Synthesis of Novel Monomers and Copolymers from 1‐Vinylpyrrolidin‐2‐one: Attractive Materials for Drug Delivery Systems?

Summary: Polyvinylpyrrolidone (PVP) is a synthetic, non‐toxic, water‐soluble polymer commonly used in a wide range of applications including several pharmaceutical applications. One example of an important application is the controlled release and delivery of therapeutic agents into sites of inflammation or tumours. However, PVP lacks reactive groups, which limits the possibility of adding new functions to the polymer in order to modify its physical and chemical properties. Furthermore, large differences in radical reactivity between 1‐vinylpyrrolidin‐2‐one (NVP) and most other monomers lead to compositional drift during copolymerization. This complicates the introduction of reactive groups into the polymer using this method. Monomers that are derivatives of NVP itself are expected to show smaller differences in radical reactivity and therefore provide a way of preparing PVP with adjustable properties. Here we present the synthesis of five NVP‐based monomers and their use in the preparation of functional PVP with adjustable properties in terms of solubility, loading of functional groups, and molar mass. The results show the possibility of tailoring PVP for different biomedical applications e.g. drug delivery systems.

Copolymers from 1‐vinylpyrrolidin‐2‐one.     

Radical Cation,Dimer Radical Cation and Neutral Radical of 2,3‐Dihydropyran – Possible Initiators of its Polymerisation?

The radical cation, distonic dimer radical cation, and radical of 2,3‐dihydropyran (DHP), which may play an important role in mechanism of radical polymerisations of DHP, were radiolytically generated at low temperatures in freon matrices and investigated by electron paramagnetic resonance (EPR) spectroscopy, as well as by quantum chemical methods. DHP radical cation with a half‐chair conformation and six coupling protons (0.88, 0.18, 4.60, 1.88, 1.27, 0.56 mT) was found to be stable in CF₃CCl₃ between 77 and 145 K. The same radical cation was observed at 77 K also in CF₂ClCFCl₂, but on increasing temperature, transformation into the neutral 4‐dihydropyryl radical occurred; the latter also shows the half‐chair conformation at 140 K and is characterised by six coupling protons (0.14, 2.31, 0.92, 1.42, 0.28, 1.35 mT). At a high DHP concentration in CF₂ClCFCl₂ a distonic DHP dimer radical cation, with strongly separated spin and charge and only two coupling protons (1.8 and 3.2 mT) was identified at 100 K, also yielding, at higher temperatures, the 4‐dihydropyryl radical.

The radiolytically generated species from DHP and their observed EPR spectra.     

The gift of life – does it apply to donation for research?

In his influential study, “The Gift Relationship” [1970], Richard Titmuss coined the idea of voluntary, non‐paid, blood donation being the gift of life for a fellow citizen. This metaphor has been powerful in mobilising donors. It conveys a direct relationship between blood donation and patients’ vitality, as well as a difference between gains and costs. As the gift of life, blood donation is seen to symbolise pure altruism and promoting solidarity between strangers. But can we apply the metaphor as successfully to donating blood for research? I interviewed a group of Finnish blood donors on what if the FRC Blood Service invited them to give a blood sample and personal information for research. The blood donors were usually willing to contribute to research for the public benefit, because they saw great potential in science to create solutions to help patients in the future. However, based on our interview data and previous research, I suggest that the analogy between the gift of life and donation for research did not work all the way. The metaphor fails to address donors’ questions on the new types of relationships, interests and risks related to the use of personal data for research. Left unanswered, these could discourage donating for research. Hence, I argue that the gift of life metaphor is not applicable to donor recruitment in the research context. I propose to look for new metaphors that resonate better with donors’ perceptions of research participation and serve the communication needs of data collectors.     

Integration of two models, or dominance of one?

Hobbis and Sutton attempted to integrate Cognitive Behavior Therapy (CBT) with the Theory of Planned Behavior (TPB). The possibility of such an integration portends exciting opportunities since behavioral interventions have had limited impact on behavior change. The integration, however, may more easily occur if Hobbis and Sutton had selected a formulation of the TPB that incorporated emotional variables, which is a primary focus of CBT. Furthermore, more work may be necessary to integrate the specific cognitive constructs between CBT and the TPB. Empirical research will be necessary to validate that the integration occurred in a meaningful way.     

7‐T MR—from research to clinical applications?

Over 20 000 MR systems are currently installed worldwide and, although the majority operate at magnetic fields of 1.5 T and below (i.e. about 70%), experience with 3‐T (in high‐field clinical diagnostic imaging and research) and 7‐T (research only) human MR scanners points to a future in functional and metabolic MR diagnostics. Complementary to previous studies, this review attempts to provide an overview of ultrahigh‐field MR research with special emphasis on emerging clinical applications at 7 T. We provide a short summary of the technical development and the current status of installed MR systems. The advantages and challenges of ultrahigh‐field MRI and MRS are discussed with special emphasis on radiofrequency inhomogeneity, relaxation times, signal‐to‐noise improvements, susceptibility effects, chemical shifts, specific absorption rate and other safety issues. In terms of applications, we focus on the topics most likely to gain significantly from 7‐T MR, i.e. brain imaging and spectroscopy and musculoskeletal imaging, but also body imaging, which is particularly challenging. Examples are given to demonstrate the advantages of susceptibility‐weighted imaging, time‐of‐flight MR angiography, high‐resolution functional MRI, ¹H and ³¹P MRSI in the human brain, sodium and functional imaging of cartilage and the first results (and artefacts) using an eight‐channel body array, suggesting future areas of research that should be intensified in order to fully explore the potential of 7‐T MR systems for use in clinical diagnosis. Copyright © 2011 John Wiley & Sons, Ltd.     

“Why do they have to grow up so fast?” Parental separation anxiety and emerging adults' pathology of separation‐individuation

This study examined associations between parental separation anxiety, controlling parenting, and difficulties in the separation-individuation process, as manifested in separation-individuation pathology. In a sample of emerging adults involved in the process of home leaving (N = 232) and their parents, it was found that parental separation anxiety is positively related to separation-individuation pathology in emerging adults. Dependency-oriented controlling parenting served as an intervening variable in the relationship between parents' feelings of separation anxiety and pathology of the separation-individuation process in emerging adults. These associations were not moderated by emerging adults' residential status (i.e., living with parents or (semi-)independently), suggesting that parental characteristics and behaviors remain important antecedents of separation-individuation pathology even when one no longer lives in the parental household.     

Induction of apoptosis in monocytes and lymphocytes by serum from patients with systemic lupus erythematosus − an additional mechanism to increased autoantigen load?

The most likely source of autoantigens in systemic lupus erythematosus (SLE) is apoptotic material. Because increased levels of circulating apoptotic cells are found in SLE we wanted to investigate the capacity of serum from patients with SLE or other autoimmune or infectious diseases and normal healthy donors (NHD) to induce apoptosis in normal monocytes, lymphocytes and corresponding cell lines, in relation to clinical and immunological data. Monocytes and lymphocytes from healthy donors were incubated with sera from 37 SLE patients, 37 sex- and age-matched NHD and sera from patients with rheumatoid arthritis, vasculitis, sepsis and mononucleosis. Sera from SLE patients were sampled at both active and inactive disease. The apoptosis-inducing effect (AIE) of these sera was monitored with flow cytometry using annexin V and propidium iodide (PI) binding. The AIE in monocytes and lymphocytes was significantly higher in sera from SLE patients than in other patient groups and NHD (P < 0.001) and was also higher when cell lines were used. Level of C5a in cell culture supernatant correlated with AIE in monocytes (r = 0.451, P = 0.005), suggesting involvement of complement. Heat-inactivation of sera did not affect the AIE, nor did depletion of IgG by protein G absorption of serum. Kinetic analyses showed a peak in apoptosis induction at 12-16 h, with a delayed PI positivity. AIE was equally high using sera from active and inactive SLE cases, and did not correlate with the SLE Disease Activity Index (SLEDAI). Thus, SLE serum has a strong and apparently disease-specific apoptosis-inducing capacity, which could contribute to a high load of potential autoantigen.     

“C3, C4, C5 keep you alive,” or do they?

Contrary to traditional teaching in anatomy courses, historical data suggest that bilateral loss of phrenic nerve function does not necessarily result in death.     

Are 6‐month‐old foals sensitive to dam's influence?

A recent study has shown that gently handling dams in front of their few days old foals may strongly influence the development of human-foal relationships. In the present study, we test whether 6-month-old foals remain sensitive to their dams' influence. The study was performed on 16 foal-mare dyads, with half of the mares receiving positive contacts from the experimenter in presence of their 6-month-old foals (n = 8) whereas the other mares were not handled (n = 8). All foals were tested 15 and 30-35 days later under various conditions (reaction to a motionless human, approach test, saddle-pad tolerance test). We observe a positive effect of mare' handling on foals' reactions to humans but with a high interindividual variability, suggesting a higher effect of the foals' own behavioral characteristics at this age than at earlier stages.     

‘True’ antimitochondrial antibody‐negative primary biliary cirrhosis,low sensitivity of the routine assays,or both?

Anti-mitochondrial antibody (AMA) is considered the serological hallmark of primary biliary cirrhosis (PBC), but may be missing in a proportion of these patients. We assessed sensitivity and specificity of the currently available techniques for AMA detection in a large series of PBC patients and controls, and analysed their clinical and immunological features according to the AMA status. By indirect immunofluorescence on rat tissue sections and HEp-2 cells, Western immunoblot with bovine submitochondrial particles, and two ELISAs with AMA-specific recombinant proteins, we evaluated the presence of AMA in 127 PBC patients, 166 patients with type 1 autoimmune hepatitis and 100 with non alcoholic fatty liver disease. In PBC patients Western immunoblot detects AMA significantly more often than indirect immunofluorescence on HEp-2 cells (85%versus 72%, P = 0.02) or rodent tissue sections (71%, P = 0.01); both ELISAs are only slightly less sensitive than Western immunoblot (81% and 78%). Ten patients with non alcoholic fatty liver disease were AMA-positive by indirect immunofluorescence, but none recognized AMA-specific epitopes in Western immunoblot or in ELISAs. Twelve patients with type 1 autoimmune hepatitis were AMA-positive by indirect immunofluorescence, but only 6 (3.6%) reacted by Western immunoblot and ELISAs. Western immunoblot or ELISA should be regarded as first-line assay for the detection of AMA. Up to 15% of PBC patients are consistently AMA-negative, yet they share the same clinical, biochemical and histological features of AMA-positive PBC. Detection of AMA in type 1 autoimmune hepatitis might identify a subset of patients at risk of developing a hepatitic/cholestatic syndrome.     

Pig endogenous retrovirus – a threat to clinical xenotransplantation?

Transplantation shows good results for patients with end-stage disease, but there is an increasing lack of organs. Xenotransplantation, the transfer of live animal cells, tissues, or organs to another species, offers a potential solution to this shortfall. Pig is regarded as the animal of choice for this purpose. Meanwhile demonstration of pig endogenous retrovirus (PERV) in all porcine herds has caused serious concern with respect to a possible transmission of the virus to humans with a transplanted organ. Transmission to human cells has been documented under certain in vitro conditions. However, no such transmission has been demonstrated in vivo. The possible consequences of introducing PERV into immunocompromised human organisms are not known and it is necessary to collect more information. Novel and sensitive genomic assays to detect PERV infection are now available in addition to established virological, immunoserological and molecular methods. In order to minimise the risk of PERV transmission rigorous procedures should be established. International guidelines to reduce the risk should be followed. Although a number of immunological, physiological and virological questions need to be answered before the introduction of xenotransplantation as an alternative clinical treatment, some problems can only be solved by judicious clinical trials.     

The Humoral Response in TCR α–/– Mice. Can γδ‐T Cells Support the Humoral Immune Response?

An optimal humoral response requires T-cell help; however, it has been questioned if this help comes exclusively from alphabeta-T cells or whether gammadelta-T cells also contribute. We have attempted to answer this question by studying the humoral response in T-cell receptor alpha-chain knockout (alpha-/-) mice, which lack the alphabetaT cell subset. Two model antigens were used to characterize the response: the thymus-independent (TI) antigen native dextran B512 (Dx), and the thymus-dependent (TD) antigen heat shock protein (HSP65) from Mycobacterium tuberculosis. When challenged with Dx, the alpha-/- mice elicited a strong antibody response and formed rudimentary germinal centres (GCs), a T-cell dependent reaction. In contrast, the humoral response to HSP65 was poor. However, alpha-/- mice became primed when challenged with HSP65, because when supplemented with wild-type thymocytes, the antigen-primed animals were able to mount a stronger response than the nonprimed ones when challenged with HSP65. A crucial step seems to be the collaboration between gammadeltaT cells and antigen presenting cells (APCs), as splenocytes from alpha-/- mice were able to respond to HSP65 in an environment containing primed-APCs. Based on these results, we propose a model for B-cell activation in the alpha-/- mice.