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101.
Our group recently described recurrent somatic mutations of the miRNA processing gene DICER1 in non‐epithelial ovarian cancer. Mutations appeared to be clustered around each of four critical metal‐binding residues in the RNase IIIB domain of DICER1. This domain is responsible for cleavage of the 3′ end of the 5p miRNA strand of a pre‐mRNA hairpin. To investigate the effects of these cancer‐associated 'hotspot' mutations, we engineered mouse DICER1‐deficient ES cells to express wild‐type and an allelic series of the mutant DICER1 variants. Global miRNA and mRNA profiles from cells carrying the metal‐binding site mutations were compared to each other and to wild‐type DICER1. The miRNA and mRNA profiles generated through the expression of the hotspot mutations were virtually identical, and the DICER1 hotspot mutation‐carrying cells were distinct from both wild‐type and DICER1‐deficient cells. Further, miRNA profiles showed that mutant DICER1 results in a dramatic loss in processing of mature 5p miRNA strands but were still able to create 3p strand miRNAs. Messenger RNA (mRNA) profile changes were consistent with the loss of 5p strand miRNAs and showed enriched expression for predicted targets of the lost 5p‐derived miRNAs. We therefore conclude that cancer‐associated somatic hotspot mutations of DICER1, affecting any one of four metal‐binding residues in the RNase IIIB domain, are functionally equivalent with respect to miRNA processing and are hypomorphic alleles, yielding a global loss in processing of mature 5p strand miRNA. We further propose that this resulting 3p strand bias in mature miRNA expression likely underpins the oncogenic potential of these hotspot mutations. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.  相似文献   
102.
103.
Accurate assessment of sleep can be fundamental for monitoring, managing and evaluating treatment outcomes within diseases. A proliferation of consumer activity trackers gives easy access to objective sleep. We evaluated the performance of a commercial device (Fitbit Alta HR) relative to a research‐grade actigraph (Actiwatch Spectrum Pro) in measuring sleep before and after a cognitive behavioural intervention in insomnia disorder. Twenty‐five individuals with DSM‐5 insomnia disorder (M = 50.6 ± 15.9 years) wore Fitbit and Actiwatch and completed a sleep diary during an in‐laboratory polysomnogram, and for 1 week preceding and following seven weekly sessions of cognitive‐behavioural intervention for insomnia. Device performance was compared for sleep outcomes (total sleep time, sleep latency, sleep efficiency and wake after sleep onset). The analyses assessed (a) agreement between devices across days and pre‐ to post‐treatment, and (b) whether pre‐ to post‐treatment changes in sleep assessed by devices correlated with clinical measures of change. Devices generally did not significantly differ from each other on sleep variable estimates, either night to night, in response to sleep manipulation (pre‐ to post‐treatment) or in response to changes in environment (in the laboratory versus at home). Change in sleep measures across time from each device showed some correlation with common clinical measures of change in insomnia, but not insomnia diagnosis as a categorical variable. Overall, the Fitbit provides similar estimates of sleep outside the laboratory to a research grade actigraph. Despite the similarity between Fitbit and Actiwatch performance, the use of consumer technology is still in its infancy and caution should be taken in its interpretation.  相似文献   
104.
The pruritic, papular eruption of human immunodeficiency virus with associated peripheral eosinophilia is well documented. We describe a 32-year-old African American man with advanced acquired immunodeficiency syndrome; a generalized painful, pruritic, papular rash; peripheral blood eosinophilia; and perineural eosinophilic infiltrates with eosinophilic panniculitis. To our knowledge, the latter 2 features have not been previously described in the literature on human immunodeficiency virus dermatoses. We propose that eosinophilic neuritis and eosinophilic panniculitis may represent additional findings in the spectrum of cutaneous disease seen in patients with advanced acquired immunodeficiency syndrome.  相似文献   
105.
BACKGROUND: Clinical judgments about the likelihood of suicide attempt would be aided by an index of risk factors that could be quickly assessed in diverse settings. We sought to develop such a risk index for 12-month suicide attempts among suicide ideators. METHOD: The National Comorbidity Survey Replication (NCS-R), a household survey of adults aged 18+, assessed the 12-month occurrence of suicide ideation, plans and attempts in a subsample of 5692 respondents. Retrospectively assessed correlates include history of prior suicidality, sociodemographics, parental psychopathology and 12-month DSM-IV disorders. RESULTS: Twelve-month prevalence estimates of suicide ideation, plans and attempts are 2.6, 0.7 and 0.4% respectively. Although ideators with a plan are more likely to make an attempt (31.9%) than those without a plan (9.6%), 43% of attempts were described as unplanned. History of prior attempts is the strongest correlate of 12-month attempts. Other significant correlates include shorter duration of ideation, presence of a suicide plan, and several sociodemographic and parental psychopathology variables. Twelve-month disorders are not powerful correlates. A four-category summary index of correlates is strongly related to attempts among ideators [area under the receiver operator characteristic curve (AUC)=0.88]. The distribution (conditional probability of attempt) of the risk index is: 19.0% very low (0.0%), 51.1% low (3.5%), 16.2% intermediate (21.3%), and 13.7% high (78.1%). Two-thirds (67.1%) of attempts were made by ideators in the high-risk category. CONCLUSIONS: A short, preliminary risk index based on retrospectively reported responses to fully structured questions is strongly correlated with 12-month suicide attempts among ideators, with a high concentration of attempts among high-risk ideators.  相似文献   
106.
High-risk injection drug use and its accompanying sexual behaviors have large social and financial costs. However, little is known about how age and age at first drug use are related to high-risk injection or sex behaviors. The current study draws on life course perspectives and data from the NIDA Cooperative Agreement to examine the relationship between eight high-risk behavior variables and age and age at first drug use. Random effects negative binomial regression models reveal that the frequency of high-risk sexual behaviors in the past month decreases up to 28% with each decade of age, although the frequency of high-risk injection behaviors in the past month increases by up to 62% with each decade of age. Both high-risk injection and high-risk sex behaviors are lower among those who initiated first drug use at later ages. Previous research has indicated the importance of interventions to reduce the high-risk sexual behaviors of older drug users. The current study suggests a refocusing of public health efforts on their high-risk injection habits.  相似文献   
107.
Bronchoalveolar lavage (BAL) was performed on 28 asthma patients, 7 patients with emphysema and 11 control subjects. Total and differential cell counts were performed and cellular metabolic activity was assessed using luminol and lucigenin amplified chemiluminescence. BAL supernatants were assayed for platelet-activating factor (PAF) and lyso-PAF using a sensitive guinea-pig bioassay. Eight of the asthma patients but none of the emphysema patients or control subjects had PAF in their BAL fluid. Lyso-PAF was measurable in BAL fluid in most subjects and no differences were detected between groups. Among the asthma patients, the presence of PAF in BAL supernatant was significantly associated with a combination of low neutrophil and high lymphocyte counts (p less than 0.05) and with macrophage metabolic activity as assessed by lucigenin chemiluminescence (p less than 0.05).  相似文献   
108.
AIMS--To assess the distribution of gamma delta T-cells in the human bronchial tree; and to compare quantitatively the differences between gamma delta T-cell numbers in different parts of the airway wall in smokers and non-smokers. METHODS--Full thickness bronchial wall sections were taken from 10 whole lung specimens from both smokers and non-smokers. Serial cryostat sections stained with the monoclonal antibodies CD3 and TCR delta-1 were examined with the aid of interactive image analysis to assess gamma delta T-cell numbers both in absolute terms and as a proportion of total T lymphocyte numbers. RESULTS--In all cases gamma delta T-cells were demonstrable throughout the airway wall. Although in absolute terms they tend to occur predominantly in the bronchial epithelium, this seems to reflect higher numbers of T lymphocytes in the epithelium in general compared with the submucosa. No genuine epitheliotropism is evident. Comparison by smoking status shows a significant increase in gamma delta T-cell numbers in the bronchial glands of smokers compared with non-smokers. CONCLUSIONS--gamma delta T-cells form an integral though variable component of the immunocompetent cell population of the human airway in both smokers and non-smokers. Although epitheliotropism does not exist in the bronchial tree, gamma delta T-cells seem to form a significant part of the bronchial gland inflammation associated with smoking.  相似文献   
109.
Purpose

With housing costs increasing faster than incomes and a limited supply of social housing options, many households face unaffordable housing. Housing affordability problems may negatively impact mental health; however, longitudinal evidence is limited. This study investigates the association between trajectories of housing affordability problems and mental health.

Methods

We used data from 30,025 households from Understanding Society, a longitudinal household survey from the UK. Participants spending 30% or more of household income on housing were categorised as facing housing affordability problems. We estimated group-based trajectories of housing affordability problems from 9 waves of data (2009–2019). We used linear regression to calculate the association between the trajectories and mental health problems, as measured by General Health Questionnaire (GHQ) score in Wave 10 (2018–2020).

Results

We found six distinct trajectories of housing affordability problems. Those in the ‘stable low’ group had a consistently low probability of affordability problems, whilst those in ‘high falling’ group had a sustained high probability in the earlier waves of the study, subsequently decreasing over time. The adjusted analysis showed that trajectory group membership over the first nine waves of data predicted GHQ score in 2018–2020 (Wave 10). Compared to the ‘stable low’ group, those in the ‘high falling’ group had a GHQ score that was 1.06 (95% CI 0.53–1.58) points higher.

Conclusion

This study provides evidence that sustained exposure to housing affordability problems is associated with long-term worse mental health, even in the absence of more recent problems.

  相似文献   
110.
Parkinson's disease is associated with increased oscillatory firing patterns in basal ganglia output, which are thought to disrupt thalamocortical activity. However, it is unclear how specific thalamic nuclei are affected by these changes in basal ganglia activity. The thalamic parafascicular nucleus (PFN) receives input from basal ganglia output nuclei and directly projects to the subthalamic nucleus (STN), striatum and cortex; thus basal ganglia-mediated changes on PFN activity may further impact basal ganglia and cortical functions. To investigate the impact of increased oscillatory activity in basal ganglia output on PFN activity after dopamine cell lesion, PFN single-unit and local field potential activities were recorded in neurologically intact (control) rats and in both non-lesioned and dopamine lesioned hemispheres of unilateral 6-hydroxydopamine lesioned rats anesthetized with urethane. Firing rates were unchanged 1–2 weeks after lesion; however, significantly fewer spontaneously active PFN neurons were evident. Firing pattern assessments after lesion showed that a larger proportion of PFN spike trains had 0.3–2.5 Hz oscillatory activity and significantly fewer spike trains exhibited low threshold calcium spike (LTS) bursts. In paired recordings, more PFN–STN spike oscillations were significantly correlated, but as these oscillations were in-phase, results are inconsistent with feedforward control of PFN activity by inhibitory oscillatory basal ganglia output. Furthermore, the decreased incidence of LTS bursts is incompatible with inhibitory basal ganglia output inducing rebound bursting in PFN after dopamine lesion. Together, results show that robust oscillatory activity observed in basal ganglia output nuclei after dopamine cell lesion does not directly drive changes in PFN oscillatory activity.  相似文献   
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