High incidence of candidaemia in a nationwide cohort: Underlying diseases, risk factors and mortality.

BACKGROUND: Denmark has a high incidence rate of candidaemia. A Nordic study suggested a higher Danish prevalence of haematological malignancies as an underlying reason. This nationwide study ascertained clinical characteristics of Danish candidaemia patients and investigated potential factors contributing to the high incidence and mortality. METHODS: Microbiological and clinical data for candidaemia patients in 2010-2011 were retrieved. 30-day mortality was estimated by hazard ratios (HR) with 95% confidence intervals (CI, Cox regression). RESULTS: Data were available for 912/973 candidaemia episodes (93.7%). Intensive care unit (ICU) held the largest share of patients (43.2%). Prevalent host factors were multi-morbidity (≥2 underlying diseases, 74.2%) and gastrointestinal disease (52.5%). Haematological disease was infrequent (7.8%). Risk factors included antibiotic exposure (90.5%), CVC (71.9%) and Candida colonisation (66.7%). 30-day mortality was 43.4%, and 53.6% in ICU. Mortality was lower for patients with recent abdominal surgery (HR 0.70, 95% CI: 0.54-0.92). CONCLUSION: A substantial prevalence of multi-morbidity and a high 30-day mortality was found. We hypothesise, that an increasing population of severely ill patients with prolonged supportive treatment and microbiological testing may in part explain the high candidaemia incidence in Denmark. Nationwide studies are warranted to clarify this issue.

Update from a 12-Year Nationwide Fungemia Surveillance: Increasing Intrinsic and Acquired Resistance Causes Concern.

New data from the years 2012 to 2015 from the Danish National Fungemia Surveillance are reported, and epidemiological trends are investigated in a 12-year perspective (2004 to 2015). During 2012 to 2015, 1,900 of 1,939 (98%) fungal bloodstream isolates were included. The average incidence was 8.4/100,000 inhabitants, and this appears to represent a stabilizing trend after the increase to 10.1/100,000 in 2011. The incidence was higher in males than females (10.0 versus 6.8) and in patients above 50 years, and those changes were mainly driven by an increasing incidence among 80-to-89-year-old males (65.3/100,000 in 2014 to 2015). The proportion of Candida albicans isolates decreased from 2004 to 2015 (64.4% to 42.4%) in parallel with a doubling of the proportion of Candida glabrata isolates (16.5% to 34.6%, P < 0.0001). C. glabrata was more common among females (34.0% versus 30.4% in males). Following an increase in 2004 to 2011, the annual drug use stabilized during the last 2 to 3 years of that time period but remained higher than in other Nordic countries. This was particularly true for the fluconazole and itraconazole use in the primary health care sector, which exceeded the combined national levels of use of these compounds in each of the other Nordic countries. Fluconazole susceptibility decreased (68.5%, 65.2%, and 60.6% in 2004 to 2007, 2008 to 2011, and 2012 to 2015, respectively, P < 0.0001), and echinocandin resistance emerged in Candida (0%, 0.6%, and 1.7%, respectively, P < 0.001). Amphotericin B susceptibility remained high (98.7%). Among 16 (2.7%) echinocandin-resistant C. glabrata isolates (2012 to 2015), 13 harbored FKS mutations and 5 (31%) were multidrug resistant. The epidemiological changes and the increased incidence of intrinsic and acquired resistance emphasize the importance of continued surveillance and of strengthened focus on antifungal stewardship.

Singlet oxygen luminescence kinetics in a heterogeneous environment - identification of the photosensitizer localization in small unilamellar vesicles.

In vivo measurement of singlet oxygen luminescence kinetics is affected by the heterogeneity of biological samples. Even though singlet oxygen luminescence detection is technically getting easier, the analysis of signals from biological samples is still far from quantitative real time surveillance as it is aspired by the community. In this paper small unilamellar vesicles (SUVs) are used for modelling the general behaviour of heterogeneous samples. The geometry of the SUVs can be determined independently using dynamic light scattering. Therefore an accurate theoretical description of the generation, deactivation and diffusion of the singlet oxygen is possible. The theoretical model developed here perfectly fits the experimental results. Thus the location of the singlet oxygen generating a photosensitizer molecule can be exactly determined from the kinetics of the singlet oxygen luminescence. The application of the used theoretical approach thus allows for accurate quantitative measurements in SUVs.

Inhibition of green algae growth by corrole-based photosensitizers.

AIMS: This study was performed to examine the potential of photodynamic inactivation for growth inhibition of green algae through generation of singlet oxygen. METHODS AND RESULTS: Two cationic and two anionic corroles were investigated according to their photoinhibitive effect on two strains of green algae using visible light for photoexcitation. The development of biomass over the experimental period of 18 days was followed using absorptive properties of the algae samples. The anionic photosensitizers showed no significant phototoxicity, whereas the cationic photosensitizers caused a drastic reduction of biomass on a short time scale and also displayed long-term inhibition of algae growth. CONCLUSIONS: In general, it was proven that photodynamic inactivation of green algae is possible. Concluding from the results of this study, cationic photosensitizers are favourable for this task, while anionic photosensitizers are not suited. SIGNIFICANCE AND IMPACT OF THE STUDY: Phototrophic biofilms are an important factor in biofouling and biodeterioration of building materials, causing great damage to historic and contemporary constructions. Growth inhibition of phototrophic organisms using photodynamic inactivation could pose an alternative to the use of biocides. To this end, successful application of this approach on green algae is a vital step in the development of suitable photosensitizers.

Effect of Some Substituents Increasing the Solubility of Zn(II) and Al(III) Phthalocyanines on Their Photophysical Properties.

Water solubility of phthalocyanines (Pcs) usually increases by the introduction of charged or carboxy substituents in the peripheral positions of the macrocycle. As a result, such structural changes influence their photophysical and photochemical properties as photosensitizers. Phthalocyanines substituted with four or eight terminal carboxyl groups and having in some cases additional eight positive charges (water soluble phthalocyanines) were studied in order to evaluate the spectroscopic and photophysical effects of these side residues on the chromophore properties. The quantum yield of singlet oxygen ((1)O2) generation, the triplet-triplet absorption, and the transient absorption spectra were measured and linked to the structure of the substituents. It was shown that charged substituents did not change the quantum yields of (1)O2 generation but decrease its lifetimes. The introduction of the charged substituents not only increases the water solubility but also significantly changes absorption, fluorescence, and transient absorption spectra of water soluble Pcs.

Epidemiological changes with potential implication for antifungal prescription recommendations for fungaemia: data from a nationwide fungaemia surveillance programme.

Significant changes in the management of fungaemia have occurred over the last decade with increased use of fluconazole prophylaxis, of empirical treatment and of echinocandins as first-line agents for documented disease. These changes may impact the epidemiology of fungaemia. We present nationwide data for Denmark from 2010 to 2011. A total of 1081 isolates from 1047 episodes were recorded in 995 patients. The numbers of patients, episodes and recovered isolates increased by 13.1%, 14.5% and 14.1%, respectively, from 2010 to 2011. The incidence rate was significantly higher in 2011 (10.05/100 000) than in 2010 (8.82/100 000), but remained constant in the age groups 0-79 years. The incidence rate was highest at the extremes of age and in males. Candida albicans accounted for 52.1% but declined during 2004-11 (p 0.0155). Candida glabrata accounted for 28% and increased during 2004-2011 (p <0.0001). Candida krusei, Candida tropicalis and Candida parapsilosis remained rare (3.3-4.2%). The species distribution changed with increasing age (fewer C. parapsilosis and more C. glabrata) and by study centre. Overall, the susceptibility rates were: amphotericin B 97.3%, anidulafungin 93.8%, fluconazole 66.7%, itraconazole 69.6%, posaconazole 64.2% and voriconazole 85.0%. Acquired echinocandin resistance was molecularly confirmed in three isolates. The use of systemic antifungals doubled over the last decade (2002-2011) (from 717 000 to 1 450 000 defined daily doses/year) of which the vast majority (96.9%) were azoles. The incidence of fungaemia continues to increase in Denmark and is associated with a decreasing proportion being susceptible to fluconazole. Changes in demography, higher incidence in the elderly and higher antifungal consumption can at least in part explain the changes.

[Risk communication of the Federal Institute for Risk Assessment during a food-related outbreak]. / Risikokommunikation des Bundesinstituts für Risikobewertung bei einem lebensmittelbedingten Ausbruch.

Information about and explanation of risks as well as the initiation of behavioral changes and preventive actions are core tasks of risk communication. During the EHEC/HUS outbreak in spring 2011, the governmental agencies responsible for risk communication mainly focused on these tasks. In general, risk communication is understood as a continuous, long-term process that aims at an adequate handling of risks. In contrast, crisis communication is focused rather on an acute event and aims at timely information and behavioral measures. During the EHEC/HUS outbreak, risk communication partly changed over to crisis communication. The risk communication activities of the Federal Institute for Risk Assessment (Bundesinstitüt für Risikobewertung, BfR) during the EHEC/HUS outbreak are presented here. The results of a representative survey that was conducted in Germany shortly after the outbreak show details of the success of these risk communication activities. Finally, the necessity of communication about scientific uncertainty is addressed and new ways in risk communication with regard to new media are highlighted.

Alpha-1-Fetoprotein (AFP): international proficiency study with different test systems.

BACKGROUND: The present proficiency study aimed to elucidate the comparability and reliability of test systems for the determination of AFP concentrations. METHODS: 25 laboratories using 8 different commercial test systems used liquid BIOREF-AFP control serum in their routine internal quality control over a period of one year. For statistical analysis the results were collected centrally. RESULTS: The statistical analysis of the test results revealed considerable variation for the different laboratories. The deviations of the mean values of different laboratories from the overall mean value varied between 0.1 and 26.1%, and for most of the laboratories the deviation was round about 10%. The precision of measured values in the individual laboratories was in most cases acceptable: Nevertheless, the coefficients of variation of the individual laboratories ranged from 13 to 16.1%. CONCLUSIONS: In conclusion, this study indicates that AFP results vary between different laboratories albeit an international standard for AFP is available. Therefore, every laboratory should participate in external ring studies and should use a quality control serum independent of the test kit manufacturer for the internal quality control.

Water-soluble polymer conjugates of ZnPP for photodynamic tumor therapy.

Zn-protoporphyrin (ZnPP) is a promising candidate for cancer therapy. It is known to inhibit heme-oxygenase-1 (HO-1), resulting in suppressed biliverdin/bilirubin production accompanying lowered antioxidative capacity. As a consequence, a significant suppression of tumor growth in vivo was reported. Recent findings also showed that ZnPP efficiently generated reactive singlet oxygen under illumination of visible light. In the present report, we describe the photosensitizing capabilities of water-soluble polymer conjugates of ZnPP as novel compounds for photodynamic therapy against solid tumors. The polymer conjugation made ZnPP water-soluble, thus possible for injection for its aqueous solution. The cellular uptake and photobiological activity of ZnPP derivatives have been tested using a human T-cell leukemia cell line in vitro and demonstrated most potent phototoxic effects of SMA-ZnPP followed by PEG-ZnPP under aerobic conditions.

Lipid nanoparticles for skin penetration enhancement-correlation to drug localization within the particle matrix as determined by fluorescence and parelectric spectroscopy.

With topical treatment of skin diseases, the requirement of a high and reproducible drug uptake often still is not met. Moreover, drug targeting to specific skin strata may improve the use of agents which are prone to cause local unwanted effects. Recent investigations have indicated that improved uptake and skin targeting may become feasible by means of nanoparticular systems such as solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC) and nanoemulsions (NE). Here we describe techniques to characterize drug loading to carrier systems and skin penetration profiles by using the lipophilic dye nile red as a model agent. Since the mode of drug association with the particle matrix may strongly influence the efficiency of skin targeting, parelectric spectroscopy (PS) was used to differentiate between matrix incorporation and attachment to the particle surface and fluorescence spectroscopy (FS) to solve dye distribution within NLC particles. Nile red was incorporated into the lipid matrix or the covering tensed shell, respectively, of SLN and NLC with all the lipids studied (Compritol, Precirol, oleic acid, Miglyol). In NLC, the dye was enriched in the liquid phase. Next, nile red concentrations were followed by image analysis of vertical sections of pigskin treated with dye-loaded nanoparticular dispersions and an oil-in-water cream for 4 and 8 h in vitro. Following the SLN dispersions, dye penetration increased about fourfold over the uptake obtained following the cream. NLC turned out less potent (

Respiratory syncytial virus infection--risk factors for hospital admission: a case-control study.

UNLABELLED: Most infants are infected with respiratory syncytial virus (RSV) during the first 2 y of life. The majority have only a mild upper respiratory tract infection, but 1-2% develop a more severe illness and are admitted to hospital. AIM: To carry out a study of risk factors for hospital admission because of RSV infection in Denmark in children aged less than 2 y of age. METHODS: The study population included all 1252 children admitted to hospital with verified RSV infection in two Danish counties during the 5-y period 1990-1994. The investigation comprised a retrospective case-control study with five matched controls per case. In a multivariate analysis the risk factors included medical and demographic variables, and in infants <3 mo of age at hospitalization, two aspects of innate immunity: mannose-binding lectin (MBL) concentration and maternal RSV serum antibody titre, measured on eluates from stored dried blood from the infants' 4th day of life. The effect of each risk factor is expressed as an odds ratio, corresponding to the relative risk of being a case rather than a control if the risk factor is present. RESULTS: The following independent risk factors were identified: age, sex, month of birth, gestational age, birthweight, presence of a sibling, up to 5 y older than the case, and maternal smoking during pregnancy. There was a marginal effect of maternal RSV antibody levels, but no effect of neonatal serum MBL concentration or of crowding in the household. CONCLUSIONS: Ninety percent of cases and 80% of controls had one or more risk factors. Even though several factors were found to increase the risk for hospitalization for RSV disease, all the effects were small and no single specific factor could be identified to explain the hospitalization of the minority of children with RSV infection.

Methylammonium groups at the solid walls of nanometer-sized, water-filled monolayer gaps as binding sites for a tetraanionic porphyrin.

Long-chain hydrosulfides containing two secondary amide functions and either electron-poor or electron-rich carbon-carbon double bonds were self-assembled on gold surfaces around a flat-lying, octaanionic porphyrin. Rigid and reactive surface monolayers with 2 nm-wide, porphyrin-based gaps were thus obtained. The gold electrodes were then immersed in water, and the double bonds on the gaps' surfaces reacted with methylamine. It was added to the double bonds either by Michael addition or by bromination with hypobromite followed by methylamine substitution. Only the double bonds at the border of the gaps were accessible to methylamine dissolved in the bulk water volume and could react. The walls of the rigid membrane gaps now contained methylammonium groups at the sites of the double bonds in defined heights. A tetracationic copper(II) porphyrinate could not diffuse any more into the gap and did not quench the fluorescence of the octaanionic porphyrin on the bottom of the gap. A tetraanionic porphyrin, on the other hand, was fixated by the ring of ammonium groups. The bound porphyrin then acted as molecular cover for the gap with respect to ferricyanide transport from bulk water to the electrode. It was removed by raising the pH to a value of 12, where the methylammonium groups were neutralized to amines. Lowering the pH to 7 again and addition of more of the anionic porphyrin reclosed the gap.The porphyrin "cover" should be localized at distances of 8-10 and 20 A from the bottom porphyrin by multiple charge interactions. The 8-10 A distance is ideal for studies of photoinduced electron transfer between two porphyrin monomers of different redox potential. Furthermore it was found, that redox-active tyrosine could be trapped in the water volume above the porphyrin on gold.

Auditory memory in congenitally blind adults: a behavioral-electrophysiological investigation.

Blind people must rely more than sighted people on auditory input in order to acquire information about the world. The present study was designed to test the hypothesis that blind people have better memory than sighted individuals for auditory verbal material and specifically to determine whether memory encoding and/or retrieval are improved in blind adults. An incidental memory paradigm was employed in which 11 congenitally blind people and 11 matched sighted controls first listened to 80 sentences which ended either with a semantically appropriate or inappropriate word. Immediately following, the recognition phase occurred, in which all sentence terminal words were presented again randomly intermixed with the same number of new words. Participants indicated whether or not they had heard the word in the initial study phase. Event-related brain potentials (ERPs) were recorded from 28 electrode positions during both the encoding and the retrieval phase. Blind participants' memory performance was superior to that of sighted controls. In addition, during the recognition phase, previously presented words elicited ERPs with larger positive amplitudes than new words, particularly over the right hemisphere. During the study phase, words that would subsequently be recognized elicited a more pronounced late positive potential than words that were not subsequently recognized. These effects were reliable in the congenitally blind participants but could only be obtained in the subgroup of sighted participants who had the highest memory performance. These results imply that blind people encode auditory verbal material more efficiently than matched sighted controls and that this in turn allows them to recognize these items with a higher probability.

Inhibition of return and oculomotor control in the blind.

Our attentional systems orient reflexively to novel environmental stimuli. Such attentive orienting is typically followed by a prolonged period of inhibition, known as inhibition of return (IOR), thought to be linked to the eye movement system. It is widely believed that IOR may provide a tagging mechanism that prevents perseveration, and thus facilitates attentional search. Using a tactile variant of the peripheral spatial cuing paradigm, we show IOR in congenitally blind adults and in an individual who had no eyes. These results demonstrate for the first time that spatial IOR can occur in the absence of oculomotor control.

Event-related potentials during auditory language processing in congenitally blind and sighted people.

While behavioral studies have documented delayed language acquisition in blind children, other studies have revealed better speech discrimination abilities for blind than sighted adults. Several brain imaging studies have provided evidence for cortical reorganization due to visual deprivation but the cerebral organization of language in blind humans is not known yet. We hypothesized that the increasing specialization of language systems normally observed during development may not take place to the same degree in blind individuals since posterior visual areas do not receive their adequate input. On the other hand, we hypothesized that blind people, due to their greater reliance upon the auditory language signal, may process speech faster than sighted people. To test these assumptions, event-related potentials were recorded while 11 congenitally blind and 11 sighted adults matched in age, gender, handedness and education were engaged in a language task. Participants listened to sentences in order to decide after each sentence if it was meaningful or not. Incongruous sentence-final words elicited an N400 effect in both groups. The N400 effect had a left-lateralized fronto-central scalp distribution in the sighted but a symmetric and broad topography in the blind. Furthermore, the N400 effect started earlier in the blind than in the sighted. Closed class compared to open class sentence middle words elicited a more pronounced late negativity in the blind than in the sighted. These results suggest that blind people process auditory language stimuli faster than sighted people and that some language functions may be reorganized in the blind.

Photophysical studies of the pheophorbide a dimer.

This work reports on a monomer-dimer equilibrium state of pheophorbide a in solution. A methodology for controlling the equilibrium constant by use of temperature and solvent variation is described. The absorption spectrum of the dimer is calculated, using different prepared equilibria of monomer and dimer in solution. We propose that these aggregates provide a good model for understanding the dimerization process in tetrapyrroles.

[Staphylococcus aureus endocarditis in Denmark 1982-1991. Clinical picture, complications and antibiotic therapy in non-drug addicts]. / Staphylococcus aureus-endocarditis i Danmark 1982-1991. Klinisk billede, komplikationer og antibiotisk behandling hos ikke-narkomaner.

The central S. aureus surveillance in Denmark made it possible to analyze the clinical features of S. aureus endocarditis in a nation-wide population of non-drug addicts. Almost all cases of bacteraemia with S. aureus are reported to the Staphylococcus laboratory, Copenhagen. The medical records were reviewed in cases from 1982 to 1991 in which the diagnosis of endocarditis was reported or suspected. Two hundred and sixty patients fulfilled the diagnostic criteria. In 83 patients the diagnosis of endocarditis was not suspected clinically. The overall mortality rate among those patients whose disease was diagnosed clinically was 46% and significantly associated with late congestive heart failure, age and involvement of the central nervous system. A more frequent use of echocardiography as a screening method seems essential to improve the prognosis of patients with S. aureus endocarditis. Involvement of the CNS constitutes a relative indication for early valve replacement.

Spatial attention to central and peripheral auditory stimuli as indexed by event-related potentials.

Young adult subjects attended selectively to brief noise bursts delivered in free-field via central and peripheral arrays of four loudspeakers each that were arranged along a semi-circle extending from the midline to 90 degrees right of center. Frequent "standard" stimuli (90%) and infrequent "target/deviant" stimuli (10%) of increased bandwidth were delivered at a fast rate in random order and equiprobably from all eight speakers. In separate runs, the subject's task was to selectively attend to the center or rightmost speaker, and to press a button to the infrequent "target" stimuli occurring at the designated (spatial) location. Behavioral detection rates and concurrently recorded event-related potentials (ERPs) indicated that auditory attention was deployed as a finely tuned gradient around the attended source. The attentional gradients were steeper for the central than the peripheral array, indicating that attention can be more sharply focused upon sound sources directly in front of the listener. The ERP data suggested that selection for location is accomplished in two distinct stages, with an initial broadly tuned filtering, followed by a more narrowly focused selection of attended-location deviants.

Improved auditory spatial tuning in blind humans.

Despite reports of improved auditory discrimination capabilities in blind humans and visually deprived animals, there is no general agreement as to the nature or pervasiveness of such compensatory sensory enhancements. Neuroimaging studies have pointed out differences in cerebral organization between blind and sighted humans, but the relationship between these altered cortical activation patterns and auditory sensory acuity remains unclear. Here we compare behavioural and electrophysiological indices of spatial tuning within central and peripheral auditory space in congenitally blind and normally sighted but blindfolded adults to test the hypothesis (raised by earlier studies of the effects of auditory deprivation on visual processing) that the effects of visual deprivation might be more pronounced for processing peripheral sounds. We find that blind participants displayed localization abilities that were superior to those of sighted controls, but only when attending to sounds in peripheral auditory space. Electrophysiological recordings obtained at the same time revealed sharper tuning of early spatial attention mechanisms in the blind subjects. Differences in the scalp distribution of brain electrical activity between the two groups suggest a compensatory reorganization of brain areas in the blind that may contribute to the improved spatial resolution for peripheral sound sources.

Effects of interstimulus interval on auditory event-related potentials in congenitally blind and normally sighted humans.

To test the hypothesis of auditory compensation after early visual deprivation, congenitally blind and sighted adults performed an auditory discrimination task. They had to detect a rare target tone among frequent standard tones. Stimuli were presented with different interstimulus intervals (ISIs) (200, 1000, 2000 ms) and the auditory-event related potentials to all tones and reaction times to targets were recorded. Increasing ISIs resulted in an increasing amplitude of the vertex response (N1-P2) in both groups, but this amplitude recovery was more pronounced in the blind. Furthermore, targets elicited larger and more posteriorly distributed N2 responses in the blind than in the sighted. Since target detection times were shorter in the blind as well, these findings imply compensatory adaptations within the auditory modality in humans blind from birth.