Exposure to individual and multiple carcinogenic metals during paediatric age: an experience from an Italian urban scenario.

BACKGROUND: Exposure to single and multiple carcinogenic metals and/or semimetals represents a major environmental risk factor for public health. In particular, children are more susceptible to environmental pollutants than adults, but specific studies are still limited. The aims of the present study were: 1) to trace the exposure and co-exposure profiles to eight known or suspected carcinogenic metals and semimetals (As, Be, Cd, Co, Cr, Ni, Pb, and Sb); and: 2) to evaluate the influence of some possible interfering/confounding factors on the exposure to these elements during childhood. STUDY DESIGN: Cross-sectional study. METHODS: We recruited 159 healthy Italian children attending a primary school of the urban area of Rome, Italy. Selected metals were determined by inductively coupled plasma mass spectrometry on urinary samples collected at the end of a "typical" day (one sample for each child), while information about possible confounding/interfering factors were collected via questionnaires. RESULTS: The great part of the studied children resulted co-exposed to the monitored metals: 83.2%, 69.2%, 51.0% and 29.3% of the participants were concurrently exposed to at least two, three, four and five trace elements, respectively. Gender was the only one among the investigated variable that significantly influenced the co-exposure, with females resulting at lower risk (OR = 0.392; 95 IC = 0.156 - 0.989; p < 0.047). CONCLUSIONS: Given the importance of protecting child's health and the risks related to the exposure to carcinogenic metals, especially when they occur simultaneously, other researches in this field are strongly recommended.

Sialendoscopic management of autoimmune sialadenitis: a review of literature.

Autoimmune diseases of major salivary glands include Sjögren's syndrome and a complex of disorders classified as immunoglobulin G4-related diseases. These pathologies are characterised by an autoimmune reaction mediated by T-helper lymphocytes that targets the ducts of exocrine glands in Sjögren's syndrome and glandular parenchyma in immunoglobulin G4-related diseases. Immunoglobulin G4-related diseases represent recently introduced multi-organ diseases that also involve the salivary glands. However, the morbid conditions once known as Mikulicz's disease and Kuttner's tumour were recently considered as two variants of immunoglobulin G4-related diseases affecting the major salivary glands ( immunoglobulin G4-related sialadenitis). This review briefly summarises the pathogenesis and clinical features of autoimmune diseases of the major salivary glands, focusing on the diagnostic and therapeutic role of sialendoscopy.

Cancer mortality in Rieti province (Latium Region, Italy) for the years 2006-2010: evaluation of temporal and spatial trends and comparison with the other Latium provinces.

BACKGROUND: The present research aims to obtain information on cancer deaths in the five Latium provinces in the years 2006-2010 and to highlight similarities and differences between them. METHODS: The survey was carried through statistical elaboration of cancer mortality data for the years 2006-2010 obtained from the National Institute of Statistics. RESULTS: The mortality due to oncological diseases in Rieti province showed a decreasing temporal trend for the years investigated. Among all the Latium provinces, Rieti presented the lowest standardized mortality rates. This phenomenon could be related to specific environmental conditions and low levels of air, water and soil pollution affecting the Rieti province. CONCLUSION: The results of the present study show that the "healthy" environment of Rieti province could be considered as a benchmark for studies in oncological diseases.

Outcomes of interventional sialendoscopy for obstructive salivary gland disorders: an Italian multicentre study.

Interventional sialendoscopy has become the predominant therapeutic procedure for the management of obstructive salivary disorders, but only a few multicentre studies of large series of patients with a long-term follow-up have been published. This Italian multicentre study involved 1152 patients (553 females; mean age 50 years) who, after at least a clinical and ultrasonographic evaluation, underwent a total of 1342 diagnostic and interventional sialendoscopies, 44.6% of which involved the parotid gland. 12% (n = 138) of patients underwent multiple treatments. The procedure was successful in 1309 cases. In 33 cases (2.4%) the procedure could not be concluded mainly because of complete duct stenosis (21 cases). Salivary stones were the main cause of obstruction (55%), followed by ductal stenosis and anomalies (16%), mucous plugs (14.5%) and sialodochitis (4.7%). Complete therapeutic success was obtained in 92.5% of patients after one or more procedures, and was ineffective in < 8%. Untoward effects (peri and postoperative complications) were observed in 5.4% of cases. Sialendoscopy proved to be an effective, valid and safe procedure in the diagnostic and therapeutic management of non-neoplastic obstructive salivary gland diseases.

Cancer stem cells in laryngeal cancer: what we know.

Cancer stem cells (CSCs) are a group of cells with eternal life or infinite self-renewal ability, which have high migrating, infiltrative, and metastatic abilities. Though CSCs only account for a small proportion in tumors, the high resistance to traditional therapy exempts them from therapy killing and thus they can reconstruct tumors. Previous studies found that heterogeneity of cancer cells extensively exists in head and neck cancers. Our current knowledge, about CSCs in the laryngeal cancer (LC), largely depends on head and neck studies. Given the lack of systematic data about CSCs in LC, we propose a review of the literature, reporting the evidences of CSCs in tumorigenesis of LC, with the purpose to provide new insights into the prevention and/or treatment of laryngeal carcinoma.

Epidemiological profile of cancer mortality in a province of central Italy for the years 2008 and 2009: preliminary analysis.

BACKGROUND: The aim of the study was to perform a preliminary analysis of the mortality data for cancer as widely as possible, in order to obtain useful information for planning specific public health interventions. For this purpose, data on cancer mortality in the province of Rieti (Latium, central Italy) have been collected and analysed. To date, in the Rieti province a Cancer Registry record is not available. METHODS: The study was conducted through statistical analysis of cancer mortality data related to the years 2008 and 2009, obtained from the National Institute of Statistics. Data were cumulative for the province of Rieti and specific for the five districts in which the province is divided. RESULTS: The standardized mortality rates obtained for Rieti province resulted lower than those reported for the other provinces of the Latium region, for Italy and for the European Community, both for 2008 and 2009. In these years, the anatomical areas more affected in terms of mortality were "trachea, bronchus and lung", "colorectal" and "stomach", but gender differences were evidenced. CONCLUSIONS: The present study, also considering the limitation of two years studied only, leads to some basic insights about the importance of updating mortality data to trace an epidemiological profile, to evaluate the presence of risk and protective factors, to program strategically health interventions, and to assess the effectiveness of these interventions.

Tracheocutaneous fistula in patients undergoing supracricoid partial laryngectomy: the role of chronic aspiration.

The aim of the present retrospective controlled study was to analyse and compare risk factors for tracheocutaneous fistula in patients who received tracheostomy after supracricoid partial laryngectomy with those who received tracheostomy for other causes. We enrolled 39 patients with tracheocutaneous fistulas who were divided into two groups. The first received temporary tracheostomy for supracricoid partial laryngectomies (n = 21), while the control group consisted of patients who received temporary tracheostomy for other causes (n = 18). Risk factors believed to play a role in the pathogenesis of tracheocutaneous fistula were examined including advanced age, cardiopathy, local infections, radiotherapy, elevated body mass index, malnutrition, decannulation time and aspiration grade. The Leipzig and Pearson scale score was significantly higher in the supracricoid partial laryngectomy group (p = 0.006 and 0.031 for univariate and multivariate analyses, respectively). The penetration/aspiration scale score was significantly higher in the supracricoid partial laryngectomy group as determined by univariate analysis (p = 0.014). The decannulation time was significantly lower in the supracricoid partial laryngectomy group (p = 0.004 and 0.0004 for univariate and multivariate analyses, respectively). The number of surgical closures for tracheocutaneous fistula was significantly higher in the supracricoid partial laryngectomy group by univariate analysis (p = 0.027). These results suggest that chronic aspiration and related cough may be important pathogenic factors for tracheocutaneous fistula and could be responsible for the significantly higher rates of closure failure in patients after supracricoid partial laryngectomy.

Contact X-ray microscopy of living cells by using LiF crystal as imaging detector.

In this paper, the use of lithium fluoride (LiF) as imaging radiation detector to analyse living cells by single-shot soft X-ray contact microscopy is presented. High resolved X-ray images on LiF of cyanobacterium Leptolyngbya VRUC135, two unicellular microalgae of the genus Chlamydomonas and mouse macrophage cells (line RAW 264.7) have been obtained utilizing X-ray radiation in the water window energy range from a laser plasma source. The used method is based on loading of the samples, the cell suspension, in a special holder where they are in close contact with a LiF crystal solid-state X-ray imaging detector. After exposure and sample removal, the images stored in LiF by the soft X-ray contact microscopy technique are read by an optical microscope in fluorescence mode. The clear image of the mucilaginous sheath the structure of the filamentous Leptolyngbya and the visible nucleolus in the macrophage cells image, are noteworthiness results. The peculiarities of the used X-ray radiation and of the LiF imaging detector allow obtaining images in absorption contrast revealing the internal structures of the investigated samples at high spatial resolution. Moreover, the wide dynamic range of the LiF imaging detector contributes to obtain high-quality images. In particular, we demonstrate that this peculiar characteristic of LiF detector allows enhancing the contrast and reveal details even when they were obscured by a nonuniform stray light.

Sialoendoscopy: state of the art, challenges and further perspectives. Round Table, 101(st) SIO National Congress, Catania 2014.

This draft of the Official Round Table held during the 101(st) SIO National Congress is an updated review on sialoendoscopy, a technique used for diagnosis and treatment of obstructive pathologies of salivary glands in a minimally invasive fashion. This review treats many aspects of salivary gland endoscopy, starting from anatomy to deal with the more advanced surgical techniques and analyses the main decisional algorithms proposed in the literature. In addition, particular attention was directed to the current limitations of this technique and to the potential developments that sialoendoscopy could have in the near future.

Laryngotracheal stenosis treated with multiple surgeries: experience, results and prognostic factors in 70 patients.

Laryngotracheal stenosis is a complex condition that usually requires multiple procedures to restore physiological respiration. The aim of this study was to evaluate the percentage of decannulation compared to different or multiple surgical treatments. We retrospectively reviewed the charts of 70 patients treated between 1990 and 2005 for laryngotracheal stenosis of various aetiology: iatrogenic stenosis (n = 55), post-traumatic stenosis (n = 11) or other causes (autoimmune disease, n = 3; diphtheria, n = 1). In order to maintain laryngotracheal patency, a Montgomery Safe-T tube was used in all patients as a single dilation treatment or associated with endoscopic and/or open-neck surgery. Fifty-four of the 70 patients (77.1%) were eventually decannulated; 39 of these (72.2%) underwent 3 or fewer surgical procedures, showing a significant difference compared to patients who underwent more than 3 surgeries (p = 0.00002). A total of 257 surgeries were performed. Only seven of 54 patients (13%) were decannulated after more than 5 surgical procedures. Patients over 60 years of age and with a higher grade of stenosis showed a significantly lower success rate (p = 0.0017 and p = 0.007, respectively). There was no significant correlation between the rate of decannulation and gender, aetiology, site of stenosis or surgery. Patients undergoing dilation for laryngotracheal stenosis usually require multiple procedures. The T tube plays an important role in the treatment of this pathology. However, if the tracheostomy is not removed within 3 surgical interventions, the odds of decannulating the patient decrease significantly, and additional surgeries may be of questionable therapeutic benefit.

SNOM images of X-ray radiographs at nano-scale stored in a thin layer of lithium fluoride.

In this work, we report a method to observe soft X-ray radiographs at nanoscale of various kind of samples, biological and metallic, stored in a thin layer of lithium fluoride, employing scanning near-field optical microscopy with an optical resolution that reaches 50 nm. Lithium fluoride material works as a novel image detector for X-ray nano-radiographs, due to the fact that extreme ultraviolet radiation and soft X-rays efficiently produce stable point defects emitting optically stimulated visible luminescence in a thin surface layer. The bi-dimensional distribution of the so-created defects depends on the local nanostructure of the investigated sample.

Analysis of high- n dielectronic Rydberg satellites in the spectra of Na -like Zn XX and Mg -like Zn XIX.

We have observed spectra from highly charged zinc ions in a variety of laser-produced plasmas. Spectral features that are Na - and Mg -like satellites to high- n Rydberg transitions in the Ne -like Zn XXI spectrum are analyzed and modeled. Identifications and analysis are made by comparison with highly accurate atomic structure calculations and steady state collisional-radiative models. Each observed Zn XX and Zn XIX feature comprises up to approximately 2 dozen individual transitions, these transitions are excited principally by dielectronic recombination through autoionizing levels in Na - and Mg -like Zn19+ and Zn18+. We find these satellites to be ubiquitous in laser-produced plasmas formed by lasers with pulse lengths that span four orders of magnitude, from 1 ps to approximately 10 ns. The diagnostic potential of these Rydberg satellite lines is demonstrated.

Influence of optical thickness and hot electrons on Rydberg spectra of Ne-like and F-like copper ions.

Spectra in the 7.10 to 8.60 A range from highly charged copper ions are observed from three different laser-produced plasmas (LPPs). The LPPs are formed by a 15-ns Nd:glass laser pulse (type I: E(pulse)=1-8 J, lambda=1.064 microm), a 1-ps Nd:glass laser pulse (type II: E(pulse)=1 J, lambda=1.055 microm), and a 60-fs Ti:sapphire laser pulse (type III: E(pulse)=800 mJ, lambda=790 nm). The spectra of high-n (n

A fast and efficient determination of amines and preservatives in cough and cold liquid and suspension formulations using a single isocratic ion-pairing high performance [correction of power] liquid chromatography method.

A single, highly selective ion-pairing reverse phase-high power liquid chromatography (RP-HPLC) method has been developed for the determination of amines and preservatives in a wide range of Tylenol((R)) liquid and suspension liquid products. As with many OTC products, the challenge is to quantitatively extract the analytes from difficult matrices and specifically analyze them in the presence of various excipients and flavors. Historically, separate analytical methods were used for each class of analytes (acids, bases and neutral compounds). In this method a mobile phase consisting of a buffered ion-pairing agent with acetonitrile, methanol and tetrahydrofuran was used to separate the charged amines from neutral and acidic compounds on a Phenomenex LUNA C8(2) 75 x 4.6 mm i.d. analytical column with a 3-microm particle size. The analytes include acids (benzoic acid), bases (pseudoephedrine, chlorpheniramine, dextromethorphan, doxylamine and diphenhydramine) and a neutral compound (butylparaben). The effects of pH, the chain length of the ion-pairing reagent, ionic strength and organic modifiers on the separation are discussed. The method is linear from 15 to 150% of the target amounts. The optimized method proves to be specific, robust and accurate for the analysis of the compounds.

Synthesis and structure-activity relationships of phenylenebis(methylene)-linked bis-azamacrocycles that inhibit HIV-1 and HIV-2 replication by antagonism of the chemokine receptor CXCR4.

Bis-tetraazamacrocycles such as the bicyclam AMD3100 are a class of potent and selective anti-HIV-1 and HIV-2 agents that inhibit virus replication by binding to the chemokine receptor CXCR4, the co-receptor for entry of X4 viruses. With the aim of optimizing the anti-HIV-1 and HIV-2 activity of bis-azamacrocycles, a series of analogues were synthesized which contain neutral heteroatom (oxygen, sulfur) or heteroaromatic (of lower pK(a) than a secondary amine) replacements for the amino groups of AMD3100. The introduction of one or more heteroatoms such as oxygen or sulfur into the macrocyclic ring of p-phenylenebis(methylene)-linked dimers (to give N(3)X or N(2)X(2) bis-macrocycles) gave analogues with substantially reduced anti-HIV-1 (III(B)) and anti-HIV-2 (ROD) potency. In addition, the bis-sulfur analogue was also markedly more cytotoxic to MT-4 cells. However, bis-tetraazamacrocycles featuring a single pyridine group incorporated within the macrocyclic framework exhibited anti-HIV-1 and HIV-2 potency comparable to that of their saturated, aliphatic counterparts. The p-phenylenebis(methylene)-linked dimer of the py[14]aneN(4) macrocycle inhibited HIV-1 replication at a 50% effective concentration (EC(50)) of 0.5 microM while remaining nontoxic to MT-4 cells at concentrations approaching 200 microM. A series of analogues containing macrocyclic heteroaromatic groups of varying pK(a) were also synthesized, and their ability to inhibit HIV replication was evaluated. Replacing the pyridine moiety of the py[14]aneN(4) macrocyclic ring with pyrazine or pyridine groups substituted in the 4-position (with electron-withdrawing or -donating groups) either reduced antiviral potency or increased cytotoxicity to MT-4 cells. Finally, we synthesized a series of analogues in which the ring size of the bis-pyridyl macrocycles was varied between 12 and 16 members per ring including the py[iso-14]aneN(4) ring system, an isomer of the py[14]aneN(4) macrocycle. The p-phenylenebis(methylene)-linked dimer of the py[iso-14]aneN(4) (AMD3329) displayed the highest antiviral activity of the bis-azamacrocyclic analogues reported to date, exhibiting EC(50)'s against the cytopathic effects of HIV-1 and HIV-2 replication of 0.8 and 1.6 nM, respectively, that is, about 3-5-fold lower than the EC(50) of AMD3100. AMD3329 also inhibited the binding of a specific CXCR4 mAb and the Ca(2+) flux induced by SDF-1alpha, the natural ligand for CXCR4, more potently than AMD3100. Furthermore, AMD3329 also interfered with virus-induced syncytium formation at an EC(50) of 12 nM.

Metal complexes of bleomycin: evaluation of [Rh-105]-bleomycin for use in targeted radiotherapy.

Bleomycin has been used as a carrier for several radioisotopes; however, its potential for clinical use has been limited either by the in vivo stability of the complexes or the half-life of the isotope used. The chemical, biological, and radiological properties of 105Rhodium appear to make it an ideal choice for targeted radiotherapy. The synthesis and purification of a hereto unreported 105Rhodium-bleomycin (105Rh-BLM) complex is described. The stability of this complex in plasma is sufficient to allow targeted delivery of the radioisotope. 57Cobalt-bleomycin was studied under identical conditions for comparative purposes. The suitability of 105Rh-BLM for targeted therapy, which appears to be limited by the renal clearance of this agent, is discussed.

Synthesis and structure-activity relationships of phenylenebis(methylene)-linked bis-tetraazamacrocycles that inhibit human immunodeficiency virus replication. 2. Effect of heteroaromatic linkers on the activity of bicyclams.

A series of bicyclam analogs connected through a heteroaromatic linker have been synthesized and evaluated for their inhibitory effects on HIV-1 (IIIB) and HIV-2 (ROD) replication in MT-4 cells. The activity of pyridine- and pyrazine-linked bicyclams was found to be highly dependent upon the substitution of the heteroaromatic linker connecting the cyclam rings. For example, 2,6- and 3,5-pyridine-linked bicyclams were potent inhibitors of HIV-1 and HIV-2 replication, whereas the 2,5- and 2,4-substituted pyridine-linked compounds exhibited substantially reduced activity and, in addition, were found to be highly toxic to MT-4 cells. We have subsequently discovered that these effects are not unique; amino-substituted linkers also have the potential to deactivate phenylenebis(methylene)-linked bicyclams. A model is proposed to explain the deactivating effects of the pyridine group in certain substitution patterns based on the ability of the pyridine nitrogen to participate in pendant conformations (complexation) with the adjacent azamacrocyclic ring, which may involve hydrogen bonding or coordination to a transition metal. The introduction of a sterically hindering group such as phenyl at the 6-position of the 2,4-substituted pyridine-linked bicyclam appears to prevent pendant conformations, providing an analog with comparable anti-HIV-1 and anti-HIV-2 activities to the parent m-phenylenebis(methylene)-linked bicyclam. The results of this study have been used to develop a quantitative structure-activity relationship model with improved predictive capability in order to aid the design of antiviral bis-azamacrocyclic analogs.

Synthesis and structure-activity relationships of phenylenebis(methylene)-linked bis-tetraazamacrocycles that inhibit HIV replication. Effects of macrocyclic ring size and substituents on the aromatic linker.

We have previously described the potent and selective inhibition of several strains of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) by JM2763, an n-propyl-linked dimer of the 1,4,8,11-tetraazamacrocyclic (cyclam) ring system. Upon further investigation, we have also found that incorporating an aromatic rather than aliphatic linker leads to analogs with higher antiviral potency. The prototype, JM3100 (19a, isolated as the octahydrochloride salt), which contains a p-phenylenebis(methylene) moiety linking the cyclam rings, inhibited the replication of HIV-1 (IIIB) and HIV-2 (ROD) at EC50's of 4.2 and 5.9 nM, respectively, while remaining nontoxic to MT-4 cells at concentrations exceeding 421 microM. In order to identify the structural features of bis-tetraazamacrocycles required for potent activity, we have prepared a novel series of phenylenebis(methylene)-linked analogs, in which the macrocyclic ring size was varied from 12 to 16 ring members. Depending upon the substitution of the phenylenebis(methylene) linker (para or meta), sub-micromolar anti-HIV activity was exhibited by analogs bearing macrocycles of 12-14 ring members but with varying cytotoxicity to MT-4 cells. Furthermore, while we found that identical macrocyclic rings are not required for activity, substituting an acyclic polyamine equivalent for one of the cyclam rings in 19a resulted in a substantial reduction in anti-HIV potency, clearly establishing the importance of the constrained macrocyclic structure. A short series of transition metal complexes of 19a were also prepared and evaluated. Complexes of low kinetic stability such as the bis-zinc complex retained activity comparable to that of the parent compound. Finally, the activity of bicyclam analogs appears to be insensitive to the electron-withdrawing or -donating properties of substituents introduced onto the linker, but sterically hindering groups such as phenyl markedly reduced activity. As a result, several analogs with anti-HIV potency comparable to that of 19a have been identified.

Pharmacokinetics of antiviral polyoxometalates in rats.

Polyoxometalates are soluble mineral compounds formed principally of oxide anions and early transition metal cations. The polyoxometalates K12H2[P2W12O48].24H2O (JM 1591), K10[P2W18Zn4(H2O)2O68].20H2O (JM 1596), and [(CH3)3NH]8[Si2W18Nb6O77] (JM 2820) demonstrate potent antiviral activity against human immunodeficiency virus types 1 and 2, herpes simplex virus, and cytomegalovirus in vitro. The preclinical pharmacokinetics of these three compounds were characterized after single-dose intravenous administration of 50 mg/kg to rats. Plasma, urine, and feces were collected for 168 h, and polyoxometalate concentrations were determined by atomic emission. Serum protein binding was measured by equilibrium dialysis. All three compounds were highly bound to serum proteins in a concentration-dependent manner. Total and unbound concentrations of the three compounds in plasma declined in a triexponential manner with terminal half-lives of 246.0 +/- 127.0, 438.4 +/- 129.4, and 32.2 +/- 5.37 h (mean +/- standard deviation) for JM 1591, JM 1596, and JM 2820, respectively. Systemic clearances based on total concentrations in plasma were low, averaging 0.016 +/- 0.002, 0.015 +/- 0.002, and 0.018 +/- 0.003 liter/h/kg for JM 1591, JM 1596, and JM 2820, respectively. The clearances of unbound compounds from plasma averaged 0.966 +/- 0.136, 0.050 +/- 0.005, and 0.901 +/- 0.165 liter/h/kg for JM 1591, JM 1596, and JM 2820, respectively. For JM 1596, the clearance of unbound compound from the kidneys was lower than the glomerular filtration rate (0.086 liter/h/kg), suggesting this polyoxometalate underwent renal tubular reabsorption. However, JM 1591 and JM 2820 appeared to undergo tubular secretion. The fraction of the dose recovered in urine was 11.5, 46.8, and 10.6% for JM 1591, JM 1596, and JM 2820, respectively. Approximately 5% of the dose of each polyoxometalate was recovered in feces. The steady-state volume of distribution based on total concentrations averaged 1.44 liters/kg for JM 1591, 2.39 liters/kg for JM 1596, and 0.59 liter/kg for JM 2820, indicating moderate to wide distribution throughout the body. All three compounds were detected in various tissues 1 week after single-dose administrations, with the highest levels found in the kidneys and liver. The results of this study indicate that the disposition of polyoxometalates is highly dependent on their molecular structure.