Search

Pathogens often occur at different prevalence along environmental gradients. This is of particular importance for gradients of anthropogenic impact such as rural-urban transitions presenting a changing interface between humans and wildlife. The assembly of parasite communities is affected by both the external environmental conditions and individual host characteristics. Hosts with low body weight (smaller individuals or animals with poor body condition) might be more susceptible to infection. Furthermore, parasites' mode of transmission might affect their occurrence: rural environments with better availability of intermediate hosts might favour trophic transmission, while urban environments, typically with dense definitive host populations, might favour direct transmission. We here study helminth communities (141 intestinal samples) within the red fox (Vulpes vulpes), a synanthropic host, using DNA metabarcoding of multiple marker genes. We analysed the effect of urbanisation, seasonality and host-intrinsic (weight, sex) variables on helminth communities. Helminth species richness increased in foxes with lower body weight and in winter and spring. Season and urbanisation, however, had strong effects on the community composition, i.e., on the identity of the detected species. Surprisingly, transmission in two-host life cycles (trophic transmission) was more pronounced in urban Berlin than in rural Brandenburg. This disagrees with the prevailing hypothesis that trophically transmitted helminths are less prevalent in urban areas than in rural areas. Generally, co-infestations with multiple helminths and high infection intensity are associated with lighter (younger, smaller or low body condition) animals. Both host-intrinsic traits and environmental drivers together shape parasite community composition and turnover along urban-rural gradients., Competing Interests: Declaration of competing interest Emanuel Heitlinger reports financial support was provided by German Research Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Elevated pulmonary vascular resistance (PVR) is broadly accepted as an imminent risk factor for mortality after heart transplantation (HTx). However, no current HTx recipient risk score includes PVR or other hemodynamic parameters. This study examined the utility of various hemodynamic parameters for risk stratification in a contemporary HTx population., Methods: Patients from seven German HTx centers undergoing HTx between 2011 and 2015 were included retrospectively. Established risk factors and complete hemodynamic datasets before HTx were analyzed. Outcome measures were overall all-cause mortality, 12-month mortality, and right heart failure (RHF) after HTx., Results: The final analysis included 333 patients (28% female) with a median age of 54 (IQR 46-60) years. The median mean pulmonary artery pressure was 30 (IQR 23-38) mm Hg, transpulmonary gradient 8 (IQR 5-10) mm Hg, and PVR 2.1 (IQR 1.5-2.9) Wood units. Overall mortality was 35.7%, 12-month mortality was 23.7%, and the incidence of early RHF was 22.8%, which was significantly associated with overall mortality (log-rank HR 4.11, 95% CI 2.47-6.84; log-rank p < .0001). Pulmonary arterial elastance (Ea) was associated with overall mortality (HR 1.74, 95% CI 1.25-2.30; p < .001) independent of other non-hemodynamic risk factors. Ea values below a calculated cutoff represented a significantly reduced mortality risk (HR 0.38, 95% CI 0.19-0.76; p < .0001). PVR with the established cutoff of 3.0 WU was not significant. Ea was also significantly associated with 12-month mortality and RHF., Conclusions: Ea showed a strong impact on post-transplant mortality and RHF and should become part of the routine hemodynamic evaluation in HTx candidates., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Beta glucans are complex glucose polymers well known for their immune modulatory properties. Therefore they are used and advertised in dietary supplements. Unfortunately there is no standardized test system for quality control of such health-related foods. This approach combined wet chemical and enzyme-based quantification methods (e.g. aniline blue, Glucatell®) with a cytokine secretion assay as parameter for immune activation to resolve this problem and to establish a quality control system for β-glucan containing products and extracts. Commercially available pure β-glucans with different origin and structure were used in this study. None of the methods allowed an accurate β-glucan quantification. Most promising was the test kit K-EBHLG (Megazyme). However, cytokine secretion from whole blood was detectable under the influence of β-glucans, but there was no correlation with the quantification results using the commercially available kits. Therefore, the quality control of β-glucan containing products needs further efforts., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Comparison of different lines of research on statistical intuitions and probabilistic reasoning reveals several puzzling contradictions. Whereas babies seem to be intuitive statisticians, surprisingly capable of statistical learning and inference, adults' statistical inferences have been found to be inconsistent with the rules of probability theory and statistics. Whereas researchers in the 1960s concluded that people's probability updating is "conservatively" proportional to normative predictions, probability updating research in the 1970s suggested that people are incapable of following Bayes's rule. And whereas animals appear to be strikingly risk savvy, humans often seem "irrational" when dealing with probabilistic information. Drawing on research on the description-experience gap in risky choice, we integrate and systematize these findings from disparate fields of inquiry that have, to date, operated largely in parallel. Our synthesis shows that a key factor in understanding inconsistencies in statistical intuitions research is whether probabilistic inferences are based on symbolic, abstract descriptions or on the direct experience of statistical information. We delineate this view from other conceptual accounts, consider potential mechanisms by which attributes of first-hand experience can facilitate appropriate statistical inference, and identify conditions under which they improve or impair probabilistic reasoning. To capture the full scope of human statistical intuition, we conclude, research on probabilistic reasoning across the lifespan, across species, and across research traditions must bear in mind that experience and symbolic description of the world may engage systematically distinct cognitive processes., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Distinguishing meaningful structure from unpredictable randomness is a key challenge in many domains of life. We examined whether collaborating three-person groups (n = 81) outperform individuals (n = 81) in facing this challenge with a two-part repeated choice task, where outcomes were either serially independent (probabilistic part) or fixed in a particular sequence (pattern part). Groups performed as well as the best individuals in the probabilistic part but groups' accuracy did not credibly exceed that of the average individual in the pattern part. Qualitative coding of group discussion data revealed that failures to identify existing patterns were related to groups accepting probability maximizing as a "good enough" strategy rather than expending effort to search for patterns. These results suggest that probability maximizing can arise via two routes: recognizing that probabilistic processes cannot be outdone (maximizing as optimizing) or settling for an imperfect but easily implementable strategy (maximizing as satisficing)., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Hepatozoon canis is a blood parasite of the suborder Adeleorina infecting wild and domestic canids. Transmission occurs by oral uptake of Rhipicephalus sanguineus sensu lato vector ticks infected with H. canis, but vertical transmission is also assumed to be possible. In German foxes, a high prevalence of H. canis has previously been reported despite the fact that R. sanguineus s.l. is not endemic. In the absence of knowledge about local transmission pathways, foxes should be considered to be possible reservoirs of H. canis and contribute to infection of domestic dogs. The present study aimed to determine how often foxes and dogs are infected in Brandenburg (Germany) and if identical or different H. canis 18S rRNA haplotypes are found in these host species. Hepatozoon spp. were detected by PCR in 46/1050 (4.4 %) of dog blood and 176/201 (77.6 %) of fox spleen samples from Brandenburg. Sequencing of 19 dog and 56 fox samples identified all as H. canis. For nine positive dogs, owners stated that they had never left Germany suggesting that autochthonous transmission occurs not only in foxes but also in dogs. Sequences for seven of these possible autochthonous cases were obtained and six were identical to the predominant haplotype found in the foxes. Haplotype network analysis confirmed that many dogs, including some without travel history, carried the same or very similar 18S rRNA haplotypes as the foxes suggesting that both hosts participate in the same epidemiological cycle., (Copyright © 2020. Published by Elsevier GmbH.)

Lung cancer screening with low-dose computed tomography (LDCT) reduces lung cancer mortality, yet few eligible high-risk patients receive it annually. This protocol describes a community-partnered intervention (Toolkit) designed to support primary care practices in making referrals for lung screening and guiding patients into appropriate screening pathways. This study uses a stepped-wedge implementation design. Screening centers are randomized by readiness level to enter the intervention phase in three-month "steps" with pre-intervention data serving as the control. The primary outcome is whether delivery of the Toolkit to primary care practices results in a monthly increase in number of initial LDCT screenings. Six participating centers will identify 10 practices and reach 2-3 providers per practice to train them to use the Toolkit. The Toolkit will address known barriers to screening and referral at the patient and provider levels and provide support for required elements of screening. Toolkit components include adaptable evidence-based interventions to maximize compatibility with workflows. We hypothesize that after nine months of intervention delivery, the number of initial screening per center will double. Involving 60 practices achieves 80% power at 5% level of significance. Implementation outcomes such as adoption, acceptability, feasibility, adaptation, and sustainability will be assessed through field-notes and activity logs. LDCT for lung cancer screening currently reaches a small fraction of eligible adults. To reach the full potential to reduce mortality, primary care practices are an important venue for increasing appropriate referrals. This multidisciplinary trial will encourage acceptability and sustainability by using local knowledge and promoting partnership between providers and patients. Trial registration: ClinicalTrials.gov, NCT03958253., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aims: B-type natriuretic peptide (BNP) has been suggested to improve risk prediction of cardiovascular (CV) events and mortality. We aimed to evaluate the value of BNP to predict the composite primary endpoint of CV events and mortality alongside traditional and HIV specific risk factors in a HIV-infected population., Methods: In this prospective multicenter HIV-HEART study we followed 808 HIV-positive subjects in the German Ruhr area for a median follow up of 120 (IQR:113-129) months since 2004. Association of BNP with the composite primary endpoint was assessed using Cox regression adjusting for traditional cardiovascular and HIV specific risk factors., Results: At baseline, median BNP was 10.3 (IQR 5.4-18.9) pg/ml. The composite endpoint occurred in 158 (19.6%) patients. Subjects with high BNP levels showed significantly increased frequencies of CV events and death (22% for BNP ≤5 pg/ml, 30% for BNP >5 up to ≤20 pg ml, 38% for BNP >20 up to ≤35 pg ml, 59% for BNP >35 up to ≤100 pg ml and 86% for BNP >100 pg/ml, p-value < 0.01). In the fully adjusted model that included traditional CV risks as well as HIV specific factors, after a log 2 transformation, doubling of BNP was significantly associated with increased risk for the composite endpoint (HR:1.16 (95%CI 1.01-1.33); p = 0.031). Comparing BNP of <5 pg/ml to BNP > 100 pg/ml, HR in the fully adjusted model was 3.25 (95%CI 1.50-7.08; p < 0.001)., Conclusions: Increased BNP is associated with significant excess of incident CV events and mortality in HIV-infected patients. BNP is a valuable marker to improve the prediction of CV events and mortality., (Copyright © 2019 Elsevier B.V. All rights reserved.)

A 5-years-old moose (Alces alces) cow kept in a zoo in the German Federal State of Brandenburg aborted a female foetus of 44cm crown rump length (CRL). Pathohistological analysis revealed several Neospora (N.) caninum infected cells and cysts, as well as multifocal gliosis, necrosis, haemorrhages, dystrophic mineralisation and haemosiderosis in the brain, predominantly in cerebrum and brainstem. In addition, mild lymphocytic meningitis was present. Together with the fresh foetus, a mummified foetus of 16cm CRL was expelled. Neither focal necrosis, nor inflammation was detected in the brain of the mummified foetus. By two polymerase chain reactions (PCR) targeting the pNc5 gene of N. caninum (i.e. an end point PCR and a real-time PCR), by two serological methods (immunofluorescence test and immunoblot), by histological and immunohistochemical analyses, transplacental N. caninum infection was confirmed in the fresh foetus and interpreted as possible cause of abortion. Infection with other agents causing abortion including Bovine Herpesvirus 1 (BHV1), Bluetongue Virus (BTV), Bovine Virus Diarrhoea Virus (BVDV), Brucella spp., Chlamydia spp., Coxiella burnetii and Toxoplasma gondii were excluded. Our findings show that control measures may be necessary to protect captive moose against accidental N. caninum infection. Further studies are needed to explore the importance of neosporosis in wild and captive moose., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Nowadays, biomaterials can be used to maintain or replace several functions of the human body if necessary. Titanium and its alloys, i.e. Ti6Al4V are the most common materials (70 to 80%) used for structural orthopedic implants due to their unique combination of good mechanical properties, corrosion resistance and biocompatibility. Addition of β-stabilizers, e.g. niobium, can improve the mechanical properties of such titanium alloys further, simultaneously offering excellent biocompatibility. In this in vitro study, human osteoblasts and fibroblasts were cultured on different niobium specimens (Nb Amperit, Nb Ampertec), Nb sheets and Ti-42Nb (sintered and 3D-printed by selective laser melting, SLM) and compared with forged Ti6Al4V specimens. Furthermore, human osteoblasts were incubated with particulates of the Nb and Ti-42Nb specimens in three concentrations over four and seven days to imitate influence of wear debris. Thereby, the specimens with the roughest surfaces, i.e. Ti-42Nb and Nb Ampertec, revealed excellent and similar results for both cell types concerning cell viability and collagen synthesis superior to forged Ti6Al4V. Examinations with particulate debris disclosed a dose-dependent influence of all powders with Nb Ampertec showing the highest decrease of cell viability and collagen synthesis. Furthermore, interleukin synthesis was only slightly increased for all powders. In summary, Nb Ampertec (sintered Nb) and Ti-42Nb materials seem to be promising alternatives for medical applications compared to common materials like forged or melted Ti6Al4V., (Copyright © 2016 Elsevier B.V. All rights reserved.)

In recent years the raccoon dog population in Germany has risen dramatically and a steady westward expansion can still be seen. In addition to the highest Trichinella prevalence in wild boar and the most reported Trichinella cases in domestic swine from backyard farms, the North-Eastern part of Germany also has the highest raccoon dog density in the country. Due to their distinct scavenging behavior, raccoon dogs play a significant role as Trichinella reservoir. Therefore, to increase the knowledge on Trichinella spp. in raccoon dogs, we performed a study on the occurrence of Trichinella in the North-Eastern federal state of Brandenburg. In total 1527 raccoon dogs were examined between 2000 and 2014. An average of 1.9% of the raccoon dogs were Trichinella spp. positive. 90% of the positive animals were infected with Trichinella spiralis and one animal each with Trichinella britovi and Trichinella pseudospiralis. In T. spiralis infected animals, the number of larvae found in the muscle tissue ranged between 0.5 and 235 larvae per gram (lpg), with a median of 14 larvae. A tentative temporal increase in Trichinella occurrence was seen between the time periods 2008 to 2010 and 2011 to 2014. Based on the size of the raccoon dog hunting bags of the past decade, the species spread in westerly and north-westerly direction is evident. An interesting question is how the raccoon dog will influence the Trichinella prevalence in the sylvatic cycle in these regions in the years to come., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Dirofilaria repens is endemic in eastern and southern European regions but was recently found in Germany in dogs, mosquitoes and one human patient. Since some of the positive dog and mosquito samples were collected in Brandenburg, it was aimed to systematically assess the prevalence of D. repens and other canine vector-borne pathogens in Brandenburg. Dog owners also received a questionnaire and were asked to provide more information about the dogs including travel history. In total, 1023 dog blood samples as well as 195 fox spleen and 179 fox blood samples were collected. DNA was analysed by PCR for the presence of filariae, piroplasms, anaplasmataceae and Rickettsia spp. Filariae were detected in six dogs (0.6%), two were positive for DNA from D. repens, two from Dirofilaria immitis and two from Acanthocheilonema reconditum. One of the D. repens positive dogs originated from an animal shelter in Brandenburg, but the origin of the other one remained unknown. Interestingly, both D. repens ITS-1 sequences showed 100% identity to a D. repens sample obtained from a Japanese woman that travelled in Europe and were 97% identical to a newly proposed species Dirofilaria sp. 'hongkongensis' described from Hong Kong. However, identity to other D. repens sequences from Thailand was considerably lower (81%). Identity of 12S rRNA and cytochrome oxidase I to D. repens samples from southern Europe was 99%. Due to the low number of Dirofilaria spp. positive dogs and since the origin of these was unknown, endemic occurrence of Dirofilaria in Brandenburg could not be confirmed. Anaplasma phagocytophilum was found in 15 dogs (1.5%), Candidatus Neoehrlichia mikurensis in three dogs (0.3%) and E. canis in one dog (0.1%), which was co-infected with D. repens. Rickettsia spp. were detected in 8 dogs (0.8%), seven were Rickettsia raoultii and one was Rickettsia felis. To the author's knowledge, R. raoultii DNA was detected for the first time in dogs in Germany in this study and Candidatus N. mikurensis for the second time. In spleen samples of red foxes with 47.5% a high prevalence of piroplasms was found. Sequencing of 11 samples identified 10 as Theileria annae. Despite the high prevalence of this pathogen in its reservoir host, it was absent in dog samples. In one dog (0.1%), Babesia canis was detected but there was no further information about the dog's origin. Evaluation of the questionnaire identified a high proportion of dogs (74.2%, n=233) which was not protected by ectoparasiticides. Moreover, 21.2% (n=236) of the dogs originated from inland or abroad shelters, and therefore might potentially come from areas endemic for dirofilariosis or babesiosis., (Copyright © 2016 Elsevier B.V. All rights reserved.)

How do people solve the explore-exploit trade-off in a changing environment? In this paper we present experimental evidence from an "observe or bet" task, in which people have to determine when to engage in information-seeking behavior and when to switch to reward-taking actions. In particular we focus on the comparison between people's behavior in a changing environment and their behavior in an unchanging one. Our experimental work is motivated by rational analysis of the problem that makes strong predictions about information search and reward seeking in static and changeable environments. Our results show a striking agreement between human behavior and the optimal policy, but also highlight a number of systematic differences. In particular, we find that while people often employ suboptimal strategies the first time they encounter the learning problem, most people are able to approximate the correct strategy after minimal experience. In order to describe both the manner in which people's choices are similar to but slightly different from an optimal standard, we introduce four process models for the observe or bet task and evaluate them as potential theories of human behavior., (Copyright © 2016 Elsevier Inc. All rights reserved.)

In a world of limited resources, scarcity and rivalry are central challenges for decision makers-animals foraging for food, corporations seeking maximal profits, and athletes training to win, all strive against others competing for the same goals. In this article, we establish the role of competitive pressures for the facilitation of optimal decision making in simple sequential binary choice tasks. In two experiments, competition was introduced with a computerized opponent whose choice behavior reinforced one of two strategies: If the opponent probabilistically imitated participant choices, probability matching was optimal; if the opponent was indifferent, probability maximizing was optimal. We observed accurate asymptotic strategy use in both conditions irrespective of the provision of outcome probabilities, suggesting that participants were sensitive to the differences in opponent behavior. An analysis of reinforcement learning models established that computational conceptualizations of opponent behavior are critical to account for the observed divergence in strategy adoption. Our results provide a novel appraisal of probability matching and show how this individually 'irrational' choice phenomenon can be socially adaptive under competition., (Copyright © 2015 Elsevier Inc. All rights reserved.)

From soon after their first birthdays young children are able to make inferences from a communicator's referential act (e.g., pointing to a container) to her overall social goal for communication (e.g., to inform that a searched-for toy is inside; see Behne, Carpenter, & Tomasello, 2005; Behne, Liszkowski, Carpenter, & Tomasello, 2012). But in such cases the inferential distance between referential act and communicative intention is still fairly close, as both container and searched-for toy lie in the direction of the pointing gesture. In the current study we tested 18- and 26-month-old children in a situation in which referential act and communicative goal were more distant: In the midst of a game, the child needed a certain toy. The experimenter then held up a key (that they knew in common ground could be used to open a container) to the child ostensively. In two control conditions the experimenter either inadvertently moved the key and so drew the child's attention to it non-ostensively or else held up the key for her own inspection intentionally but non-communicatively. Children of both ages took only the ostensive showing of the key, not the accidental moving or the non-ostensive but intentional inspection of the key, as an indirect request to take the key and open the container to retrieve the toy inside. From soon after they start acquiring language young children thus are able to infer a communicator's social goal for communication not only from directly-referential acts, but from more indirect communicative acts as well., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Recently, many researchers have focused on analysis of different X-chromosomal STRs as they bear the potential to efficiently complement the analysis of autosomal and Y-chromosomal STRs in solving special complex kinship deficiency cases. In the current study we examined a sample of 250 unrelated Egyptian males with the Investigator Argus X-12 kit (Qiagen GmbH, Hilden, Germany) which detects 12 X-STR markers distributed over the entire X-chromosome as four closely linked clusters. Microvariant off ladder alleles as well as null alleles have been detected in some loci. Furthermore, discordant results were observed between the Investigator Argus X-12 and the Mentype(®) Argus X-8 kits (Biotype AG, Dresden, Germany). New primers were designed for loci DXS10101, DXS10146 and DXS10148 to correct the allele drop outs observed in these loci with the Investigator Argus X-12 kit. Additionally, DNA sequence analysis revealed the polymorphisms responsible for the allele drop outs. Furthermore, six additional X-STRs (DXS10161, DXS10159, DXS10162, DXS10163, DXS10164 and DXS10165) located in the centromere region at Xp11.21-Xq11.1 were examined in a single multiplex reaction. Allele and haplotype frequencies as well as different forensic statistical parameters of the 18 X-STR loci tested indicated that they are highly informative in different forensic applications in the Egyptian population. However, some modifications still need to be performed on the Investigator Argus X-12 kit before its use in forensic casework is validated., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Anaplasma phagocytophilum is an obligate intracellular and tick-transmitted bacterium, which causes granulocytic anaplasmosis in animals and humans. Although infection with A. phagocytophilum in domestic animals and vector ticks is documented, there is sparse information on the occurrence of A. phagocytophilum in wild animals. Red foxes (Vulpes vulpes) as well as raccoon dogs (Nyctereutes procyonoides) are wildlife species highly abundant in certain areas of Germany and represent a potential wildlife reservoir for zoonotic diseases. To obtain data about the occurrence of A. phagocytophilum in these animals, red fox and raccoon dog carcasses (hunted or found dead) were collected from January to September 2009 in the Federal State of Brandenburg, Germany. Lung tissue samples were subjected to DNA extraction and were examined for the presence of A. phagocytophilum DNA by means of real-time PCR. Anaplasma phagocytophilum was detected in 10 out of 122 (8.2%) lungs of red foxes and in 3 out of 13 (23%) lungs of raccoon dogs. To the best of our knowledge, A. phagocytophilum was detected for the first time in red foxes and raccoon dogs in Germany., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

Background: Oxaliplatin is a platinum-based cytotoxic agent commonly used to treat colorectal cancers. Despite its effectiveness, oxaliplatin administration is associated with the development of cold-induced peripheral neuropathy. This potentially permanent side effect is provoked by cold exposure and can range from mild and self limited to severe and debilitating. Even with tumor shrinkage, these painful side effects can force dose reduction or discontinuation of treatment. Neither the mechanism of action of oxaliplatin nor that of cold-induced neuropathy is understood. Paclitaxel, an entirely different chemotherapeutic agent used to treat a variety of malignancies, also is associated with the development of peripheral neuropathy. Unlike oxaliplatin, neurotoxicity arising from paclitaxel treatment was previously found to have profound effects on intracellular calcium signaling., Methods and Results: In this study we examined the effects of oxaliplatin on calcium signaling pathways and found that acute exposure of either a neuroblastoma cell line or primary neurons with therapeutic concentrations of oxaliplatin had no effect on intracellular calcium signaling. We also found that cellular temperature sensors (transient receptor potential [TRP] channels) were also not activated by oxaliplatin. Interestingly, prolonged exposure of oxaliplatin sensitized cells to subsequent stimuli and enhanced the magnitude of intracellular calcium responses., Conclusions: Taken together, our results suggest that acute oxaliplatin exposure will not induce abnormal calcium signaling but oxaliplatin-primed cells do exhibit enhanced sensitivity. These findings provide new insight to the mechanism behind oxaliplatin-induced neuropathy., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Systemic lupus erythematosus (SLE) is an autoimmune disease with very prominent chronic inflammatory aspects that render into multiple symptoms and clinical signs. The precise etiology of SLE remains elusive; however, it is known that its etiopathogenesis is of multifactorial nature. The production of autoantibodies (AAb) targeting double stranded DNA (dsDNA) and other nuclear autoantigens is the main characteristic of this disease. These target antigens are often modified and/or translocated when apoptotic cells undergo secondary necrosis as a consequence of the clearance deficiency in patients with SLE. In healthy individuals, dead and dying cells are rapidly removed by macrophages in an anti-inflammatory context; this does not elicit immune responses. In SLE, apoptotic cells are often not properly cleared; autoantigens leak out, and are subsequently presented to B cells by follicular dendritic cells (FDC) in secondary lymphoid tissues. This defect challenges the peripheral self-tolerance. Autoreactive B cell activation and production of anti-nuclear AAb result as the first step in the etiopathogenesis of SLE. The second step is the formation of immune complexes (IC) with apoptotic cell-derived nuclear remnants either in situ or deposited in various tissues. Nucleic acid-containing IC may also be ingested by phagocytes, which subsequently produce pro-inflammatory cytokines. Both processes result in chronic organ and tissue damage, development and maintenance of the systemic autoimmune disease. In conclusion, clearance deficiency may contribute to SLE in two ways: first, in germinal centres it enables the affinity maturation of autoreactive B cells and second, in peripheral tissues it leads to the accumulation of accessible nuclear autoantigens. Chronic inflammation in SLE is consequently promoted by the persistently binding of AAb with their cognate autoantigens forming a binary weapon: the nucleic acid-containing IC., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Neosporosis is an important cause of reproductive failure in cattle worldwide. Two different abortion patterns associated with Neospora caninum infection have been observed in cattle herds: endemic and epidemic abortion outbreaks. The endemic pattern is characterized by an abortion problem in a herd persisting for several months or years, and is assumed to be caused by reactivation of a chronic infection. In epidemic outbreaks, abortions concentrate within a short period of time, most likely due to a recent point source exposure of naïve animals to N. caninum. The aim of the study was to characterize five N. caninum-associated epidemic abortion outbreaks in Germany by serological and molecular techniques, including a p38-avidity-ELISA and typing of N. caninum in clinical samples by multilocus-microsatellite analysis. DNA extracts from the brain of 18 N. caninum infected fetuses from epidemic abortion outbreaks were characterized using 10 N. caninum-microsatellite markers. Nested-PCR protocols were developed to amplify the marker regions MS1B, MS3, MS5, MS6A, MS6B, MS7, MS12 and MS21 from clinical samples for subsequent analysis by capillary electrophoresis. Microsatellites MS2 and MS10 were analyzed by previously reported sequencing techniques. Most dams which had aborted showed a low-avidity IgG response to the N. caninum p38-antigen, and in three of the five studied herds, the majority of the dams at risk, which had not aborted, had also low-avidity responses suggesting that infection with N. caninum had recently occurred in most animals. A common microsatellite pattern prevailed in all fetuses from each individual epidemic outbreak. This pattern was unique for each herd. Although the number of epidemic abortion outbreaks analyzed was limited, the observation of a common microsatellite pattern, accompanied by a low-avidity IgG response against N. caninum in the dams, supports the hypothesis of a recent infection from a common point source. The genetic diversity of N. caninum observed among these outbreaks may indicate that not a particular N. caninum genotype but the horizontal infection route determines the occurrence of epidemic abortions., (Copyright 2010 Elsevier B.V. All rights reserved.)

Synthetic nanoscaled metal oxides are mainly produced by pyrogenic decomposition of precursors in the gas phase using a hot-wall or plasma reactor. Due to their low production rate and limited scalability, these processes are of minor technical relevance in manufacturing commercial quantities of nanoparticles. The most common and by far the most important industrial process is flame hydrolysis. In this process, a gaseous mixture of a metal chloride precursor, hydrogen and air is introduced in a closed and continuously operated flame reactor. The general mechanism of formation and growth of particles (e.g. silica) occurring in the flame is dominated by nucleation, coalescence (sintering) and coagulation (collision) of primary particles forming aggregated structures. The term 'aggregate' describes clusters of particles held together by strong chemical bonds. Agglomerates, however, are defined as loose accumulations of particles held together by hydrogen bonds for example. Although, a variety of physico-chemical methods exist to characterise pyrogenic oxides, the most important ones are analysis of the specific surface area by the so-called BET method, determination of the aggregate size by transmission electron microscopy (TEM) and characterisation of the phase composition by means of X-ray analysis.

The functional spectrum of human galectins is currently explored, with a wide range of activities being described. The role of galectin-3 as adhesin for bacteria is based on its strong binding to lipopolysaccharides (LPSs), which brings the possibility of such a contamination in galectin preparations to awareness. This assumption was verified in three independent functional assay systems using polymyxin B as inhibitor of LPS-dependent effects. Moreover, a commercial LPS quantification kit also revealed LPS in galectin preparations. Chromatography was effective in removing LPS, suggesting that such a technique needs to be applied to prevent assigning cellular responses to galectins rather than LPS.

Cell death plays a pivotal role in development and homeostasis of multicellular organisms. Apoptosis represents the physiological and anti-inflammatory form of cell death. Advanced apoptosis and necrosis are rather pro-inflammatory. Several "find-me"- and "eat-me"-signals support the "swift and silent" removal of dying cells. If the highly controlled process of dying cell removal fails, they may progress to secondary necrosis and provoke autoimmunity. There are several reports describing clearance deficiency as a possible mechanism in the etiopathogenesis of SLE. Under certain conditions, increased phagocytosis of nuclear material may be found in a subgroup of patients with SLE. Complement proteins and autoantibodies may modify engulfment of apoptotic remnants and shift the clearance process towards inflammation. Taken together, clearance deficiency leads to the accumulation of apoptotic remnants and breaking of tolerance to self. Besides, enhanced uptake of nuclear immune complexes may maintain chronic autoimmunity in patients with SLE.

The common characteristics of amyloid and amyloid-like fibrils from disease- and non-disease-associated proteins offer the prospect that well-defined model systems can be used to systematically dissect the driving forces of amyloid formation. We recently reported the de novo designed cc beta peptide model system that forms a native-like coiled-coil structure at low temperatures and which can be switched to amyloid-like fibrils by increasing the temperature. Here, we report a detailed molecular description of the system in its fibrillar state by characterizing the cc beta-Met variant using several microscopic techniques, circular dichroism spectroscopy, X-ray fiber diffraction, solid-state nuclear magnetic resonance, and molecular dynamics calculations. We show that cc beta-Met forms amyloid-like fibrils of different morphologies on both the macroscopic and atomic levels, which can be controlled by variations of assembly conditions. Interestingly, heterogeneity is also observed along single fibrils. We propose atomic models of the cc beta-Met amyloid-like fibril, which are in good agreement with all experimental data. The models provide a rational explanation why oxidation of methionine residues completely abolishes cc beta-Met amyloid fibril formation, indicating that a small number of site-specific hydrophobic interactions can play a major role in the packing of polypeptide-chain segments within amyloid fibrils. The detailed structural information available for the cc beta model system provides a strong molecular basis for understanding the influence and relative contribution of hydrophobic interactions on native-state stability, kinetics of fibril formation, fibril packing, and polymorphism.

Study Objectives: We performed an open-label multicenter study to evaluate the safety and efficacy of the dual endothelin receptor antagonist bosentan in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH)., Patients: Nineteen patients with inoperable CTEPH were enrolled., Measurements: The primary end point was a change in pulmonary vascular resistance (PVR). Secondary end points included 6-min walk test, peak oxygen uptake (V(O2)), New York Heart Association functional class, serum levels of N-terminal-pro brain natriuretic peptide (NT-pro-BNP), and various other hemodynamic parameters., Results: After 3 months of treatment with bosentan, PVR decreased from 914 +/- 329 to 611 +/- 220 dyne.s.cm(-5) (p < 0.001). Functional class and peak V(O2) remained unchanged, but 6-min walk distance increased from 340 +/- 102 to 413 +/- 130 m (p = 0.009), and serum NT-pro BNP levels improved from 2,895 +/- 2,620 to 2,179 +/- 2,301 (p = 0.027). One patient died, presumably from influenza A infection, and another patient experienced progressive fluid retention despite reduction of PVR. Other than that, treatment was well tolerated by all patients., Conclusions: This open-label pilot trial suggests that bosentan may offer a therapeutic option for patients with inoperable CTEPH. Randomized controlled trials are warranted to confirm these findings.

A newly defined family of fungal lectins displays no significant sequence similarity to any protein in the databases. These proteins, made of about 140 amino acid residues, have sequence identities ranging from 38% to 65% and share binding specificity to N-acetyl galactosamine. One member of this family, the lectin XCL from Xerocomus chrysenteron, induces drastic changes in the actin cytoskeleton after sugar binding at the cell surface and internalization, and has potent insecticidal activity. The crystal structure of XCL to 1.4 A resolution reveals the architecture of this new lectin family. The fold of the protein is not related to any of the several lectin folds documented so far. Unexpectedly, the structure similarity is significant with actinoporins, a family of pore-forming toxins. The specific structural features and sequence signatures in each protein family suggest a potential sugar binding site in XCL and a possible evolutionary relationship between these proteins. Finally, the tetrameric assembly of XCL reveals a complex network of protomer-protomer interfaces and generates a large, hydrated cavity of 1000 A3, which may become accessible to larger solutes after a small conformational change of the protein.

Background: Atrioventricular disruption (AVD) is a rare (1%-2%) but fatal complication after mitral valve procedures; the intraoperative mortality is more than 50% despite the current standard procedure of surgical closure of the defect. We compared the outcome of 9 patients with intraoperative AV disruption, 4 being surgically treated on-pump and 5 receiving epicardial tissue sealing off-pump., Methods: Between March 1998 and May 2002 a total of 9 patients presented with AV disruption intraoperative. The first 4 patients were treated with surgical repair on-pump by reconstruction of the defects with patch or buttressed suture. The second series of 5 patients were treated with a biodegradable collagen system with fibrinogen-based coating off-pump. Three to six layers were placed over the bleeding site with manual pressure for 30-60 minutes on the beating heart until bleeding was stopped. Cell saved blood was retransfused., Results: In the on-pump surgical repair group 3 patients (75%) died within the first day after repair either because of persistent bleeding or cardiac tamponade. One patient survived at 30 days and 1 year. In the off-pump tissue sealing group 30 days and 1 year survival was 100%. Postoperative echocardiography showed normal left ventricular (LV) function with no regional wall motion abnormalities., Conclusions: Our data show that epicardial tissue sealing off-pump results in successful termination of bleeding from AVD and considerably improves survival when compared with the standard procedure. Because of this tremendous improvement in patient survival we now consider this technique as standard therapy for AV disruption in our center.

Alpha-tocopherol transfer protein (alpha-TTP) is a liver protein responsible for the selective retention of alpha-tocopherol from dietary vitamin E, which is a mixture of alpha, beta, gamma, and delta-tocopherols and the corresponding tocotrienols. The alpha-TTP-mediated transfer of alpha-tocopherol into nascent VLDL is the major determinant of plasma alpha-tocopherol levels in humans. Mutations in the alpha-TTP gene have been detected in patients suffering from low plasma alpha-tocopherol and ataxia with isolated vitamin E deficiency (AVED). The crystal structure of alpha-TTP reveals two conformations. In its closed tocopherol-charged form, a mobile helical surface segment seals the hydrophobic binding pocket. In the presence of detergents, an open conformation is observed, which probably represents the membrane-bound form. The selectivity of alpha-TTP for RRR-alpha-tocopherol is explained from the van der Waals contacts occurring in the lipid-binding pocket. Mapping the known mutations leading to AVED onto the crystal structure shows that no mutations occur directly in the binding pocket.

Treating rare, primary cardiac soft-tissue sarcomas (C-STS) with heart transplantation (HTx) is controversial. Conventional tumor resection only partially alleviates the disease, and patients die of local recurrence of the tumor or of distant metastases. Heart transplantation offers the opportunity to eradicate the primary malignancy completely. In our experience of 4 patients with C-STS indicates, HTx followed by post-operative chemotherapy does not affect the long-term outcome. However, pre-operative chemotherapy can regress tumors in chemosensitive C-STS and potentially eradicate early micrometastases. Consecutive HTx for responders may then offer a chance of long-term survival.

New plastic composite electrodes with appliance in medical diagnostic are described. The new electrode material offers the possibility of specific electrical enrichment and electrochemical analysis of nucleic acid sequences. To facilitate selective enrichment of target nucleic acids, specific probe oligonucleotides were attached covalently to free carboxyl groups of conducting polycarbonate/carbon fiber electrodes. Complementary oligonucleotides were enriched from analyte solutions by electric field supported methods. The analysis of the PCR product shows the efficiency and selectivity of the electrical enrichment. We have also shown that inexpensive and robust solid electrodes made of polycarbonate and conductive carbon powder are suitable for electrochemical examination of nucleic acids. The combination of electrochemical enrichment of DNA and subsequent electrochemical detection is a promising approach towards an inexpensive molecular diagnosis kit.

The Geography-referenced regional exposure assessment tool for European rivers (GREAT-ER) 1.0 was developed in the context of environmental risk assessment of chemicals to calculate the aquatic fate of 'down-the-drain' chemicals in surface waters due to point release. As a follow-up project, the river Rur catchment in Germany was incorporated into the system. This included aspects of data collection, modelling and monitoring. Investigated substances are the four detergent and cleaning agent ingredients boron, linear alkylbenzene sulfonate (LAS), nitrilotriacetate (NTA) and ethylenediaminetetraacetate (EDTA). Results of the catchment's incorporation into the system and a comparison of GREAT-ER simulations with different monitoring results are both given. It is shown that data sets derived from a literature review can be used to calculate concentration profiles that are in the range of measured values. Since the model establishes a causal relationship between emission sites and data on the one hand, and observed concentrations in the receiving surface waters on the other, the simulation results can be used to explain monitoring data.

Background: In order to minimize surgical trauma, video-assisted mitral valve operation has been started using the Port-Access technique with the addition of a three-dimensional visualization system (Vista Cardiothoracic Systems Inc, Westborough, MA) and a voice-controlled camera-holding robotic arm (Aesop; Computer Motion Inc, Goleta, CA)., Methods: Port-Access mitral valve replacement or repair (PAMVR) was undertaken using an endovascular cardiopulmonary bypass (CPB) system. Fifty patients underwent Port-Access mitral valve replacement or repair. A three-dimensional thoracoscope was inserted allowing complete three-dimensional projection of the mitral valve (Vista). In the last 20 patients, the camera was attached to a robotic arm (Aesop), which allowed stabilization and voice-activated movement of the camera. Mitral valve repair was performed in 26 patients, and the valve was replaced in 24 patients with a mechanical valve prosthesis., Results: Median time of operation was 4.2 hours, aortic cross-clamp time 83 minutes, CPB time 125 minutes, intensive care unit stay 1.5 days and hospitalization 9.0 days. Three months follow-up was complete in 40 patients, with 34 patients (85%) in New York Heart Association class I and 6 patients in class II. Mortality was 0% and rate of reoperation was 2%, with a follow-up time up to 1.5 years postoperatively., Conclusions: Using three-dimensional video and robotic assistance, it was possible to minimize the length of skin incision, but at the same time to optimally visualize the whole mitral valve apparatus in order to perform true Port-Access mitral valve operation, including various repair techniques.

Background: Cytokines and growth factors released as part of the immune response to alloantigenic stimuli are capable of regulating endothelin-1 expression in the allograft. Endothelin plays a significant role as a modulator of coronary vascular reactivity in the early stages of atherosclerosis and may be important as a participant in and marker for cardiac allograft vasculopathy., Methods: We characterized a possible relationship between morphological and functional coronary changes, transcardiac plasma endothelin level and myocardial endothelin-mRNA expression in 33 cardiac transplant recipients in the early, stable phase 5+/-3 months after orthotopic heart transplantation. Coronary microvascular function was determined as endothelium-dependent with acetylcholine and endothelium-independent with adenosine using intracoronary Doppler-FloWire. The percentage of the epicardial diameter changes was measured using quantitative coronary angiography. Intravascular ultrasound was performed to quantify intimal hyperplasia. Cardiac endothelin uptake or release was determined by measuring plasma endothelin levels in the coronary sinus and aorta. Myocardial endothelin-gene expression was determined using semiquantitative RT-PCR., Results: The aortic endothelin levels were significantly increased in transplant recipients compared to nontransplanted patients (11.8+/-2.2 vs 7.2+/-0.9 fmol/mL; P < 0.001). Endothelin uptake was noticed in the majority of patients, and the amount of endothelin uptake was correlated to microvascular (r = 0.37; P < 0.05) and epicardial (r = 0.41; P < 0.03) endothelium-dependent vasodilatation. High mRNA signal intensity was associated with significantly reduced coronary flow response to acetylcholine compared to patients with low myocardial gene expression (coronary flow reserve 2.4+/-0.9 vs 3.4+/-0.8, respectively; P < 0.005). Morphological coronary changes early after transplantation were not correlated to endothelin plasma levels or myocardial gene expression., Conclusion: Coronary endothelial vasomotor dysfunction after cardiac transplantation is associated with an increased myocardial endothelin mRNA expression and decreased endothelin-uptake by the heart. We postulate that early activation in the endothelin system may have a pivotal role in the acceleration of the atherosclerotic process in transplant patients.

Background: Within the past 5 years several surgical techniques have been developed for less invasive surgical treatment of coronary artery disease. The aim of this study was to define specific indications for the various minimally invasive coronary artery surgical procedures., Methods: Minimally invasive direct coronary artery bypass grafting through a minithoracotomy was performed in 67 patients. The left internal mammary artery was anastomosed on the beating heart with the use of a pressure or suction stabilizer without the use of extracorporeal circulation. In 58 other patients with multivessel disease, the off-pump coronary artery bypass grafting technique through a sternotomy was applied with a left internal mammary artery to left anterior descending artery and additional vein grafts without extracorporeal circulation. In a third group, Port-Access (Heartport Inc, Redwood City, CA) coronary artery bypass grafting was performed through a left minithoracotomy with the use of an endovascular extracorporeal circulation system and cardioplegic arrest. Angiographic follow-up was complete in 64% of the patients., Results: There was minimal perioperative or postoperative mortality (0.5%). The medium surgical procedure time for all minimally invasive and off-pump procedures was 2.5 hours; it was 4.5 hours for Port-Access procedures. The median postoperative intensive care unit stay was 1.0 days, and the median hospitalization was 5.0 days. Overall graft patency was 97.3%; in 8 patients (4.1%) a stenosis either at or distal to the graft anastomosis was dilated with coronary angioplasty., Conclusions: For single-vessel disease of the left anterior descending artery, the minimally invasive coronary artery bypass grafting procedure can be performed safely without the use of extracorporeal circulation. In case of hemodynamic instability or anatomic variation, the Port-Access procedure can be applied without additional necessity for sternotomy. For multivessel disease, the off-pump bypass grafting procedure with sternotomy can be recommended depending on the coronary arteries involved. In case of necessary grafts to the lateral marginal or circumflex branches, Port-Access grafting can be recommended and may play an important role in the future for the development of fully endoscopic robot-assisted coronary artery bypass grafting.

Extensive research has been carried out in recent years to discover the potential risk factors contributing to cardiac allograft atherogenesis. Injury to endothelial cells has been regarded as an important early mechanism in the development of transplant atherosclerosis; it leads to the manifestation of epicardial and microvascular endothelial dysfunction and development of intimal hyperplasia. Moreover, continuous minor endothelial cell damage contributes to endothelial dysfunction which reflects one of the first measurable steps in the cascade of atherogenesis without macroscopic evidence of vascular lesions. The discovery of two important vasoactive substances nitric oxide (NO) and endothelin (ET) has brought new insights but also new unsolved questions regarding the mechanisms leading to atherosclerosis. To date it is known that both substances play a major role in both prevention and development of atherosclerosis. NO appears to be protective in low concentrations by inhibiting leukocyte and platelet activation/adherence and smooth muscle cell proliferation. Impaired endothelial NO production, as one cause of endothelial dysfunction may occur in early stages of atherosclerosis before macroscopic lesions are evident. In addition, increased endothelin release also results in endothelial dysfunction by inducing vasoconstriction; it promotes vascular lesion formation due to endothelial- and vascular smooth muscle cell proliferation. Direct and indirect manipulation of both the NO and ET signal transduction systems may provide novel preventive and therapeutic approaches for limiting transplant atherogenesis and to treat native atherosclerosis. This review summarizes important experimental and clinical evidence which points to nitric oxide and endothelin as potential therapeutic targets in the process of cardiac allograft vasculopathy.

Background: To compare the efficacy and safety of tacrolimus and cyclosporine in heart transplantation, this single-center, prospective, randomized, open-label clinical trial was undertaken., Methods: Seventy-three adult patients were randomly assigned at the time of transplantation to receive either tacrolimus (n=43) or cyclosporine (n=30) as the primary immunosuppressant. Ten of the 43 patients in the tacrolimus group received the drug intravenously in the perioperative period; all other patients received only oral tacrolimus., Results: With a mean follow-up of 27 months, patient survival rates (tacrolimus 83%, cyclosporine 81%) were similar. Fewer patients experienced acute rejection in the tacrolimus group (79%) than in the cyclosporine group (100%), but the difference was not statistically significant. The number of infections and dialysis and insulin requirements were similar for the 2 treatment groups, but the proportion of patients requiring multidrug antihypertensive regimens was lower in the tacrolimus group (12.5% vs 50.0% at month 6; p=.025). The interpatient variance in pharmacokinetic parameters in a subset of 10 patients was much higher after the first oral dose of tacrolimus than at steady-state (eg, first-dose time at which maximal concentration is reached (t(max)): 3.5+/-2.5h, steady-state t(max): 2.0+/-0.7h), and patients treated with intravenous tacrolimus (n=13) rather than oral tacrolimus (n=30) reached target concentrations faster and with less interpatient variability (eg, at day 0: 9.72+/-10.9 ng/mL intravenously vs 3.31+/-8.1 orally)., Conclusions: Tacrolimus was associated with similar efficacy and safety profiles compared with cyclosporine. The higher interpatient variance in absorption associated with oral tacrolimus during the first few days after transplantation would suggest that intravenous tacrolimus should be used during the perioperative period.

Acute myocardial rejection refractory to treatment still contributes significantly to patient death after intrathoracic transplantation. A historical series of 25 patients who received OKT3 (5 mg/day for 10 days) was compared with our current experience with 14 patients treated with tacrolimus (0.1 mg/kg/day targeting whole blood concentrations of 13 to 18 ng/ml): all 39 patients having persistent rejection unresponsive to treatment at the time of conversion. Mean periods of follow-up were 842.9 days and 342.6 days, respectively. Actuarial 1-year patient survival rates were 64.0% and 76.2% for the OKT3 and tacrolimus treatment groups, with most of the deaths in the OKT3 group occurring early (p = 0.064). Causes of death for patients receiving OKT3 included acute rejection (n = 5), infection (n = 3), carcinoma (n = 2), multiorgan failure (n = 1) and graft vessel disease (n = 1). The two deaths in the tacrolimus treatment group were the result of infections. Eighty percent of patients treated with OKT3 subsequently experienced further rejection episodes, in many cases necessitating methotrexate therapy. In contrast, only one patient (7.1%) from the tacrolimus group was diagnosed with rejection after conversion (p < 0.001). In conclusion, when compared with OKT3 therapy, a switch in baseline immunosuppression from cyclosporine to tacrolimus seems to be markedly more effective, as well as being safe for the treatment of persistent acute rejection.