A shortest path-based approach to the multileaf collimator sequencing problem

AbstractThe multileaf collimator sequencing problem is an important component in effective cancer treatment delivery. The problem can be formulated as finding a decomposition of an integer matrix into a weighted sequence of binary matrices whose rows satisfy a consecutive ones property. Minimising the cardinality of the decomposition is an important objective and has been shown to be strongly NP-hard, even for a matrix restricted to a single column or row. We show that in this latter case it can be solved efficiently as a shortest path problem, giving a simple proof that the one-row problem is fixed-parameter tractable in the maximum intensity. We develop new linear and constraint programming models exploiting this result. Our approaches significantly improve the best known for the problem, bringing real-world sized problem instances within reach of exact algorithms

MILP-based local search procedures for minimizing total tardiness in the No-idle Permutation Flowshop Problem

We consider the No-idle Permutation Flowshop Scheduling Problem (NPFSP) with a total tardiness criterion. We present two Mixed Integer Linear Programming (MILP) formulations based on positional and precedence variables, respectively. We study six local search procedures that explore two different neighborhoods by exploiting the MILP formulations. Our computational experiments show that two of the proposed procedures strongly outperform the state-of-the-art metaheuristic. We update 63% of the best known solutions of the instances in Taillards’ benchmark, and 77% if we exclude those instances for which we proved that the previous best known solutions are optimal

Theobromine and related methylxanthines as inhibitors of Primary Amine Oxidase

Methylxanthines are the most widely consumed drugs in the world and evidence of their health benefits has been growing in recent years. Primary Amine Oxidase (PrAO) has been recognised as a therapeutic target for amelioration of inflammatory, vascular and neurodegenerative diseases. Previous work in our laboratories showed that caffeine inhibited Bovine PrAO with a Ki of 1.0mM using benzylamine as substrate. This study aimed to extend our previous work and explore the possibility that related methylxanthines might influence PrAO activity. While paraxanthine, theophylline and 7-methylxanthine had little effect on PrAO, theobromine was a noncompetitive inhibitor with a Ki of 276±44µM. The specific structural elements of methylxanthines that are required for inhibition allow us to suggest that their binding site on PrAO may be a target for therapeutics. The health benefits associated with dietary methylxanthine consumption could involve PrAO inhibition

Methylxanthines Inhibit Primary Amine Oxidase and Monoamine Oxidase Activities of Human Adipose Tissue

Abstract: Background: Methylxanthines including caffeine and theobromine are widely consumed compounds and were recently shown to interact with bovine copper-containing amine oxidase. To the best of our knowledge, no direct demonstration of any interplay between these phytochemicals and human primary amine oxidase (PrAO) has been reported to date. We took advantage of the coexistence of PrAO and monoamine oxidase (MAO) activities in human subcutaneous adipose tissue (hScAT) to test the interaction between several methylxanthines and these enzymes, which are involved in many key pathophysiological processes. Methods: Benzylamine, methylamine, and tyramine were used as substrates for PrAO and MAO in homogenates of subcutaneous adipose depots obtained from overweight women undergoing plastic surgery. Methylxanthines were tested as substrates or inhibitors by fluorimetric determination of hydrogen peroxide, an end-product of amine oxidation. Results: Semicarbazide-sensitive PrAO activity was inhibited by theobromine, caffeine, and isobutylmethylxanthine (IBMX) while theophylline, paraxanthine, and 7-methylxanthine had little effect. Theobromine inhibited PrAO activity by 54% at 2.5 mM. Overall, the relationship between methylxanthine structure and the degree of inhibition was similar to that seen with bovine PrAO, although higher concentrations (mM) were required for inhibition. Theobromine also inhibited oxidation of tyramine by MAO, at the limits of its solubility in a DMSO vehicle. At doses higher than 12 % v/v, DMSO impaired MAO activity. MAO was also inhibited by millimolar doses of IBMX, caffeine and by other methylxanthines to a lesser extent. Conclusions: This preclinical study extrapolates previous findings with bovine PrAO to human tissues. Given that PrAO is a potential target for anti-inflammatory drugs, it indicates that alongside phosphodiesterase inhibition and adenosine receptor antagonism, PrAO and MAO inhibition could contribute to the health benefits of methylxanthines, especially their anti-inflammatory effects

Novel Facet of an Old Dietary Molecule? Direct Influence of Caffeine on Glucose and Biogenic Amine Handling by Human Adipocytes

Caffeine is a plant alkaloid present in food and beverages consumed worldwide. It has high lipid solubility with recognized actions in the central nervous system and in peripheral tissues, notably the adipose depots. However, the literature is scant regarding caffeine’s influence on adipocyte functions other than lipolysis, such as glucose incorporation into lipids (lipogenesis) and amine oxidation. The objective of this study was to explore the direct effects of caffeine and of isobutylmethylxanthine (IBMX) on these adipocyte functions. Glucose transport into fat cells freshly isolated from mice, rats, or humans was monitored by determining [3H]-2-deoxyglucose (2-DG) uptake, while the incorporation of radiolabeled glucose into cell lipids was used as an index of lipogenic activity. Oxidation of benzylamine by primary amine oxidase (PrAO) was inhibited by increasing doses of caffeine in human adipose tissue preparations with an inhibition constant (Ki) in the millimolar range. Caffeine inhibited basal and insulin-stimulated glucose transport as well as lipogenesis in rodent adipose cells. The antilipogenic action of caffeine was also observed in adipocytes from mice genetically invalidated for PrAO activity, indicating that PrAO activity was not required for lipogenesis inhibition. These caffeine inhibitory properties were extended to human adipocytes: relative to basal 2-DG uptake, set at 1.0 ± 0.2 for 6 individuals, 0.1 mM caffeine tended to reduce uptake to 0.83 ± 0.08. Insulin increased uptake by 3.86 ± 1.11 fold when tested alone at 100 nM, and by 3.21 ± 0.80 when combined with caffeine. Our results reinforce the recommendation of caffeine’s potential in the treatment or prevention of obesity complications

Epidemiological findings and medical, legal, and public health challenges of an investigation of severe soft tissue infections and deaths among injecting drug users: Ireland, 2000.

In May 2000, public health authorities in Dublin, Ireland, identified a cluster of unexplained severe illness among injecting drug users (IDUs). Similar clusters were also reported in Scotland and England. Concurrent investigations were undertaken to identify the aetiology and source of the illnesses. In Dublin, 22 IDUs were identified with injection-site inflammation resulting in hospitalization or death; eight (36%) died. Common clinical findings among patients with severe systemic symptoms included leukaemoid reaction and cardiogenic shock. Seventeen (77%) patients reported injecting heroin intramuscularly in the 2 weeks before illness. Of 11 patients with adequate specimens available for testing, two (18%) were positive by 16S rDNA PCR for Clostridium novyi. Clinical and laboratory findings suggested that histotoxic Clostridia caused a subset of infections in these related clusters. Empiric treatment for infections among IDUs was optimized for anaerobic organisms, and outreach led to increased enrolment in methadone treatment in Dublin. Many unique legal, medical, and public health challenges were encountered during the investigation of this outbreak

Changes in plasma levels of N-arachidonoyl ethanolamine and N-palmitoylethanolamine following bariatric surgery in morbidly obese females with impaired glucose homeostasis

Aim: We examined endocannabinoids (ECs) in relation to bariatric surgery and the association between plasma ECs and markers of insulin resistance. Methods: A study of 20 participants undergoing bariatric surgery. Fasting and 2-hour plasma glucose, lipids, insulin, and C-peptide were recorded preoperatively and 6 months postoperatively with plasma ECs (AEA, 2-AG) and endocannabinoid-related lipids (PEA, OEA). Results: Gender-specific analysis showed differences in AEA, OEA, and PEA preoperatively with reductions in AEA and PEA in females postoperatively. Preoperatively, AEA was correlated with 2-hour glucose (r = 0.55, P = 0.01), HOMA-IR (r = 0.61, P = 0.009), and HOMA %S (r = -0.71, P = 0.002). OEA was correlated with weight (r = 0.49, P = 0.03), waist circumference (r = 0.52, P = 0.02), fasting insulin (r = 0.49, P = 0.04), and HOMA-IR (r = 0.48, P = 0.05). PEA was correlated with fasting insulin (r = 0.49, P = 0.04). 2-AG had a negative correlation with fasting glucose (r = -0.59, P = 0.04). Conclusion: Gender differences exist in circulating ECs in obese subjects. Females show changes in AEA and PEA after bariatric surgery. Specific correlations exist between different ECs and markers of obesity and insulin and glucose homeostasis

A simple radionuclide-driven single-ion source

We describe a source capable of producing single barium ions through nuclear recoils in radioactive decay. The source is fabricated by electroplating 148Gd onto a silicon {\alpha}-particle detector and vapor depositing a layer of BaF2 over it. 144Sm recoils from the alpha decay of 148Gd are used to dislodge Ba+ ions from the BaF2 layer and emit them in the surrounding environment. The simultaneous detection of an {\alpha} particle in the substrate detector allows for tagging of the nuclear decay and of the Ba+ emission. The source is simple, durable, and can be manipulated and used in different environments. We discuss the fabrication process, which can be easily adapted to emit most other chemical species, and the performance of the source

Technology Innovation Enabling Falls Risk Assessment in a Community Setting

Approximately one in three people over the age of 65 will fall each year, resulting in significant financial, physical, and emotional cost on the individual, their family, and society. Currently, falls are managed using on-body sensors and alarm pendants to notify others when a falls event occurs. However these technologies do not prevent a fall from occurring. There is now a growing focus on falls risk assessment and preventative interventions. Falls risk is currently assessed in a clinical setting by expert physiotherapists, geriatricians, or occupational therapists following the occurrence of an injurious fall. As the population ages, this reactive model of care will become increasingly unsatisfactory, and a proactive community-based prevention strategy will be required. Recent advances in technology can support this new model of care by enabling community-based practitioners to perform tests that previously required expensive technology or expert interpretation. Gait and balance impairment is one of the most common risk factors for falls. This paper reviews the current technical and non-technical gait and balance assessments, discusses how low-cost technology can be applied to objectively administer and interpret these tests in the community, and reports on recent research where body-worn sensors have been utilized. It also discusses the barriers to adoption in the community and proposes ethnographic research as a method to investigate solutions to these barriers

Perfusion by Arterial Spin Labelling following Single Dose Tadalafil in Small Vessel Disease (PASTIS): study protocol for a randomized controlled trial

Background Cerebral small vessel disease is a common cause of vascular cognitive impairment in older people, with no licensed treatment. Cerebral blood flow is reduced in small vessel disease. Tadalafil is a widely prescribed phosphodiesterase-5 inhibitor that increases blood flow in other vascular territories. The aim of this trial is to test the hypothesis that tadalafil increases cerebral blood flow in older people with small vessel disease. Methods/design Perfusion by Arterial Spin labelling following Single dose Tadalafil In Small vessel disease (PASTIS) is a phase II randomised double-blind crossover trial. In two visits, 7-30 days apart, participants undergo arterial spin labelling to measure cerebral blood flow and a battery of cognitive tests, pre- and post-dosing with oral tadalafil (20 mg) or placebo. Sample size: 54 participants are required to detect a 15% increase in cerebral blood flow in subcortical white matter (p < 0.05, 90% power). Primary outcomes are cerebral blood flow in subcortical white matter and deep grey nuclei. Secondary outcomes are cortical grey matter cerebral blood flow and performance on cognitive tests (reaction time, information processing speed, digit span forwards and backwards, semantic fluency). Discussion Recruitment started on 4th September 2015 and 36 participants have completed to date (19th April 2017). No serious adverse events have occurred. All participants have been recruited from one centre, St George’s University Hospitals NHS Foundation Trust. Trial registration European Union Clinical Trials Register: EudraCT number 2015-001235-20. Registered on 13 May 2015