Analyse optimaler Bestellmengen für unterschiedliche Preisabsatzfunktionen und Rabattarten

Die Beschaffung von Gütern umfasst die Bereitstellung des Materials in der optimalen Menge. EOQ-Modelle (Economic Order Quantity) stellen eine Hilfe zur Optimierung dieser dar. Frühere Studien beschäftigten sich bereits mit Verfahren zur Berechnung der optimalen Bestellmenge bei einer preisabhängigen Nachfrage und mengenabhängigen Preisen. Burwell et al. entwickelten ein Verfahren zur Bestellmengenoptimierung mit preisabhängiger Nachfrage und Mengenrabatten für den Einkaufspreis und die Frachtkosten. Der Mengenrabatt ist entweder inkrementell oder ein Gesamtmengenrabatt. Burwell et al. betrachten die Nachfrage für den Monopolfall. Wir untersuchen den Konkurrenzfall. Die angegebene Beispielrechnung veranschaulicht die Methode.The procurement of commodities covers supply of the optimal quantities of material. EOQ models are a means to compute optimal quantities. Previous studies have dealt with algorithms that find optimal lot sizes when demand depends on price and quantity discounts are offered. Burwell et al. developed an algorithm to optimize order quantities when demand is considered to be dependent upon price and incorporate quantity and freight discounts. The quantity discount is either incremental or all-unit. Burwell et al. consider the monopolistic case. We study the case of competition. A numerical example is given that illustrates the method

Comment on: Successful use of nitrous oxide during lumbar punctures: a call for nitrous oxide in pediatric oncology clinics

No abstract available

Drug interactions may be important risk factors for methotrexate neurotoxicity, particularly in pediatric leukemia patients

Purpose: Methotrexate administration is associated with frequent adverse neurological events during treatment for childhood acute lymphoblastic leukemia. Here, we present evidence to support the role of common drug interactions and low vitamin B12 levels in potentiating methotrexate neurotoxicity. Methods: We review the published evidence and highlight key potential drug interactions as well as present clinical evidence of severe methotrexate neurotoxicity in conjunction with nitrous oxide anesthesia and measurements of vitamin B12 levels among pediatric leukemia patients during therapy. Results: We describe a very plausible mechanism for methotrexate neurotoxicity in pediatric leukemia patients involving reduction in methionine and consequential disruption of myelin production. We provide evidence that a number of commonly prescribed drugs in pediatric leukemia management interact with the same folate biosynthetic pathways and/or reduce functional vitamin B12 levels and hence are likely to increase the toxicity of methotrexate in these patients. We also present a brief case study supporting out hypothesis that nitrous oxide contributes to methotrexate neurotoxicity and a nutritional study, showing that patients. Conclusions: Use of nitrous oxide in pediatric leukemia patients at the same time as methotrexate use should be avoided especially as many suitable alternative anesthetic agents exist. Clinicians should consider monitoring levels of vitamin B12 in patients suspected of having methotrexate- induced neurotoxic effects

Reply: Methotrexate neurotoxicity due to drug interactions: an inadequate folinic acid effect

No abstract available

Effect of methotrexate/vitamin B12 on DNA methylation as a potential factor in leukemia treatment-related neurotoxicity

Methotrexate (MTX) is administered to treat childhood acute lymphoblastic leukemia (ALL). It acts by inhibiting dihydrofolate reductase which reduces methyltetrahydrofolate, a key component in one carbon metabolism, thus reducing cell proliferation. Further perturbations to one carbon metabolism, such as reduced Vitamin B12 levels via the use of nitrous oxide for sedation during childhood ALL treatment, may increase neurotoxicity risk. With B12 as an enzymatic cofactor, methyltetrahydrofolate is essential to produce methionine, which is critical for DNA methylation. We investigated global and gene specific DNA methylation in neuronal cell lines in response to MTX treatment and Vitamin B12 concentration individually, and in combination. Results: MTX treatment alone significantly increased LINE-1 methylation in SH-SY5Y (p = 0.040) and DAOY (p < 0.001), and increased FKBP5 methylation in MO3.13 cells (p = 0.009). Conclusion: We conclude that altered DNA methylation of brain/central nervous system cells could be one mechanism involved in MTX treatment-related neurotoxicities and neurocognitive late effects in ALL survivors

Steady-state kinetic characterization of the mouse B0AT1 sodium-dependent neutral amino acid transporter

The members of the neurotransmitter transporter family SLC6A exhibit a high degree of structural homology; however differences arise in many aspects of their transport mechanisms. In this study we report that mouse B0AT1 (mouse Slc6a19) mediates the electrogenic transport of a broad range of neutral amino acids but not of the chemically similar substrates transported by other SLC6A family members. Cotransport of L-Leu and Na+ generates a saturable, reversible, inward current with Michaelis-Menten kinetics (Hill coefficient ~1) yielding a K0.5 for L-Leu of 1.16mM and for Na+ of 16mM at a holding potential of −50mV. Changing the membrane voltage influences both substrate binding and substrate translocation. Li+ can substitute partially for Na+ in the generation of L-Leu-evoked inward currents, whereas both Cl− and H+ concentrations influence its magnitude. The simultaneous measurement of charge translocation and L-Leu uptake in the same cell indicates that B0AT1 transports one Na+ per neutral amino acid. This appears to be accomplished by an ordered, simultaneous mechanism, with the amino acid binding prior to the Na+, followed by the simultaneous translocation of both co-substrates across the plasma membrane. From this kinetic analysis, we conclude that the relatively constant [Na+] along the renal proximal tubule both drives the uptake of neutral amino acids via B0AT1 thermodynamically and ensures that, upon binding, these are translocated efficiently into the cel

Ex-formation as a method for mapping smellscapes

‘Every city, let me teach you, has its own smell.’ This quote, from an early chapter of E.M. Forster’s ‘A Room With a View’, points to a humanistic understanding of global urban smellscapes with the potential therein for shared understanding. Exploring options for the communication of Singapore’s ‘own smell’ this visual essay suggests how ‘ex-formation’ may be used as to probe one ontological view of the map…. The main characteristic of an ex-formation approach is ‘unlikely combination as suggestion’ e.g. tarmac roads in place of a river surface alluding to the changing scale of a river from trickle to delta, inedible organic matter packaged in white styrofoam with clear food product labelling suggesting a hygienic trust of shrink-wrapped food over natural produce, miniature underwear on inanimate objects suggesting that objects too might have nudity... Smell and visual is one such unlikely combination suggesting that invisible smell objects can be pervasive and imbued with colour

Investigating the mechanisms of methotrexate neurotoxicity in patients with childhood leukaemia and long-term survivors.

Background/Objectives Adverse neurological events are common (4-20%) during treatment for pediatric acute lymphoblastic leukaemia (ALL) and include seizures, stroke like syndrome and leukoencephalopathy. In addition, chronic neurotoxicity is emerging as a worrying late effect of treatment with long-term survivors experiencing decreased executive function, processing speed and memory function. Survivors are also at increased risk of experiencing learning difficulties, social withdrawal issues and inattention hyperactivity disorders. Methotrexate, an anti-folate chemotherapy agent, is a mainstay of pediatric leukemia treatment regimens globally and is widely implicated as a cause of these neurological side effects. We hypothesise that methotrexate disrupts DNA methylation via effects on S-adenosyl methionine, a key metabolic component that has previously been described to regulate genes involved in myelination. Design/Methods Using both the oligodendrocytic-like cell line MO3.13 and glial cells derived from induced pluripotent stem cells (iPSC) treated with methotrexate, we assayed for changes in DNA methylation and effects on gene expression using whole-genome methylation arrays and RNAseq, respectively. Genes with corresponding methylation and expression changes were selected for further studies of expression by real-time qPCR and assessment of protein levels. Results We identified DNA methylation and corresponding expression changes in genes involved in neurodevelopmental pathways and neurological disorders. Of particular interest was dose-dependent demethylation and increased gene expression of IRS1, a vital component of insulin signalling pathways that is highly expressed in neural tissue and implicated in regulating cognitive performance. We also detected altered DNA methylation within the PLP1 gene, which encodes the most prevalent protein component of myelin. We found that methotrexate treatment in iPSC-derived oligodendrocytes resulted in increased PLP1 methylation associated with a reduction in PLP1 transcript levels as well as PLP1 protein levels. Conclusions Our work provides insight as to the biological mechanisms behind methotrexate-induced neurological side effects for the first time and implicates altered insulin signalling and myelination pathways as a potential causative factor in neurotoxicity. Further work including the use of animal models is warranted for advancing these results towards informing clinical practice

Creative forms: booklets by the hospital senses collective.

This article details the creation of a series of booklets designed to explore sensory encounters with hospitals and healthcare environments. The booklets were devised as a series of prompts or provocations, created to attend to and examine embodied, sensory encounters with health/care settings rather than to present research findings. Bringing together an expansive range of backgrounds and skill sets the booklets were created to sit within and beyond language through their design, form and content. Within this article we share the ways in which the works are deliberately unfinished and exploratory as this necessitates that those interacting with them create their own meanings and explore how they think and feel about health/care environments. The form and design promote a certain attentiveness and embodied engagement. For example, users must engage with the works carefully, gently turning and unfurling the fragile pages. This is further illustrated through qualitative insights collected from users of the booklets. Throughout this paper we argue for multiplicity in the ways in which we explore and present sensory-focused research. Our attention to multiplicity is supported not only through the design, form and content of the physical booklets but through the creative audio description, text and images created to complement and support these works. These are available online to ensure that our provocations are widely accessible. Within this paper we critique how a reliance on narrative form can limit the ways in which we engage with spatial, sensory and emotional concepts. Such concepts are by their very nature challenging to articulate and arguably require more-than-text-based approaches. We propose that embracing creative, exploratory and seemingly risky routes to examining and presenting such concepts is critical in expanding research. [Abstract copyright: © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.

Mitochondrial echoes of first settlement and genetic continuity in El Salvador

Background: From Paleo-Indian times to recent historical episodes, the Mesoamerican isthmus played an important role in the distribution and patterns of variability all around the double American continent. However, the amount of genetic information currently available on Central American continental populations is very scarce. In order to shed light on the role of Mesoamerica in the peopling of the New World, the present study focuses on the analysis of the mtDNA variation in a population sample from El Salvador. Methodology/Principal Findings: We have carried out DNA sequencing of the entire control region of the mitochondrial DNA (mtDNA) genome in 90 individuals from El Salvador. We have also compiled more than 3,985 control region profiles from the public domain and the literature in order to carry out inter-population comparisons. The results reveal a predominant Native American component in this region: by far, the most prevalent mtDNA haplogroup in this country (at ~90%) is A2, in contrast with other North, Meso- and South American populations. Haplogroup A2 shows a star-like phylogeny and is very diverse with a substantial proportion of mtDNAs (45%; sequence range 16090–16365) still unobserved in other American populations. Two different Bayesian approaches used to estimate admixture proportions in El Salvador shows that the majority of the mtDNAs observed come from North America. A preliminary founder analysis indicates that the settlement of El Salvador occurred about 13,400±5,200 Y.B.P.. The founder age of A2 in El Salvador is close to the overall age of A2 in America, which suggests that the colonization of this region occurred within a few thousand years of the initial expansion into the Americas. Conclusions/Significance: As a whole, the results are compatible with the hypothesis that today's A2 variability in El Salvador represents to a large extent the indigenous component of the region. Concordant with this hypothesis is also the observation of a very limited contribution from European and African women (~5%). This implies that the Atlantic slave trade had a very small demographic impact in El Salvador in contrast to its transformation of the gene pool in neighbouring populations from the Caribbean facade