Hypophosphatemia after high-dose iron repletion with ferric carboxymaltose and ferric derisomaltose-the randomized controlled HOMe aFers study.

BACKGROUND: In patients with iron deficiency anemia, ferric carboxymaltose (FCM) and ferric derisomaltose (FDI) allow high-dose iron repletion. While FCM is reported to induce hypophosphatemia, the frequency of hypophosphatemia after an equivalent dosage of FDI had not been assessed prospectively. METHODS: In the prospective, single-center, double-blind HOMe aFers study, 26 women with iron deficiency anemia (hemoglobin < 12 g/dL plus either plasma ferritin ≤ 100 ng/mL or a plasma ferritin ≤ 300 ng/mL and transferrin saturation (TSAT) ≤ 30%) were randomized to a single intravenous infusion of 20 mg/kg body weight (up to a maximum of 1000 mg) FCM or FDI. The primary endpoint was the incidence of hypophosphatemia (plasma phosphorus levels < 2.0 mg/dL at day 1, day 7 ± 2, and/or day 35 ± 2 after the infusion). In order to investigate potential skeletal and cardiovascular implications, we assessed changes in other components of mineral and bone metabolism, left ventricular function, and arrhythmias. RESULTS: Hypophosphatemia occurred more frequently in women treated with FCM (9 out of 12 [75%]) than in those treated with FDI (1 out of 13 [8%]; p = 0.001). Within 24 h after iron supplementation, women in the FCM group had significant higher plasma intact FGF23 (p < 0.001) and lower plasma 1.25-dihydroxyvitamin D (p < 0.001). As an indicator of urinary phosphorus losses, urinary fractional phosphorus excretion was higher in the FCM group (p = 0.021 at day 7 ± 2 after iron supplementation). We did not observe differences in skeletal and cardiovascular markers, potentially because of the limited number of participants. CONCLUSIONS: While both FCM and FDI provide efficient iron repletion in participants with iron deficiency anemia, FCM induced hypophosphatemia more often than FDI. TRIAL REGISTRATION: Clinical Trials.gov NCT02905539. Registered on 8 September 2016. 2015-004808-36 (EudraCT Number) U1111-1176-4563 (WHO Universal Trial Number) DRKS00010766 (Deutsches Register Klinischer Studien).

Endoscopic full-thickness resection (eFTR) of colorectal lesions: results from the Dutch colorectal eFTR registry.

BACKGROUND: Endoscopic full-thickness resection (eFTR) is a minimally invasive resection technique that allows definite diagnosis and treatment for complex colorectal lesions ≤ 30 mm unsuitable for conventional endoscopic resection. This study reports clinical outcomes from the Dutch colorectal eFTR registry. METHODS: Consecutive patients undergoing eFTR in 20 hospitals were prospectively included. The primary outcome was technical success, defined as macroscopic complete en bloc resection. Secondary outcomes were: clinical success, defined as tumor-free resection margins (R0 resection); full-thickness resection rate; and adverse events. RESULTS : Between July 2015 and October 2018, 367 procedures were included. Indications were difficult polyps (non-lifting sign and/or difficult location; n = 133), primary resection of suspected T1 colorectal cancer (CRC; n = 71), re-resection after incomplete resection of T1 CRC (n = 150), and subepithelial tumors (n = 13). Technical success was achieved in 308 procedures (83.9 %). In 21 procedures (5.7 %), eFTR was not performed because the lesion could not be reached or retracted into the cap. In the remaining 346 procedures, R0 resection was achieved in 285 (82.4 %) and full-thickness resection in 288 (83.2 %). The median diameter of resected specimens was 23 mm. Overall adverse event rate was 9.3 % (n = 34/367): 10 patients (2.7 %) required emergency surgery for five delayed and two immediate perforations and three cases of appendicitis. CONCLUSION : eFTR is an effective and relatively safe en bloc resection technique for complex colorectal lesions with the potential to avoid surgery. Further studies assessing the role of eFTR in early CRC treatment with long-term outcomes are needed.

Impact of systemic alitretinoin treatment on skin barrier gene and protein expression in patients with chronic hand eczema.

BACKGROUND: Chronic hand eczema (CHE) is a common inflammatory skin disease that affects approximately 10% of the population. Systemic alitretinoin has been shown to be effective in patients with CHE who are refractory to topical corticosteroids. OBJECTIVES: To analyse the impact of alitretinoin on the skin barrier genes and protein expression in the skin lesions of patients with CHE. MATERIALS AND METHODS: Fifteen patients with CHE were treated with 30 mg daily of alitretinoin for up to 27 weeks. Disease severity was assessed using a clinical score. Skin biopsies from all the patients were evaluated before and after therapy for the expression of Ki-67, various skin barrier genes and thymic stromal lymphopoietin (TSLP) by real-time quantitative polymerase chain reaction and immunohistochemistry. RESULTS: After alitretinoin application, an improvement in the clinical severity of CHE was observed in the majority of patients. Analysis of skin biopsies before treatment showed a significant increase in Ki-67-positive cells in the suprabasal layer and a dysregulated expression of various skin barrier genes, such as claudin 1, loricrin, filaggrin and cytokeratin 10, which were normalized after treatment. TSLP was significantly upregulated in patients with CHE and also normalized after alitretinoin treatment and negatively correlated with filaggrin. CONCLUSIONS: Our data indicate that the expression of barrier genes and proteins was normalized following treatment with alitretinoin in patients with CHE. The change in expression levels of these genes correlated with the clinical efficacy, suggesting that alitretinoin exhibits a disease-modifying activity. TSLP is upregulated in CHE and seems to counteract filaggrin expression in the skin.

Impaired T cell activation and cytokine production by calcitriol-primed human B cells.

The biologically active form of vitamin D3 , 1, 25-dihydroxyvitamin D3 (calcitriol), is a potent modulator of the immune response. We have shown previously that calcitriol modulates the immunoglobulin response in vitro and in vivo in mice and humans. To analyse the underlying molecular mechanisms we studied whether calcitriol-primed B cells modulate T cell activation and function. Human B cells were stimulated with anti-CD40 and interleukin (IL)-4 in the presence of increasing concentrations of calcitriol. After removal of calcitriol, primed B cells were co-cultured with autologous CD4(+) T cells; the B cell phenotype T cell activation and their consecutive cytokine production were also assessed. Naive T cells co-cultured with calcitriol-primed naive B cells showed a reduced expansion, nuclear factor of activated T cells, cytoplasmic 2 (NFATc2) expression and cytokine production upon restimulation. CD86 expression on B cells after calcitriol priming was identified as an underlying mechanism, as T cell activation and expansion was rescued by activating anti-CD28 antibodies. Our data indicate that calcitriol-primed B cells display an impaired capacity to activate T cells. Taken together, we identified a novel B cell-dependent vitamin D immune regulatory mechanism, namely by decreased co-stimulation of calcitriol-primed B cells.

Association of vitamin D receptor gene polymorphisms with severe atopic dermatitis in adults.

BACKGROUND: Vitamin D mediates immunomodulatory functions, and beneficial functions in allergic diseases have been suggested. Vitamin D receptor gene (VDR) polymorphisms are known but have not been studied in patients with atopic dermatitis (AD). OBJECTIVES: To investigate the frequency of four common VDR gene polymorphisms in patients with AD, and their potential functional relevance. METHODS: In this case-control study, 265 patients with AD [n=142 severe AD, Scoring AD index (SCORAD) > 40; n=123 moderate AD, SCORAD 15-40] and 265 healthy controls were genotyped for four common VDR gene polymorphisms by restriction fragment length polymorphism analysis. The VDR haplotype sequences were analysed in silico. Baseline and activation-induced gene expression of VDR and the vitamin D metabolizing enzyme CYP24A1 were analysed in monocytes of homozygous VDR haplotype carriers by quantitative reverse transcription-polymerase chain reaction. RESULTS: In patients with severe AD, the VDR BsmI (rs1544410) G allele, ApaI (rs7975232) C allele and TaqI (rs731236) T alleles were over-represented compared with healthy controls. These single nucleotide polymorphisms (SNP) were tightly linked, and the VDR haplotype GCT was correlated with severe AD and complementary AAC with protection from AD. The VDR haplotype GCT region is evolutionarily conserved. The VDR FokI (rs2228570) SNP was not associated with AD. Baseline VDR expression in monocytes and short-term activation were haplotype independent. CONCLUSION: A specific VDR haplotype is more frequent in patients with severe AD. These data indicate that VDR contributes to the control of AD, e.g. by regulation of the epidermal barrier function and/or local immune response.

Targeting the vitamin D receptor inhibits the B cell-dependent allergic immune response.

BACKGROUND: 1α,25-dihydroxyvitamin D(3) (calcitriol), the biologically active form of vitamin D, is an immunomodulatory hormone, e.g. it inhibits IgE synthesis in B cells. As its clinical application is limited by hypercalcemia, synthetic vitamin D receptor (VDR) agonists that mediate immunomodulatory activities without adverse hypercalcemic effects are of great interest. This study aimed to investigate the impact of a low-calcemic VDR agonist on the IgE immune response in vitro and in vivo. METHODS: Human peripheral B cells were cultured under IgE inducing conditions in the presence of VDR ligands. B cells were analyzed by quantitative RT-PCR, enzyme-linked immunosorbent assays, enzyme-linked immunospot technique, and flow cytometry. BALB/c mice were sensitized with ovalbumin (OVA)/alum followed by the therapeutic VDR agonist treatment and analyzed regarding the humoral immunoglobulin profile. RESULTS: The natural VDR ligand calcitriol, but also a low-calcemic VDR agonist, profoundly suppressed IgE production by human peripheral B cells by 63.9 ± 5.9%. The potential mechanisms involved are the reduction of the transcript for activation-induced deaminase (AID) and the reduction of IgE immunoglobulin-secreting cells by 68.1 ± 12.7%. By using an in vivo approach, we finally demonstrate that the humoral IgE response in a type I allergy mouse model was impaired by the VDR agonist. CONCLUSION: Our results show that targeting the VDR modulates the humoral immune response including IgE. Whether it might be useful for clinical applications has to be determined in appropriate clinical trials.

Vitamin D deficiency in patients with cutaneous lupus erythematosus is prevalent throughout the year.

BACKGROUND: Vitamin D mediates immunomodulatory functions and its deficiency has been associated with an increased prevalence of immunological diseases including systemic lupus erythematosus (SLE). Chronic discoid or subacute cutaneous lupus erythematosus (CLE) are ultraviolet (UV)-triggered skin diseases. As vitamin D is mostly UV-derived and not from nutrition, its deficiency is frequent especially during the UV-deprived winter months. OBJECTIVE: To compare the vitamin D status of patients with CLE with patients with type I allergy and healthy individuals during the summer or winter months. METHODS: The vitamin D status of patients with CLE (n = 41) was compared with patients with type I allergy (n = 24), healthy individuals (n = 25) and a reference pool (n = 1951) by means of concentrations of circulating storage metabolite 25-hydroxyvitamin D in the summer and winter. RESULTS: Serum 25-hydroxyvitamin D concentrations were lower during the winter in the reference population, and type I allergic and healthy individuals (29.2­35.5 nmol L)1) compared with the summer months (56.3­89.8 nmol L)1) and paralleled by the prevalence of vitamin D deficiency (serum 25-hydroxyvitamin D< 50 nmol L)1; winter: 70.8­73.4%, summer: 34.9­39.4%). In contrast, vitamin D deficiency in patients with CLE was prevalent throughout the year (summer: 85.7%,winter: 97.1%). In patients with CLE with concomitant prednisolone treatment, the 25-hydroxyvitamin D serum levels were comparable with (mean daily intake 877 IU) or without vitamin D supplementation during summer or winter (P = 0.75 and P = 0.14, respectively). CONCLUSIONS: Our data identify vitamin D deficiency in patients with CLE throughout the year and indicate that monitoring and correcting the vitamin D status should be considered to prevent bone demineralization and fractures and to modulate beneficially immunological dysfunction.

Allergen extract-induced interleukin-10 in human memory B cells inhibits immunoglobulin E production.

BACKGROUND: Elevated specific IgE antibody levels are common in atopic individuals, caused by T-helper type 2-dominated B cell activation. The induction of antigen-specific IL-10 secreting T cells is discussed as an important mechanism during specific immunotherapy. By contrast the presence and function of B cell-derived IL-10 is not well defined yet. OBJECTIVE: We investigated whether type-I allergen extracts induce IL-10 expression in human B cells and analysed its functional role on IgE production. METHODS: Human peripheral B cells were stimulated with grass pollen, house dust mite (HDM) (Dermatophagoides pteronyssimus; Der p) and dog allergen extract. Expression of IL-10 by activated human B cells was determined by flow cytometric analysis and ELISA. Functional analysis considering immunoglobulin production was assayed by ELISA. RESULTS: The allergen extracts studied induced IL-10 expression in B cells. However, the ability to induce IL-10 differed between the allergen extracts. The most potent allergen extract was dog (169+/-28 pg/mL), followed by grass pollen (141+/-10 pg/mL) and HDM allergen (125+/-11 pg/mL). Upon allergen extract stimulation only CD27 expressing memory B cells produced IL-10 and co-expressed the very early activation antigen CD69. The addition of allergen extracts to B cells activated by anti-CD40 and IL-4 selectively inhibited IgE which was dependent on allergen extract-induced IL-10. By contrast the other immunoglobulin subclasses like IgA, IgG or IgM were not altered upon allergen extract challenge. CONCLUSION: Our data indicate that allergen-activated memory B cells can modulate IgE production through secretion of IL-10.

Association of the toll-like receptor 2 A-16934T promoter polymorphism with severe atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease with a multifactorial pathogenesis and increasing incidence in the Western world. A genetically determined defective function of pattern recognition receptors such as toll-like receptors (TLRs) has been proposed as a candidate mechanism in the pathogenesis of AD. AIM: To study the impact of genetic predisposition of five genes encoding for pattern recognition-related molecules for the phenotype of AD. METHODS: We examined nine different single-nucleotide polymorphism (SNP) frequencies in the genes encoding TLR1, -2, -4, -9 and the adapter molecule TIRAP by PCR with subsequent melting curve analysis in a case/control cohort of 136 adult AD patients and 129 age and gender matched non-atopic, healthy individuals. TLR2-expression and -function in cells from genotyped individuals were analysed. RESULTS: For the SNPs examined, similar genotype frequencies were found in both groups. In a subgroup of patients suffering from severe AD (SCORAD >50), a significantly increased representation of the A-allele in position -16934 of the tlr2 gene was present (P = 0.004). Constitutive tlr2 mRNA expression in peripheral monocytes was independent of this tlr2 promoter SNP. Stimulation assays indicated that IL-6, but not TNF-alpha secretion following TLR2 stimulation is reduced in homozygous tlr2-16934-A allele carriers. CONCLUSION: These data indicate that TLR2 is relevant for the phenotype of severe AD in adults.

Transanal endoscopic microsurgery versus endoscopic mucosal resection for large rectal adenomas (TREND-study).

BACKGROUND: Recent non-randomized studies suggest that extended endoscopic mucosal resection (EMR) is equally effective in removing large rectal adenomas as transanal endoscopic microsurgery (TEM). If equally effective, EMR might be a more cost-effective approach as this strategy does not require expensive equipment, general anesthesia and hospital admission. Furthermore, EMR appears to be associated with fewer complications.The aim of this study is to compare the cost-effectiveness and cost-utility of TEM and EMR for the resection of large rectal adenomas. METHODS/DESIGN: Multicenter randomized trial among 15 hospitals in the Netherlands. Patients with a rectal adenoma > or = 3 cm, located between 1-15 cm ab ano, will be randomized to a TEM- or EMR-treatment strategy. For TEM, patients will be treated under general anesthesia, adenomas will be dissected en-bloc by a full-thickness excision, and patients will be admitted to the hospital. For EMR, no or conscious sedation is used, lesions will be resected through the submucosal plane in a piecemeal fashion, and patients will be discharged from the hospital. Residual adenoma that is visible during the first surveillance endoscopy at 3 months will be removed endoscopically in both treatment strategies and is considered as part of the primary treatment. Primary outcome measure is the proportion of patients with recurrence after 3 months. Secondary outcome measures are: 2) number of days not spent in hospital from initial treatment until 2 years afterwards; 3) major and minor morbidity; 4) disease specific and general quality of life; 5) anorectal function; 6) health care utilization and costs. A cost-effectiveness and cost-utility analysis of EMR against TEM for large rectal adenomas will be performed from a societal perspective with respectively the costs per recurrence free patient and the cost per quality adjusted life year as outcome measures. Based on comparable recurrence rates for TEM and EMR of 3.3% and considering an upper-limit of 10% for EMR to be non-inferior (beta-error 0.2 and one-sided alpha-error 0.05), 89 patients are needed per group. DISCUSSION: The TREND study is the first randomized trial evaluating whether TEM or EMR is more cost-effective for the treatment of large rectal adenomas. TRIAL REGISTRATION NUMBER: (trialregister.nl) NTR1422.

CD14(++)CD16+ monocytes but not total monocyte numbers predict cardiovascular events in dialysis patients.

Migration of monocytes into the vessel wall contributes to the onset and progression of atherosclerosis. Because monocytes are a heterogeneous population, we determined potential associations between monocyte subsets and cardiovascular events in a prospective cohort of 94 dialysis patients followed for 35 months. The incidence of cardiovascular events and death measured by Kaplan-Meier plots and flow cytometric analysis of monocyte subsets showed that total leukocyte and monocyte numbers failed to predict event-free survival. Among monocyte subsets, a high CD14(++)CD16(+) monocyte number was associated with higher rates of cardiovascular events and death. In a multivariate proportional hazards model adjusted for classical cardiovascular risk factors, patients with CD14(++)CD16(+) monocyte numbers in the top quartile were at higher risk of cardiovascular events and death compared to patients in the lowest quartile. Our study suggests that the number of CD14(++)CD16(+) monocytes was independently associated with cardiovascular events and death in a high-risk population of dialysis patients.

Proinflammatory CD14+CD16+ monocytes are associated with subclinical atherosclerosis in renal transplant patients.

Atherosclerotic cardiovascular disease is a major cause of death in renal transplant (TX) recipients. Atherosclerotic lesions are characterized by monocytic infiltration. Circulating monocytes can be divided into functionally distinct subpopulations, among which CD14++CD16+ and CD14+CD16+ monocytes (summarized as CD16+ monocytes) are proinflammatory cells. We hypothesized that the frequency of circulating CD16+ monocytes is associated with subclinical atherosclerosis in TX patients. Monocyte subpopulations were quantified in 95 TX and 31 hemodialysis patients (HD). In TX patients, subclinical atherosclerosis was determined by carotid intima media thickness (IMT) measurement. TX patients had lower frequencies of CD16+ monocytes than HD patients. When stratifying by immunosuppressive treatment, patients on methylprednisolone (MP) therapy had fewer CD14+CD16+ monocytes than patients not receiving MP. CD14+CD16+ monocytes decrease very shortly after transplantation. CD14+CD16+ monocyte frequency correlated with IMT in TX recipients (r = 0.34, p < 0.001). This correlation was most pronounced among patients without MP treatment (r = 0.55, p = 0.02). In a multivariate regression analysis, the association of CD14+CD16+ monocytes with IMT was independent from traditional cardiovascular risk factors. The frequency of proinflammatory CD14+CD16+ monocytes is independently associated with subclinical atherosclerosis in transplant recipients. Further studies on the association between circulating leukocytes and atherosclerosis should take monocyte heterogeneity into account.

Haemolytic anaemia as a first sign of Wilson's disease.

A 19-year-old female presented with haemolytic anaemia and subsequently developed liver failure. This raised suspicion of Wilson's disease, which was confirmed by Kayser-Fleischer rings, a low ceruloplasmin level, raised 24-hour urinary copper excretion and two mutations in the 'Wilson gene'. She was successfully treated with D-penicillamine and zinc. In young patients with unexplained haemolysis, liver dysfunction or neuro-psychiatric symptoms, Wilson's disease should be considered.

Immunomodulation by vitamin D.

Vitamin D exerts several immunological functions in addition to its homeostatic functions on calcium and bone metabolism. Current data show that relative vitamin D deficiency (< 75 nmol/l 25-hydroxyvitamin D) as well as acquired seasonal vitamin D deficiency (< 50 nmol/l) are frequent in Germany. As confirmed by our own data, UV exposure plays a major role for maintenance of vitamin D status, e.g., in patients with UV-triggered diseases, vitamin D deficiency is more frequent, even throughout the year. The beneficial impact of vitamin D on immune functions is highlighted by epidemiologic, genetic, and experimental evidence. In the past years, numerous publications have presented associations between vitamin D deficiency, on the one hand, and severity and prevalence of allergic asthma in children and adults, on the other hand.

On attitudes about colorectal cancer screening among gastrointestinal specialists and general practitioners in the Netherlands.

AIM: To find out whether there are differences in attitudes about colorectal cancer (CRC) screening among gastrointestinal (GI) specialists and general practitioners (GPs) and which method is preferred in a national screening program. METHODS: Four hundred and twenty Dutch GI specialists in the Netherlands and 400 GPs in Amsterdam were questioned in 2004. Questions included demographics, affiliation, attitude towards screening both for the general population and themselves, methods of screening, family history and individual risk. RESULTS: Eighty-four percent of the GI specialists returned the questionnaire in comparison to 32% of the GPs (P < 0.001). Among the GI specialists, 92% favoured population screening whereas 51% of GPs supported population screening (P < 0.001). Of the GI specialists 95% planned to be screened themselves, while 30% of GPs intended to do so (P < 0.001). Regarding the general population, 72% of the GI specialists preferred colonoscopy as the screening method compared to 27% of the GPs (P < 0.001). The method preferred for personal screening was colonoscopy in 97% of the GI specialists, while 29% of the GPs favoured colonoscopy (P < 0.001). CONCLUSION: Screening for CRC is strongly supported by Dutch GI specialists and less by GPs. The major health issue is possibly misjudged by GPs. Since GPs play a crucial role in a successful national screening program, CRC awareness should be realized by increasing knowledge about the incidence and mortality, thus increasing awareness of the need for screening among GPs.

Milestone in gastrointestinal endoscopy: double-balloon enteroscopy of the small bowel.

The small bowel (SB) has been largely bypassed by flexible endoscopy because of inaccessibility. Push enteroscopy is now in the past, with recent innovations now making visualization of the SB possible. Wireless capsule endoscopy (CE) and double-balloon endoscopy (DBE) have been introduced. In this review, we focus on the diagnostic and therapeutic modalities of DBE, which may be a suitable replacement for push enteroscopy, preoperative endoscopy and to some extent of SB fall-through and CT scan. DBE is a new method of endoscopy developed and described by Yamamoto et al. in Jichi, Japan, in cooperation with Fujinon. Introduced to the market in 2003, it is possible with this endoscope to observe the entire SB in steps of 20-40 cm. Measuring the depth of insertion is also possible. Obscure gastrointestinal bleeding can be explained and treated in the majority of cases. Biopsy sampling, hemostasis, polypectomy, dilatation and tattoo are possible in the SB. Guidelines for FAB and Peutz-Jeghers syndrome will probably be reviewed in the next few years. The safety and efficacy of DBE have been demonstrated. DBE improves SB disease management and can substitute for more complex investigations. Additional data will come to light in years to come. Combining DBE with CE, CT/MRI enteroclysis in a new era for SB work-up and treatment is the likely future.

Brain injury and proteomics/peptidomics: is it relevant? an overview.

Proteomics and peptidomics are different and supplemental to genomics, since in contrast to the basically constant genome - the proteome and peptidome are dynamic, constantly changing, and complex networks. Proteomics is traditionally linked to 2D-gel electrophoresis techniques. Concerning peptidomics, three different approaches are currently available, all using mass spectrometry as a key element. The use of proteomics or peptidomics in traumatic brain injury (TBI) research is demanding. From the technical point of view there are high-level requirements concerning the preanalytical phase, specific machinery, sophisticated software and skilled manpower/intellectual input. There are currently no bedside techniques and most methods are suitable for experimental TBI research in specialized laboratories. In screening experiments of CSF following controlled cortical impact in rats we identified several peptides, which, although previously known, were so far not reported in the TBI context or in CSF. Peptidomics and proteomics, as highly complex screening technologies, thus seem to carry a large potential to lead TBI science. Newly "discovered" peptide targets have to be validated with different methodology to establish a real diagnostic or therapeutic value.

Monocyte subsets in atherosclerosis.

Endothelial dysfunction and chronic inflammation of the arterial wall continuously drive the development of atherosclerotic lesions. Monocytes, as cells of the innate immunity, are particularly involved in this process. In the last decade, heterogeneity of circulating monocytes has widely been acknowledged, and a recent consensus nomenclature subdivides classical, intermediate and nonclassical monocytes. Accumulating experimental and clinical data suggest a differential, subset-specific contribution of monocytes to the pathology of atherosclerosis. This review summarizes recent key findings on human and mouse monocyte subpopulations, specifically highlighting their phenotype, functional characteristics and mechanisms of recruitment at homeostatic conditions, in atherosclerotic vascular disease, and after acute myocardial infarction.

Structural and phylogenetic characterization of human SLURP-1, the first secreted mammalian member of the Ly-6/uPAR protein superfamily.

Members of the Ly-6/uPAR protein family share one or several repeat units of the Ly-6/uPAR domain that is defined by a distinct disulfide bonding pattern between 8 or 10 cysteine residues. The Ly-6/uPAR protein family can be divided into two subfamilies. One comprises GPI-anchored glycoprotein receptors with 10 cysteine residues. The other subfamily includes the secreted single-domain snake and frog cytotoxins, and differs significantly in that its members generally possess only eight cysteines and no GPI-anchoring signal sequence. We report the purification and structural characterization of human SLURP-1 (secreted mammalian Ly-6/uPAR related protein 1) from blood and urine peptide libraries. SLURP-1 is encoded by the ARS (component B)-81/s locus, and appears to be the first mammalian member of the Ly-6/uPAR family lacking a GPI-anchoring signal sequence. A phylogenetic analysis based on the SLURP-1 primary protein structure revealed a closer relationship to the subfamily of cytotoxins. Since the SLURP-1 gene maps to the same chromosomal region as several members of the Ly-6/uPAR subfamily of glycoprotein receptors, it is suggested that both biologically distinct subfamilies might have co-evolved from local chromosomal duplication events.