Drugs affecting the renin-angiotensin system and survival from cancer: a population based study of breast, colorectal and prostate cancer patient cohorts

Background: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are commonly prescribed to the growing number of cancer patients (more than two million in the UK alone) often to treat hypertension. However, increased fatal cancer in ARB users in a randomized trial and increased breast cancer recurrence rates in ACEI users in a recent observational study have raised concerns about their safety in cancer patients. We investigated whether ACEI or ARB use after breast, colorectal or prostate cancer diagnosis was associated with increased risk of cancer-specific mortality.

Methods: Population-based cohorts of 9,814 breast, 4,762 colorectal and 6,339 prostate cancer patients newly diagnosed from 1998 to 2006 were identified in the UK Clinical Practice Research Datalink and confirmed by cancer registry linkage. Cancer-specific and all-cause mortality were identified from Office of National Statistics mortality data in 2011 (allowing up to 13 years of follow-up). A nested case–control analysis was conducted to compare ACEI/ARB use (from general practitioner prescription records) in cancer patients dying from cancer with up to five controls (not dying from cancer). Conditional logistic regression estimated the risk of cancer-specific, and all-cause, death in ACEI/ARB users compared with non-users.

Results: The main analysis included 1,435 breast, 1,511 colorectal and 1,184 prostate cancer-specific deaths (and 7,106 breast, 7,291 colorectal and 5,849 prostate cancer controls). There was no increase in cancer-specific mortality in patients using ARBs after diagnosis of breast (adjusted odds ratio (OR) = 1.06 95% confidence interval (CI) 0.84, 1.35), colorectal (adjusted OR = 0.82 95% CI 0.64, 1.07) or prostate cancer (adjusted OR = 0.79 95% CI 0.61, 1.03). There was also no evidence of increases in cancer-specific mortality with ACEI use for breast (adjusted OR = 1.06 95% CI 0.89, 1.27), colorectal (adjusted OR = 0.78 95% CI 0.66, 0.92) or prostate cancer (adjusted OR = 0.78 95% CI 0.66, 0.92).

Conclusions: Overall, we found no evidence of increased risks of cancer-specific mortality in breast, colorectal or prostate cancer patients who used ACEI or ARBs after diagnosis. These results provide some reassurance that these medications are safe in patients diagnosed with these cancers.

Keywords: Colorectal cancer; Breast cancer; Prostate cancer; Mortality; Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers

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.

Impact of tooth replacement strategies on the nutritional status of partially-dentate elders

OBJECTIVE: To investigate the impact of tooth replacement on the nutritional status of partially dentate older patients, and, to compare two different tooth replacement strategies; conventional treatment using removable partial dentures and functionally orientated treatment based on the shortened dental arch.

BACKGROUND: Amongst older patients, diet plays a key role in disease prevention, as poor diets have been linked to numerous illnesses. Poor oral health and loss of teeth can have very significant negative effects on dietary intake and nutritional status for elderly patients. There is evidence that good oral health generally, has positive effects on the nutritional intake of older adults.

MATERIALS AND METHODS: A randomised, controlled clinical trial was designed to investigate the impact of tooth replacement on the nutritional status of partially dentate elders. Forty-four patients aged over 65 years completed the trial, with 21 allocated to conventional treatment and 23 allocated to functionally orientated treatment. Nutritional status was accessed at baseline and after treatment using the Mini Nutritional Assessment (MNA) and a range of haematological markers.

RESULTS: At baseline, relationships were observed between the number of occluding tooth contacts and some measures of nutritional status. As the number of contacts increased, MNA scores (R = 0.16), in addition to vitamin B12 (R = 0.21), serum folate (R = 0.32) and total lymphocyte count (R = 0.35), also increased. After treatment intervention, the only measure of nutritional status that showed a statistically significant improvement for both treatment groups was MNA score (p = 0.03). No significant between group differences were observed from analysis of the haematological data.

CONCLUSION: In this study, prosthodontic rehabilitation with both conventional treatment and functionally orientated treatment resulted in an improvement in MNA score. Haematological markers did not illustrate a clear picture of improvement in nutritional status for either treatment group.

Accelerated rehabilitation of an edentulous patient with an implant retained dental prosthesis: a case report

This case report details the successful rehabilitation of an edentulous patient using a complete upper prosthesis and a lower implant retained overdenture. The provision of care was split between a specialist centre and a primary care setting. This approach reduced inconvenience to the patient. Modern surgical and prosthodontic techniques also reduced the total delivery time. After initial consultation a new set of complete dentures was prescribed with changes in design to the originals. The patient was also planned for placement of two mandibular implants to stabilise and retain the mandibular denture. The first line of treatment involved provision of a new set of dentures constructed by the patient's general dental practitioner. Dental implants were then placed in a specialist centre and the patient returned to the dental practice for attachment of the lower denture to the dental implants. The benefits and success of mandibular implant retained dentures are well documented. With delivery of the overdenture, the patient reported increased satisfaction with his prostheses which allowed him to eat a greater range of foods and enabled him to feel confident when speaking and socialising.

Rules and Stereoelectronic Guidelines for the Anionic Nucleophilic Displacement of Furanoside and Furanose O-sulfonates

Rules for predicting anionic S_N2 displacement viability in furanose and furanoside sulfonates are presented

Comparative analysis of Klebsiella pneumoniae genomes identifies a phospholipase D family protein as a novel virulence factor

BACKGROUND: Klebsiella pneumoniae strains are pathogenic to animals and humans, in which they are both a frequent cause of nosocomial infections and a re-emerging cause of severe community-acquired infections. K. pneumoniae isolates of the capsular serotype K2 are among the most virulent. In order to identify novel putative virulence factors that may account for the severity of K2 infections, the genome sequence of the K2 reference strain Kp52.145 was determined and compared to two K1 and K2 strains of low virulence and to the reference strains MGH 78578 and NTUH-K2044.

RESULTS: In addition to diverse functions related to host colonization and virulence encoded in genomic regions common to the four strains, four genomic islands specific for Kp52.145 were identified. These regions encoded genes for the synthesis of colibactin toxin, a putative cytotoxin outer membrane protein, secretion systems, nucleases and eukaryotic-like proteins. In addition, an insertion within a type VI secretion system locus included sel1 domain containing proteins and a phospholipase D family protein (PLD1). The pld1 mutant was avirulent in a pneumonia model in mouse. The pld1 mRNA was expressed in vivo and the pld1 gene was associated with K. pneumoniae isolates from severe infections. Analysis of lipid composition of a defective E. coli strain complemented with pld1 suggests an involvement of PLD1 in cardiolipin metabolism.

CONCLUSIONS: Determination of the complete genome of the K2 reference strain identified several genomic islands comprising putative elements of pathogenicity. The role of PLD1 in pathogenesis was demonstrated for the first time and suggests that lipid metabolism is a novel virulence mechanism of K. pneumoniae.

Seasonal and geographical differences in aflatoxin exposures in Senegal

The aim of the study was to determine the geographical and seasonal variations in aflatoxin dietary exposure levels in adults from Senegal. A total of 168 adults (50% male) were recruited from three districts: Nioro du Rip (n=90), located in the Sudan Savannah agro-ecological zone where rainfall is sufficient for groundnut growth; Saint-Louis (n=40) and Mboro (n=38), located in the Sahel zone where groundnuts are produced under irrigated conditions. Diet information and samples were collected at groundnut harvest and post-harvest seasons. Plasma aflatoxin-albumin adducts (AF-alb) and total aflatoxin in household groundnut samples were measured by ELISA and a quantitative thin layer chromatography method, respectively. The blood AF-alb geometric mean was 45.7 pg/mg albumin (range 5.5-588.2 pg/mg). Nioro du Rip had a higher AF-alb level at harvest than Saint-Louis and Mboro (80.0 vs 15.6 and 33.3 pg/mg, P<0.001). Similar trends were observed at post-harvest (P<0.05). Seasonal trends were not consistent across the districts as Nioro du Rip had a higher AF-alb level at harvest than post-harvest (80.0 vs 58.6 pg/mg, P=0.026), whereas Saint-Louis had a higher level at post-harvest than harvest (25.6 vs 15.6 pg/mg, P=0.032). It is clear that aflatoxin exposure is prevalent in adults from Senegal and that season and geographical location are strong determinants of aflatoxin exposure.

Improving composite damage modelling through automatic placement of cohesive elements

Numerous experimental studies of damage in composite laminates have shown that intralaminar (in-plane) matrix cracks lead to interlaminar delamination (out-of-plane) at ply interfaces. The smearing of in-plane cracks over a volume, as a consequence of the use of continuum damage mechanics, does not always effectively capture the full extent of the interaction between the two failure mechanisms. A more accurate representation is obtained by adopting a discrete crack approach via the use of cohesive elements, for both in-plane and out-of-plane damage. The difficulty with cohesive elements is that their location must be determined a priori in order to generate the model; while ideally the position of the crack migration, and more generally the propagation path, should be obtained as part of the problem’s solution. With the aim of enhancing current modelling capabilities with truly predictive capabilities, a concept of automatic insertion of interface elements is utilized. The consideration of a simple traction criterion in relation to material strength, evaluated at each node of the model (or of the regions of the model where it is estimated cracks might form), allows for the determination of initial crack location and subsequent propagation by the insertion of cohesive elements during the course of the analysis. Several experimental results are modelled using the commercial package ABAQUS/Standard with an automatic insertion subroutine developed in this work, and the results are presented to demonstrate the capabilities of this technique.

Metabolomics reveals novel biomarkers of illegal 5-nitromimidazole treatment in pigs. Further evidence of drug toxicity uncovered

The aim of the study was to investigate the potential of a metabolomics platform to distinguish between pigs treated with ronidazole, dimetridazole and metronidazole and non-medicated animals (controls), at two withdrawal periods (day 0 and 5). Livers from each animal were biochemically profiled using UHPLC–QTof-MS in ESI+ mode of acquisition. Several Orthogonal Partial Least Squares-Discriminant Analysis models were generated from the acquired mass spectrometry data. The models classified the two groups control and treated animals. A total of 42 ions of interest explained the variation in ESI+. It was possible to find the identity of 3 of the ions and to positively classify 4 of the ionic features, which can be used as potential biomarkers of illicit 5-nitroimidazole abuse. Further evidence of the toxic mechanisms of 5-nitroimidazole drugs has been revealed, which may be of substantial importance as metronidazole is widely used in human medicine.