Estimates of Environmental Exposure to Radiofrequency Electromagnetic Fields and Risk of Lymphoma Subtypes.

We investigated the association between environmental exposure to radiofrequency electromagnetic fields (RF-EMF) and risk of lymphoma subtypes in a case-control study comprised of 322 patients and 444 individuals serving as controls in Sardinia, Italy in 1998-2004. Questionnaire information included the self-reported distance of the three longest held residential addresses from fixed radio-television transmitters and mobile phone base stations. We georeferenced the residential addresses of all study subjects and obtained the spatial coordinates of mobile phone base stations. For each address within a 500-meter radius from a mobile phone base station, we estimated the RF-EMF intensity using predictions from spatial models, and we performed RF-EMF measurements at the door in the subset of the longest held addresses within a 250-meter radius. We calculated risk of lymphoma and its major subtypes associated with the RF-EMF exposure metrics with unconditional logistic regression, adjusting by age, gender and years of education. In the analysis of self-reported data, risk associated with residence in proximity (within 50 meters) to fixed radio-television transmitters was likewise elevated for lymphoma overall [odds ratio = 2.7, 95% confidence interval = 1.5-4.6], and for the major lymphoma subtypes. With reference to mobile phone base stations, we did not observe an association with either the self-reported, or the geocoded distance from mobile phone base stations. RF-EMF measurements did not vary by case-control status. By comparing the self-reports to the geocoded data, we discovered that the cases tended to underestimate the distance from mobile phone base stations differentially from the controls ( P = 0.073). The interpretation of our findings is compromised by the limited study size, particularly in the analysis of the individual lymphoma subtypes, and the unavailability of the spatial coordinates of radio-television transmitters. Nonetheless, our results do not support the hypothesis of a link between environmental exposure to RF-EMF from mobile phone base stations and risk of lymphoma subtypes.

Bullous pemphigoid induced by m-TOR inhibitors in renal transplant recipients.

BACKGROUND: Bullous pemphigoid (BP) is an acquired autoimmune disease, with typical histology and immune pathological findings, which might be associated with drug therapy. The list of responsible drugs increases every year, but a current literature revision do not include the mammalian target of rapamycin (mTOR) inhibitors. By converse, bullous pemghigoid cases have been described in renal transplant recipients and associated with the allogenic graft itself, causing a cross reaction against the skin, or unbalancing the immune response, through a chronic cell-mediated suppression, non-specifically favouring the autoantibody production. OBJECT AND RESULTS: Two cases of BP occurred, respectively, 10 days to 2 months after the addition to their current regimen of everolimus in a 35-year-old woman and sirolimus in a 65-year-old man. The graft functionality was within normal range. General corticosteroids therapy resistance, immediate improvement after drug discontinuation (dechallenge) and relapse after re-exposure (rechallenge) were striking criteria supporting a causative role of the drugs, grouped in the mTOR inhibitors class. CONCLUSIONS: The diagnosis of drug-induced events is crucial for early management, and particularly bullous eruptions affect patients' health and quality of life. Additional research is necessary to confirm the m-TOR inhibitors association, which exploit the possible mechanisms and eventually point out preventive measures.

New chemotherapeutic strategies against malaria, leishmaniasis and trypanosomiases.

Due to the persistent lack of suitable vaccines, chemotherapy remains the only option for the treatment of patients infected by protozoan parasites. However, most available antiparasitic drugs have serious disadvantages, ranging from high cost and poor compliance to high toxicity and rapid induction of resistance. In recent decades basic research laboratories identified a considerable number of promising new molecules, but their development has not been pursued in depth by pharmaceutical firms because of poor prospects of economic return. The establishment of adequately funded public-private partnerships is currently reversing the trend. This review deals with new drugs against Plasmodium, Leishmania and Trypanosoma parasites, focusing on the molecules that are in the most advanced stage of development. The purpose of this article is to provide the reader with a panoramic view of the updated literature on the challenges and strategies of contemporary antiprotozoal drug research, paying the due attention to the already published reviews.

New antimicrobial frontiers.

New antimicrobials able to counteract bacterial resistance are needed to maintain the control of infectious diseases. The last 40 years have seen the systematic tailoring and refinement of previously identified antibiotics, to produce a multitude of semi-synthetic derivatives that share their mechanism of action with the original molecules. The major limit of this approach is the emergence of multi- and cross-resistant bacterial strains, favoured by the selective pressure inherent to the targeting of specific enzymes. The most promising new strategies aim to the development of molecules that, targeting essential bacterial structures instead of specific enzymatic activities, achieve infection control without enforcing a selective pressure on bacteria. This review, based on the consultation of the up-to-date literature, deals with antimicrobial peptides and some antivirulence factors.

Estimates of HIV burden in emergencies.

OBJECTIVE: To quantify the proportion of people living with HIV who are being affected by emergencies. METHODS: Emergencies were defined as conflict, natural disaster and/or displacement. Country-specific estimates of populations affected by emergencies were developed based on eight publicly available databases and sources. These estimates were calculated as proportions and then combined with updated country-level HIV estimates for the years 2003, 2005 and 2006 to obtain estimates of the number of men, women and children living with HIV who were also affected by emergencies. RESULTS: In 2006, 1.8 (range 1.3-2.5) million people living with HIV (PLHIV) were also affected by conflict, disaster or displacement, representing 5.4% (range 4.0-7.6%) of the global number of PLHIV. In the same year, an estimated 930 000 (range 660 000-1.3 million) women and 150 000 (range 110 000-230 000) children under 15 years living with HIV were affected by emergencies. In emergency settings, the estimated numbers of PLHIV in 2003 and 2005 were 2.6 million (range 2.0-3.4 million) and 1.7 million (range 1.4-2.1 million), respectively, representing 7.9% and 5.1% of the global number of PLHIV). CONCLUSIONS: These estimates provide a rationale to ensure that HIV interventions are integrated into rapid assessment of all emergency and preparedness and response plans to prevent HIV infections and address excess suffering, morbidity and mortality among these often overlooked vulnerable groups.

Phenotypic and genotypic characterization of Pseudomonas aeruginosa from cystic fibrosis patients.

Pseudomonas aeruginosa accounts for about one half of all pulmonary infections of cystic fibrosis (CF) patients. In this study, we analyzed 135 P. aeruginosa strains isolated from the expectorations of 55 CF adult patients attending a CF referral center over a period of five years. We assessed the genotype of the strains by pulsed-field gel electrophoresis (PFGE) and analyzed some phenotypic characteristics, such as O serotype, enzyme and mucous production, antibiotics susceptibility, and motility. PFGE allowed the typification of 97.1% of strains, revealing the presence of nine different genomic patterns. The pattern indicated as B was the most frequent, whereas patterns H and I were the most uncommon. Serotyping failed to identify 37.8% of strains and 29 out of 55 patients harbored almost one non-typable (NT) strain. During the five years of the study, we observed a progressive reduction of O6 and O10 types, but an increase of the O1 type and of NT strains. Most strains produced protease, hemolysin, and gelatinase, and were mobile. Several patients harbored the same serotype or genotype in sequential isolates, though characterized by a different susceptibility to antimicrobials. We did not observe a relationship between bacterial genotype and phenotype. This could be due to the fact that PFGE is not sensitive enough to detect subtle genotypic differences. The epidemiological importance of the genotypic characterization of bacteria-colonizing CF subjects and the surveillance measures to be adopted in CF centers are briefly discussed.

Streptococcus agalactiae in pregnant women: phenotypic and genotypic characters.

OBJECTIVE: Streptococcus agalactiae (GBS) is considered a leading cause of neonatal sepsis. We evaluated the phenotypic and genotypic characters of 73 S. agalactiae strains isolated from different women at the 35-37 weeks of pregnancy. METHODS: Isolates were characterized by serotyping (direct agglutination) and by pulsed-field-gel-electrophoresis (PFGE). Resistance to antimicrobials (penicillin, macrolides, lincosamides, quinolones and tetracyclines) was assessed. RESULTS: All isolates were serologically typeable and ascribable to one of the six tested serotypes (Ia, Ib, II, III, IV, and V) and many strains of the same serotype were genetically heterogeneous. Strains belonging to serotypes III, V and Ia were the most prevalent and the most resistant to macrolides. CONCLUSIONS: This work reports GBS colonization rate (about 18%) and the prevalent capsular serotypes among pregnant women in Turin (Italy). Penicillin and erythromycin can be still considered the first and second choice drugs for prophylaxis and treatment of early-onset GBS infections in our district. The relevance of phenotypic and genotypic characterization of strains to monitor and control Streptococcus agalactiae infections is briefly discussed.

Pseudomonas aeruginosa and Burkholderia cenocepacia infections in patients affected by cystic fibrosis: serum resistance and antibody response.

Pseudomonas aeruginosa and Burkholderia cenocepacia are opportunistic pathogens causing important chronic pulmonary infections in patients affected by cystic fibrosis (CF). The interplay of bacterial and host factors involved in the establishment and evolution of these infections needs further clarification. We investigated the susceptibility of P. aeruginosa and B. cenocepacia derived from CF patients or from the environment to hyperimmune sera obtained from the same CF patients and evaluated the amount of specific antibodies present in these sera. Our data indicate that the bactericidal activity of human serum against these two bacteria is mostly complement-mediated, and that the mucous layer probably confers serum-resistance to B. cenocepacia. The mean amount of antibodies against P. aeruginosa was higher than that against B. cenocepacia. The contribution of these data to the assessment of the importance of the humoral immune response in CF pulmonary infections by Pseudomonas and Burkholderia is briefly discussed.

In vitro and in vivo immune stimulating effects of a new standardized Echinacea angustifolia root extract (Polinacea).

Polinacea is a new standardized hydroethanolic extract obtained from Echinacea angustifolia roots containing echinacoside (>4%), the high molecular weight polysaccharide IDN 5405 (>5%) and a isobutylamide fraction (<0.1%). For in vitro tests, a bacterial lipopolysaccharide-free (LPS-free) Polinacea has been prepared in order to avoid non-specific responses of immunocompetent cells. LPS-free Polinacea enhanced the immune functions as highlighted by the proliferation rate and gamma-interferon production in murine T-lymphocyte cell cultures stimulated by anti-CD3. LPS-free Polinacea did not have a direct role on macrophage response as measured in the nitric oxide production test using the J774 macrophage cells line. In vivo, Polinacea showed an immune stimulating activity by reducing the Candida albicans induced mortality both in normal and in cyclosporin A-treated mice.

Leishmaniasis of the lip in a patient with Down's syndrome.

Cutaneous leishmaniasis is an endemic protozoan infection in Sardinia, one of the major islands of the Mediterranean Basin. The main causative strain in this country is Leishmania infantum, which rarely involves mucocutaneous areas, but has the potential to cause visceral leishmaniasis. An atypical leishmaniasis involving the inferior lip of a 57-year-old female with Down's syndrome was observed at the Dermatology Department of Cagliari (italy). The diagnosis was mainly based upon histopathological examination, revealing intra- and extra-cellular leishmania amastigotes. The leishmania infantum zymodeme MON-111 was identified by isoenzymatic characterization. Laboratory investigations revealed a normal complete blood count and biochemistry profile, except for an inverted CD4/CD8 ratio. Treatment with meglumine antimoniate 60 mg/kg/day (Glucantime) intramuscularly for 15 days, followed by intralesional administration 1 ml weekly for 4 weeks led to complete recovery. No relapses were observed at 6-month follow-up. The unusual localization is likely to be a reflection of the uncommon site of inoculation of the protozoa, transmitted by bites from flying vectors. Nevertheless, the presence of Down's syndrome in our patient may have contributed to the atypical presentation by traumatic exacerbation of the lesion, due to repeated auto-induced microtraumas of the inferior lip accompanied by subclinical immunodeficiency. In fact, the specific immune response to Leishmania infection depends on a host-cell-mediated immune response, reported as defective in Down's syndrome patients. Differential diagnosis and early detection of the infection are necessary in order to start effective treatment and prevent more serious complications.

Cryptic 1p36.3/6q25.2 translocation in three generations ascertained through a foetus with IUGR and cerebral malformations.

Here we describe a foetus with intrauterine growth retardation (IUGR), cerebral malformations and a 46,XY,der(1),t(1;6)(p36.3;q25.2) karyotype owing to a familial cryptic translocation segregating in three generations. A balanced translocation was present in the mother, the maternal uncle, the aunt and the grandmother. A female first cousin with dysmorphisms, hydrocephalus and mental retardation was a carrier of a partial trisomy 1p and a partial monosomy 6q. Multiple miscarriages were present in the family pedigree. Parents of the foetus had three other pregnancies: a male with a balanced translocation, and two foetuses with 1p36.3-pter monosomy and 6q25.2-qter trisomy.

Psoriasis is associated with a SNP haplotype of the corneodesmosin gene (CDSN).

A psoriasis susceptibility locus has been mapped to the HLA region in the proximity of the HLA-C locus. This critical region also contains the CDSN gene coding for the corneodesmosin protein. In a case-control association study of psoriasis in the Sardinian population, we analyzed the allele distribution of eight intragenic SNPs (positions 619, 767, 1215, 1118, 1236, 1243, 1331, 1593) of the CDSN gene and the six haplotypes that are coded by these SNPs. Our study showed that these CDSN haplotypes are very stable and well-conserved in the Sardinian population. The CDSN2 haplotype was found to be associated with susceptibility to psoriasis. The association did not depend upon any one of the intragenic SNPs taken separately. At the HLA-C locus, the Cw6 and Cw7 alleles were dragged along by linkage disequilibrium with the CDSN2 haplotype and only revealed a trend towards association with the disease. Therefore, the intragenic SNPs of the CDSN gene and the HLA-Cw6 and Cw7 alleles are not directly involved in susceptibility to psoriasis. However, the strong association of the CDSN2 haplotype suggests a possible role for the CDSN gene and its chromosome region in susceptibility to psoriasis.

Gram-negative bacterial toe web infection: a survey of 123 cases from the district of Cagliari, Italy.

BACKGROUND: Foot intertrigo is mostly caused by dermatophytes and yeasts, less frequently by gram-positive and gram-negative bacteria. Nevertheless, the importance of polymicrobial infections and especially colonizations of Pseudomonas aeruginosa can cause therapy problems in relation to antibiotic resistance and the risk of potentially lethal complications. OBJECTIVE: The aim of this study was to evaluate the main epidemiologic and clinical features of intertrigo from gram-negative bacteria, the function of promoting factors, and the measures taken to treat and prevent this disorder. METHODS: Between 1989 and 1998, 123 cases of intertrigo from gram-negative bacteria were observed at the Cagliari University Dermatology Department. Routine clinical and blood examinations, repeated bacterioscopic and mycologic examinations, cultures aimed at identifying the responsible bacteria, and antibiograms were performed. RESULTS: P aeruginosa was found to be the prevailing pathogen, both alone and associated with other gram-negative bacteria (such as Escherichia coli, Proteus mirabilis, Morganella morganii) and gram-positive bacteria. Clinical manifestations were similar in the majority of patients: erythema, vesicopustules, erosions, and marked maceration caused by abundant, malodorous exudate. Lesions affected the interdigital spaces of both feet and frequently extended to the planta and the back of the toes. Patients complained of burning and pain. Successful therapies were achieved with combined topical and systemic treatment; to avoid the risk of antimicrobial resistance, the choice of the active antibiotic was guided by antibiograms. CONCLUSION: In all symptomatic toe web infections, the presence of gram-negative germs, such as P aeruginosa, should be investigated to avoid the risk of treatment failures and more severe local or systemic complications.

Interaction of Bartonella henselae with the murine macrophage cell line J774: infection and proinflammatory response.

Bartonella henselae is the causative agent of cat scratch disease (CSD), a self-limiting condition characterized by a subacute regional lymphadenopathy that may develop into disseminated bartonellosis in immunocompromised subjects. Mice experimentally infected with B. henselae display typical liver and spleen granulomas rich in T cells and macrophages. So far there are no data on the interaction between bartonellae and macrophages. In order to clarify this topic, we investigated the interaction of B. henselae with J774, a mouse macrophage cell line. Analysis of bacterial uptake by functional assays and transmission electron microscopy indicates that bartonellae can enter and survive inside J774. Entry occurred within 30 min postinfection and reached a plateau at 160 min. Infection of J774 was followed by a dose-dependent release of the proinflammatory cytokines tumor necrosis factor alpha, interleukin 1beta (IL-1beta), and IL-6. Bartonellae persisted intracellularly without loss of viability for at least 8 h, and their number slightly decreased 24 h postinfection. Gamma interferon (IFN-gamma) treatment of J774 significantly decreased the number of recoverable bacteria at 8 and 24 h. This enhancement of macrophage bactericidal activity was associated with nitric oxide (NO) release and was prevented by the addition of the competitive inhibitor of NO synthesis N(G)-monomethyl L-arginine. These findings suggest that IFN-gamma-mediated activation of macrophages may be important for the clearing of B. henselae infection and that anti-B. henselae microbicidal activity of IFN-gamma-activated macrophages is mediated to a large extent by NO production.

Macrolide resistance in group A streptococci.

Two hundred and twenty one Streptococcus pyogenes isolates collected from throat swabs of untreated children with uncomplicated pharyngotonsillitis living in two centres situated in the north of Italy were tested to evaluate their macrolide resistance phenotype. Isolates were also typed for T protein and assayed for opacity factor (OF) and protease production. Resistance to macrolides was found to be similar in the two centres. Fifty-one point two per cent of Torino strains and 43.5% of Pinerolo strains were not inhibited by erythromycin. Resistant strains belonged to one of three phenotypes: CR, constitutive resistance (37.9 and 42.5% in Torino and Pinerolo, respectively); IR, inducible resistance (40.9 and 17. 5%); NR, new resistance phenotype (21.2 and 40%). All the resistant and some of the susceptible strains were analysed by pulsed-field gel electrophoresis and genomic patterns were defined on the basis of band size and number. Five DNA profiles were found among erythromycin-resistant strains: three patterns characterized the NR resistance phenotype and one each the IR and CR phenotypes. The distribution of resistant strains according to their genomic patterns appears to be related to the resistance phenotype and only in some cases to the T serotype of bacteria. We conclude that the S. pyogenes strains analysed are genetically heterogeneous and therefore the high rate of erythromycin resistance observed is not caused by the spread of a single clone nor is it related to a particular serotype.

Lack of correlation between morphometric analysis and presence of microsatellite alterations in proliferative ductal lesions of the breast.

OBJECTIVE: To apply morphometric studies using an image analyzer to a previously reported group of proliferative duct lesions and to compare results to see if there was a correlation between nuclear size range and monoclonality. STUDY DESIGN: Fifteen proliferative lesions of the breast from 12 subjects who had no history of breast malignancy were retrieved from archival pathology specimens. Evidence of monoclonality was studied using a panel of polymerase chain reaction primers to examine microsatellite alterations on microdissected paraffin-embedded specimens. Variation in nuclear size was studied using an image analyzer. RESULTS: Of six proliferative breast lesions with demonstrated genetic instability, three showed cytologic evidence of uniformity in nuclear size, a cytologic feature of malignancy. One of the six, which showed microsatellite alterations at three loci, demonstrated a wide range of nuclear size variation. Of the eight proliferative lesions that showed no genetic instability, three showed very uniform nuclear size, and five showed significant variations in nuclear size. One lesion, which fell into the "uncertain but probably genetic instable" category, showed diverse nuclear size ranges. CONCLUSION: This study demonstrated that there is no correlation between monoclonality and monomorphic cell cytology of histologic proliferative breast lesions.

Human monocytes constitutively express membrane-bound, biologically active, and interferon-gamma-upregulated interleukin-15.

Interleukin-15 (IL-15) is a potent regulator of T-, B-, and natural killer cell proliferation and displays unusually tight controls of secretion. Even though IL-15 mRNA is constitutively expressed in monocytes/macrophages and is upregulated by a variety of stimuli, evidence for IL-15 cytokine secretion is only found exceptionally, eg, conditions of pathological, chronic inflammation. This raises the possibility that monocytes express membrane-bound IL-15 rather than secrete it. The current study explores this hypothesis. We demonstrate here that biologically active IL-15 is indeed detectable in a constitutively expressed, membrane-bound form on normal human monocytes, as well as on monocytic cell lines (MONO-MAC-6, THP-1, and U937), but not on human T or B cells (MT4, M9, C5966, JURKAT, DAUDI, RAJI, and Epstein-Barr virus-immortalized B-cell clones). Furthermore, cell surface-bound IL-15 is upregulated upon interferon-gamma stimulation. Interestingly, monocyte/macrophage inhibitory cytokines such as IL-4 and IL-13 fail to downregulate both constitutive and induced cell-surface expression of IL-15. Membrane-bound IL-15 does not elute with acetate buffer or trypsin treatment, suggesting that it is an integral membrane protein and that it is not associated with the IL-15 receptor complex. Finally, membrane-bound IL-15 stimulates T lymphocytes to proliferate in vitro, indicating that it is biologically active. These findings enlist IL-15 in the fairly small family of cytokines for which the presence of a biologically active membrane-bound form has been demonstrated (eg, IL-1, tumor necrosis factor-alpha, and IL-10) and invites the speculation that most of the biological effects of IL-15 under physiological conditions are exerted by the cell surface-bound form.

Interleukin-15 activates proinflammatory and antimicrobial functions in polymorphonuclear cells.

Interleukin-15 (IL-15) is a recently discovered cytokine produced by a wide range of different cell types including fibroblasts, keratinocytes, endothelial cells, and macrophages in response to lipopolysaccharide or microbial infection. This suggests that IL-15 may play a crucial role in the activation of phagocytic cells against pathogens. We studied polymorphonuclear leukocyte (PMN) activation by IL-15, evaluated as enhancement of PMN anti-Candida activity as well as IL-8 production, following stimulation with the cytokine. The PMN response to IL-15 depends on binding to the IL-15 receptor. Our experiments show that binding of a biotinylated human IL-15-immunoglobulin G2b IgG2b fusion protein was competed by the addition of human recombinant IL-15 (rIL-15) or of human rIL-2, suggesting that IL-15 binding to PMN might involve the IL-2Rbeta and IL-2Rgamma chains, which have been shown to be constitutively expressed by PMN. In addition, we show by reverse transcription-PCR and by flow cytometry with a specific anti-IL-15Ralpha chain monoclonal antibody that PMN express the IL-15Ralpha chain at the mRNA and protein levels. Incubation with IL-15 activated PMN to secrete the chemotactic factor IL-8, and the amount secreted was increased by costimulation with heat-inactivated Candida albicans. In addition, IL-15 primed the metabolic burst of PMN in response to formyl-methionyl-leucyl-phenylalanine but was not sufficient to trigger the respiratory burst or to increase the production of superoxide in PMN exposed to C. albicans. IL-15 also increased the ability of PMN to phagocytose heat-killed C. albicans organisms in a dose-dependent manner, without opsonization by antibodies or complement-derived products. In the same concentration range, IL-15 was as effective as gamma interferon (IFN-gamma) and IL-2 in increasing the C. albicans growth-inhibitory activity of PMN. Taken together, these results suggest that IL-15 is a potent stimulant of both proinflammatory and antifungal activities of PMN, activating several antimicrobial functions of PMN involved in the cellular response against C. albicans.

Evaluation of the immune response in visceral leishmaniasis.

Detection of parasites in culture or by microscopy is still necessary to make diagnosis of visceral leishmaniasis (VL). Serological methods still need assessment, as they are quick but not very sensitive, especially in immunosuppressed subjects. This paper compares the results obtained with three serological methods (indirect immunofluorescence test (IFAT), direct agglutination test (DAT), and enzyme-linked immunosorbent assay (ELISA) and the specific cell-mediated immune response, evaluated as proliferation and IFN-gamma production by peripheral blood lymphocytes (PBL) following stimulation with heat-killed L. infantum promastigotes. PBL and sera were obtained from 10 healthy donors, 3 VL patients in acute phase, and 3 patients recovering after two glucantim treatment courses. No false positive results were observed with the serological methods. IFAT can be considered the most sensitive and best suited for follow-up, as it allowed a good discrimination between the acute and remission phase. DAT did not discriminate between healthy donors and remission-phase patients, whereas ELISA is unsuited for follow-up, as it did not show any significant difference between remission- and acute-phase patients. Assessment of the cellular response is not recommended for making a diagnosis, because false positive results are frequent. However, a strong cellular response in a patient stands for a successful treatment. IFN-gamma titration is preferable to the proliferation test, because it gives earlier results and does not require the use of radioactive isotopes.