Search

The Natural Background Level (NBL), suggested by UE BRIDGE project, is suited for spatially distributed datasets providing a regional value that could be higher than the Threshold Value (TV) set by every country. In hydro-geochemically dis-homogeneous areas, the use of a unique regional NBL, higher than TV, could arise problems to distinguish between natural occurrences and anthropogenic contaminant sources. Hence, the goal of this study is to improve the NBL definition employing a geostatistical approach, which reconstructs the contaminant spatial structure accounting geochemical and hydrogeological relationships. This integrated mapping is fundamental to evaluate the contaminant's distribution impact on the NBL, giving indications to improve it. We decided to test this method on the Drainage Basin of Venice Lagoon (DBVL, NE Italy), where the existing NBL is seven times higher than the TV. This area is notoriously affected by naturally occurring arsenic contamination. An available geochemical dataset collected by 50 piezometers was used to reconstruct the spatial distribution of arsenic in the densely populated area of the DBVL. A cokriging approach was applied exploiting the geochemical relationships among As, Fe and NH4+. The obtained spatial predictions of arsenic concentrations were divided into three different zones: i) areas with an As concentration lower than the TV, ii) areas with an As concentration between the TV and the median of the values higher than the TV, and iii) areas with an As concentration higher than the median. Following the BRIDGE suggestions, where enough samples were available, the 90th percentile for each zone was calculated to obtain a local NBL (LNBL). Differently from the original NBL, this local value gives more detailed water quality information accounting the hydrogeological and geochemical setting, and contaminant spatial variation. Hence, the LNBL could give more indications about the distinction between natural occurrence and anthropogenic contamination., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Palliative sedation therapy (PST) is indicated for and used to control refractory symptoms in cancer patients undergoing palliative care. We aimed to evaluate whether PST has a detrimental effect on survival in terminally ill patients., Methods: This multicenter, observational, prospective, nonrandomized population-based study evaluated overall survival in two cohorts of hospice patients, one submitted to palliative sedation (A) and the other managed as per routine hospice practice (B). Cohorts were matched for age class, gender, reason for hospice admission, and Karnofsky performance status., Results: Of the 518 patients enrolled, 267 formed cohort A and 251 cohort B. In total, 25.1% of patients admitted to the participating hospices received PST. Mean and median duration of sedation was 4 (standard deviation 6.0) and 2 days (range 0-43), respectively. Median survival of arm A was 12 days [90% confidence interval (CI) 10-14], while that of arm B was 9 days (90% CI 8-10) (log rank = 0.95, P = 0.330) (unadjusted hazard ratio = 0.92, 90% CI 0.80-1.06)., Conclusion: PST does not shorten life when used to relieve refractory symptoms and does not need the doctrine of double effect to justify its use from an ethical point of view.

The means by which methotrexate (MTX) mediates immunosuppression at low doses remains to be elucidated. MTX has been shown to inhibit the adherence of neutrophils and fibroblasts to endothelial cells in vitro. The hypothesis that MTX treatment may affect cellular adherence by downregulating cell adhesion molecule expression formed the rationale for these studies. Previous studies of rat cardiac transplant recipients in our laboratory demonstrated that low-dose MTX treatment alone significantly inhibits the expression of the leucocyte beta 2 integrin subunit, CD18. These investigations have addressed whether low-dose MTX treatment might also affect the expression of the beta-integrin counter-receptor, ICAM-1, a cell adhesion molecule which may be induced on endothelial cells during an immune response. The degree to which low-dose cyclosporine A and low-dose MTX treatment alone, and in combination, impact cell adhesion molecule expression has been studied in Brown Norway (BN) to Lewis (Lew) rat accessory cervical heart allografts. According to both Northern blot and immunohistochemical analysis, ICAM-1 expression was upregulated in graft regional lymph nodes and in the spleen of untreated cardiac allograft recipients within 6 h post-transplantation. Despite induction of VCAM-1 expression, ICAM-1 expression remained low or undetectable in cardiac allograft tissue as measured both by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemical analysis. These data suggest that ICAM-1 may function in leucocyte trafficking through lymphoid organs, such as the lymph nodes and spleen, but not directly in graft leucocyte recruitment during BN to Lew rat cardiac allograft rejection. Despite prolonged allograft survival with cyclosporine A alone and combination cyclosporine A/MTX, these treatments did not result in diminished steady-state ICAM-1 mRNA levels in regional lymph nodes or spleen of cardiac allograft recipients. MTX treatment alone, however, substantially diminished ICAM-1 expression in allograft recipient lymphoid tissues. These studies demonstrate for the first time in vivo using a rat model of acute allograft rejection that MTX but not cyclosporine treatment downregulates cell adhesion molecule expression. Low-dose MTX treatment alone, however, is not sufficient to result in prolonged BN to Lew rat cardiac allograft survival. The means by which combination low-dose cyclosporine A and MTX treatment results in prolonged rat cardiac allograft survival over low-dose cyclosporine treatment alone remain(s) to be clarified.

Recent advances in the study of the molecular basis of inflammation suggest that cell-cell interactions mediated by specific adhesion molecules could be new targets for immunosuppression. Methotrexate (MTX)-treated cells in vitro have demonstrated decreased neutrophil-endothelial cell adhesion associated with increased release of adenosine from endothelial cells, while the direct role of cyclosporine A (CSA) in the regulation of cell adhesion molecule (CAM) expression is less well-defined. Since the adhesion of leucocytes to endothelial cells via CAMs is necessary for leucocyte extravasation and infiltration into graft tissue during allograft rejection, these studies have addressed the hypothesis that MTX treatment of cardiac transplant recipients may affect cellular adherence by downregulating cell adhesion molecule expression. Using a vascularized method of rat cardiac transplantation, our studies have previously demonstrated that low doses of the immunosuppressive agents CSA and MTX, when used in combination, significantly increase allograft survival. According to reverse transcriptase-polymerase chain reaction (RT-PCR) methodology to measure changes in steady-state CD18 mRNA levels, and immunohistochemistry to assess transplant CD18 protein levels in situ, both CD18 transcript and protein levels were significantly increased in untreated allografts when compared to isograft tissues on days 3 through to 7 post-transplant. Whereas, both low-dose CSA alone and low-dose MTX alone treatment resulted in similar levels of graft leucocyte infiltration, MTX-treated recipients demonstrated lower levels of CD18 expression when compared to low-dose CSA alone treatment. The results of immunohistochemical staining for T cells, where significantly fewer T cells were observed in rat cardiac allografts after low-dose MTX treatment alone compared to low-dose CSA treatment, were noteworthy. Results of these studies indicate that CD18 expression and infiltrating T cell numbers in Brown Norway (BN) to Lewis (Lew) rat cardiac allografts are significantly diminished with low-dose MTX treatment. The immunosuppressive effects of MTX, therefore, may be related to its ability to interfere with an early step during the cell-mediated immune response, namely the firm binding or 'adhesion' of leucocytes to the endothelium during transendothelial migration.

Experimental and clinical studies have yet to determine the extent to which methotrexate (MTX) or cyclosporine A (CSA) treatment alone affects the expression in vivo of tumour necrosis factor-alpha (TNF alpha), a cytokine produced primarily by macrophages and believed to be directly involved in the pathogenesis of cardiac allograft rejection. In light of previously published findings from this laboratory examining the effects of combination CSA/MTX treatment, these studies were designed to examine the individual effects of CSA and MTX upon TNF alpha gene expression post-transplant (post-tx) using an accessory cervical heart transplant model in the rat. These studies have focused on a highly sensitive method with which to detect changes in gene expression, reverse transcriptase-polymerase chain reaction (RT-PCR) methodology and enzyme-linked immunosorbent assay (ELISA) assessment of transplant TNF alpha protein levels. Both techniques consistently demonstrated biphasic TNF alpha expression in cardiac transplant tissue obtained from untreated allograft recipients during the first week post-tx in contrast to isograft recipients. Previously demonstrated in combination to prolong cardiac allograft survival, low-dose MTX and low-dose CSA were each evaluated alone in the course of these studies to determine their impact on TNF alpha gene expression. While TNF alpha levels were up-regulated during untreated allograft rejection, both TNF alpha RNA and protein were significantly diminished with low-dose combination CSA/MTX treatment, with CSA alone, but not significantly with MTX treatment alone. In conclusion, TNF alpha gene expression in untreated allografts is consistent with the hypothesis that TNF alpha may play a role in events leading to allograft rejection. Results of these studies indicate that TNF alpha levels are significantly regulated in vivo by CSA but not by MTX treatment. These studies further implicate a role for low-dose MTX in mediating statistically significant immunosuppressive effects in conjunction with low-dose CSA.

Background: Since 1990 the combination of 5-fluorouracil plus levamisole has been considered the standard therapy for stage B2-C resected colon cancer in the adjuvant setting. Since 1992, 14 cases of multifocal leukoencefalopathy following 5-fluorouracil and levamisole therapy have been reported., Patients and Methods: Two cases of this rare but severe neurological syndrome, observed at our Institution within the scope of the INTACC (Intergruppo Nazionale Terapia Adiuvante Colon Carcinoma, Italy) 01 study, are described., Conclusions: The clinical and radiological features of the syndrome and the relationships between therapy (with the possible pivotal role played by levamisole) and onset of the multifocal leukoencephalopathy are analyzed in light of the literature data.

Cyclosporine A (CSA) is the standard immunosuppressive agent used in human cardiac transplantation to prevent rejection; however, adverse side effects have been reported at therapeutic doses. Therefore, a need remains for the implementation of specific therapies designed to achieve transplant success with a minimum of undesirable side effects. The aims of the present study were: (1) to evaluate the efficacy of a low-dose CSA (1.0 mg/kg/day) / methotrexate (MTX) (450 micrograms/kg/week) combination therapy in prolonging rat cardiac allograft survival, and (2) to determine the effects of low-dose CSA/MTX on interleukin-2 (IL-2) gene expression in rat cardiac allografts. The average time to rejection of newborn donor Brown Norway (BN) rat hearts transplanted into the ear pinnae of CSA/MTX-treated adult Lewis recipients, measured by the absence of electrocardiographic (ECG) activity, more than doubled from day 8 post-transplantation (post-tx) to day 18 post-tx when compared to allografts in untreated control recipients (p < or = 0.01). Northern blot analysis demonstrated that IL-2 mRNA transcripts in cardiac allografts treated with low-dose CSA/MTX were detected as early as day 1 post-tx, and at increasing levels as rejection progressed post-tx. When IL-2 gene expression in allografts from CSA/MTX-treated recipients was compared to levels in allografts from untreated recipients, no significant difference in the pattern of IL-2 induction was observed. In contrast, IL-2 mRNA transcripts were not detected post-tx in allografts from recipients treated with high-dose (15 mg/kg/day) CSA or in cardiac isografts. The presence of IL-2 gene transcripts, therefore, appears to be allograft-specific.(ABSTRACT TRUNCATED AT 250 WORDS)

The association between MHC polymorphisms and autoimmune thyroid disease has been complicated by the observation of MHC class II antigen expression by the human thyroid gland. It is possible that the MHC associations observed in animal and human population studies may have mechanistic explanations at the level of the thyroid cell. There is evidence for expression of HLA-DR allospecific antigen in both normal and abnormal human thyroid cells, with enhanced expression in patients with autoimmune thyroid disease. Such MHC class II expression appears to be mediated primarily by lymphokine secretion from intrathyroidal T lymphocytes. Thyroid cell HLA-DR antigen participates in activation and amplification of T cells and is likely to be involved in presentation of thyroid antigen to the immune system. The relationship between these immune interactions and the initial events leading to the development of autoimmune thyroid disease remains to be understood.