Assessing the impact of tourist flows on emergency department treatment speed for residents and tourists. The case of Sorrento

Tourism is a fundamental lever of the economic and cultural development of a location. Large tourist flows can negatively impact the provision of public services, such as healthcare. This study aims to investigate emergency department (ED) treatment speed under increased demand caused by tourism. The analysis was conducted on data (covering March–October 2018) collected from the ED of a hospital in Sorrento, a renowned coastal tourist destination in Campania, Italy, by using a two-step strategy. First, we resort to the Kaplan-Meier method to compare treatment in the ED between residents and tourists. Second, through the Cox proportional hazards model, we study the impact of group-specific characteristics on the speed of treatment. The main empirical findings highlight that treatment speed is highly influenced by age and by the languages spoken by tourists. Foreign tourists are best served in off-peak periods, while in the peak arrival period, the healthcare system experiences difficulties, especially for those facing higher language barriers. What emerges is the necessity for a tourism destination to adopt measures to cope with the language heterogeneity of tourists. In a multi-cultural touristic context, healthcare providers and institutions should address the challenge of language barriers by using specialist interpreter services

Crystal structure and substrate specificity of the 8-oxo-dGTP hydrolase NUDT1 from Arabidopsis thaliana

Arabidopsis thaliana NUDT1 (AtNUDT1) belongs to the Nudix family of proteins, which have a diverse range of substrates, including oxidized nucleotides such as 8-oxo-dGTP. The hydrolysis of oxidized dNTPs is highly important as it prevents their incorporation into DNA, thus preventing mutations and DNA damage. AtNUDT1 is the sole Nudix enzyme from A. thaliana shown to have activity against 8-oxo-dGTP. We present the structure of AtNUDT1 in complex with 8-oxo-dGTP. Structural comparison with bacterial and human homologues reveals a conserved overall fold. Analysis of the 8-oxo-dGTP binding mode shows that the residues Asn76 and Ser89 interact with the O8 atom of the substrate, a feature not observed in structures of protein homologues solved to date. Kinetic analysis of wild-type and mutant AtNUDT1 confirmed that these active site residues influence 8-oxo-dGTP hydrolysis. A recent study showed that AtNUDT1 is also able to hydrolyze terpene compounds. The diversity of reactions catalyzed by AtNUDT1 suggests that this Nudix enzyme from higher plants has evolved in a manner distinct to those from other organisms

Understanding concurrent earcons: applying auditory scene analysis principles to concurrent earcon recognition

Two investigations into the identification of concurrently presented, structured sounds, called earcons were carried out. One of the experiments investigated how varying the number of concurrently presented earcons affected their identification. It was found that varying the number had a significant effect on the proportion of earcons identified. Reducing the number of concurrently presented earcons lead to a general increase in the proportion of presented earcons successfully identified. The second experiment investigated how modifying the earcons and their presentation, using techniques influenced by auditory scene analysis, affected earcon identification. It was found that both modifying the earcons such that each was presented with a unique timbre, and altering their presentation such that there was a 300 ms onset-to-onset time delay between each earcon were found to significantly increase identification. Guidelines were drawn from this work to assist future interface designers when incorporating concurrently presented earcons

Water-soluble Ru(II)- and Ru(III)-halide-PTA complexes (PTA=1,3,5-triaza-7-phosphaadamantane): Chemical and biological properties

Four structurally related Ru(II)-halide-PTA complexes, of general formula trans- or cis-[Ru(PTA)4X2] (PTA = 1,3,5-triaza-7-phosphaadamantane, X = Cl (1, 2), Br (3, 4), were prepared and characterized. Whereas compounds 1 and 2 are known, the corresponding bromo derivatives 3 and 4 are new. The Ru(III)-PTA compound trans-[RuCl4(PTAH)2]Cl (5, PTAH = PTA protonated at one N atom), structurally similar to the well-known Ru(III) anticancer drug candidates (Na)trans-[RuCl4(ind)2] (NKP-1339, ind = indazole) and (Him)trans-[RuCl4(dmso-S)(im)] (NAMI-A, im = imidazole), was also prepared and similarly investigated. Notably, the presence of PTA confers to all complexes an appreciable solubility in aqueous solutions at physiological pH. The chemical behavior of compounds 1\u20135 in water and in physiological buffer, their interactions with two model proteins \u2013 cytochrome c and ribonuclease A \u2013 as well as with a single strand oligonucleotide (5\u2032-CGCGCG-3\u2032), and their in vitro cytotoxicity against a human colon cancer cell line (HCT-116) and a myeloid leukemia (FLG 29.1) were investigated. Upon dissolution in the buffer, sequential halide replacement by water molecules was observed for complexes 1\u20134, with relatively slow kinetics, whereas the Ru(III) complex 5 is more inert. All tested compounds manifested moderate antiproliferative properties, the cis compounds 2 and 4 being slightly more active than the trans ones (1 and 3). Mass spectrometry experiments evidenced that all complexes exhibit a far higher reactivity towards the reference oligonucleotide than towards model proteins. The chemical and biological profiles of compounds 1\u20135 are compared to those of established ruthenium drug candidates in clinical development

MutT homologue 1 (MTH1) removes N6-methyl-dATP from the dNTP pool

MutT homologue 1 (MTH1) removes oxidized nucleotides from the nucleotide pool and thereby prevents their incorporation into the genome and thereby reduces genotoxicity. We previously reported that MTH1 is an efficient catalyst of O6-methyl-dGTP hydrolysis suggesting that MTH1 may also sanitize the nucleotide pool from other methylated nucleotides. We here show that MTH1 efficiently catalyzes the hydrolysis of N6-methyl-dATP to N6-methyl-dAMP and further report that N6-methylation of dATP drastically increases the MTH1 activity. We also observed MTH1 activity with N6-methyl-ATP, albeit at a lower level. We show that N6-methyl-dATP is incorporated into DNA in vivo, as indicated by increased N6-methyl-dA DNA levels in embryos developed from MTH1 knock-out zebrafish eggs microinjected with N6-methyl-dATP compared with noninjected embryos. N6-methyl-dATP activity is present in MTH1 homologues from distantly related vertebrates, suggesting evolutionary conservation and indicating that this activity is important. Of note, N6-methyl-dATP activity is unique to MTH1 among related NUDIX hydrolases. Moreover, we present the structure of N6-methyl-dAMP–bound human MTH1, revealing that the N6-methyl group is accommodated within a hydrophobic active-site sub-pocket explaining why N6-methyl-dATP is a good MTH1 substrate. N6-methylation of DNA and RNA has been reported to have epigenetic roles and to affect mRNA metabolism. We propose that MTH1 acts in concert with adenosine deaminase–like protein isoform 1 (ADAL1) to prevent incorporation of N6-methyl-(d)ATP into DNA and RNA. This would hinder potential dysregulation of epigenetic control and RNA metabolism via conversion of N6-methyl-(d)ATP to N6-methyl-(d)AMP, followed by ADAL1 catalyzed deamination producing (d)IMP that can enter the nucleotide salvage pathway

Case-Control Study of Fetal Microchimerism and Breast Cancer

Prior pregnancy is known to protect against development of breast cancer. Recent studies have demonstrated that pregnancy has the capacity to establish small numbers of immunologically active fetal-derived cells in the mother, a phenomenon known as fetal microchimerism (FMc). We asked whether presence of FMc, routinely acquired during pregnancy, is a protective factor for breast cancer.DNA extracts from peripheral blood specimens were obtained from a population-based case-control study of risk factors for breast cancer in women 21 to 45 years old. Specimens were tested with quantitative PCR for presence and concentrations of male DNA presumed to derive from prior pregnancies with a male fetus. Odds ratios (OR) and 95% confidence intervals (CI) were estimated with consideration of multiple established reproductive and environmental risk factors for breast cancer. FMc results were generated on 99 parous women, 54 with primary invasive breast cancer and 45 general population controls. FMc prevalence was 56% (25/45) and 26% (14/54) in controls and cases, respectively. Women harboring FMc were less likely to have had breast cancer (OR = 0.29, 95% CI 0.11-0.83; p = 0.02, adjusting for age, number of children, birth of a son, history of miscarriage, and total DNA tested). In addition, FMc concentrations were higher in controls versus cases (p = 0.01). Median concentrations were 2 (0-78) and 0 (0-374) fetal genomes/10(6) maternal genomes in controls and cases, respectively.Results suggest that the enigma of why some parous women are not afforded protection from breast cancer by pregnancy might in part be explained by differences in FMc. Mechanistic studies of FMc-derived protection against breast cancer are warranted

Immunosuppressive Activity of Abatacept on Circulating T Helper Lymphocytes from Juvenile Idiopathic Arthritis Patients

BACKGROUND: Abatacept is used in the treatment of juvenile idiopathic arthritis (JIA) patients, but the activity of the drug on T helper cell function is not yet fully known. METHODS: The ability of abatacept to affect cytokine production in vitro and the proliferative response to both recall antigens and polyclonal stimulation was firstly assessed in healthy donors. Then, 10 JIA patients who were due to start abatacept treatment were recruited and longitudinally evaluated during the first 90 days of therapy. Both their clinical response to the treatment and in vitro analysis aimed to assess the proliferative response to recall antigens and the proportions of circulating T helper subsets. RESULTS: Abatacept reduced the proliferative response to recall antigens and the production of proinflammatory cytokines such as IFN-\u3b3 and TNF-\u3b1 in healthy donors in vitro. It was also efficient in improving symptoms and reducing parameters of inflammation in JIA patients. Abatacept reduced the proliferative response to recall antigens, and this effect was significant soon after drug infusion (2 days). Regarding the proportions of circulating CD4+ T lymphocytes, only a reduction in the frequencies of circulating Treg cells was observed. CONCLUSIONS: Abatacept in vitro inhibits proliferation and cytokine production in healthy donors, and reduces parameters of inflammation in vivo in JIA patients. The reduction of the proliferative response to recall antigens induced by abatacept was evident only soon after drug administration, suggesting that its immunosuppressive activity is maintained only for a short time

Crystal structures of NUDT15 variants enabled by a potent inhibitor reveal the structural basis for thiopurine sensitivity

The enzyme NUDT15 efficiently hydrolyzes the active metabolites of thiopurine drugs, which are routinely used for treating cancer and inflammatory diseases. Loss-of-function variants in NUDT15 are strongly associated with thiopurine intolerance, such as leukopenia, and preemptive NUDT15 genotyping has been clinically implemented to personalize thiopurine dosing. However, understanding the molecular consequences of these variants has been difficult, as no structural information was available for NUDT15 proteins encoded by clinically actionable pharmacogenetic variants because of their inherent instability. Recently, the small molecule NUDT15 inhibitor TH1760 has been shown to sensitize cells to thiopurines, through enhanced accumulation of 6-thio-guanine in DNA. Building upon this, we herein report the development of the potent and specific NUDT15 inhibitor, TH7755. TH7755 demonstrates a greatly improved cellular target engagement and 6-thioguanine potentiation compared with TH1760, while showing no cytotoxicity on its own. This potent inhibitor also stabilized NUDT15, enabling analysis by X-ray crystallography. We have determined high-resolution structures of the clinically relevant NUDT15 variants Arg139Cys, Arg139His, Val18Ile, and V18_V19insGlyVal. These structures provide clear insights into the structural basis for the thiopurine intolerance phenotype observed in patients carrying these pharmacogenetic variants. These findings will aid in predicting the effects of new NUDT15 sequence variations yet to be discovered in the clinic

UVA/UVA1 phototherapy and PUVA photochemotherapy in connective tissue diseases and related disorders: a research based review

BACKGROUND: Broad-band UVA, long-wave UVA1 and PUVA treatment have been described as an alternative/adjunct therapeutic option in a number of inflammatory and malignant skin diseases. Nevertheless, controlled studies investigating the efficacy of UVA irradiation in connective tissue diseases and related disorders are rare. METHODS: Searching the PubMed database the current article systematically reviews established and innovative therapeutic approaches of broad-band UVA irradiation, UVA1 phototherapy and PUVA photochemotherapy in a variety of different connective tissue disorders. RESULTS: Potential pathways include immunomodulation of inflammation, induction of collagenases and initiation of apoptosis. Even though holding the risk of carcinogenesis, photoaging or UV-induced exacerbation, UVA phototherapy seems to exhibit a tolerable risk/benefit ratio at least in systemic sclerosis, localized scleroderma, extragenital lichen sclerosus et atrophicus, sclerodermoid graft-versus-host disease, lupus erythematosus and a number of sclerotic rarities. CONCLUSIONS: Based on the data retrieved from the literature, therapeutic UVA exposure seems to be effective in connective tissue diseases and related disorders. However, more controlled investigations are needed in order to establish a clear-cut catalogue of indications