Familial Mediterranean fever (FMF) is an autosomal recessive autoin lammatory disease caused by mutation(s) in the Mediterranean fever (MEFV, pyrinmarenostrin) gene [1,2]. FMF is characterized by recurrent fever crises combined with serosal, synovial, or cutaneous in lammation and, in some individuals, by the eventual development, in the long-term, of systemic amyloidosis [3,4]. FMF mainly affects peoples living along eastern Mediterranean Sea (Turks, Sephardic Jews, Armenians) and it is not a rare disease in other Mediterranean areas such as Greeks, Italians and Iranians [4,6]. Until now, more than 304 sequence variants have been recorded [6]. In Italy M694V, V726A, M680I, M694I and E148Q are the most frequent FMF-associated mutations [7].

Hereditary angioedema (HAE) is a rare autosomic-dominant disorder characterized by a deficiency of C1 esterase inhibitor which causes episodic swellings of subcutaneous tissues, bowel walls and upper airways that are disabling and potentially life-threatening. We evaluated n = 17 patients with confirmed HAE diagnosis during attack and remission state and n = 19 healthy subjects. The samples were tested for a panel of IL (Interleukin)-17-type cytokines (IL-1β, IL-6, IL-10, granulocyte–macrophage colony stimulating factor (GM-CSF), IL-17, IL-21, IL-22, IL-23) and transforming growth factor-beta (TGF-β) subtypes. Data indicate that there are variations of cytokine levels in HAE subjects comparing the condition during the crisis respect to the value in the remission phase, in particular type 17 signature cytokines are increased, whereas IL-23 is unmodified and TGF-β3 is significantly reduced. When comparing healthy and HAE subjects in the remission state, we found a significant difference for IL-17, GM-CSF, IL-21, TGF-β1 and TGF-β2 cytokines. These results confirm and extend our previous findings indicating that in HAE there is operating an inflammatory activation process, which involves also T helper 17 (Th17) cytokines and TGF-β isoforms, associated with localized angioedema attacks and characterized by elevated bradykinin levels.

The microbiota has been selected to optimize the host reproductive success and it is crucial for the development and the function of the immune system. Here, it is discussed how the microbial communities using metabolites [short-chain fatty acids (SCFAs), ligands for aryl hydrocarbon receptor (AHR), polyamines], or their components [polysaccarde A (PSA), D-glycero-B-D-manno-heptose-1,7-biphosphate (HBP) and formyl peptides] regulate homeostasis and the defence against pathogens, being, at the same time, involved in the pathogenesis of various disorders. Furthermore, the causes and consequences of bacterial dysbiosis are discussed on the basis of the involvement in the aetiology of some autoimmune diseases. A short mention for the therapeutic approaches is reported.

Introduction Hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE type I) or dysfunction (C1-INH-HAE type II) is a rare disease characterized by recurrent episodes of edema with an estimated frequency of 1:50,000 in the global population without racial or gender differences. In this study we present the results of a nationwide survey of C1-INH-HAE patients referring to 17 Italian centers, the Italian network for C1-INH-HAE, ITACA. Methods Italian patients diagnosed with C1-INH-HAE from 1973 to 2013 were included in the study. Diagnosis of C1-INH-HAE was based on family and/or personal history of recurrent angioedema without urticaria and on antigenic and/or functional C1-INH deficiency. Results 983 patients (53% female) from 376 unrelated families were included in this survey. Since 1973, 63 (6%) patients diagnosed with C1-INH-HAE died and data from 3 patients were missing when analysis was performed. Accordingly, the minimum prevalence of HAE in Italy in 2013 is 920:59,394,000 inhabitants, equivalent to 1:64,935. Compared to the general population, patients are less represented in the early and late decades of life: men start reducing after the 5 th decade and women after the 6 th . Median age of patients is 45 (IQ 28-57), median age at diagnosis is 26 years (IQ 13-41). C1-INH-HAE type 1 are 87%, with median age at diagnosis of 25 (13-40); type 2 are 13% with median age at diagnosis of 31 (IQ 16-49). Functional C1INH is ≤50% in 99% of patients. Antigen C1INH is ≤50% in 99% of type 1. C4 is ≤50% in 96% of patients. The chance of having C1-INH-HAE with C4 plasma levels >50% is < 0.05. Conclusion This nationwide survey of C1-INH-HAE provides for Italy a prevalence of 1:64,935. C1-INH-HAE patients listed in our database have a shorter life expectancy than the general population. An increased awareness of the disease is needed to reduce this discrepancy. Measurement of C4 antigen can exclude diagnosis of C1-INH-HAE with an accuracy > 95%. This parameter should be therefore considered for initial screening in differential diagnosis of angioedema.

Hereditary angioedema (HAE) is a rare autosomal dominant disorder, due to C1-inhibitor deficiency, which causes episodic swellings of subcutaneous tissues, bowel walls and upper airways which are disabling and potentially life-threatening. We evaluated n = 17 patients with confirmed HAE diagnosis in basal and crisis state and n = 19 healthy subjects. The samples were tested for IL-17, FGFb, G-CSF and GM-CSF, using Bio-plex kit. Data analysis was performed via nonparametric Spearman’s correlations and two sets of linear mixed models. When comparing HAE subjects during basal and crisis states, we found out significantly (i.e., p value <0.05) higher values in crisis states rather than in basal states for the three growth factors and cytokine IL-17. When comparing healthy subjects versus HAE patients at basal state, we found out significantly higher values in HAE subjects only for GM-CSF, FGFb and IL-17, but not for G-CSF. In HAE patients, there is a connection between IL-17 and growth factors. The low-grade inflammation in absence of attacks is demonstrated by constant higher amount of IL-17, FGFb and GM-CSF with respect to healthy patients. This could indicate that in this disease there is a level of activation that maintains the system in a “tick-over state,” that can be activate by several stimuli that are able to induce a increase in inflammatory mediators during the acute attack.

aPatologia Clinica Presidio Ospedaliero V. Cervello, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy (until March 2010). *Corresponding author: Enrico Cillari, Department of Clinical Pathology, Ospedali Riuniti Villa Sofia-Cervello, Cervello Hospital, Palermo, Italy, E-mail: enrico.cillari@tiscali.it Francesco Arcoleo, Marilisa Salemi and Antonio La Porta: Ospedali Riuniti Villa Sofia-Cervello, Cervello Hospital, Clinical Pathology Laboratories, Palermo, Italy Valentina Selvaggio: Tempor Agengy, Genova, Italy Vitalba Mandalà and Vito Muggeo: University of Palermo, Department of Statistical and Mathematical Sciences “Vianelli”, Palermo, Italy Gabriella Misiano, Salvatore Milano and Giuseppina Colonna Romano: University of Palermo, Department of Pathobiology and Medical and Forensic Biotechnologies, Palermo, Italy

L’angioedema ereditario è causato da una carenza genetica di C1-inibitore, fattore che regola una serie di pathways infiammatori. I pazienti affetti da HAE hanno crisi intermittenti caratterizzate da edemi cutanei o mucosali legati a un malfunzionamento del meccanismo di controllo della produzione locale di bradichinina. L’edema solitamente evolve in diverse ore e persiste per 2–5 giorni. Oltre all’angioedema oro-facciale, edemi non accompagnati a dolore possono colpire i distretti periferici con conseguente alterazione dei connotati e interferenza con il lavoro e altre attività della vita quotidiana. L’angioedema del tratto gastrointestinale e dei visceri addominali causa dolore severo spesso associato a ostruzione edematosa dell’intestino e vomito. Circa il 2% degli edemi coinvolge la laringe e può rivelarsi fatale se non trattato; circa il 50% dei pazienti ha, nel corso della vita, attacchi laringei.

To evaluate seroprevalence of B. henselae infection both in Sicilian children and healthy blood donors. Furthermore, circulation of Bartonella in the natural reservoir was also studied. Two hundred forty-three children, living in Sicily (Palermo), affected by various diseases, without clinical features suggesting B. henselae infection, together with 122 healthy blood donors were serologically investigated for IgG and IgM antibodies by indirect fluorescent antibody test (IFAT). One hundred twenty stray and 62 pet cats were also analyzed only for IgG. Among children 25.1% had IgG antibodies to B. henselae; 18.5% showed a titer 1: 64, 2.4% 1: 128, 2.4% 1: 256, 0.8% 1: 512, 0.4% 1: 1024, and 0.4% 1: 5120. Among healthy blood donors 11.4% had IgG class antibodies to B. henselae; 9.8% showed a titer 1: 64 and 1.6% 1:128. All the human serum samples did not show positive results for B. henselae IgM class antibodies. Stray cats (68.3%) and pet cats (35.4%) also had IgG class antibodies to B. henselae. We demonstrated high frequency of serologic evidence of past B. henselae infection, in young Italian children, affected by various diseases, apparently free of any clinical features suggesting B. henselae infection. This observation is supported by high circulation of Bartonella in cats.

The background of this article is as follows: Few data are available about the persistence of serum-specific IgG antibodies to L. infantum after acute VL. The objective of this article is to evaluate the persistence of antibodies against L. infantum in patients healed from acute VL, and the kinetic of the same antibodies observed in 2 cases of VL relapse and 2 cases of resistance to therapy. The methods which we used to obtain our objective are the following: 55 apparently immunocompetent, HIV-negative patients were examined for antibodies to L. infantum by IFAT over 14 years period, and we got the following results: Serum-specific IgG antibodies titers decrease slowly, but constantly. In the patients with a diagnosis of VL relapse, the kinetic of antibodies was characterized by an initial reduction, and a subsequent antibody levels rapidly increase, while in the patients with a clinical and parasitological diagnosis of VL not responding to specific therapy, we demonstrated persistent high level of antibodies to L. infantum. Finally, we conclude that specific antibodies to L. infantum might persist for many years, and decrease slowly, but steadily. The persistence of these specific antibodies is not related to poor therapeutic response or prognosis, but an acute increase in their levels might be a sentinel of a VL relapse, while persistence of high antibody levels could suggest a resistance to therapy.

Human rickettsial diseases comprise a variety of clinical entities caused by microorganisms belonging to the genera Rickettsia , Orientia , Ehrlichia , and Anaplasma . These microorganisms are characterized by a strictly intracellular location which has, for long, impaired their detailed study. In this paper, the critical steps taken by these microorganisms to play their pathogenic roles are discussed in detail on the basis of recent advances in our understanding of molecular Rickettsia -host interactions, preferential target cells, virulence mechanisms, three-dimensional structures of bacteria effector proteins, upstream signalling pathways and signal transduction systems, and modulation of gene expression. The roles of innate and adaptive immune responses are discussed, and potential new targets for therapies to block host-pathogen interactions and pathogen virulence mechanisms are considered.

Cardiovascular diseases, i.e. high blood pressure, coronary heart disease, and stroke, and osteoporosis are public health problems, with several epidemiological links, and they might be related to each other in terms of pathogenesis and therapeutic agents. Bisphosphonates inhibit bone resorption and are used in the treatment of osteoporosis, whereas statins inhibit cholesterol biosynthesis and are used for the treatment of atherosclerosis and lipid metabolic disorders. Some late clinical studies suggested bisphosphonates may have beneficial effect in vivo on atherosclerotic progression, lipid profiles, and cardiovascular morbidity and mortality, whereas statins might increase bone density, and reduce fracture risk, even if properly designed prospective studies are needed to clearly define clinical effects and potential new roles for these old agents. Moreover mechanism by which these two classes of drugs act, at cellular level, may not be mutually exclusive, and the common target of action might be the mevalonate pathway. In this review, we focused on in vitro and in vivo interactions between mevolanate pathway, bisphosphonates, and statins, examining the possible therapeutic consequences of these links.

Nowadays leishmaniasis is an increasing, severe, public health problem, and its control is strictly connected to vaccine development and therapeutic manipulations of the immune system. The clinical outcome of leishmaniasis is related to cytokine response profile. Immune system type-1 response and IFN-g production provide well-known protective activity against Leishmania, whereas role of T helper (T-H) 2 cytokines in non-healing infections requires further exploration. As a matter of fact, IL-4 and IL-13 (T(H)2 cytokines) promote disease progression in cutaneous leishmaniasis, whereas IL-4 seems to enhance protective type-1 responses in visceral leishmaniasis. Thus, immune response to intracellular parasites should dismiss the T(H)1/T(H)2 paradigm of resistance/susceptibility, embracing theory of a more complicated network of regulatory/counter regulatory interactions. Moreover, the presence of antigen specific regulatory T cell subsets may provide an environment that contributes to the balance between T(H)1 and T(H)2 cells. Finally, the involvement of CD8(+) T cells has been described, but the modality of their role and function, in this kind of infection, has not been outspreed so far.

The aim of the study was to analyze the acute inflammatory response after implantation of a heavyweight mesh of polypropylene (PP) compared with a composite mesh of light PP and polyglactin 910 (PG) in patients undergoing inguinal hernioplasty. A total of 30 male patients with inguinal hernia were included in the study and divided into 2 groups (PP and PP-PG) according to the mesh used. Changes of leukocytes, cytokines, growth factors, and acute phase proteins were evaluated in the sera. Leukocytes and acute phase proteins were significantly increased postoperatively in both groups, and the values were slightly higher in the PP group. Cytokine levels were significantly increased postoperatively in both groups; a slight increase was observed in the PP-PG group, especially for the proinflammatory cytokine. Growth factors decreased significantly in both groups immediately after surgery. The authors found that the use of the mesh is a stimulator of inflammatory response, and the 2 types of mesh induce a similar inflammatory response.

BACKGROUNDHereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms. Icatibant is a selective bradykinin B2 receptor antagonist.METHODSIn two double-blind, randomized, multicenter trials, we evaluated the effect of icatibant in patients with hereditary angioedema presenting with cutaneous or abdominal attacks. In the For Angioedema Subcutaneous Treatment (FAST) 1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary end point was the median time to clinically significant relief of symptoms.RESULTSA total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary end point was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P=0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P<0.001). In the FAST-1 study, 3 recipients of icatibant and 13 recipients of placebo needed treatment with rescue medication. The median time to first improvement of symptoms, as assessed by patients and by investigators, was significantly shorter with icatibant in both trials. No icatibant-related serious adverse events were reported.CONCLUSIONSIn patients with hereditary angioedema having acute attacks, we found a significant benefit of icatibant as compared with tranexamic acid in one trial and a nonsignificant benefit of icatibant as compared with placebo in the other trial with regard to the primary end point. The early use of rescue medication may have obscured the benefit of icatibant in the placebo trial. (Funded by Jerini; ClinicalTrials.gov numbers, NCT00097695 and NCT00500656.)

Background: The technology to recognize nucleated red blood cells (NRBC) automatically has only recently been developed. Modern hematology analyzers allow for rapid and accurate NRBC counts. The goal of our study was to evaluate NRBC counts and the concentrations of serum transferrin receptor (sTfR) in patients affected by different thalassemia syndromes and hereditary spherocytosis. We wished to gain a better understanding of the meaning of the presence of NRBC in peripheral blood and the relationship of the two parameters with effective and ineffective erythropoiesis in the different thalassemia syndromes.Methods: NRBC counts in peripheral blood were evaluated in a large group of patients with thalassemia (36 thalassemia major, 55 thalassemia intermedia and 61 Sb-thalassemia patients) and compared with data from 29 patients with hereditary spherocytosis; in all the patients the concentration of sTfR was evaluated as an index of global erythropoiesis.Results: The NRBC count showed a good relationship with ineffective erythropoiesis: highest counts were observed in the thalassemia syndromes characterized by almost completely ineffective erythropoiesis. NRBCs were absent in patients affected by hereditary spherocitosis, a disease characterized by effective erythropoiesis.Conclusions: The NRBC count can be useful for better defining ineffective erythropoiesis in patients with thalassemia, and can help optimize transfusion therapy in severe thalassemia syndromes. Clin Chem Lab Med 2009;47:1539-42.

ABSTRACT The acute phase of Mediterranean spotted fever (MSF) is characterized by dramatic changes in cytokine production patterns, clearly indicating their role in the immunomodulation of the response against the microorganism, and the differences in cytokine production seem to influence the extent and severity of the disease. In this study, the single nucleotide polymorphisms (SNPs) of tumor necrosis factor alpha (TNF-α) −308G/A (rs1800629) and interleukin-10 (IL-10) −1087G/A (rs1800896), −824C/T (rs1800871), and −597C/A (rs1800872) and the gamma interferon (IFN-γ) T/A SNP at position +874 (rs2430561) were typed in 80 Sicilian patients affected by MSF and in 288 control subjects matched for age, gender, and geographic origin. No significant differences in TNF-α −308G/A genotype frequencies were observed. The +874TT genotype, associated with an increased production of IFN-γ, was found to be significantly less frequent in MSF patients than in the control group (odds ratio [OR], 0.18; 95% confidence interval [95% CI], 0.06 to 0.51; P corrected for the number of genotypes [Pc], 0.0021). In addition, when evaluating the IFN-γ and IL-10 genotype interaction, a significant increase of +874AA/−597CA (OR, 5.31; 95% CI, 2.37 to 11.88; Pc, 0.0027) combined genotypes was observed. In conclusion, our data strongly suggest that finely genetically tuned cytokine production may play a crucial role in the regulation of the immune response against rickettsial infection, therefore influencing the disease outcomes, ranging from nonapparent or subclinical condition to overt or fatal disease.

Se revisa el concepto de lesiones precancerosas orales, de cáncer oral y su diagnóstico precoz. Con las palabras clave: premalignant oral lesions prevention se realiza una búsqueda de los 10 últimos años. También se buscan los ensayos clínicos desde enero de 2011 hasta la actualidad con las palabras clave: oral cancer prevention AND dentistry. Se destaca que no hay cambios significativos relacionados con el concepto de lesión precancerosa y cáncer, y que en cuanto al diagnóstico precoz, si bien se describen numerosos métodos de cribado, la biopsia sigue siendo la prueba más útil y, por tanto, imprescindible, más aún si consideramos las nuevas posibilidades de estudios moleculares.We reviewed the concept of oral precancerous lesions, oral cancer, and the possibility of early diagnosis. With the keywords: premalignant oral lesions prevention, a search was performed over the past 10 years. Also clinical trials are searched from January 2011 until today with the keywords: oral cancer prevention AND dentistry. It is emphasized that there can be no significant changes related to the concept of precancerous lesions and cancer, and those relating to the early diagnosis. Despite the numerous described methods of screening, biopsy remains the most useful test, and therefore it is essential, mainly if we consider the new possibilities of molecular studies.

Background The aim of the present study was the detection of asymptomatic coronary re-stenosis after percutaneous coronary intervention (PCI). Methods We studied 26 subjects who had been recently implanted with a paclitaxel-eluting coronary stent by both a conventional exercise test and the determination of plasma B-type natriuretic peptide (BNP) levels. Results At control coronary angiography, nine months after initial PCI, six patients had re-stenosis and 20 were re-stenosis free. We found that re-stenosis was best predicted by the combination of a basal plasma BNP level ≥ 50 pg/ml and a positive or uncertain conventional exercise test (positive likelihood ratio of the combination = 10). The best predictor of absence of re-stenosis was a low (< 50 pg/ml) plasma BNP level (negative likelihood ratio = 0.26). Conclusions Accordingly, basal BNP level testing can be recommended in the follow-up evaluation of coronary patients after PCI, to improve both the detection and the exclusion of asymptomatic re-stenosis.