The Facioscapulohumeral muscular dystrophy region on 4qter and the homologous locus on 10qter evolved independently under different evolutionary pressure

BACKGROUND: The homologous 4q and 10q subtelomeric regions include two distinctive polymorphic arrays of 3.3 kb repeats, named D4Z4. An additional BlnI restriction site on the 10q-type sequence allows to distinguish the chromosomal origin of the repeats. Reduction in the number of D4Z4 repeats below a threshold of 10 at the 4q locus is tightly linked to Facioscapulohumeral Muscular Dystrophy (FSHD), while similar contractions at 10q locus, are not pathogenic. Sequence variations due to the presence of BlnI-sensitive repeats (10q-type) on chromosome 4 or viceversa of BlnI-resistant repeats (4q-type) on chromosome 10 are observed in both alleles. RESULTS: We analysed DNA samples from 116 healthy subiects and 114 FSHD patients and determined the size distributions of polymorphic 4q and 10q alleles, the frequency and the D4Z4 repeat assortment of variant alleles, and finally the telomeric sequences both in standard and variant alleles. We observed the same frequency and types of variant alleles in FSHD patients and controls, but we found marked differences between the repeat arrays of the 4q and 10q chromosomes. In particular we detected 10q alleles completely replaced by the 4q subtelomeric region, consisting in the whole set of 4q-type repeats and the distal telomeric markers. However the reciprocal event, 10q-type subtelomeric region on chromosome 4, was never observed. At 4q locus we always identified hybrid alleles containing a mixture of 4q and 10q-type repeats. CONCLUSION: The different size distribution and different structure of 10q variant alleles as compared with 4q suggests that these loci evolved in a different manner, since the 4q locus is linked to FSHD, while no inheritable disease is associated with mutations in 10qter genomic region. Hybrid alleles on chromosome 4 always retain a minimum number of 4q type repeats, as they are probably essential for maintaining the structural and functional properties of this subtelomeric region. In addition we found: i) several instances of variant alleles that could be misinterpreted and interfere with a correct diagnosis of FSHD; ii) the presence of borderline alleles in the range of 30–40 kb that carried a qA type telomere and were not associated with the disease

Refined physical map of the human PAX2/HOX11/NFKB2 cancer gene region at 10q24 and relocalization of the HPV6AI1 viral integration site to 14q13.3-q21.1

BACKGROUND: Chromosome band 10q24 is a gene-rich domain and host to a number of cancer, developmental, and neurological genes. Recurring translocations, deletions and mutations involving this chromosome band have been observed in different human cancers and other disease conditions, but the precise identification of breakpoint sites, and detailed characterization of the genetic basis and mechanisms which underlie many of these rearrangements has yet to be resolved. Towards this end it is vital to establish a definitive genetic map of this region, which to date has shown considerable volatility through time in published works of scientific journals, within different builds of the same international genomic database, and across the differently constructed databases. RESULTS: Using a combination of chromosome and interphase fluorescent in situ hybridization (FISH), BAC end-sequencing and genomic database analysis we present a physical map showing that the order and chromosomal orientation of selected genes within 10q24 is CEN-CYP2C9-PAX2-HOX11-NFKB2-TEL. Our analysis has resolved the orientation of an otherwise dynamically evolving assembly of larger contigs upstream of this region, and in so doing verifies the order and orientation of a further 9 cancer-related genes and GOT1. This study further shows that the previously reported human papillomavirus type 6a DNA integration site HPV6AI1 does not map to 10q24, but that it maps at the interface of chromosome bands 14q13.3-q21.1. CONCLUSIONS: This revised map will allow more precise localization of chromosome rearrangements involving chromosome band 10q24, and will serve as a useful baseline to better understand the molecular aetiology of chromosomal instability in this region. In particular, the relocation of HPV6AI1 is important to report because this HPV6a integration site, originally isolated from a tonsillar carcinoma, was shown to be rearranged in other HPV6a-related malignancies, including 2 of 25 genital condylomas, and 2 of 7 head and neck tumors tested. Our finding shifts the focus of this genomic interest from 10q24 to the chromosome 14 site

Cost-utility analysis of different treatments for post-traumatic stress disorder in sexually abused children

<p>Abstract</p> <p>Background</p> <p>Post-traumatic stress disorder (PTSD) is diagnosed in 20% to 53% of sexually abused children and adolescents. Living with PTSD is associated with a loss of health-related quality of life. Based on the best available evidence, the NICE Guideline for PTSD in children and adolescents recommends cognitive behavioural therapy (TF-CBT) over non-directive counselling as a more efficacious treatment.</p> <p>Methods</p> <p>A modelled economic evaluation conducted from the Australian mental health care system perspective estimates incremental costs and Quality Adjusted Life Years (QALYs) of TF-CBT, TF-CBT combined with selective serotonin reuptake inhibitor (SSRI), and non-directive counselling. The "no treatment" alternative is included as a comparator. The first part of the model consists of a decision tree corresponding to 12 month follow-up outcomes observed in clinical trials. The second part consists of a 30 year Markov model representing the slow process of recovery in non-respondents and the untreated population yielding estimates of long-term quality-adjusted survival and costs. Data from the 2007 Australian Mental Health Survey was used to populate the decision analytic model.</p> <p>Results</p> <p>In the base-case and sensitivity analyses, incremental cost-effectiveness ratios (ICERs) for all three active treatment alternatives remained less than A$7,000 per QALY gained. The base-case results indicated that non-directive counselling is dominated by TF-CBT and TF-CBT + SSRI, and that efficiency gain can be achieved by allocating more resources toward these therapies. However, this result was sensitive to variation in the clinical effectiveness parameters with non-directive counselling dominating TF-CBT and TF-CBT + SSRI under certain assumptions. The base-case results also suggest that TF-CBT + SSRI is more cost-effective than TF-CBT.</p> <p>Conclusion</p> <p>Even after accounting for uncertainty in parameter estimates, the results of the modelled economic evaluation demonstrated that all psychotherapy treatments for PTSD in sexually abused children have a favourable ICER relative to no treatment. The results also highlighted the loss of quality of life in children who do not receive any psychotherapy. Results of the base-case analysis suggest that TF-CBT + SSRI is more cost-effective than TF-CBT alone, however, considering the uncertainty associated with prescribing SSRIs to children and adolescents, clinicians and parents may exercise some caution in choosing this treatment alternative.</p

A next-generation liquid xenon observatory for dark matter and neutrino physics

The nature of dark matter and properties of neutrinos are among the most pressing issues in contemporary particle physics. The dual-phase xenon time-projection chamber is the leading technology to cover the available parameter space for weakly interacting massive particles, while featuring extensive sensitivity to many alternative dark matter candidates. These detectors can also study neutrinos through neutrinoless double-beta decay and through a variety of astrophysical sources. A next-generation xenon-based detector will therefore be a true multi-purpose observatory to significantly advance particle physics, nuclear physics, astrophysics, solar physics, and cosmology. This review article presents the science cases for such a detector

Cosmogenic production of 37Ar in the context of the LUX-ZEPLIN experiment

We estimate the amount of 37Ar produced in natural xenon via cosmic ray-induced spallation, an inevitable consequence of the transportation and storage of xenon on the Earth's surface. We then calculate the resulting 37Ar concentration in a 10-tonne payload~(similar to that of the LUX-ZEPLIN experiment) assuming a representative schedule of xenon purification, storage and delivery to the underground facility. Using the spallation model by Silberberg and Tsao, the sea level production rate of 37Ar in natural xenon is estimated to be 0.024~atoms/kg/day. Assuming the xenon is successively purified to remove radioactive contaminants in 1-tonne batches at a rate of 1~tonne/month, the average 37Ar activity after 10~tonnes are purified and transported underground is 0.058--0.090~μBq/kg, depending on the degree of argon removal during above-ground purification. Such cosmogenic 37Ar will appear as a noticeable background in the early science data, while decaying with a 35~day half-life. This newly-noticed production mechanism of 37Ar should be considered when planning for future liquid xenon-based experiments