RNA polymerase I-specific subunits promote polymerase clustering to enhance the rRNA gene transcription cycle.

RNA polymerase I (Pol I) produces large ribosomal RNAs (rRNAs). In this study, we show that the Rpa49 and Rpa34 Pol I subunits, which do not have counterparts in Pol II and Pol III complexes, are functionally conserved using heterospecific complementation of the human and Schizosaccharomyces pombe orthologues in Saccharomyces cerevisiae. Deletion of RPA49 leads to the disappearance of nucleolar structure, but nucleolar assembly can be restored by decreasing ribosomal gene copy number from 190 to 25. Statistical analysis of Miller spreads in the absence of Rpa49 demonstrates a fourfold decrease in Pol I loading rate per gene and decreased contact between adjacent Pol I complexes. Therefore, the Rpa34 and Rpa49 Pol I–specific subunits are essential for nucleolar assembly and for the high polymerase loading rate associated with frequent contact between adjacent enzymes. Together our data suggest that localized rRNA production results in spatially constrained rRNA production, which is instrumental for nucleolar assembly.

Old drug, New target:Ellipticines selectively inhibit RNA Polymerase I transcription

Transcription byRNApolymerase I (Pol-I) is the main driving force behind ribosome biogenesis, a fundamental cellular process that requires the coordinated transcription of all three nuclear polymerases. Increased Pol-I transcription and the concurrent increase in ribosome biogenesis has been linked to the high rates of proliferation in cancers. The ellipticine family contains a number of potent anticancer therapeutic agents, some having progressed to stage I and II clinical trials; however, the mechanism by which many of the compounds work remains unclear. It has long been thought that inhibition of Top2 is the main reason behind the drugs antiproliferative effects. Here we report that a number of the ellipticines, including 9-hydroxyellipticine, are potent and specific inhibitors of Pol-I transcription, with IC50 in vitro and in cells in the nanomolar range. Essentially, the drugs did not affect Pol-II and Pol-III transcription, demonstrating a high selectivity.Wehave shown that Pol-I inhibition occurs by a p53-, ATM/ATR-, and Top2-independent mechanism. We discovered that the drug influences the assembly and stability of preinitiation complexes by targeting the interaction between promoter recognition factor SL1 and the rRNA promoter. Our findings will have an impact on the design and development of novel therapeutic agents specifically targeting ribosome biogenesis.

Cost-effectiveness of tooth replacement strategies for partially dentate elderly: a randomized controlled clinical trial

OBJECTIVE: To conduct a cost-effectiveness analysis comparing two different tooth replacement strategies for partially dentate older patients, namely partial removable dental prostheses (RDP) and functionally orientated treatment based on the shortened dental arch concept (SDA).

METHODS: Ninety-two partially dentate older patients completed a randomized controlled clinical trial. Patients were randomly allocated to two treatment groups: the RDP group and the SDA group. Treatment effect was measured using impact on oral health-related quality of life (OHrQOL), and the costs involved in providing and maintaining care were recorded for all patients. Patients were followed for 12 months after treatment intervention. All treatment was provided by a single operator.

RESULTS: The total cost of achieving the minimally important clinical difference (MID) in OHrQOL for an average patient in the RDP group was €464.64. For the SDA group, the cost of achieving the MID for an average patient was €252.00. The cost-effectiveness ratio was therefore 1:1.84 in favour of SDA treatment.

CONCLUSION: With an increasingly ageing population, many patients will continue to benefit from removable prostheses to replace their missing natural teeth. From a purely economic standpoint, the results from this analysis suggest that the treatment of partially dentate older adults should be focused on functionally orientated treatment because it is simply more cost-effective.

A preliminary report of the cost-effectiveness of tooth replacement strategies for partially dentate elders

OBJECTIVE: To compare the cost-effectiveness of conventional treatment using partial dentures with functionally orientated treatment to replace missing teeth for partially dentate elders using a randomised controlled clinical trial.

BACKGROUND: In many countries, including the Republic of Ireland, the only publically funded treatment option offered to partially dentate older patients is a removable partial denture. However, evidence suggests that these removable prostheses are unpopular with patients and can potentially increase the risk of further dental disease and subsequent tooth loss.

MATERIALS AND METHODS: Fourty-four partially dentate patients aged 65 years and older were recruited. Patients were randomly assigned to the two treatment arms of the study. The conventional treatment group received removable partial dentures to replace all missing natural teeth. The functionally orientated group was restored to a Shortened Dental Arch (SDA) of 10 occluding contacts using resin-bonded bridgework (RBB). The costs associated with each treatment were recorded. Effectiveness was measured in terms of the impact on oral health-related quality of life (OHRQoL) using OHIP-14.

RESULTS: Both groups reported improvements in OHRQoL 1 month after completion of treatment. The conventional treatment group required 8.3 clinic visits as compared to 4.4 visits for the functionally orientated group. The mean total treatment time was 183 min 19 s for the conventional group vs. 124 min 8 s for the functionally orientated group. The average cost of treatment for the conventional group was 487.74 Euros compared to 356.20 Euros for the functional group.

CONCLUSIONS: Functionally orientated treatment was more cost-effective than conventional treatment in terms of treatment effect and opportunity costs to the patients' time.

Tooth replacement for partially dentate elders: a randomised controlled trial

Objective: This study aimed to compare two different tooth replacement strategies for partially dentate older patients namely; removable partial dentures (RPDs) and functionally orientated treatment based on the shortened dental arch (SDA) concept. Method: 88 partially dentate older patients (mean age 69.4 years) completed a randomised controlled clinical trial. 43 patients received RPDs and 45 received functionally orientated treatment where resin bonded bridgework was used to provide 10 pairs of occluding contacts. Patients were followed for 1 year after treatment intervention. The impact of treatment on oral health-related quality of life (OHrQOL) and cost effectiveness were used as outcome measures. Each patient completed the short form of the Oral Health Impact Profile (OHIP-14) at baseline, 6 months and 1 year after treatment intervention. All costs involved in providing and maintaining each intervention were recorded including dental laboratory bills, materials and professional time. Result: Both the RPD (p=0.004) and the functionally orientated (p<0.001) treatment groups demonstrated statistically significant improvements in OHrQOL 1 year after treatment intervention. On average 9.4 visits were required to complete and maintain the RPDs over the 1 year period as compared to 5.3 visits for the functionally orientated group. The average laboratory cost for the RPDs was $537.45 per patient versus $367.89 for functionally orientated treatment. The cost of achieving the Minimally Important Difference of 5 scale points in OHIP-14 score with RPDs was $732.17. For the functionally orientated group the cost was $356.88. Therefore, functionally orientated treatment was more than twice as cost effective (1:2.05). Conclusion: For partially dentate older patients, functionally orientated treatment based on the SDA concept resulted in sustained, significant improvements in OHrQOL. Provision of functionally orientated treatment was also more than twice as cost effective compared to conventional treatment using RPDs.

PAlliative Care in chronic Kidney diSease: the PACKS study—quality of life, decision making, costs and impact on carers in people managed without dialysis

BACKGROUND: The number of patients with advanced chronic kidney disease opting for conservative management rather than dialysis is unknown but likely to be growing as increasingly frail patients with advanced renal disease present to renal services. Conservative kidney management includes ongoing medical input and support from a multidisciplinary team. There is limited evidence concerning patient and carer experience of this choice. This study will explore quality of life, symptoms, cognition, frailty, performance decision making, costs and impact on carers in people with advanced chronic kidney disease managed without dialysis and is funded by the National Institute of Health Research in the UK.

METHODS: In this prospective, multicentre, longitudinal study, patients will be recruited in the UK, by renal research nurses, once they have made the decision not to embark on dialysis. Carers will be asked to 'opt-in' with consent from patients. The approach includes longitudinal quantitative surveys of quality of life, symptoms, decision making and costs for patients and quality of life and costs for carers, with questionnaires administered quarterly over 12 months. Additionally, the decision making process will be explored via qualitative interviews with renal physicians/clinical nurse specialists.

DISCUSSION: The study is designed to capture patient and carer profiles when conservative kidney management is implemented, and understand trajectories of care-receiving and care-giving with the aim of optimising palliative care for this population. It will explore the interactions that lead to clinical care decisions and the impact of these decisions on informal carers with the intention of improving clinical outcomes for patients and the experiences of care givers.

Protocol: Quality of Life, Decision Making, Costs and Impact on Carers in People Managed without Dialysis - The PACKS Study

Renal palliative care – where to after the PACKS study?

The PAlliative Care in chronic Kidney diSease study (PACKS study) is examining quality of life, decision making and decisional conflict, costs and mortality in patients with advanced chronic kidney disease who have opted for palliative care. It is also exploring the impact of the decision on the quality of life of carers. The study includes adult patients with end stage (stage 5) chronic kidney disease who have opted for palliative care, adult carers of these patients and renal physicians/clinical nurse specialists who have experience of treating patients with end stage chronic kidney disease who have opted for palliative care.
Early initial findings relate to clinician perspectives on patient decisional conflict, in making complex decisions between dialysis and conservative management. Interviews were conducted with nephrologists and clinical nurse specialists across 10 renal centres in the UK. Themes with associated subthemes include “Frequent changing of mind regarding treatment options,” “A paternalistic approach to decision-making and “Intricacy of the decision”. These findings will be presented and recommendations for future research and education made. Clinicians need to take a more patient centered approach to decision-making. Interventions aimed at increasing understanding of renal disease and its treatments may reduce decisional conflict and raise decisional quality but require testing in the renal specialty.