CircHIPK2 facilitates phenotypic switching of vascular smooth muscle cells in hypertension.

Hypertension is a clinical syndrome characterized by increased systemic arterial blood pressure, affecting about 1.4 billion people currently worldwide with only one in seven cases adequately controlled. It is the main contributing factor of cardiovascular diseases (CVDs), often co-existing with other CVDs risk factors to impair the structure and function of important organs such as heart, brain, and kidney, and ultimately lead to multi-organ failure. Vascular remodeling is a critical process in the development of essential hypertension, and phenotype switching of vascular smooth muscle cells (VSMCs) was reported contributing substantially to vascular remodeling. circHIPK2 is a circular RNA (circRNA) derived from the second exon of homeodomain-interacting protein kinase 2 (HIPK2). Several studies revealed that circHIPK2 functions in various diseases by serving as a microRNA (miRNA) sponge. However, the functional roles and molecular mechanisms of circHIPK2 in VSMC phenotype switching and hypertension are not clear. In the present study, we showed that the expression of circHIPK2 was significantly upregulated in the VSMCs of hypertensive patients. Functional studies showed that circHIPK2 promoted the Angiotensin II (AngII)-induced VSMC phenotype switching by acting as the sponge of miR-145-5p, thereby upregulating the expression of a disintegrin and metalloprotease (ADAM) 17. Collectively, our study provides a new therapeutic target for hypertension.

Regulatory roles of external cholesterol in human airway epithelial mitochondrial function through STARD3 signalling.

BACKGROUND: Hypercholesterolemia is found in patients with chronic lung inflammation, during which airway epithelial cells play important roles in maintenance of inflammatory responses to pathogens. The present study aims at molecular mechanisms by which cholesterol changes airway epithelial sensitivity in response to smoking. METHODS: Human bronchial epithelial cells (HBEs) were stimulated with cigarette smoke extract (CSE) and mice were exposed to CS/lipopolysaccharide (LPS) as models in vitro and in vivo. Severe COPD patients and healthy volunteers were also enrolled and the level of cholesterol in plasma was detected by metabolomics. Filipin III and elisa kits were used to stain free cholesterol. Mitochondrial function was detected by mitotracker green, mitotracker green, and Seahorse. Mitochondrial morphology was detected by high content screening and electron microscopy. The mRNA and protein levels of mitochondrial dynamics-related proteins were detected by RT-qPCR and Western blot,respectively. BODIPY 493/503 was used to stain lipid droplets. Lipidomics was used to detect intracellular lipid components. The mRNA level of interleukin (IL)-6 and IL-8 were detected by RT-qPCR. RESULTS: We found that the cholesterol overload was associated with chronic obstructive pulmonary disease (COPD) and airway epithelia-driven inflammation, evidenced by hypercholesterolemia in patients with COPD and preclinical models, alteration of lipid metabolism-associated genes in CSE-induced airway epithelia and production of ILs. External cholesterol altered airway epithelial sensitivity of inflammation in response to CSE, through the regulation of STARD3-MFN2 pathway, cholesterol re-distribution, altered transport and accumulation of cholesterol, activities of lipid transport regulators and disorder of mitochondrial function and dynamics. MFN2 down-regulation increased airway epithelial sensitivity and production of ILs after smoking, at least partially by injuring fatty acid oxidation and activating mTOR phosphorylation. CONCLUSIONS: Our data provide new insights for understanding molecular mechanisms of cholesterol-altered airway epithelial inflammation and for developing diagnostic biomarkers and therapeutic targets to improve patient outcomes.

Evaluation of the indirect impact of the 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine in a cluster-randomised trial.

BACKGROUND: In the nation-wide double-blind cluster-randomised Finnish Invasive Pneumococcal disease trial (FinIP, ClinicalTrials.gov NCT00861380, NCT00839254), we assessed the indirect impact of the 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against five pneumococcal disease syndromes. METHODS: Children 6 weeks to 18 months received PHiD-CV10 in 48 clusters or hepatitis B/A-vaccine as control in 24 clusters according to infant 3+1/2+1 or catch-up schedules in years 2009-2011. Outcome data were collected from national health registers and included laboratory-confirmed and clinically suspected invasive pneumococcal disease (IPD), hospital-diagnosed pneumonia, tympanostomy tube placements (TTP) and outpatient antimicrobial prescriptions. Incidence rates in the unvaccinated population in years 2010-2015 were compared between PHiD-CV10 and control clusters in age groups <5 and ≥5 years (5-7 years for TTP and outpatient antimicrobial prescriptions), and in infants <3 months. PHiD-CV10 was introduced into the Finnish National Vaccination Programme (PCV-NVP) for 3-month-old infants without catch-up in 9/2010. RESULTS: From 2/2009 to 10/2010, 45398 children were enrolled. Vaccination coverage varied from 29 to 61% in PHiD-CV10 clusters. We detected no clear differences in the incidence rates between the unvaccinated cohorts of the treatment arms, except in single years. For example, the rates of vaccine-type IPD, non-laboratory-confirmed IPD and empyema were lower in PHiD-CV10 clusters compared to control clusters in 2012, 2015 and 2011, respectively, in the age-group ≥5 years. CONCLUSIONS: This is the first report from a clinical trial evaluating the indirect impact of a PCV against clinical outcomes in an unvaccinated population. We did not observe consistent indirect effects in the PHiD-CV10 clusters compared to the control clusters. We consider that the sub-optimal trial vaccination coverage did not allow the development of detectable indirect effects and that the supervening PCV-NVP significantly diminished the differences in PHiD-CV10 vaccination coverage between the treatment arms.

Overexpression of TRIM3 protects against LPS-induced acute kidney injury via repressing IRF3 pathway and NLRP3 inflammasome.

PURPOSE: The pathological process of sepsis involves multiple system organs, including kidney. Sepsis-induced acute kidney injury (AKI) has high morbidity and high mortality. Overproduced inflammatory factors contribute to the occurrence and evolvement of AKI. Here, the role and underlying mechanism of tripartite motif containing 3 (TRIM3) and in AKI was explored. METHODS: Lipopolysaccharide (LPS) was used for constructing AKI model both in vitro and in vivo. RT-PCR and western blot were performed to detect TRIM3, Interferon regulatory factor 3 (IRF3) and NLRP3-ASC-Caspase1 inflammasome. Upon selectively regulating the TRIM3 or IRF3 expression, the proliferation, apoptosis and inflammatory response were detected. The interaction between TRIM3 and IRF3 was verified by Immunoprecipitation (IP). RESULTS: TRIM3 was down-regulated in mediated injury renal tubular epithelial cell line HK-2 treated with LPS. Overexpression of TRIM3 promoted cell viability and reduced apoptosis. In addition, overexpression of TRIM3 inhibited the expression of inflammatory factors (IL-1ß, IL-6, TNF-α and IL-18), dampened the phosphorylation of IRF3 and repressed NLRP3 inflammasome activation. Furthermore, TRIM3 overexpression significantly eased the LPS-induced damage on AKI rat model and decreased the serum creatinine and urea nitrogen levels in rat kidney tissues. The results of immunohistochemistry (IHC) and Western blot manifested that TRIM3 was increased dramatically after TRIM3 was overexpressed in the rat kidney tissues, while IRF3 and NLRP3-ASC-Caspase1 inflammasome were significantly repressed following TRIM3 upregulation in the kidney tissues. Mechanistically, TRIM3 interacted with IRF3 and inhibited its phosphorylation. CONCLUSION: Overexpression of TRIM3 protected against LPS-induced AKI by inhibiting the IRF3 pathway and NLRP3 inflammasome activation.

Efficacy and safety of maralixibat treatment in patients with Alagille syndrome and cholestatic pruritus (ICONIC): a randomised phase 2 study.

BACKGROUND: Alagille syndrome is a rare genetic disease that often presents with severe cholestasis and pruritus. There are no approved drugs for management. Maralixibat, an apical, sodium-dependent, bile acid transport inhibitor, prevents enterohepatic bile acid recirculation. We evaluated the safety and efficacy of maralixibat for children with cholestasis in Alagille syndrome. METHODS: ICONIC was a placebo-controlled, randomised withdrawal period (RWD), phase 2b study with open-label extension in children (aged 1-18 years) with Alagille syndrome (NCT02160782). Eligible participants had more than three times the normal serum bile acid (sBA) levels and intractable pruritus. After 18 weeks of maralixibat 380 µg/kg once per day, participants were randomly assigned (1:1) to continue maralixibat or receive placebo for 4 weeks. Subsequently, all participants received open-label maralixibat until week 48. During the long-term extension (204 weeks reported), doses were increased up to 380 µg/kg twice per day. The primary endpoint was the mean sBA change during the RWD in participants with at least 50% sBA reduction by week 18. Cholestastic pruritus was assessed using observer-rated, patient-rated, and clinician-rated 0-4 scales. The safety population was defined as all participants who had received at least one dose of maralixibat. This trial was registered with ClinicalTrials.gov, NCT02160782, and is closed to recruitment. FINDINGS: Between Oct 28, 2014, and Aug 14, 2015, 31 participants (mean age 5·4 years [SD 4·25]) were enrolled and 28 analysed at week 48. Of the 29 participants who entered the randomised drug withdrawal period, ten (34%) were female and 19 (66%) were male. In the RWD, participants switched to placebo had significant increases in sBA (94 µmol/L, 95% CI 23 to 164) and pruritus (1·7 points, 95% CI 1·2 to 2·2), whereas participants who continued maralixibat maintained treatment effect. This study met the primary endpoint (least square mean difference -117 µmol/L, 95% CI -232 to -2). From baseline to week 48, sBA (-96 µmol/L, -162 to -31) and pruritus (-1·6 pts, -2·1 to -1·1) improved. In participants who continued to week 204 (n=15) all improvements were maintained. Maralixibat was generally safe and well tolerated throughout. The most frequent adverse events were gastrointestinal related. Most adverse events were self-limiting in nature and mild-to-moderate in severity. INTERPRETATION: In children with Alagille syndrome, maralixibat is, to our knowledge, the first agent to show durable and clinically meaningful improvements in cholestasis. Maralixibat might represent a new treatment paradigm for chronic cholestasis in Alagille syndrome. FUNDING: Mirum Pharmaceuticals.

p32 promotes melanoma progression and metastasis by targeting EMT markers, Akt/PKB pathway, and tumor microenvironment.

Melanoma originates from melanin-producing cells called melanocytes. Melanoma poses a great risk because of its rapid ability to spread and invade new organs. Cellular metastasis involves alteration in the gene expression profile and their transformation from epithelial to mesenchymal state. Despite of several advances, metastatic melanoma being a key cause of therapy failure and mortality remains poorly understood. p32 has been found to be involved in various physiological and pathophysiological conditions. However, the role of p32 in melanoma progression and metastasis remains underexplored. Here, we identify the role of p32 in the malignancy of both murine and human melanoma. p32 knockdown leads to reduced cell proliferation, migration, and invasion in murine and human melanoma cells. Furthermore, p32 promotes in vitro tumorigenesis, inducing oncogenes and EMT markers. Mechanistically, we show p32 regulates tumorigenic and metastatic properties through the Akt/PKB signaling pathway in both murine and human melanoma. Furthermore, p32 silencing attenuates melanoma tumor progression and lung metastasis in vivo, modulating the tumor microenvironment by inhibiting the angiogenesis, infiltration of macrophages, and leukocytes in mice. Taken together, our findings identify that p32 drives melanoma progression, metastasis, and regulates the tumor microenvironment. p32 can be a target of a novel therapeutic approach in the regulation of melanoma progression and metastasis.

LTP allergy/sensitization in a pediatric population

Plant lipid transfer proteins (LTPs) are widespread plant food allergens, highly resistant to food processing and to the gastrointestinal environment, which have been described as the most common food allergens in the Mediterranean area. LTP allergy is widely described in adults, but it represents an emerging allergen also in the pediatric population. Little is known about the real prevalence and the clinical features of this allergy in children and it still often remains underdiagnosed in these patients. An early identification and a deeper knowledge of this allergy in childhood can avoid severe systemic reactions and improve the child's quality of life. Pediatricians should always consider the possibility of LTP involvement in cases of plant-derived food allergy

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Nickel allergy in lipid transfer protein sensitized patients: Prevalence and clinical features.

Nickel (Ni), the main responsible for allergic contact dermatitis worldwide, is also involved in systemic condition called "Systemic Nickel Sulfate Allergy Syndrome (SNAS)." Likewise, IgE-mediated reactivity to Lipid Transfer Protein (LTP) represents the main cause of primary food allergy in adults of Mediterranean countries. We evaluated the prevalence of SNAS in LTP allergic patients and investigated patients' clinical features with double sensitization (LTP and Ni). A retrospective, single-center, observational study was conducted performing a complete allergological work-up including: (1) skin prick tests; (2) serum specific IgE for plant food allergens and rPru p3 (LTP); (3) patch test with 5% Ni sulfate in petrolatum. We enrolled 140 LTP allergic patients of which 36 patients (25.7% of sample) showed additional positivity to Ni patch test. Patients with double sensitization were more frequently females and reported fewer cutaneous symptoms. Higher values of sIgE for peach, apple, peanut, walnut, grain, corn, and garlic were found in LTP allergic patients, while higher values for hazelnut in the other subgroup. The prevalence of SNAS in the LTP allergic population is clinically relevant. Moreover, the clinical and immunological profiles of patients with double sensitization were different from patients monosensitized to LTP.

LTP allergy/sensitization in a pediatric population.

Plant lipid transfer proteins (LTPs) are widespread plant food allergens, highly resistant to food processing and to the gastrointestinal environment, which have been described as the most common food allergens in the Mediterranean area. LTP allergy is widely described in adults, but it represents an emerging allergen also in the pediatric population. Little is known about the real prevalence and the clinical features of this allergy in children and it still often remains underdiagnosed in these patients. An early identification and a deeper knowledge of this allergy in childhood can avoid severe systemic reactions and improve the child's quality of life. Pediatricians should always consider the possibility of LTP involvement in cases of plant-derived food allergy.

A randomized trial of vonapanitase (PATENCY-1) to promote radiocephalic fistula patency and use for hemodialysis.

OBJECTIVE: Arteriovenous fistulas created in patients with chronic kidney disease often lose patency and fail to become usable. This prospective trial evaluated the efficacy of vonapanitase, a recombinant human elastase, in promoting radiocephalic fistula patency and use for hemodialysis. METHODS: PATENCY-1 was a double-blind, placebo-controlled trial that enrolled 349 patients on or approaching hemodialysis and being evaluated for radiocephalic arteriovenous fistula creation. Of these, 313 were randomized and 311 treated. Patients were assigned to vonapanitase (n = 210) or placebo (n = 103). The study drug solution was applied topically to the artery and vein for 10 minutes immediately after fistula creation. The primary and secondary end points were primary patency (time to first thrombosis or corrective procedure) and secondary patency (time to abandonment). Tertiary end points included use of the fistula for hemodialysis, fistula maturation by ultrasound, and procedure rates. RESULTS: The Kaplan-Meier estimates of 12-month primary patency were 42% (95% confidence interval [CI], 35-49) and 31% (95% CI, 21-42) for vonapanitase and placebo (P = .25). The Kaplan-Meier estimates of 12-month secondary patency were 74% (95% CI, 68-80) and 61% (95% CI, 51-71) for vonapanitase and placebo (P = .048). The proportions of vonapanitase and placebo patients were 39% and 25% (P = .035) with unassisted use for hemodialysis and 64% and 44% (P = .006) with unassisted plus assisted use. CONCLUSIONS: Vonapanitase treatment did not significantly improve primary patency but was associated with increased secondary patency and use for hemodialysis. Further research is needed to evaluate these end points.

Evaluation of serum IgE in peach-allergic patients with systemic reaction by using recombinant Pru p 7 (gibberellin-regulated protein)

BACKGROUND: Lipid transfer protein (LTP) is a major fruit allergen. It has, however, recently been revealed that the systemic reaction in peach-allergic patients is related not only to LTP (Pru p 3) but also to gibberellin-regulated protein (Pru p 7). We investigated recombinant Pru p 7 (rPru p 7) for its potential use in worldwide standardization for the diagnosis of peach allergy. METHODS: Natural Pru p 7 (nPru p 7) was purified from peach crude extract using a monoclonal antibody affinity column. Complementary DNA for Pru p 7 was cloned and expressed in Escherichia coli and Pichia pastoris. Serum immunoglobulin (Ig) E in peach-allergic patients was examined by enzyme-linked immunosorbent assay (ELISA) using nPru p 7 and rPru p 7 (E. coli product: erPru p 7 and P. pastoris product: prPru p 7). RESULTS: Peach-allergic patients (n = 27) were diagnosed and categorized into oral reaction (n=10) or systemic reaction (n = 17). The nPru p 7 positivity based on serum IgE levels was 52% in the systemic-reaction group and 0% in the oral-reaction group (P<0.05). In the systemic-reaction group, there was no significant difference in reactivity between nPru p 7 and prPru p 7, but the reactivity of erPru p 7 was significantly lower than those of nPru p 7 and prPru p 7 (P < 0.05). CONCLUSIONS: We found that prPru p 7 exhibited reactivity in ELISA comparable to that of nPru p 7 for the diagnosis of peach allergy with systemic reaction

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Food Allergies Caused by Allergenic Lipid Transfer Proteins: What Is behind the Geographic Restriction?

PURPOSE OF REVIEW: To critically examine evidence suggesting that food allergy induced by lipid transfer proteins (LTPs) follows a geographic pattern. RECENT FINDINGS: LTP syndrome remains most common in the Mediterranean basin, with a clear gradient seen in prevalence of LTP sensitization between northern and southern Europe. We hypothesize that high levels of birch pollen seem to protect against LTP allergy, as these higher levels correlate with a lower prevalence of LTP hypersensitivity. Nevertheless, LTP food allergy cases still appear in areas having a high environmental level of birch pollen. Food allergy caused by LTP may be related to (1) primary sensitization to a food LTP allergen in the absence of pollinosis, (2) primary sensitization to LTP from a pollen source, and (3) co-sensitization to LTP from pollen and food.

Evaluation of serum IgE in peach-allergic patients with systemic reaction by using recombinant Pru p 7 (gibberellin-regulated protein).

BACKGROUND: Lipid transfer protein (LTP) is a major fruit allergen. It has, however, recently been revealed that the systemic reaction in peach-allergic patients is related not only to LTP (Pru p 3) but also to gibberellin-regulated protein (Pru p 7). We investigated recombinant Pru p 7 (rPru p 7) for its potential use in worldwide standardization for the diagnosis of peach allergy. METHODS: Natural Pru p 7 (nPru p 7) was purified from peach crude extract using a monoclonal antibody affinity column. Complementary DNA for Pru p 7 was cloned and expressed in Escherichia coli and Pichia pastoris. Serum immunoglobulin (Ig) E in peach-allergic patients was examined by enzyme-linked immunosorbent assay (ELISA) using nPru p 7 and rPru p 7 (E. coli product: erPru p 7 and P. pastoris product: prPru p 7). RESULTS: Peach-allergic patients (n=27) were diagnosed and categorized into oral reaction (n=10) or systemic reaction (n=17). The nPru p 7 positivity based on serum IgE levels was 52% in the systemic-reaction group and 0% in the oral-reaction group (P<0.05). In the systemic-reaction group, there was no significant difference in reactivity between nPru p 7 and prPru p 7, but the reactivity of erPru p 7 was significantly lower than those of nPru p 7 and prPru p 7 (P<0.05). CONCLUSIONS: We found that prPru p 7 exhibited reactivity in ELISA comparable to that of nPru p 7 for the diagnosis of peach allergy with systemic reaction.

A Potential New Risk Factor for Stroke: Streptococcus Mutans With Collagen-Binding Protein.

BACKGROUND: Among human oral bacteria, particular kinds of Streptococcus mutans (SM) known as dental caries pathogens contain a collagen-binding protein, Cnm, and show platelet aggregation inhibition and matrix metalloproteinase-9 activation. We have previously reported that these strains may be a risk factor for intracerebral hemorrhage. As a major sample-providing hospital, we report the clinical details, including intracranial aneurysms and ischemic stroke. METHODS: After the study received approval from the Ethical Committee, 429 samples of whole saliva were obtained from patients who were admitted to or visited our hospital between February 16, 2010, and February 28, 2011. The study cohort comprised 48 patients with cardioembolic stroke (CES), 151 with non-CES infarct, 54 with intracerebral hemorrhage (ICH), 43 with ruptured intracranial aneurysm (RIA), and 97 with unruptured intracranial aneurysm (UIA). Cultured SM was identified as Cnm-positive when the corresponding gene was positive. The results were compared with those from 79 healthy volunteers. Relationships between Cnm-positive SM and known risk factors, including hypertension, diabetes, hyperlipidemia, smoking, and alcohol consumption, were analyzed. RESULTS: A statistically significant high Cnm-positive rate was observed in patients with CES, non-CES infarct, ICH, and RIA (P = 0.002, 0.039, 0.013, and 0.009, respectively). There were no relationships between Cnm-positive SM and known risk factors. CONCLUSIONS: Specific types of oral SM can be a risk factor for cardioembolic infarct, intracerebral hemorrhage, and intracranial aneurysm rupture. Further study is needed.

Impact of protein D-containing pneumococcal conjugate vaccines on non-typeable Haemophilus influenzae acute otitis media and carriage.

INTRODUCTION: Protein D-containing vaccines may decrease acute otitis media (AOM) burden and nasopharyngeal carriage of non-typeable Haemophilus influenzae (NTHi). Protein D-containing pneumococcal conjugate vaccine PHiD-CV (Synflorix, GSK Vaccines) elicits robust immune responses against protein D. However, the phase III Clinical Otitis Media and PneumoniA Study (COMPAS), assessing PHiD-CV efficacy against various pneumococcal diseases, was not powered to demonstrate efficacy against NTHi; only trends of protective efficacy against NTHi AOM in children were shown. Areas covered: This review aims to consider all evidence available to date from pre-clinical and clinical phase III studies together with further evidence emerging from post-marketing studies since PHiD-CV has been introduced into routine clinical practice worldwide, to better describe the clinical utility of protein D in preventing AOM due to NTHi and its impact on NTHi nasopharyngeal carriage. Expert commentary: Protein D is an effective carrier protein in conjugate vaccines and evidence gathered from pre-clinical, clinical and observational studies suggest that it also elicits immune response that can help to reduce the burden of AOM due to NTHi. There remains a need to develop improved vaccines for prevention of NTHi disease, which could be achieved by combining protein D with other antigens.

Arteriovenous fistula patency in the 3 years following vonapanitase and placebo treatment.

OBJECTIVE: This study explored the long-term outcomes of arteriovenous fistulas treated with vonapanitase (recombinant human elastase) at the time of surgical creation. METHODS: This was a randomized, double-blind, placebo-controlled trial of 151 patients undergoing radiocephalic or brachiocephalic arteriovenous fistula creation who were randomized equally to placebo, vonapanitase 10 µg, or vonapanitase 30 µg. The results after 1 year of follow-up were previously reported. The current analysis occurred when the last patient treated was observed for 3 years. For the current analysis, the primary end point was primary patency; the secondary end points included secondary patency, use of the fistula for hemodialysis, and rate of procedures to restore or to maintain patency. RESULTS: There was no significant difference in the risk of primary patency loss with vonapanitase 10 µg or 30 µg vs placebo. When seven initial patency loss events related to cephalic arch and central vein balloon angioplasty were excluded, the risk of patency loss was reduced with vonapanitase overall (hazard ratio [HR], 0.63; P = .049) and 30 µg (HR, 0.51; P = .03). In patients with radiocephalic fistulas (n = 67), the risks of primary and secondary patency loss were reduced with 30 µg (HR, 0.37 [P = .02] and 0.24 [P = .046], respectively). The rate of procedures to restore or to maintain fistula patency was reduced with 30 µg vs placebo (0.23 vs 0.72 procedure days/patient/year; P = .03) and also reduced in patients with radiocephalic fistulas with 30 µg vs placebo (0.17 vs 0.85 procedure days/patient/year; P = .048). CONCLUSIONS: In this study, vonapanitase did not significantly improve primary patency in the primary analysis but did significantly improve primary patency in an analysis that excluded patency loss due to cephalic arch and central vein balloon angioplasty. In patients with radiocephalic fistulas, 30 µg significantly improved primary and secondary patency. Vonapanitase 30 µg decreased the rate of procedures to restore or to maintain patency in the analysis that included all patients and in the subset with radiocephalic fistulas.

Lettuce Allergy Is a Lipid Transfer Syndrome-Related Food Allergy With a High Risk of Severe Reactions.

BACKGROUND AND OBJECTIVE: Lipid transfer protein (LTP) sensitization is the most common cause of food allergy in the Mediterranean area, with peach allergy acting as the primary sensitizer in most cases. Lettuce has been described as a common offending food in patients with LTP syndrome. The aim of the study was to investigate the frequency and clinical expression of LTP syndrome in a sample of lettuceallergic patients. METHODS: We determined specific IgE to Pru p 3 and lettuce in a sample of 30 patients with a diagnosis of lettuce allergy. Symptoms elicited by other LTP-containing plant-derived foods and the presence of cofactors were assessed. RESULTS: The clinical symptoms of lettuce allergy were frequently severe, with 18 of the 30 patients experiencing anaphylaxis. All the patients had allergic reactions to other plant foods. Cofactors were involved in the clinical reactions of 13 of the 30 patients. Sensitization to pollens was found in 90% of patients. CONCLUSIONS: Lettuce allergy is found not as an isolated condition but in the context of LTP syndrome and it is characterized by severe reactions and frequent cofactor association.