Cells deficient in the base excision repair protein, DNA polymerase beta, are hypersensitive to oxaliplatin chemotherapy

A significant proportion of human cancers overexpress DNA polymerase beta (Pol beta), the major DNA polymerase involved in base excision repair. The underlying mechanism and biological consequences of overexpression of this protein are unknown. We examined whether Pol beta, expressed at levels found in tumor cells, is involved in the repair of DNA damage induced by oxaliplatin treatment and whether the expression status of this protein alters the sensitivity of cells to oxaliplatin. DNA damage induced by oxaliplatin treatment of HCT116 and HT29 colon cancer cells was observed to be associated with the stabilization of Pol beta protein on chromatin. In comparison with HCT116 colon cancer cells, isogenic oxaliplatin-resistant (HCT-OR) cells were found to have higher constitutive levels of Pol beta protein, faster in vitro repair of a DNA substrate containing a single nucleotide gap and faster repair of 1,2-GG oxaliplatin adduct levels in cells. In HCT-OR cells, small interfering RNA knockdown of Pol beta delayed the repair of oxaliplatin-induced DNA damage. In a different model system, Pol beta-deficient fibroblasts were less able to repair 1,2-GG oxaliplatin adducts and were hypersensitive to oxaliplatin treatment compared with isogenic Pol beta-expressing cells. Consistent with previous studies, Pol beta-deficient mouse fibroblasts were not hypersensitive to cisplatin treatment. These data provide the first link between oxaliplatin sensitivity and DNA repair involving Pol beta. They demonstrate that Pol beta modulates the sensitivity of cells to oxaliplatin treatment. Oncogene (2010) 29, 463-468; doi:10.1038/onc.2009.327; published online 19 October 2009

Cholinesterase Inhibitor and Memantine Use in Newly Admitted Nursing Home Residents with Dementia

OBJECTIVES: To quantify the use of cholinesterase inhibitors (ChEIs) and memantine in nursing home (NH) residents with dementia upon NH admission and 3 months later and to examine factors associated with reduction in therapy.

DESIGN: Retrospective cohort study.

SETTING: Nationwide sample of U.S. NHs.

PARTICIPANTS: Three thousand ?ve hundred six NH residents with dementia newly admitted in 2006.

MEASUREMENTS: Data from pharmacy dispensing records were used to determine ChEI and memantine medication use upon NH admission and at 3-month follow-up. The Minimum Data Set was used to determine resident- and facility-level characteristics. Severity of dementia was de?ned using the Cognitive Performance Scale (CPS).

RESULTS: Overall, 40.1% (n51,407) of newly admitted NH residents with dementia received ChEIs and memantine on NH admission. Use of ChEIs and memantine on admission was significantly greater in residents with mild to moderately severe dementia (41.2%) than in those with advanced dementia (33.3%, P5.001). After 3 months, ChEI and memantine use decreased by about half in both groups (48.6% with mild to moderately severe dementia vs 57.0% with advanced dementia, Po.05). NH residents with advanced dementia were significantly more likely reduce their use of ChEIs and memantine than those with mild to moderately severe dementia (odds ratio 51.44, 95% con?dence interval 51.03–2.01, P5.04).

CONCLUSION: Many NH residents with advanced dementia receive ChEIs and memantine upon NH admission, and approximately half of these decrease their medication use over the ensuing months. Further study is required to optimize use of ChEIs and memantine in NH populations and to determine the effects of withdrawing therapy on resident outcomes.

Antimicrobial prescribing in Nursing Homes in Northern Ireland: Results of Two Point-Prevalence Surveys

BACKGROUND: In 2005, the European Commission recommended that all member states should establish or strengthen surveillance systems for monitoring the use of antimicrobial agents. There is no evidence in the literature of any surveillance studies having been specifically conducted in nursing homes (NHs) in Northern Ireland (NI).

OBJECTIVE: The aim of this study was to determine the prevalence of antimicrobial prescribing and its relationship with certain factors (e.g. indwelling urinary catheterization, urinary incontinence, disorientation, etc.) in NH residents in NI.

METHODS: This project was carried out in NI as part of a wider European study under the protocols of the European Surveillance of Antimicrobial Consumption group. Two point-prevalence surveys (PPSs) were conducted in 30 NHs in April and November 2009. Data were obtained from nursing notes, medication administration records and staff in relation to antimicrobial prescribing, facility and resident characteristics and were analysed descriptively.

RESULTS: The point prevalence of antimicrobial prescribing was 13.2% in April 2009 and 10.7% in November 2009, with a 10-fold difference existing between the NHs with the highest and lowest antimicrobial prescribing prevalence during both PPSs. The same NH had the highest rate of antimicrobial prescribing during both April (30.6%) and November (26.0%). The group of antimicrobials most commonly prescribed was the penicillins (April 28.6%, November 27.5%) whilst the most prevalent individual antimicrobial prescribed was trimethoprim (April 21.3%, November 24.3%). The majority of antimicrobials were prescribed for the purpose of preventing urinary tract infections (UTIs) in both April (37.8%) and in November (46.7%), with 5% of all participating residents being prescribed an antimicrobial for this reason. Some (20%) antimicrobials were prescribed at inappropriate doses, particularly those which were used for the purpose of preventing UTIs. Indwelling urinary catheterization and wounds were significant risk factors for antimicrobial use in April [odds ratio {OR} (95% CI) 2.0 (1.1, 3.5) and 1.8 (1.1, 3.0), respectively] but not in November 2009 [OR (95% CI) 1.6 (0.8, 3.2) and 1.2 (0.7, 2.2), respectively]. Other resident factors, e.g. disorientation, immobility and incontinence, were not associated with antimicrobial use. Furthermore, none of the NH characteristics investigated (e.g. number of beds, hospitalization episodes, number of general practitioners, etc.) were found to be associated with antimicrobial use in either April or November 2009.

CONCLUSIONS: This study has identified a high overall rate of antimicrobial use in NHs in NI, with variability evident both within and between homes. More research is needed to understand which factors influence antimicrobial use and to determine the appropriateness of antimicrobial prescribing in this population in general and more specifically in the management of recurrent UTIs.

Sedative load of medications prescribed for older people with dementia in care homes

The objective of this study was to determine the sedative load and use of sedative and psychotropic medications among older people with dementia living in (residential) care homes.

Antimicrobial prescribing in residential homes.

Objectives: Research in residential homes has been limited to date and the extent of systemic and topical antimicrobial prescribing is largely unknown. The aim of this study was to investigate antimicrobial prescribing in residential homes in Northern Ireland (NI).

Methods: Point prevalence studies (PPSs) were completed in November 2010 (PPS1) and April 2011 (PPS2) in 30 residential homes. Data were obtained from care plans, medication administration records and staff in relation to antimicrobial prescribing and facility and resident characteristics, and analysed descriptively.

Results: The point prevalence of systemic antimicrobial prescribing was 9.4% in PPS1 and 9.2% in PPS2 (range 0.0%–33.3% during both PPSs). Trimethoprim was the most commonly prescribed systemic antimicrobial and the main indication was the prevention of urinary tract infections. Almost 25% of systemic antimicrobials were prescribed at inappropriate doses. The point prevalence of topical antimicrobial prescribing was 6.4% (range 0.0%–22.2%) in PPS1 and 5.9% (range 0.0%–21.1%) in PPS2. The most commonly prescribed topical antimicrobials were chloramphenicol eye preparations in PPS1 and fusidic acid skin preparations in PPS2; treatment with these topical antimicrobials was generally prolonged. More than 25% of all systemic and 55% of all topical antimicrobials were initiated following telephone consultations as opposed to face-to-face consultations.

Conclusions: The prevalence of systemic antimicrobial prescribing in residential homes in NI is relatively high compared with care homes (particularly nursing homes) in other countries. Systemic and topical antimicrobial prescribing is not always appropriate in terms of the doses prescribed and the duration of use. It is apparent that current strategies employed in NI are insuf?cient to ensure prudent antimicrobial prescribing within this environment.

PLASTID DNA RESTRICTION ANALYSIS LINKS THE HETEROMORPHIC PHASES OF AN APOMICTIC RED ALGAL LIFE-HISTORY

Gymnogongrus sp. (Phyllophoraceae) from Nova Scotia, Canada, identified tentatively as G. devoniensis (Greville) Schotter, grows in association with an Erythrodermis-like crust that forms chains of tetrasporangia or bisporangia. The crust resembles tetrasporophytic phases of other Gymnogongrus species, but in culture both it and the G. ?devoniensis gametophytes cycle independently by apomictic reproduction.

"They come with multiple morbidities":a qualitative assessment of pharmacist prescribing

This paper presents qualitative findings from a larger sequential mixed methods study which sought to provide an in-depth understanding of pharmacist prescribing from the perspective of pharmacist prescribers, medical colleagues and key stakeholders in Northern Ireland. Transcriptions were analyzed using thematic analysis as the interviews progressed and emergent themes were identified and coded (along with supporting quotes) independently and by consensus of the research team. Three major themes emerged in relation to pharmacist prescribing: the effect on patient care; challenges facing pharmacist prescribers and the importance of the interprofessional team (where two or more different professions with varied, yet complementary experience work together with a common purpose). Pharmacist prescribing may have the potential to reduce the medication burden for patients (as reported by pharmacists) as pharmacists tend to provide a more comprehensive medication review than doctors; the additional time for consultations made this possible. Further research is required on how interprofessional team working can be maximized in the context of pharmacist prescribing, particularly in relation to the management of multi-morbidity.

Withholding, discontinuing and withdrawing medications in dementia patients at the end of life:a neglected problem in the disadvantaged dying?

Recent years have seen a growing recognition that dementia is a terminal illness and that patients with advanced dementia nearing the end of life do not currently receive adequate palliative care. However, research into palliative care for these patients has thus far been limited. Furthermore, there has been little discussion in the literature regarding medication use in patients with advanced dementia who are nearing the end of life, and discontinuation of medication has not been well studied despite its potential to reduce the burden on the patient and to improve quality of life. There is limited, and sometimes contradictory, evidence available in the literature to guide evidence-based discontinuation of drugs such as acetylcholinesterase inhibitors, antipsychotic agents, HMG-CoA reductase inhibitors (statins), antibacterials, antihypertensives, antihyperglycaemic drugs and anticoagulants. Furthermore, end-of-life care of patients with advanced dementia may be complicated by difficulties in accurately estimating life expectancy, ethical considerations regarding withholding or withdrawing treatment, and the wishes of the patient and/or their family. Significant research must be undertaken in the area of medication discontinuation in patients with advanced dementia nearing the end of life to determine how physicians currently decide whether medications should be discontinued, and also to develop the evidence base and provide guidance on systematic medication discontinuation.