Zika virus disease in Spain. Surveillance results and epidemiology on reported cases, 2015-2017. / La enfermedad por virus Zika en España. Resultados de la vigilancia y epidemiología de los casos notificados en 2015-2017.

INTRODUCTION AND OBJECTIVE: Zika virus disease is a challenge for public health due to its rapid spread and potential foetal complications. Although it is imported in Spain, there is a risk of autochthonous transmission due to Aedes albopictus presence. Zika disease and congenital cases have been under surveillance since 2016. The objective of this study is to explore the epidemiology of disease and pregnancies result. MATERIAL AND METHODS: A descriptive study was carried out into cases reported to the National Surveillance Network (RENAVE) during the 30/11/2015 to 31/12/2017 period. The case definition and the survey are included in the RENAVE protocol. The variables were: date; notifying region (Autonomous Community (AC)); pregnancy and its evolution; case classification; mode of transmission; country or region of infection; socio-demographical, clinical and microbiological data. A descriptive analysis of the cases and their distribution according to the other variables was carried out. RESULTS: A total of 512 cases were reported by 17 ACs. 507 were non-congenital, of which 327 (64.5%) were women (52.5% of childbearing age). 403 cases (79.5%) corresponded to 2016 and 193 (38.1%) resided in regions with A. albopictus presence between May and October. 96.1% of imported cases were infected in America (51.7% while visiting relatives). Three cases (3.9%) of congenital Zika virus infection were detected among 77 pregnant women. CONCLUSIONS: The evolution of reported cases was in accordance with that of the epidemic in America. The largest group of travellers was young women who travelled to Latin America on family visits. Pregnancy monitoring resulted in the identification of Zika related foetal complications.

Climate induced human demographic and cultural change in northern Europe during the mid-Holocene.

The transition from hunter-gatherer-fisher groups to agrarian societies is arguably the most significant change in human prehistory. In the European plain there is evidence for fully developed agrarian societies by 7,500 cal. yr BP, yet a well-established agrarian society does not appear in the north until 6,000 cal. yr BP for unknown reasons. Here we show a sudden increase in summer temperature at 6,000 cal. yr BP in northern Europe using a well-dated, high resolution record of sea surface temperature (SST) from the Baltic Sea. This temperature rise resulted in hypoxic conditions across the entire Baltic sea as revealed by multiple sedimentary records and supported by marine ecosystem modeling. Comparison with summed probability distributions of radiocarbon dates from archaeological sites indicate that this temperature rise coincided with both the introduction of farming, and a dramatic population increase. The evidence supports the hypothesis that the boundary of farming rapidly extended north at 6,000 cal. yr BP because terrestrial conditions in a previously marginal region improved.

Association of BRCA1 germline mutations in young onset triple-negative breast cancer (TNBC).

BACKGROUND: BRCA1-associated breast cancers have been associated to a triple-negative phenotype. The prevalence of BRCA1 germline mutations in young onset TNBC based on informativeness of family history has not been reported. PATIENTS AND METHODS: From January 2008 to May 2009 were collected blood and tumor samples from patients with TNBC younger than 50 years and without a family history of breast and ovarian cancer in first- and second-degree relatives. Analysis of BRCA1 germline mutations was made. Age at diagnosis and informativeness of family history (presence of female in first- and second-degree relatives alive until age 45) was collected in all cases. Immunohistochemistry of basal-like features was performed centrally in all available tumors. RESULTS: Seven pathogenic mutations were detected in 92 patients (7.6 %), two of them in patients younger than 35 years (28.6 %) (Fisher's exact test, p = 0.631). Three non-classified variants were detected (3.2 %). Family history was informative in two patients with a pathogenic mutation (28.6 %) and not informative in five (71.4 %) (Fisher's exact test, p = 0.121). Of the seven patients with a pathogenic mutation, four had a basal-like phenotype. CONCLUSION: Patients with apparently sporadic TNBC younger than 50 years and a non-informative family history are candidates for germline genetic testing of BRCA1.

The fate of nanocarriers as nanomedicines in vivo: important considerations and biological barriers to overcome.

Many pharmaceuticals on the market suffer from two significant limitations to their activity: lack of specificity toward the pathological site and poor aqueous solubility. Both factors therefore require the application of a large total dose of a drug to achieve high local concentration, causing numerous off-target toxic effects. Consequently, the grand aim of targeted drug delivery - the often-referred "magic bullet" - promises to improve drug concentration at the target site and maximize therapeutic response. Nanomaterial drug delivery systems have been explored extensively in the recent years for just this purpose. In the field of medicine, nanocarriers (NCs) have the potential to improve the biodistribution and pharmacokinetic characteristics of drugs, thereby reducing side effects while improving the therapeutic effect of drugs. Many nanomaterials are exquisitely designed and possess potent properties, yet it is extremely important to note that a general understanding of the interaction of nanomaterials with biological systems is essential for any such model properties to be effective in vivo, since the body presents a host of biological 'barriers' that will be encountered drug NCs. This review offers a general overview of the different biological obstacles that a NC must negotiate before it can carry out its desired role as a medicinal agent. From this standpoint we suggest aspects that should be considered for the rational design of novel nanomaterials possessing physicochemical properties that are appropriate for therapeutic or theragnostic applications.

Application of magnetically induced hyperthermia in the model protozoan Crithidia fasciculata as a potential therapy against parasitic infections.

BACKGROUND: Magnetic hyperthermia is currently a clinical therapy approved in the European Union for treatment of tumor cells, and uses magnetic nanoparticles (MNPs) under time-varying magnetic fields (TVMFs). The same basic principle seems promising against trypanosomatids causing Chagas disease and sleeping sickness, given that the therapeutic drugs available have severe side effects and that there are drug-resistant strains. However, no applications of this strategy against protozoan-induced diseases have been reported so far. In the present study, Crithidia fasciculata, a widely used model for therapeutic strategies against pathogenic trypanosomatids, was targeted with Fe(3)O(4) MNPs in order to provoke cell death remotely using TVMFs. METHODS: Iron oxide MNPs with average diameters of approximately 30 nm were synthesized by precipitation of FeSO(4) in basic medium. The MNPs were added to C. fasciculata choanomastigotes in the exponential phase and incubated overnight, removing excess MNPs using a DEAE-cellulose resin column. The amount of MNPs uploaded per cell was determined by magnetic measurement. The cells bearing MNPs were submitted to TVMFs using a homemade AC field applicator (f = 249 kHz, H = 13 kA/m), and the temperature variation during the experiments was measured. Scanning electron microscopy was used to assess morphological changes after the TVMF experiments. Cell viability was analyzed using an MTT colorimetric assay and flow cytometry. RESULTS: MNPs were incorporated into the cells, with no noticeable cytotoxicity. When a TVMF was applied to cells bearing MNPs, massive cell death was induced via a nonapoptotic mechanism. No effects were observed by applying TVMF to control cells not loaded with MNPs. No macroscopic rise in temperature was observed in the extracellular medium during the experiments. CONCLUSION: As a proof of principle, these data indicate that intracellular hyperthermia is a suitable technology to induce death of protozoan parasites bearing MNPs. These findings expand the possibilities for new therapeutic strategies combating parasitic infection.

Functionalized Fe3O4@Au superparamagnetic nanoparticles: in vitro bioactivity.

The interaction of nanoparticles with cells has been a focus of interest during the past decade. We report the fabrication and characterization of hydrosoluble Fe3O4@Au nanoparticles functionalized with biocompatible and fluorescent molecules and their interaction with cell cultures by visualizing them with confocal microscopy. Gold covered iron oxide nanoparticles were synthesized by reducing metal salts in the presence of oleylamine and oleic acid. The functionalization of these particles with an amphiphilic polymer provides a water soluble corona as well as the possibility to incorporate different molecules relevant for bio-applications such as poly(ethylene glycol), glucose or a cadaverine derived dye. The particle size, and the presence of polymer layers and conjugated molecules were characterized and confirmed by transmission electron microscopy, thermogravimetric measurements and infrared spectroscopy. A complete magnetic study was performed, showing that gold provides an optimum coating, which enhances the superparamagnetic behaviour observed above 10-15 K in this kind of nanoparticle. The interaction with cells and the cytotoxicity of the Fe3O4@Au preparations were determined upon incubation with the HeLa cell line. These nanoparticles showed no cytotoxicity when evaluated by the MTT assay and it was demonstrated that nanoparticles clearly interacted with the cells, showing a higher level of accumulation in the cells for glucose conjugated nanoparticles.

First autochthonous malaria case due to Plasmodium vivax since eradication, Spain, October 2010.

In October 2010, one case of autochthonous malaria due to Plasmodium vivax was diagnosed in Spain. The case occurred in Aragon, north-eastern Spain, where the vector Anopheles atroparvus is present. Although the source of infection could not be identified, this event highlights that sporadic autochthonous transmission of vector-borne diseases in continental Europe is possible and calls for enhanced surveillance and vector control measures.

Risk factors for disease severity among hospitalised patients with 2009 pandemic influenza A (H1N1) in Spain, April - December 2009.

We describe the clinical and epidemiological characteristics of patients hospitalised with confirmed 2009 pandemic influenza A(H1N1) in Spain from April to December 2009 and the risk factors associated with a worse outcome (admission to an intensive care unit or death) in adults. Case-based epidemiological information was collected as part of the national strategy for the surveillance of severe cases. Of 3,025 patients, 852 were admitted to an intensive care unit and overall, 200 died. The median patient age was 38 years (range: 0­94). A total of 662 (26%) patients had no underlying risk conditions. Antiviral therapy was initiated within 48 hours after symptom onset in only 35.2% (n=711); the median length of time before treatment was four days. In a multivariate analysis, the start of antiviral therapy more than 48 hours after symptom onset (odds ratio (OR) 2.39; 95% confidence interval (CI): 1.79 to 3.2), morbid obesity (OR: 2.01; 95% CI 1.38 to 2.94), cardiovascular disease (OR: 1.79; 95% CI: 1.2 to 2.67) and chronic obstructive pulmonary disease (OR: 1.51; 95% CI: 1.03 to 2.2) were significantly associated with a worse outcome in adults.

[Usefulness of the 14-3-3 test for the diagnosis of sCJD evaluated by a Spanish reference center]. / Utilidad del inmunoensayo de la proteína 14-3-3 en el diagnóstico de la enfermedad de Creutzfeldt-Jakob examinada desde un centro de referencia nacional.

INTRODUCTION: The performance of the 14-3-3 protein test has been shown to be adequate for sporadic Creutzfeldt-Jakob disease (sCJD) diagnosis in selected populations, but its routine validity has been questioned. METHODS: One thousand and sixty-eight patients with clinically suspected sCJD were analyzed in a Spanish reference center. In order to explore the influence of the clinical context on the performance of the immunoassay, the patients were classified at sample reception according to the World Health Organization (WHO) diagnostic criteria excluding the 14-3-3 test results. The yield of the immunoassay was evaluated in each subgroup with criteria of probable, possible sCJD or non-sCJD. RESULTS: In the set of patients with suspicion of sCJD the inclusion of the 14-3-3 test produces a significant increase in the diagnosis certainty (positive likelihood ratio: 10.1) compared to the WHO's criteria, excluding the 14-3-3 test. For patients classified at sample reception as probable sCJD (n=166), possible sCJD (n=129) and non-sCJD (n=773), the positive predictive values for the test were 98.4%, 97.5% and 31%, and the negative predictive values were 22.2%, 73.4% and 100%, respectively. CONCLUSIONS: The predictive values of the assay vary according to the previous diagnostic certainty. Therefore, in order to interpret correctly the test, it is necessary to evaluate the degree of initial clinical suspicion of the patient at the moment of the cerebrospinal fluid (CSF) extraction. This study offers up-to-date information, referenced to the Spanish population, and in useful format, and it is intended to serve as a guideline for 14-3-3 test results interpretation to the clinicians in our community.

Influenza vaccination coverages among Spanish children, adults and health care workers.

BACKGROUND: This study aimed at describing influenza vaccination coverage among Spanish children, adults and health care workers (HCWs). PATIENTS AND METHODS: We analyzed 27,791 questionnaires on subjects aged 6 months or over, drawn from the 2003 Spanish National Health Survey. As the dependent variable, we took the answer to the question, "Did you (or your child) have a flu shot in the last campaign?". Independent variables were age group, gender, nationality, occupation (HCWs) and coexistence of chronic conditions. RESULTS: Overall influenza vaccination coverage for the total sample was 19.58%. Coverage for the pediatric population was 5.55%, with 20.74% of those with and 4.67% of those without chronic condition being vaccinated. Vaccination coverages were: 63.7% among subjects aged > or = 65 years; 30.5% among high-risk subjects aged < 65 years; and 19.65% among HCWs. CONCLUSIONS: We conclude that the available results show low levels of influenza vaccination coverage among high-risk subjects aged under 65 years, children in particular, and HCWs.

[Costs of accidental punctures in hospital health personnel]. / Costes de las inoculaciones accidentales en personal sanitario de un hospital.

OBJECTIVES: The aim of this study was to calculate the average cost of each hepatitis B, C and HIV follow-up carried out in the health personnel that have suffered an exposure to blood and body fluids and to estimate the cost for each of the different types of sources as well as to identify the items that account for the main part of the cost. METHODS: A cost analysis was carried out. The post-exposure programme was modelled in a decision tree combining probabilities (percentage of each type of source in dependence of its positivity for the three viruses and immunization state of the health personnel against hepatitis B) and monetary costs (pesetas from 1994). Costs included: salaries, laboratory, chemist, energy, cleaning, telephone, medical and office equipment, amortization and lost productivity. A sensitivity analysis was carried out with the real fulfillment of the programme. RESULTS: The average cost was 39,564 ptas. (29,750 ptas. applying the sensitivity analysis), with a range from 86,864 ptas. (source positive for the three viruses and injured subject not immunized) to 23,074 ptas. (source negative for the three viruses). If the source was hepatitis B positive, the average cost was 86,093 ptas. when the injured subject was not immunized and 53,232 ptas. if he was immunized. Serologic tests account for the main part of the cost (range from 72.8% to 87.7%). CONCLUSIONS: High cost suggests an appropriate risk evaluation in order to avoid unnecessary follow-ups. The model used allows to know the cost of each potentially avoided episode and it could be used for any hospital in order to make an economical evaluation of new preventive devices.

[Minimizing the costs of prescription of anti-infective drugs in two areas of primary health care]. / Un estudio de minimización de costes en la prescripción de antiinfecciosos en dos areas de atención primaria.

BACKGROUND: Pharmaceutical costs are the main cost item in basic health care. The need to contain health care expenditure has led to the search for alternatives in this area, one of which would be to foster a prescription policy which uses the cheapest presentation for each active principle. The aim of this study was to evaluate the amount which would be saved by prescribing the cheapest alternative from a selection of anti-infective drugs. METHODS: Pharmacy prescriptions in two different health areas were analyzed using the database on turnover of pharmaceutical products for 1995. Single principle drugs with anti-infective action were selected, and for each active principle and presentation the most economic alternative was sought using the records provided by the Ministry of Health and a cost minimisation analysis was undertaken. The cost of applying this prescription policy was not considered. RESULTS: Total pharmaceutical expenditure in the areas was pesetas 8.547 bn in 1995. Expenditure on selected anti-infective drugs was pesetas 522 million (6.1% of the total). The overall saving estimated was 7.63% (pesetas 39,901,778). This saving was centred on the following subgroups: penicillins, quinolones, cephalosporins and macrolides. Of potential savings identified, 75% would be achieved by prescribing the cheaper alternative of 2 active principles: amoxacillin and cyprofloxacine. CONCLUSIONS: The study shows the possibility of containing expenditure in our area and offers a basis for action in this direction. It would be advisable to increase information and training for prescribers and dispensers in order to stimulate the use of the most economical alternative of each medicament prescribed, especially in cases in which there are significant margins to be saved.

[Effects of exercise in the elderly with chronic renal failure]. / Efectos del entrenamiento en el insuficiente renal crónico anciano.

The population studied in this paper is composed of 10 patients under hemodialysis, who have underwent a general exploration, a stress test, a spirometry, an analytic control and assessment of exercise their psychological situation, before and after the programme. At the end of the training programme there is an important increase in the SVC and the FVC, as well as the power and time of the stress test. The psychological state improves as well as the anaemia.

[Nephrotic syndrome associated with symmetrical multiple lipomatosis (Madelung's disease)]. / Síndrome nefrótico asociado a la lipomatosis múltiple simétrica. Enfermedad de Madelung.

We present a case of multiple symmetric lipomatosis Type I (Madelung's disease) with severe organic affection, hepatic cirrhosis, sever sensitive polyneuropathy and neuropathic ulceration at the left lower limb. A nephrotic syndrome developed in a larval form due to proliferative glomerulonephritis as the result of a metainfectious complications of the infection at the lower limb. We discuss the etiopathogenicity of the organic affection and we highlight the pathogenic links between the disease and its complications.

Comparative in vitro and in vivo activities of six new monofluoroquinolone and difluoroquinolone 3-carboxylic acids with a 7-azetidin ring substituent.

E-4502, E-4501, E-4500, E-4480, E-4474, and E-4441 are new monofluorinated or difluorinated quinolone agents that are chemically characterized by the presence of an azetidin ring, with different C'-3 substituents, at position 7 of the molecular structure. The MICs of the difluorinated compounds E-4501, E-4474, and E-4441 for 90% of isolates were 0.06 to 1, 0.06 to 1, and 0.12 to 1 microgram/ml, respectively, against gram-positive organisms (staphylococci, streptococci, and Enterococcus faecalis); 0.0015 to 0.12, 0.015 to 0.12, and 0.03 to 0.12 microgram/ml, respectively, against members of the family Enterobacteriaceae except Providencia spp.; and 1, 1, and 2 micrograms/ml, respectively, against Pseudomonas aeruginosa. E-4501, E-4474, and E-4441 inhibited all anaerobic bacteria at concentrations of 1, 2, and 4 micrograms/ml, respectively. Difluorinated compounds were significantly more active than the corresponding monofluorinated analogs E-4502, E-4500, and E-4480 against aerobic and facultatively anaerobic organisms, as well as against anaerobes. Considering monofluorinated and difluorinated compounds, activity in moderate ascending order was observed in quinolones containing an amine and a methyl group (E-4441 and E-4480), an amine group (E-4474 and E-4500), and a methylamine group (E-4501 and E-4502) in the C'-3 position of the azetidin ring. E-4501, E-4474, and E-4441 were more active than norfloxacin and DR-3355 [S-(-)-ofloxacin], had activities comparable to or slightly lower than that of ciprofloxacin against gram-negative bacteria, and were more active than all the reference quinolones against gram-positive organisms and anaerobes. E-4502 and E-4501, which were used to determine the effect of pH, were less active in acidic medium. In general, E-4502, E-4501, E-4500, E-4480, E-4474, and E-4441 activities were not affected or increased in medium containing serum but decreased in the presence of 10 mM Mg2+ or in human urine at pH 5.5. The protective effect of E-4501, E-4474, and E-4441 after oral administration against systemic infections with Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa in mice was greater than that of ciprofloxacin.

Antimicrobial activity of E-4441, a representative azetidine quinolone.

E-4441 is a third-generation difluoroquinolone characterized by the presence in position 7 of an azetidine ring, disubstituted in position 3 by amine and methyl groups. E-4322 is another difluoroquinolone which differs from the former in having a 3-acetidinol substitution in position 7. E-4441 shows satisfactory levels of activity, both in vitro and in vivo, its activity against G(+) aerobic bacteria and anaerobic bacteria being generally notable.

Activity of E-3846, a new fluoroquinolone, in vitro and in experimental cystitis and pyelonephritis in rats.

The in vitro antibacterial activity of E-3846, a new fluoroquinolone carboxylic acid derivative with a pyrrol ring substituent at position 7, was evaluated in comparison with norfloxacin and ciprofloxacin. E-3846 was more active than the reference quinolones against Staphylococcus species, including methicillin-resistant strains. E-3846 was similar to ciprofloxacin and more active than norfloxacin against Streptococcus (Enterococcus) faecalis. In general, E-3846 was more active than norfloxacin against members of the family Enterobacteriaceae, but less active than ciprofloxacin. For Pseudomonas aeruginosa, the MICs giving 90% inhibition for E-3846, norfloxacin, and ciprofloxacin were 2, 1, and 0.25 micrograms/ml, respectively. The activity of E-3846 increased at acid pH; in contrast, acid pH caused a pronounced decrease in the activity of norfloxacin and ciprofloxacin. In vivo, E-3846 demonstrated excellent therapeutic efficacy in treating experimental S. faecalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa cystitis and pyelonephritis in rats.