Pharmacological assessment of ibuprofen arginate on platelet aggregation and colon cancer cell killing.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, are amongst the most commonly used medications and produce their anti-inflammatory and analgesic benefits by blocking cyclooxygenase (COX)-2. These drugs also have the potential to prevent and treat cancer and some members of the class including ibuprofen can produce anti-platelet effects. Despite their utility, all NSAIDs are associated with increased risk of cardiovascular side effects which our recent work suggests could be mediated by increased levels of the endogenous NO synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) leading to reduced endothelial NOS activity and associated endothelial cell dysfunction. ADMA is a cardiotoxic hormone and biomarker of cardiovascular risk whose effects can be prevented by l-arginine. The ibuprofen salt, ibuprofen arginate (Spididol®) was created to increase drug solubility but we have previously established that it not only effectively blocks COX-2 but also provides an arginine source able to reverse the effects of ADMA in vitro and in vivo. Here we have gone on to explore whether the formulation of ibuprofen with arginine influences the potency and efficacy of the parent molecule using a range of simple in vitro assays designed to test the effects of NSAIDs on (i) platelet aggregation and (iii) colon cancer cell killing. Our findings demonstrate that ibuprofen arginate retains these key functional effects of NSAIDs with similar or increased potency compared to ibuprofen sodium, further illustrating the potential of ibuprofen arginate as an efficacious drug with the possibility of improved cardiovascular safety.

High rate of hepatitis C virus (HCV) recurrence in HIV-infected individuals with spontaneous HCV RNA clearance.

OBJECTIVES: Following resolution of hepatitis C virus (HCV) infection, recurrence has been shown to occur in some persons with repeated exposure to HCV. We aimed to investigate the rate and factors associated with HCV RNA recurrence among HIV-1-infected patients with prior spontaneous HCV RNA clearance in the EuroSIDA cohort. METHODS: All HIV-infected patients with documented prior spontaneous HCV clearance, and at least one subsequently collected plasma sample, were examined. The last sample was tested for HCV RNA and those with HCV RNA ≥ 615 IU/mL were defined as having HCV recurrence and their characteristics were compared with those of patients who were still aviraemic. Logistic regression was used to identify factors associated with HCV recurrence. RESULTS: Of 191 eligible patients, 35 [18.3%; 95% confidence interval (CI) 12.8-23.8%] had HCV recurrence. Thirty-three (94.3%) were injecting drug users (IDUs). The median time between the first and last samples was 3.6 years (interquartile range 2.0-5.8 years). After adjustment, those on combination antiretroviral therapy [odds ratio (OR) 0.44; 95% CI 0.20-0.99; P = 0.046] and older persons (OR 0.51 per 10 years older; 95% CI 0.28-0.95; P = 0.033) were less likely to have HCV RNA recurrence, whereas IDUs were over 6 times more likely to have HCV RNA recurrence compared with non-IDUs (OR 6.58; 95% CI 1.48-29.28; P = 0.013). CONCLUSIONS: Around 1 in 5 HIV-infected patients with prior spontaneous HCV RNA clearance had detectable HCV RNA during follow-up. Our findings underline the importance of maintaining focus on preventive measures to reduce IDU and sharing of contaminated needles. Clinicians should maintain a high degree of vigilance to identify patients with new HCV infection early.

Altered bacterial profiles in saliva from adults with caries lesions: a case-cohort study.

The aim of this study was to learn whether presence of caries in an adult population was associated with a salivary bacterial profile different from that of individuals without untreated caries. Stimulated saliva samples from 621 participants of the Danish Health Examination Survey were analyzed using the Human Oral Microbe Identification Microarray technology. Samples from 174 individuals with dental caries and 447 from a control cohort were compared using frequency and levels of identified bacterial taxa/clusters as endpoints. Differences at taxon/cluster level were analyzed using Mann-Whitney's test with Benjamini-Hochberg correction for multiple comparisons. Principal component analysis was used to visualize bacterial community profiles. A reduced bacterial diversity was observed in samples from subjects with dental caries. Five bacterial taxa (Veillonella parvula, Veillonella atypica, Megasphaera micronuciformis, Fusobacterium periodontium and Achromobacter xylosoxidans) and one bacterial cluster (Leptotrichia sp. clones C3MKM102 and GT018_ot417/462) were less frequently found in the caries group (adjusted p value <0.01) while two bacterial taxa (Solobacterium moorei and Streptococcus salivarius) and three bacterial clusters (Streptococcus parasanguinis I and II and sp. clone BE024_ot057/411/721, Streptococcus parasanguinis I and II and sinensis_ot411/721/767, Streptococcus salivarius and sp. clone FO042_ot067/755) were present at significantly higher levels (adjusted p value <0.01). The principal component analysis displayed a marked difference in the bacterial community profiles between groups. Presence of manifest caries was associated with a reduced diversity and an altered salivary bacterial community profile. Our data support recent theories that ecological stress-induced changes of commensal microbial communities are involved in the shift from oral health to tooth decay.

The time course of development and impact from viral resistance against ganciclovir in cytomegalovirus infection.

(Val)ganciclovir is used to treat cytomegalovirus (CMV) infection following solid organ (SOT) or hematopoietic stem cell (HSCT) transplantation. Treatment failures occur, but the contribution from 39 known ganciclovir-related mutations (GRMs) in the CMV-UL97 gene remains controversial. We propose a categorization of these GRMs potentially useful when interpreting sequence analyses in clinical settings. The UL97 gene was sequenced from first/recurrent CMV infections among consecutive SOT or HSCT recipients during 2004-2009. GRMs were categorized as: Signature GRM (sGRM) if in vitro ganciclovir IC(50) ratio for mutated versus wild-type virus >2 (n = 24); polymorphic GRM (pGRM) if ratio <2 (n = 15). (Val)ganciclovir treatment failure was defined as persistent viremia for 30 days or switch to foscarnet within this period. Of 99 (49 HSCT and 50 SOT) recipients with one CMV infection episode, 15 (13 HSCT and 2 SOT) experienced a total of 19 recurrent infection episodes. The prevalence of sGRM was 0% at start of first episode, whereas at start of recurrent episodes, prevalence was 37%. Only one sGRM was present at a time in individual patients. Patients with CMV containing an sGRM (vs. wild type)-but not with a pGRM-were at excess risk of treatment failure (odds ratio = 70.6 [95% CI:8.2-609.6]; p < 0.001). sGRMs emerged only following longer termed use of antiherpetic drugs and usually in recurrent CMV infection episodes. Risk of ganciclovir treatment failure was raised if an sGRM was detected.

An Update to the Malthus Model for Radiotherapy Utilisation in England.

AIMS: The Malthus Programme predicts national and local radiotherapy demand by combining cancer incidence data with decision trees detailing the indications, and appropriate dose fractionation, for radiotherapy. Since the last model update in 2017, technological advancements and the COVID-19 pandemic have led to increasing hypofractionation of radiotherapy schedules. Indications for radiotherapy have also evolved, particularly in the context of oligometastatic disease. Here we present a brief update on the model for 2021. We have updated the decision trees for breast, prostate, lung and head and neck cancers, and incorporated recent cancer incidence data into our model, generating a current estimate of fraction demand for these four cancer sites across England. MATERIALS AND METHODS: The decision tree update was based on evidence from practice-changing randomised controlled trials, published guidelines, audit data and expert opinion. Site- and stage-specific incidence data were taken from the National Disease Registration Service. We used the updated model to estimate the proportion of patients who would receive radiotherapy (appropriate rate of radiotherapy) and the fraction demand per million population at a national and Clinical Commissioning Group level in 2021. RESULTS: The total predicted fraction demand has decreased by 11.4% across all four cancer sites in our new model, compared with the 2017 version. This reduction can be explained primarily by greater use of hypofractionated treatments (including stereotactic ablative radiotherapy) and a shift towards earlier stage presentation. The only large change in appropriate rate of radiotherapy was an absolute decrease of 3% for lung cancer. CONCLUSIONS: Compared with our previous model, the current version predicts a reduction in fraction demand across England. This is driven principally by hypofractionation of radiotherapy regimens, using technology that requires increasingly complex planning. Treatment complexity and local service factors need to be taken into account when translating fraction burden into linear accelerator demand or throughput.

Variations in Demand across England for the Magnetic Resonance-Linac Technology, Simulated Utilising Local-level Demographic and Cancer Data in the Malthus Project.

AIMS: Cancer incidence varies across England, which affects the local-level demand for treatments. The magnetic resonance-linac (MR-linac) is a new radiotherapy technology that combines imaging and treatment. Here we model the demand and demand variations for the MR-linac across England. MATERIALS AND METHODS: Initial clinical indications were provided by the MR-linac consortium and introduced into the Malthus radiotherapy clinical decision trees. The Malthus model contains Clinical Commissioning Group (CCG) population, cancer incidence and stage presentation data (for lung and prostate) and simulated the demand for the MR-linac for all CCGs and Radiotherapy Operational Delivery Networks (RODN) across England. RESULTS: Based on the initial target clinical indications, the MR-linac could service 16% of England's fraction burden. The simulated fractions/million population demand/annum varies between 3000 and 10 600 fractions/million at the CCG level. Focussing only on the cancer population, the simulated fractions/1000 cancer cases demand/annum ranges from 1028 to 1195 fractions/1000 cases. If a national average for fractions/million demand was then used, at the RODN level, the variation from actual annual demand ranges from an overestimation of 8400 fractions to an underestimation of 5800 fractions. When using the national average fractions/1000 cases, the RODN demand varies from an overestimation of 3200 fractions to an underestimation of 3000 fractions. CONCLUSIONS: Planning cancer services is complex due to regional variations in cancer burden. The variations in simulated demand of the MR-linac highlight the requirement to use local-level data when planning to introduce a new technology.

Determining the parameter space for effective oxygen depletion for FLASH radiation therapy.

There has been a recent revival of interest in the FLASH effect, after experiments have shown normal tissue sparing capabilities of ultra-high-dose-rate radiation with no compromise on tumour growth restraint. A model has been developed to investigate the relative importance of a number of fundamental parameters considered to be involved in the oxygen depletion paradigm of induced radioresistance. An example eight-dimensional parameter space demonstrates the conditions under which radiation may induce sufficient depletion of oxygen for a diffusion-limited hypoxic cellular response. Initial results support experimental evidence that FLASH sparing is only achieved for dose rates on the order of tens of Gy s-1or higher, for a sufficiently high dose, and only for tissue that is slightly hypoxic at the time of radiation. We show that the FLASH effect is the result of a number of biological, radiochemical and delivery parameters. Also, the threshold dose for a FLASH effect occurring would be more prominent when the parameterisation was optimised to produce the maximum effect. The model provides a framework for further FLASH-related investigation and experimental design. An understanding of the mechanistic interactions producing an optimised FLASH effect is essential for its translation into clinical practice.

Antibiotic resistance in Pseudomonas aeruginosa strains with increased mutation frequency due to inactivation of the DNA oxidative repair system.

The chronic Pseudomonas aeruginosa infection of the lungs of cystic fibrosis (CF) patients is characterized by the biofilm mode of growth and chronic inflammation dominated by polymorphonuclear leukocytes (PMNs). A high percentage of P. aeruginosa strains show high frequencies of mutations (hypermutators [HP]). P. aeruginosa is exposed to oxygen radicals, both those generated by its own metabolism and especially those released by a large number of PMNs in response to the chronic CF lung infection. Our work therefore focused on the role of the DNA oxidative repair system in the development of HP and antibiotic resistance. We have constructed and characterized mutT, mutY, and mutM mutants in P. aeruginosa strain PAO1. The mutT and mutY mutants showed 28- and 7.5-fold increases in mutation frequencies, respectively, over that for PAO1. These mutators had more oxidative DNA damage (higher levels of 7,8-dihydro-8-oxodeoxyguanosine) than PAO1 after exposure to PMNs, and they developed resistance to antibiotics more frequently. The mechanisms of resistance were increased beta-lactamase production and overexpression of the MexCD-OprJ efflux-pump. Mutations in either the mutT or the mutY gene were found in resistant HP clinical isolates from patients with CF, and complementation with wild-type genes reverted the phenotype. In conclusion, oxidative stress might be involved in the development of resistance to antibiotics. We therefore suggest the possible use of antioxidants for CF patients to prevent the development of antibiotic resistance.

Mechanistic modelling supports entwined rather than exclusively competitive DNA double-strand break repair pathway.

Following radiation induced DNA damage, several repair pathways are activated to help preserve genome integrity. Double Strand Breaks (DSBs), which are highly toxic, have specified repair pathways to address them. The main repair pathways used to resolve DSBs are Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR). Cell cycle phase determines the availability of HR, but the repair choice between pathways in the G2 phases where both HR and NHEJ can operate is not clearly understood. This study compares several in silico models of repair choice to experimental data published in the literature, each model representing a different possible scenario describing how repair choice takes place. Competitive only scenarios, where initial protein recruitment determines repair choice, are unable to fit the literature data. In contrast, the scenario which uses a more entwined relationship between NHEJ and HR, incorporating protein co-localisation and RNF138-dependent removal of the Ku/DNA-PK complex, is better able to predict levels of repair similar to the experimental data. Furthermore, this study concludes that co-localisation of the Mre11-Rad50-Nbs1 (MRN) complexes, with initial NHEJ proteins must be modeled to accurately depict repair choice.

Clinically relevant nanodosimetric simulation of DNA damage complexity from photons and protons.

Relative Biological Effectiveness (RBE), the ratio of doses between radiation modalities to produce the same biological endpoint, is a controversial and important topic in proton therapy. A number of phenomenological models incorporate variable RBE as a function of Linear Energy Transfer (LET), though a lack of mechanistic description limits their applicability. In this work we take a different approach, using a track structure model employing fundamental physics and chemistry to make predictions of proton and photon induced DNA damage, the first step in the mechanism of radiation-induced cell death. We apply this model to a proton therapy clinical case showing, for the first time, predictions of DNA damage on a patient treatment plan. Our model predictions are for an idealised cell and are applied to an ependymoma case, at this stage without any cell specific parameters. By comparing to similar predictions for photons, we present a voxel-wise RBE of DNA damage complexity. This RBE of damage complexity shows similar trends to the expected RBE for cell kill, implying that damage complexity is an important factor in DNA repair and therefore biological effect.

In Silico Models of DNA Damage and Repair in Proton Treatment Planning: A Proof of Concept.

There is strong in vitro cell survival evidence that the relative biological effectiveness (RBE) of protons is variable, with dependence on factors such as linear energy transfer (LET) and dose. This is coupled with the growing in vivo evidence, from post-treatment image change analysis, of a variable RBE. Despite this, a constant RBE of 1.1 is still applied as a standard in proton therapy. However, there is a building clinical interest in incorporating a variable RBE. Recently, correlations summarising Monte Carlo-based mechanistic models of DNA damage and repair with absorbed dose and LET have been published as the Manchester mechanistic (MM) model. These correlations offer an alternative path to variable RBE compared to the more standard phenomenological models. In this proof of concept work, these correlations have been extended to acquire RBE-weighted dose distributions and calculated, along with other RBE models, on a treatment plan. The phenomenological and mechanistic models for RBE have been shown to produce comparable results with some differences in magnitude and relative distribution. The mechanistic model found a large RBE for misrepair, which phenomenological models are unable to do. The potential of the MM model to predict multiple endpoints presents a clear advantage over phenomenological models.

The endothelin system as a therapeutic target in cardiovascular disease: great expectations or bleak house?

There is considerable evidence that the potent vasoconstrictor endothelin-1 (ET-1) contributes to the pathogenesis of a variety of cardiovascular diseases. As such, pharmacological manipulation of the ET system might represent a promising therapeutic goal. Many clinical trials have assessed the potential of ET receptor antagonists in cardiovascular disease, the most positive of which have resulted in the licensing of the mixed ET receptor antagonist bosentan, and the selective ET(A) receptor antagonists, sitaxsentan and ambrisentan, for the treatment of pulmonary arterial hypertension (PAH). In contrast, despite encouraging data from in vitro and animal studies, outcomes in human heart failure have been disappointing, perhaps illustrating the risk of extrapolating preclinical work to man. Many further potential applications of these compounds, including resistant hypertension, chronic kidney disease, connective tissue disease and sub-arachnoid haemorrhage are currently being investigated in the clinic. Furthermore, experience from previous studies should enable improved trial design and scope remains for development of improved compounds and alternative therapeutic strategies. Although ET-converting enzyme inhibitors may represent one such alternative, there have been relatively few suitable compounds developed, and consequently, clinical experience with these agents remains extremely limited. Recent advances, together with an increased understanding of the biology of the ET system provided by improved experimental tools (including cell-specific transgenic deletion of ET receptors), should allow further targeting of clinical trials to diseases in which ET is involved and allow the therapeutic potential for targeting the ET system in cardiovascular disease to be fully realized.

Mathematical Modelling for Patient Selection in Proton Therapy.

Proton beam therapy (PBT) is still relatively new in cancer treatment and the clinical evidence base is relatively sparse. Mathematical modelling offers assistance when selecting patients for PBT and predicting the demand for service. Discrete event simulation, normal tissue complication probability, quality-adjusted life-years and Markov Chain models are all mathematical and statistical modelling techniques currently used but none is dominant. As new evidence and outcome data become available from PBT, comprehensive models will emerge that are less dependent on the specific technologies of radiotherapy planning and delivery.

In Silico Non-Homologous End Joining Following Ion Induced DNA Double Strand Breaks Predicts That Repair Fidelity Depends on Break Density.

This work uses Monte Carlo simulations to investigate the dependence of residual and misrepaired double strand breaks (DSBs) at 24 hours on the initial damage pattern created during ion therapy. We present results from a nanometric DNA damage simulation coupled to a mechanistic model of Non-Homologous End Joining, capable of predicting the position, complexity, and repair of DSBs. The initial damage pattern is scored by calculating the average number of DSBs within 70 nm from every DSB. We show that this local DSB density, referred to as the cluster density, can linearly predict misrepair regardless of ion species. The models predict that the fraction of residual DSBs is constant, with 7.3% of DSBs left unrepaired following 24 hours of repair. Through simulation over a range of doses and linear energy transfer (LET) we derive simple correlations capable of predicting residual and misrepaired DSBs. These equations are applicable to ion therapy treatment planning where both dose and LET are scored. This is demonstrated by applying the correlations to an example of a clinical proton spread out Bragg peak. Here we see a considerable biological effect past the distal edge, dominated by residual DSBs.

Tumour Volume and Dose Influence Outcome after Surgery and High-dose Photon Radiotherapy for Chordoma and Chondrosarcoma of the Skull Base and Spine.

AIMS: To evaluate the long-term outcomes of patients with chordoma and low-grade chondrosarcoma after surgery and high-dose radiotherapy. MATERIALS AND METHODS: High-dose photon radiotherapy was delivered to 28 patients at the Neuro-oncology Unit at Addenbrooke's Hospital (Cambridge, UK) between 1996 and 2016. Twenty-four patients were treated with curative intent, 17 with chordoma, seven with low-grade chondrosarcoma, with a median dose of 65 Gy (range 65-70 Gy). Local control and survival rates were calculated using the Kaplan-Meier method. RESULTS: The median follow-up was 83 months (range 7-205 months). The 5 year disease-specific survival for chordoma patients treated with radical intent was 85%; the local control rate was 74%. The 5 year disease-specific survival for chondrosarcoma patients treated with radical intent was 100%; the local control rate was 83%. The mean planning target volume (PTV) was 274.6 ml (median 124.7 ml). A PTV of 110 ml or less was a good predictor of local control, with 100% sensitivity and 63% specificity. For patients treated with radical intent, this threshold of 110 ml or less for the PTV revealed a statistically significant difference when comparing local control with disease recurrence (P = 0.019, Fisher's exact test). Our data also suggest that the probability of disease control may be partly related to both target volume and radiotherapy dose. CONCLUSION: Our results show that refined high-dose photon radiotherapy, following tumour resection by a specialist surgical team, is effective in the long-term control of chordoma and low-grade chondrosarcoma, even in the presence of metal reconstruction. The results presented here will provide a useful source for comparison between high-dose photon therapy and proton beam therapy in a UK setting, in order to establish best practice for the management of chordoma and low-grade chondrosarcoma.

Cytomegalovirus (CMV) Disease Despite Weekly Preemptive CMV Strategy for Recipients of Solid Organ and Hematopoietic Stem Cell Transplantation.

BACKGROUND: Transplant recipients presenting with cytomegalovirus (CMV) disease at the time of diagnosis of CMV DNAemia pose a challenge to a preemptive CMV management strategy. However, the rate and risk factors of such failure remain uncertain. METHODS: Solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT) recipients with a first episode of CMV polymerase chain reaction (PCR) DNAemia within the first year posttransplantation were evaluated (n = 335). Patient records were reviewed for presence of CMV disease at the time of CMV DNAemia diagnosis. The distribution and prevalence of CMV disease were estimated, and the odds ratio (OR) of CMV disease was modeled using logistic regression. RESULTS: The prevalence of CMV disease increased for both SOT and HSCT with increasing diagnostic CMV PCR load and with screening intervals >14 days. The only independent risk factor in multivariate analysis was increasing CMV DNAemia load of the diagnostic CMV PCR (OR = 6.16; 95% confidence interval, 2.09-18.11). Among recipients receiving weekly screening (n = 147), 16 (10.8%) had CMV disease at the time of diagnosis of CMV DNAemia (median DNAemia load 628 IU/mL; interquartile range, 432-1274); 93.8% of these cases were HSCT and lung transplant recipients. CONCLUSIONS: Despite application of weekly screening intervals, HSCT and lung transplant recipients in particular presented with CMV disease at the time of diagnosis of CMV DNAemia. Additional research to improve the management of patients at risk of presenting with CMV disease at low levels of CMV DNAemia and despite weekly screening is warranted.

Impact of Oral Hygiene Discontinuation on Supragingival and Salivary Microbiomes.

The purpose of the present study was to characterize and compare supragingival and salivary microbiotas during a 10-d period of oral hygiene discontinuation. We tested the hypothesis that the composition of the salivary microbiota will reflect local microbial changes associated with accumulated biofilm formation and maturation. Pooled supragingival plaque (n = 145) and stimulated saliva (n = 145) samples were collected and plaque and gingival indices were recorded from 29 orally healthy individuals at baseline, during oral hygiene discontinuation (days 4, 7, and 10), and 14 d after resumption of oral hygiene. Supragingival and salivary microbiotas were processed by next-generation sequencing (Human Oral Microbe Identification using Next Generation Sequencing) and microbial community profiles were compared. Microbial composition of supragingival plaque samples collected after 4, 7, and 10 d of oral hygiene discontinuation, as well as 14 d after reuptake of oral hygiene, differed significantly from baseline samples, by a 3-fold increase in relative abundance Leptotrichia species and a 2-fold decrease in Streptococcus species (adjusted P < 0.01). In saliva samples, a significant increase in relative abundance of Leptotrichia species (adjusted P < 0.01) was evident at day 7 but completely reversed 14 d after resumption of oral hygiene. While the salivary microbiota was resistant to accumulated local biofilm formation, data from this study showed that compositional changes of supragingival microbiotas were not reversed 14 d after resumption of oral hygiene, despite the restoration of plaque to baseline levels. (ClinicalTrials.gov UCPH_OI_002, NCT02913235). Knowledge Transfer Statement: Data from this study showed compositional changes of supragingival microbiotas as a consequence of a 10-d period of oral hygiene discontinuation, that was not reversed 14 d after resumption of oral hygiene. Notably, oral hygiene discontinuation was associated with a significant increase in relative abundance of potential cariogenic Leptotrichia species and a decrease in Streptococcus species. Thus, findings from this study highlight the necessity of regular oral hygiene in the maintenance of oral homeostasis.

Early radiotherapy dose response and lack of hypersensitivity effect in normal brain tissue: a sequential dynamic susceptibility imaging study of cerebral perfusion.

AIMS: To determine if magnetic resonance perfusion markers can be used as an analytical marker of subclinical normal brain injury after radiotherapy, by looking for a dose-effect relationship. MATERIALS AND METHODS: Four patients undergoing conformal radiotherapy to 54Gy in 30 fractions for low-grade gliomas were imaged with conventional T(2)-weighted and fluid attenuated inversion recovery imaging as well as dynamic contrast susceptibility perfusion imaging. Forty regions of interest were determined from the periventricular white matter. All conventional sequences were examined for evidence of radiation-induced changes. Patients were imaged before radiotherapy, after one fraction, at the end of treatment and then at 1 and 3 months from the end of radiotherapy. For each region the relative cerebral blood volume (rCBV), relative cerebral blood flow (rCBF) and mean transit time (MTT) expressed as a ratio of the baseline value, and radiotherapy dose were determined. RESULTS: Of the 40 regions, seven occurred within the gross tumour volume and a further four occurred in regions later infiltrated by tumour, and were thus excluded. Regions within the 80% isodose showed a reduction in rCBV and rCBF over the 3 month period. There was no significant alteration in rCBV or rCBF in regions outside the 60% isodose (i.e. <32Gy). MTT did not alter in any region. There seemed to be a threshold effect at 132 days from the end of radiotherapy of 47% (standard error of the mean 11.5, about 25.4Gy) for rCBV and 59% (standard error of the mean 14.2, about 31.9Gy) for rCBF. CONCLUSIONS: There was a dose-related reduction in rCBV and rCBF in normal brain after radiotherapy at higher dose levels. Although this study used a limited number of patients, it suggests that magnetic resonance perfusion imaging seems to act as a marker of subclinical response of normal brain and that there is an absence of an early hypersensitivity effect with small doses per fraction. Further studies are required with larger groups of patients to show that these results are statistically robust.

Health implications of radon distribution in living rooms and bedrooms in U.K. dwellings--a case study in Northamptonshire.

Environmental radon exposure of residents of domestic premises in the United Kingdom (UK) and elsewhere in Europe is estimated on the basis of the measured radon concentrations in, and the relative occupancies of, the principal living room and bedroom. While studies on radon concentration variability in the individual units in apartment blocks in various countries have been described, little data has been reported on variability in two-storey single-family dwellings, and the majority of extant studies consolidate living room and bedroom data early in the analysis. To investigate this further, detailed analysis was made of radon concentration data from a set of thirty-four homes situated in areas of Northamptonshire known to exhibit high radon levels. All homes were of typical UK construction of brick/block/stone walls under a pitched tile/slate roof. Approximately 50% of the sample were detached houses, the remainder being semi-detached (duplex) or terraced (row-house). Around 25% of the sample possessed cellars, while 12% were single-storey dwellings (bungalows), reflecting the typical incidence of this type of dwelling in England. In the two-storey homes, all monitored bedrooms were on the upper floor. Distribution of the ratios of bedroom/living room radon concentrations (BR/LR ratio) in individual properties was left-skewed (mean 0.67, median 0.73, range 0.05-1.05) with a tail extending to just above 1.0. The mean is consistent with the outcome of earlier extensive studies in England, while the variability depends principally on the characteristics of the property, and not on seasonal factors. In a small set of homes, the BR/LR ratio was anomalously low, (mean 0.3). BR/LR ratios in single-storey homes clustered around a value of 1.0, indicating that house design, rather than lifestyle, is the dominant factor in determining bedroom radon concentrations. Homes with higher mean annual radon concentrations showed lower BR/LR ratios, supporting our proposal that, in some homes, radon emanation from building materials may comprise a significant component of the overall radon level.

Aerobic exercise training lowers platelet reactivity and improves platelet sensitivity to prostacyclin in pre- and postmenopausal women.

Essentials It is unknown how regular exercise affects platelet function after menopause. We studied the effect of 3-months of high-intensity exercise in pre- and postmenopausal women. Platelet sensitivity to the inhibitory effect of arterially infused prostacyclin was increased. Reduced basal platelet reactivity was seen in the premenopausal women only. SUMMARY: Background The risk of atherothrombotic events increases after the menopause. Regular physical activity has been shown to reduce platelet reactivity in younger women, but it is unknown how regular exercise affects platelet function after the menopause. Objectives To examine the effects of regular aerobic exercise in late premenopausal and recent postmenopausal women by testing basal platelet reactivity and platelet sensitivity to prostacyclin and nitric oxide. Methods Twenty-five sedentary, but healthy, late premenopausal and 24 matched recently postmenopausal women, mean (95% confidence interval) 49.1 (48.2-49.9) and 53.7 (52.5-55.0) years old, participated in an intervention study: 3-month high-intensity supervised aerobic spinning-cycle training (1 h, × 3/week). Basal platelet reactivity was analyzed in platelet-rich plasma from venous blood as agonist-induced % aggregation. In a subgroup of 13 premenopausal and 14 postmenopausal women, platelet reactivity was tested ex vivo after femoral arterial infusion of prostacyclin, acetylcholine, a cyclooxygenase inhibitor, and after acute one-leg knee extensor exercise. Results Basal platelet reactivity (%aggregation) to TRAP-6 (1 µm) was higher in the postmenopausal, 59% (50-68), than the premenopausal women, 45% (35-55). Exercise training reduced basal platelet reactivity to collagen (1 µg mL-1 ) in the premenopausal women only: from 63% (55-71%) to 51% (41-62%). After the training intervention, platelet aggregation was more inhibited by the arterial prostacyclin infusion and the acute exercise in both premenopausal and postmenopausal women. Conclusions These results highlight previously unknown cardioprotective aspects of regular aerobic exercise in premenopausal and postmenopausal women, improving their regulation of platelet reactivity through an increased platelet sensitivity to prostacyclin, which may counterbalance the increased atherothrombotic risk associated with the menopause.