Healthcare professionals' perceptions of the contributions of rehabilitation coordinators to patients in Swedish psychiatric care: a qualitative descriptive study.

BACKGROUND: Rehabilitation coordinators have gradually been introduced into Swedish psychiatric care to support individuals on sick leave to return-to-work or enter work. AIM: To explore healthcare professionals' perspectives on the contributions a rehabilitation coordinator can make to patients in psychiatric care. MATERIALS AND METHODS: A descriptive qualitative design was used, and data were collected through interviews. Twelve healthcare professionals in psychiatric care participated in individual semi-structured interviews. Data were analysed using thematic analysis. RESULTS: An overarching theme evolved: "The rehabilitation coordinator promotes security and reduces stress in the vocational rehabilitation process", based on two themes: (1) "Adaptations and support based on the patient's needs" and (2) "Rehabilitation coordinator efforts as relevant for care". The themes, in turn, consist of six subthemes. CONCLUSIONS: This study showed that healthcare professionals perceived employment as important for patients' health and well-being. Therefore, the rehabilitation coordination efforts were not only seen as beneficial for addressing patients' challenges and needs in managing the vocational rehabilitation process but also as an integral part of the patient's care.

Siplizumab combination therapy with belatacept or abatacept broadly inhibits human T cell alloreactivity in vitro.

Combined antigen-specific T cell receptor stimulation and costimulation are needed for complete T cell activation. Belatacept and abatacept are nondepleting fusion proteins blocking CD28/B7 costimulation, whereas siplizumab is a depleting antiCD2 immunoglobulin G1 monoclonal antibody targeting CD2/CD58 costimulation. Herein, the effect of siplizumab combination therapy with abatacept or belatacept on T cell alloreactivity in mixed lymphocyte reactions was investigated. In contrast to monotherapy, the combination of siplizumab with belatacept or abatacept induced near-complete suppression of T cell proliferation and increased the potency of siplizumab-mediated T cell inhibition. Furthermore, dual targeting of CD2 and CD28 costimulation enhanced the selective depletion of memory T cells compared with monotherapy. Although siplizumab monotherapy leads to significant regulatory T cell enrichment, high doses of cytotoxic T-lymphocyte-associated antigen 4 and a human IgG1 Fc fragment in the combination therapy reduced this effect. These results support the clinical evaluation of dual costimulation blockade, combining siplizumab with abatacept or belatacept, for the prophylaxis of organ transplant rejection and improvement of long-term outcomes following transplantation. Ongoing investigative research will elucidate when other forms of siplizumab-based dual costimulatory blockade may be able to induce similarly strong inhibition of T cell activation although still allowing for enrichment of regulatory T cells.

Evaluation of Spin Columns for Human Plasma Depletion to Facilitate MS-Based Proteomics Analysis of Plasma.

High abundant protein depletion is a common strategy applied to increase analytical depth in global plasma proteomics experiment setups. The standard strategies for depletion of the highest abundant proteins currently rely on multiple-use HPLC columns or multiple-use spin columns. Here we evaluate the performance of single-use spin columns for plasma depletion and show that the single-use spin reduces handling time by allowing parallelization and is easily adapted to a nonspecialized lab environment without reducing the high plasma proteome coverage and reproducibility. In addition, we evaluate the effect of viral heat inactivation on the plasma proteome, an additional step in the plasma preparation workflow that allows the sample preparation of SARS-Cov2-infected samples to be performed in a BSL3 laboratory, and report the advantage of performing the heat inactivation postdepletion. We further show the possibility of expanding the use of the depletion column cross-species to macaque plasma samples. In conclusion, we report that single-use spin columns for high abundant protein depletion meet the requirements for reproducibly in in-depth plasma proteomics and can be applied on a common animal model while also reducing the sample handling time.

Direct interaction of the ATP-sensitive K+ channel by the tyrosine kinase inhibitors imatinib, sunitinib and nilotinib.

The ATP-regulated K+ channel (KATP) plays an essential role in the control of many physiological processes, and contains a ATP-binding site. Tyrosine kinase inhibitors (TKI) are commonly used drugs, that primarily target ATP-binding sites in tyrosine kinases. Herein, we used the patch-clamp technique to examine the effects of three clinically established TKIs on KATP channel activity in isolated membrane patches, using a pancreatic ß-cell line as a KATP channel source. In excised inside-out patches, the activity of the KATP channel was dose-dependently inhibited by imatinib with half-maximal concentration of approximately 9.4 µM. The blocking effect of imatinib was slow and reversible. No effect of imatinib was observed on either the large (KBK) or the small (KSK) conductance, Ca2+-regulated K+ channel. In the presence of ATP/ADP (ratio 1) addition of imatinib increased channel activity approximately 1.5-fold. Sunitinib and nilotinib were also found to decrease KATP channel activity. These findings are compatible with the view that TKIs, designed to interact at the ATP-binding pocket on the tyrosine receptor, also interact at the ATP-binding site on the KATP channel. Possibly, this might explain some of the side effects seen with TKIs.

Organ transplants of the future: planning for innovations including xenotransplantation.

The future clinical application of animal-to-human transplantation (xenotransplantation) is of importance to society as a whole. Favourable preclinical data relevant to cell, tissue and solid organ xenotransplants have been obtained from many animal models utilizing genetic engineering and protocols of pathogen-free husbandry. Findings have reached a tipping point, and xenotransplantation of solid organs is approaching clinical evaluation, the process of which now requires close deliberation. Such discussions include considering when there is sufficient evidence from preclinical animal studies to start first-in-human xenotransplantation trials. The present article is based on evidence and opinions formulated by members of the European Society for Organ Transplantation who are involved in the Transplantation Learning Journey project. The article includes a brief overview of preclinical concepts and biology of solid organ xenotransplantation, discusses the selection of candidates for first-in-human studies and considers requirements for study design and conduct. In addition, the paper emphasizes the need for a regulatory framework for xenotransplantation of solid organs and the essential requirement for input from public and patient stakeholders.

Work-life balance predicted work ability two years later: a cohort study of employees in the Swedish energy and water sector.

BACKGROUND: Work-life balance (WLB) is the extent to which individual's multiple life roles and demands carry over between each role. WLB can be divided into work interference with personal life (WIPL) and personal life interference with work (PLIW). This study aimed to investigate longitudinal associations between WIPL, PLIW and work ability outcomes. METHODS: In this cohort study, 224 employees in the energy and water sector in Sweden were followed-up over 2 years. Three questions derived from the Work Ability Index were used for measuring work ability outcome: current work ability compared with lifetime best; work ability regarding physical; and mental demands. Logistic regression models were used to analyse longitudinal associations between work ability and WIPL and WIPL respectively, controlling for workplace (company), position at work, experience of leadership quality, demographics, and work ability. RESULTS: Work ability compared to lifetime best were associated with WIPL in the adjusted logistic regression models (odds ratio (OR) 1.77, 95% confidence interval (CI) 1.15-2.73), and PLIW (OR 3.34, 95% CI 1.66-6.74). Work ability regarding physical demands was associated with WIPL (OR 1.60, 95% CI 1.07-2.40). Work ability regarding mental demands was associated with WIPL (OR 1.59, 95% CI 1.03-2.44) and PLIW (OR 2.88, 95% CI 1.31-6.32). CONCLUSION: In this two-year longitudinal study, lower WIPL predicted good/excellent overall work ability compared with lifetime best, higher work ability regarding physical and mental demands, and lower PLIW predicted good/excellent overall work ability compared with lifetime best and higher work ability regarding and mental demands.

Strategies for Liver Transplantation Tolerance.

Liver transplant (LT) recipients require life-long immunosuppression (IS) therapy to preserve allograft function. The risks of chronic IS include an increased frequency of malignancy, infection, renal impairment, and other systemic toxicities. Despite advances in IS, long-term LT outcomes have not been improved over the past three decades. Standard-of-care (SoC) therapy can, in rare cases, lead to development of operational tolerance that permits safe withdrawal of maintenance IS. However, successful IS withdrawal cannot be reliably predicted and, in current prospective studies, is attempted several years after the transplant procedure, after considerable exposure to the cumulative burden of maintenance therapy. A recent pilot clinical trial in liver tolerance induction demonstrated that peri-transplant immunomodulation, using a regulatory T-cell (Treg) approach, can reduce donor-specific alloreactivity and allow early IS withdrawal. Herein we review protocols for active tolerance induction in liver transplantation, with a focus on identifying tolerogenic cell populations, as well as barriers to tolerance. In addition, we propose the use of novel IS agents to promote immunomodulatory mechanisms favoring tolerance. With numerous IS withdrawal trials underway, improved monitoring and use of novel immunomodulatory strategies will help provide the necessary knowledge to establish an active liver tolerance induction protocol for widespread use.

Phase I trial evaluating safety and efficacy of intratumorally administered inflammatory allogeneic dendritic cells (ilixadencel) in advanced gastrointestinal stromal tumors.

BACKGROUND: The majority of patients with advanced gastrointestinal stromal tumor (GIST) develop resistance to imatinib, and subsequent treatments have limited efficacy. Ilixadencel (allogeneic inflammatory dendritic cells) is a cell-based immune primer injected intratumorally that previously has been clinically investigated in metastatic renal cell carcinoma and hepatocellular carcinoma. METHODS: The trial was a single arm phase I trial assessing safety and efficacy of ilixadencel in subjects with progressing advanced/metastatic GIST despite ongoing treatment with second or later lines of tyrosine kinase inhibitors (TKI). Three patients were progressing while on sunitinib (second line), one on regorafenib (third line), and two on pazopanib (fourth line). TKI treatment was maintained throughout, while two intratumoral injections of ilixadencel (10 × 106 viable and HLA-DR expressing cells per dose) were administered. RESULTS: No severe adverse events were found to be related to ilixadencel administration. Four patients showed continued tumor progression at 3 months per RECIST 1.1 and Choi criteria. One patient (on third line regorafenib) had stable disease for 9 months and another patient (on second line sunitinib) had stable disease at end of study (12 months) as per RECIST 1.1. These two patients developed a partial response as per Choi criteria with a duration of 3 and 6 months, respectively. The median progression-free survival (PFS) was 4.0 months. CONCLUSION: Ilixadencel treatment presented an acceptable safety profile among advanced GIST patients who developed resistance to TKI. Encouraging radiological tumor responses were detected in 33% of treated patients, supporting further investigation. Clinical trial registration www.clinicaltrials.gov ; NCT: 02432846; registration date: February 22, 2016.

Pharmacokinetic and pharmacodynamic study of a clinically effective anti-CD2 monoclonal antibody.

The humanized IgG1κ monoclonal antibody siplizumab and its rat parent monoclonal IgG2b antibody BTI-322 are directed against the CD2 antigen. Siplizumab is species-specific, reacting with human and chimpanzee cells but not with cells from any other species, including other non-human primates. Because siplizumab treatment has recently shown great potential in clinical transplantation, we now present the results of our previous pharmacokinetic, pharmacodynamic and safety studies of both antibodies. Fourteen chimpanzees received 1-3 doses of 0.143 to 5.0 mg/kg iv The effects were followed with flow cytometry on peripheral lymphocytes and staining of lymph nodes. Side effects were recorded. Serum antibody concentrations were followed. Across the doses, a rapid, transient depletion of CD2, CD3, CD4 and CD8 lymphocytes and NK cells was observed for both antibodies. Immune reconstitution was more rapid for BTI-322 compared to siplizumab. Paracortical lymph node T cell depletion was moderate, estimated at 45% with doses of >0.6 mg/kg. Restoration of lymph node architecture was seen after two weeks to two months for all animals. All four subjects receiving BTI-322 experienced AEs on the first dosing day, while the eight subjects dosed with siplizumab experienced few mild, transient AEs. Infusion with siplizumab and BTI-322 resulted in rapid depletion of CD2+ cells in circulation and tissue. Siplizumab had a longer t1/2 and fewer AEs compared to BTI-322.

Safety and pharmacodynamics of anti-CD2 monoclonal antibody treatment in cynomolgus macaques - an experimental study.

Anti-CD2 treatment provides targeted immunomodulatory properties that have demonstrated clinical usefulness to condition the immune system and to treat transplant rejection. The treatment is species-specific due to structural CD2 antigen differences between nonhuman primates and humans. Herein, we report the safety profile and efficacy of two modifications of the same anti-CD2 monoclonal antibody in cynomolgus macaques. Twelve subjects received one i.v. anti-CD2 (of rat or rhesus type) dose each, range 1-4 mg/kg, and were followed for 1-7 days. Treatment effects were evaluated with flow cytometry on peripheral blood and histopathological evaluation of secondary lymphoid organs. In vitro inhibitory activity on primary MHC disparate mixed lymphocyte reactions (MLRs) was determined. Upon anti-CD2 treatment, CD4+ , CD8+ memory subsets were substantially depleted. Naïve T cells and Tregs were relatively spared and exhibited lower CD2 expression than memory T cells. Early immune reconstitution was noted for naïve cells, while memory counts had not recovered after one week. Both antibodies displayed a concentration-dependent MLR inhibition. Lymph node examination revealed no significant lymphocyte depletion. None of the animals experienced any significant study drug-related adverse events. This study outlines the safety and pharmacodynamic profile of primate-specific anti-CD2 treatment, relevant for translation of anti-CD2-based animal models into clinical trials.

Rehabilitation coordinator intervention versus control in psychiatric specialist care for return to work and reduced sick leave: study protocol of a randomised controlled trial.

BACKGROUND: Mental disorders are the most common reason for sick leave in Sweden. Knowledge about effective methods to help these individuals to return to work (RTW)/entry into work or studies is limited. Rehabilitation coordinators (RC's) have been introduced within healthcare with the purpose to promote cooperation, streamline the sick leave and rehabilitation process, and facilitate RTW for sick-listed patients. The function of RC's has shown positive results by reducing sick leave within primary healthcare. However, the function has not been evaluated in terms of specialist psychiatry. This paper describes the design of a study to evaluate effects of a RC intervention on sick leave and RTW/entry in work or studies in patients with moderate to severe affective and/or moderate to severe anxiety disorders within specialist psychiatric care. METHODS: A randomised controlled trial (RCT) comparing an intervention group receiving support from a RC with a control group receiving treatment as usual (TAU). The target group is patients on sick leave, treated for affective and/or anxiety disorder, aged 25-64, with or without employment. DISCUSSION: This study gives the possibility to evaluate a RC intervention for individuals with mental disorders. If the study has promising vocational outcomes, it may be of importance for the participants in many ways, e.g. increase participation in society, provide economic benefits and improve health and wellbeing. This would be valuable for the individual as well as for the society. TRIAL REGISTRATION: The study is registered at the Clinicaltrials.gov Register Platform (ID NCT03729050) in 2 November 2018.

miR-125a-5p regulation increases phosphorylation of FAK that contributes to imatinib resistance in gastrointestinal stromal tumors.

The use of imatinib mesylate has greatly improved the clinical outcome for gastrointestinal stromal tumor (GIST) patients. However, imatinib resistance is still a major clinical challenge, and the molecular mechanisms are not fully understood. We have previously shown that miR-125a-5p and its mRNA target PTPN18 modulate imatinib response in GIST cells. Herein, we evaluated phosphorylated FAK (pFAK) as a candidate downstream target of PTPN18 and the possible association of this regulation with imatinib resistance in GIST. FAK and pFAK expressions were evaluated in GIST882 cells transfected with short hairpin RNA or short interfering RNA targeting PTPN18 or miR-125a-5p mimic, imatinib-resistant GIST882R subclones and clinical samples using Western blot analyses. FAK phosphorylation was blocked using the FAK inhibitor 14 (FAKi) and the effects on cell viability and apoptosis were evaluated using WST-1 assay and cleaved PARP expression. Clinical associations of FAK and pFAK expression with imatinib resistance, KIT mutation and patient outcome were assessed by Fisher's exact test or log-rank test. Over-expression of miR-125a-5p and silencing of PTPN18 increased pFAK, but not FAK, expression in GIST cells. Higher pFAK expression was observed in the GIST882R subclones with acquired imatinib resistance compared to their imatinib-sensitive parental cells. Treatment with FAKi in imatinib-resistant GIST882R cells reduced cell viability and increased apoptosis upon imatinib treatment. Additionally, FAKi could rescue the imatinib resistance effect mediated by miR-125a-5p over-expression. In clinical samples, high FAK and pFAK expressions were associated with KIT mutation status, and high FAK expression was also associated with metastasis in GIST. Higher pFAK was found in cases with shorter overall survival. Our findings highlight an important role for miR-125a-5p regulation and its downstream target pFAK for imatinib resistance in GIST. pFAK and FAK may have prognostic values in GIST.

Liver transplantation for acute liver failure - a 30-year single center experience.

OBJECTIVE: To determine overall long-term patient and graft survival rates among the recipients liver transplanted due to acute liver failure (ALF). Secondary aims included assessment of whether diagnosis, donor-recipient blood group compatibility and time-era of transplantation affected the outcome, and whether prescription-free availability of acetaminophen increased the need for liver transplantation (LTx). MATERIALS AND METHODS: A Retrospective cohort study of 78 patients who underwent LTx for ALF at Karolinska University Hospital 1984-2014. Patients were divided into two cohorts according to two 15-year periods: early cohort transplanted 1984-1999 (n = 40) and late cohort transplanted 2000-2014 (n = 38). Survival rates were established using Kaplan-Meier analyses. RESULTS: ALF patient survival rates for 1-year, 5-years, 10-years and 20-years were 71%, 63%, 52% and 40%, respectively. Survival for the late cohort at 1, 5 and 10 years was 82%, 76% and 71%, respectively. A high early mortality rate was noted during the first three months after transplantation when compared to LTx patients with chronic disease. Long-term survival rates were comparable between patients with ALF and chronic liver disease. Prescription-free access to acetaminophen did not increase the need for LTx. There was a strong trend towards improved survival in blood group identical donor-recipient pairs and blood group O recipients may have benefitted from this. CONCLUSIONS: The high early mortality rate most likely reflects the critical pre-transplant condition in these patients and the urgent need to sometimes accept a marginal donor liver. Long-term survival improved significantly over time and variation in patient access to acetaminophen did not influence the rate of LTx in our region.

Length of time periods in treatment effect descriptions and willingness to initiate preventive therapy: a randomised survey experiment.

BACKGROUND: Common measures used to describe preventive treatment effects today are proportional, i.e. they compare the proportions of events in relative or absolute terms, however they are not easily interpreted from the patient's perspective and different magnitudes do not seem to clearly discriminate between levels of effect presented to people. METHODS: In this randomised cross-sectional survey experiment, performed in a Swedish population-based sample (n = 1041, response rate 58.6%), the respondents, aged between 40 and 75 years were given information on a hypothetical preventive cardiovascular treatment. Respondents were randomised into groups in which the treatment was described as having the effect of delaying a heart attack for different periods of time (Delay of Event, DoE): 1 month, 6 months or 18 months. Respondents were thereafter asked about their willingness to initiate such therapy, as well as questions about how they valued the proposed therapy. RESULTS: Longer DoE:s were associated with comparatively greater willingness to initiate treatment. The proportions accepting treatment were 81, 71 and 46% when postponement was 18 months, 6 months and 1 month respectively. In adjusted binary logistic regression models the odds ratio for being willing to take therapy was 4.45 (95% CI 2.72-7.30) for a DoE of 6 months, and 6.08 (95% CI 3.61-10.23) for a DoE of 18 months compared with a DoE of 1 month. Greater belief in the necessity of medical treatment increased the odds of being willing to initiate therapy. CONCLUSIONS: Lay people's willingness to initiate preventive therapy was sensitive to the magnitude of the effect presented as DoE. The results indicate that DoE is a comprehensible effect measure, of potential value in shared clinical decision-making.

Strengthened General Self-Efficacy with Multidisciplinary Vocational Rehabilitation in Women on Long-Term Sick Leave: A Randomised Controlled Trial.

Purpose To investigate the effects of two vocational rehabilitation interventions on self-efficacy, for women on long-term sick leave ≥ 1 year due to chronic pain and/or mental illness. Methods This study uses data from a randomised controlled trial consisting of two phases and comprising 401 women on long-term sick leave. They were allocated to either (1) a multidisciplinary team assessment and multimodal intervention (TEAM), (2) acceptance and commitment therapy (ACT), or (3) control group. Data were collected through repeated measurements from self-reported questionnaires before intervention, 6 and 12 months later and registry data. Data from measurements of general self-efficacy, sociodemographics, anxiety and depression were analysed with linear regression analyses. Results During the intervention period, the women in the TEAM group's self-efficacy mean increased from 2.29 to 2.74. The adjusted linear regression model, which included group allocation, sociodemographics, self-efficacy pre-treatment, anxiety and depression showed increased self-efficacy for those in the TEAM intervention at 12 months (B = 0.25, 95% CI 0.10-0.41). ACT intervention had no effect on self-efficacy at 12 months (B = 0.02, 95% CI - 0.16 to 0.19). The results in the adjusted model also showed that higher self-efficacy at pre-treatment was associated with a higher level of self-efficacy at 12 months (B = 0.68, 95% CI 0.54-0.81). Conclusion A multidisciplinary team assessment and multimodal intervention increased self-efficacy in women on sick leave for an extremely long time (mean 7.8 years) who had a low mean level of self-efficacy prior to inclusion. Thus, self-efficacy needs to be addressed in vocational rehabilitation.

Contactin-1 regulates myelination and nodal/paranodal domain organization in the central nervous system.

Myelin, a multilayered membrane sheath formed by oligodendrocytes around axons in the CNS, enables rapid nerve impulse conduction and sustains neuronal health. The signals exchanged between axons and oligodendrocytes in myelin remain to be fully elucidated. Here we provide genetic evidence for multiple and critical functions of Contactin-1 in central myelin. We document dynamic Contactin-1 expression on oligodendrocytes in vivo, and progressive accumulation at nodes of Ranvier and paranodes during postnatal mouse development. Nodal and paranodal expression stabilized in mature myelin, but overall membranous expression diminished. Contactin-1-deficiency disrupted paranodal junction formation as evidenced by loss of Caspr, mislocalized potassium Kv1.2 channels, and abnormal myelin terminal loops. Reduced numbers and impaired maturation of sodium channel clusters accompanied this phenotype. Histological, electron microscopic, and biochemical analyses uncovered significant hypomyelination in Contactin-1-deficient central nerves, with up to 60% myelin loss. Oligodendrocytes were present in normal numbers, albeit a minor population of neuronal/glial antigen 2-positive (NG2(+)) progenitors lagged in maturation by postnatal day 18, when the mouse null mutation was lethal. Major contributing factors to hypomyelination were defects in the generation and organization of myelin membranes, as judged by electron microscopy and quantitative analysis of oligodendrocyte processes labeled by GFP transgenically expressed from the proteolipid protein promoter. These data reveal that Contactin-1 regulates both myelin formation and organization of nodal and paranodal domains in the CNS. These multiple roles distinguish central Contactin-1 functions from its specific role at paranodes in the periphery, and emphasize mechanistic differences in central and peripheral myelination.

Secretome protein signature of human gastrointestinal stromal tumor cells.

Strategies for correct diagnosis, treatment evaluation and recurrence prediction are important for the prognosis and mortality rates among cancer patients. In spite of major improvements in clinical management, gastrointestinal stromal tumors (GISTs) can still be deadly due to metastasis and recurrences, which confirms the unmet need of reliable follow-up modalities. Tumor-specific secreted, shed or leaked proteins (collectively known as secretome) are considered promising sources for biomarkers, and suitable for detection in biofluids. Herein, we stimulated cell secretion in the imatinib-sensitive GIST882 cell line and profiled the secretome, collected as conditioned media, by using a shotgun proteomics approach. We identified 764 proteins from all conditions combined, 51.3% being predicted as classically/non-classically secreted. The protein subsets found were dependent on the stimulatory condition. The significant increase in protein release by the classical pathway was strongly associated with markers already found in other cancer types. Furthermore, most of the released proteins were non-classically released and overlapped to a high degree with proteins of exosomal origin. Imatinib pre-treatment radically changed these secretory patterns, which can have clinical implications when investigating biomarkers in imatinib-treated versus non-treated GIST patients. Our results show, for the first time, that GISTs contain a secretome signature. In the search for suitable biomarkers in the more complex GIST patient samples, this study aids in the understanding of basic GIST secretome characteristics.

Composition of growth factors and cytokines in lysates obtained from fresh versus stored pathogen-inactivated platelet units.

BACKGROUND: Platelet lysate is a readily available source of growth factors, and other mediators, which has been used in a variety of clinical applications. However, the product remains poorly standardized and the present investigation evaluates the composition of platelet lysate obtained from either fresh or stored pathogen-inactivated platelet units. MATERIALS AND METHODS: Platelet pooled units (n = 10) were obtained from healthy blood donors and tested according to standard procedures. All units were pathogen inactivated using amotosalen hydrochloride and UVA exposure. Platelet lysate was subsequently produced at two separate time-points, either from fresh platelet units or after 5 days of storage, by repeated freeze-thaw cycles. The following mediators were determined at each time-point: EGF, FGF-2, VEGF, IGF-1, PDGF-AB/BB, BMP-2, PF4, TGF-ß isoform 1, IL-1ß, IL-2, IL-6, IL-10, IL-12p70, 1L-17A, TNF-α, and IFN-γ. RESULTS: The concentration of growth factors and cytokines was affected by time in storage. Notably, TGF-ß, PDGF-AB/BB, and PF4 showed an increase of 27.2% (p < 0.0001), 29.5% (p = 0.04) and 8.2% (p = 0.0004), respectively. A decrease was seen in the levels of IGF-1 and FGF-2 with 22% (p = 0.041) and 11% (p = 0.01), respectively. Cytokines were present only in very low concentrations and all other growth factors remained stable with time in storage. CONCLUSION: The composition of mediators in platelet lysate obtained from pathogen-inactivated platelet units differs when produced from fresh and stored platelet units, respectively. This underscores the need for further standardization and optimization of this important product, which potentially may influence the clinical effects.

Health and wellbeing in informal caregivers and non-caregivers: a comparative cross-sectional study of the Swedish general population.

BACKGROUND: Informal caregiving by relatives is a great resource for individuals as well as for society, but the caregiving role is associated with health problems for the caregiver. This study aimed to compare caregivers' self-rated health, number of recent days with poor health and psychological wellbeing with that of non-caregivers in a general Swedish population. METHODS: From 2004 to 2013, 90,845 Swedish people completed a postal questionnaire about their health, number of recent days with poor health during last month, psychological wellbeing and if they were performing caregiving or not. Descriptive statistics, chi-square analysis, ANOVA, logistic regressions and negative binomial regression models were used to investigate associations between being a caregiver or not and health and wellbeing. Negative binomial regression was used to assess the relation between caregiver status and recent days with poor health or functioning. RESULTS: Eleven percent reported having a caregiving role. Caregivers reported poorer self-rated health compared to non-caregivers, also in adjusted models; odds ratio (OR): 1.07 with a 95% confidence interval (CI): 1.01-1.13. Caregivers also reported lower psychological wellbeing compared to non-caregivers; OR: 1.22, CI: 1.15-1.30. Caregiving status was associated with more recent days with poor physical health and more recent days with poor mental health. CONCLUSIONS: This study suggests that caregivers have worse perceptions in self-rated health and psychological wellbeing compared with non-caregivers, indicating that the role of caregiver is adversely associated with health. This association also appears in terms of reporting days of poor health in the last month. The underlying mechanism of these associations, including the potential detrimental health effects of being a caregiver, needs to be investigated in longitudinal studies.

Functional role of the Ca²âº-activated Cl⁻ channel DOG1/TMEM16A in gastrointestinal stromal tumor cells.

DOG1, a Ca(2+)-activated Cl(-) channel (CaCC), was identified in 2004 to be robustly expressed in gastrointestinal stromal tumors (GIST). It was rapidly included as a tumor marker in routine diagnostics, but the functional role remained unknown. CaCCs are important regulators of normal physiological functions, but also implicated in tumorigenesis, cancer progression, metastasis, cell migration, apoptosis, proliferation and viability in several malignancies. We therefore investigated whether DOG1 plays a role in the three latter in GIST by utilizing in vitro cell model systems. Confocal microscopy identified different subcellular localizations of DOG1 in imatinib-sensitive and imatinib-resistant cells. Electrophysiological studies confirmed that DOG1-specific pharmacological agents possess potent activating and inhibiting properties. Proliferation assays showed small effects up to 72 h, and flow cytometric analysis of adherent cells with 7-AAD/Annexin V detected no pharmacological effects on viable GIST cells. However, inhibition of DOG1 conveyed pro-apoptotic effects among early apoptotic imatinib-resistant cells. In conclusion, DOG1 generates Cl(-) currents in GIST that can be regulated pharmacologically, with small effects on cell viability and proliferation in vitro. Inhibition of DOG1 might act pro-apoptotic on some early apoptotic GIST cell populations. Further studies are warranted to fully illuminate the function of DOG1 and its potential as therapeutic target.