An unusual neurological presentation in a patient with primary hypereosinophilic syndrome.

Hypereosinophilic syndromes are characterized by an increased number of blood eosinophils (usually more than 1.5 × 109) infiltrating tissues and causing organ damage through over-production of pro-inflammatory cytokines with heterogeneous clinical presentation. Here we present a case of a 47 years old male, with an unremarkable previous medical history, with a sudden onset of subungual hemorrhage and low back pain. Admitted for right arm weakness and vomiting, was raised the suspicion of acute cerebrovascular syndrome, but a brain CT scan with angiogram and perfusion sequences did not show any signs of early ischaemic lesions; conversely, lab tests revealed an increased peripheral eosinophil blood count. Clinical conditions rapidly worsened and a brain MRI showed multiple sub-acute ischaemic lesions compatible with vasculitis while EEG was in favor of widespread cortical distress. Diagnosis of the hypereosinophilic syndrome was made through peripheral blood smear and osteo-medullar biopsy, which showed a rich prevalence of eosinophils. The molecular biology testing showed FIP1L1-PDGRA gene mutation. Despite the prompt therapy beginning with intravenous corticosteroids and tyrosine-kinase inhibitors with normalization of cell blood count in a few days, the patient remained in minimal consciousness. When facing unusual symptoms onset (low back pain with weakness in one limb) and a highly impaired WBC not consistent with other courses (such as infections, vasculitis, allergies, and other diseases involving the immune system) clinicians should take into account the possibility of a hematological disorder and treat it as soon as possible to avoid a poor prognosis.

Drug use and abuse and the risk of adverse events in soccer players: results from a survey in Italian second league players.

Summary: Objective. Drug use in athletes has been frequently investigated in the last three decades, especially regarding its misuse for doping. However, little is known about the use of permitted drugs for medical purposes and less studies have investigated the relationship between adverse drugs reactions (ADRs) and sports. Methods. An observational cross-sectional investigation analyzing a group of second league soccer players (the second-highest division in Italy) was performed. Anamnestic and physical examinations as well as a validated questionnaire (AQUA©) were performed in a group of 378 Italian second league soccer players. Results. Most players (91.8%) reported the use of NSAIDs in the previous year, and one third of them were regular users. Analgesics were used in 64% of the players, while 52.1% had taken antibiotics in the previous year. 29.20% of players used intraarticular treatments in the previous year. In 7,4% of players, an ADRs was reported: 3,47% reacted to NSAIDs, 2,6% to antibiotics, 1,05% to analgesics and 1 of them to supplements. For intra-articular injections, only 2 players experienced ADRs. One quarter of players experienced reactions as urticaria-angioedema syndrome or more severe conditions as bronchospasm or anaphylaxis. Conclusions. This study shows that drug misuse/abuse in soccer is a real matter of debate, especially with regards to NSAIDs, exposing athletes to predictable and/or unpredictable risks for their health.

Helicobacter pylori HP(2-20) induces eosinophil activation and accumulation in superficial gastric mucosa and stimulates VEGF-alpha and TGF-beta release by interacting with formyl-peptide receptors.

Eosinophils participate in the immune response against Helicobacter pylori, but little is known about their role in the gastritis associated to the infection. We recently demonstrated that the Hp(2-20) peptide derived from H. pylori accelerates wound healing of gastric mucosa by interacting with N-formyl peptide receptors (FPRs) expressed on gastric epithelial cells. The aim of the present study was to investigate whether eosinophils play a role in the repair of gastric mucosa tissue during H. pylori infection. Immuno-histochemistry and transmission electron microscopy were used to detect eosinophils in gastric mucosal biopsies. Eosinophil re-distribution occurred in the gastric mucosa of H. pylori-infected patients: their density did not change in the deep mucosal layer, whereas it increased in the superficial lamina propria just below the foveolar epithelium; eosinophils entered the epithelium itself as well as the lumen of foveolae located close to the area harboring bacteria, which in turn were also engulfed by eosinophils. The H. pylori-derived peptide Hp(2-20) stimulated eosinophil migration through the engagement of FPR2 and FPR3, and also induced production of VEGF-A and TGF-beta, two key mediators of tissue remodelling. We also demonstrate that Hp(2-20) in vivo induced eosinophil infiltration in rat gastric mucosa after injury brought about by indomethacin. This study suggests that eosinophil infiltrate could modulate the capacity of gastric mucosa to maintain or recover its integrity thereby shedding light on the role of eosinophils in H. pylori infection.

Expression and function of Angiopoietins and their tie receptors in human basophils and mast cells.

The Angiopoietin/Tie system is a key regulator of vascular remodeling, maturation, angiogenesis and lymphangiogenesis. In humans there are three angiopoietins: Angiopoietin-1 (Ang1), Angiopoietin-2 (Ang2), and Angiopoietin-4 (Ang4). Ang1 and Ang2 are the best characterized angiopoietins. The angiopoietin receptor system consists of two type I tyrosine kinase receptors (Tie1 and Tie2). Tie2 binds all known angiopoietins. We sought to characterize Ang1, Ang2, Tie1 and Tie2 expression and functions in human basophils and mast cells. Basophils, LAD-2 cells and Human Lung Mast Cells (HLMCs) constitutively express Ang1 and Ang2 mRNA. Intracellular staining for Ang1 and Ang2 was stronger in basophils than in mast cells. Immunoelectron microscopy demonstrated Ang1 in cytoplasmic vesicles of basophils. The protein kinase C activators phorbol diester (PMA) and bryostatin 1 (Bryo1) stimulated basophils to rapidly release a large amount of Ang1. PMA-induced Ang1 release was inhibited by brefeldin A. Tie1 and Tie2 mRNAs were expressed in basophils, LAD-2 and HLMCs. Basophils, LAD-2 and HLMCs expressed Tie1 on the cell surface. HLMCs and LAD-2 expressed Tie2 on the cell surface, whereas basophils did not. Ang1, but not Ang2, induced migration of mast cells through the engagement of Tie2. Neither Ang1 nor Ang2 induced basophil chemotaxis. We have identified a novel mechanism of cross-talk between human basophils and mast cells mediated by the Ang1/Tie2 system that might be relevant in the orchestration of inflammatory and neoplastic angiogenesis.

Role(s) of formyl-peptide receptors expressed in nasal epithelial cells.

Chronic rhinosinusitis is one of the most frequent chronic diseases in humans. Little is known about stimuli initiating tissue remodeling process that determines the morphological expression of the disease. N-formyl peptide receptors (FPRs) are innate immunity receptors important in tissue remodeling of gastric and intestinal epithelium. The expression and functions of FPRs in nasal epithelial cells were examined to evaluate whether they could be important in the remodeling of nasal mucosa. The aim of this study is to examine FPR expression in a nasal epithelial cell line (RPMI-2650) at mRNA and protein levels. To determine whether FPRs were functional, chemotaxis experiments were carried out. In addition the effects of FPRs agonists on the expression (PCR and ELISA) of VEGF-A and TGF-beta, two key mediators of tissue remodelling, were examined. Here we demonstrate that RPMI-2650 express FPR and FPRL2, but not FPRL1. fMLP, a bacterial product active on FPR, and uPAR(84-95), an inflammatory mediator agonist for FPRL2, stimulated migration of nasal epithelial cells. fMLP and uPAR(84-95) induce expression and secretion of VEGF-A and TGF-beta. Our results suggest a possible mechanisms initiating tissue remodeling observed during chronic rhinosinusitis. This study provides further evidence that FPRs play a more complex role in human pathophysiology than bacterial recognition.

Crohn's disease and Takayasu's arteritis: are they associated?

OBJECTIVE: Different types of vasculitis can occur in patients with inflammatory bowel disease [IBD], but large vessels vasculitis seems to be the most prevalent. Indeed, the presence of both Crohn's disease [CD] and Takayasu's arteritis [TAK] has previously been reported, with higher prevalence in young women between the second and the third decade of life. This article aims to provide clinicians with an accurate picture of the most common clinical features and current treatment strategy for patients with both CD and TAK. PATIENTS AND METHODS: We described the coexistence of CD and TAK in three young women and also performed an extensive literature review about the association of these two immune-related disorders. Research on PubMed server was performed typing the terms "Takayasu's arteritis and inflammatory bowel disease", "Takayasu's arteritis and Crohn's disease", and "Takayasu's arteritis and Ulcerative colitis". RESULTS: Although the association of CD with TAK is uncommon, due to the severity of both diseases, concomitance in the same patient may significantly complicate the diagnostic and therapeutic work-up. In addition, since TAK can compromise intestinal vasculature, it may possibly exacerbate the clinical course of patients with IBD. All patients we reported underwent surgery due to IBD complications and two of them started biological therapy with different outcomes. CONCLUSIONS: Early detention of these conditions has a great importance for both gastroenterologists and immunologists, for ensuring a tailored multidisciplinary management, possibly in order to identify a common therapy for these two immune-related disorders.

Effects of Polyurethane Foam Dressings as an Add-on Therapy in the Management of Digital Ulcers in Scleroderma Patients.

Digital ulcers (DUs) represent a severe and common complication occurring in patients affected by Systemic Sclerosis (SSc), with a consistent impact on the quality of life and often resulting in longer hospitalization than unaffected patients. Conventional treatment of SSc ulcers consists of both topical and systemic (oral or intravenous) pharmacological therapies. Several surgical options are also available, but there is overall a lack of official guidelines or recommendations. The aim of this study was to evaluate the efficacy of a novel local therapy based on polyurethane foam dressings, namely the Highly Hydrophilic Polyurethane Foam (HPF), in addition to the conventional pharmacological treatment, in a cohort of 41 SSc patients with at least one active ulcer. Our results showed that the addition of HPF to the conventional treatment based on systemic drugs induced i) a significant reduction in the number of active DUs (p=0.0034); ii) a significant reduction of the mean duration of ulcer-related hospitalization as compared with standard therapy (p=0.0001); iii) a significant improvement of patients' Quality of Life, as evaluated through the Scleroderma Health Assessment Questionnaire (SHAQ) (p=0.00011). Therefore, in our experience, the combined management of DUs can improve both the onset of new DUs and DU's healing thus leading to a better outcome.

First report of qacG, qacH and qacJ genes in Staphylococcus haemolyticus human clinical isolates.

OBJECTIVES: To investigate phenotypically and genotypically the presence of MDR efflux pumps in 21 clinical isolates of Staphylococcus haemolyticus collected over a period of 10 years. METHODS: MICs of different antibiotics and biocides were determined by the broth dilution method in the presence/absence of carbonyl cyanide-m-chlorophenylhydrazone (CCCP), an efflux pump inhibitor. PCR followed by sequencing was performed to detect the qac genes that encode for antiseptic resistance. Clonal relationships were determined by PFGE SmaI patterns using a standard protocol. RESULTS: All the isolates were resistant to gentamicin, 15 to erythromycin, 18 to ciprofloxacin, 7 to chloramphenicol and 1 to tetracycline. They showed higher susceptibility to antibiotics when they were exposed to CCCP. The MICs of ethidium bromide, SDS and benzalkonium chloride were also decreased, whereas the MIC of triclosan was decreased in only four isolates in the presence CCCP. Of the 21 isolates, qacA/B was detected in 5 isolates, smr in all of the isolates, qacG in 11 isolates, qacH in 10 isolates and qacJ in 4 isolates. PFGE analysis of the 21 isolates clustered them into 14 clones at 90% similarity corresponding to differences of between 7 and 16 bands among the clones. CONCLUSIONS: The efflux mechanism seems to be an important mechanism to confer resistance to antibiotics and biocides through MDR pumps. It was observed that several qac genes coexist in some of the isolates and seem to act simultaneously in the removal of different compounds out of the bacterial cell. The qac genes are horizontally spread among different clones.

A 15 year-review of peritoneal dialysis-related peritonitis: microbiological trends and patterns of infection in a teaching hospital in Argentina.

This study reports the infectious peritonitis rates in 44 patients on peritoneal dialysis in three different systems over the last 15 years, covering clinical outcomes, exit-site infections, tunnel infections, causative microorganisms, and the history of susceptibility of organisms causing peritonitis, in order to establish our center-specific selection of empiric therapy. Two microbiological procedures were herein used: method A, where 100 ml of dialysate were centrifuged and cultured in standard media and into blood-culture bottles; and method B, where 10 ml were directly injected into blood-culture bottles. Swabs from the exit-site or tunnel were taken when purulent drainage was observed. There were 96 episodes of peritonitis during 110.43 patient-years (0.87 episodes/patient-year). Sensitivity of method A was 96.88% (93/96 episodes) versus 81.25% (78/96) of method B (p=0.001). Gram stain sensitivity was 36.46%. The etiologic agents were 64 (56.64%) gram-positive cocci, 22 (19.47%) gram-negative fermentative rods, 20 (17.7%) gram-negative non fermentative rods, 5 (4.43%) yeasts, 1 (0.88%) micelial fungus, and 1 (0.88%) anaerobic rod. Fifty-five exit-site infections were documented (0.5 episodes/patient-year). Ceftazidime and imipenem showed excellent activity on gram-negative rods. There were 92.3% of methicillin-susceptible Staphylococcus aureus but only 33.3% of methicillin-susceptible coagulase-negative staphylococci; vancomycin was active against 100% of the gram-positive cocci. The clinical outcomes of peritonitis were 73 initial cure, 19 catheter removal and four related deaths. The empiric therapy in our center should be vancomycin plus ceftazidime or imipenem. Once the etiological agent and its susceptibility pattern are known, the deescalating therapy must be applied to avoid the emergence and spread of vancomycin-resistant microorganisms.

Peptide Hp(2-20) accelerates healing of TNBS-induced colitis in the rat.

BACKGROUND AND AIMS: Hp(2-20), a Helicobacter pylori-derived peptide interacting with N-formyl peptide receptors (FPRs), accelerates the healing of gastric injury in rats. Whether Hp(2-20) affects the recovery of inflamed colonic mucosa is unknown. We evaluated whether Hp(2-20) accelerated the healing of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis and explored the mechanism(s) underlying any such effect. METHODS: Fifteen rats underwent rectal administration of Hp(2-20) 250-500 µg/kg/day, or of its control peptide Hp1 for 10 days, following induction of colitis with TNBS. Macroscopic and histological damage was quantified using predetermined injury scores. FPR1, COX-2, TNF-α, TGF-ß, HB-EGF and tissue transglutaminase (t-TG) messenger RNA (mRNA) expression in colonic tissue was determined by quantitative polymerase chain reaction; FPR1, TNF-α and COX-2 protein levels by Western blotting. RESULTS: (1) Hp(2-20) accelerated healing of TNBS-induced colitis compared to controls consistently with the expression of FPRs in colonic mucosa; (2) TNBS upregulated mRNA mucosal expression of COX-2, TNF-α, TGF-ß, HB-EGF and t-TG and (3) this, with the exception of HB-EGF, was significantly counteracted by Hp(2-20). CONCLUSIONS: Hp(2-20), an FPR agonist, accelerates the healing of TNBS-induced colitis in the rat. This effect is associated with a significant reduction in colonic tissue levels of COX-2, TGF-ß, TNF-α and t-TG. We postulate that FPR-dependent pathways may be involved in the repair of inflamed colonic mucosa.

Role of Formyl Peptide Receptors in Gastrointestinal Healing.

The wound healing and the barrier restoration of the gastrointestinal (GI) mucosa must be continuously ensured to allow homeostasis of the gastrointestinal tract and of all the surrounding tissues. Several lines of the evidence report a key role of innate immunity, and in particular of Pattern Recognition Receptors (PRRs), in controlling the homeostasis of GI tract by sensing commensal and pathogen bacteria, activating the immune response and regulating epithelial repair, thus guaranteeing the morphological and functional recovery of the injured tissue. We will discuss the role of a particular class of PRRs - the Formyl Peptide Receptors - in the homeostasis of GI mucosa. We here report the results of studies that strongly suggest the possibility that the activation of FPRs is crucial in the maintenance of homeostasis of the GI tract and provide indications of the potential clinical relevance of new treatment regimens involving FPR modulation for several GI disorders.

Fungal peritonitis in patients on peritoneal dialysis: twenty five years of experience in a teaching hospital in Argentina.

Fungal peritonitis is a rare but serious complication of peritoneal dialysis. The aim of this study was to analyze peritonitis rates, associated factors, clinical course, microbiological aspects, therapeutic regimens, and outcome of patients with fungal peritonitis in the dialysis center of a teaching hospital over the last 25 years. A hundred and eighty three episodes of peritonitis were detected and microbiologically documented in 57 patients. Fungi were identified in eight episodes (4.37%) occurring in seven female patients. The fungal peritonitis rate was 0.06 episodes/patient-year. Gram and Giemsa stains were positive in five out of eight dialysate fluids. The causative microorganisms were: Candida albicans in five episodes, and Candida parapsilosis, Candida glabrata, and Neosartorya hiratsukae in the remaining three. Antibiotics were administered to all but one patient, within 3 months before fungal peritonitis was detected. All patients required hospitalization, and antifungal therapy was administered in all episodes. The Tenckhoff catheter was removed in seven out of eight fungal peritonitis. All patients recovered from the fungal episodes. In the group of patients studied, it is concluded that recent exposure to antibiotics and female sex, were strongly associated with the development of fungal peritonitis by yeasts. The peritonitis caused by the environmental filamentous fungus did not require antibiotic pressure. Direct microscopy of the dialysate pellet was extremely useful for the prompt management of the fungal episode. Fungal peritonitis preceded by multiple episodes of bacterial peritonitis always determined the definitive dropout of the patient from the peritoneal dialysis program. Patients with de novo yeast-related peritonitis could continue on the program.

Combination therapy with Bosentan and Sildenafil improves Raynaud's phenomenon and fosters the recovery of microvascular involvement in systemic sclerosis.

The aim of this study was to evaluate in systemic sclerosis (SSc) retrospectively the effect of Bosentan and Sildenafil and their combination on Raynaud's phenomenon (RP), function, and capillaroscopic patterns. One hundred and twenty-three SSc patients (mean age ± sd, 57.69 ± 14.07 years) were retrospectively evaluated and divided into two groups according to American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification score: group 1 score < 10, group 2 score > 10. Each group was divided into three subgroups according to treatment: Bosentan, Sildenafil, and Bosentan + Sildenafil. Nailfold videocapillaroscopy (NVC), Scleroderma Health Assessment Questionnaire (SHAQ) and Raynaud Condition Score (RCS) were performed at baseline and after 3 and 6 months. In Bosentan (29 patients: 12, group 1; 17, group 2), NVC changed significantly in both groups, after 3 and 6 months (p = 0.00439, group 1; p = 0.00035, group 2). In group 1, the "active" and the "late" patterns reduced, and the "aspecific" increased. In group 2, there was a reduction of late patterns, a worsening of SHAQ (p < 0.005) and an improvement of RCS (p = 0.00014). In Sildenafil (63 patients: 35, group 1; 28, group 2), after 3 months, NVC patterns changed significantly in both groups(p = 0.042 group 1, p = 0.00089 group 2). In group 1, the late and early patterns increased, and the aspecific decreased. In group 2, a significant change of NVC pattern was observed also after 6 months (p = 0.00089): the late pattern increased while the active one reduced. After 6 months, SHAQ was significantly reduced in group 1 (p = 0.00027) and in group 2 (p = 0.0043). RCS improved in both groups (p = 0.0042, group 1; p = 0.0016, group 2). Combination therapy (Bosentan + Sildenafil) (31 patients: 14, group 1; 17, group 2) induced significant changes on NVC only in group 1 after 3 (p = 0.00256) and 6 months (p = 0.000349) with a reduction of the late and active patterns and an increase of the early pattern. In both groups, after 6 months, SHAQ (p < 0.05, group 1; p = 0.00049, group 2) and RCS significantly reduced (group 1, p = 0.00024; group 2, p = 0.0021). Patients treated with Bosentan + Sildenafil show a significant improvement of RCS and NVC. This combination therapy may exert a vascular activity achieving an amelioration of the structure of microvasculature in SSc.

Mechanisms of IgE elevation in HIV-1 infection.

Serum IgE levels are high in adults and children with HIV-1 infection and could be a marker of poor prognosis. Allergic reactions and adverse reactions to drugs also tend to increase in HIV-1-infected individuals. An imbalance between a "T(H)1-like" and a "T(H)2-like" cytokine profile has been documented in HIV-1 infection. We have demonstrated that HIV-1 gp 120 from different clades is a stimulus for histamine and cytokine (IL-4 and IL-13) release from basophils. Gp 120 acts as a viral superantigen, interacting with the V(H)3 region of IgE to induce mediator release from human Fc epsilonRI+ cells. Human basophils and mast cells express the chemokine receptor CCR3, which binds the chemokines eotaxin and RANTES. By interacting with the CCR3 receptor on Fc epsilonRI+ cells, HIV-I Tat protein is a potent chemoattractant for human basophils and lung mast cells. Preincubation of basophils with Tat protein upregulates mRNA CCR3 and the surface expression of this chemokine receptor. Tat also induces IL-4 and IL-13 release from basophils. Extracellular Tat can influence the directional migration of human Fc epsilonRI+ cells, the expression of chemokine receptor CCR3, and the release of T(H)2 cytokines. Our results indicate two novel mechanisms by which two HIV-1 proteins, gp120 and Tat, trigger the release of cytokines critical for T(H)2 polarization from human Fc epsilonRI+ cells.

The formyl peptide receptor 1 exerts a tumor suppressor function in human gastric cancer by inhibiting angiogenesis.

N-formyl peptide receptors (FPR1, FPR2 and FPR3) are involved in innate immunity, inflammation and cancer. FPR expression, initially described in immune cells, was later observed in non-hematopoietic cell populations and tissues. Several studies suggested a role for FPRs in the progression of various tumor histotypes, including gastric cancer (GC), for which a positive association with a specific FPR1 polymorphism has recently been described. We previously showed that FPRs are expressed on gastric epithelium and are required for wound repair and restitution of barrier integrity. Here we assess the role of FPRs in GC. We characterized the functions of FPRs in GC epithelial cells (MKN28, AGS and MKN45) cultured in vitro by assessing migration, proliferation, resistance to apoptosis and activation of the epithelial-to-mesenchymal transition. Activation of each FPR induced the epithelial-to-mesenchymal transition, proliferation, resistance to apoptosis and migration of GC cells in culture. Blocking compounds or RNA interference of each FPR reverted these effects. We also defined the in vivo tumorigenic potential of GC epithelial cells silenced for FPRs by xenograft experiments in immunocompromised mice. Interestingly, FPR1 silencing in GC cells (shFPR1) significantly enhanced xenograft growth with respect to shCTR, shFPR2 and shFPR3 xenografts, because of augmented vessel density and cell proliferation. Accordingly, HIF-1α and VEGF mRNA levels were higher in shFPR1 xenografts than in controls. Moreover, the in vitro production of proangiogenic factors in response to FPR2/3 agonists (WKYMVm, LL-37, uPA, uPAR84-95, AnxA1) or to other proinflammatory mediators (IL-1α) was higher in shFPR1 GC cells than in shCTR, shFPR2 and shFPR3 cells, suggesting that FPR1 functions as an inhibitor of CG angiogenesis. Thus, we propose that FPR1 stimulation may represent a novel therapeutic approach to counteract tumor angiogenesis.

Mast cells induce epithelial-to-mesenchymal transition and stem cell features in human thyroid cancer cells through an IL-8-Akt-Slug pathway.

There is increasing evidence that mast cells (MCs) and their mediators are involved in the remodeling of the tumor microenvironment and promote tumor growth, angiogenesis and metastasis. We have found that an increased density of MCs in thyroid cancer (TC) correlates with enhanced invasiveness. However, the MC-derived factors responsible for this activity and the mechanisms by which they enhance TC invasiveness remain unidentified. Here, we report that MCs, when activated by TC cells, produce soluble factors that induce epithelial-to-mesenchymal transition (EMT) and stemness features of TC cells. We identified CXCL8/interleukin (IL)-8 as the main mediator contained in activated MC conditioned media (CM) capable of inducing both EMT and stemness of TC cells. Mechanistically, MC CM or exogenous IL-8 stimulated Akt phosphorylation and Slug expression in TC cells. The inhibition of the Akt pathway or depletion of the Slug transcription factor by RNA interference, reverted EMT and stemness responses. TC cells stably transfected with exogenous IL-8 underwent EMT, displayed increased stemness and enhanced tumorigenicity with respect to control cells. The analysis of TC surgical specimens by immunohistochemical analysis demonstrated a positive correlation between MC density (Tryptase(+) cells) and stemness features (OCT4 staining). Taken together, our data identify an MC-dependent IL-8-Akt-Slug pathway that sustains EMT/stemness of TC cells. The blockade of this circuit might be exploited for the therapy of advanced TC.

Anti-inflammatory effect of FK-506 on human skin mast cells.

FK-506 and the structurally related macrolide rapamycin are high-affinity ligands for a specific binding protein (FK-506 binding protein). We examined the effects of FK-506 and rapamycin on the release of pre-formed (histamine) and de novo synthesized inflammatory mediators (prostaglandin D2) from mast cells isolated from human skin tissue. FK-506 (0.1 to 100 nM) concentration-dependently inhibited (5 to 65%) histamine release from skin mast cells activated by anti-IgE. FK-506 was more potent in skin mast cells than in basophils (IC40 = 2.15 +/- 0.78 nM versus 5.12 +/- 1.34 nM; p < 0.001), whereas the maximal inhibitory effect was higher in basophils than in skin mast cells (88.77 +/- 2.44% versus 67.30 +/- 3.98%; p < 0.01). FK-506 had little or no inhibitory effect on histamine release from skin mast cells challenged with compound A23187 and substance P, respectively, whereas it completely suppressed A23187-induced histamine release from basophils. FK-506 (0.1 to 100 nM) also inhibited (up to 65%) the de novo synthesis of prostaglandin D2 from skin mast cells challenged with anti-IgE. Despite its structural similarity to FK-506, rapamycin (10 to 300 nM) had little or no effect on the release of histamine from skin mast cells induced by anti-IgE, A23187, and substance P. However, rapamycin competitively antagonized the inhibitory effect of FK-506 on anti-IgE-induced histamine release from skin mast cells with a dissociation constant of about 14 nM. These data indicate that FK-506, but not rapamycin, is a potent anti-inflammatory agent acting on skin mast cells presumably by binding to the FK-506 binding protein. It thus appears that binding to the FK-506 binding protein is necessary, but not sufficient, to deliver an inhibitory signal to skin mast cells.

Anti-inflammatory effect of cyclosporin A on human skin mast cells.

We have examined the effects of cyclosporin A (CsA) and cyclosporin H (CsH), which bind with different affinity to cyclophilin, to evaluate the role of this protein in the release of preformed (histamine) and de novo synthesized (prostaglandin D2[PGD2]) mediators of inflammatory reactions from human skin mast cells (HSMC). CsA (2.4-800 nM)-inhibited (5-60%) histamine release from HSMC challenged with anti-IgE. CsA exerted little, if any, inhibitory effect on histamine release from HSMC challenged with compound A23187 and substance P, whereas it completely suppressed A23187-induced histamine release from human basophils. Inhibition of histamine release from HSMC challenged with anti-IgE was extremely rapid and was not abolished by washing (three times) the cells before anti-IgE challenge. CsA (2.4-800 nM) markedly inhibited (25-70%) the de novo synthesis of PGD2 from HSMC challenged with anti-IgE. CsH, which has an extremely low affinity for cyclophilin, had no effect on skin mast-cell mediator release. These data suggest that CsA is a potent anti-inflammatory agent acting on HSMC, presumably by interacting with cyclophilin.

[Vulvar lesions caused by Papillomavirus (HPV): effectiveness of thymopentin (Syntomoduline). First results and experiences]. / Lesioni vulvari da papillomavirus (HPV): efficacia della timopentina (Sintomodulina). Nostri primi risultati ed esperienze.

The study included two different sized groups of patients suffering from various degrees of valvular microcondylomatosis. A group of 40 patients was treated using combined therapy while a second group of 20 patients received immunomodulating therapy alone with Sintomodulin. In particular, possible changes in the T-cell line of the immune system and correlations between the viral lesion and variations in serum levels of lymphocyte subpopulations were assessed. Results were analysed up to one year after the end of therapy.