The global prevalence of primary psychodermatologic disorders: a systematic review.

The management of primary psychodermatologic disorders (PPDs) (i.e. psychiatric disorders with dermatologic presentation) is challenging. The scarceness of reported prevalence hinders the development of coordinated interventions to improve healthcare delivery. This review aimed to explore the global prevalence of PPDs. The review was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analyses statement. Of the 4632 identified publications, 59 were included. Five PPDs were investigated from the included studies: delusional parasitosis (n = 9), skin picking disorder (n = 26), trichotillomania (n = 26), tanning dependence (n = 5) and repetitive nail biting (n = 6). Delusional parasitosis was rare in the general population (prevalence ranging from 0.0002% to 0.03%), with higher rates in psychiatric settings (outpatient = 0.5%; inpatient = 0.1%). Other pathologic or subclinical forms of PPDs had a minimum prevalence of 0.3% (median = 7.0%; mean = 17.0%). The distribution of the prevalence rates was highly skewed, with large differences based on the study setting (e.g. dermatologic settings, psychiatric settings, and general population). The most common condition was pathologic skin picking (prevalence, 1.2%-11.2%) in the general population. Its rates were higher in the psychiatric settings (obsessive-compulsive disorder, 38.5%; Tourette syndrome, 13.0%; body dysmorphic disorder, 26.8%-64.7%). The prevalence of trichotillomania in the general population ranged from 0.6% to 2.9%, while that of pathologic tanning and nail biting could not be ascertained as the studies were mainly in students (range; 12.0%-39.3% and 3.0%-10.1%, respectively). In conclusion, PPDs are common, especially in the dermatologic and psychiatric settings. Further population-based studies are needed to determine more accurate prevalence rates.

Analysis of interleukin-10 levels in lesions of vitiligo following treatment with topical tacrolimus.

BACKGROUND: Vitiligo is an acquired dermatological condition that is characterized by depigmentation of patches of skin. It is relatively common, occuring in about 0.38-0.50% of the general population, and can engender significant cosmetic disfigurement and psychological sequelae in the affected individual. Recent studies demonstrate that topical tacrolimus (Protopic; Astellas, Markham, ON, Canada) is efficacious in the treatment of vitiligo. We propose that the successful treatment of vitiligo with topical tacrolimus involves the unique immunosuppressive actions of the T lymphocyte T-helper (Th) 2 cytokine, interleukin (IL)-10. OBJECTIVES: We aimed to monitor clinical changes in lesions of vitiligo treated with topical tacrolimus 0.1% ointment and quantify IL-10 cytokine levels in nonvitiliginous skin, as well as lesions of vitiligo before and following topical tacrolimus therapy. METHODS: Clinical evaluation of lesions of vitiligo on the basis of surface area and follicular repigmentation under Wood's lamp was performed in 20 enrolled adult patients. Biopsy specimens were obtained from nonvitiliginous skin, as well as lesions of vitiligo before and following topical tacrolimus therapy. Specimens were processed and analysed for expression of IL-10 using the method of enzyme-linked immunosorbent assay. RESULTS: A statistically significant mean +/- SEM decrease in vitiligo lesion size of 41.0 +/- 5.2% was observed following 3 months of treatment. A pattern of follicular repigmentation was noted by the third month of treatment for all patients completing the study. In addition, there was a statistically significant difference between IL-10 expression in vitiligo lesions following treatment for 3 months with topical tacrolimus compared with untreated vitiligo lesions (P = 0.017) and normal skin (P = 0.004). CONCLUSIONS: These results confirm that topical tacrolimus is an effective treatment for vitiligo. We propose that topical tacrolimus increases IL-10 expression in vitiligo lesions, and thereby inhibits melanocyte destruction triggered by unchecked Th1 pathways in vitiligo.

First case series on the use of imiquimod for morphoea.

BACKGROUND: Morphoea is characterized by fibrosis, which is mediated by cytokines including transforming growth factor (TGF)-beta. OBJECTIVE: Our objective was to use imiquimod 5% cream (Aldara), an inducer of interferon-gamma, known to inhibit TGF-beta, to treat morphoea. METHODS: Patients with morphoea were treated with imiquimod and evaluated during their follow-up visits to 6 months. RESULTS: The dyspigmentation, induration and erythema of 12 patients with morphoea lesions improved. The histology of the skin also showed a decrease in dermal thickness. CONCLUSION: This is the first case series describing the successful application of imiquimod in the management of morphoea.

Alpha-actinin accumulation in epithelial cells infected with attaching and effacing gastrointestinal pathogens.

Fluorescent F-actin staining utilizing phalloidin, a highly toxic mushroom poison, is used as an indirect test to detect attaching and effacing (AE) bacteria. A study was done to determine if accumulation of alpha-actinin in infected tissue culture cells is a consistent feature and whether it corresponds with the AE response. Rearrangement of alpha-actinin was detected using immunofluorescence microscopy by incubation of infected cells with a murine monoclonal anti-alpha-actinin antibody. Foci of alpha-actinin-specific fluorescence corresponding to areas of bacterial adhesion were detected by transmission electron microscopy in HEp-2 and gastric KATO-III cells infected with only those bacterial strains that formed AE lesions. Therefore, this study shows that alpha-actinin accumulation is a consistent, specific manifestation of the AE phenotype and forms the basis for the development of a safe alternative test for detecting AE bacteria.

Signal transduction responses following adhesion of verocytotoxin-producing Escherichia coli.

Attaching and effacing adhesion to epithelial cells is a pathognomonic feature of infection by both enteropathogenic Escherichia coli (EPEC) and certain strains of verocytotoxin-producing E. coli (VTEC). EPEC adhesion to tissue culture epithelial cells results in activation of the phosphatidylinositol pathway, with elevated levels of inositol 1,4,5-triphosphate and cytosolic free calcium. In this report, we show that VTEC also activate this signal transduction pathway in infected epithelial cells. Specifically, increased levels of inositol 1,4,5-triphosphate and intracellular free calcium were observed in HEp-2 cells infected with VTEC of serotype O157:H7. VTEC of serotypes O157:H7 and O113:H21 also induced increases in intracellular calcium levels in the human intestinal crypt-like cell line T84, even with minimal or no attaching and effacing activity as monitored by transmission electron microscopy. In contrast to EPEC, VTEC failed to induce tyrosine phosphorylation of epithelial cell proteins in HEp-2 and T84 cells, as determined by indirect immunofluorescence microscopy. These findings suggest that signal transduction responses to VTEC, including elevated levels of inositol triphosphates and intracellular free calcium, are independent of formation of the attaching and effacing lesion. Our findings also show that VTEC pathogenesis may involve signal transduction pathways that are distinct from those induced by EPEC infection.

Comparison of Helicobacter mustelae and Helicobacter pylori adhesion to eukaryotic cells in vitro.

BACKGROUND & AIMS: Bacterial adhesion to mucosal surfaces is an important pathogenic mechanism for Helicobacter-induced gastritis. The aims of this study were to compare binding of selected Helicobacter mustelae and Helicobacter pylori strains to lipids extracted from HEp-2, Chinese hamster ovary, human embryonic lung cells, and ferret gastrointestinal tissues as well as to intact tissue culture cells and to analyze the fatty acids of the receptor. METHODS: Thin-layer chromatography overlay binding and a receptor-based immunoassay detected adhesion of bacteria to commercial lipids and to individual species within the lipid extracts. H. mustelae binding to tissue culture cells was performed by whole cell bacterial adhesion assay. RESULTS: H. mustelae and H. pylori both bound to phosphatidylethanolamine and lysophosphatidylethanolamine. Adhesion of H. mustelae to intact eukaryotic cells correlated with the amount of phosphatidylethanolamine. Binding of helicobacters was greater to lipids derived from ferret antrum compared with colon (P < 0.05). Biochemical analysis suggested that heterogeneity in fatty acid composition of phosphatidylethanolamine could influence the degree of Helicobacter binding. CONCLUSIONS: Adhesion of Helicobacter strains correlates with the quantity of phosphatidylethanolamine present in the epithelial cell and with the differences in the fatty acid profile of the lipid.

Increased adherence of Escherichia coli RDEC-1 to human tissue culture cells results in the activation of host signaling pathways.

Attaching and effacing (AE) adhesion is associated with the pathogenesis of enteropathogenic Escherichia coli (EPEC) and rabbit diarrheogenic E. coli (RDEC-1). Although RDEC-1 provides an animal model for investigating pathophysiology of EPEC infection, RDEC-1 does not adhere to human cell lines, thereby limiting in vitro investigation. Therefore, transformed RDEC-1 strains expressing adhesins derived from human diarrheogenic E. coli were studied. These adhesins promoted AE adhesion of RDEC-1 and led to the accumulation of alpha-actinin aggregates in the cytoplasm of infected cells. Furthermore, these strains induced host signal transduction pathways, resulting in tyrosine phosphorylation of host proteins and an intracellular elevation of calcium. These results demonstrate that RDEC-1 and EPEC stimulate similar signal transduction pathways in infected epithelial cells, thus lending additional support for the use of RDEC-1 as a model for the study of human EPEC infection.

Expression of interleukin 8 and CD54 by human gastric epithelium after Helicobacter pylori infection in vitro.

BACKGROUND/AIMS: Helicobacter pylori is associated with neutrophil infiltrates, although the mechanism of their recruitment is only partially defined. The aim of the study was to determine if Kato III, a human gastric epithelial cell line, expressed cytokines and the intercellular adhesion molecule 1 (ICAM-1), which could contribute to the initiation of inflammation during infection with H. pylori. METHODS: Kato III cells were stimulated with H. pylori and were examined for evidence of infection, cytokine production, and the expression of ICAM-1. RESULTS: The expression of interleukin 8 messenger RNA and immunoreactive protein by Kato III cells was significantly increased over constitutive levels within 3 hours of infection with H. pylori. Infected Kato III supernatants activated neutrophils as evidenced by increased CD11b/CD18 and decreased L-selectin that could be blocked by anti-interleukin 8. In contrast, Campylobacter jejuni, lipopolysaccharide, killed H. pylori, and supernatants from cultures of H. pylori did not increase interleukin 8. Interleukins 2 and 6; interferons alfa, beta, and gamma; and tumor necrosis factor were not produced by resting or H. pylori-stimulated Kato III cells. In addition to producing interleukin 8, Kato III constitutively expressed surface ICAM-1, which acts as an intercellular adhesion molecule for neutrophils. CONCLUSIONS: Our results indicate that H. pylori stimulates the gastric epithelium to initiate inflammation and neutrophil recruitment and activation.

Distinct binding properties of eaeA-negative verocytotoxin-producing Escherichia coli of serotype O113:H21.

Infection of humans with verotoxin-producing Escherichia coli (VTEC) O113:H21 is associated with clinical features comparable to those associated with infection with attaching and effacing VTEC strains including those of serotype O157:H7. We have shown previously that the adhesion phenotype of VTEC O157:H7 is influenced by the presence of a homolog of the chromosomal eaeA (for E. coli attaching and effacing) gene. In contrast, by colony blot hybridization, VTEC O113:H21 is negative for the eaeA gene. Therefore, the aim of this study was to define the adhesion phenotype of VTEC O113:H21 strain CL-15 to both cultured epithelial cells (HEp-2) and rabbit intestine in vivo. Under transmission electron microscopy, areas of microvillus effacement were observed in regions directly beneath the organism in CL-15-infected cells both in vitro and in vivo. However, F-actin adhesion pedestals on the host plasma membrane were absent. Failure of CL-15 to induce polymerization of actin was confirmed by using staining of F-actin with fluorescein-labeled phalloidin. Under indirect immunofluorescence microscopy, CL-15-infected HEp-2 cells also failed to demonstrate the recruitment of another cytoskeletal element, alpha-actinin, below foci of bacterial adhesion. In contrast, VTEC O157:H7 infection of HEp-2 cells was associated with increased alpha-actinin immunofluorescence. These findings suggest that bacterial factors distinct from those of EaeA are necessary for the adhesion phenotype of VTEC O113:H21.

Signal transduction in human epithelial cells infected with attaching and effacing Escherichia coli in vitro.

BACKGROUND/AIMS: Human enteropathogenic Escherichia coli infection of epithelial cells is characterized by attaching and effacing adhesion. To determine if signal transduction responses are involved in this adhesion phenotype, levels of inositol 1,4,5-triphosphate and cytosolic free calcium were measured in tissue culture cells infected with enteropathogenic E. coli strain E2348 (serotype O127:H6). METHODS: Inositol triphosphate levels were measured by using a commercial binding assay, and intracellular calcium levels were determined by spectrofluorometry. RESULTS: Elevated levels of both inositol triphosphate (182% +/- 52%; P < 0.05) and intracellular calcium (125% +/- 40%, mean +/- SE; P < 0.05) were seen after infection of HEp-2 cells with strain E2348. In contrast, inositol triphosphate and intracellular calcium levels were not elevated in HEp-2 cells infected with six E. coli strains that did not cause attaching and effacing lesions. Subcellular calcium localization using oxalate precipitation and electron microscopy showed calcium accumulation within the terminal web subjacent to regions of attaching and effacing adhesion. Depleting external calcium did not eliminate formation of attaching and effacing lesions, whereas treatment of HEp-2 cells with an intracellular calcium chelator prevented attaching and effacing lesions. CONCLUSIONS: Enteropathogenic E. coli infection elevates both inositol triphosphate and intracellular calcium levels in cultured epithelial cells.

Expression and characterization of the eaeA gene product of Escherichia coli serotype O157:H7.

In enteropathogenic Escherichia coli, the eaeA gene produces a 94-kDa outer membrane protein called intimin which has been shown to be necessary but not sufficient to produce the attaching-and-effacing lesion. The purpose of this study was to characterize the intimin specified by the eaeA allele of the enterohemorrhagic E. coli (EHEC) serotype O157:H7 strain CL8 and to determine its role in adherence. The carboxyl-terminal 266 amino acids of the CL8 intimin were expressed as a protein fusion with glutathione S-transferase, which was used to raise antiserum in rabbits. The antiserum reacted in Western immunoblots with a 97-kDa outer membrane protein of EHEC strains of serogroups O5, O26, O111, and O157 and enteropathogenic E. coli strains of serogroups O55 and O127. Surface labelling of CL8 with 125I showed that intimin was surface exposed. An eaeA insertional inactivation mutant of CL8 was produced and was designated CL8-KO1. Total adherence of CL8-KO1 to HEp-2 cells was not significantly different from that of CL8, but CL8-KO1 gave a negative result in the fluorescent actin staining test. The eaeA gene expressed alone in E. coli HB101 also gave a negative fluorescent actin staining test result. The eaeA gene of CL8 was able to complement the eaeA deletion mutation in CVD206. We conclude that the product of the EHEC eaeA gene is a 97-kDa surface-exposed protein and propose that it be designated intiminO157. Sherman et al. described a 94-kDa outer membrane protein which played an important role in adherence of E. coli O157:H7 (Infect. Immun. 59:890-899, 1991). Western immunoblotting and indirect fluorescent antibody studies showed that the protein described by Sherman et al. is not intimin.

Multiple determinants of verotoxin-producing Escherichia coli O157:H7 attachment-effacement.

Verotoxin-producing Escherichia coli strains of the serotype O157:H7 belong to a class of gastrointestinal pathogens that adhere to epithelial cells in a characteristic pattern known as attaching and effacing. Recent insight into the nature of E. coli O157:H7 adhesion was provided by the cloning and sequencing of the chromosomal eaeA (for E. coli attaching and effacing) gene homolog (G. Beebakhee, M. Louie, J. De Azavedo, and J. Brunton, FEMS Microbiol. Lett. 91:63-68, 1992, and J. Yu and J. B. Kaper, Mol. Microbiol. 6:411-417, 1992) and isolation of a 60-MDa plasmid referred to as pO157 (I. Toth, M. L. Cohen, H. S. Rumschlag, L. W. Riley, E. H. White, J. H. Carr, W. W. Bond, and I. K. Wachsmuth, Infect. Immun. 58:1223-1231, 1990, and S. Tzipori, H. Karch, K. I. Wachsmuth, R. M. Robins-Browne, A. D. O'Brien, H. Lior, M. L. Cohen, J. Smithers, and M. M. Levine, Infect. Immun. 55:3117-3125, 1987) and an approximately 94-kDa outer membrane protein (94-kDa OMP; P. Sherman, F. Cockerill III, R. Soni, and J. Brunton, Infect. Immun. 59:890-899, 1991). In this study, we examined the gene products of both eaeA and pO157 in relation to the 94-kDa OMP and as candidate effectors for O157:H7 attachment-effacement. Peptide sequencing and immunoassay demonstrated that the C. coli O157:H7 eaeA gene product is distinct from the 94-kDa OMP. Using ultrastructural analyses, we found that both parent and pO157 plasmid-cured O157:H7 strains demonstrated attaching and effacing adhesion to host epithelial cells and reacted equally well to rabbit antiserum raised against the 94-kDa OMP. By both transmission electron microscopy and light microscopy, E. coli HB101 transformed separately with the cloned eaeA gene and the pO157 plasmid did not form attaching and effacing lesions on cultured epithelial cells in vitro and rabbit intestinal tissues in vivo. Since additional determinants may mediate the attaching and effacing phenotype, we examined transposon TnphoA mutants constructed from E. coli O157:H7 strain CL8. Two TnphoA mutants were found deficient in bacterial factors that are necessary for O157:H7 attachment-effacement and likely distinct from the eaeA gene product.

Comparison of Helicobacter pylori and attaching-effacing Escherichia coli adhesion to eukaryotic cells.

Adhesion of Helicobacter pylori was reported previously to be morphologically identical to "attaching and effacing" Escherichia coli. Therefore, the aim of the present study was to define the adhesion phenotype of H. pylori LC-11 to HEp-2, KATO-III, HEL, and CHO tissue culture cells. By using both staining of F-actin with fluorescein-labeled phalloidin and ultrastructural analysis, diffuse bacterial adhesion to discrete microvillus-denuded regions of the plasma membrane was observed in each of the infected cell lines. However, strain LC-11 did not induce formation of F-actin adhesion pedestals on the eukaryotic cells. H. pylori was negative by colony blot hybridization with an E. coli attaching and effacing gene probe. Elevations in inositol triphosphates followed infection of HEp-2 cells with H. pylori (405% of control values +/- 147%; P < 0.05). To correlate the observed histopathology with expression of the H. pylori phosphatidylethanolamine receptor, a thin-layer chromatography overlay-binding assay was used to identify receptors in each of the cell lines. H. pylori adhered to eukaryotic cells regardless of the presence (HEp-2, KATO-III, and CHO cells) or absence (HEL cells) of the lipid receptor as detected under the assay conditions. However, in comparison to cell lines that possess the phosphatidylethanolamine receptor, HEL cells demonstrated less quantitative H. pylori binding. These findings suggest that mechanisms distinct from E. coli enteropathogens underlie the adhesion of H. pylori to mucosal surfaces. In addition to the phosphatidylethanolamine H. pylori receptor, another host factor(s) likely mediates the attachment of H. pylori to human eukaryotic cells.