A peptide inhibitor of vascular adhesion protein-1 (VAP-1) blocks leukocyte-endothelium interactions under shear stress

Vascular adhesion protein-1 (VAP-1) is an endothelial adhesion molecule mediating leukocyte interactions with blood vessels during leukocyte extravasation. Molecularly VAP-1 is a cell-surface-expressed ecto-enzyme belonging to the group of semicarbazide-sensitive amine oxidases (SSAO; EC 2.4.6.3), which deaminate primary amines. Here we asked whether peptides displaying a suitable free amine group could be a substrate or inhibitor of SSAO and thus regulate VAP-1-mediated leukocyte adhesion. On the basis of a molecular model of VAP-1, we designed synthetic peptides that fit to the substrate channel of VAP-1. One of these lysine-containing peptides effectively inhibits VAP-1-dependent lymphocyte rolling and firm adhesion to primary endothelial cells under physiologically relevant shear conditions. The same peptide inhibits the SSAO activity of endothelial and recombinant VAP-1 in a selective and long-lasting manner. We also show that all enzymatically active VAP-1 is displayed on the cell surface. Our results suggest that, in addition to soluble amines, specific cell-surface-bound molecules containing free NH(2) groups in a suitable position may modulate the enzymatic activity of SSAO. Moreover, the inhibitory peptide diminishes leukocyte interactions with endothelial cells under conditions of shear, and thus it may be useful to treat inflammatory conditions.     

Function-blocking antibodies to human vascular adhesion protein-1: a potential anti-inflammatory therapy

Human vascular adhesion protein-1 (VAP-1) is a homodimeric 170-kDa sialoglycoprotein that is expressed on the surface of endothelial cells and functions as a semicarbazide-sensitive amine oxidase and as an adhesion molecule. Blockade of VAP-1 has been shown to reduce leukocyte adhesion and transmigration in in vivo and in vitro models, suggesting that VAP-1 is a potential target for anti-inflammatory therapy. In this study we have constructed mouse-human chimeric antibodies by genetic engineering in order to circumvent the potential problems involved in using murine antibodies in man. Our chimeric anti-VAP-1 antibodies, which were designed to lack Fc-dependent effector functions, bound specifically to cell surface-expressed recombinant human VAP-1 and recognized VAP-1 in different cell types in tonsil. Furthermore, the chimeric antibodies prevented leukocyte adhesion and transmigration in vitro and in vivo. Hence, these chimeric antibodies have the potential to be used as a new anti-inflammatory therapy.     

Apparent genotype–phenotype correlation in childhood,adolescent, and adult Chediak‐Higashi syndrome

Chediak‐Higashi syndrome (CHS) is a rare autosomal recessive disorder characterized by severe immunologic defects, reduced pigmentation, bleeding tendency, and progressive neurological dysfunction. Most patients present in early childhood and die unless treated by bone marrow transplantation. About 10–15% of patients exhibit a much milder clinical phenotype and survive to adulthood, but develop progressive and often fatal neurological dysfunction. Very rare patients exhibit an intermediate adolescent CHS phenotype, presenting with severe infections in early childhood, but a milder course by adolescence, with no accelerated phase. Here, we describe the organization and genomic DNA sequence of the CHS1 gene and mutation analysis of 21 unrelated patients with the childhood, adolescent, and adult forms of CHS. In patients with severe childhood CHS, we found only functionally null mutant CHS1 alleles, whereas in patients with the adolescent and adult forms of CHS we also found missense mutant alleles that likely encode CHS1 polypeptides with partial function. Together, these results suggest an allelic genotype–phenotype relationship among the various clinical forms of CHS. © 2002 Wiley‐Liss, Inc.     

Urinary arginine and ornithine in occupational exposure to 2-ethylhexanoic acid

Nine sawmill workers were divided into two groups according to their exposure to 2-ethylhexanoic acid, (EHA), a pesticide which has replaced the older pentochlorophenol. The men with lower exposure excreted 30±10 nmol EHA/mmol creatinine (mean ±SD,n=4) in urine samples taken after the workshift, whereas men with higher exposure excreted 1.8±1.6 mol EHA/mmol creatinine (mean±SD,n=5,p<0.01). The urinary ornithine and arginine concentrations were at the lower exposure 1.4±0.4 and 1.5±0.8 mol/mmol creatinine, respectively (mean±SD,n=4), and they increased significantly (p<0.01) to 4.5±2.5 and 3.2±1.5mol/mmol (mean±SD,n=5), respectively, at the higher exposure. This might have been caused by the inhibitory effect of EHA on urea synthesis which was partially compensated for by elevated arginine and ornithine concentrations to drive the urea cycle more efficiently.     

Neurotransmitter markers in the cerebrospinal fluid of normal subjects effects of aging and other confounding factors

Summary We have investigated neurotransmitter-related markers of the cerebrospinal fluid (CSF) in a carefully screened series of normally aging subjects in standardized conditions in order to find out the influence of age and other confounding factors on CSF measures. The levels of 3-methoxy-4-hydroxyglycol (MHPG) and the activity of acetylcholinesterase (AChE) also increased with age, while homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5 HIAA) and immunoreactivities of somatostatin (SLI), beta-endorphin (BLI) and adrenocorticotropic hormone (ACTH) were unrelated to age. The gender of subjects had no significant effect on the levels of neurotransmitter markers, while seasonal changes, as well as height and weight of the subjects seemed to cause some variations in the levels of HVA, dopamine--hydroxylase (DBH) and ACTH. The study underscores the importance of standardized conditions and matched patient groups in the CSF studies.     

Transient interference of right hemispheric function due to automatic emotional processing

We examined the effects of emotional stimuli on right and left hemisphere detection performance in a hemifield visual discrimination task. A group of 18 healthy subjects were asked to discriminate between upright and inverted triangles (target). Targets were randomly presented in the left or right visual hemifield (150 ms target duration). A brief emotional picture (pleasant or unpleasant; 150 ms stimulus duration) or neutral picture selected from the International Affective Picture System was randomly presented either in the same (47%) or the opposite (47%) spatial location to the subsequent target. Emotional or neutral stimuli offset 150 ms prior to the subsequent target. Subjects were instructed to ignore the pictures and respond to the targets as quickly and accurately as possible. Independent of field of presentation, emotional stimuli prolonged reaction times (P < 0.01) to LVF targets, with unpleasant stimuli showing a greater effect than pleasant stimuli. The current study shows that brief emotional stimuli selectively impair right hemispheric visual discrimination capacity. The findings suggest automatic processing of emotional stimuli captures right hemispheric processing resources and transiently interferes with other right hemispheric functions.     

Prospective randomized comparison of endonasal endoscopic dacryocystorhinostomy and external dacryocystorhinostomy

Objectives and Study Design: The advent of the rigid endonasal endoscope and the development of functional endoscopic sinus surgery (FESS) technique have awakened interest in an endonasal endoscopic dacryocystorhinostomy (EESC-DCR) in treating nasolacrimal obstruction. This prospective, randomized study compares EESC-DCR with traditional external dacryocystorhinostomy (EXT-DCR) for their success rates, surgical duration, and postoperative symptoms. Patients and Methods: Sixty-four cases in 60 patients with primary acquired nasolacrimal sac or duct obstruction were divided into two subgroups by symptoms (simple epiphora/ chronic dacryocystitis). These patients were randomized within both subgroups into two operation groups. Altogether 32 EESC-DCRs and 32 EXT-DCRs were performed. The final follow-up visit was at 1 year. The patency of the lacrimal passage was investigated by irrigation and patients were questioned about their symptoms. Results: The success rate at 1 year after surgery was 75% for EESC-DCR and 91% for EXT-DCR after primary surgery. The difference was not statistically significant (P = .18). The success rate after secondary surgery with a follow-up time of 1 year was 97% in both study groups. The average duration for EESC-DCR was 38 minutes, and 78 minutes for EXT-DCR, (P < .001). Conclusions: EXT-DCR, when compared with EESC-DCR, appears to give a higher, although not statistically significant, primary success rate, but the secondary success rates are equal, indicating that these two different DCR techniques are acceptable alternatives.     

Determinants for preventive oral health care need among community‐dwelling older people: a population‐based study

The aim was to study the determinants of preventive oral health care need among community‐dwelling old people. The study population consisted of 165 participants, a subpopulation in the Geriatric Multidisciplinary Strategy for Good Care of Elderly People (GeMS) study. Fifty‐five percent of the edentate participants with full dentures and 82% of the dentate had a need for preventive oral health care. In the total study population, the need for preventive care was associated with co‐morbidity (measured by means of the Modified Functional Co‐morbidity Index) odds ratios (OR) 1.2 (confidence intervals [CI] 1.0–1.5), being pre‐frail or frail, OR 2.5 (CI 1.2–5.1), presence of natural teeth, OR 4.8 (CI 2.2–10.4), and among dentate participants, the use of a removable partial denture, OR 12.8 (CI 1.4–114.4). Primary care clinicians should be aware of the high need for preventive care and the importance of nonoral conditions as determinants of preventive oral health care need.     

A Case of Abnormal Lymphatic-Like Differentiation and Endothelial Progenitor Cell Activation in Neovascularization Associated with Hemi-Retinal Vein Occlusion

PurposePathological vascular differentiation in retinal vein occlusion (RVO)-related neovessel formation remains poorly characterized. The role of intraocular lymphatic-like differentiation or endothelial progenitor cell activity has not been studied in this disease.MethodsVitrectomy was performed in an eye with hemi-RVO; the neovessel membrane located at the optic nerve head was removed and subjected to immunohistochemistry. Characterization of the neovascular tissue was performed using hematoxylin and eosin, α-smooth muscle actin, and the pan-endothelial cell (EC) adhesion molecule CD31. The expression of lymphatic EC markers was studied by lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), podoplanin (PDPN), and prospero-related homeobox protein 1 (Prox-1). Potential vascular stem/progenitor cells were identified by active cellular proliferation (Ki67) and expression of the stem cell marker CD117.ResultsThe specimen contained blood vessels lined by ECs and surrounded by pericytes. Immunoreactivity for LYVE-1 and Prox-1 was detected, with Prox-1 being more widely expressed in the active Ki67-positive lumen-lining cells. PDPN expression was instead found in the cells residing in the extravascular tissue. Expression of the stem cell markers CD117 and Ki67 suggested vascular endothelial progenitor cell activity.ConclusionsIntraocular lymphatic-like differentiation coupled with progenitor cell activation may be involved in the pathology of neovessel formation in ischemia-induced human hemi-RVO.Key Words: Hemi-retinal vein occlusion, Endothelial progenitor cell, Platelet endothelial cell adhesion molecule 1, Podoplanin, Prospero-related homeobox gene 1, Lymphatic endothelial cell, Lymphatic vessel endothelial hyaluronan receptor 1, Immunohistochemistry, Proliferative diabetic retinopathy, Vascular endothelial stem cell