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Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic lung disease of unknown aetiology. There is growing evidence that the lung microbiota may play a role in IPF. However, no study has investigated the functional impact of the short-chain fatty acids (SCFAs) on primary bronchial epithelial cells (PBECs) and disease pathogenesis. Therefore, we investigated the influence of acetate, propionate, and butyrate on PBECs from healthy controls and subjects with IPF. Subjects diagnosed with IPF (n=201) and healthy controls (n=40) were prospectively recruited and underwent bronchoalveolar lavage. Bacterial DNA was isolated and 16S rRNA gene sequencing undertaken to characterise bacterial communities. Untargeted 1H nuclear magnetic resonance spectroscopy-based metabolomics and targeted gas chromatography-mass spectrometry captured the metabolic profile of these samples. PBECs from healthy controls and subjects with IPF were differentiated at air-liquid interface (ALI) and either left untreated or exposed to the SCFAs. The IPF microbiota was less diverse (P Subjects with IPF display an altered microbiome which is associated with a distinct metabolic signature in the lower airways. Differences in specific bacterial genera and an increased bacterial burden in IPF results in changes in the SCFAs in the airways. In vitro work demonstrates the potential of these SCFAs to shape immunological responses in the lung, mediating the pathogenesis of fibrosis.

Chronic hypersensitivity pneumonitis (CHP) is a scarring lung disease that arises following repeated exposure to antigens. While the lung microbiome is increasingly implicated in respiratory disease, to date, no study has investigated the composition of microbial communities and metabolites in the lower airways in CHP. We prospectively recruited individuals diagnosed with CHP (n=110), idiopathic pulmonary fibrosis (IPF) (n=45) and controls (n=28). Subjects underwent bronchoalveolar lavage with differential cell counts. Bacterial DNA was isolated, quantified by qPCR and 16S rRNA gene sequencing performed to characterise bacterial communities. 1H Nuclear Magnetic Resonance spectroscopy was utilised to capture the metabolic profile of these individuals. Lymphocyte and neutrophil proportions were higher in CHP and IPF, respectively. Evident alterations in the composition and microbial community structure (β-diversity) of the respiratory microbiome were observed in CHP compared to IPF; Staphylococcus was increased in CHP and Actinomyces and Veillonella in IPF. There was an increased bacterial burden in cases compared to controls. Individuals with CHP had significantly reduced α-diversity and bacterial load compared to subjects with IPF. Metabolomics analysis revealed decreased levels of the short-chain fatty acids acetate, propionate and butyrate in CHP compared to IPF. Subjects with CHP and IPF displayed an altered microbiome and a distinct metabolic signature in the lower airways. Collectively, differences in specific bacterial genera may provide a low-level antigenic stimulus for repetitive alveolar injury. Further elucidation of these differences will improve our understanding of crosstalk between microbe and host and its role in the progression of fibrosis.

Introduction: The optimal treatment for small, asymptomatic, nonfunctioning pancreatic neuroendocrine neoplasms (NF-PanNEN) is still controversial. European Neuroendocrine Tumor Society (ENETS) guidelines recommend a watchful strategy for asymptomatic NF-PanNEN 18 years, the presence of asymptomatic sporadic NF-PanNEN ≤2 cm proven by a positive fine-needle aspiration (FNA) or by the presence of a measurable nodule on high-quality imaging techniques that is positive at 68Gallium DOTATOC-PET scan. Conclusion: The ASPEN study is designed to investigate if an active surveillance of asymptomatic NF-PanNEN ≤2 cm is safe as compared to surgical approach. © Copyright © 2020 Partelli, Ramage, Massironi, Zerbi, Kim, Niccoli, Panzuto, Landoni, Tomazic, Ibrahim, Kaltsas, Bertani, Sauvanet, Segelov, Caplin, Coppa, Armstrong, Weickert, Butturini, Staettner, Boesch, Cives, Moulton, He, Selberherr, Twito, Castaldi, De Angelis, Gaujoux, Almeamar, Frilling, Vigia, Wilson, Muffatti, Srirajaskanthan, Invernizzi, Lania, Kwon, Ewald, Rinzivillo, Nessi, Smid, Gardini, Tsoli, Picardi, Hentic, Croagh, Toumpanakis, Citterio, Ramsey, Mosterman, Regi, Gasteiger, Rossi, Smiroldo, Jang and Falconi.

This research work presents new insights regarding biomonitoring studies, source apportionment at a local scale, and influence of wind and topography on dispersion of atmospheric pollutants in a complex scenario. The monitoring network consisted of transplanted Tillandsia capillaris biomonitors throughout 3 sampling periods in order to assess the effects of the different emission sources and their atmospheric dispersions in a region from the province of Córdoba, Argentina. The elements Mn, Fe, Co, Ni, Cu, Zn, Cd and Pb, were analyzed by Flame Atomic Absorption Spectrometry (FAAS, pseudo-total metal content) and As, Ba, Ca, Ce, Cr, Cs, Eu, Fe, Hf, La, Lu, Na, Rb, Sb, Sc, Se, Sm, Ta, Tb, Th, U, Yb and Zn, by Neutron Activation Analysis (NAA, total metal content). The following atmospheric emission sources were characterized in the study area: cement plant, with emissions of Cd, Pb, CoFAAS, Ni and Ca; waste dumping site fires, with emissions of the elements Sm, Yb, Ba, La, ZnNAA, Ce, Th and Hf; brick kilns with emissions of the elements Na, Ba, As, Se, Cr, Tb, Sc, FeNAA, CoNAA, Ta; vehicular traffic with emissions of ZnFAAS and Sb and soil re-suspension with emissions of Ni, ZnFAAS, Br, U, Mn, Rb and Eu. It was noticeable that topography played an important role in the dispersion of the pollutants in the study area and this was reflected in the biomonitors. Our results provide a step forward in the application field of this biomonitoring species for characterizing emission sources in a complex scenario at a local scale. Fil: Abril, Gabriela Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Instituto Multidisciplinario de Biología Vegetal (p); Argentina Fil: Wannaz, Eduardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Instituto Multidisciplinario de Biología Vegetal (p); Argentina Fil: Mateos, Ana Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Instituto Multidisciplinario de Biología Vegetal (p); Argentina Fil: Invernizzi, R.. Comision Nacional de Energia Atomica; Argentina Fil: Plá, R. R.. Comision Nacional de Energia Atomica; Argentina Fil: Pignata, M. L.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Instituto Multidisciplinario de Biología Vegetal (p); Argentina

A monoclonal anti-idiotype antibody (IgG1k MoAb 3B11D4) raised against the amyloidogenic DEP lambda chain dimer binds a conformational idiotope also present on the monoclonal DEP IgA immunoglobulin. MoAb 3B11D4 does not recognize the reduced and alkylated lambda chain monomers, nor the 15-17-kDa fibrillar light chain fragments which have the same N-terminal sequence of the urinary light chains. The lack of about 70 amino acid residues of the C terminal of the protein prevents the formation of the self-limiting dimer and may facilitate the deposition of the fragments into amyloid fibrils. MoAb 3B11D4 recognizes the plasma cell clone in bone marrow and 9% of circulating B lymphocytes. Panning experiments demonstrate that this antibody has the capability to selectively eliminate the idiotype positive cells from peripheral blood. Antibodies with these characteristics could become a useful tool for better understanding the pathogenesis of the disease and for new therapeutic options.

The main aim of this study is evaluating the suicide/homicide rate of the Italian security guards population compared to other armed and general populations during a recent period.The authors reviewed the incidence of suicides and homicides among security guards from 1996 to 2006 and, where information was available, a comparison was made with Italian population adapted by age. Comparisons with the general population were also made.The average rate of firearms related suicide among the security guards population during the established period was 11.7 per 100,000 persons-years (95% CI = 6.6-16.7) compared to a guns-related suicide rate of 0.7 per 100,000 person-years, (95% CI = 0.6-0.7) and a non-guns related rate of 5.5 per 100,000 persons-years, (95% CI = 5.2-5.9) for the general population adjusted for age. The overall homicide rate among security guards during the period was 11.4 per 100,000 person-years (95% CI = 6.2-15.4) compared with the homicide rate for the Italian population of 5.4 per 100,000 persons-years, (95% CI = 7.3-15.4).The rate of suicide and homicide among the Italian security guards population was higher than the suicide/homicide rate in the general population. These results show that the phenomenon we have described needs attention and specific prevention activities.

Summary This retrospective epidemiologic study on 256 cases of Acute Promyelocitic Leukemia (APL) observed in 20 Italian hematology centers between 1980 and 1988 demonstrated that APL is different from the other acute non-lymphocytic leukemias (ANLL). The male/female ratio was 0.9; median age at diagnosis was 40 years (with 80% of patients between 15 and 54 years of age). The minimal annual incidence of APL in Italy per 1,000,000 inhabitants was estimated to be 0.6; an increased incidence was observed in spring and in autumn. The overall median survival duration of APL patients was 12.6 months. From an epidemiological point of view APL is a distinctive subtype of ANLL.

High-dose dexamethasone (HD-Dex) has been reported to benefit AL amyloidosis patients with varying response rates. Our preliminary experience with the usual HD-Dex schedule indicated that the induction phase was rather toxic in AL patients. We therefore adopted a milder schedule consisting of dexamethasone 40 mg on d 1-4 q21 d for up to eight cycles. Overall 8 out of 23 (35%) treated patients responded to treatment in a median time of 4 months (range 2-6 months) without significant toxicity. This regimen may be considered front-line therapy when autologous stem cell transplantation is not feasible and when a rapid response is particularly important.

Missense mutations in the alpha-synuclein gene were associated with a familial Parkinson's disease, and alpha-synuclein is a major component of Lewy bodies, the intracellular inclusions that neuropathologically characterize Parkinson's disease. We investigated the neurotoxic activity of the nonamyloid component (NAC) of senile plaque, the fibrillogenic fragment (61-95) of alpha-synuclein, in vitro and in vivo. Rat primary mesencephalic neurons were exposed for 6 days to low concentrations of preaggregated NAC (0.5-10.0 microM). The number of dopaminergic neurons and dopamine content were both reduced with no effect on the general viability of the cells. At higher concentrations (25-100 microM), the neurotoxic effect of NAC was extended to all neurons. Preaggregated NAC was also toxic on a PC12 dopaminergic cell line differentiated with nerve growth factor. The intracellular localization of NAC has been identified by the exposure of neuronal cells to fluorescent peptide. In vivo application of aggregated NAC in the substantia nigra induced loss of dopaminergic neurons. Our data illustrate the selective neurotoxic effect of NAC for dopaminergic neurons and support the central role of alpha-synuclein in the pathogenesis of Parkinson's disease.

The objective of this study was to evaluate the cycling status of cord blood (CB)-derived colony-forming cells (CFC) and long-term culture-initiating cells (LTC-IC), and their recruitment into the S-phase of the cell cycle. By using the cytosine arabinoside (Ara-C) suicide approach, we found that only small proportions of both CFC and LTC-IC were in the S-phase of the cell cycle. These estimates were confirmed by flow cytometric DNA analysis, which showed that 96 +/- 2% of CB-derived CD34+ cells were in G0/G1 and only 1.6 +/- 0.4% in the S-phase. Staining of CD34+ cells with an antistatin monoclonal antibody, a marker of the G0 phase, indicated that among CD34+ cells with a flow cytometric DNA content typical of the G0/G1 phase 68 +/- 7% of cells were in the G0 phase of the cell cycle. Incubation (24 h) with interleukin 3 (IL-3), recombinant human stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) significantly increased the proportion of cells in the S-phase for both CFC and LTC-IC without inducing any loss in numbers. Flow cytometric DNA analysis also showed an increase in CD34+ cells in the S-phase upon continuous exposure to these cytokines. Our findings indicate that: (i) very few CB-derived CFC or LTC-IC were in the S-phase of the cell cycle; (ii) a substantial amount of CD34+ cells with a flow cytometric DNA content typical of the G0/G1 fraction was cycling, as found in the G1 phase of the cell cycle; and (iii) 24-h incubation with IL-3, SCF and G-CSF could drive a proportion of progenitor cells into the S-phase without reducing their number. These data might be useful for gene transfer protocols and the ex vivo expansion of CB-derived progenitor cells.

Despite the fact that several prognostic systems for myelodysplastic syndromes (MDS) have been proposed, few studies have been designed to test their effectiveness in independent patient populations. The aim of this study was to compare the prognostic value of 8 previously described prognostic systems in a series of consecutive MDS patients observed at a single institution over a 10-year period.One hundred and forty-three patients were diagnosed as having myelodysplastic syndrome (MDS) according to the French-American-British (FAB) criteria. They were studied retrospectively in order to assess the prognostic value of the FAB classification and 7 other prognostic systems.On the basis of data at diagnosis, all investigated systems effectively stratified patients into groups with different life expectancies and identified a subset of patients with poor clinical outcome. However, the systems had different outcomes concerning median survival of patients classified as low-risk, ranging from less than 3 years for the Mufti scoring system to more than 8 years for the FAB classification modified according to Rosati et al. Moreover, patient distribution into different risk categories was quite different with the different prognostic systems.When applied to our case series, some of the prognostic systems had a much lower prognostic value than in the patient population from which they derived. This evidence suggests that testing of prognostic systems in independent case series is necessary before using the systems in clinical practice.

Between July 1992 and June 1996, 901 new cases of adult acute lymphoblastic leukaemia were recorded in the GIMEMA Archive of Adult Acute Leukaemia; 21 of them (2.3%) had a previous primary malignancy (PM). We found that secondary acute lymphoblastic leukaemia cases (sALL) presented with older age, a high incidence of pre-pre-B immunophenotype and a significantly higher prevalence of cancer among relatives compared to de novo ALL. The leukaemogenic activity of the cytotoxic drugs employed for the treatment of PM may have played a potential role in only a proportion of patients, opening the possibility that some sALL patients may have developed two or more malignancies due to individual predisposing factors.

Multiple myeloma (MM) with meningeal involvement is a very rare phenomenon. Only 37 cases of plasma cell neoplasia (MM and plasma cell leukemia) with meningeal involvement have been reported.A 60-year-old male with stage IIIA light lambda chain MM returned nine months after the diagnosis with back pain, lower right extremity paresthesias and gait disturbance. A lumbar puncture revealed atypical plasma cells in the cerebrospinal fluid (CSF), and immunocytochemical studies showed a cytoplasmic monoclonal light lambda chain. A diagnosis of myelomatous meningitis was made, and the patient received intrathecal chemotherapy and craniospinal irradiation. He died six months after the diagnosis of meningeal disease.The present case and a review of the literature show that clinical manifestations of meningeal myeloma are non-specific. MM with meningeal involvement is accompanied frequently by circulating atypical plasma cells or plasma cell leukemia. Atypical plasma cells in the CSF are an important finding for the diagnosis of meningeal myeloma, and their neoplastic nature can be best identified by immunocytochemical analyses. Patients with meningeal myelomatosis can have a good response to treatment initially, but their prognosis is poor.

A 23-year-old male patient developed aplastic anemia and was treated with cyclosporin A and rhG-CSF. Bone marrow biopsy showed an improvement in cellularity with a recovery of all hematopoietic precursors after nine weeks of therapy. WBC increased after two weeks of treatment, mostly due to an increase in the absolute granulocyte cell count. Hb, RBC, Plts and reticulocytes showed an increase six weeks after the beginning of therapy. Of the serum cytokines, EPO levels progressively decreased, while sTfR increased in peripheral blood. A reverse correlation between blood neutrophil count and serum levels of G-CSF was observed, indicating an increased clearance of G-CSF. Finally, sIL-2R showed a rapid increase in the first week of treatment and prior to the increase in PMN cells. Thus, the use of cyclosporin A and rhG-CSF in our patient induced a complete recovery of hemopoiesis, and this may be explained by a synergic effect induced by the capacity of cyclosporin A to remove inhibitory factors and the stimulatory activity of rhG-CSF.

The authors present a prospective trial in 34 patients undergoing elective colo-rectal surgery. Seventeen patients received 2 g of piperacillin; intravenously, 30' min before surgery, and again 5 times, postoperatively, every 6 hours. The other 17 patients received 2 g of the same drug, intravenously, every 12 hours, immediately after surgery, at least for 5 days. The first group showed postoperative wound infections, with a rate of 11.75%. In the second group 5 patients showed postoperative infection, with a rate of 29.41%. There were 3 wound infections, one urinary tract infection and two pleuropolmonitis (a patient had two infections simultaneously). No side effects were registered. The better results registered in the first group, suggest the use of piperacillin in shortterm prophylaxis. This choice is attractive because of the comparison with other antibiotics, used in a similar way, shows similar results.

Although Kaposi's sarcoma became very well-known with the outbreak of AIDS, this pathology in the classic Mediterranean form is still unusual and obscure. Nowadays we identify four types of Kaposi's sarcoma: 1) the classic Mediterranean form, 2) the endemic African one, 3) the therapeutical in immunosuppressed patients, 4) the epidemic AIDS-related one. We report a very rare case of familial Kaposi's sarcoma: the father (72 y.o.) manifested Kaposi's sarcoma in 1989 with several angiomatoid nodules on the penis and hands; the son (31 y.o.) presented in 1991 only one little nodule on the penis. The right therapy in these cases (patients with a small number of localizations) was to remove all the tumors and to wait: whereas in other cases it's preferable to use radio- or chemo-therapy or immunomodulator agents. We studied the patients and identified their form of Kaposi like the classic one not completely related (the son) to the HLA DR5, which is the HLA-phenotype most frequent in this sarcoma. Moreover we stress the rarity of genital localization in the classic form, instead it is very common (20%) in the AIDS-related one.

The effect of amineptine (1.25-20 mg/kg i.p.), an antidepressant inhibiting dopamine uptake, on extracellular concentrations of dopamine was studied in the rat striatum and nucleus accumbens by using the microdialysis technique and two Ca++ concentrations (1.26 and 3.4 mM) in the perfusion medium. In one experiment the effect of amineptine was studied on extracellular concentrations of dopamine and noradrenaline in the frontal cortex perfused with a medium containing 1.26 mM Ca++. Basal extracellular concentrations of dopamine in the striatum and nucleus accumbens were significantly higher at 3.4 mM Ca++. At 5 to 20 mg/kg, amineptine dose-dependently increased extracellular dopamine in the striatum and nucleus accumbens. No differences were found in the effect of amineptine in the two brain regions at the two calcium concentrations. When extracellular dopamine was expressed as a percentage of basal values, amineptine (20 mg/kg) caused greater increases in rats perfused with 1.26 mM Ca++ than in rats perfused with 3.4 mM Ca++ in both brain regions. A similar effect was found when 10 microM amineptine was infused through the dialysis fiber. The effect of 10 mg/kg i.p. of amineptine on dopamine output in the two brain regions was prevented by infusing 1 microM tetrodotoxin in the dialysis fiber. In the frontal cortex, 10 and 20 mg/kg of amineptine significantly raised dopamine and noradrenaline concentrations, whereas 5 mg/kg only increased noradrenaline output significantly. At 10 mg/kg i.p., amineptine also increased extracellular noradrenaline in the dorsal hippocampus. Amineptine had no consistent effects on the concentrations of dihydroxyphenylacetic acid and homovanillic acid in the various brain regions.(ABSTRACT TRUNCATED AT 250 WORDS)

In this paper we describe a successfully treated case of hyperosmolar hyperglycemic non ketotic coma (HHNC). The HHNC was observed in a patient affected by Waldenström's macroglobulinemia, associated with type II diabetes and complicated by pulmonary tuberculosis. Hyperosmolar hyperglycemic nonketotic coma is a clinical condition with a high mortality rate associated with a severe increase in blood viscosity. This increase in blood viscosity justifies several clinical manifestations of the HHNC. We believe that an increase in the blood viscosity produced by the simultaneous presence of the single diseases mentioned above may have encouraged the development of hyperosmolar coma in the case reported.

Granular acute lymphoblastic leukemia (ALL) is a rare morphological variant of ALL, characterized by cytoplasmic azurophil granules or inclusions, positive for aspecific esterase and acid phosphatase, with heterogeneous features at the ultrastructural level.In an attempt to determine whether the presence of granules or inclusions marks a biologically distinct variety of ALL with peculiar clinical features, a prospective morphological review was undertaken of children entering AIEOP protocols for ALL in the period from 1985 to 1989.Of 531 cases examined, 16 (3%) were found to have greater than 1% granular bone marrow blasts, with 7 cases (1.3%) having greater than 10%. The presence of granules or inclusions was associated with the immunophenotype of "common" ALL. There was no clear association with FAB type L1 or L2 nor with particular clinical or hematological findings at presentation. Complete remission was achieved in all cases; one patient died of infection in remission at 3 months and 2 patients relapsed after 12 and 32 months, respectively, while the others are still in remission after a minimum follow-up of 24 months.In conclusion, granular morphology seems to have no prognostic importance in children ALL.

The authors report the clinical and biological findings of a case of a rare haematological malignant entity, morphologically characterised by a bizarre nuclear abnormality in granulocytes, consisting of exaggerated chromatin clumping and apparent fragmentation of the nucleus, with a loss of segmentation. They emphasize the coexistence of proliferative and dysplastic characteristics as a distinctive marker of this disorder and suggest it may represent a distinct rare morphological entity among the atypical chronic myeloid leukaemias, Ph1 and ber negative.

Publisher Summary Industrial bimetallic catalysts based on titanium and hafnium (Hf) supported on MgCl2 show high activity for the polymerization of ethylene, and an appreciable activity in the polymerization of 4-methyl-1-pentene. The increasing interest acquired by MgCl2 supported catalytic systems containing Hf in the production of polyolefins has recently stimulated the research on the behavior of this metal in polymerization processes. Studies concerning both heterogeneous and homogeneous systems demonstrated the capability of Hf-catalyst to produce high molecular weight polyethylene even if activity is generally lower than with titanium. Thus, the polymer produced by abimetallic catalyst based on MgCl2 supported Hf and Ti should consist of a large amount of moderate molecular weight polyethylene produced on Ti-active sites, and of a small amount of very high molecular weight polyethylene produced on Hf-active sites. The chapter describes the main features of these industrial bimetallic catalysts to use them for producing polyethylenes with different and broad molecular weight distributions. For this purpose, two industrial bimetallic catalysts have been tested in laboratory under industrial conditions; analogous tests are performed with similar catalytic systems containing Titanium or Hf to clarify the relative importance of the two metals on the characteristics of the polyethylene. Finally, experiments with 4-methyl-1-pentene have been performed for a better characterization of the active sites.

Summary Morphine, pentazocine, methadone and pethidine were tested for their ability to modify serotonin metabolism and the depletion of serotonin induced by fenfluramine in the rat forebrain and brainstem. Their analgesic effect was also studied in animals with electrolytic lesions of the nucleus medianus raphe. Except for a reduction of the effect of fenfluramine on brainstem serotonin by the highest dose of pethidine (30 mg/kg), none of the narcotics examined, unlike chlorimipramine, counteracted the depletion of serotonin induced by fenfluramine in forebrain and brainstem. Increased levels of 5-hydroxy-indoleacetic acid in the forebrain and brainstem were found in animals treated with morphine, whereas pentazocine increased serotonin metabolism only in the forebrain. Of methadone and pethidine only the latter significantly decreased serotonin metabolism in the brainstem. All the compounds examined had less analgesic effect in rats with electrolytic lesions of the nucleus medianus raphe. These findings indicate a complex but significant interaction between the various narcotic analgesics and brain serotonin but are against a relationship between their analgesic activity and their inhibition of serotonin uptake into central neurons.