427 research outputs found
Estimating prevalence of distant metastatic breast cancer: a means of filling a data gap
PURPOSE: To develop and validate a method for estimating numbers of people with distant cancer metastases, for evidence-based service planning. METHODS: Estimates were made employing an illness-death model with distant metastatic cancer as the illness state- and site-specific mortality as an outcome, using MIAMOD software. To demonstrate the method, we estimated numbers of females alive in Australia following detection of distant metastatic breast cancer during 1980-2004, using data on patient survival from an Australian population-based cancer registry. We validated these estimates by comparing them with direct prevalence counts. RESULTS: Relative survival at 10 years following detection of distant metastases was low (5-20 %), with better survival experienced by: (1) females where distant metastatic disease was detected at initial diagnosis rather than subsequently (e.g., at recurrence); (2) those diagnosed in more recent calendar years; and (3) younger age groups. For Australian females aged less than 85 years, the modeled cumulative risk of detection of distant metastatic breast cancer (either at initial diagnosis or subsequently) declined over time, but numbers of cases with this history rose from 71 per 100,000 in 1980 to 84 per 100,000 in 2004. The model indicated that there were approximately 3-4 prevalent distant metastatic breast cancer cases for every breast cancer death. Comparison of estimates with direct prevalence counts showed a reasonable level of agreement. CONCLUSIONS: The method is straightforward to apply and we recommend its use for breast and other cancers when registry data are insufficient for direct prevalence counts. This will provide estimates of numbers of people who would need ongoing medical surveillance and care following detection of distant metastase
Biallelic variants in ADARB1, encoding a dsRNA-specific adenosine deaminase, cause a severe developmental and epileptic encephalopathy
Background: Adenosine-to-inosine RNA editing is a co-transcriptional/post-transcriptional modification of double-stranded RNA, catalysed by one of two active adenosine deaminases acting on RNA (ADARs), ADAR1 and ADAR2. ADARB1 encodes the enzyme ADAR2 that is highly expressed in the brain and essential to modulate the function of glutamate and serotonin receptors. Impaired ADAR2 editing causes early onset progressive epilepsy and premature death in mice. In humans, ADAR2 dysfunction has been very recently linked to a neurodevelopmental disorder with microcephaly and epilepsy in four unrelated subjects.
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Methods: We studied three children from two consanguineous families with severe developmental and epileptic encephalopathy (DEE) through detailed physical and instrumental examinations. Exome sequencing (ES) was used to identify ADARB1 mutations as the underlying genetic cause and in vitro assays with transiently transfected cells were performed to ascertain the impact on ADAR2 enzymatic activity and splicing.
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Results: All patients showed global developmental delay, intractable early infantile-onset seizures, microcephaly, severe-to-profound intellectual disability, axial hypotonia and progressive appendicular spasticity. ES revealed the novel missense c.1889G>A, p.(Arg630Gln) and deletion c.1245_1247+1 del, p.(Leu415PhefsTer14) variants in ADARB1 (NM_015833.4). The p.(Leu415PhefsTer14) variant leads to incorrect splicing resulting in frameshift with a premature stop codon and loss of enzyme function. In vitro RNA editing assays showed that the p.(Arg630Gln) variant resulted in a severe impairment of ADAR2 enzymatic activity.
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Conclusion: In conclusion, these data support the pathogenic role of biallelic ADARB1 variants as the cause of a distinctive form of DEE, reinforcing the importance of RNA editing in brain function and development
Biallelic variants in ADARB1, encoding a dsRNA-specific adenosine deaminase, cause a severe developmental and epileptic encephalopathy.
BACKGROUND: Adenosine-to-inosine RNA editing is a co-transcriptional/post-transcriptional modification of double-stranded RNA, catalysed by one of two active adenosine deaminases acting on RNA (ADARs), ADAR1 and ADAR2. ADARB1 encodes the enzyme ADAR2 that is highly expressed in the brain and essential to modulate the function of glutamate and serotonin receptors. Impaired ADAR2 editing causes early onset progressive epilepsy and premature death in mice. In humans, ADAR2 dysfunction has been very recently linked to a neurodevelopmental disorder with microcephaly and epilepsy in four unrelated subjects. METHODS: We studied three children from two consanguineous families with severe developmental and epileptic encephalopathy (DEE) through detailed physical and instrumental examinations. Exome sequencing (ES) was used to identify ADARB1 mutations as the underlying genetic cause and in vitro assays with transiently transfected cells were performed to ascertain the impact on ADAR2 enzymatic activity and splicing. RESULTS: All patients showed global developmental delay, intractable early infantile-onset seizures, microcephaly, severe-to-profound intellectual disability, axial hypotonia and progressive appendicular spasticity. ES revealed the novel missense c.1889G>A, p.(Arg630Gln) and deletion c.1245_1247+1 del, p.(Leu415PhefsTer14) variants in ADARB1 (NM_015833.4). The p.(Leu415PhefsTer14) variant leads to incorrect splicing resulting in frameshift with a premature stop codon and loss of enzyme function. In vitro RNA editing assays showed that the p.(Arg630Gln) variant resulted in a severe impairment of ADAR2 enzymatic activity. CONCLUSION: In conclusion, these data support the pathogenic role of biallelic ADARB1 variants as the cause of a distinctive form of DEE, reinforcing the importance of RNA editing in brain function and development
Glatiramer Acetate Treatment Normalizes Deregulated microRNA Expression in Relapsing Remitting Multiple Sclerosis
The expression of selected microRNAs (miRNAs) known to be involved in the regulation of immune responses was analyzed in 74 patients with relapsing remitting multiple sclerosis (RRMS) and 32 healthy controls. Four miRNAs (miR-326, miR-155, miR-146a, miR-142-3p) were aberrantly expressed in peripheral blood mononuclear cells from RRMS patients compared to controls. Although expression of these selected miRNAs did not differ between treatment-naïve (n = 36) and interferon-beta treated RRMS patients (n = 18), expression of miR-146a and miR-142-3p was significantly lower in glatiramer acetate (GA) treated RRMS patients (n = 20) suggesting that GA, at least in part, restores the expression of deregulated miRNAs in MS
Increased RPA1 gene dosage affects genomic stability potentially contributing to 17p13.3 duplication syndrome
A novel microduplication syndrome involving various-sized contiguous duplications in 17p13.3 has recently been described, suggesting that increased copy number of genes in 17p13.3, particularly PAFAH1B1, is associated with clinical features including facial dysmorphism, developmental delay, and autism spectrum disorder. We have previously shown that patient-derived cell lines from individuals with haploinsufficiency of RPA1, a gene within 17p13.3, exhibit an impaired ATR-dependent DNA damage response (DDR). Here, we show that cell lines from patients with duplications specifically incorporating RPA1 exhibit a different although characteristic spectrum of DDR defects including abnormal S phase distribution, attenuated DNA double strand break (DSB)-induced RAD51 chromatin retention, elevated genomic instability, and increased sensitivity to DNA damaging agents. Using controlled conditional over-expression of RPA1 in a human model cell system, we also see attenuated DSB-induced RAD51 chromatin retention. Furthermore, we find that transient over-expression of RPA1 can impact on homologous recombination (HR) pathways following DSB formation, favouring engagement in aberrant forms of recombination and repair. Our data identifies unanticipated defects in the DDR associated with duplications in 17p13.3 in humans involving modest RPA1 over-expression
Factors influencing overweight children's commencement of and continuation in a resistance training program
<p>Abstract</p> <p>Background</p> <p>In light of the child overweight and obesity problem in Australia, resistance training programs have been trialled as an innovative way of assisting children increase lean body mass and reduce body fat. The purpose of this study was to investigate the factors influencing overweight children's participation in a resistance training trial program.</p> <p>Method</p> <p>Parent-child pairs who participated in the trial program were invited to take part in a follow-up individual interview to discuss their program experiences. In total, 22 semi-structured interviews were conducted with 11 parent-child pairs.</p> <p>Results</p> <p>The factors found to be most relevant to program commencement among parents were a desire for their child to lose weight and gain confidence, the proximity of the venue, and no cost for participation. For children, the most relevant factors were the opportunity to build strength and improve fitness and having supportive parents who facilitated program initiation. The factors most relevant to continuation for parents were the quality of the program management, being able to stay for the sessions, the child's improved weight status, coordination, and confidence, and no cost for participation. Weight loss and improved confidence were also motivators for continuation among the children, along with pleasant social interaction with peers and trainers and ongoing parental support.</p> <p>Conclusion</p> <p>Different factors variably influence program commencement and program continuation in both parents and children. This has important implications for future interventions that aim to successfully recruit and retain intervention participants.</p
Injectable and Oral Contraceptive Use and Cancers of the Breast, Cervix, Ovary, and Endometrium in Black South African Women: Case–Control Study
A case-control study conducted in South Africa provides new estimates of the risk of specific cancers of the female reproductive system associated with use of injectable and oral contraceptives
Genetic Diversity and Population Parameters of Sea Otters, Enhydra lutris, before Fur Trade Extirpation from 1741–1911
All existing sea otter, Enhydra lutris, populations have suffered at least one historic population bottleneck stemming from the fur trade extirpations of the eighteenth and nineteenth centuries. We examined genetic variation, gene flow, and population structure at five microsatellite loci in samples from five pre-fur trade populations throughout the sea otter's historical range: California, Oregon, Washington, Alaska, and Russia. We then compared those values to genetic diversity and population structure found within five modern sea otter populations throughout their current range: California, Prince William Sound, Amchitka Island, Southeast Alaska and Washington. We found twice the genetic diversity in the pre-fur trade populations when compared to modern sea otters, a level of diversity that was similar to levels that are found in other mammal populations that have not experienced population bottlenecks. Even with the significant loss in genetic diversity modern sea otters have retained historical structure. There was greater gene flow before extirpation than that found among modern sea otter populations but the difference was not statistically significant. The most dramatic effect of pre fur trade population extirpation was the loss of genetic diversity. For long term conservation of these populations increasing gene flow and the maintenance of remnant genetic diversity should be encouraged
Chronic non-specific low back pain - sub-groups or a single mechanism?
Copyright 2008 Wand and O'Connell; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background: Low back pain is a substantial health problem and has subsequently attracted a
considerable amount of research. Clinical trials evaluating the efficacy of a variety of interventions
for chronic non-specific low back pain indicate limited effectiveness for most commonly applied
interventions and approaches.
Discussion: Many clinicians challenge the results of clinical trials as they feel that this lack of
effectiveness is at odds with their clinical experience of managing patients with back pain. A
common explanation for this discrepancy is the perceived heterogeneity of patients with chronic
non-specific low back pain. It is felt that the effects of treatment may be diluted by the application
of a single intervention to a complex, heterogeneous group with diverse treatment needs. This
argument presupposes that current treatment is effective when applied to the correct patient.
An alternative perspective is that the clinical trials are correct and current treatments have limited
efficacy. Preoccupation with sub-grouping may stifle engagement with this view and it is important
that the sub-grouping paradigm is closely examined. This paper argues that there are numerous
problems with the sub-grouping approach and that it may not be an important reason for the
disappointing results of clinical trials. We propose instead that current treatment may be ineffective
because it has been misdirected. Recent evidence that demonstrates changes within the brain in
chronic low back pain sufferers raises the possibility that persistent back pain may be a problem of
cortical reorganisation and degeneration. This perspective offers interesting insights into the
chronic low back pain experience and suggests alternative models of intervention.
Summary: The disappointing results of clinical research are commonly explained by the failure of
researchers to adequately attend to sub-grouping of the chronic non-specific low back pain
population. Alternatively, current approaches may be ineffective and clinicians and researchers may
need to radically rethink the nature of the problem and how it should best be managed
p150 ADAR1 isoform involved in maintenance of HeLa cell proliferation
BACKGROUND: RNA-specific adenosine deaminase ADAR1 is ubiquitously expressed in a variety of mammalian cells and tissues. Although its physiological importance in non-nervous tissues has been confirmed by analysis of null mutation phenotypes, few endogenous editing substrates have been identified in numerous peripheral tissues and biological function of ADAR1 has not been fully understood. METHODS: A conditional site-specific, ribozyme-based gene knock-down strategy was utilized to study the function of full-length isoform of ADAR1 (p150 protein) in HeLa cell. Double-stable HeLa cell lines were developed by transfecting HeLa Tet-On cells with a pTRE-derived plasmid that can express a hammerhead ribozyme against mRNA of p150 ADAR1 isoform under induction condition. Semi-quantitative RT-PCR and Western blotting were performed to measure the expression of p150 in selected cell clones. Cell proliferation was evaluated by means of MTT assay and growth curve analysis. Cellular morphological changes were observed under light microscope. Flow Cytometry was used for cell cycle analysis. Growth rate of cell transplants in BALB/c nude mice was also investigated. RESULTS: Both HeLa cell proliferation in vitro and the growth rate of transplanted HeLa cell-derived tumors in nude mice in vivo were significantly inhibited due to reduced expression of ADAR1 p150. Additionally, cell cycle analysis showed that cell progression from G1 phase to S phase was retarded in the ADAR1 p150 suppressed cells. CONCLUSION: Our results suggest that normal expression and functioning of p150 ADAR1 is essential for the maintenance of proper cell growth. The mechanisms underlying ADAR1's action might include both editing of currently unknown double-stranded RNAs and interacting with other cellular dsRNA-related processes
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