Interleukin-18 Is an Essential Element in Host Resistance to Experimental Group B Streptococcal Disease in Neonates

Previous studies demonstrated that interleukin-12 (IL-12)-dependent gamma interferon (IFN-γ) responses have a major role in restricting in vivo bacterial growth during infection of mice with group B streptococci (GBS), important human pathogens. Like IL-12, IL-18 is a potent IFN-γ inducer. The role of IL-18 in experimental GBS infection was investigated here. Significant elevations of IL-18 levels over baseline values were detected in plasma samples from neonatal mice rendered septic with GBS. Neutralization of IL-18 significantly increased mortality and bacterial burden (P < 0.05). In contrast, administration of recombinant IL-18 (rIL-18) before or after GBS challenge remarkably improved survival and decreased blood colony counts, in association with increased IFN-γ production by spleen cells. The beneficial effects of rIL-18 were counteracted by administration of neutralizing anti-IFN-γ monoclonal antibodies, indicating that the effects of IL-18 were mediated by IFN-γ. Finally, low rIL-18 doses that had no effect of their own on bacterial burden could act in synergy with rIL-12 to protect neonatal mice during GBS infection. Collectively, our data indicate that IL-18 responses have an important role in host defenses against GBS and that rIL-18 may be useful in alternative strategies to treat neonatal GBS disease

Bacteroides fragilis-Derived Lipopolysaccharide Produces Cell Activation and Lethal Toxicity via Toll-Like Receptor 4

Bacteroides fragilis, which is part of the normal intestinal flora, is a frequent cause of serious disease, especially in diabetic and surgical patients. In these conditions, B. fragilis lipopolysaccharide (LPS) is likely to play a major pathophysiologic role. B. fragilis LPS is structurally different from classical enterobacterial LPS, whose biological activities are mediated by Toll-like receptor 4 (TLR4) activation. The ability of B. fragilis LPS to activate TLR4 and TLR2 was investigated here, since evidence on this issue is scarce and controversial. Each of four different protein-free B. fragilis LPS preparations could induce interleukin-8 responses in cells cotransfected with TLR4/CD14/MD2 but not TLR4/CD14 alone. Two of the preparations also induced cytokine production in cells cotransfected with TLR2/CD14 or in peritoneal macrophages from TLR4 mutant C3H/HeJ mice. Both of these activities, however, were lost after repurification with a modified phenol reextraction procedure. Importantly, all preparations could induce endotoxic shock in TLR2-deficient mice, but not in TLR4 mutant C3H/HeJ mice. Consistent with these findings, anti-TLR4 and anti-CD14, but not anti-TLR2, antibodies could inhibit B. fragilis LPS-induced cytokine production in human monocytes. Collectively, these results indicate that B. fragilis LPS signals via a TLR4/CD14/MD2-dependent pathway, and it is unable to activate TLR2. Moreover, our data document the occurrence of TLR2-activating contaminants even in highly purified B. fragilis LPS preparations. This may explain earlier contradictory findings on the ability of B. fragilis LPS to activate cells in the absence of functional TLR4. These data may be useful to devise strategies to prevent the pathophysiologic changes observed during B. fragilis sepsis and to better understand structure-activity relationships of LPS

IFN-alpha/beta signaling is required for polarization of cytokine responses toward a protective type 1 pattern during experimental cryptococcosis

The antiviral activities of type I IFNs have long been established. However, comparatively little is known of their role in defenses against nonviral pathogens. We examined here the effects of type I IFNs on host resistance against the model pathogenic yeast Cryptococcus neoformans. After intratracheal or i.v. challenge with this fungus, most mice lacking either the IFN-alpha/beta receptor (IFN-alpha/beta R) or IFN-beta died from unrestrained pneumonia and encephalitis, while all wild-type controls survived. The pulmonary immune response of IFN-beta/BR-/- mice was characterized by increased expression of IL-4, IL-13, and IL-10, decreased expression of TNF-alpha, IFN-gamma, inducible NO synthetase, and CXCL10, and similar levels of IL-12 mRNA, compared with wild-type controls. Histopathological analysis showed eosinophilic infiltrates in the lungs of IFN-alpha/beta(-/-) mice, although this change was less extensive than that observed in similarly infected IFN-gamma R-deficient animals. Type I IFN responses could not be detected in the lung after intratracheal challenge. However, small, but statistically significant, elevations in IFN-beta levels were measured in the supernatants of bone marrow-derived macrophages or dendritic cells infected with C neoformans. Our data demonstrate that type I IFN signaling is required for polarization of cytokine responses toward a protective type I pattern during cryptococcal infection

The Oncogenic Activity of RET Point Mutants for Follicular Thyroid Cells May Account for the Occurrence of Papillary Thyroid Carcinoma in Patients Affected by Familial Medullary Thyroid Carcinoma

Activating germ-line point mutations in the RET receptor are responsible for multiple endocrine neoplasia type 2-associated medullary thyroid carcinoma (MTC), whereas somatic RET rearrangements are prevalent in papillary thyroid carcinomas (PTCs). Some rare kindreds, carrying point mutations in RET, are affected by both cancer types, suggesting that, under specific circumstances, point mutations in RET can drive the generation of PTC. Here we describe a family whose siblings, affected by both PTC and MTC, carried a germ-line point mutation in the RET extracellular domain, converting cysteine 634 into serine. We tested on thyroid follicular cells the transforming activity of RET(C634S), RET(K603Q), another mutant identified in a kindred with both PTC and MTC, RET(C634R) a commonly isolated allele in MEN2A, RET(M918T) responsible for MEN2B and also identified in kindreds with both PTC and MTC, and RET/PTC1 the rearranged oncogene that characterizes bona fide PTC in patients without MTC. We show that the various RET point mutants, but not wild-type RET, scored constitutive kinase activity and exerted mitogenic effects for thyroid PC Cl 3 cells, albeit at significantly lower levels compared to RET/PTC1. The low mitogenic activity of RET point mutants paralleled their reduced kinase activity compared to RET/PTC. Furthermore, RET point mutants maintained a protein domain, the intracellular juxtamembrane domain, that exerted negative effects on the mitogenic activity. In conclusion, RET point mutants can behave as dominant oncogenes for thyroid follicular cells. Their transforming activity, however, is rather modest, providing a possible explanation for the rare association of MTC with PTC

An Italian prospective multicenter survey on patients suspected of having non-celiac gluten sensitivity.

Background: Non-celiac gluten sensitivity (NCGS) is still an undefined syndrome with several unsettled issues despite the increasing awareness of its existence. We carried out a prospective survey on NCGS in Italian centers for the diagnosis of gluten-related disorders, with the aim of defining the clinical picture of this new syndrome and to establish roughly its prevalence compared with celiac disease. Methods: From November 2012 to October 2013, 38 Italian centers (27 adult gastroenterology, 5 internal medicine, 4 pediatrics, and 2 allergy) participated in this prospective survey. A questionnaire was used in order to allow uniform and accurate collection of clinical, biochemical, and instrumental data. Results: In total, 486 patients with suspected NCGS were identified in this 1-year period. The female/male ratio was 5.4 to 1, and the mean age was 38 years (range 3–81). The clinical picture was characterized by combined gastrointestinal (abdominal pain, bloating, diarrhea and/or constipation, nausea, epigastric pain, gastroesophageal reflux, aphthous stomatitis) and systemic manifestations (tiredness, headache, fibromyalgia-like joint/muscle pain, leg or arm numbness, 'foggy mind,' dermatitis or skin rash, depression, anxiety, and anemia). In the large majority of patients, the time lapse between gluten ingestion and the appearance of symptoms varied from a few hours to 1 day. The most frequent associated disorders were irritable bowel syndrome (47%), food intolerance (35%) and IgE-mediated allergy (22%). An associated autoimmune disease was detected in 14% of cases. Regarding family history, 18% of our patients had a relative with celiac disease, but no correlation was found between NCGS and positivity for HLA-DQ2/-DQ8. IgG anti-gliadin antibodies were detected in 25% of the patients tested. Only a proportion of patients underwent duodenal biopsy; for those that did, the biopsies showed normal intestinal mucosa (69%) or mild increase in intraepithelial lymphocytes (31%). The ratio between suspected NCGS and new CD diagnoses, assessed in 28 of the participating centers, was 1.15 to 1. Conclusions: This prospective survey shows that NCGS has a strong correlation with female gender and adult age. Based on our results, the prevalence of NCGS seems to be only slightly higher than that of celiac disease

PRODUCTION OF CHARMED MESONS IN Z DECAYS

The production of charmed mesons D0(-), D+/-, and D*+/- is studied in a sample of 478,000 hadronic Z decays. The production rates are measured to be GAMMA(Z --> D*+/- X)/GAMMA(had) = 0.187 +/- 0.015 (exp.) +/- 0.013 (BR), GAMMA(Z --> D+/- X) = 0.251 +/- 0.026 (exp.) +/- 0.025 (BR), GAMMA(Z --> D0(-) X)/GAMMA(had) = 0.518 +/- 0.052 (exp.) +/- 0.035 (BR), where the errors from this analysis are separated from those coming from the D branching ratios (BR). The D *+/momentum distribution is extracted separately for Z --> cc and Z --> bbBAR events with the help of event shape variables. It is consistent with the prediction of the JETSET Monte Carlo program after adjustment of the charm fragmentation function. Constraining the shape of the Z --> bbBAR contribution, the average fraction of the beam energy taken by a D* meson produced in the fragmentation of a charm quark is extracted by a parametric fit to be [X(E)]c = 0.495 +/- 0.011 +/- 0.007. Evidence for D**0 (D1(2420)0 and/or D2*(2460)0) production is found in the D*+/-pi-/+ channel, accounting for a fraction (18 +/- 5 +/- 2)% of all D*+/- production. The relative production of vector and pseudoscalar mesons is dicussed, together with the possible effects of D** production. The c-quark forward-backward Z-pole asymmetry is determined from that of high momentum D*+/- to be A(FB)0,c = (7.7 +/- 4.4)%

A STUDY OF BOSE-EINSTEIN CORRELATIONS IN E+E- ANNIHILATION AT 91 GEV

This paper describes a study of Bose-Einstein correlations made using the ALEPH detector at LEP. The correlations are found to enhance the two particle differential cross section for pairs of identical pions by a factor which can be roughly parametrized by R(Q) = 1 + lambda exp(-Q2-sigma(2)), where Q is the difference in the 3-momenta of the two pions in their centre of mass frame, lambda = 0.51 +/- 0.04 +/- 0.11 and sigma = 3.3 +/- 0.2 +/- 0.8 GeV-1, which corresponds to a source size of 0.65 +/- 0.04 +/- 0.16 fm. The large systematic errors on these results reflect their strong dependence on the choice of the reference sample used in the analysis. This problem is believed to occur primarily because of uncertainties in the rates of resonance production and a lack of knowledge about the pion-pion strong interaction. No significant correlations are seen amongst like-charged pion-kaon pairs

K0 production in one prong tau decays

From a sample of about 75000 τ decays identified with the ALEPH detector, K0 production in 1-prong hadronic decays is investigated by tagging the KL0 component in a hadronic calorimeter. Results are given for the final states ντh−K0 and ντh−π0K0 where the h− is separated into π and K contributions by means of the dE/dx measurement in in the central detector. The resulting branching ratios are: (Bτ → ντπ−K0) = (0.88±0.14±0.09)%, (Bτ → ντK−K0) = (0.29±0.12±0.03)%, (Bτ → ντπ−π0K0) = (0.33±0.14±0.07)% aand (Bτ → ντK−π0K0) = (0.05±0.05±0.01)%. The K∗ decay rate in the K0π channel agrees with that in the Kπ0 mode: the combined value for the branching ratio is