André J A M van der Ven

Radboud University Nijmegen, Nymegen, Gelderland, Netherlands

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Publications (73)372.23 Total impact

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    ABSTRACT: Background Male injecting drug users drove the onset of the HIV epidemic in Indonesia but over time more women have been diagnosed. We examined the relative proportion of female patients in an HIV cohort and characterized their probable transmission route and reproductive profile. Designs Prospective cohort study in a referral hospital in West Java. Methods Interviews with standardized questionnaires, physical and laboratory examinations were done for 2622 individuals enrolled in HIV care between 2007 and 2012. The proportion of women in this cohort was compared with national estimates. The general characteristics of HIV-infected women and men as well as the sexual and reproductive health of HIV-infected women were described. Results The proportion of female patients enrolled in HIV care increased from 22.2 % in 2007 to 38.3 % in 2012, in line with national estimates. Women were younger than men, fewer reported a history of IDU (16.1 vs. 73.8 %, p < 0.001) and more were tested for HIV because of a positive partner (25.5 vs. 4.0 %, p < 0.001). The majority of women were in their reproductive age, had children, and were not using contraceptives at the time of enrolment. Conclusion HIV-infected women in Indonesia have specific characteristics that differ them from women in the general population. Further research to elucidate the characteristics of women exposed to HIV, their access to testing and care and sexual and reproductive needs can help reduce transmission to women and children in the context of concentrated HIV epidemic in Indonesia.
    Full-text · Article · Dec 2015 · BMC Research Notes
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    ABSTRACT: Background: A transient endothelial hyperpermeability is a hallmark of severe dengue infections. Sphingosine-1-phosphate (S1P) maintains vascular integrity and protects against plasma leakage. We related plasma S1P levels to dengue-induced plasma leakage and studied mechanisms that may underlie the decrease in S1P levels in dengue. Methods: We determined circulating levels of S1P in 44 Indonesian adults with acute dengue and related levels to plasma leakage, as determined by daily ultrasonography, and to levels of its chaperone apolipoprotein M, other lipoproteins and platelets. Results: Plasma S1P levels were decreased during dengue and patients with plasma leakage had lower median levels compared to those without (638 vs. 745 nM; p < 0.01). ApoM and other lipoprotein levels were also decreased during dengue, but did not correlate to S1P levels. Platelet counts correlated positively with S1P levels, but S1P levels were not higher in frozen-thawed platelet rich plasma, arguing against platelets as an important cellular source of S1P in dengue. Conclusions: Decreased plasma S1P levels during dengue are associated with plasma leakage. We speculate that decreased levels of ApoM underlies the lower S1P levels. Modulation of S1P levels and its receptors may be a novel therapeutic intervention to prevent plasma leakage in dengue.
    No preview · Article · Jul 2015 · The Journal of infection
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    ABSTRACT: Background: Hepatitis C virus (HCV)/HIV-coinfected patients respond worse to dual therapy with ribavirin (RBV)/peginterferon compared with HCV-monoinfected patients. Several trials found that lower RBV plasma concentrations are associated with impaired virological response rates. The aim of this study was to determine RBV plasma concentrations in a cohort of HCV-monoinfected and HCV/HIV-coinfected patients. Our hypothesis is that HCV/HIV- coinfected patients have lower RBV plasma concentrations, which may in part explain their inferior response to dual therapy. Methods: A retrospective cohort study was performed in chronic HCV-monoinfected and HCV/HIV-coinfected patients who received peginterferon and weight-based RBV. Plasma RBV concentrations were determined at weeks 4 and 12 by a validated highperformance liquid chromatography assay. RBV concentrations were compared between monoinfected and coinfected patients. We calculated the proportion of patients with a subtherapeutic RBV plasma concentration defined as <2.0 mg/L. Results: A total of 61 HCV-infected patients were included, of whom 21 (34%) were coinfected with HIV. Although there was no difference in the weight-based dose of RBV between monoinfected and coinfected patients, RBV exposure was significantly lower in HCV/HIV-coinfected patients than in HCV-monoinfected patients: the mean ± SD RBV plasma concentrations were 1.82 ± 0.63 mg/L versus 2.25 ± 0.80 mg/L (P = 0.04) at week 4 and 2.14 ± 0.65 mg/L versus 2.62 ± 0.81 mg/L (P = 0.05) at week 12, respectively. The percentage of patients with subtherapeutic plasma concentrations of RBV in coinfected patients versus monoinfected patients was 62% versus 46% (P = 0.240) at week 4 and 50% versus 16% (P = 0.01) at week 12 of treatment, respectively. Conclusions: HIV/HCV-coinfected patients yield significantly lower plasma concentrations of RBV than HCV-monoinfected patients. This puts them at an increased risk of not achieving sustained virological response.
    No preview · Article · Jun 2015 · Therapeutic drug monitoring
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    ABSTRACT: Background: Activated monocytes/macrophages and T-lymphocytes that produce a cytokine storm are assumed to play a pivotal role in the pathogenesis dengue. Interleukin(IL)-18 is a pro-inflammatory cytokine that is increased during dengue and known to induce interferon(IFN)-γ, which is crucial for dengue-immune response. No data are available regarding the balance between IL-18 and its natural inhibitor IL-18 binding protein (IL-18BP), and how they interact within the inflammatory reaction of patients with dengue infections. Methods: Circulating levels of IL-18, IL-18BP, free biologically active IL-18, the IL-18-dependent pro-inflammatory cytokine IFN-γ, monocyte-derived cytokines, and ferritin were assessed in adult Indonesian dengue patients (n=95). Healthy individuals (n=22), leptospirosis (n=19) and enteric fever patients (n=6) served as controls. Results: Total IL-18 levels were increased during dengue, leptospirosis and enteric fever compared to healthy controls. However, due to a concurrent increase in IL-18BP levels, biologically active IL-18 levels remained similar in the different phases of dengue and in patients with leptospirosis. Biologically active IL-18 levels were also similar in patients with severe and non-severe dengue.
    No preview · Article · Jun 2015 · Clinical and Vaccine Immunology
  • Andre J A M van der Ven · Mihai G Netea · Jos W M van der Meer · Quirijn de Mast

    No preview · Article · Feb 2015
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    ABSTRACT: Opioid use may affect HIV infection through altered expression of HIV co-receptors. This was examined in Indonesia among antiretroviral therapy (ART)-naive HIV patients, many of whom use drugs. CCR5 expression on CD4 cells was higher in heroin (P = 0.007), methadone (P = 0.024) and former opioid users (P = 0.003) compared to nonusers, whereas production of RANTES and other CCR5 ligands was similar or lower. This suggests that opioids can affect HIV susceptibility through up-regulation of CCR5 or down-regulation of its ligands.
    Full-text · Article · Dec 2014 · AIDS

  • No preview · Article · Jun 2014 · Haematologica
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    ABSTRACT: Candida albicans can cause candidemia in neutropenic and critically ill patients and oropharyngeal candidiasis in human immunodeficiency virus (HIV)–positive patients with low CD4+ counts. Because all patients at risk do not develop Candida infections, it is possible that a patient's genetic background might play a role in his or her susceptibility to infection. Autophagy mediates pathogen clearance and modulation of inflammation. Our aim was to assess the effect of genetic variations in the ATG16L1 and IRGM autophagy genes on the susceptibility of patients with candidemia and oropharyngeal candidiasis. We assessed genetic variations in the ATG16L1 and IRGM genes in a cohort of candidemia patients of both African and European origin. In addition, we evaluated the effect of these polymorphisms on the susceptibility to oropharyngeal candidiasis of an HIV-positive cohort from Tanzania. Functional studies have been performed to assess the effect of the ATG16L1 and IRGM genetic variants on both in vitro and in vivo cytokine production. The results indicate that ATG16L1 variants modulate production of tumor necrosis factor-alpha, but not other cytokines, while no effects were seen in the presence of IRGM polymorphisms. In addition, no significant associations between the single-nucleotide polymorphisms in the ATG16L1 and IRGM genetic variants and the incidence of candidemia or oropharyngeal candidiasis were identified. Despite moderate effects on the modulation of proinflammatory cytokine production, genetic variation in the autophagy genes ATG16L1 and IRGM has a minor impact on the susceptibility to both mucosal and systemic Candida infections.
    Full-text · Article · Apr 2014 · Medical mycology: official publication of the International Society for Human and Animal Mycology
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    ABSTRACT: Background It remains unclear whether the natural course of human immunodeficiency virus (HIV) differs in subjects infected through injecting drug use (IDU) and no data have been published from low- or middle-income countries. We addressed this question in an urban cohort in Indonesia, which is experiencing a rapidly growing HIV epidemic strongly driven by IDU. Methods All antiretroviral treatment (ART) naïve HIV-positive patients who had at least two subsequent CD4 cell counts available before starting ART were included in this study. We examined the association between IDU and CD4 cell decline using a linear mixed model, with adjustment for possible confounders such as HIV viral load and hepatitis C antibodies. Results Among 284 HIV-positive ART naïve patients, the majority were male (56%) with a history of IDU (79% among men). People with a history of IDU had a statistically significant faster decline in CD4 cells (p<0.001). Based on our data, patients with a history of IDU would have an average 33% decline in CD4 cells after one year without ART, compared with a 22% decline among non-users. At two years, the decline would average 66 and 40%, respectively. No other factor was significantly associated with CD4 cell decline. Conclusions We show that a history of IDU is associated with a more rapid CD4 cell natural decline among HIV-positive individuals in Indonesia. These findings have implications for monitoring ART naïve patients with a history of IDU and for starting ART in this group.
    Full-text · Article · Jan 2014 · Journal of the International AIDS Society
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    ABSTRACT: Identification of dengue patients at risk for progressing to severe disease is difficult. Significant plasma leakage is a hallmark of severe dengue infection which can suddenly lead to hypovolemic shock around the time of defervescence. We hypothesized that the detection of subclinical plasma leakage may identify those at risk for severe dengue. The aim of the study was to determine the predictive diagnostic value of serial ultrasonography for severe dengue. Daily bedside ultrasounds were performed with a handheld ultrasound device in a prospective cohort of adult Indonesians with dengue. Timing, localization and relation to dengue severity of the ultrasonography findings were determined, as well as the relation with serial hematocrit and albumin values. The severity of dengue was retrospectively determined by WHO 2009 criteria. A total of 66 patients with proven dengue infection were included in the study of whom 11 developed severe dengue. Presence of subclinical plasma leakage at enrollment had a positive predictive value of 35% and a negative predictive value of 90% for severe dengue. At enrollment, 55% of severe dengue cases already had subclinical plasma leakage, which increased to 91% during the subsequent days. Gallbladder wall edema was more pronounced in severe than in non-severe dengue patients and often preceded ascites/pleural effusion. Serial hematocrit and albumin measurements failed to identify plasma leakage and patients at risk for severe dengue. Serial ultrasonography, in contrast to existing markers such as hematocrit, may better identify patients at risk for development of severe dengue. Patients with evidence of subclinical plasma leakage and/or an edematous gallbladder wall by ultrasonography merit intensive monitoring for development of complications.
    Full-text · Article · Jun 2013 · PLoS Neglected Tropical Diseases
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    ABSTRACT: Volunteers immunized under chloroquine chemoprophylaxis with Plasmodium falciparum sporozoites (CPS) develop complete, long-lasting protection against homologous sporozoite challenge. Chloroquine affects neither sporozoites nor liver-stages, but kills only asexual forms in erythrocytes once released from the liver into the circulation. Consequently, CPS immunization exposes the host to antigens from both preerythrocytic and blood stages, and induced immunity might target either of these stages. We therefore explored the life cycle stage specificity of CPS-induced protection. Twenty-five malaria-naïve volunteers were enrolled in a clinical trial, 15 of whom received CPS immunization. Five immunized subjects and five controls received a sporozoite challenge by mosquito bites, whereas nine immunized and five control subjects received an i.v. challenge with P. falciparum-infected erythrocytes. The latter approach completely bypasses preerythrocytic stages, enabling a direct comparison of protection against either life cycle stage. CPS-immunized subjects (13 of 14) developed anticircumsporozoite antibodies, whereas only one volunteer generated minimal titers against typical blood-stage antigens. IgG from CPS-immunized volunteers did not inhibit asexual blood-stage growth in vitro. All CPS-immunized subjects (5 of 5) were protected against sporozoite challenge. In contrast, nine of nine CPS-immunized subjects developed parasitemia after blood-stage challenge, with identical prepatent periods and blood-stage multiplication rates compared with controls. Intravenously challenged CPS-immunized subjects showed earlier fever and increased plasma concentrations of inflammatory markers D-dimer, IFN-γ, and monokine induced by IFN-γ than i.v. challenged controls. The complete lack of protection against blood-stage challenge indicates that CPS-induced protection is mediated by immunity against preerythrocytic stages. However, evidence is presented for immune recognition of P. falciparum-infected erythrocytes, suggesting memory responses unable to generate functional immunity.
    Full-text · Article · Apr 2013 · Proceedings of the National Academy of Sciences
  • Susanne van Santen · Quirijn de Mast · Dorine W Swinkels · André J.A.M. van der Ven
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    ABSTRACT: Epidemiological studies have demonstrated an association between malaria and invasive non-typhoid Salmonella (NTS) infections, especially in children. We explore the role of iron as a possible cofactor in this association. Malarial disease, among others, is associated with enhanced erythrophagocytosis and inflammation, which increases the iron content of macrophages and thereby also the survival of Salmonella spp. within macrophages. Whether iron supplementation programs augment the risk of invasive NTS infections in malaria-endemic regions is an important global health issue that still needs to be determined.
    No preview · Article · Apr 2013 · Trends in Parasitology
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    ABSTRACT: Controlled human malaria infection with sporozoites is a standardized and powerful tool for evaluation of malaria vaccine and drug efficacy but so far only applied by exposure to bites of Plasmodium falciparum (Pf)-infected mosquitoes. We assessed in an open label phase 1 trial, infection after intradermal injection of respectively 2,500, 10,000, or 25,000 aseptic, purified, vialed, cryopreserved Pf sporozoites (PfSPZ) in three groups (N = 6/group) of healthy Dutch volunteers. Infection was safe and parasitemia developed in 15 of 18 volunteers (84%), 5 of 6 volunteers in each group. There were no differences between groups in time until parasitemia by microscopy or quantitative polymerase chain reaction, parasite kinetics, clinical symptoms, or laboratory values. This is the first successful infection by needle and syringe with PfSPZ manufactured in compliance with regulatory standards. After further optimization, the use of such PfSPZ may facilitate and accelerate clinical development of novel malaria drugs and vaccines.
    Full-text · Article · Nov 2012 · The American journal of tropical medicine and hygiene
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    ABSTRACT: Objective: Highly active antiretroviral therapy (HAART) has been associated with lipodystrophy (LD) in adults but data are more limited for children. The purpose of this study was to determine the prevalence of and risk factors for LD in Tanzanian children receiving HAART by clinical assessment and to compare the results with anthropometric data. Design and methods: A cross-sectional study was performed in a cohort of HIV-infected children aged 1-18 years receiving HAART in a single center in Moshi, Tanzania. Age, gender, past and current medication regimens and anthropometric measurements were recorded. A clinical scoring method was used to assess LD. Backward binary multivariate logistic regression was used to determine relationships between anthropometric measurements and the presence of clinical LD. Results: Among 210 HIV-infected children, the prevalence of LD was 30% (95% confidence interval [CI]: 23.8-36.2) overall, 19% (95% CI: 13.7-24.3) for lipoatrophy only, 3.8% (95% CI: 1.2-6.4) for lipohypertrophy only and 7.1% (95% CI: 3.6-10.6) for the mixed type. Most cases were mild. Older age and use of stavudine increased the risk of LD. Overall, the study population was stunted but not underweight. In children with relatively lower weight-for-height (<1), only the mid-upper arm circumference was found to be associated with lipoatrophy, while nearly all anthropometric measurements were associated with lipoatrophy in the well-nourished (weight-for-height ≥1) children. Conclusions: Our findings demonstrate that LD is a significant problem among Tanzanian HIV-infected children receiving HAART. Anthropometric measurements predicted LD in well-nourished children but generally failed to do so in relatively wasted children. Our findings support current efforts to avoid stavudine use in children.
    No preview · Article · Oct 2012 · The Pediatric Infectious Disease Journal
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    ABSTRACT: The pathogenesis of plasma leakage during dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) is largely unknown. Angiopoietins are key regulators of vascular integrity: Angiopoietin-1 is stored in platelets and maintains vascular integrity, and endothelium-derived angiopoietin-2 promotes vascular leakage. We determined Angiopoietin-1 and Angiopoietin-2 levels in a cohort of children in Indonesia with DHF/DSS and related them to plasma leakage markers. Patients with DHF/DSS had reduced Angiopoietin-1 and increased Angiopoietin-2 plasma levels on the day of admission when compared with levels at discharge and in healthy controls. There was an inverse correlation between angiopoietin-1 and markers of plasma leakage and a positive correlation between angiopoietin-2 and markers of plasma leakage. Angiopoietin-1 levels followed the same trend as the soluble platelet activation marker P-selectin and correlated with platelet counts. Dengue-associated thrombocytopenia and endothelial activation are associated with an imbalance in angiopoietin-2: angiopoietin-1 plasma levels. This imbalance may contribute to the transient plasma leakage in DHF/DSS.
    No preview · Article · Sep 2012 · The American journal of tropical medicine and hygiene
  • Roos Visser · Quirijn de Mast · Romana T Netea-Maier · Andre J.A.M. van der Ven
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    ABSTRACT: An immune reconstitution inflammatory syndrome (IRIS) may complicate immune restoration following start of antiretroviral therapy (ART) in human immunodeficiency virus (HIV)-infected patients. The occurrence of Graves' disease in the setting of an IRIS is well recognized. We hereby report a case of Hashimoto's thyroiditis, presenting as an acute painful thyroiditis, and as a complication of IRIS. A painful acute thyroiditis with thyrotoxicosis occurred in a 37-year-old HIV-infected woman 10 months after initiation of ART. This thyroiditis was associated with the appearance of a high titer of anti-thyroid peroxidase (anti-TPO) antibodies and was followed by persistent hypothyroidism, requiring thyroxine replacement therapy. Hashimoto's thyroiditis may present as an acute thyroiditis with thyrotoxicosis in HIV-infected patients after initiation of ART. Clinicians caring for HIV-infected patients should be aware of this possible association.
    No preview · Article · Jul 2012 · Thyroid: official journal of the American Thyroid Association
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    ABSTRACT: Abstract Vitamin D(3) is known to have an effect on the immune function. We investigated the immunomodulatory capability of vitamin D(3) in HIV-infected patients and studied the expression of chemokine receptors on regulatory T cells (Treg). Vitamin D(3)-deficient HIV-1-seropositive subjects were treated with cholecalciferol (vitamin D(3)) at a dose of 800 IU daily for 3 months (n=9) or 25,000 IU weekly for 2 months (n=7). Peripheral blood mononuclear cells (PBMCs) were isolated and analyzed for skin-homing (CCR4 and CCR10) and gut-homing (CCR9 and integrin α(4)β(7)) marker expression on Treg, by flow cytometry, before and after supplementation. Serum 25(OH)D(3) and parathyroid hormone (PTH) levels were determined at baseline and after the treatment period. Weekly doses of 25,000 IU cholecalciferol effectively achieved the optimal target serum 25(OH)D(3) concentration of >75 nmol/liter (30 ng/ml) in HIV-infected patients. High-dose cholecalciferol supplementation differentially influenced skin-homing markers on Treg with an increased level of CCR10 expression and while a reduction in CCR4 expression level was observed together with a lower percentage of Treg expressing CCR4. For both dosing regimens, there were no significant differences in the expression of gut-homing markers, CCR9, and integrin α(4)β(7). High-dose vitamin D(3) supplementation is needed to reverse vitamin D(3) deficiency in HIV-infected individuals and this results in modulation of skin-homing markers but not gut-homing markers expression on Treg. At a standard dose of 800 IU/day, vitamin D(3) is not effective in achieving an optimal 25(OH)D(3) concentration in patients with an underlying T cell dysfunction and is unable to exert any immunomodulatory effects.
    No preview · Article · Jun 2012 · AIDS research and human retroviruses
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    ABSTRACT: Exposing healthy human volunteers to Plasmodium falciparum-infected mosquitoes is an accepted tool to evaluate preliminary efficacy of malaria vaccines. To accommodate the demand of the malaria vaccine pipeline, controlled infections are carried out in an increasing number of centers worldwide. We assessed their safety and reproducibility. We reviewed safety and parasitological data from 128 malaria-naïve subjects participating in controlled malaria infection trials conducted at the University of Oxford, UK, and the Radboud University Nijmegen Medical Center, The Netherlands. Results were compared to a report from the US Military Malaria Vaccine Program. We show that controlled human malaria infection trials are safe and demonstrate a consistent safety profile with minor differences in the frequencies of arthralgia, fatigue, chills and fever between institutions. But prepatent periods show significant variation. Detailed analysis of Q-PCR data reveals highly synchronous blood stage parasite growth and multiplication rates. Procedural differences can lead to some variation in safety profile and parasite kinetics between institutions. Further harmonization and standardization of protocols will be useful for wider adoption of these cost-effective small-scale efficacy trials. Nevertheless, parasite growth rates are highly reproducible, illustrating the robustness of controlled infections as a valid tool for malaria vaccine development.
    Full-text · Article · Jun 2012 · PLoS ONE
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    ABSTRACT: Thrombocytopenia, bleeding and plasma leakage are cardinal features of severe dengue. Endothelial cell activation with exocytosis of Weibel-Palade bodies (WPBs) may play an etiological role in this condition. In a cohort of 73 Indonesian children with dengue hemorrhagic fever (DHF), of which 30 with dengue shock syndrome (DSS), we measured plasma levels of the WPB constituents von Willebrand factor antigen (VWF:Ag), VWF propeptide and osteoprotegerin (OPG), together with activity levels of the VWF-cleaving enzyme ADAMTS-13 and the amount of VWF in a platelet binding conformation (VWF activation factor). Compared with healthy controls (n = 17), children with DHF/DSS had significantly higher levels of VWF:Ag, VWF propeptide and OPG and decreased ADAMTS-13 activity. The VWF activation factor was also significantly higher in DHF/DSS and highest in children who died. There were significant differences in the kinetics of the various WPB constituents: VWF propeptide and OPG levels decreased toward discharge, while VWF:Ag levels were lower than expected at enrollment with plasma levels increasing toward discharge. Moreover, VWF propeptide levels correlated better with markers of disease severity (platelet count, liver enzymes, serum albumin and pleural effusion index) than corresponding VWF levels. Together, these findings suggest that there is consumption of VWF in DHF/DSS. In 4 out of 15 selected children with low ADAMTS-13 levels on admission, we found a remarkable reduction in the large and intermediate VWF multimers in the discharge blood samples, consistent with an acquired von Willebrand disease. These findings suggest that severe dengue is associated with exocytosis of WPBs with increased circulating levels of VWF:Ag, VWF propeptide and OPG. High circulating levels of VWF in its active conformation, together with low ADAMTS-13 activity levels, are likely to contribute to the thrombocytopenia and complications of dengue. During the convalescence phase, qualitative defects in VWF with loss of larger VWF multimers may develop.
    Full-text · Article · May 2012 · PLoS Neglected Tropical Diseases
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    ABSTRACT: It is well-recognized that vitamin D₃ has immune-modulatory properties and that the variation in ultraviolet (UV) exposure affects vitamin D₃ status. Here, we investigated if and to what extent seasonality of vitamin D₃ levels are associated with changes in T cell numbers and phenotypes. Every three months during the course of the entire year, human PBMC and whole blood from 15 healthy subjects were sampled and analyzed using flow cytometry. We observed that elevated serum 25(OH)D₃ and 1,25(OH)(2)D₃ levels in summer were associated with a higher number of peripheral CD4+ and CD8+ T cells. In addition, an increase in naïve CD4+CD45RA+ T cells with a reciprocal drop in memory CD4+CD45RO+ T cells was observed. The increase in CD4+CD45RA+ T cell count was a result of heightened proliferative capacity rather than recent thymic emigration of T cells. The percentage of Treg dropped in summer, but not the absolute Treg numbers. Notably, in the Treg population, the levels of forkhead box protein 3 (Foxp3) expression were increased in summer. Skin, gut and lymphoid tissue homing potential was increased during summer as well, exemplified by increased CCR4, CCR6, CLA, CCR9 and CCR7 levels. Also, in summer, CD4+ and CD8+ T cells revealed a reduced capacity to produce pro-inflammatory cytokines. In conclusion, seasonal variation in vitamin D₃ status in vivo throughout the year is associated with changes in the human peripheral T cell compartment and may as such explain some of the seasonal variation in immune status which has been observed previously. Given that the current observations are limited to healthy adult males, larger population-based studies would be useful to validate these findings.
    Full-text · Article · Jan 2012 · PLoS ONE