Health care professional barriers and facilitators to discontinuing antidepressant use: A systematic review and thematic synthesis.

INTRODUCTION: Long-term antidepressant (AD) use, much longer than recommended, is very common and can lead to potential harms. OBJECTIVE: To investigate the existing literature on perspectives of health professionals (HPs) regarding long-term AD treatment, focusing on barriers and facilitators to discontinuation. METHODS: A systematic review with thematic synthesis. Eight electronic databases were searched until August 2023 including MEDLINE, PubMed, Embase, PsycINFO, CINAHL, AMED, Health Management Information Consortium, and the Networked Digital Library of Theses and Dissertation. RESULTS: Thirteen studies were included in the review. Of these, nine focused on general practitioner perspectives, one on psychiatrist perspectives, and three on a mix of HPs perspectives. Barriers and facilitators to discontinuing long-term ADs emerged within eight themes, ordered chronologically based on HP considerations during an AD review: perception of AD use, fears, HP role and responsibility, HPs' perception of AD discontinuation, HPs' confidence regarding their ability to manage discontinuation, perceived patient readiness to stop, support from patient's trusted people, and support from other HPs. LIMITATIONS: Coding and development of subthemes and themes was performed by one researcher and further developed through discussion within the research team. CONCLUSION: Deprescribing long-term ADs is a challenging concept for HPs. The review found evidence that the barriers far outweigh the facilitators with fear of relapse as a main barrier. HP education, reassurance and confidence-building is essential to increase the initiation of the discontinuation process. Further research into the perspectives of pharmacists and mental health workers is needed as well as exploring the role of trusted people.

Tools and guidelines to assess the appropriateness of medication and aid deprescribing: An umbrella review.

AIMS: The aim of this umbrella review was to identify tools and guidelines to aid the deprescribing process of potentially inappropriate medications (PIMs), evaluate development and validation methods, and describe evidence levels for medication inclusion. METHODS: Searches were conducted on MEDLINE (Ovid), Embase.com, Cochrane CDSR, CINAHL (EBSCO), Web of Science Core Collection and guideline databases from the date of inception to 7 July 2022. Following the initial search, an additional search was conducted to identify an updated versions of tools on 17 July 2023. We analysed the contents of tools and guidelines. RESULTS: From 23 systematic reviews and guidelines, we identified 95 tools (72 explicit, 12 mixed and 11 implicit) and nine guidelines. Most tools (83.2%) were developed to use for older persons, including 14 for those with limited life expectancy. Seven tools were for children <18 years (7.37%). Most explicit/mixed tools (78.57%) and all guidelines were validated. We found 484 PIMs and 202 medications with different appropriateness independent of disease for older persons with normal and limited life expectancy, respectively. Only two tools and eight guidelines reported the evidence level, and a quarter of medications had high-quality evidence. CONCLUSIONS: Tools are available for a diversity of populations. There were discrepancies, with the same medication being classified as inappropriate in some tools and appropriate in others, possibly due to low-quality evidence. In particular, tools for patients with limited life expectancy were developed based on very limited evidence, and research to generate this evidence is urgently needed. Our medication lists, along with the level of evidence, could facilitate efforts to strengthen the evidence.

High-Risk Medication in Home Care Nursing: A Delphi Study.

AIMS: The aims of the study were to reach consensus on which medications in home care nursing should be considered high-risk medication (HRM) and to obtain recommendations about which interventions home care nurses can perform to improve quality of care and safety in managing these HRM. DESIGN: This is an international Delphi study with 13 purposively selected experts from 4 different countries. METHODS: A 3-round iterative Delphi survey was conducted from May 2018 to October 2018, based on a list of 32 medications previously reported as HRM in community care. A proposal for HRM was based on this literature search, and experts were asked to reflect on which (groups of) medications should be considered HRM by home care nurses (completeness of the list, risk assessment per [group of] medication, the need for home care nurse interventions, and the need for an HRM care procedure). The cutoff point for consensus was set at 80% of expert agreement. RESULTS: The panel assessed the initial list and added 30 (groups of) medications. In the last round, consensus of 80% or more was reached for 27 (groups of) medications to be considered HRM by home care nurses. For 28 medications, additional interventions by a home care nurse were considered warranted. A procedure or protocol for home care nurses was deemed necessary for 12 medications. CONCLUSIONS: We identified a set of (groups of) medications that should primarily be considered HRM by home care nurses.Impact:• What problem did the study address? This study clarified which medications should be considered HRM by home care nurses.• What were the main findings? Experts identified a set of 27 (groups of) medications that should primarily be considered HRM by home care nurses.• Where and on whom will the research have an impact? The results provide essential information for home care agencies when setting up an HRM policy.

General practitioners' perspectives on discontinuation of long-term antidepressants in nursing homes.

BACKGROUND: Long-term use of antidepressant drugs (AD), much longer than recommended by guidelines, in nursing homes (NH) is common. NH home residents may have a relatively higher risk of adverse events. Moreover, in an NH setting nursing staff and relatives are intensively involved in the decision-making process. In many countries, General Practitioners' (GPs) provide care for residents in NHs. Little is known about GPs' perspectives on discontinuation of long-term AD in NH residents. OBJECTIVES: To explore GPs' views of discontinuing long-term AD in NH residents. METHODS: An exploratory qualitative study, with semi-structured interviews, was conducted with a purposive sample of 20 Belgian GPs. Interviews, conducted over six months in 2019, were analysed by thematic analysis. RESULTS: Twenty interviews were conducted until data saturation. The first theme, 'reluctance to rock the boat: not worth taking the risk', describes that GPs perceive discontinuation as an unpredictable risk without clear benefits. GPs' main concern was the risk of destabilising the fragile balance in an older patient. Second, 'it takes at least three to tango', captures the unspoken alliance between GPs, nursing staff and relatives and suggests that agreement of at least these three partners is required. The third, 'Opening the door: triggers to discontinue', points to severe health problems and dementia as strong facilitators for discontinuation. CONCLUSION: Discontinuation of long-term AD in NHs is a complex process for GPs. More evidence and attention to the role nursing staff and relatives play are needed to better guide the discontinuation of AD in older NH patients.

Should I, can I, dare I? Patients' view on stopping long-term antidepressant use, a qualitative study.

BACKGROUND AND AIM: The rise in long-term antidepressant use is concerning. Long-term antidepressant (AD) use, much longer than recommended by guidelines, can result in risk of adverse events and generate unnecessary costs. In order to mitigate these risks, patients views about their antidepressants and how to discontinue need to be taken into account. We aimed to explore patients' experiences and views of discontinuing long-term AD, barriers and facilitators of discontinuation and required support. METHODS: Semi-structured face to face interviews were conducted with 14 patients with long-term AD use in primary care. Interviews were analysed thematically. RESULTS: Participants describe various perceptions about discontinuation. There is fear of returning to their depression, even in those who were ambivalent about the effectiveness and safety of AD continuation. Participants describe low confidence in their own coping resources, fear of stress, and previous negative experiences with stopping. This enhances their perception of AD dependence. Participants indicate the importance of the support of their GP and their social network to help them withdraw. CONCLUSION: Discontinuation of long-term antidepressants is a complex issue for patients. More awareness of the lack of evidence and the potential risks of long-term AD continuation is required. By raising the issue and offering support during discontinuation GPs can help their patients stop AD. A greater focus on non-pharmacological approaches of depression in primary care is needed to reduce unnecessary AD use.

Improving Health Literacy Responsiveness: A Randomized Study on the Uptake of Brochures on Doctor-Patient Communication in Primary Health Care Waiting Rooms.

Presenting attractive and useful health education materials in waiting rooms can help improve an organization's health literacy responsiveness. However, it is unclear to what extent patients may be interested in health education materials, such as brochures. We conducted a three-week field study in waiting rooms of three primary care centers in Groningen. Three versions of a brochure on doctor-patient communication were randomly distributed, 2250 in total. One version contained six short photo stories, another version was non-narrative but contained comparable photos, and the third version was a traditional brochure. Each day we counted how many brochures were taken. We also asked patients (N = 471) to participate in a brief interview. Patients who consented (N = 390) were asked if they had noticed the brochure. If yes (N = 135), they were asked why they had or had not browsed the brochure, and why they had or had not taken it. Interview responses were categorized by two authors. Only 2.9% of the brochures were taken; no significant association with brochure version was found. Analysis of the interview data showed that the version with the photo narrative was noticed significantly more often than the non-narrative version or the traditional version. These results suggest that designing attractive and comprehensible health materials is not enough. Healthcare organizations should also create effective strategies to reach their target population.

Approaches for discontinuation versus continuation of long-term antidepressant use for depressive and anxiety disorders in adults.

BACKGROUND: Depression and anxiety are the most frequent indication for which antidepressants are prescribed. Long-term antidepressant use is driving much of the internationally observed rise in antidepressant consumption. Surveys of antidepressant users suggest that 30% to 50% of long-term antidepressant prescriptions had no evidence-based indication. Unnecessary use of antidepressants puts people at risk of adverse events. However, high-certainty evidence is lacking regarding the effectiveness and safety of approaches to discontinuing long-term antidepressants. OBJECTIVES: To assess the effectiveness and safety of approaches for discontinuation versus continuation of long-term antidepressant use for depressive and anxiety disorders in adults. SEARCH METHODS: We searched all databases for randomised controlled trials (RCTs) until January 2020. SELECTION CRITERIA: We included RCTs comparing approaches to discontinuation with continuation of antidepressants (or usual care) for people with depression or anxiety who are prescribed antidepressants for at least six months. Interventions included discontinuation alone (abrupt or taper), discontinuation with psychological therapy support, and discontinuation with minimal intervention. Primary outcomes were successful discontinuation rate, relapse (as defined by authors of the original study), withdrawal symptoms, and adverse events. Secondary outcomes were depressive symptoms, anxiety symptoms, quality of life, social and occupational functioning, and severity of illness. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by Cochrane. MAIN RESULTS: We included 33 studies involving 4995 participants. Nearly all studies were conducted in a specialist mental healthcare service and included participants with recurrent depression (i.e. two or more episodes of depression prior to discontinuation). All included trials were at high risk of bias. The main limitation of the review is bias due to confounding withdrawal symptoms with symptoms of relapse of depression. Withdrawal symptoms (such as low mood, dizziness) may have an effect on almost every outcome including adverse events, quality of life, social functioning, and severity of illness. Abrupt discontinuation Thirteen studies reported abrupt discontinuation of antidepressant. Very low-certainty evidence suggests that abrupt discontinuation without psychological support may increase risk of relapse (hazard ratio (HR) 2.09, 95% confidence interval (CI) 1.59 to 2.74; 1373 participants, 10 studies) and there is insufficient evidence of its effect on adverse events (odds ratio (OR) 1.11, 95% CI 0.62 to 1.99; 1012 participants, 7 studies; I² = 37%) compared to continuation of antidepressants, without specific assessment of withdrawal symptoms. Evidence about the effects of abrupt discontinuation on withdrawal symptoms (1 study) is very uncertain. None of these studies included successful discontinuation rate as a primary endpoint. Discontinuation by "taper" Eighteen studies examined discontinuation by "tapering" (one week or longer). Most tapering regimens lasted four weeks or less. Very low-certainty evidence suggests that "tapered" discontinuation may lead to higher risk of relapse (HR 2.97, 95% CI 2.24 to 3.93; 1546 participants, 13 studies) with no or little difference in adverse events (OR 1.06, 95% CI 0.82 to 1.38; 1479 participants, 7 studies; I² = 0%) compared to continuation of antidepressants, without specific assessment of withdrawal symptoms. Evidence about the effects of discontinuation on withdrawal symptoms (1 study) is very uncertain. Discontinuation with psychological support Four studies reported discontinuation with psychological support. Very low-certainty evidence suggests that initiation of preventive cognitive therapy (PCT), or MBCT, combined with "tapering" may result in successful discontinuation rates of 40% to 75% in the discontinuation group (690 participants, 3 studies). Data from control groups in these studies were requested but are not yet available. Low-certainty evidence suggests that discontinuation combined with psychological intervention may result in no or little effect on relapse (HR 0.89, 95% CI 0.66 to 1.19; 690 participants, 3 studies) compared to continuation of antidepressants. Withdrawal symptoms were not measured. Pooling data on adverse events was not possible due to insufficient information (3 studies). Discontinuation with minimal intervention Low-certainty evidence from one study suggests that a letter to the general practitioner (GP) to review antidepressant treatment may result in no or little effect on successful discontinuation rate compared to usual care (6% versus 8%; 146 participants, 1 study) or on relapse (relapse rate 26% vs 13%; 146 participants, 1 study). No data on withdrawal symptoms nor adverse events were provided. None of the studies used low-intensity psychological interventions such as online support or a changed pharmaceutical formulation that allows tapering with low doses over several months. Insufficient data were available for the majority of people taking antidepressants in the community (i.e. those with only one or no prior episode of depression), for people aged 65 years and older, and for people taking antidepressants for anxiety. AUTHORS' CONCLUSIONS: Currently, relatively few studies have focused on approaches to discontinuation of long-term antidepressants. We cannot make any firm conclusions about effects and safety of the approaches studied to date. The true effect and safety are likely to be substantially different from the data presented due to assessment of relapse of depression that is confounded by withdrawal symptoms. All other outcomes are confounded with withdrawal symptoms. Most tapering regimens were limited to four weeks or less. In the studies with rapid tapering schemes the risk of withdrawal symptoms may be similar to studies using abrupt discontinuation which may influence the effectiveness of the interventions. Nearly all data come from people with recurrent depression.   There is an urgent need for trials that adequately address withdrawal confounding bias, and carefully distinguish relapse from withdrawal symptoms. Future studies should report key outcomes such as successful discontinuation rate and should include populations with one or no prior depression episodes in primary care, older people, and people taking antidepressants for anxiety and use tapering schemes longer than 4 weeks.

Detection of potentially inappropriate prescribing in older patients with the GheOP³S-tool: completeness and clinical relevance.

OBJECTIVES: The Ghent Older People's Prescriptions community Pharmacy Screening (GheOP3S-) tool was recently developed as an explicit screening method to detect Potentially Inappropriate Prescribing (PIP) in the community pharmacy. We aimed to validate the GheOP3S-tool as an effective screening method for PIP. METHODS: All patients admitted to the acute geriatric ward of the Sint-Vincentius hospital (Belgium) were consecutively screened for inclusion (≥70 years,≥5 drugs chronically). PIP prevalence was evaluated by applying the GheOP3S-tool on the complete medication history. For each PIP-item, clinical relevance of the detected item, relevance of proposed alternative and subsequent acceptance by the treating geriatrician and a general practitioner were evaluated. Additionally, contribution to the current admission and preventability was assessed by the geriatrician. The completeness of a PIP-screening with the GheOP3S-tool was evaluated through comparison with the adapted Medication Appropriateness Index (aMAI). RESULTS: We detected 250 GheOP3S-items in 57 of 60 included patients (95%) (median: four PIP-items per patient; IQR: 3-5). Both the geriatrician and the general practitioners scored the clinical relevance of the detected items 'serious' or 'significant' in over 70% of cases. Proposed alternative treatment plans were accepted for 79% of the PIP-items (n = 198). The aMAI detected 536 items, of which 145 were also detected by the GheOP3S-tool. A total of 119 PIP-items were additionally detected by the GheOP3S-tool. CONCLUSION: The clinical relevance of the PIP-items detected with the GheOP3S-tool is high, likewise the acceptance rate of proposed alternatives.

Discontinuation of Long-Term Antipsychotic Drug Use for Behavioral and Psychological Symptoms in Older Adults Aged 65 Years and Older With Dementia.

BACKGROUND: Antipsychotic drugs are often used to treat behavioral and psychological symptoms (BPSD) in adults aged 65 years and older with dementia, although there is uncertainty about the effectiveness of long-term use for this indication and there are concerns that they may cause harm. OBJECTIVES: To evaluate whether discontinuation of long-term antipsychotic drugs for BPSD is successful in adults aged 65 years and older with dementia. This article is based on a Cochrane review updated in 2018. DESIGN: A Cochrane systematic review and meta-analysis. SETTING AND PARTICIPANTS: Eight databases were searched in January 2018 to identify 10 randomized controlled trials with 632 older adults. MEASURES: We used standard methodological procedures according to the Cochrane Handbook for Systematic Reviews of Interventions. We assessed the number of patients completing the study. We considered sustained withdrawal of antipsychotics until the end of the study period as successful outcome. RESULTS: Based on assessment of 7 studies (n = 446), discontinuation may make little or no difference to whether or not participants complete the study (low-quality evidence). In 2 trials, including participants with psychosis, agitation, or aggression who had responded to antipsychotic treatment, discontinuation of antipsychotics was associated with a higher risk of leaving the study prematurely because of symptomatic relapse or a shorter time to symptomatic relapse. We found low-quality evidence from 7 trials (n = 519) that discontinuation may make little or no difference to overall BPSD, measured using various scales. There was some evidence from subgroup analyses in 2 trials that discontinuation may be associated with a worsening of BPSD in participants with more severe BPSD at baseline. CONCLUSIONS: Our meta-analysis revealed that there is low-quality evidence that long-term antipsychotic drugs for BPSD may be successfully discontinued in most adults aged 65 and older.

Withdrawal versus continuation of long-term antipsychotic drug use for behavioural and psychological symptoms in older people with dementia.

BACKGROUND: Antipsychotic agents are often used to treat neuropsychiatric symptoms (NPS) in people with dementia although there is uncertainty about the effectiveness of their long-term use for this indication and concern that they may cause harm, including higher mortality. When behavioural strategies have failed and treatment with antipsychotic drugs is instituted, regular attempts to withdraw them have been recommended in guidelines. Physicians, nurses and families of older people with dementia may be reluctant to stop antipsychotics, fearing deterioration of NPS.This is an update of a Cochrane Review published in 2013. OBJECTIVES: To evaluate whether withdrawal of antipsychotic agents is successful in older people with dementia and NPS in primary care or nursing home settings, to list the different strategies for withdrawal of antipsychotic agents in older participants with dementia and NPS, and to measure the effects of withdrawal of antipsychotic agents on participants' behaviour and assess safety. SEARCH METHODS: We searched the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (ALOIS), theCochrane Library, MEDLINE, Embase, PsycINFO, CINAHL, LILACS, clinical trials registries and grey literature sources up to 11 January 2018. SELECTION CRITERIA: We included all randomised, controlled trials comparing an antipsychotic withdrawal strategy to continuation of antipsychotics in people with dementia who had been treated with an antipsychotic drug for at least three months. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures according to the Cochrane Handbook for Systematic Reviews of Interventions. We rated the quality of evidence for each outcome using the GRADE approach. MAIN RESULTS: We included 10 studies involving 632 participants. One new trial (19 participants) was added for this update.One trial was conducted in a community setting, eight in nursing homes and one in both settings. Different types of antipsychotics at varying doses were discontinued in the studies. Both abrupt and gradual withdrawal schedules were used. Reported data were predominantly from studies at low or unclear risk of bias.We included nine trials with 575 randomised participants that used a proxy outcome for overall success of antipsychotic withdrawal. Pooling data was not possible due to heterogeneity of outcome measures used. Based on assessment of seven studies, discontinuation may make little or no difference to whether or not participants complete the study (low-quality evidence).Two trials included only participants with psychosis, agitation or aggression who had responded to antipsychotic treatment. In these two trials, stopping antipsychotics was associated with a higher risk of leaving the study early due to symptomatic relapse or a shorter time to symptomatic relapse.We found low-quality evidence that discontinuation may make little or no difference to overall NPS, measured using various scales (7 trials, 519 participants). There was some evidence from subgroup analyses in two trials that discontinuation may reduce agitation for participants with less severe NPS at baseline, but may be associated with a worsening of NPS in participants with more severe NPS at baseline.None of the studies assessed withdrawal symptoms. Adverse effects of antipsychotics (such as falls) were not systematically assessed. Low-quality evidence showed that discontinuation may have little or no effect on adverse events (5 trials, 381 participants), quality of life (2 trials, 119 participants), or cognitive function (5 trials, 365 participants).There were insufficient data to determine whether discontinuation of antipsychotics has any effect on mortality (very low-quality evidence). AUTHORS' CONCLUSIONS: There is low-quality evidence that antipsychotics may be successfully discontinued in older people with dementia and NPS who have been taking antipsychotics for at least three months, and that discontinuation may have little or no important effect on behavioural and psychological symptoms. This is consistent with the observation that most behavioural complications of dementia are intermittent and often do not persist for longer than three months. Discontinuation may have little or no effect on overall cognitive function. Discontinuation may make no difference to adverse events and quality of life. Based on the trials in this review, we are uncertain whether discontinuation of antipsychotics leads to a decrease in mortality.People with psychosis, aggression or agitation who responded well to long-term antipsychotic drug use, or those with more severe NPS at baseline, may benefit behaviourally from continuation of antipsychotics. Discontinuation may reduce agitation for people with mild NPS at baseline. However, these conclusions are based on few studies or small subgroups and further evidence of benefits and harms associated with withdrawal of antipsychotic is required in people with dementia and mild and severe NPS.The overall conclusions of the review have not changed since 2013 and the number of available trials remains low.

Noncovalent triblock copolymers based on a coiled-coil peptide motif.

The formation of a noncovalent triblock copolymer based on a coiled-coil peptide motif is demonstrated in solution. A specific peptide pair (E and K) able to assemble into heterocoiled coils was chosen as the middle block of the polymer and conjugated to poly(ethylene glycol) (PEG) and polystyrene (PS) as the outer blocks. Mixing equimolar amounts of the polymer-peptide block copolymers PS-E and K-PEG resulted in the formation of coiled-coil complexes between the peptides and subsequently in the formation of the amphiphilic triblock copolymer PS-E/K-PEG. Aqueous self-assembly of the separate peptides (E and K), the block copolymers (PS-E and K-PEG), and equimolar mixtures thereof was studied by circular dichroism, dynamic light scattering, and cryogenic transmission electron microscopy. It was found that the noncovalent PS-E/K-PEG copolymer assembled into rodlike micelles, while in all other cases, spherical micelles were observed. Temperature-dependent studies revealed the reversible nature of the coiled-coil complex and the influence of this on the morphology of the aggregate. A possible mechanism for these transitions based on the interfacial free energy and the free energy of the hydrophobic blocks is discussed. The self-assembly of the polymer-peptide conjugates is compared to that of polystyrene-b-poly(ethylene glycol), emphasizing the importance of the coiled-coil peptide block in determining micellar structure and dynamic behavior.

Stepwise noncovalent synthesis leading to dendrimer-based assemblies in water.

We provide detailed insight into complex supramolecular assembly processes by fully characterizing a multicomponent model system using dynamic light scattering, cryogenic transmission electron microscopy, atomic force microscopy, and various NMR techniques. First, a preassembly of a host molecule (the fifth-generation urea-adamantyl poly(propylene imine) dendrimer) and 32 guest molecules (a water- and chloroform-soluble ureidoacetic acid guest) was made in chloroform. The association constant in chloroform is concealed by guest self-association and is therefore higher than 10(3) M(-1). Via the neat state the single-host complex was transferred to water, where larger dendrimer-based assemblies were formed. The core of these assemblies, consisting of multiple host molecules (on average three), is kinetically trapped upon dissolution in water, and its size is constant irrespective of the concentration. The guest molecules forming the corona of the assemblies, however, stay dynamic since they are still in rapid exchange on the NMR time scale, as they were in chloroform. A stepwise noncovalent synthesis provides a means to obtain metastable dynamic supramolecular assemblies in water, structures that cannot be formed in one step.

Molecular recognition in poly(epsilon-caprolactone)-based thermoplastic elastomers.

The molecular recognition properties of the hydrogen bonding segments in biodegradable thermoplastic elastomers were explored, aiming at the further functionalization of these potentially interesting biomaterials. A poly(epsilon-caprolactone)-based poly(urea) 2 was synthesized and characterized in terms of mechanical properties, processibility and histocompatibility. Comparison of the data with those obtained from the structurally related poly(urethane urea) 1 revealed that the difference in hard segment structure does not significantly affect the potency for application as a biomaterial. Nevertheless, the small differences in hard block composition had a strong effect on the molecular recognition properties of the hydrogen bonding segments. High selectivity was found for poly(urea) 2 in which bisureidobutylene-functionalized azobenzene dye 3 was selectively incorporated while bisureidopentylene-functionalized azobenzene dye 4 was completely released. In contrast, the incorporation of both dyes in poly(urethane urea) 1 led in both cases to their gradual release in time. Thermal analysis of the polymers in combination with variable temperature infrared experiments indicated that the hard blocks in 1 showed a sharp melting point, whereas those in 2 showed a very broad melting trajectory. This suggests a more precise organization of the hydrogen bonding segments in the hard blocks of poly(urea) 2 compared to poly(urethane urea) 1 and explains the results from the molecular recognition experiments. Preliminary results revealed that a bisureidobutylene-functionalized GRGDS peptide showed more supramolecular interaction with the PCL-based poly(urea), containing the bisureidobutylene recognition unit, as compared to HMW PCL, lacking this recognition unit.

Cancer specific Mucin-1 glycoforms are expressed on multiple myeloma.

Present therapies cannot cure the large majority of patients with multiple myeloma (MM) and therefore new treatment strategies are imperative. This study analysed the different glycosylation profiles of Mucin-1 (MUC1) on MM and acute myeloid leukaemia (AML) cells using a series of anti-MUC1 antibodies. Seventy-three per cent of the MM patients had plasma cells that expressed the fully glycosylated forms of MUC1. In contrast to controls, normal bone marrow cells and AML cells, the differentiation-dependent and cancer-associated glycoforms of MUC1 were present on 59% and 36% MM tumour cells respectively. This indicated that aberrantly glycosylated MUC1 is a potential immunotherapeutic target in MM patients.

Chemical and biological properties of supramolecular polymer systems based on oligocaprolactones.

We show that materials with a diverse range of mechanical and biological properties can be obtained using a modular approach by simply mixing different ratios of oligocaprolactones that are either end-functionalized or chain-extended with quadruple hydrogen bonding ureido-pyrimidinone (UPy) moieties. The use of two UPy-synthons allows for easy synthesis of UPy-modified polymers resulting in high yields. Comparison of end-functionalized UPy-polymers with chain-extended UPy-polymers shows that these polymers behave distinctively different regarding their material and biological properties. The end-modified UPy-polymer is rather stiff and brittle due to its high crystallinity. Disks made of this material fractures after subcutaneous implantation. The material shows a low inflammatory response which is accompanied by the formation of a fibrous capsule, reflecting the inertness of the material. The chain-extended UPy-material on the contrary is practically free of crystalline domains and shows clear flexible properties. This material deforms after in-vivo implantation, accompanied with cellular infiltration. By mixing both polymers, materials with intermediate properties concerning their mechanical and biological behaviour can be obtained. Surprisingly, a 20:80 mixture of both polymers with the chain-extended UPy-polymer in excess shows flexible properties without visible deformation upon implantation for 42 days. This mixture, a blend formed by intimate mixing through UPy-UPy interaction, also shows a mild tissue response accompanied with the formation of a thin capsule. The material does not become more crystalline upon implantation. Hence, this mixture might be an ideal scaffold material for soft tissue engineering due to its flexibility and diminished fibrous tissue formation, and illustrates the strength of the modular approach.

Mucin-1 is expressed on dendritic cells, both in vitro and in vivo.

Dendritic cells (DCs) are the best professional antigen-presenting cells to stimulate cytotoxic as well as T helper cells and are therefore appropriate candidates for establishing immunotherapy. The concept of our vaccination program is to introduce the tumor-associated antigen mucin-1 (MUC1) into DCs. Analysis of immature and mature DCs--before transducing the antigen MUC1--already demonstrated expression of MUC1 on in vitro monocyte-derived DCs upon maturation. Different culture methods as well as maturation cocktails showed similar results concerning the upregulation of MUC1 expression. Furthermore, we studied the expression of MUC1 on DCs in vivo. No MUC1 expression was found on blood DCs, or on thymic or tonsil DCs. On the other hand, synovial fluid from patients with arthritis contained DCs that were found to express MUC1. This study shows for the first time that the tumor-associated antigen MUC1 is expressed on in vivo DCs. We further show that MUC1 is also expressed on in vitro cultured bone marrow-derived DCs of human MUC1 transgenic mice, supporting the relevance of this mouse model to the human situation. The observation that MUC1 is present on in vivo DCs suggests a functional role, but this physiological function remains to be elucidated.

Aspirin inhibits Chlamydia pneumoniae-induced nuclear factor-kappa B activation, cytokine expression, and bacterial development in human endothelial cells.

OBJECTIVE: Chlamydia pneumoniae has been associated with atherosclerosis. Infection of vascular endothelial cells with C pneumoniae increases the expression of proatherogenic cytokines mediated by nuclear factor (NF)-kappaB, a transcription factor. The present study was designed to test the effect of aspirin on C pneumoniae-induced NF-kappaB activation, interleukin expression, and bacterial development in cultured human endothelial cells. METHODS AND RESULTS: Aspirin, its metabolite salicylic acid, and 2 other unrelated NF-kappaB inhibitors showed a strong concentration-dependent inhibitory effect on chlamydial growth, indicated by the reduction of bacterial inclusions and the titer of infectious progeny. Involvement of the transcription factor NF-kappaB was confirmed by electrophoretic mobility shift assay and by transfection experiments with appropriate decoy oligodeoxynucleotides. Attenuation of the C pneumoniae-induced activation of NF-kappaB by aspirin also reduced the secretion of interleukin-6 and interleukin-8, indicating efficient inhibition of NF-kappaB gene expression. Reduction of chlamydial growth was not caused by apoptosis of the host cell, as determined by monitoring characteristic chromatin condensation. CONCLUSIONS: These data provide evidence that NF-kappaB-mediated gene activation represents a crucial step in the developmental cycle of C pneumoniae. Aspirin exerts an anti-chlamydial effect that is due to the inhibition of C pneumoniae-induced NF-kappaB activation, which might account for some of the cardioprotective activity of aspirin.