts to improve QoL for those with poorer QoL should additionally address functional impairment, isolation, and disadvantage related to social structure
Rapid progression and mortality of lysosomal acid lipase deficiency presenting in infants
PurposeThe purpose of this study was to enhance understanding of lysosomal acid lipase deficiency (LALD) in infancy.MethodsInvestigators reviewed medical records of infants with LALD and summarized data for the overall population and for patients with and without early growth failure (GF). Kaplan-Meier survival analyses were conducted for the overall population and for treated and untreated patients.ResultsRecords for 35 patients, 26 with early GF, were analyzed. Prominent symptom manifestations included vomiting, diarrhea, and steatorrhea. Median age at death was 3.7 months; estimated probability of survival past age 12 months was 0.114 (95% confidence interval (CI): 0.009-0.220). Among patients with early GF, median age at death was 3.5 months; estimated probability of survival past age 12 months was 0.038 (95% CI: 0.000-0.112). Treated patients (hematopoietic stem cell transplant (HSCT), n = 9; HSCT and liver transplant, n = 1) in the overall population and the early GF subset survived longer than untreated patients, but survival was still poor (median age at death, 8.6 months).ConclusionsThese data confirm and expand earlier insights on the progression and course of LALD presenting in infancy. Despite variations in the nature, onset, and severity of clinical manifestations, and treatment attempts, clinical outcome was poor.Genet Med 18 5, 452-458
Longitudinal Predictors of Informant-Rated Involvement of People with Dementia in Everyday Decision-Making: Findings from the IDEAL Program
This is the final version. Available on open access from SAGE Publications via the DOI in this recordData Availability: IDEAL data were deposited with the UK data archive in April 2020 and will be available to access from April 2023. Details of how the data can be accessed after that date can be found here: http://reshare.ukdataservice.ac.uk/854293/The extent to which people with dementia are involved in everyday decision-making is unclear. We explored informant-rated involvement of people with dementia in everyday decision-making over 2Ā years and whether functional, behavioral, and psychological factors related to the person with dementia and the caregiver explain variability in involvement of people with dementia in everyday decision-making. We used IDEAL data for 1182 people with dementia and their caregivers. Baseline mean score on the decision-making involvement scale was 31/45; it minimally declined over time. People with dementia who were female, single, and/or whose caregiver was younger had greater involvement in everyday decision-making than those without these characteristics. Better cognition, fewer functional difficulties, fewer neuropsychiatric symptoms, less caregiver stress, and better informant-rated relationship quality were associated with higher involvement in everyday decision-making. Cognitive and functional rehabilitation, and educational resources for caregivers, could prolong involvement of people with dementia in everyday decision-making.Economic and Social Research Council (ESRC)National Institute for Health and Care Research (NIHR)Alzheimerās Societ
Integrated metastate functional connectivity networks predict change in symptom severity in clinical high risk for psychosis
The ability to identify biomarkers of psychosis risk is essential in defining effective preventive measures to potentially circumvent the transition to psychosis. Using samples of people at clinical high risk for psychosis (CHR) and Healthy controls (HC) who were administered a task fMRI paradigm, we used a framework for labelling time windows of fMRI scans as āintegratedā FC networks to provide a granular representation of functional connectivity (FC). Periods of integration were defined using the ācartographic profileā of time windows and kāmeans clustering, and subānetwork discovery was carried out using Network Based Statistics (NBS). There were no network differences between CHR and HC groups. Within the CHR group, using integrated FC networks, we identified a subānetwork negatively associated with longitudinal changes in the severity of psychotic symptoms. This subānetwork comprised brain areas implicated in bottomāup sensory processing and in integration with motor control, suggesting it may be related to the demands of the fMRI task. These data suggest that extracting integrated FC networks may be useful in the investigation of biomarkers of psychosis risk
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