Dendritic cell-mediated HIV-1 transmission to T cells of LAD-1 patients is impaired due to the defect in LFA-1

BACKGROUND: Dendritic cells (DC) have been proposed to mediate sexual HIV-1 transmission by capturing the virus in the mucosa and subsequently presenting it to CD4(+ )T cells. We have demonstrated before that DC subsets expressing higher levels of intercellular adhesion molecule-1 (ICAM-1) are better HIV-1 transmitters. ICAM-1 binds leukocyte function-associated molecule-1 (LFA-1) on T cells, an integrin responsible for adhesion and signaling at the immunological synapse. To corroborate the importance of the ICAM-1— LFA-1 interaction, we performed transmission experiments to LFA-1 negative leukocytes from Leukocyte Adhesion Deficiency type 1 (LAD-1) patients. RESULTS: We clearly show that DC-mediated HIV-1 transmission to LAD-1 T cells is impaired in comparison to healthy controls. Furthermore, HIV-1 transmission to T cells from a unique LAD-1 patient with a well characterized LFA-1 activation defect was impaired as well, demonstrating that activation of LFA-1 is crucial for efficient transmission. Decreased cell adhesion between DC and LAD-1 T cells could also be illustrated by significantly smaller DC-T cell clusters after HIV-1 transmission. CONCLUSION: By making use of LFA-1 defect cells from unique patients, this study provides more insight into the mechanism of HIV-1 transmission by DC. This may offer new treatment options to reduce sexual transmission of HIV-1

How to improve newly qualified midwives' transition-into-practice:A Delphi study

BACKGROUND: In the Netherlands, newly qualified midwives start work as registered midwives without any formal transition support. Research shows that newly qualified midwives do not feel sufficiently confident and competent in their work during the period following graduation. This could impact the quality of care provided by newly registered midwives. The aim of this study is to seek consensus with stakeholders concerning viable components of support for newly qualified midwives working in midwifery care in the Netherlands.METHODS: A Delphi study was conducted among maternity care stakeholders in the Netherlands. During two rounds, sixteen statements derived from a theoretical framework of organizational socialization theory and previous studies were assessed (round 1, n = 56; round 2, n = 52). Stakeholders (N = 61) were invited and completed an online questionnaire that included spaces for opinions and remarks.RESULTS: Stakeholders agreed about an introductory support period for newly qualified midwives, involving performance feedback and regional-level backup from fellow midwives during shifts. They further agreed on the responsibilities of established professionals that they should support newcomers in practice and provide mentoring or group coaching, although they face organizational barriers for supporting newcomers.CONCLUSIONS: Stakeholders found consensus upon several components of support at the workplace. In addition, a stable work environment seemed less important in their opinion while previous research suggests otherwise. Practice organisations need to improve the employment conditions and support for newly qualified midwives to ensure the quality of midwifery care is guaranteed.</p

The initiation of Dutch newly qualified hospital-based midwives in practice, a qualitative study

In the Netherlands, a percentage of newly qualified midwives start work in maternity care as a hospital-based midwife, although prepared particularly for working autonomously in the community. Aim: This study aimed to explore newly qualified Dutch midwives' perceptions of their job demands and resources during their initiation to hospital-based practice. Design: We conducted a qualitative study with semi structured interviews using the Job Demands-Resources model as theoretical framework. Methods: Twenty-one newly qualified midwives working as hospital-based midwives in the Netherlands were interviewed individually between January and July 2018. Transcripts were analyzed using thematic content analysis. Findings: High workload, becoming a team member, learning additional medical procedures and job insecurity were perceived demands. Participants experienced the variety of the work, the teamwork, social support, working with women, and employment conditions as job resources. Openness for new experiences, sociability, calmness and accuracy were experienced as personal resources, and perfectionism, self-criticism, and fear of failure as personal demands. Conclusion: Initiation to hospital-based practice requires from newly qualified midwives adaptation to new tasks: working with women in medium and high-risk care, managing tasks, as well as often receiving training in additional medical skills. Sociability helps newly qualified midwives in becoming a member of a multidisciplinary team; neuroticism and perfectionism hinders them in their work. Clear expectations and a settling-in period may help newly qualified midwives to adapt to practice. The initiation phase could be better supported by preparing student midwives for working in a hospital setting and helping manage expectations about the settling-in period

Dendritic cells internalize staphylococcus aureus more efficiently than staphylococcus epidermidis, but do not differ in induction of antigen-specific t cell proliferation

Staphylococcus aureus and Staphylococcus epidermidis are related species which can cause predominantly acute and subacute infections, respectively. Differences in human adaptive immune responses to these two species are not well understood. Dendritic cells (DCs) have an important role in the control and regulation of anti-staphylococcal T cell responses. Therefore, we aimed to compare the ability of S. aureus and S. epidermidis to influence the essential steps in human DC activation and subsequent antigen-specific CD4+ T cell proliferation, and to investigate the underlying mechanisms. Using multiple strains of both species, we observed that S. aureus was internalized more effectively than S. epidermidis by DCs but that both species were equally potent in activating these host cells, as evidenced by similar induction of DC maturation marker expression and antigen loading onto MHC-II molecules. The DCs stimulated by S. aureus strains not harboring superantigen (SAg) genes or by any of the S. epidermidis strains, induced low, likely physiological levels of T cell proliferation. Only DCs stimulated with S. aureus strains harboring SAg genes induced high levels of T cell proliferation. Taken together, S. aureus and S. epidermidis do not differently affect DC activation and ensuing antigen-specific T cell proliferation, unless a strain has the capacity to produce SAgs

Determinants of use of care provided by complementary and alternative health care practitioners to pregnant women in primary midwifery care:A prospective cohort study

Background: Pregnant women visit complementary/alternative health care practitioners in addition to regular maternal health care practitioners. A wide variation has been reported with regard to rates and determinants of use of complementary/alternative medicine (CAM), which may be due to heterogeneous populations. The aim of this study was to examine the prevalence and determinants of use of CAM practitioners by a homogeneous population of low-risk pregnant women in the Netherlands. Methods: Data from the population-based DELIVER study was used, concerning 1500 clients from twenty midwifery practices across the Netherlands in 2009 and 2010. CAM use was measured based on patient reports. Potential determinants were derived from Andersen's behavioural model of health care utilization. Results: The prevalence of CAM practitioner use by low-risk pregnant women was 9.4 %. Women were more likely to use CAM if they had supplementary health care insurance (OR 3.11; CI 1.41-6.85), rated their health as 'bad/fair' (OR 2.63; CI 1.65-4.21), reported a chronic illness or handicap (OR 1.93; CI 1.14-3.27), smoked during pregnancy (OR 1.88; CI 1.06-3.33), or used alcohol during pregnancy (OR 2.30; CI 1.46-3.63). Conclusions: CAM is relatively frequently used by low-risk pregnant women. Determinants revealed in this study diverge from other studies using heterogeneous populations. Maternal health care practitioners must be aware of CAM use by low-risk pregnant women and incorporate this knowledge into daily practice by actively discussing this subject with pregnant women

Is disturbed clearance of apoptotic keratinocytes responsible for UVB-induced inflammatory skin lesions in systemic lupus erythematosus?

Apoptotic cells are thought to play an essential role in the pathogenesis of systemic lupus erythematosus (SLE). We hypothesise that delayed or altered clearance of apoptotic cells after UV irradiation will lead to inflammation in the skin of SLE patients. Fifteen SLE patients and 13 controls were irradiated with two minimal erythemal doses (MEDs) of ultraviolet B light (UVB). Subsequently, skin biopsies were analysed (immuno)histologically, over 10 days, for numbers of apoptotic cells, T cells, macrophages, and deposition of immunoglobulin and complement. Additionally, to compare results with cutaneous lesions of SLE patients, 20 biopsies of lupus erythematosus (LE) skin lesions were analysed morphologically for apoptotic cells and infiltrate. Clearance rate of apoptotic cells after irradiation did not differ between patients and controls. Influx of macrophages in dermal and epidermal layers was significantly increased in patients compared with controls. Five out of 15 patients developed a dermal infiltrate that was associated with increased epidermal influx of T cells and macrophages but not with numbers of apoptotic cells or epidermal deposition of immunoglobulins. Macrophages were ingesting multiple apoptotic bodies. Inflammatory lesions in these patients were localised near accumulations of apoptotic keratinocytes similar as was seen in the majority of LE skin lesions. In vivo clearance rate of apoptotic cells is comparable between SLE patients and controls. However, the presence of inflammatory lesions in the vicinity of apoptotic cells, as observed both in UVB-induced and in LE skin lesions in SLE patients, suggests that these lesions result from an inflammatory clearance of apoptotic cells

Do pregnant women contact their general practitioner? A register-based comparison of healthcare utilisation of pregnant and non-pregnant women in general practice

BACKGROUND: Midwives and obstetricians are the key providers of care during pregnancy and postpartum. Information about the consultations with a general practitioner (GP) during this period is generally lacking. The aim of this study is to compare consultation rates, diagnoses and GP management of pregnant women with those of non-pregnant women. METHODS: Data were retrieved from the Netherlands Information Network of General Practice (LINH), a nationally representative register. This register holds longitudinal data on consultations, prescriptions and the referrals of all patients listed at 84 practices in the Netherlands in 2007–2009, including 15,123 pregnant women and 102,564 non-pregnant women in the same age-range (15 to 45 years). We compared consultation rates (including all contacts with the practice), diagnoses (ICPC-1 coded), medication prescriptions (coded according to the Anatomical Therapeutic Chemical classification system), and rate and type of referrals from the start of the pregnancy until six weeks postpartum (336 days). RESULTS: Pregnant women contacted their GP on average 3.6 times, compared to 2.2 times for non-pregnant women. The most frequently recorded diagnoses for pregnant women were ‘pregnancy’ and ‘cystitis/urinary infection’, and ‘cystitis/urinary infection’ and ‘general disease not otherwise specified’ for non-pregnant women. The mean number of prescribed medications was lower in pregnant women (2.1 against 4.4). For pregnant women, the most frequent referral indication concerned obstetric care, for non-pregnant women this concerned physiotherapy. CONCLUSIONS: GP consultation rates in pregnancy and postpartum shows that GPs are important providers of care for pregnant women. Therefore, the involvement of GPs in collaborative care during pregnancy and postpartum should be reinforced

Modulating local airway immune responses to treat allergic asthma: lessons from experimental models and human studies

With asthma affecting over 300 million individuals world-wide and estimated to affect 400 million by 2025, developing effective, long-lasting therapeutics is essential. Allergic asthma, where Th2-type immunity plays a central role, represents 90% of child and 50% of adult asthma cases. Research based largely on animal models of allergic disease have led to the generation of a novel class of drugs, so-called biologicals, that target essential components of Th2-type inflammation. Although highly efficient in subclasses of patients, these biologicals and other existing medication only target the symptomatic stage of asthma and when therapy is ceased, a flare-up of the disease is often observed. Therefore, it is suggested to target earlier stages in the inflammatory cascade underlying allergic airway inflammation and to focus on changing and redirecting the initiation of type 2 inflammatory responses against allergens and certain viral agents. This focus on upstream aspects of innate immunity that drive development of Th2-type immunity is expected to have longer-lasting and disease-modifying effects, and may potentially lead to a cure for asthma. This review highlights the current understanding of the contribution of local innate immune elements in the development and maintenance of inflammatory airway responses and discusses available leads for successful targeting of those pathways for future therapeutics

Glycan dependent phenotype differences of HIV-1 generated from macrophage versus CD4+ T helper cell populations

Human immunodeficiency virus type 1 (HIV-1) is able to infect a variety of cell types with differences in entry efficiency and replication kinetics determined by the host cell type or the viral phenotype. The phenotype of the virus produced from these various cell types, including infectivity, co-receptor usage and neutralisation sensitivity, may also be affected by the characteristics of the producing cell. This can be due to incorporation of variant cell-specific molecules or differences in post-translational modifications of the gp41/120 envelope. In this study we produced genetically identical virus strains from macrophages, CD4-enriched lymphocytes as well as Th1 and Th2 CD4+ cell lines and compared each different virus stock for their infectivity in various cell types and sensitivity to neutralisation. In order to study the effect of the producer host cell on the virus phenotype, virus stocks were normalised on infectivity and were sequenced to confirm env gene homogeneity. Virus production by Th1 or Th2 cells did not compromise infectivity of the variant cell types tested. We observed no difference in sensitivity to co-receptor blocking agents upon viral passage through Th1 and Th2 CD4+ cell lineages nor did this affect DC-SIGN-mediated viral capture as measured in a transfer assay to CD4+ lymphocytes. Virus produced by macrophages was comparably sensitive to CC-chemokine inhibition as was virus generated from the array of CD4+ lymphocytes. We identified that virus produced from macrophages was fourteen times more resistant to 2G12 neutralisation than virus produced from CD4+ lymphocytes. Macrophage-produced dual-tropic (R5/X4) virus was six times more efficiently transmitted to CD4+ cells than lymphocyte-derived HIV-1 (p&amp;lt;0.0001) after DCSIGN capture. These results provide further insights to what extent the host cell influences viral phenotype and thereby various aspects of HIV-1 pathogenesis but suggest that viruses generated from Th1 versus Th2 cells are consistent in phenotype.</jats:p

Hyaluronic Acid in Synovial Fluid Prevents Neutrophil Activation in Spondyloarthritis

Spondyloarthritis (SpA) patients suffer from joint inflammation resulting in tissue damage, characterized by the presence of numerous neutrophils in the synovium and synovial fluid (SF). As it is yet unclear to what extent neutrophils contribute to the pathogenesis of SpA, we set out to study SF neutrophils in more detail. We analyzed the functionality of SF neutrophils of 20 SpA patients and 7 disease controls, determining ROS production and degranulation in response to various stimuli. In addition, the effect of SF on neutrophil function was determined. Surprisingly, our data show that SF neutrophils in SpA patients have an inactive phenotype, despite the presence of many neutrophil-activating stimuli such as GM-CSF and TNF in SF. This was not due to exhaustion as SF neutrophils readily responded to stimulation. Therefore, this finding suggests that one or more inhibitors of neutrophil activation may be present in SF. Indeed, when blood neutrophils from healthy donors were activated in the presence of increasing concentrations of SF from SpA patients, degranulation and ROS production were dose-dependently inhibited. This effect was independent of diagnosis, gender, age, and medication in the patients from which the SF was isolated. Treatment of SF with the enzyme hyaluronidase strongly reduced the inhibitory effect of SF on neutrophil activation, indicating that hyaluronic acid that is present in SF may be an important factor in preventing SF neutrophil activation. This finding provides novel insights into the role of soluble factors in SF regulating neutrophil function and may lead to the development of novel therapeutics targeting neutrophil activation via hyaluronic acid or associated pathways