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There is little evidence about possible effects of pelvic anatomical characteristics on proctological complications. The aim of our study was to investigate the potential correlation between sagittal pelvic position and rectal prolapse.A study was conducted on a proctology patients and patients without any specific history of proctological disorders who were divided into two groups according to the presence or the absence of rectal prolapse. In all cases, the pelvic angle was measured with a pelvic goniometer and categorized as posterior ( 10°), neutral (10°-15°), and anterior ( 15°). To minimize effects of potential confounders in the analysis, 3:1 nearest neighbor propensity score matching (PSM) method was implemented using age, sex, and diagnose of rectal disorders as confounding variables.Among the 143 screened patients, posterior tilt was more frequent in the 19 patients with rectal prolapse than in those without prolapse (42 vs. 18%; p = 0.027). This result was also confirmed in the post-PSM analysis (42 vs. 14%; p = 0.036) using 35 propensity score (PS)-matched controls compared with the rectal prolapse group. Posterior tilt was associated with an increased risk of prolapse in both the unmatched population (odds ratio = 3.37; p = 0.020) and PS-matched subset (odds ratio = 4.36; p = 0.028).A posterior pelvic angle was more frequently associated with the diagnosis of rectal prolapse. In both the entire population and in the PS-matched subset, posterior tilt was a significant risk factor for rectal prolapse. The easy-to-do investigation of the pelvic angle can provide several benefits in terms of rectal prolapse prevention and more precise management of post-surgical prolapse recurrence.

A new laser powder bed fusion prototype for in situ monitoring of defects and in situ and inline flaw removal has been developed at and patented by Politecnico di Milano (Italy). This prototype allows the identification of a defective layer thanks to an innovative in situ monitoring approach that combines image and video-image data in the visible and infrared ranges. When an alarm is issued, the layer containing the defect is removed in situ and inline, thanks to a novel self-repairing system acting as a grinder on the powder bed. After this removal step, subsequent layers are additively produced starting from the healed height. By comparing specimens obtained with and without such intermediate layer removal, the aim of this preliminary study is to investigate the feasibility of the methodology, revealing that no discontinuity is introduced into the part by the novel inline removal operation. This solution is conceived to enable novel zero-defect and first-time-right capabilities in additive manufacturing.

Introduction/Background The maternal diagnosis of cancer complicates approximately 0,1% of all pregnancies. The most frequently diagnosed malignancies are breast cancer, cervical cancer, lymphoma, ovarian cancer and melanoma. Although chemotherapy can be administered during pregnancy, its effects on obstetric and neonatal outcome are still largely unknown. The aim of this study is to describe the oncologic management as well as the obstetric and perinatal outcomes in a consecutive series of patients with cancer during pregnancy. Methodology We provided descriptive oncologic, obstetric and neonatal data from a cohort of pregnant patients diagnosed with primary invasive cancer between August 2004 and April 2019, retrospectively collected from clinical databases of IRCCS Policlinico di Milano and Istituto Europeo Di Oncologia (Milan, Italy). Results We observed 86 consecutive patients with a diagnosis of malignancy during pregnancy: breast cancer was the most common type (70,9%), followed by lymphomas (11,6%). Patients with ongoing or missing oncological, obstetrical or neonatal data were excluded. Of the 62 eligible patients, 12,9% received surgical treatment, 24% chemotherapy and 54,8% a combination of both. For almost all pregnancies, timing of delivery was previously planned: 38% with labor inductions and 54% with elective cesarean sections, at a mean gestational age of 36 weeks. All pregnancies ended in a livebirth. Half of deliveries were preterm, mainly iatrogenic due to obstetric or oncologic indications: 3.2% were very low preterm, 6,4% moderate preterm and 45% late preterm. The frequency of small for gestational age (birthweight Conclusion This study confirms a high overall frequency of premature birth in pregnant patients with cancer, showing a lower rate of small for gestational age than described in literature. In order to have a better assessment of the toxicity of chemotherapy during pregnancy, we are currently investigating its fetal sequelae through histologic analysis of placental tissue and pediatric follow-up. Disclosure Nothing to disclose.

Many studies, focused on identifying new biomarkers for coronary artery disease (CAD) risk computation and monitoring, suggested a potential diagnostic role for fatty acids (FA). In the present study, we explored the potential diagnostic role of FA by using a data mining approach based on fourth generation artificial neural networks (ANN). Forty-one male subjects were enrolled. According to coronary angiography, 31 displayed CAD and 10 did not (non-CAD, control group). FA analysis was performed on plasma samples using a gas chromatography-mass spectrometry system and analyses were performed by an ANN method. The variables most closely related to CAD were low levels of alpha-linolenic acid, eicosapentaenoic acid, eicosatetraenoic and docosahexaenoic acids. High levels of 1,1-dimethoxyhexadecane, total dimethyl acetals and docosatetraenoic acid were related to non-CAD condition. This subset of variables, which were most closely correlated to the target diagnosis, achieved a consistent predictive rate. The average accuracy obtained was 76.5%, with 93% of sensitivity and 60% of specificity. The area under the ROC curve was equal to 0.79. In conclusion, our study highlighted the association between different plasma FA species, CAD and non-CAD conditions. The specific subset of variables could be of interest as a new diagnostic tool for CAD management.

This study, carried out in two Italian Institutions, assesses the frequency of 27 potential autism risk factors related to pregnancy and peri- and postnatal periods by interviewing mothers who had children with autism, children with autism and one or two typically developing siblings, or only typically developing children. The clinical sample included three case groups: 73 children and adolescents with autism (Group A), 35 children and adolescents with autism (Group A1) having 45 siblings (Group B) and 96 typically developing children (Group C) matched for gender and age. Twenty-five out of 27 of risk factors presented a higher frequency in Group A in comparison with Group C and for nine of them a statistically significant difference was found. Twenty-one out of 27 of risk factors presented a higher frequency in Group A in comparison with Group B. A higher prevalence of environmental risk factors was observed in 11 risk factors in the Group A1 in comparison with Group B and for nine of them an odds ratio higher than 1.5 was found. For 13 factors there was a progressive increase in frequency going from Group C, B and A and a statistically higher prevalence of the mean number of stressful events per pregnancy was recorded in Group A when compared with Groups B and C. The results suggest that environmental, incidental phenomena and stressful life events can influence pregnancy outcome in predisposed subjects, pointing out a possible threshold effect in women who are predisposed to have suboptimal pregnancies.

The Editors-in-Chief are retracting this article [1]. After publication concerns were raised with respect to inconsistencies between this trial protocol and the trial registry entry. Subsequent investigation has shown that patient recruitment had been completed before submission of the protocol to the journal, which is a breach of the journals editorial policy. Concerns have also been raised that one of the reviewers was added to this article as an author after revision. Michele Carenini and Wendy Moreno Pea agree with this retraction and Angelo Compare does not agree with this retraction. Vassilis Kouloulias, Vontas Apostolos, Enrico Molinari, Enzo Grossi and Efstathopoulos Efstathios did not reply to correspondence about this retraction. © 2018 The Author(s).

SummaryAfter acute myocardial infarction (MI) the damaged heart has to be repaired. Factor XIII (FXIII) is considered a key molecule in promoting heart healing. FXIII deficiency was associated to cardiac rupture and anomalous remodelling in MI. During MI, FXIII contributes firstly to the intracoronary thrombus formation and shortly after to heal the myocardial lesion. To quantify the real contribution of FXIII in this process, and to explore its possible prognostic role, we monitored the FXIII-A subunit levels in 350 acute MI patients during the first six days (d0-d5) plus a control at 30–60 days (d30). A one-year follow-up was performed for all the patients. A transient drop in the FXIII-A mean level was noted in the whole cohort of patients (FXIII-Ad0 99.48 ± 30.5 vs FXIII-Ad5 76.51 ± 27.02; p< 0.0001). Interestingly, those who developed post-MI heart failure showed the highest drop (FXIII-Ad5 52.1 ± 25.2) and they already presented with low levels at recruitment. Similarly, those who died showed the same FXIII-A dynamic (FXIII-Ad5 54.0 ± 22.5). Conversely, patients who remained free of major adverse cardiac events, had lower consuming (FXIII-Ad0 103.6 ± 29.1 vs FXIII-Ad5 84.4 ± 24.5; p< 0.0001). Interestingly, the FXIII-A drop was independent from the amount of injury assessed by TnT and CKMB levels. The survival analysis ascribed an increased probability of early death or heart failure inversely related to FXIII-A quartiles (FXIII-A25th< 59.5 %; hazard ratio 4.25; 2.2–5.1; p< 0.0001). Different FXIII-A dynamics and levels could be utilised as early prognostic indicators during acute MI, revealing the individual potential to heal and suggesting tailored treatments to avoid heart failure or its extreme consequence.Note: This paper was presented in part at the 14th Congress of the International Society on Thrombosis and Haemostasis, Amsterdam, Netherlands, June 29 – July 24, 2013.

BACKGROUND: Different lifestyle and dietetic factors have been linked with the onset and severity of acne. OBJECTIVE: To assess the complex interconnection between dietetic variables and acne. METHODS: This was a reanalysis of data from a case-control study by using a semantic connectivity map approach. 563 subjects, aged 10-24 years, involved in a case-control study of acne between March 2009 and February 2010, were considered in this study. The analysis evaluated the link between a moderate to severe acne and anthropometric variables, family history and dietetic factors. Analyses were conducted by relying on an artificial adaptive system, the Auto Semantic Connectivity Map (AutoCM). RESULTS: The AutoCM map showed that moderate-severe acne was closely associated with family history of acne in first degree relatives, obesity (BMI ≥ 30), and high consumption of milk, in particular skim milk, cheese/yogurt, sweets/cakes, chocolate, and a low consumption of fish, and limited intake of fruits/vegetables. CONCLUSION: Our analyses confirm the link between several dietetic items and acne. When providing care, dermatologists should also be aware of the complex interconnection between dietetic factors and acne.

BACKGROUND Limited evidence is available on the impact of socioeconomic factors in drug prescriptions for psoriasis. OBJECTIVES To investigate factors influencing prescription of conventional versus biological treatment for psoriatic patients, based on the Psocare registry with a special focus on socioeconomic factors. METHODS This was a cross-sectional study evaluating the baseline data of patients included in the Italian Psocare Registry. All of the consecutive adult patients with a diagnosis of chronic plaque psoriasis (Ps) or psoriatic arthritis and who were prescribed a systemic treatment for Ps at the participating centres were included in this study. Univariate and multivariate analyses of the baseline factors associated with a biologics prescription were performed. RESULTS From September 2005 to September 2009, 12,838 patients were identified. A multivariate analysis revealed that, among other factors, completing a level of education higher than lower secondary school and being employed as a manager or a professional were independent factors associated with a biologics prescription at entry in the registry. Additional analyses on the association between these two variables and a severe Ps condition (i.e., psoriasis area and severity index [PASI] score > 20) revealed a significant increasing trend of severe disease towards lower educational attainment, while unemployed patients were more likely to have a more severe condition as compared to the other categories of workers. CONCLUSIONS We documented inequalities of drug prescriptions for Ps in Italy, with a trend towards a higher frequency of prescription for more expensive biologics in higher socio-economic sectors of the population. This article is protected by copyright. All rights reserved.

SummaryAtrial fibrillation (AF) patients are at high risk for thrombotic and vascular events related to their cardiac arrhythmia and underlying systemic atherosclerosis. Ankle-Brachial Index (ABI) is a non-invasive tool in evaluating systemic atherosclerosis, useful in predicting cardiovascular events in general population; no data are available in AF patients. ARAPACIS is a prospective multicentre observational study performed by the Italian Society of Internal Medicine, analysing association between low ABI (≤0.90) and vascular events in NVAF out- or in-patients, enrolled in 136 Italian centres. A total of 2,027 non-valvular AF (NVAF) patients aged > 18 years from both sexes followed for a median time of 34.7 (interquartile range: 22.0–36.0) months, yielding a total of 4,614 patient-years of observation. Mean age was 73 ± 10 years old with 55% male patients. A total of 176 patients (8.7%) experienced a vascular event, with a cumulative incidence of 3.81%/patient-year. ABI≤ 0.90 was more prevalent in patients with a vascular event compared with patients free of vascular events (32.2 vs 20.2%, p< 0.05). On Cox proportional hazard analysis, ABI≤ 0.90 was an independent predictor of vascular events (hazard ratio (HR): 1.394, 95% confidence interval (CI): 1.042–1.866; p=0.02), vascular death (HR: 2.047, 95% CI: 1.255-3.338; p=0.004) and MI (HR: 2.709, 95%> CI: 1.485-5.083; p=0.001). This latter association was also confirmed after excluding patients with previous MI (HR: 2.901, 95% CI: 1.408-5.990, p=0.004). No association was observed between low ABI and stroke/transient ischaemic attack (p=0.91). In conclusion, low ABI is useful to predict MI and vascular death in NVAF patients and may independently facilitate cardiovascular risk assessment in NVAF patients.Note: The review process for this paper was fully handled by C. Weber, Editor in Chief.Listed in the Supplementary Online Appendix Material which is available online at www.thrombosis-online.com.

Class switching consists in the substitution of the heavy-chain constant region of immunoglobulin M (IgM) with that of IgG, IgA, or IgE. This enables antibodies to acquire new effector functions that are crucial to combat invading pathogens. Class switching usually requires engagement of CD40 on B cells by CD40 ligand (CD40L) on antigen-activated CD4 + T cells and the production of cytokines. The process must be regulated tightly because abnormal IgG and IgA production favors the onset of autoimmunity, whereas increased switching to IgE leads to atopy. These inflammatory disorders can be triggered or exacerbated by costimulatory signals. Although thoroughly investigated on T cells, the roles of the inhibitory receptors CD85j, LAIR-1, and CD152 on B-cell functions have not been fully elucidated. In this study we show that cross-linking of the B-cell inhibitory receptors by specific monoclonal antibodies inhibits IgG and IgE production, reduces the percentage of IgG- and IgE-expressing B cells, and down-regulates interleukin 8 (IL-8), IL-10, and tumor necrosis factor alpha production. These effects were demonstrated using different B-cell stimulatory pathways (recall antigens, CD40L-transfected cells plus IL-4, and lipopolysaccharide plus IL-4). It thus appears that CD85j, LAIR-1, and CD152 play a central role for the control of IL-4-driven isotype switching.

Generation of immune responses against B cell chronic lymphocytic leukemia (B-CLL) has been the aim of several studies that have demonstrated a poor antigen presenting ability of B-CLL cells and an inconsistent emergence of T cells capable of killing efficiently the leukemic cells. CD1d is a restriction element structurally related to the major histocompatibility complex (MHC) and capable of presenting lipid antigens to CD1d-restricted T cells (also defined as natural killer-T [NKT] cells). The synthetic lipid alpha-galactosylceramide (alpha-GalCer) has been characterized as a potent stimulator of CD1d-restricted T cells. We have investigated the expression of CD1d on B-CLL cells. CD1d was detected by flow cytometric analyses on leukemic cells of all B-CLL cases studied (n = 38) and was expressed at higher density on cells carrying unmutated immunoglobulin variable region (IgV) genes. In addition, CD1d on B-CLL cells mediated the presentation of alpha-GalCer to CD1d-restricted T cells, which in turn induced B-CLL cell death. At variance with another study (Metelitsa et al., Leukemia 2003;17:1068-77), no correlation between expression levels of CD1d and susceptibility to NKT cell lysis was observed. Proliferation and production of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) by CD1d-restricted T cells, in the presence of B-CLL cells loaded with alpha-GalCer, were also observed. Our study demonstrates that B-CLL cells express a monomorphic restriction element that is functionally capable of antigen presentation and can be useful to design novel B-CLL immunotherapies.

Thymic T cell maturation depends on interactions between thymocytes and cells of epithelial and hematopoietic lineages that control a selective process whereby developing T cells with inappropriate or self-reactive receptors die. Molecules involved in this process are the TCR expressed on thymocytes together with the CD3 complex and MHC-peptide on accessory cells. However, other molecules may favor or prevent death of thymocytes, thus playing a role in selection. CD38 is expressed by the majority of human thymocytes, mainly at the double-positive (DP) stage. In contrast, CD38 is not found on subcapsular double-negative (DN) thymocytes and on a proportion of medullary single-positive (SP) thymocytes. CD38 enhances death of thymocytes when it is cross-linked by goat anti-mouse (GAM) antiserum or by one of its ligands, CD31, expressed by thymic epithelial cells or transfected into murine fibroblasts (L cells). As most thymocytes are at an intermediate (DP) stage of development, it is likely that these cells are most vulnerable to death mediated via MHC-peptide-TCR interactions that is increased by CD38 cross-linking. DN and SP thymocytes are refractory to CD38-induced apoptosis. Accessory molecules, e.g. CD38, are expressed during thymic cell maturation and their presence is relevant for the survival or death of DP T cells in the course of selection. Based on our data, CD38 enhances thymocyte death by interacting with CD31 expressed by accessory cells. In addition, CD28 expression on developing thymocytes also appears to play a role for their selection and it synergizes with CD38 to induce apoptosis of DP thymocytes.

Objective: Sialyl Lewisx (sLex) is one ligand for E selectin (CD62E), a glycoprotein that is expressed on activated endothelial cells. Adhesion mediated by endothelial E selectin and sLex expressed on human tumor cells could be relevant for the development of metastases. The aim of this study was to investigate whether or not a correlation exists between pre-operative levels of ganglioside serum sLex and disease-free interval and survival in colorectal cancer patients. Patients and Methods: Thirty Duke’s B and 52 Duke’s C patients undergoing resection for colorectal cancer were studied. The median follow-up time was 34.8 months. A pool of 57 sera from normal subjects was used as an Internal Normal Standard (INS). sLex analyses were performed by a thin layer chromatography (TLC) immunostaining technique. Results were expressed as the ratio (R) between bands of INS and bands from each neoplastic serum. Results: The median R value was 0.80 in normal subjects, 0.70 in Duke’s B patients and 1.0 in Duke’s C patients. No significant differences were detected between sLex concentrations in sera from normal and neoplastic subjects (p = 0.1). Using an arbitrary cutoff of R = 0.9, the mean disease-free interval in the whole series was 47.4 months for R Conclusions: High serum levels of ganglioside sLex significantly correlate with a favorable prognosis and with a lower occurrence of metastases. It is conceivable that soluble sLex may compete with membrane-bound sLex in the course of interactions between activated endothelium and tumor cells that have reached the circulation.

Antigen-specific cytolytic CD4+T lymphocytes controlMycobacterium tuberculosisinfection by secreting cytokines and by killing macrophages that have phagocytosed the pathogen. However, lysis of the latter cells promotes microbial dissemination, and other macrophages engulf the released bacteria. Subsequently, CD4+T-cell-mediated killing of macrophages goes on, and this persistent process may hamper control of infection, unless regulatory mechanisms maintain a subtle balance between lysis of macrophages by cytolytic CD4+cells and activation of cytolytic CD4+cells by infected macrophages. We asked whether inhibitory molecules expressed by CD4+cytolytic T lymphocytes could play a role in such a balance. To this end, human CD4+T-cell clones specific forM. tuberculosiswere produced that displayed an autologous major histocompatibility complex class II-restricted lytic ability against purified protein derivative (PPD)-pulsed antigen-presenting cells. All T-cell clones expressed CD152 (cytotoxic T-lymphocyte antigen 4 [CTLA-4]) and CD85/leukocyte immunoglobulin-like receptor 1 (LIR-1)/immunoglobulin-like transcript 2 (ILT2) inhibitory receptors, but not CD94 and the killer inhibitory receptor (or killer immunoglobulin-like receptor [KIR]) p58.2. CD3-mediated activation of the clones was inhibited in a redirected killing assay in which CD152 and CD85/LIR-1/ILT2 were cross-linked. Specific antigen-mediated proliferation of the clones was also sharply reduced when CD152 and CD85/LIR-1/ILT2 were cross-linked by specific monoclonal antibody (MAb) followed by goat anti-mouse antiserum. In contrast, blockade of the receptors by specific MAb only increased their proliferation. Production of interleukin 2 (IL-2) and gamma interferon (IFN-γ) by the T-cell clones was also strongly reduced when CD152 and CD85/LIR-1/ILT2 were cross-linked. The lytic activity of the T-cell clones against PPD-pulsed autologous monocytes or Epstein-Barr virus-activated B cells was increased by blockade and decreased by cross-linking of the receptors. These results indicate that CD152 and CD85/LIR-1/ILT2 play a role in the regulation of the antigen-specific activity of CD4+cytolytic T lymphocytes against PPD-presenting cells.

IL-12 promotes generation of LAK activity in short-term-cultured NK cells, but information on the structure and function of IL-12-induced LAK cells is not yet available. The latter issues have been here investigated with emphasis on interactions between IL-12 and IL-2. Peripheral blood mononuclear cells (MNC) exposed to IL-12 for 5-7 days displayed a decrease in the amount and density of the matrix of large granular lymphocyte (LGL)-associated granules. In cells cultured with IL-12 and IL-2 for 5-7 days, empty vacuoles were predominant and the electron-dense matrix was scanty. In MNC incubated with IL-2 for 5-7 days, most granules were loaded with electron-dense matrix. IL-12 and IL-2 displayed an additive effect on LAK cell cytotoxicity until approximately 48 h in culture which was followed by a sharp decline. Immunocytochemical and biochemical studies demonstrated that MNC cultured for 5-7 days with IL-12 and IL-2 displayed downregulated perforin expression and upregulated granzyme B expression. Fas ligand expression was virtually undetectable in MNC cultured for 5-7 days with or without cytokines. It appears that perforin downregulation plays a major role in the reduced cytotoxicity of MNC cultured with IL-12 and IL-2 for 5-7 days.

Two parallel trials were carried out with levothyroxine sodium salt in 50 and 100 microg strengths, respectively, giving 100 microg day-1(50x2 microg day-1 or 100x1 microg day-1) in both trials in a repeated dose regimen. Twenty patients suffering from primary hypothyroidism under treatment with 100 microg day-1 of thyroxine sodium salt were enrolled in each trial. They were clinically and chemically euthyroid. Each trial lasted 114 days, with 57 days being devoted to the first treatment (test or reference) and 57 days to the other (reference or test), according to a two-period, two-sequence, two-formulation design in a steady state without wash-out. The test formulation was prepared with a technological improvement and is being produced to replace that at present on the market. Serum concentrations of free and total levothyroxine, and free and total levotriiodothyronine were assayed repeatedly during the treatment and in timed samples after the last dose of each formulation, using radioimmunoassays. Cmax and AUCss,tau were considered to be target parameters for bioequivalence which was assessed through 90% confidence intervals in the 0.80-1.25 range, as required by EU and US FDA operating guidelines. The results have shown that of these hormones, the free and total parent compound thyroxine is that which most clearly showed a peak after dosing, whereas its metabolite, free and total triiodothyronine, fluctuated around pre-dose concentrations. Bioequivalence was fully assessed with Cmax and AUCss,tau, with all four hormones tested and at both strengths administered. The two test formulations in 50 and 100 microg are thus bioequivalent with the two reference preparations. Tolerability was very good in all cases.

In a previous study, we described a cell line (BRG-P) derived from a woman with Burkitt's lymphoma (BL) and acquired immunodeficiency syndrome that shared the same characteristic cytogenetic abnormalities as the patient's malignant cells. This cell line contained subclones that displayed an isotype switch from IgM to IgA1 and an accumulation of point mutations in the Vh region genes. Because these two features suggested an antigen-driven process, we began a search for the antigen responsible for the stimulation of the malignant B cells. Specifically, we hypothesized that because the patient's tumor had presented as a lymphomatous infiltration of the breast, the malignant B cells were recruited to this site because of the reactivity of their surface lg with breast tissue. A hybridoma (BRG-H) was obtained by fusing BRG-M cells (an IgM producing subclone of the BRG-P cell) with an appropriate cellular partner. The monoclonal antibody (BRG MoAb) produced by this hybridoma reacted strongly with two of five breast cancer cell lines and stained normal and malignant ductal epithelial cells on breast tissue sections. The antigen recognized by the BRG MoAb consisted of a single, minimally glycosylated polypeptide chain of 45 kD (p45). The BRG MoAb failed to react with a panel of human cell lines from different tissues, except for one cell line from a uterine cervical carcinoma. No reactivity was detected for a panel of exogenous antigens from various pathogens, including human immunodeficiency virus and self- antigens frequently recognized by polyspecific antibodies. Experiments were performed to investigate the functional consequences of the interaction of surface IgM with its specific ligand. Coculture of BRG-M cells with p45+, but not with p45-, breast cells caused apoptosis of BRG-M cells. The specificity of the interaction was shown by the observation that apoptosis was prevented by pretreatment of BRG-M cells with a monovalent F(ab′) fragment of rabbit IgG antibody to human mu chains. Moreover, only BRG-M cells, but not other BL cells, underwent apoptosis after exposure to p45+ breast cells. The interaction between the CD40 molecule expressed by BRG-M cells and its specific ligand (CD40L) prevented p45-induced cell apoptosis. Because this interaction mimics that occurring in vivo between T and B cells during immune responses, our data suggest that various events contributed to the emergence of the BL, in this particular patient, including antigenic stimulation possibly assisted by T-cell help.

In this paper the authors have analyzed the long-term survival of women with Stage III ovarian cancer due to lymph node metastasis.This retrospective study included 27 patients with FIGO Stage IIIC epithelial ovarian carcinoma due to lymph node metastases observed consecutively at the Mangiagalli Clinic of Milan from 1982 to 2008.Two cases had Fallopian tube carcinoma. A total of ten recurrences were observed. Median time to recurrence was 158 months. The five-year disease-free survival (DFS) was 57.7%. The ten-year corresponding value was 53.2%. Median survival time was 158 months, with median follow-up time of 169 months. The five-year (overall survival) OS rate was 77.1%; the ten-year rate was 55.4%.Women with ovarian cancer Stage IIIC due to nodal involvement have a five-year OS of about 80% and a ten-year OS of about 50%.

To the Editor: Nonvalvular atrial fibrillation (NVAF) is the most common sustained arrhythmia encountered in clinical practice and is associated with a 5-fold increased risk for stroke (1). Moreover, patients with NVAF often suffer from atherosclerotic complications such as acute myocardial infarction (AMI) (2). Peripheral artery disease (PAD) is an established marker of systemic atherosclerosis but its prevalence in NVAF is still unclear. We reasoned that inclusion of ankle-brachial index (ABI), which is an established tool for diagnosis of PAD (3), in the CHA2DS2-VASc (4) score would better define the prevalence of vascular disease. To address this issue, the Italian Society of Internal Medicine (SIMI) established an Italian registry documenting ABI in NVAF patients. The Atrial Fibrillation Registry for the ARAPACIS (Ankle-brachial Index Prevalence Assessment: Collaborative Italian Study) study is an independent research project involving all Regional Councils of SIMI. The first objective of the study was to estimate the prevalence of ABI ≤0.90 in NVAF patients. Consecutive patients with NVAF referred to internal medicine wards were eligible for the enrollment. Enrollment started in October 2010 and continued until October 30, 2012. Patients were enrolled if they were 18 years or older and had a diagnosis of NVAF, recording during the qualifying admission/consultation or in the preceding 12 months, and if it was possible to obtain the ABI measurement. Exclusion criteria included the following: acquired or congenital valvular AF, active cancer, disease with life expectancy 0.90 (93% vs. 82%; p < 0.0001). Logistic regression analysis demonstrated that ABI ≤0.90 was significantly associated with a smoking habit (odds ratio [OR]: 1.99; 95% confidence interval [CI]: 1.48 to 2.66; p < 0.0001), diabetes (OR: 1.93; 95% CI: 1.51 to 2.46; p < 0.0001), age class 65 to 74 years (OR: 2.05; 95% CI: 1.40 to 3.07; p < 0.0001), age class ≥75 years (OR: 3.12; 95% CI: 2.16 to 4.61; p < 0.0001), and history of previous transient ischemic attack/stroke (OR: 1.64; 95% CI: 1.20 to 2.24; p = 0.002). Vascular disease, as assessed by the history elements of CHA2DS2VASc score, was recorded in 17.3% of patients; inclusion of ABI ≤0.90 in the definition of vascular disease yielded a total prevalence of 33%. A higher prevalence of vascular disease was detected if ABI ≤0.90 was included in the CHA2DS2VASc score (Fig. 1). CHA2DS2VASc including ABI ≤0.90 was more associated with previous stroke (43%; OR: 1.85; 95% CI: 1.41 to 2.44; p < 0.0001) compared to CHA2DS2VASc with ABI 0.91 to 1.39 (23%; OR: 1.52; 95% CI: 1.10 to 2.11; p = 0.0117). To the best of our knowledge, there is no large-scale study that specifically examined the prevalence of ABI ≤0.90 in NVAF. In our population, 21% had ABI ≤0.90 indicating that NVAF is often associated with systemic atherosclerosis. The CHADS2 has been recently refined with the CHA2DS2-VASc score, which includes vascular disease as documented by a history of AMI, symptomatic PAD, or detection of atherosclerotic plaque in the aortic arch (4). Comparison of vascular prevalence as assessed by CHA2DS2-VASc score and/or ABI ≤0.90 is of interest to define the potentially positive impact of measuring ABI in the management of NVAF patients. Inclusion of ABI ≤0.90 in the definition of vascular disease greatly increased the prevalence of vascular disease, which increased from 17.3% (based on history alone) to 33% (based on ABI) in the entire population. If ABI ≤0.90 was encompassed in the definition of vascular disease of CHA2DS2-VASc score the prevalence of vascular disease increased in every risk class. Inclusion of ABI ≤0.90 in the CHA2DS2-VASc score allowed us to better define the risk profile of NVAF patients with an up-grading of the risk score in each CHA2DS2-VASc score category. This may have important therapeutic implications if the new score could be tested prospectively, as a higher number of NVAF patients would potentially be candidates for an anticoagulant treatment by measuring ABI. A prospective study is, therefore, necessary to validate the risk score of this new definition of vascular disease. In conclusion, this study provides the first evidence that one-fifth of NVAF patients had an ABI ≤0.90, indicating that it may represent a simple and cheap method to better define the prevalence of vascular disease in NVAF.

Binge eating disorder (BED) is a complex and multifaceted eating disorder, and the literature indicates that BED patients show greater difficulty in identifying and making sense of emotional states, and that they have limited access to emotion regulation strategies. Findings show many links between mindfulness and emotional regulation, however there has been no previous research on mindfulness traits in BED patients.One hundred fifty BED patients (N=150: women=98, men=52; age 49.3±4.1) were matched for gender, age, marital status and educational level with 150 non-bingeing obese and 150 normal-weight subjects. All were assessed with the Five Facet Mindfulness Questionnaire (FFMQ), Binge Eating Scale (BES), Objective bulimic episodes (EDE-OBEs) and Body Uneasiness Test (BUT). For all the participants past or current meditation experience was an exclusion criteria.Findings showed that Mindfulness-global, Non reactivity to experience, Acting with awareness, Describing with words and Observation of experience scores were significantly lower in BED than control groups (p0.05). However, on the mindfulness measures, the obese control group did not differ from the normal weight control group. Moreover, correlations showed that mindfulness was more widely negatively correlated with the BED's OBEs, BES and BUT-GSI scores. Meanwhile, binge eating behaviours, frequency and severity (OBEs and BES) were more negatively correlated with action (Nonreactivity- to-experience and Acting-with-awareness scores). Body Uneasiness was more negatively correlated with mental processes (Describing-with-words and Observation-ofexperience) and mindfulness features.Implications on understanding of the mechanisms underlying the development and maintenance of problematic eating in BED were considered. Moreover, clinical considerations on treatment targets of mindfulnessbased eating awareness training were discussed.

Azithromycin is a recently developed antibacterial agent belonging to a new class of azalide antibiotics with an improved spectrum of activity against gram-negative organisms, most notably Haemophilus influenzae . Azithromycin also has good in vitro activity against most other common respiratory pathogens, including Moraxella catarrhalis, Streptococcus pneumoniae, Mycoplasma pneumoniae , and Chlamydia species. The purpose of this multicenter study was to compare the efficacy and safety of once-daily azithromycin (for 3 days) with josamycin (given thrice daily over 7 days) in children with community-acquired pneumonia. One hundred ten patients with pneumonia from 19 university and hospital pediatric departments were enrolled in the study. Clinical response to therapy, which was classified as cure, improvement, or failure, was assessed at day 4 and day 8 of treatment. Azithromycin was significantly ( P

The patients, 206 adults with acute exacerbation of chronic bronchitis, were randomly assigned to receive 500 mg of azithromycin once daily for 3 days (n = 102) or 250 mg of clarithromycin twice daily for 7 days (n = 104). On days 4 and 8 after the start of treatment, patients receiving azithromycin showed significantly fewer signs and symptoms of bronchitis and on day 4 significantly more were rated as clinically improved than the patients in the clarithromycin group. Significantly more pathogens were eradicated in azithromycin-treated patients (93%) than in clarithromycin-treated patients (75%). Side effects were reported by four patients in the azithromycin group (abdominal pain, erythema, and diarrhea) and by none of the clarithromycin-treated patients. It is concluded that azithromycin is more effective than clarithromycin in the treatment of acute exacerbation of chronic bronchitis.

Targeting of T lymphocytes against epidermal growth-factor-receptor (EGF-R)+ tumor cells was achieved by constructing a hybrid hybridoma which secretes an anti-EGF-R/anti-CD3 bispecific monoclonal antibody (biMAb) of hybrid isotype (IgG1/IgG2a). Purification of biMAb molecules from parental anti-EGF-R and anti-CD3 MAbs was performed by protein-A chromatography. The purified biMAb was able to trigger the lysis of EGF-R+ tumor cell lines (A431, IGROV-1, MDA-468 and U-87) and of NIH-3T3 transfectants expressing human EGF-R by cytolytic T lymphocytes, but it was ineffective in the case of EGF-R-negative tumor targets. Normal EGF-R+ cells (keratinocytes and endometrial cells) were also susceptible to biMAb-targeted cytolysis. However, the amount of biMAb required to induce half-maximal cytolysis of tumor cells over-expressing the EGF-R molecule (A431) was considerably lower than that required to induce lysis of EGF-R+ tumor or normal cells which express EGF-R at considerably lower density. The ability of such biMAbs to deliver activation signals to T cells was evaluated by Ca++ mobilization and lymphokine production experiments. The soluble anti-EGF-R/anti-CD3 biMAb failed to induce intracellular Ca++ increases, which occurred only after cross-linking induced by an anti-mouse IgG antibody. Secretion of lymphokines (IFN-gamma, TNF-alpha and GM-CSF) was induced by contact of the biMAb-coated effector cells with the relevant tumor target, whereas the soluble biMAb was virtually ineffective. In addition, biMAb-coated effector cells retained the ability to recognize and to lyse EGF-R+ tumor cells for a prolonged period of time. Our data indicate that activation of effector cells targeted by biMAbs can only occur at the tumor site, where cross-linking of surface CD3 molecules is induced by contact with the tumor cells.

Appropriate experimental conditions were devised to demonstrate that CD58 (LFA-3), CD54 (ICAM-1) and CD11a/CD18 (LFA-1) adhesion molecules are the source of signals that regulate nonspecific major histocompatibility complexunrestricted and CD3/T cell receptor (TcR)-triggered cytotoxicity. Using anti-LFA-3 monoclonal antibody (mAb)-treated, interleukin-2 (IL-2)-cultured peripheral blood lymphocytes (PBL) or cloned CD3+/CD8+ cells as lymphocyteactivated killer (LAK) effectors, and ligand (CD2)-negative tumor cell lines as targets, a down-regulation of CD3− and CD3+ cell-mediated LAK activity was consistently observed. Anti-LFA-3 mAb also down-regulated tumor cell lysis when T cell clones were triggered to kill P815 cells through stimulation of the CD3/TcR complex by an anti-CD3 mAb. The inhibitory effect of anti-LFA-3 mAb was not prevented by stimulatory anti-CD2 mAb. Anti-ICAM-1 mAb treatment of IL-2-cultured PBL consistently up-regulated LAK cytotoxicity against tumor target cells. However, this effect was only exerted on CD3− LAK effectors. Anti-LFA-1 mAb blocked conjugate formation between effector cells and tumor target cells, thus rendering this model unsuitable to evaluate the regulatory role of LFA-1. Therefore, a cytotoxicity model system was applied in which a hybrid anti-CD3/anti-human red blood cell (HuRBC) mAb triggers cytolytic T cells to lyse HuRBC. In these experiments, anti-LFA-1 mAb markedly up-regulated the lytic ability of IL-2-cultured PBL. We conclude that mAb against LFA-3, ICAM-1 and LFA-1 molecules deliver regulatory signals for LAK cells and cytotoxic T lymphocytes. As these stimuli may be delivered by ligands expressed on tumor targets as well as on other immune competent and inflammatory cells, the present observations are relevant in the context of both the host's immune response against tumors and the general functioning of the immune system.

A minor subset of T lymphocytes express a TCR composed of gamma and delta chains. This subset differs from conventional T cells for a number of phenotypic and functional characteristics. TCR gamma/delta+ cells simultaneously lack both CD4 and CD8 antigens. Cloning of CD4-8- peripheral blood lymphocytes, under limiting dilution conditions, revealed that they are homogeneously composed of cytolytic cells which efficiently lyse tumor target cells. Formal proofs have been provided that TCR gamma/delta+ cells are able to recognize antigens. For example, they proliferated in response to allogeneic mixed lymphocyte culture (MLC); in addition, MLC-derived TCR gamma/delta+ cells specifically lysed PHA-induced blast cells bearing the stimulating alloantigens. The selection of monoclonal antibodies specific for TCR gamma/delta molecules allowed to identify two distinct subsets of TCR gamma/delta+ cells. Both of these mABs, termed BB3 and delta TCS-1 respectively, induced specific activation of cloned cells expressing the corresponding antigenic determinants (as assessed by measurements of intracellular Ca++ and/or lymphokine production or cytolytic activity). Analysis of the distribution of subsets expressing different forms of TCR gamma/delta, showed that the BB3-reactive form is prevalent in the peripheral blood. In contrast, delta-TCS-1-reactive cells are relatively infrequent in peripheral blood but represent the majority of TCR gamma/delta+ cells in tissues.

Dilated cisternae of the ER resembling Russell Bodies (RBs) are induced in light (L) chain producing myeloma cell lines by transfection of a mu heavy (H) chain gene lacking the first constant domain (mu delta CH1). RBs do not appear to be tissue specific, since they are also induced in a rat glioma cell line transfected with mu delta CH1 and L chain genes. Efficient RB biogenesis requires H-L assembly and polymerization. The mutant Ig is partially degraded in a pre-Golgi compartment. The remnant, however, becomes an insoluble lattice when intersubunit disulphide bonds are formed. The resulting insoluble aggregate accumulates in RBs. Replacing the COOH-terminal cysteine of mu delta CH1 chains with alanine reverses the RB-phenotype: the double mutant mu ala delta CH1 chains assemble noncovalently with L and are secreted as H2L2 complexes. Similarly, secretion of mu delta CH1 chains can be induced by culturing transfectant cells in the presence of reducing agents. The presence of RBs does not alter transport of other secretory or membrane molecules, nor does it affect cell division. Resident proteins of the ER and other secretory proteins are not concentrated in RBs, implying sorting at the ER level. Sorting could be the result of the specific molecular structure of the insoluble lattice. We propose that RBs represent a general response of the cell to the accumulation of abundant, nondegradable protein(s) that fail to exit from the ER.

A patient is described who presented with a chronic lymphocytic leukemia (CLL) and later developed a lymphoblastic lymphoma. The cells from the CLL were typical mature B lymphocytes as could be assessed by morphologic, cytochemical, and surface marker analyses. The cells from the lymphoblastic lymphoma were immature B cells that expressed CD10, CD20, and HLA-DR markers, but not surface Ig or cytoplasmic mu chains, and were negative for terminal deoxynucleotidyl transferase (TdT). The cells of two continuous cell lines, obtained from the bone marrow and the peripheral blood of the patient, had the same phenotype as the lymphoblastic lymphoma cells, did not contain the Epstein-Barr virus genome, and displayed malignant features in vitro, including the capacity to form colonies in agar. The two cell lines also shared identical chromosomal abnormalities, a finding which suggests that they derived from the same malignant cell already present in vivo. Such chromosomal abnormalities were not seen in the karyotype of the peripheral blood cells at the onset of the disease. Analysis of the Ig heavy chain genes using a DJ-specific probe showed the very same monoclonal rearrangement in the cells from the B-CLL, the lymphoblastic lymphoma and the two cell lines, thus demonstrating their common clonal origin. By contrast, a monoclonal rearrangement of the lambda chain gene locus was found in the B-CLL cells only, a finding consistent with their exclusive capacity to express surface IgM lambda. This patient represents a rare case in whom a chronic lymphoproliferative disorder with mature malignant cells transforms into a lymphoblastic lymphoma characterized by cells frozen at a very early maturational stage. The possible mechanisms leading to such transformation within the same cell clone are discussed.

Thymocytes differentiate in the thymic microenvironment into immunocompetent T cell through the interaction with a variety of accessory cells, including thymic epithelial cells (TEC). TEC plays an important role in the selection process presenting self antigens in association with major histocompatibility complex (MHC) molecules to the maturing T cells. The T cell receptor recognizes the self antigen-MHC complex, but other surface molecules help stabilize this interaction. Thus, the CD2/LFA-3 and LFA-1/intercellular adhesion molecule 1 pairs have been shown to participate in the binding between lymphoid cells and TEC. Here we describe an integrin of the very late activation antigen subfamily composed by the known beta 1 chain and by a novel alpha chain. This adhesion molecule is expressed on the surface of medullary TEC and is involved in the adhesion between TEC and thymocytes, but not peripheral blood T lymphocytes.