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After a brief outline of general aspects of conformal field theories in coordinate space, in a first part we review the solution of the conformal constraints of three- and four-point functions in momentum space in dimensions $d\geq 2$, in the form of conformal Ward identities (CWI's). We center our discussion on the analysis of correlators containing stress-energy tensors $(T)$, conserved currents $(J)$, and scalar operators $(O)$. For scalar four-point functions, we briefly discuss our method for determining the dual conformal solutions of such equations, identified only by the CWI's, and related to the conformal Yangian symmetry, introduced by us in previous work. In correlation functions with $T$ tensors, evaluated around a flat spacetime, the conformal anomaly is characterized by the (non-local) exchange of massless poles in specific form factors, a signature that has been investigated both in free field theory and non-perturbatively, by solving the conformal constraints. We discuss the anomaly effective action, and illustrate the derivation of the CWI's directly from its path integral definition and its Weyl symmetry, which is alternative to the standard operatorial approach used in conformal field theories in flat space. For two- and three-point functions, we elaborate on the matching of these types of correlators to free-field theories. Perturbative realizations of CFTs at one-loop provide the simplest expressions of the general solutions identified by the CWI's, for generic operators $T$, $J$, and scalars of specific scaling dimensions, by an appropriate choice of their field content. In a technical appendix we offer details on the reconstruction of the $TTO$ and $TTT$ correlators in the approach of Bzowski, McFadden and Skenderis, and specifically on the secondary Ward identities of the method, in order to establish a complete match with the perturbative description., 110 pages, 5 Figures. To appear on Physics Reports

Butyrate is a major gut microbiome metabolite that regulates several defense mechanisms against infectious diseases. Alterations in the gut microbiome, leading to reduced butyrate production, have been reported in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A new butyrate releaser, useful for all the known applications of butyrate, presenting physiochemical characteristics suitable for easy oral administration, (N-(1-carbamoyl-2-phenyl-ethyl) butyramide (FBA), has been recently developed. We investigated the protective action of FBA against SARS-CoV-2 infection in the human small intestine and enterocytes. Relevant aspects of SARS-CoV-2 infection were assessed: infectivity, host functional receptor angiotensin-converting enzyme-2 (ACE2), transmembrane protease serine 2 (TMPRSS2), neuropilin-1 (NRP1), pro-inflammatory cytokines expression, genes involved in the antiviral response and the activation of Nf-kB nuclear factor (erythroid-derived 2-like) 2 (Nfr2) pathways. We found that FBA positively modulates the crucial aspects of the infection in small intestinal biopsies and human enterocytes, reducing the expression of ACE2, TMPRSS2 and NRP1, pro-inflammatory cytokines interleukin (IL)-15, monocyte chemoattractant protein-1 (MCP-1) and TNF-α, and regulating several genes involved in antiviral pathways. FBA was also able to reduce the number of SARS-CoV-2-infected cells, and ACE2, TMPRSS2 and NRP1 expression. Lastly, through the inhibition of Nf-kB and the up-regulation of Nfr2, it was also able to reduce the expression of pro-inflammatory cytokines IL-15, MCP-1 and TNF-α in human enterocytes. The new butyrate releaser, FBA, exerts a preventive action against SARS-CoV-2 infection. It could be considered as an innovative strategy to limit COVID-19.

We present a general study of 3-point functions of conformal field theory in momentum space, following a reconstruction method for tensor correlators, based on the solution of the conformal Ward identities (CWI' s), introduced in recent works by Bzowski, McFadden and Skenderis (BMS). We investigate and detail the structure of the CWI's, their non-perturbative solutions and the transition to momentum space, comparing them to perturbation theory by taking QED as an example. We then proceed with an analysis of the $TJJ$ correlator, presenting independent and detailed re-derivations of the conformal equations in the reconstruction method of BMS, originally formulated using a minimal tensor basis in the transverse traceless sector. A careful comparison with a second basis introduced in previous studies shows that this correlator is affected by one anomaly pole in the graviton (T) line, induced by renormalization. The result shows that the origin of the anomaly, in this correlator, should be necessarily attributed to the exchange of a massless effective degree of freedom. Our results are then exemplified in massless QED at one-loop in $d$-dimensions, expressed in terms of perturbative master integrals. An independent analysis of the Fuchsian character of the solutions, which bypasses the 3K integrals, is also presented. We show that the combination of field theories at one-loop - with a specific field content of degenerate massless scalar and fermions - is sufficient to generate the complete non-perturbative solution, in agreement with a previous study in coordinate space. The result shows that free conformal field theories, in specific dimensions, arrested at one-loop, reproduce the general result for the $TJJ$. Analytical checks of this correspondence are presented in $d=3,4$ and $5$ spacetime dimensions[..]., 79 pages, 3 Figures. Final version, with changes in section 8. Accepted for publication in Nuclear Physics B

Nowadays, direct bone anchored systems are an increasingly adopted approach in the therapeutic landscape for amputee patients. However, the percutaneous nature of these devices poses a major challenge to obtain a stable and lasting proper adhesion between the implant surface and the skin. A systematic review was carried out in three databases (PubMed, Scopus, Web of Science) to provide an overview of the innovative strategies tested with preclinical models (in vitro and in vivo) in the last ten years to improve the skin adhesion of direct bone anchored systems. Fifty five articles were selected after screening, also employing PECO question and inclusion criteria. A modified Cochrane RoB 2.0 tool for the in vitro studies and the SYRCLE tool for in in vivo studies were used to assess the risk of bias. The evidence collected suggests that the implementation of porous percutaneous structures could be one of the most favorable approach to improve proper skin adhesion, especially in association with bioactive coatings, as hydroxyapatite, and exploiting the field of nanostructure. Some issues still remain open as (a) the identification and characterization of the best material/coating association able to limit the shear stresses at the interface and (b) the role of keratinocyte turnover on the skin/biomaterial adhesion and integration processes. This journal is

Celiac disease (CD) is a chronic intestinal inflammation caused by gluten ingestion in genetically predisposed individuals. Overt-CD and potential-CD are the two main forms of gluten intolerance in pediatric patients with different grades of intestinal mucosa lesion and clinical management. For overt-CD patients the gluten-free diet is mandatory, while for potential-CD the dietary therapy is recommended only for those subjects becoming clinically symptomatic overtime. To date, specific early biomarkers of evolution to villous atrophy in potential-CD are lacking. We recently observed an expansion of TCRγδ+ T cells and a concomitant disappearance of IL4-producing T cells in the intestinal mucosa of overt-CD patients compared to potential-CD children, suggesting the involvement of these two cells subsets in the transition from potential-CD to overt-CD. In this study, we demonstrated that the intestinal densities of IL4+ T cells inversely correlated with TCRγδ+ T cell expansion (p &lt, 0.005) and with the serum levels of anti-tissue transglutaminase antibodies (p &lt, 0.01). The changes of these two cell subsets strongly correlated with mucosal lesions, according to the histological Marsh classification, as the transition from M0 to M3 lesions was associated with a significant reduction of IL4+ T cells (M0 vs. M1 p &lt, 0.04, M0 vs. M3 p &lt, 0.007) and an increase of TCRγδ+ T cells (M0 vs. M1 p &lt, 0.05, M0 vs. M3 p &lt, 0.0006). These findings strongly suggest that the detection of TCRγδ+ and IL4+ T cells could serve as cellular biomarkers of mucosal lesion and targets of novel immunomodulatory therapies for CD.

Within the human tibiofemoral joint, meniscus plays a key role due to its peculiar time-dependent mechanical characteristics, inhomogeneous structure and compositional features. To better understand the pathophysiological mechanisms underlying this essential component, it is mandatory to analyze in depth the relationship between its structure and the function it performs in the joint. Accordingly, the aim of this study was to evaluate the behavior of both solid and fluid phases of human meniscus in response to compressive loads, by integrating mechanical assessment and histological analysis. Cubic specimens were harvested from seven knee lateral menisci, specifically from anterior horn, pars intermedia and posterior horn; unconfined compressive tests were then performed according to three main loading directions (i.e., radial, circumferential and vertical). Fibril modulus, matrix modulus and hydraulic permeability of the tissue were thence estimated through a fibril-network-reinforced biphasic model. Tissue porosity and collagen fibers arrangement were assessed through histology for each region and related to the loading directions adopted during mechanical tests. Regional and strain-dependent constitutive parameters were finally proposed for the human lateral meniscus, suggesting an isotropic behavior of both the horns, and a transversely isotropic response of the pars intermedia. Furthermore, the histological findings supported the evidences highlighted by the compressive tests. Indeed, this study provided novel insights concerning the functional behavior of human menisci by integrating mechanical and histological characterizations and thus highlighting the key role of this component in knee contact mechanics and presenting fundamental information that can be used in the development of tissue-engineered substitutes. STATEMENT OF SIGNIFICANCE: This work presents an integration to the approaches currently used to model the mechanical behavior of the meniscal tissue. This study assessed in detail the regional and directional contributions of both the meniscal solid and fluid phases during compressive response, providing also complementary histological evidence. Within this updated perspective, both knee computational modeling and meniscal tissue engineering can be improved to have an effective impact on the clinical practice.

The number of total knee and/or hip replacements are expected to exceed 5 million a year by 2030; the incidence of biofilm-associated complications can vary from 1% in primary implants to 5.6% in case of revision. The purpose of this study was to test the ability of sHA-DA, a partially sulphated hyaluronic acid (sHA) functionalized with a dopamine (DA) moiety, to prevent acute bacterial growth in an in vivo model of an intra-operatively highly contaminated implant. Previously, in vitro studies showed that the DA moiety guarantees good performance as binding agent for titanium surface adhesion, while the negatively charged sHA has both a high efficiency in electrostatic binding of positively charged antibiotics, and bone regenerative effects. The in vitro testing also highlighted the effectiveness of the sHA-DA system in inhibiting bacterial spreading through a sustained release of the antibiotic payload from the implant coating. In this study the chemical stability of the sHA-DA to β-ray sterilization was demonstrated, based on evaluation by NMR, SEC-TDA Omnisec and HPLC-MS analysis, thus supporting the approach of terminal sterilization of the coated implant with no loss of efficacy. Furthermore, an in vivo study in rabbits was performed according to UNI EN ISO 10993-6 to assess the histocompatibility of titanium nails pre-coated with sHA-DA. The implants, placed in the femoral medullary cavity and harvested after 12 weeks, proved to be histocompatible and to allow bone growth in adhesion to the metal surface. Finally, an in vivo model of bacterial contamination was set up by injecting 1 mL of bacterial suspension containing 104 or 106 CFU of methicillin-resistant Staphylococcus aureus (MRSA) into the femoral medullary cavity of 30 rabbits. Titanium nails either uncoated or pre-coated with sHA-DA and loaded directly by the surgeon with 5% vancomycin were implanted in the surgical site. After 1 week, only the animals treated with pre-coated nails did not show the presence of systemic or local bacterial infection, as confirmed by microbiology and histology (Smeltzer score). Further insights into the animal model setup are crucial, however the results obtained suggest that the system can be effective in preventing the onset of the bacterial infective process.

We derive and analyze the conformal Ward identities (CWI's) of a tensor 4-point function of a generic CFT in momentum space. The correlator involves the stress-energy tensor $T$ and three scalar operators $O$ ($TOOO$). We extend the reconstruction method for tensor correlators from 3- to 4-point functions, starting from the transverse traceless sector of the $TOOO$. We derive the structure of the corresponding CWI's in two different sets of variables, relevant for the analysis of the 1-to-3 (1 graviton $\to$ 3 scalars) and 2-to-2 (graviton + scalar $\to$ two scalars) scattering processes. The equations are all expressed in terms of a single form factor. In both cases, we discuss the structure of the equations and their possible behaviors in various asymptotic limits of the external invariants. A comparative analysis of the systems of equations for the $TOOO$ and those for the $OOOO$, both in the general (conformal) and dual-conformal/conformal (dcc) cases, is presented. We show that in all the cases the Lauricella functions are homogenous solutions of such systems of equations, also described as parametric 4K integrals of modified Bessel functions., 46 pages, 5 figures

Celiac disease (CD) is a systemic disease that primarily affects the small intestine. The presence of anti-tissue transglutaminase 2 (anti-TG2) antibodies in the serum, as well as the presence of autoimmune phenomena, account for the inclusion of CD among autoimmune diseases. Anti-TG2 autoantibodies are produced at intestinal level, where they are deposited even before they appear in circulation. The pathogenic events that lead to their production are still not completely defined, but a central role seems to be played by gliadin-specific T cells. Interestingly, limited somatic mutations have been observed in VH and VL genes in TG2-specific plasma cells, another important aspect being the biased use of a heavy chain encoded by the VH5 gene. Conflicting data have been produced over the years on the effect of anti-TG2 antibodies on TG2 function. Although the presence of anti-TG2 antibodies in serum is considered a hallmark of CD and relevant from a clinical viewpoint, the role of these autoantibodies in the development of the celiac lesion remains to be defined. In the years, different technical approaches have been implemented to detect and measure intestinal CD-associated autoantibody production. Two aspects can make intestinal anti-TG2 antibodies relevant: from a clinical viewpoint: the first is their proposed ability in potential coeliac patients to predict the development of a full-blown enteropathy; the second is their possible role in revealing a condition of reactivity to gluten in patients with no circulating CD-associated autoantibodies. In fact, the detection of CD-specific autoantibodies production in the intestine, in the absence of serum positivity for the same antibodies, could be suggestive of a very early condition of gluten reactivity; alternatively, it could be not specific for CD and merely attributable to intestinal inflammation. In conclusion, the role of mucosal anti-TG2 antibodies in pathogenesis of CD is unknown. Their presence, the modalities of their production, their gluten dependence render them a unique model to study autoimmunity.

The conformal anomaly in curved spacetime generates a nontrivial anomalous vertex, given by the three-point correlation function $TTT$ of the energy-momentum tensor $T^{\mu\nu}$. We show that a temperature inhomogeneity in a gas of charged massless particles generates, via the $TTT$ vertex, a pressure anisotropy with respect to the axis of the temperature variation. This very particular signature may provide an experimental access to the elusive gravitational coefficient $b$ which determines the anomaly contribution of the Weyl tensor to the trace of the energy-momentum tensor in curved spacetime. We present an estimate of the pressure anisotropy both for fermionic quasiparticles in the solid-state environment of Dirac semimetals as well as for a quark-gluon plasma in relativistic heavy-ion collisions. In both cases, the pressure anisotropy is small compared to the mean thermal pressure., Comment: 9 pages, 2 figures. Revised final version accepted for publication on Physics Letters B

Stress-energy correlation functions in a general Conformal Field Theory (CFT) in four dimensions are described in a fully covariant approach, as metric variations of the quantum effective action in an arbitrary curved space background field. All Conservation, Trace and Conformal Ward Identities (CWIs), including contact terms, are completely fixed in this covariant approach. The Trace and CWIs are anomalous. Their anomalous contributions may be computed unambiguously by metric variation of the exact 1PI quantum effective action determined by the conformal anomaly of $\left\langle T^{\mu\nu}\right\rangle$ in $d = 4$ curved space. This action implies the existence of massless propagator poles in three and higher point correlators of $T^{\mu\nu}$ . The metric variations of the anomaly effective action in its local form in terms of a scalar conformalon field are carried out explicitly for the case of the correlator of three CFT stress-energy tensors, and the result is shown to coincide with the algebraic reconstruction of $\left\langle TTT\right\rangle$ from its transverse, tracefree parts, determined independently by the solution of the CWIs in d dimensional flat space in the momentum representation. This demonstrates that the specific analytic structure and massless poles predicted by the general curved space anomaly effective action are in fact a necessary feature of the exact solution of the anomalous CWIs in any $d = 4$ CFT., Comment: 24 pages, Published version

Background & Aims Potential celiac disease is characterized by positive results from serologic tests for tissue transglutaminase antibodies (anti-TG2) but normal duodenal architecture (Marsh stages 0–1). There is controversy over the best way to manage these patients. We investigated risk factors associated with the development of villous atrophy in children with potential celiac disease. Methods We performed a prospective study of 280 children (ages 2–18 years) in Italy with suspected celiac disease, followed for up to 12 years (range, 18–150 months; median 60 months). The subjects had 2 consecutive positive results from tests for anti-TG2, tested positive for the endomysial antibody (anti-EMA), had total serum levels of immunoglobulin A in the normal range, normal duodenal architecture (Marsh stages 0–1) in 5 biopsies, and HLA DQ2- or DQ8-positive haplotypes. The children underwent serologic tests and clinical analyses every 6 months and a small bowel biopsy was taken every 2 years. A total of 210 patients of the original cohort were assessed at the 9-year follow-up evaluation. We performed multivariate analyses of clinical, genetic, and histologic data to identify factors associated with progression to villous atrophy. Results During the follow-up period, 42 (15%) of 280 children developed villous atrophy, whereas 89 (32%) children no longer tested positive for anti-TG2 or anti-EMA. The cumulative incidence of progression to villous atrophy was 43% at 12 years. In multivariate analysis, the baseline factors most strongly associated with development of villous atrophy were numbers of γδ intraepithelial lymphocyte cells followed by age and homozygosity for the HLA DQB1*02. In discriminant analysis, these baseline factors identified 80% of the children who developed baseline atrophy. Conclusions In a long-term study of 280 children with suspected celiac disease (based on anti-TG2 and anti-EMA) on gluten-containing diets, the cumulative incidence of progression to villous atrophy was 43% over a 12-year period. We identified factors that can be used to identify children at highest risk for villous atrophy. This approach might be used to determine whether children with suspected celiac disease should immediately start a gluten-free diet or be monitored on their regular diet.

Summary In coeliac disease (CD), anti-tissue transglutaminase 2 immunoglobulin (Ig)A antibodies (anti-TG2) are produced and deposited in the intestine. PreventCD (www.preventcd.com) is a European multi-centre study, which investigates the influence of infant nutrition and that of genetic, immunological and other environmental factors on the risk of developing CD. The aim of the current study was to evaluate the appearance of intestinal anti-TG2 deposits in very early intestinal biopsies from at-risk infants and their predictive value for villous atrophy. Sixty-five small bowel biopsies, performed in 62 children, were investigated for the presence of intestinal anti-TG2 extracellular IgA deposits by using double immunofluorescence. The biopsies were performed in the presence of elevated serum levels of CD-associated antibodies and/or symptoms suggesting disease. Deposits of anti-TG2 IgA were present in 53 of 53 CD patients and three of three potential CD patients. In potential CD patients, mucosal deposits showed a patchy distribution characterized by some areas completely negative, whereas active CD patients had uniformly present and evident mucosal deposits. Only one of six patients without CD (negative for serum anti-TG2 and with normal mucosa) had intestinal deposits with a patchy distribution and a weak staining. Two of the 53 CD patients received a definitive diagnosis of CD after a second or third biopsy; mucosal deposits of anti-TG2 IgA were evaluated in all samples. Before developing villous atrophy, both patients had anti-TG2 deposits in normal mucosal architecture, antibodies in one patient being absent in serum. We demonstrated that in CD the intestinal deposits of anti-TG2 are a constant presence and appear very early in the natural history of disease.

Background Exosomes are nanovesicles actively secreted by potentially all cell types, including tumour cells, with the primary role of extracellular systemic communication mediators, both at autocrine and paracrine levels, at short and long distances. Recently, different studies have used exosomes as a delivery system for a plethora of different molecules, such as drugs, microRNAs and proteins. This has been made possible thanks to the simplicity in exosomes engineering, their great stability and versatility for applications in oncology as well as in regenerative medicine. Scope of review The aim of this review is to provide information on the state-of-the-art and possible applications of engineered exosomes, both for cargo and specific cell-targeting, in different pathologies related to the musculoskeletal system. Major conclusions The use of exosomes as therapeutic agents is rapidly evolving, different studies explore drug delivery with exosomes using different molecules, showing an enormous potential in various research fields such as oncology and regenerative medicine. General significance However, despite the significant progress made by the different studies carried out, currently, the use of exosomes is not a therapeutic reality for the considerable difficulties to overcome.

We investigate the emergence of a conformal anomaly pole in conformal field theories in the case of the $TJJ$ correlator. We show how it comes to be generated in dimensional renormalization, using a basis of 13 form factors (the $F$-basis), where only one of them requires renormalization $(F_{13})$, extending previous studies. We then combine recent results on the structure of the non-perturbative solutions of the conformal Ward identities (CWI's) for the $TJJ$ in momentum space, expressed in terms of a minimal set of 4 form factors ($A-$ basis), with the properties of the $F$-basis, and show how the singular behaviour of the corresponding form factors in both basis can be related. The result proves the centrality of such massless effective interactions induced by the anomaly, which have recently found realization in solid state, in the theory of topological insulators and of Weyl semimetals. This pattern is confirmed in massless abelian and nonabelian theories (QED and QCD) investigated at one-loop., Comment: 15 pages, 1 figure, few typos corrections, final version accepted for publication in Physics Letters B

We present a general study of 3-point functions of conformal field theory (CFT) in momentum space, following a reconstruction method for tensor correlators, based on the solution of the conformal Ward identities (CWIs), introduced in recent works. We investigate and detail the structure of the CWIs and their non-perturbative solutions, and compare them to perturbation theory, taking QED and QCD as examples. Exact solutions of CFT's in the flat background limit in momentum space are matched by the perturbative realizations in free field theories, showing that the origin the conformal anomaly is related to efffective scalar interactions, generated by the renormalization of the longitudinal components of the corresponding operators., 5 pages. Proceedings of the Workshop QCD@work 2018, 25-28 June 2018, Matera, Italy

Objective. Most of the recent studies suggest that oats are well tolerated by celiac disease (CD) patients. However, it is still possible that different oat cultivars may display different biological properties relevant for CD pathogenesis. We aimed to investigate biological and immunological properties of two oat varieties, Avena genziana and Avena potenza, in relation to their safety for CD patients. Material and Methods. Phosphorylation of extracellular signal-regulated kinase (ERK) and transepithelial electrical resistance (TEER) were evaluated in CaCo-2 cells treated with peptic–tryptic (PT) digests from the two oats and from gliadin (PTG). With the same PT-digests, duodenal biopsies from 22 CD patients were treated in vitro for 24 h and density of CD25 + cells in lamina propria and of intraepithelial CD3 + T cells was measured, as well as crypt cell proliferation and epithelial expression of interleukin 15. Finally, interferon g (IFN-g) production was measured as evidence of gliadin-specific T-cell activation by PT-digests. Results. In contrast to PTG, oats PT-digests were not able to induce significant increase in ERK phosphorylation and decrease in TEER in CaCo-2 cells. In the organ culture system, oats PTdigests, unlike PTG, did not induce significant increase in crypt enterocyte proliferation, increase in interleukin 15 expression or in lamina propria CD25 + cells. Nevertheless Avena potenza increased intraepithelial T-cell density, while Avena genzianainduced IFN-g production in 3/8 CD intestinal T cell lines. Conclusions. Our data show that Avena genziana and Avena potenza do not display in vitro activities related to CD pathogenesis. Some T-cell reactivity could be below the threshold for clinical relevance.

See editorial on page 284. BACKGROUND & AIMS: The presence of celiac diseaseassociated autoantibodies (antiendomysium and antitissue transglutaminase [anti-TG2]) with normal jejunal mucosa indicate potential celiac disease. We performed a prospective, 3-year cohort study to determine the natural history of potential celiac disease in children. METHODS: The study included 106 children with potential celiac disease, based on serology analysis and normal duodenal architecture. All but 2 carried the HLA-DQ2 and/or DQ8 haplotype. In all children, every 6 months, growth, nutritional parameters, celiac disease serology, and autoimmunity were investigated. In biopsies, intraepithelial-, CD3-, and lamina propria CD25-positive cells were counted; duodenal deposits of anti-TG2 immunoglobulin A were detected. Biopsy analysis was repeated after 2 years on patients with persistent positive serology and/or symptoms. RESULTS: Celiac disease was detected primarily in firstdegree relatives and patients with autoimmune disorders (40.6%). A gluten-free diet was prescribed to 20/106 patients because of symptoms, which were relieved in only 11. Eightynine of the 106 patients entered the follow-up study, with normal daily consumption of gluten. During the follow-up antibodies disappeared in 14.6% and fluctuated in 32.6%. Villous atrophy was observed in 12/39 patients (30.8%) who underwent a repeat biopsy. CONCLUSIONS: Most children with potential celiac disease remain healthy. After 3 years, approximately 33% of patients develop villous atrophy. Intestinal deposits of anti-TG2 IgA identify children at risk for villous atrophy.

Bone metastases impair general health status, quality of life and survival of patients. Electrochemotherapy (ECT), which combines electroporation (EP) and the administration of anticancer drugs, has been recently introduced into clinical practice for the local treatment of solid tumours. In the present study, the ability of EP with bleomycin (Bleo) to induce MRMT-1 rat breast cancer cell death was investigated in vitro. Then, an in vivo model for bone metastases was set up by the inoculation of MRMT-1 cells in rat proximal tibia. 7 days after tumour induction the animals were treated with Bleo, EP, Bleo followed by EP (ECT), or left untreated. ECT eliminated the tumour in 6 out of 8 (75 %) treated metastases. Radiological evaluation showed that the Honore score in ECT-treated animals was significantly lower when compared with the other groups (p < 0.0005) and not significantly different from healthy controls. Bone morphology in ECT-treated animals, evaluated by histological and microtomographical analyses, showed intact cortical and trabecular bone structure with new bone apposition. Histomorphometric evaluation showed that ECT-treated metastases had significantly higher bone volume, trabecular number, trabecular thickness and bone mineral density compared with those of untreated metastases (respectively p < 0.0005 for BV/TV, Tb.N and BMD; p < 0.05 for Tb.Th) or metastases treated with Bleo (p < 0.05 for BV/TV, Tb.N, p < 0.005 for BMD) or EP (p < 0.005 for BV/TV, Tb.N; p < 0.0005 for BMD). These findings suggest that early ECT treatment of bone metastases is minimally invasive, safe and effective, thus providing pre-clinical evidence for its use in the treatment of human bone metastases.

OBJECTIVE Anti-tissue transglutaminase (TG2) antibodies are the serological marker of celiac disease. Given the close association between celiac disease and type 1 diabetes, we investigated the production and deposition of anti-TG2 antibodies in the jejunal mucosa of type 1 diabetic children. RESEARCH DESIGN AND METHODS Intestinal biopsies were performed in 33 type 1 diabetic patients with a normal mucosal architecture: 14 had high levels (potential celiac disease patients) and 19 had normal levels of serum anti-TG2 antibodies. All biopsy specimens were investigated for intestinal deposits of IgA anti-TG2 antibodies by double immunofluorescence. In addition, an antibody analysis using the phage display technique was performed on the intestinal biopsy specimens from seven type 1 diabetic patients, of whom four had elevated and three had normal levels of serum anti-TG2 antibodies. RESULTS Immunofluorescence studies showed that 11 of 14 type 1 diabetic children with elevated levels and 11 of 19 with normal serum levels of anti-TG2 antibodies presented with mucosal deposits of such autoantibodies. The phage display analysis technique confirmed the intestinal production of the anti-TG2 antibodies; however, whereas the serum-positive type 1 diabetic patients showed a preferential use of the VH5 antibody gene family, in the serum-negative patients the anti-TG2 antibodies belonged to the VH1 and VH3 families, with a preferential use of the latter. CONCLUSIONS Our findings demonstrate that there is intestinal production and deposition of anti-TG2 antibodies in the jejunal mucosa of the majority of type 1 diabetic patients. However, only those with elevated serum levels of anti-TG2 antibodies showed the VH usage that is typical of the anti-TG2 antibodies that are produced in patients with celiac disease.

Although there is a strong association between lower-extremity amputation (LEA) and HbA1c (A1C) in diabetic patients (1,2), little information is available on glucose control in the period preceding and following LEA (3). Our objective was to evaluate the predictors of LEA and to examine the role of blood glucose control during the year before and the year after admission. A total of 122 diabetic patients (82 men and 40 women aged 69.7 ± 10.9 years, disease duration 19.7 ± 10.4 years) consecutively admitted for diabetic foot ulcers to the Medicine Department of United Hospitals of Bergamo between January 2003 and December 2004 were enrolled in our observational study and assigned to one …

Dietary gluten has been associated with an increased risk of type 1 diabetes. We have evaluated inflammation and the mucosal immune response to gliadin in the jejunum of patients with type 1 diabetes. Small intestinal biopsies from 17 children with type 1 diabetes without serological markers of celiac disease and from 50 age-matched control subjects were examined by immunohistochemistry. In addition, biopsies from 12 type 1 diabetic patients and 8 control subjects were cultured with gliadin or ovalbumin peptic-tryptic digest and examined for epithelial infiltration and lamina propria T-cell activation. The density of intraepithelial CD3(+) and gammadelta(+) cells and of lamina propria CD25(+) mononuclear cells was higher in jejunal biopsies from type 1 diabetic patients versus control subjects. In the patients' biopsies cultured with peptic-tryptic gliadin, there was epithelial infiltration by CD3(+) cells, a significant increase in lamina propria CD25(+) and CD80(+) cells and enhanced expression of lamina propria CD54 and crypt HLA-DR. No such phenomena were observed in control subjects, even those with celiac disease-associated HLA haplotypes. In conclusion, signs of mucosal inflammation were present in jejunal biopsies from type 1 diabetic patients, and organ culture studies indicate a deranged mucosal immune response to gliadin.

BACKGROUND: Studies on intestinal T cell clones from the mucosa of patients with coeliac disease have led to the identification of immunogenic gliadin epitopes. One is HLA-DQ8 restricted, its recognition by T cells being increased by introduction of negatively charged residues operated by tissue transglutaminase. AIM: To test HLA-DQ8 restricted epitope in both native (QYPSGQGSFQPSQQNPQA) and deamidated (QYPSGEGSFQPSQENPQA) forms in an organ culture system of treated coeliac mucosa from HLA-DQ8 positive and HLA-DQ8 negative patients. PATIENTS AND METHODS: Jejunal biopsies obtained from 10 patients with coeliac disease (six HLA-DQ8 positive and four HLA-DQ8 negative) were cultured in vitro with a peptic-tryptic digest (PT) of gliadin, or with the native (peptide A) or deamidated (peptide B) peptide. Intraepithelial CD3(+) and lamina propria total CD25(+) and CD3(+)CD25(+) cells were counted, lamina propria intercellular adhesion molecule 1 (ICAM-1) expression was evaluated, as well as that of Fas molecules on epithelial cells. RESULTS: In HLA-DQ8 positive, but not in HLA-DQ8 negative, coeliacs the density of intraepithelial CD3(+) cells, lamina propria total CD25(+), and CD3(+)CD25(+) cells, as well as expression of ICAM-1 and Fas molecules were significantly increased in biopsies cultured with PT, peptide A, or peptide B compared with biopsies cultured in medium alone. CONCLUSION: These data show that the DQ8 restricted gliadin peptide is immunogenic only in the intestinal mucosa of HLA-DQ8 positive coeliac patients in both native and deamidated forms.