Biological properties of adriamycin bound to biodegradable polymeric carriers

Three different conjugates having adriamycin (ADR) bound to the side chain carboxyl groups of high-molecular weight poly (¿--glutamic acid) (PGA) either directly or by interpolation of GlyGly and GlyGlyGlyLeu spacers, respectively, were compared with respect to immunogenicity and cytotoxicity in mice as well as release of drug by lysosomal enzymes. The cytotoxic efficacy of a single i.p. dose of each conjugate (5 mg ADR-equiv./kg) against L1210 leukemia cells implanted i.p. in DBA2 mice was studied by monitoring the survival time, the body weight and the number of long-term survivors (LTS). PGA-GlyGlyGlyLeu-ADR and PGA-GlyGly-ADR significantly enhanced the mean survival time (MST) of treated animals compared with the untreated control group (T/C 148¿149%) as did free ADR (T/C 147%). The tetrapeptide-spacer containing conjugate effected the presence of LTS at day 50 (2/5) as did free ADR (1/5).\ud \ud The secondary antibody response of the drug conjugates elicited in A/J mice after repeated dosage (125 ¿g/mouse) at day 0, 14 and 28 was evaluated at day 35 using the ELISA technique. IgG titers varied from a very low value (PGA-GlyGlyGlyLeu-ADR) to moderately high levels (PGA-ADR, PGA-GlyGly-ADR) which are 2¿3 orders of magnitude below that obtained for the strong immunogen bovine IgG. The data suggest that certain parts on the surface of the conjugates are immunogenic.\ud \ud The release of extractable low-molecular weight products from the conjugates mediated by lysosomal enzymes was analyzed using reversed-phase HPLC. The release profile of ADR as well as Gly-ADR, Leu-ADR or GlyLeu-ADR was determined. The total amount of ADR released after 77 h was 3.6% for PGA-GlyGlyGly-Leu-ADR, 1.0% for PGA-GlyGly-ADR and 0.5% for PGA-ADR. With all conjugates unidentified products were produced.\ud \ud It is proposed that the mechanism of action of the polymeric conjugates under in vivo conditions may be due to pinocytic capture followed by lysosomal degradation with release of ADR

Performance prediction of advanced building controls in the design phase using ESP-r, BCVTB and Matlab

In this paper, we present a new simulation-based approach with capabilities for analysing the impact of advanced control strategies on building performance during the building design phase. This environment consists of ESP-r as building simulation tool, Matlab as software for advanced building controllers and BCVTB as middleware for data exchange per time step between the two programs. After describing the implementation details, we illustrate usability of the design support environment in a case study. This application example demonstrates model predictive control of a building with a thermally activated floor and solar shading. Furthermore, we show the use of explicit state initialization in ESP-r and a method to include uncertain weather predictions in the controller

Synthesis and biodistribution of immunoconjugates of a human IgM and polymeric drug carriers

The synthesis and purification of radiolabelled immunoconjugates, composed of a human IgM monoclonal antibody directed against an intracellular tumour-associated antigen and either poly (alpha-L-glutamic acid) (PGA) or poly[N5-(2-hydroxyethyl)-L-glutamine] (PHEG) is described. Coupling of polymers to the antibody was performed through disulfide bond formation involving a single thiol group at the C-terminus of the polymer chain and 2-pyridyldisulfide groups introduced onto the antibody. The antibody was iodinated with 131I before conjugation. The polymers contained tyrosinamide in a low degree of substitution and were radiolabelled with 125I. 125I-labelled PGA and PHEG were found to be stable for at least 3 days in murine and human plasma. The biodistribution in mice of the doubly labelled immunoconjugates was studied and was compared with the pharmacokinetics of the individual components.\ud \ud PHEG showed a relatively slow blood clearance, the half-life being approximately 10 h with low uptake in liver, kidneys and spleen. PGA was rapidly cleared from the circulation and was significantly taken up in liver, kidneys and spleen. The biodistribution of both immunoconjugates was indistinguishable from that of the IgM proper, with plasma half-lives of approximately 6 h, indicating that the pharmacokinetic properties of the immunoconjugates are largely determined by the antibody part

Investigating the potential of a novel low-energy house concept with hybrid adaptable thermal storage

In conventional buildings thermal mass is a permanent building characteristic depending on the building design. However, none of the permanent thermal mass concepts are optimal in all operational conditions. We propose a concept that combines the benefits of buildings with low and high thermal mass by applying hybrid adaptable thermal storage (HATS) systems and materials to a lightweight building. The HATS concept increases building performance and the robustness to changing user behavior, seasonal variations and future climate changes. Building performance simulation is used to investigate the potential of the novel concept for reducing heating energy demand and increasing thermal comfort. Simulation results of a case study in the Netherlands show that the optimal quantity of the thermal mass is sensitive to the change of seasons. This implies that the building performance will benefit from implementing HATS. Furthermore, the potential of HATS is quantified using a simplified HATS model. Calculations show heating energy demand reductions of up to 35% and increased thermal comfort compared to conventional thermal mass concepts

Cardiac foetal reprogramming:a tool to exploit novel treatment targets for the failing heart

As the heart matures during embryogenesis from its foetal stages, several structural and functional modifications take place to form the adult heart. This process of maturation is in large part due to an increased volume and work load of the heart to maintain proper circulation throughout the growing body. In recent years, it has been observed that these changes are reversed to some extent as a result of cardiac disease. The process by which this occurs has been characterized as cardiac foetal reprogramming and is defined as the suppression of adult and re-activation of a foetal genes profile in the diseased myocardium. The reasons as to why this process occurs in the diseased myocardium are unknown; however, it has been suggested to be an adaptive process to counteract deleterious events taking place during cardiac remodelling. Although still in its infancy, several studies have demonstrated that targeting foetal reprogramming in heart failure can lead to substantial improvement in cardiac functionality. This is highlighted by a recent study which found that by modulating the expression of 5-oxoprolinase (OPLAH, a novel cardiac foetal gene), cardiac function can be significantly improved in mice exposed to cardiac injury. Additionally, the utilization of angiotensin receptor neprilysin inhibitors (ARNI) has demonstrated clear benefits, providing important clinical proof that drugs that increase natriuretic peptide levels (part of the foetal gene programme) indeed improve heart failure outcomes. In this review, we will highlight the most important aspects of cardiac foetal reprogramming and will discuss whether this process is a cause or consequence of heart failure. Based on this, we will also explain how a deeper understanding of this process may result in the development of novel therapeutic strategies in heart failure

Generating real context data to test user dependent systems - application to multi-agent systems

First Online 26 June 2019This paper, deals with the usually need of data to simulate behavior and efficiency of proposed solutions in several fields, and also knowing that personal data always bring privacy and security issues. This work wants to promote a balanced solution between the need of personal information and the user’s privacy expectations. We propose a solution to overcome these issues, and don’t compromise the balance between security and personal comfort based on generating real context data of users, that allow to test user dependent systems.This work has been supported by FCT Fundação para a Ciência e Tecnologia within the Project Scope: UID/CEC/00319/2019

Effectiveness of adenoidectomy in children with recurrent upper respiratory tract infections: open randomised controlled trial

Objective To assess the effectiveness of adenoidectomy in children with recurrent upper respiratory tract infections

Long-term prognostic importance of a single pulmonary wedge pressure measurement after myocardial infarction: A ten-year follow-up study

To assess the influence on short- and long-term survival of haemodynamic variables measured after acute myocardial infarction, a 10-year prospective follow-up study was undertaken. A total of 304 patients (259 males, 45 females) discharged from hospital after myocardial infarction and under 66 years of age were studied. Haemodynamic variables measured shortly after admittance included pulmonary wedge pressure, mixed venous oxygen saturation, blood pressure and heart rate. In the analysis, adjustments were made for differences in age, gender, clinical parameters and cardiovascular risk factors. Pulmonary wedge pressure was found to be a strong and independent predictor of both short-term and long-term survival. A gradual increase of the 10-year mortality risk with elevated wedge pressure could be demonstrated (relative risk, 1.09/mmHg; 95% confidence interval, 1.04–1.15). Relative risks of patients in the three highest categories of wedge pressure, 12–15 mmHg, 15–19 mmHg and 19 mmHg and higher, compared with patients in the lowest category, lower than 12 mmHg, were 2.25 (95% CI, 1.11–4.55), 2.43 (95% CI, 1.20–4.92) and 2.57 (95% CI, 1.04–6.37), respectively. The other measured haemodynamic variables were found to be associated with short-term mortality only. In conclusion, haemodynamic measurements after myocardial infarction are of prognostic importance after discharge. A single measurement of an elevated wedge pressure in particular unfavourably influenced both short-term and long-term survival

Recurrence up to 3.5 years after antibiotic treatment of acute otitis media in very young Dutch children: survey of trial participants

Objective To determine the long term effects of antibiotic treatment for acute otitis media in young children