Cold Atmospheric Plasma Targeting Hematological Malignancies: Potentials and Problems of Clinical Translation.

Cold atmospheric plasma is an ionized gas produced near room temperature; it generates reactive oxygen species and nitrogen species and induces physical changes, including ultraviolet, radiation, thermal, and electromagnetic effects. Several studies showed that cold atmospheric plasma could effectively provoke death in a huge amount of cell types, including neoplastic cells, via the induction of apoptosis, necrosis, and autophagy. This technique seems able to destroy tumor cells by disturbing their more susceptible redox equilibrium with respect to normal cells, but it is also able to cause immunogenic cell death by enhancing the immune response, to decrease angiogenesis, and to provoke genetic and epigenetics mutations. Solutions activated by cold gas plasma represent a new modality for treatment of less easily reached tumors, or hematological malignancies. Our review reports on accepted knowledge of cold atmospheric plasma's effect on hematological malignancies, such as acute and chronic myeloid leukemia and multiple myeloma. Although relevant progress was made toward understanding the underlying mechanisms concerning the efficacy of cold atmospheric plasma in hematological tumors, there is a need to determine both guidelines and safety limits that guarantee an absence of long-term side effects.

Histological and Chemical Analysis of Heavy Metals in Kidney and Gills of Boops boops: Melanomacrophages Centers and Rodlet Cells as Environmental Biomarkers.

Industrialization has resulted in a massive increase in garbage output, which is frequently discharged or stored in waterways like rivers and seas. Due to their toxicity, durability, bioaccumulation, and biomagnification, heavy metals (such as mercury, cadmium, and lead) have been identified as strong biological poisons. Their presence in the aquatic environment has the potential to affect water quality parameters and aquatic life in general. Teleosts' histopathology provides a sensitive indicator of pollutant-induced stress, because their organs have a central role in the transformation of different active chemical compounds in the aquatic environment. In particular, the gills, kidneys, and liver are placed at the center of toxicological studies. The purpose of this study is to examine the morphological changes caused by heavy metals in the kidney and gills of Boops boops, with a focus on melanomacrophages centers (MMCs) and rodlet cells (RCs) as environmental biomarkers, using histological and histochemical stainings (hematoxylin/eosin, Van Gieson trichrome, Periodic Acid Schiff reaction, and Alcian Blue/PAS 2.5), and immunoperoxidase methods. Our findings show an increase of MMCs and RCs linked to higher exposure to heavy metals, confirming the role of these aggregates and cells as reliable biomarkers of potential aquatic environmental changes reflected in fish fauna. The cytological study of RCs and MMCs could be important in gaining a better understanding of the complicated immune systems of teleosts.

Effectiveness and safety of dupilumab in patients with chronic rhinosinusitis with nasal polyps and associated comorbidities: a multicentric prospective study in real life.

BACKGROUND: Biologics are currently one of the main treatment options for a number of diseases. The IgG4 monoclonal antibody dupilumab targets the Interleukin-4 receptor alpha chain, thus preventing the biological effects of the cytokines IL-4 and IL-13, that are essential for the Th2 response. Several controlled trials showed that dupilumab is effective and safe in patients with atopic dermatitis (AD), severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), thus resulting in approval by regulatory agencies. Aim of the study was to evaluate the efficacy and safety of dupilumab in adult patients with CRSwNP stratified by common overlapping comorbid conditions. METHODS: We performed a multicenter, observational, prospective study enrolling adult patients with severe CRSwNP who had started dupilumab treatment in the context of standard care from January 2021 to October 2021. Data were collected from twentynine Italian secondary care centers for allergy and clinical immunology, all of which were part of the Italian Society of Allergy, Asthma and Clinical Immunology (SIAAIC). A number of efficacy parameters were used. Patient data were compared using the Wilcoxon test for paired data. All statistical analyses were performed with SPSS version 20 (IBM, Armonk, NY, USA). RESULTS: In total, 82 patients with nasal polyposis were identified. A significant improvement was detected for all the applied efficacy parameters, i.e. 22-item Sino-Nasal Outcome Test (SNOT-22) and bilateral endoscopic nasal polyp score (NPS) scores for CRSwNP, Rhinitis Control Scoring System (RCSS) and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores for allergic perennial rhinitis, Forced Expiratory Volume in the 1st second (FEV1) and Asthma Quality of Life Questionnaire (AQLQ) scores for asthma, Eczema Area and Severity Index (EASI) and Dermatology Life Quality Index (DLQI) scores for AD. A non-significant improvement was also obtained in the Urticaria Activity Score over 7 days (UAS7) for chronic spontaneous urticaria. Treatment with dupilumab was well tolerated. CONCLUSIONS: These data suggest that dupilumab treatment in patients suffering from CRSwNP and associated comorbidities may be suitable. Such outcome, although confirmation by trials is warranted, suggests the possibility to treat different disorders with a single therapy, with favorable effects especially under the cost-effectiveness aspect.

Exosome-Mediated Therapeutic Strategies for Management of Solid and Hematological Malignancies.

Exosomes are small membrane vesicles of endocytic origin containing cytokines, RNAs, growth factors, proteins, lipids, and metabolites. They have been identified as fundamental intercellular communication controllers in several diseases and an enormous volume of data confirmed that exosomes could either sustain or inhibit tumor onset and diffusion in diverse solid and hematological malignancies by paracrine signaling. Thus, exosomes might constitute a promising cell-free tumor treatment alternative. This review focuses on the effects of exosomes in the treatment of tumors, by discussing the most recent and promising data from in vitro and experimental in vivo studies and the few existing clinical trials. Exosomes are extremely promising as transporters of drugs, antagomir, genes, and other therapeutic substances that can be integrated into their core via different procedures. Moreover, exosomes can augment or inhibit non-coding RNAs, change the metabolism of cancer cells, and modify the function of immunologic effectors thus modifying the tumor microenvironment transforming it from pro-tumor to antitumor milieu. Here, we report the development of currently realized exosome modifiers that offer indications for the forthcoming elaboration of other more effective methods capable of enhancing the activity of the exosomes.

Modulation of Cellular Redox Parameters for Improving Therapeutic Responses in Multiple Myeloma.

Raised oxidative stress and abnormal redox status are typical features of multiple myeloma cells, and the identification of the intimate mechanisms that regulate the relationships between neoplastic cells and redox homeostasis may reveal possible new anti-myeloma therapeutic targets to increase the effectiveness of anti-myeloma drugs synergistically or to eradicate drug-resistant clones while reducing toxicity toward normal cells. An alteration of the oxidative state is not only responsible for the onset of multiple myeloma and its progression, but it also appears essential for the therapeutic response and for developing any chemoresistance. Our review aimed to evaluate the literature's current data on the effects of oxidative stress on the response to drugs generally employed in the therapy of multiple myeloma, such as proteasome inhibitors, immunomodulators, and autologous transplantation. In the second part of the review, we analyzed the possibility of using other substances, often of natural origin, to modulate the oxidative stress to interfere with the progression of myelomatous disease.

AllergoOncology: Role of immune cells and immune proteins.

BACKGROUND: Immune cells and immune proteins play a pivotal role in host responses to pathogens, allergens and cancer. Understanding the crosstalk between allergic response and cancer, immune surveillance, immunomodulation, role of immunoglobulin E (IgE)-mediated functions and help to develop novel therapeutic strategies. Allergy and oncology show two opposite scenarios: whereas immune tolerance is desired in allergy, it is detrimental in cancer. AIM: The current review provides an update on the role of immune cells and immune proteins in allergy and cancer fields. METHODS: Authors investigated the role of relevant immunological markers and the correlation with cancer progression or cancer suppression. RESULTS: Activated immune cells such as macrophages 'M1', dendritic cells (DCs), innate lymphoid cells (ILC2), NK cells, Th1, follicular T helper cells (TFH), TCD8+, B lymphocytes and eosinophils have inhibitory effects on tumourigenesis, while tolerogenic cells such as macrophages 'M2,' tolerogenic DCs, ILC3, T and B regulatory lymphocytes appear to favour carcinogenesis. Mastocytes and alarmins can have both effects. RIgE antibodies and CCCL5 chemokine have an anticancer role, whereas IgG4, free light chains, Il-10, TGF-ß, lipocalin-2, CCL1 chemokine promote cancer progression. Fundamental is also the contribution of epigenetic changes regulated by the microRNA in cancer progression. CONCLUSION: This knowledge represents the key to developing new anticancer therapies.

Exposure to nanoparticles and occupational allergy.

PURPOSE OF REVIEW: To provide an update on the possible role of nanoparticles as sensitizing occupational agents and on the influence of nanoparticles-exposure on the appearance/exacerbation of occupational allergy. RECENT FINDINGS: Recent case reports, epidemiological studies, and experimental investigations in cellular and animal models demonstrated the potential for nanomaterials to favor/interfere with occupational allergy. First data are emerging on the sensitizing potential of nanoparticles that can act as haptens linking to proteins, with a formation of a 'corona'. Nanoparticles with carrier protein become a complete antigen and induce specific immune response. Moreover, they act as adjuvant favoring sensitization to bound molecules. The disruption of the respiratory and skin barrier, the modulation of immune response toward Th1 or Th2 immune reaction and the interaction with immune effector cells (mast cells and eosinophil in particular) can explain the potential for nanoparticles to exacerbate pre-existing allergic conditions. SUMMARY: the exposure to nanoparticles represents a possible risk for occupational allergy both in the respiratory tract and in the skin. A deeper knowledge on the role of nanomaterials in the etiology/development of the allergic disease will allow to implement risk assessment and preventive measures for nanosafety in the contest of technological expansion.

Specialized Intercellular Communications via Tunnelling Nanotubes in Acute and Chronic Leukemia.

Effectual cell-to-cell communication is essential to the development and differentiation of organisms, the preservation of tissue tasks, and the synchronization of their different physiological actions, but also to the proliferation and metastasis of tumor cells. Tunneling nanotubes (TNTs) are membrane-enclosed tubular connections between cells that carry a multiplicity of cellular loads, such as exosomes, non-coding RNAs, mitochondria, and proteins, and they have been identified as the main participants in healthy and tumoral cell communication. TNTs have been described in numerous tumors in in vitro, ex vivo, and in vivo models favoring the onset and progression of tumors. Tumor cells utilize TNT-like membranous channels to transfer information between themselves or with the tumoral milieu. As a result, tumor cells attain novel capabilities, such as the increased capacity of metastasis, metabolic plasticity, angiogenic aptitude, and chemoresistance, promoting tumor severity. Here, we review the morphological and operational characteristics of TNTs and their influence on hematologic malignancies' progression and resistance to therapies, focusing on acute and chronic myeloid and acute lymphoid leukemia. Finally, we examine the prospects and challenges for TNTs as a therapeutic approach for hematologic diseases by examining the development of efficient and safe drugs targeting TNTs.

Electrochemical Biosensors in the Diagnosis of Acute and Chronic Leukemias.

Until now, morphological assessment with an optical or electronic microscope, fluorescence in situ hybridization, DNA sequencing, flow cytometry, polymerase chain reactions, and immunohistochemistry have been employed for leukemia identification. Nevertheless, despite their numerous different vantages, it is difficult to recognize leukemic cells correctly. Recently, the electrochemical evaluation with a nano-sensing interface seems an attractive alternative. Electrochemical biosensors measure the modification in the electrical characteristics of the nano-sensing interface, which is modified by the contact between a biological recognition element and the analyte objective. The implementation of nanosensors is founded not on single nanomaterials but rather on compilating these components efficiently. Biosensors able to identify the molecules of deoxyribonucleic acid are defined as DNA biosensors. Our review aimed to evaluate the literature on the possible use of electrochemical biosensors for identifying hematological neoplasms such as acute promyelocytic leukemia, acute lymphoblastic leukemia, and chronic myeloid leukemia. In particular, we focus our attention on using DNA electrochemical biosensors to evaluate leukemias.

Multiple Myeloma Cell-Derived Exosomes: Implications on Tumorigenesis, Diagnosis, Prognosis and Therapeutic Strategies.

Multiple myeloma (MM) is a hematological disease that is still not curable. The bone marrow milieu, with cellular and non-cellular elements, participate in the creation of a pro-tumoral environment enhancing growth and survival of MM plasma cells. Exosomes are vesicles oscillating in dimension between 50 nm and 100 nm in size that can be released by various cells and contribute to the pathogenesis and progression of MM. Exosomes enclose proteins, cytokines, lipids, microRNAs, long noncoding RNAs, and circular RNAs able to regulate interactions between MM plasma cells and adjacent cells. Through exosomes, mesenchymal stem cells confer chemoresistance to MM cells, while myeloma cells promote angiogenesis, influence immune response, cause bone lesions, and have an impact on the outcome of MM patients. In this review, we analyze the role played by exosomes in the progression of monoclonal gammopathies and the effects on the proliferation of neoplastic plasma cells, and discuss the possible employment of exosomes as potential targets for the treatment of MM patients.

Basophils and Mast Cells in COVID-19 Pathogenesis.

Basophils and mast cells are among the principal inducers of Th2 responses and have a crucial role in allergic and anti-parasitic protective immunity. Basophils can function as antigen-presenting cells that bind antigens on their surface and boost humoral immune responses, inducing Th2 cell differentiation. Their depletion results in lower humoral memory activation and greater infection susceptibility. Basophils seem to have an active role upon immune response to SARS-CoV-2. In fact, a coordinate adaptive immune response to SARS-CoV-2 is magnified by basophils. It has been observed that basophil amount is lower during acute disease with respect to the recovery phase and that the grade of this depletion is an important determinant of the antibody response to the virus. Moreover, mast cells, present in a great quantity in the nasal epithelial and lung cells, participate in the first immune response to SARS-CoV-2. Their activation results in a hyperinflammatory syndrome through the release of inflammatory molecules, participating to the "cytokine storm" and, in a longer period, inducing pulmonary fibrosis. The literature data suggest that basophil counts may be a useful prognostic tool for COVID-19, since their reduction is associated with a worse prognosis. Mast cells, on the other hand, represent a possible therapeutic target for reducing the airway inflammation characteristic of the hyperacute phase of the disease.

Metallobiochemistry of ultratrace levels of bismuth in the rat I. Metabolic patterns of 205+206Bi3+ in the blood.

BACKGROUND: The number of the applications of bismuth (Bi) is rapidly and remarkably increasing, enhancing the chance to increase the levels to which humans are normally daily exposed. The interest to Bi comes also from the potential of Bi-based nanoparticles (BiNPs) for industrial and biomedical purposes. Like other metal-based NPs used in nanomedicine, BiNPs may release ultratrace amounts of Bi ions when injected. The metabolic fate and toxicity of these ions still needs to be evaluated. At present, knowledge of Bi metabolism in laboratory animals refers almost solely to studies under unnatural "extreme" exposures, i.e. pharmacologically relevant high-doses (up to thousand mg kg-1) in relation to its medical use, or infinitesimal-doses (pg kg-1 as non-carrier-added Bi radioisotopes) for radiobiology protection, diagnostic and radiotherapeutic purposes. No specific study exists on the "metabolic patterns" in animal models exposed to levels of Bi, i.e. at "environmental dose exposure" that reflect the human daily exposure (µg kg-1). METHODOLOGY: Rats were intraperitoneally injected with 0.8 µg Bi kg-1 bw as 205+206Bi(NO)3 alone or in combination with 59Fe for radiolabelling of iron proteins. The use of 205+206Bi radiotracers allowed the detection and measurement down to pg fg-1 of the element in the blood biochemical compartments and protein fractions as isolated by differential centrifugation, size exclusion- and ion exchange chromatography, electrophoresis, solvent extraction, precipitation and dialysis. RESULTS: 24 h after the administration, the blood concentration of Bi was 0.18 ng mL-1, with a repartition plasma/red blod cells (RBC) in a ratio of 2:1. Elution profiles of plasma from gel filtration on Sephadex G-150 showed four pools of Bi-binder proteins with different molecular sizes (> 300 kDa, 160 kDa, 70 kDa and < 6.5 kDa). In the 70 kDa fraction transferrin and albumin were identified as biomolecule carriers for Bi. In red blood cells, Bi was distributed between cytosol and membranes (ghosts) in a ratio of about 5:1. In the cytosol, low molecular components (LMWC) and the hemoglobin associated the Bi in a ratio of about 1.8:1. In the hemoglobin molecule, Bi was bound to the beta polypeptide chain of the globin. In the ghosts, Bi was detected at more than one site of the protein fraction, with no binding with lipids. Dialysis experiments and the consistently high recovery (80-90 %) of 206Bi from chromatography of 206Bi-containing biocomponents suggest that Bi was firmly complexed at physiological pH with a low degree of breaking during the applications of experimental protocols for the isolation of the 206Bi-biocomplexes. These latter were sensitive to acid buffer pH 5, and to the presence of complexing agents in the dialysis fluid. CONCLUSIONS: On the basis of an environmental biochemical toxicology approach, we have undertaken a study on the metabolic patterns of Bi3+ ions in rats at tissue, subcellular and molecular level with the identification of cellular Bi-binding components. As a first part of the study the present work reports the results concerned with the metabolic fate of ultratrace levels of 205+206Bi(NO)3 in the blood.

Enhanced Expression of miR-181b in B Cells of CLL Improves the Anti-Tumor Cytotoxic T Cell Response.

The clinical progression of B cell chronic lymphocytic leukemia (CLL) is associated with immune cell dysfunction and a strong decrease of miR-181b-5p (miR-181b), promoting the death of CLL cells. Here we investigated whether the reduction of miR-181b impairs the immune response in CLL. We demonstrate that activated CD4+ T cells increase miR-181b expression in CLL through CD40-CD40L signaling, which enhances the maturation and activity of cytotoxic T cells and, consequently, the apoptotic response of CLL cells. The cytotoxic response is facilitated by a depletion of the anti-inflammatory cytokine interleukin 10, targeted by miR-181b. In vivo experiments in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice confirmed that miR-181b promotes the apoptotic death of CLL cells only when functional T cells are restored. Overall, our findings suggest that the reinstatement of miR-181b in CLL cells could be an exploitable adjuvant therapeutic option for the treatment of CLL.

Combination of peripheral neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio is predictive of pathological complete response after neoadjuvant chemotherapy in breast cancer patients.

The immune system seems to play a fundamental role in breast cancer responsiveness to chemotherapy. We investigated two peripheral indicators of immunity/inflammation, i.e. neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR), in order to reveal a possible relationship with pathological complete response (pCR) in patients with early or locally advanced breast cancer treated with neoadjuvant chemotherapy (NACT). We retrospectively analyzed 373 consecutive patients affected by breast cancer and candidates to NACT. The complete blood cell count before starting NACT was evaluated to calculate NLR and PLR. ROC curve analysis determined threshold values of 2.42 and 104.47 as best cut-off values for NLR and PLR, respectively. The relationships between NLR/PLR and pCR, along with other clinical-pathological characteristics, were evaluated by Pearson's χ 2 or Fisher's exact test as appropriate. Univariate and multivariate analyses were performed using a logistic regression model. NLR and PLR were not significantly associated with pCR if analyzed separately. However, when combining NLR and PLR, patients with a NLRlow/PLRlow profile achieved a significantly higher rate of pCR compared to those with NLRhigh and/or PLRhigh (OR 2.29, 95% CI 1.22-4.27, p 0.009). Importantly, the predictive value of NLRlow/PLRlow was independent from common prognostic factors such as grading, Ki67, and molecular subtypes. The combination of NLR and PLR may reflect patients' immunogenic phenotype. Low levels of both NLR and PLR may thus indicate a status of immune system activation that may predict pCR in breast cancer patients treated with NACT.

Mineralogy and textures of riebeckitic asbestos (crocidolite): The role of single versus agglomerated fibres in toxicological experiments.

Asbestos may cause adverse effects, but relationship between mineralogy and texture of fibres versus toxicity is still lacking. Toxicological studies can be interpreted and compared only if quantitative features of fibres are determined. Here, riebeckitic ("crocidolite") amphibole fibres were analysed by XRPD, FTIR, SEM-EDS and EMP-WDS; only crystals with stochiometry A□BNa2C(Fe2+2.5Mg0.5)CFe3+2TSi8O22W(OH)2 are present in the starting material used for the experiments. Fibres deposited from solutions of 0.1, 1, 10, 25, 50, 75 and 100mg/L were counted by image analysis using SEM images. At 0.1 and 1mg/L the fibres are well separated, whereas between 1 and 10mg/L they start to agglomerate. In-vitro tests performed on fibres deposited at the same mg/L concentrations show that the toxic potential follows a curvilinear increasing trend with a decreasing rate. Since the range of sizes of single fibres and their mineralogy are constant, this decreasing rate can be only attributed to the increasing amount of agglomerated fibres. Hence, single versus agglomerated fibre population is a factor that cannot be neglected in defining the final adverse effects of asbestos. The analytical protocol proposed here is valuable for any aero-dispersed dust, in polluted environments, as well as in the interpretation of experimental studies.

[Allergens in occupational allergy: risk management.] / Gli allergeni nell'allergia occupazionale: management del rischio.

OBJECTIVES: The first essential aspect for the prevention of occupational allergy is related to the accurate allergen identification and characterization. At present many efforts are made to characterize the potential for a chemical to be a sensitizing agent. METHODS: 'Omics' show great promise to identify key cellular and molecular events relevant to development of an adverse outcome pathway for respiratory sensitizers. One approach that shows promise is based on the measurement of the peptide reactivity of chemicals; the potential to form stable associations with protein/peptide being a key requirement for the induction of sensitization. RESULTS: Sensitization is a dose-related phenomenon, therefore the lower the exposure the lower the risk of sensitization. CONCLUSIONS: In any way, establishing occupational exposure limits for chemical allergens presents numerous difficulties. Therefore it is important using alternative exposure recommendations and risk management practices, including medical surveillance and tertiary prevention, to aid in protecting workers from exposures to allergens.

Immunotoxicological impact of occupational and environmental nanoparticles exposure: The influence of physical, chemical, and combined characteristics of the particles.

While nanotechnology is growing exponentially, the knowledge of the impact of nanoparticles (NPs) on public health and the environment is limited so far. Current nanomaterial research is focused on the applications of nanotechnology, whereas there is little information on exposure assessment and risk characterization associated with NPs. Therefore, it is essential that the factors influencing NPs associated hazards be studied. This review seeks to survey and evaluate the current literature in order to better understand the impact of both airborne and engineered NPs exposure, the mechanisms at the cellular level, and the factors influencing their immunotoxicity. In fact, NPs do have immunotoxicological significance, as immune cells in the bloodstream and tissues do act to eliminate or interact with NPs.Proper characterization of the NPs as well as understanding the processes occurring on the NPs surface when in contact with biological systems is crucial to predict or exclude toxicological effects.

Engineered metal based nanoparticles and innate immunity.

Almost all people in developed countries are exposed to metal nanoparticles (MeNPs) that are used in a large number of applications including medical (for diagnostic and therapeutic purposes). Once inside the body, absorbed by inhalation, contact, ingestion and injection, MeNPs can translocate to tissues and, as any foreign substance, are likely to encounter the innate immunity system that represent a non-specific first line of defense against potential threats to the host. In this review, we will discuss the possible effects of MeNPs on various components of the innate immunity (both specific cells and barriers). Most important is that there are no reports of immune diseases induced by MeNPs exposure: we are operating in a safe area. However, in vitro assays show that MeNPs have some effects on innate immunity, the main being toxicity (both cyto- and genotoxicity) and interference with the activity of various cells through modification of membrane receptors, gene expression and cytokine production. Such effects can have both negative and positive relevant impacts on humans. On the one hand, people exposed to high levels of MeNPs, as workers of industries producing or applying MeNPs, should be monitored for possible health effects. On the other hand, understanding the modality of the effects on immune responses is essential to develop medical applications for MeNPs. Indeed, those MeNPs that are able to stimulate immune cells could be used to develop of new vaccines, promote immunity against tumors and suppress autoimmunity.

In vivo inflammatory effects of ceria nanoparticles on CD-1 mouse: evaluation by hematological, histological, and TEM analysis.

The attention on CeO2-NPs environmental and in vivo effects is due to their presence in diesel exhaust and in diesel filters that release a more water-soluble form of ceria NPs, as well as to their use for medical applications. In this work, acute and subacute in vivo toxicity assays demonstrate no lethal effect of these NPs. Anyhow, performing in vivo evaluations on CD-1 mouse systems, we demonstrate that it is even not correct to assert that ceria NPs are harmless for living systems as they can induce status of inflammation, revealed by hematological-chemical-clinical assays as well as histological and TEM microscope observations. TEM analysis showed the presence of NPs in alveolar macrophages. Histological evaluation demonstrated the NPs presence in lungs tissues and this can be explained by assuming their ability to go into the blood stream and lately into the organs (generating inflammation).

Nickel oral hyposensitization in patients with systemic nickel allergy syndrome.

BACKGROUND: This is the first randomized, double-blind, placebo-controlled trial (EUDRACT No. 2009-013923-43) evaluating nickel oral hyposensitizing treatment (NiOHT) in patients with "systemic nickel allergy syndrome" (SNAS), characterized by Ni-allergic contact dermatitis and systemic reactions after eating Ni-rich food. METHODS: Adults with positive Ni-patch test, who reported symptoms suggesting SNAS, which improved after Ni-poor diet, and were positive to Ni-oral challenge were eligible. Patients were randomly assigned to three treatments (1.5 µg, 0.3 µg, or 30 ng Ni/week) or placebo for a year, with progressive reintroduction of Ni-rich foods form the 5(th) month. Out of 141 patients randomized, 113 completed the trial. Endpoints were efficacy and tolerability of treatment. RESULTS: During Ni-rich food re-introduction, the 1.5 µg Ni/week group had a mean VAS score significantly higher than placebo (p = 0.044), with significant improvement of gastrointestinal symptoms (p = 0.016;) and significantly fewer rescue medications. Cutaneous manifestations also improved but without reaching statistical significance. After the treatment, oral challenge with higher Ni doses than at baseline were needed to cause symptoms to flare-up in significantly more patients given 1.5 µg Ni/week than placebo (p = 0.05). Patients reported no side-effects. CONCLUSIONS: NiOHT is effective in SNAS, in particular on gastrointestinal manifestations, with trend toward improvement of cutaneous symptoms.