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Hemophagocytic lymphopcytosis (HLH) is a life-threatening condition. It can occur either as primary form with genetic defects or secondary to other conditions, such as hematological or autoimmune diseases. Certain triggering factors can predispose individuals to the development of HLH. We report the case of a 25-year-old male patient who was diagnosed with HLH in the context of adult-onset Still's disease (AOSD) during a primary infection with Epstein-Barr virus (EBV). During therapy with anakinra and dexamethasone, he was still symptomatic with high-spiking fevers, arthralgia, and sore throat. His laboratory values showed high levels of ferritin and C-reactive protein. His condition improved after the addition of rituximab and cyclosporine to his immunosuppressive regimen with prednisolone and anakinra. This combination therapy led to a sustained clinical and serological remission of his condition. While rituximab has been used successfully for HLH in the context of EBV-associated lymphoma, its use in autoimmune diseases is uncommon. We hypothesize that the development of HLH was triggered by a primary EBV infection and that rituximab led to elimination of EBV-infected B-cells, while cyclosporine ameliorated the cytokine excess. We therefore propose that this combination immunosuppressive therapy might be successfully used in HLH occurring in the context of autoimmune diseases.

Adaptive evolution occurs when fitness covaries with genetic merit for a trait (or traits). The breeder’s equation (BE), in both its univariate and multivariate forms, allows us to predict this process by combining estimates of selection on phenotype with estimates of genetic (co)variation. However, predictions are only valid if all factors causal for trait-fitness covariance are measured. Although this requirement will rarely (if ever) be met in practice, it can be avoided by applying Robertson’s secondary theorem of selection (STS). The STS predicts evolution by directly estimating the genetic basis of trait-fitness covariation without any explicit model of selection. Here we apply the BE and STS to four morphological traits measured in Soay sheep (Ovis aries) from St. Kilda. Despite apparently positive selection on heritable size traits, sheep are not getting larger. However, although the BE predicts increasing size, the STS does not, which is a discrepancy that suggests unmeasured factors are upwardly biasing our estimates of selection on phenotype. We suggest this is likely to be a general issue, and that wider application of the STS could offer at least a partial resolution to the common discrepancy between naive expectations and observed trait dynamics in natural populations.

Oxidative stress is an important determinant not only in the pathogenesis of Alzheimer's disease (AD), but also in insulin resistance (InsRes) and diabetic complications. Forkhead box class O (FoxO) transcription factors are involved in both insulin action and the cellular response to oxidative stress, thereby providing a potential integrative link between AD and InsRes. For example, the expression of intra- and extracellular antioxidant enzymes, such as manganese-superoxide dismutase and selenoprotein P, is regulated by FoxO proteins, as is the expression of important hepatic enzymes of gluconeogenesis. Here, we review the molecular mechanisms involved in the pathogenesis of AD and InsRes and discuss the function of FoxO proteins in these processes. Both InsRes and oxidative stress may promote the transcriptional activity of FoxO proteins, resulting in hyperglycaemia and a further increased production of reactive oxygen species (ROS). The consecutive activation of c-Jun N-terminal kinases and inhibition of Wingless (Wnt) signalling may result in the formation of β-amyloid plaques and τ protein phosphorylation. Wnt inhibition may also result in a sustained activation of FoxO proteins with induction of apoptosis and neuronal loss, thereby completing a vicious circle from oxidative stress, InsRes and hyperglycaemia back to the formation of ROS and consecutive neurodegeneration. In view of their central function in this model, FoxO proteins may provide a potential molecular target for the treatment of both InsRes and AD.

Polymorphisms in the dopamine receptor D4 gene (DRD4) have been related to individual variation in novelty-seeking or exploratory behaviour in a variety of animals, including humans. Recently, the human DRD4 orthologue was sequenced in a wild bird, the great tit (Parus major) and a single nucleotide polymorphism in exon 3 of this gene (SNP830) was shown to be associated with variation in exploratory behaviour of lab-raised individuals originating from a single wild population. Here we test the generality of this finding in a large sample of free-living individuals from four European great tit populations, including the originally sampled population. We demonstrate that the association between SNP830 genotype and exploratory behaviour also exists in free-living birds from the original population. However, in the other three populations we found only limited evidence for an association: in two populations the association appeared absent; while in one there was a nonsignificant tendency. We could not confirm a previously demonstrated interaction with another DRD4 polymorphism, a 15 bp indel in the promoter region (ID15). As yet unknown differences in genetic or environmental background could explain why the same genetic polymorphism (SNP830) has a substantial effect on exploratory behaviour in one population, explaining 4.5-5.8% of the total variance-a large effect for a single gene influencing a complex behavioural trait-but not in three others. The confirmation of an association between SNP830 genotype and personality-related behaviour in a wild bird population warrants further research into potential fitness effects of the polymorphism, while also the population differences in the strength of the association deserve further investigation. Another important future challenge is the identification of additional loci influencing avian personality traits in the wild.

Avian eggs contain maternal androgens that may adjust offspring development to environmental conditions. We review evidence and functional explanations for the relationship between androgen concentrations in avian eggs and male attractiveness. Experimental studies in captive birds show generally positive relationships, but results from correlational and experimental field studies are less consistent, perhaps because they lack a within-female design to control for confounding between-female variation. We analyzed the effect of male attractiveness on yolk levels of maternal androgens in a wild bird, using a correlational and experimental approach with a within-female design. We manipulated the sexually selected UV coloration of the crown feathers of male blue tits (Cyanistes caeruleus) after their female had laid the second egg and measured the subsequent effect on androgen concentrations (testosterone and androstenedione) in the fifth, seventh, and ninth eggs relative to that in the second egg. Levels of testosterone, but not androstenedione, in eggs 5 and 7 were higher for control (attractive) than for UV-reduced (unattractive) males. This effect disappeared in the ninth egg, coinciding with the recovery of UV coloration after manipulation. This suggests that females are capable of rapid adjustments of testosterone deposition in response to changes in their mate's ornamental plumage. However, androgen concentrations in the second egg and pretreatment male crown coloration were not correlated. Possibly, the combination of relatively small variation in UV coloration before treatment and the influence of unknown confounding variables in the correlative approach resulted in insufficient statistical power to detect such a correlation. Copyright 2009, Oxford University Press.

In comparison with most animal behaviours, circadian rhythms have a well-characterized molecular genetic basis. Detailed studies of circadian clock genes in 'model' organisms provide a foundation for interpreting the functional and evolutionary significance of polymorphic circadian clock genes found within free-living animal populations. Here, we describe allelic variation in a region of the avian Clock orthologue which encodes a functionally significant polyglutamine repeat (ClkpolyQcds), within free-living populations of two passerine birds, the migratory bluethroat (Luscinia svecica) and the predominantly nonmigratory blue tit (Cyanistes caeruleus). Multiple ClkpolyQcds alleles were found within populations of both species (bluethroat: 12 populations, 7 alleles; blue tit: 14 populations, 9 alleles). Some populations of both species were differentiated at the ClkpolyQcds locus as measured by F-ST and R-ST values. Among the blue tit, but not bluethroat populations, we found evidence of latitudinal clines in (i) mean ClkpolyQcds repeat length, and (ii) the proportions of three ClkpolyQcds genotype groupings. Parallel analyses of microsatellite allele frequencies, which are considered to reflect selectively neutral processes, indicate that interpopulation allele frequency variation at the ClkpolyQcds and microsatellite loci does not reflect the same underlying demographic processes. The possibility that the observed interpopulation ClkpolyQcds allele frequency variation is, at least in part, maintained by selection for microevolutionary adaptation to photoperiodic parameters correlated with latitude warrants further study.

The exciting discovery by Hubert Schwabl (Washington State University) in the early nineties that the yolk of bird eggs contains hormones originating from the mother opened up an extremely successful research area for endocrinologists and behavioral ecologists. Since then, knowledge of both the factors that influence the amount of hormones deposited in yolk by the female, and the consequences of exposure to these maternal hormones on offspring growth, physiology, and behaviour has accumulated rapidly. The field has been dominated by the idea that mothers use yolk hormones to adaptively adjust offspring development in their interest. However, this idea neglects that the (evolutionary) interests of mother and offspring may differ. Each offspring will try to maximize its share of parental investment while the mother wants to distribute her investment among all her offspring. When there is such parent-offspring conflict the offspring are selected to respond to the yolk hormones in a way that is b Parent-offspring conflict is not the only intra-familial strife that may shape the evolution of yolk hormone deposition. Parents disagree (evolutionarily) over the amount of care each of them is willing to provide to their young. Since yolk hormones affect offspring begging behavior, females may be able to use yolk hormone deposition to modify begging traits in a way that increases the amount of parental care provided by the male. The existence of sex differences in response to offspring begging The authors therefore suggest that for a full understanding of the evolution of hormone-mediated maternal effects it is essential to study both fitness consequences, and physiological mechanisms and constraints, from the perspective of all family members. Furthermore, the authors believe that the integration of evolutionary biology and endocrinology will lead to the most rapid advance in this field - from both an evolutionary and endocrinological point of view. It may therefore not be coincidenc

Structurally-based ultraviolet (UV) coloration of plumage can signal male quality and plays a role in female mate choice in many bird species. UV-reflecting badges could also be important signals in male-male competition. We tested if territorial blue tit ( Cyanistes caeruleus ) males discriminate between conspecific male intruders which differ in the UV reflectance of their crown feathers. To this aim, we used a new experimental approach in which we simultaneously (instead of sequentially) introduced two male blue tit taxidermic mounts in the territories of resident males during the female fertile period; one mount with natural crown UV reflectance and one mount with reduced crown UV. The two mounts provoked strong aggressive reactions from resident males. Males specifically directed their aggression to conspecific intruders, as a male blue tit mount received substantially more aggression than a mount of a European robin ( Erithacus rubecula ). However, aggression of resident males did not vary between the UV-reduced and the control mount. Furthermore, the variation in natural crown UV reflectance of the resident males did not predict the intensity of their aggressive response. Contrary to previous findings our results suggest that UV signals play only a limited role in male-male interactions during territorial intrusions in the female fertile period.

To study the protein expression differences between primary fibroblasts explanted from synovial membranes of patients with rheumatoid arthritis (RA) and osteoarthritis (OA).Fibroblast cultures were obtained from 10 patients with RA and 5 patients with OA. After two-dimensional gel electrophoresis, proteins were excised and identified using peptide mass fingerprint. Expression of selected proteins was subsequently examined by immunoblot. Furthermore, we examined the cellular lysates for the presence of citrullinated proteins.The study was designed to compare expression changes of the common proteins detected in all studied fibroblast cultures (i.e. detected in all patients samples). We totally identified 191 shared proteins between RA and OA fibroblasts. A significant difference was defined as at least 2-fold upregulation or 0.6-fold downregulation of protein expression. The most obvious alteration observed in RA was the appearance of several vimentin fragments not present in OA. We did not detect citrullinated proteins in lysates from RA fibroblasts. This corroborates the current assumption that fibroblasts are not able to citrullinate proteins by themselves and that invading macrophages play a central role in this process.We demonstrated that fibroblasts from patients with RA, despite being grown under identical conditions, preserve a particular feature and generate vimentin fragments not present in fibroblasts from OA. Elevated levels of different vimentin fragments have been recently reported in several rheumatic conditions. Further studies are needed to elucidate the pathogenic mechanisms induced by vimentin fragments in RA.

Background: The standard procedure to assess for appropriate central venous catheter (CVC) placement in acute care environments is chest radiography (CXR). There are few studies examining the use of bedside echocardiography (ECO) comparing CXR using the “rapid atrial swirl sign” (RASS). The RASS consists of a bright flush after injecting 10 mL of normal saline observed within the right atrium. Aims and objective: The primary goal of this prospective study is to find out whether ECO can equally be used compared to CXR when assessing for correct CVC placement. Methods: Residents in the Intensive Care (ICU) or Intermediate Care Unit (IMC) were assigned to evaluate CVC placement using ECO. After CVC placement, CXR was ordered and time until CXR recorded. Immediately after CVC placement, ECO was performed and the duration of the examination measured. Placement was appropriate when flush was present or CXR showed a tip position ±3 cm in relation to the carina. Results: We compared the first 21 (of 100) consecutive CVC placements. There were 4 misplaced catheters identified by CXR and ECO. 2 correctly placed catheters as judged by CXR had a negative RASS. Sensitivity and specificity of ECO for appropriate tip position were 89% and 100%. Median time of ECO was 5 versus 40 minutes for CXR (p Conclusions: Bedside echocardiography is non-inferior to CXR for the evaluation of central venous catheter placement. It is faster and can be easily performed by ICU residents.

The study of primary sex ratio adjustment in birds is notorious for inconsistency of results among studies. To develop our understanding of avian sex ratio variation, experiments that test a priori predictions and the replication of previous studies are essential. We tested if female blue tits Parus caeruleus adjust the sex ratio of their offspring to the sexual attractiveness of their mates, as was suggested by a previous benchmark study on the same species. In 2 years, we reduced the ultraviolet (UV) reflectance of the crown feathers of males in the period before egg laying to decrease their attractiveness. In contrast to the simple prediction from sex allocation theory, we found that the overall proportion of male offspring did not differ between broods of UV-reduced and control-treated males. However, in 1 year, the UV treatment influenced offspring sex ratio depending on the natural crown UV reflectance of males before the treatment. The last result confirms the pattern found in the previous blue tit study, which suggests that these complex patterns of primary sex ratio variation are repeatable in this bird species, warranting further research into the adaptive value of blue tit sex ratio adjustment to male UV coloration. Key words: blue tit Parus caeruleus, male attractiveness, primary sex ratio, sex allocation, ultraviolet plumage. [Behav Ecol]

Patients with SLE display a significantly higher cardiovascular risk (CVR). Pulse wave velocity (PWV) has meanwhile been established as a reliable parameter of end-organ damage. Endothelial progenitor cells (EPCs) are critically involved in vascular repair under both physiological and pathological conditions. The aim of the study was to analyse PWV and the Vascular Augmentation Index (VAI) and EPC numbers/regeneration in a well-defined German SLE cohort. Thirty patients were included. Only two individuals displayed a PWV of above 10 m/s. There was no correlation between PWV percentiles and disease activity as reflected by the SLE Disease Activity Index. Neither EPC colonies nor percentages of circulating EPCs (CD133+/KDR+) correlated with PWV/VAI in a positive or negative manner. Thus, it can be questioned whether pulse wave analysis and/or EPC proliferation and circulating cell numbers are truly useful for CVR assessment in SLE.

Music or no music is a question that has been addressed in many studies, which is why we read with great interest the article, “Effect of noise on auditory processing in the operating room,” by Way and colleagues in the May issue of this journal. The study suggested that surgeons demonstrated poorer auditory performance with music than in quiet or with operating room noise. Another recent study also suggested that music might be a potential distractor in operating rooms during urologic procedures. There are many studies that try to further elucidate the effects of music on patient factors on one hand (anxiety, stress, need for analgesic drugs, and sedation) and surgeons and surgical staff on the other hand (communication, task performance, speed, and accuracy), as reviewed recently by Moris and Linos. In addition, the type of music seems to be important. In a study by Siu and colleagues, music with high rhythmicity had beneficial effects on surgical performance in a simulated robotic model, suggesting that music might be of value during skill acquisition and training. In mechanically ventilated patients, patient-directed music reduced anxiety and sedation frequency as compared with noise-cancelling headphones or usual care. A caveat of this study was patient selection and lack of standardization of outcomes measures. Also, the findings of this study might not apply to patients who undergo elective surgery. As health care providers, we should be dedicated to keeping the surgical patient safe in the perioperative period and ensuring that care is provided in an optimal environment. Patient safety comes first; it is mandatory that monitors and alarms are audible and necessary measures can be taken in a timely manner. Wewould like to suggest that volume levels in theoperating room should be monitored and balanced to account for the

Dispersal is a major determinant of the ecological and evolutionary dynamics of natural populations. Individuals differ greatly in the likelihood and distance of dispersal, but it is generally unclear to what extent intrinsic, possibly genetic, differences contribute. Here we present the first explicit empirical evidence for genetic coupling of local dispersal and exploratory behaviour, a key animal personality trait. Using relatedness data from a multi-generation pedigree of free-living great tits (Parus major), we find quantitative genetic variation for both the distance of local dispersal within our study area and the rate at which individuals explore a novel environment. Moreover, we find a strongly positive genetic correlation between local dispersal distance and exploration rate, despite a weak and non-significant phenotypic correlation. These findings demonstrate a potentially important behavioural mechanism underlying heritable differences in local dispersal and highlight the potential for concerted evolution of dispersal and animal personality in response to selection.

We report the case of a 19-year-old woman with progressive proliferative lupus nephritis (LN) class III after induction and maintenance therapy with mycophenolate mofetil (MMF). Despite a satisfying clinical improvement proteinuria progressed under this medication. We treated the patient with additional belimumab after discussing other options. Following treatment with belimumab, proteinuria rapidly improved to almost normal levels and clinical remission lasted. Belimumab might hold promise for this indication.

The phosphoinositide 3′-kinase (PI3 K)/Akt pathway controls the activity of a number of proteins important in the regulation of apoptosis and cell proliferation. FoxO (forkhead box, class O) transcription factors, substrates of the Ser/Thr kinase Akt, control the expression of several target genes that are crucial to the defense against oxidative stress, the regulation of cell cycle, and apoptosis in mammalian cells. Here, expression of ceruloplasmin (CP), the major copper-containing protein in blood released by the liver, was investigated. We observed a significant downregulation of CP mRNA levels after insulin treatment in H4IIE rat hepatoma cells. The PI3K inhibitor wortmannin counteracted this insulin effect on CP mRNA levels, indicating that the PI3K/Akt cascade is involved in the regulation of CP expression. Stimulation of FoxO1 was induced in H4IIE rat hepatoma cells expressing a conditionally active FoxO1 construct, resulting in significant upregulation of CP mRNA levels. This upregulation was prevented in the presence of insulin. In parallel, mRNAs of established FoxO target genes were analyzed: like CP mRNA, selenoprotein P and glucose 6-phosphatase mRNAs were upregulated by FoxO1, which was prevented by insulin. The same effects of insulin on CP mRNA levels were detected in primary rat hepatocytes. Furthermore, CP release into cell culture media was analyzed with primary hepatocytes and found to be attenuated by insulin. In line with its insulin-mimetic effects on cultured cells, Cu 2+ imitated the effect of insulin on CP expression and caused a downregulation of CP mRNA levels in rat hepatoma cells.

Sarcoidosis is a systemic, clinically heterogeneous disease characterized by the development of granulomas. Any organ system can be involved, and patients may present with any number of rheumatologic symptoms. There are no U.S. Food and Drug Administration-approved therapies for the treatment of sarcoidosis. Diagnosing sarcoidosis becomes challenging, particularly when its complications cause patients' symptoms to mimic other conditions, including polymyositis, Sjogren syndrome, or vasculitis. This review presents an overview of the etiology of and biomarkers associated with sarcoidosis. We then provide a detailed description of the rheumatologic manifestations of sarcoidosis and present a treatment algorithm based on current clinical evidence for patients with sarcoid arthritis. The discussion will focus on characteristic findings in patients with sarcoid arthritis, osseous involvement in sarcoidosis, and sarcoid myopathy. Arthritic conditions that sometimes coexist with sarcoidosis are described as well. We present two cases of sarcoidosis with rheumatologic manifestations. Our intent is to encourage a multidisciplinary, translational approach to meet the challenges and difficulties in understanding and treating sarcoidosis.

Tumor necrosis factor α (TNF-α) inhibitors are used in the treatment of rheumatoid arthritis, psoriasis, psoriatic arthritis, Crohn disease, ankylosing spondylitis, and juvenile idiopathic arthritis. Use of TNF inhibitors is associated with the induction of autoimmunity (systemic lupus erythematosus, vasculitis, psoriasis, and sarcoidosis/sarcoid-like granulomas). We report a case of interstitial granulomatous nephritis in a patient with ankylosing spondylitis after 18 months of treatment with adalimumab. Previously reported cases of sarcoid-like reactions secondary to the use of TNF-α inhibitors involved the liver, lung, lymph nodes, central nervous system, and skin. Granulomatous nephritis after adalimumab treatment has not been described. Close observation of patients undergoing treatment with TNF inhibitors for evolving signs and symptoms of autoimmunity is required. Organ involvement is unpredictable, which makes correct diagnosis and management extremely challenging.

Polymorphisms in the dopamine receptor D4 gene (DRD4) have been related to individual variation in novelty-seeking or exploratory behaviour in a variety of animals, including humans. Recently, the human DRD4 orthologue was sequenced in a wild bird, the great tit (Parus major) and a single nucleotide polymorphism in exon 3 of this gene (SNP830) was shown to be associated with variation in exploratory behaviour of lab-raised individuals originating from a single wild population. Here we test the generality of this finding in a large sample of free-living individuals from four European great tit populations, including the originally sampled population. We demonstrate that the association between SNP830 genotype and exploratory behaviour also exists in free-living birds from the original population. However, in the other three populations we found only limited evidence for an association: in two populations the association appeared absent; while in one there was a nonsignificant tendency. We could not confirm a previously demonstrated interaction with another DRD4 polymorphism, a 15 bp indel in the promoter region (ID15). As yet unknown differences in genetic or environmental background could explain why the same genetic polymorphism (SNP830) has a substantial effect on exploratory behaviour in one population, explaining 4.5-5.8% of the total variance-a large effect for a single gene influencing a complex behavioural trait-but not in three others. The confirmation of an association between SNP830 genotype and personality-related behaviour in a wild bird population warrants further research into potential fitness effects of the polymorphism, while also the population differences in the strength of the association deserve further investigation. Another important future challenge is the identification of additional loci influencing avian personality traits in the wild.

Males and females often have different requirements during early development, leading to sex-specific interactions between developing offspring. In polytocous mammals, competition for limited resources in utero may be asymmetrical between the sexes, and androgens produced by male foetuses could have adverse effects on the development of females, with potentially long-lasting consequences. We show here, in an unmanaged population of Soay sheep, that female lambs with a male co-twin have reduced birth weight relative to those with a female co-twin, while there was no such effect in male twins. In addition, females with a male co-twin had lower lifetime breeding success, which appeared to be mainly driven by differences in first-year survival. These results show that sex-specific sibling interactions can have long-term consequences for survival and reproduction, with potentially important implications for optimal sex allocation.

The biguanide derivative metformin is a potent anti-diabetic drug widely used in the treatment of type 2 diabetes mellitus. Its major effect on glucose metabolism consists in the inhibition of hepatic glucose production. Since the mechanisms of metformin action are only partially understood at the molecular level, we studied the regulation of the gene promoter activity of glucose-6-phosphatase (G6Pase), the central hepatic gluconeogenic enzyme, by this drug. We have found that both metformin and insulin inhibit the basal and dexamethasone/cAMP-stimulated G6Pase promoter activity in hepatoma cells. Since one of the pharmacological targets of metformin is AMP-activated protein kinase (AMPK) and activation of AMPK is known to inhibit hepatic glucose production by the suppression of G6Pase gene transcription, we studied the effect of AMPK in this context. Under nonstimulated conditions, the inhibitory effect of both insulin and metformin was partially counteracted to a similar extent by treatment with compound C, a specific inhibitor of AMPK. In contrast, under conditions of stimulation with dexamethasone and cAMP, treatment with compound C reversed the inhibitory effect of metformin on G6Pase promoter activity to a similar extent as compared to nonstimulated conditions, whereas the effect of insulin was almost resistant to treatment with the AMPK-antagonist. These data indicate a differential AMPK-dependent regulation of G6Pase gene expression by insulin and metformin under basal and dexamethasone/cAMP-stimulated conditions.

Ultraviolet (UV) signals are suggested to be sexually selected in a wide range of taxa. Most research, however, has focused on the role of UV signals in mate choice, whereas possible functions in intraspecific competition remain largely untested. Studies on other colors indicate that ornaments preferred by females can also function as signals of social status in competitive interactions between individuals. Whereas these colors are mainly pigment based, UV reflectance is generally caused by selective reflectance of light from surface structures. Here we test experimentally whether the structurally based UV-reflective crown plumage in the blue tit (Cyanistes caeruleus) serves as a signal of status in interindividual competition. We reduced the crown UV reflectance of free-living blue tits in winter and compared their probability of winning conflicts over food at a feeding table with control-treated and untreated individuals. Although we controlled for effects of sex, age, and distance from territory, we found no effect of reduced UV reflectance on the probability of winning nor were conflicts involving UV-reduced individuals more likely to escalate. Therefore, we conclude that the UV reflectance of the blue tit's crown does not serve as a signal of status in competition over food in winter. We suggest that the observed site-dependent dominance structure may constrain the opportunity for a status signal to evolve and that enhancing attractiveness in mate choice may be the sole function of the crown's UV reflectance. Copyright 2008, Oxford University Press.

Structurally based ultraviolet (UV)-reflective plumage parts can be important cues in mate choice. However, it remains largely unknown if UV plumage variation can also function as a signal of social status during competitive interactions. In blue tits (Cyanistes caeruleus), the UV-reflective crown plumage functions as a female mate choice cue that probably indicates male quality, as males with higher UV reflectance have been shown to have better chances of over-winter survival. Possibly, the UV crown plumage acts as a status signal in the competition over scarce food sources during winter. To test this idea, we related dominance of individuals at an artificial food source during adverse winter conditions to spectrophotometric measurements of their crown plumage. However, while controlling for the confounding effects of sex, age, and distance from territory, we found no significant effect of crown UV reflectance on dominance. Consistent with this result, we also found no relation between crown UV reflectance and over-winter survival. We conclude that the structurally based UV reflectance of the blue tit crown feathers plays little role in competition between individuals during winter despite its importance as a cue in mate choice.

A dichotomy in female extrapair copulation (EPC) behavior, with some females seeking EPC and others not, is inferred if the observed distribution of extrapair young (EPY) over broods differs from a random process on the level of individual offspring (binomial, hypergeometrical, or Poisson). A review of the literature shows such null models are virtually always rejected, with often large effect sizes. We formulate an alternative null model, which assumes that 1) the number of EPC has a random (Poisson) distribution across females (broods) and that 2) the probability for an offspring to be of extrapair origin is zero without any EPC and increases with the number of EPC. Our brood-level model can accommodate the bimodality of both zero and medium rates of EPY typically found in empirical data, and fitting our model to EPY production of 7 passerine bird species shows evidence of a nonrandom distribution of EPY in only 2 species. We therefore argue that 1) dichotomy in extrapair mate choice cannot be inferred only from a significant deviation in the observed distribution of EPY from a random process on the level of offspring and that 2) additional empirical work on testing the contrasting critical predictions from the classic and our alternative null models is required. Key words: extrapair copulation (EPC), likelihood, mate choice, null model, sexual selection. [Behav Ecol]

Laying eggs in nests of unrelated conspecific pairs to parasitize their parental care is a common phenomenon in birds. In blue tits Cyanistes caeruleus such conspecific brood parasitism (CBP) has never been reported in the literature. However, in a situation where breeding density was extremely high, we found six nests to be parasitized with eggs of conspecific females. Natural selection may favour elevated competitiveness of parasite young, since the negative consequences of increased sibling competition are incurred on the unrelated host parents and siblings, and therefore do not act as inclusive fitness costs for the parasites. Parasitizing females could achieve such a competitive advantage for their offspring by laying larger eggs or eggs with higher concentrations of testosterone in the yolk. We analyzed these parameters of the six parasitized nests, but did not find that parasite eggs differ systematically in these aspects from host eggs, nor that parasite eggs showed resemblance to host eggs. We suggest that a shortage of available nest sites caused some females to use CBP as a best-of-a bad job strategy, but that either the occurrence of CBP is too rare to lead to strong selection for egg adjustments or that parasitizing females are unable to do so.

Ultraviolet (UV) plumage is thought to be sexually selected through intra-sexual competition, female choice and differential allocation. Experimental manipulations of plumage UV reflectance are essential to demonstrate that mate choice or intra-sexual competition are causally related to UV coloration. The most widely-used technique for manipulating UV reflectance in wild birds is the application of a Mixture of UV-absorbing chemicals and preen gland fat. However, although this UV reduction technique is commonly used, little is known about the persistence of the treatment and the termporal variation in UV reflectance that it causes. We manipulated the UV crown plumage of wild and captive blue tits Parus caeruleus, and took repeated photospectrometric measurements of both UV-reduced and control-treated individuals. Our results show that the UV reduction lasts for at least Five days and that the treatment has no negative effects on the survival of wild birds.

It has recently been shown that sandpipers (Scolopacidae) abruptly switch the chemical composition of their preen gland secretions from mono- to diester waxes just before the period of courtship. The timing and context of the shift suggested that diesters could provide a visible quality signal during mate choice. We used captive red knots Calidris canutus to test whether mono- and diester preen waxes affect the light reflectance ("colour") to the plumage. We also determined light absorbance spectra of the two wax types. The reflectance of breast feathers of the breeding plumage was measured with spectrophotometry when birds secreted monoesters and six weeks later when they secreted diester preen waxes. Light reflectance was also measured after removing the mono- and diester waxes from the plumage with a solvent. The results show that: (1) diester preen waxes absorb more light, especially ultraviolet (UV) , than monoester preen waxes, but that (2) the compositional shift in the preen waxes did not change plumage reflectance and, (3) the removal of preen waxes did not change the reflectance of the plumage within the light spectrum assumed visible to birds (320-700 nm). This is not consistent with the idea that compositional shifts in the preen waxes of red knots have a visual function.

Rheumatoid arthritis (RA) is a systemic inflammatory disease characterized by joint pain, swelling, stiffness, and progressive destruction of the small joints of the hands and feet. Treatment of RA has improved over the past decade. With multiple cytokines well-known now to play a role in the pathogenesis of RA, including tumor necrosis factor alpha, interleukin (IL)-1β, and IL-6, many targeted biological treatments against these cytokines have emerged, changing the treatment of this disease. Tocilizumab (TCZ) is a recombinant humanized monoclonal antibody against the IL-6 receptor and has been approved in many countries, including the United States, for the treatment of moderate to severe RA in patients who have not adequately responded to one or more disease-modifying antirheumatic drugs (DMARDs) or cannot tolerate other approved drug classes for RA. The aim of this review is to discuss the role of IL-6 in RA, and to provide an overview of the mode of action, pharmacokinetics, and safety of TCZ. Furthermore, efficacy studies of TCZ as both monotherapy and combination therapy will be evaluated. There have been several important clinical trials evaluating the efficacy and safety of TCZ in RA patients; this review summarizes this data from 14 key trials with emphasis on Phase III trials. Review of these trials provides strong evidence that its use, both as monotherapy and in combination with methotrexate or other DMARDs, is an effective treatment in reducing the signs and symptoms of RA. TCZ showed tolerable safety but care is required for its use since there are some important safety concerns including elevated liver enzymes, elevated low-density lipoprotein, infections, and gastrointestinal perforations. Additionally, given the efficacy of TCZ in the treatment of RA, this review discusses how TCZ may be beneficial in the treatment of other autoimmune diseases, spinal disease, cardiovascular disease, organ transplantation, and malignancies where elevated levels of IL-6 may play a role in the pathogenesis of these diseases.

Introduction Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome is a life-threatening condition with various etiopathogeneses. Without therapy approximately 90% of all patients die from the disease. Case presentation We report the case of a 17-year-old Caucasian woman with widespread hematomas and headache. Due to hemolytic anemia, thrombocytopenia, and schistocytosis, thrombotic thrombocytopenic purpura-hemolytic uremic syndrome was suspected and plasma exchange therapy was initiated immediately. Since her thrombocyte level did not increase during the first week of therapy, plasma treatment had to be intensified to a twice-daily schedule. Further diagnostics showed markedly reduced activities of both ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 - also known as von Willebrand factor-cleaving protease) and factor H. Test results for antibodies against both proteins were positive. While plasma exchange therapy was continued, rituximab was given once weekly for four consecutive weeks. After the last dose, thrombocytes and activities of ADAMTS-13 and factor H increased into the normal range. Our patient improved and was discharged from the hospital. Conclusions Since no clinical symptoms/laboratory findings indicated a malignant or specific autoimmune-mediated disorder, the diagnosis made was thrombotic thrombocytopenic purpura-hemolytic uremic syndrome due to idiopathic combined, autoantibody-mediated ADAMTS-13/factor H deficiency.

Introduction Sepsis is characterized by systemic microvascular dysfunction. Endothelial progenitor cells (EPCs) are critically involved in maintaining vascular homeostasis under both physiological and pathological conditions. The aim of the present study was to analyze the endothelial progenitor cell system in patients suffering from sepsis with acute renal dysfunction. Methods Patients with newly diagnosed sepsis were recruited from the ICU in a nonrandomized prospective manner. Blood samples were obtained within the first 12 hours after the diagnosis of sepsis. For quantifying endothelial progenitor cells (EPCs), CD133+/Flk-1+ cells were enumerated by cytometric analysis. Analysis of EPC proliferation was performed by a colony-forming units (CFU) assay. Blood concentrations of proangiogenic mediators were measured by ELISA. Acute renal dysfunction was diagnosed according to the Acute Kidney Injury Network (AKIN) criteria. Depending on the overall mean creatinine concentration during the stay at the ICU, patients were either assigned to a 'normal creatinine group' or to a 'high creatinine group'. Survival rates, frequency of dialysis, the simplified acute physiology score (SAPS) II scores, and different laboratory parameters were collected/used for further clinical characterization Results Circulating EPCs were significantly higher in all sepsis patients included in the study as opposed to healthy controls. Patients within the 'high creatinine group' showed an even more pronounced EPC increase. In contrast, EPC proliferation was severely affected in sepsis. Neither total circulating EPCs nor EPC proliferation differed between patients requiring dialysis and patients without renal replacement therapy. Cell numbers and cell proliferation also did not differ between surviving patients and patients with sepsis-related death. Serum levels of vascular endothelial growth factor (VEGF), stromal derived factor-1 (SDF-1), and Angiopoietin-2 were higher in sepsis than in healthy controls. Sepsis patients within the 'high creatinine group' showed significantly higher mean serum levels of uric acid. Conclusions Sepsis significantly affects the endothelial progenitor cell system, as reflected by increased EPC numbers, increased concentrations of proangiogenic mediators, and reduced proliferative capacity of the cells. This occurs independently from the frequency of dialysis and from patient survival. Increased serum levels of uric acid are possibly responsible for stronger EPC mobilization in sepsis patients with higher average creatinine levels. peerReviewed

Female birds can influence offspring fitness by varying the relative quantities of egg components they deposit within and between clutches. Antimicrobial proteins (lysozyme, ovotransferrin, and avidin) are significant components of the avian albumen and likely aid in defense of embryos from microbial infection. Within clutches, females may enhance antimicrobial defense of early-laid eggs to protect them from the high risk of infection incurred before the onset of incubation. Among entire clutches, females may invest more resources in young sired by more attractive males because they have higher reproductive value. We tested these hypotheses by quantifying antimicrobial protein distribution within and among clutches in blue tit eggs. Contrary to our hypothesis, clutches showed no differential deposition of lysozyme or avidin within clutches, but eggs laid in the middle of the sequence had higher concentrations of ovotransferrin than eggs in the beginning and end. Consistent with our second hypothesis, we found that females produced eggs with higher concentrations of lysozyme (although not ovotransferrin or avidin) when mated to more attractive (more UV-reflective) males. Furthermore, females mated to polygynous males deposited less lysozyme than those mated to monogamous males. These data suggest that allocation of lysozyme at the clutch level may be a maternal effect mediated by male qualities.

Anti-hydroxy-methyl-glutaryl-coenzyme A reductase (HMGCR) antibody-associated myopathy was recognised as a new form of immune-mediated necrotising myopathy (IMNM) a decade ago. Due to the rarity of the disease, only limited data on clinical manifestations and therapeutic outcomes are available.We retrospectively analysed a monocentric cohort of HMGCR-associated IMNM patients treated at the University Medical Centre Göttingen. Clinical, laboratory, and biopsy data, as well as treatment outcomes, were analysed. In addition, a literature search was performed on published HMGCR IMNM cohorts in Medline and Web of Science.We identified nine patients; five were female. The median age was 68 years (47-77). Six were statin-exposed and older than statin-naive patients (71 years [65-77] vs. 51 years [47-67]). All had muscle weakness, seven myalgias. Strength (MRC sum score) was 53/65 (46-61) at baseline and increased to 63/65 (50-65) with therapy. Creatine kinase (CK) levels decreased from a median level of 12837 U/L (range 6346-25011) to 624 U/L (35-1564 U/L). All received glucocorticoids (GC) and at least one immunosuppressive therapy. The literature review identified 26 studies comprising 691 patients. 57.9% were female, 61.3% statin exposed. 95.2% had weakness, 39.1% myalgia. Dysphagia affected 28.8%. 84.9% received GC and a median of 1.5 additional immunosuppressants. Compared to published data, our patients had higher baseline CK values (12837 [6346-25011] vs. 6951 [2539-10500], p0.001), and we used azathioprine and intravenous immunoglobulins (p0.001) more frequently but methotrexate and rituximab less frequently (p0.001).HMGCR-associated IMNM is a rare subset of myositis. With systemic treatment, patients usually achieve partial or complete remission. Optimal treatment has not been established, but glucocorticoids, azathioprine, and methotrexate are generally effective with or without intravenous immunoglobulins.

Animals rely on their senses to adaptively respond to their social and non-social environment. In many animals, olfaction plays a key role in modulating social behaviour. Olfactory cues are, for example, used to discriminate kin when expressing kin-biased behaviours. Surprisingly, however, in birds the importance of olfaction in mediating social behaviour remains largely unknown, even though they are a key model in sensory ecology. Recently, there has been growing evidence suggesting that birds use olfactory cues in a range of social and non-social contexts. Furthermore, first empirical evidence suggests that competing young in the nest can recognise kin using olfactory cues. A recent experiment on wild blue tit (Cyanistes caeruleus) nestlings has shown that they beg more intensely when presented with olfactory cues from unfamiliar nestlings from a different nest compared to familiar nestlings from the same nest. Such modulation of begging behaviour in response to olfactory cues could potentially cause kin-biased begging behaviour when relatedness among competing nestlings varies due to the frequent occurrence of extra-pair paternity. However, while in natural broods nestmates may differ in relatedness due to extra-pair paternity, they are always equally familiar. Therefore, we repeated the odour discrimination experiment using cross-fostered nestlings which allowed us to test whether blue tit nestlings can also discriminate between odours of related versus unrelated conspecific nestmates which are both familiar. Focal nestlings did not beg longer to the odours of unrelated nestmates than those of related nestmates.104Hence, we found no evidence for olfactory kin discrimination. Before the start of the experiment, we preregistered our hypothesis, study design, and analysis with the Open Science Framework (OSF;https://osf.io/mghr8).