Heritability, evolvability, phenotypic plasticity and temporal variation in sperm-competition success of Drosophila melanogaster.

Sperm-competition success (SCS) is seen as centrally important for evolutionary change: superior fathers sire superior sons and thereby inherit the traits that make them superior. Additional hypotheses, that phenotypic plasticity in SCS and sperm ageing explain variation in paternity, are less considered. Even though various alleles have individually been shown to be correlated with variation in SCS, few studies have addressed the heritability, or evolvability, of overall SCS. Those studies that have addressed found low or no heritability and have not examined evolvability. They have further not excluded phenotypic plasticity, and temporal effects on SCS, despite their known dramatic effects on sperm function. In Drosophila melanogaster, we found that both standard components of sperm competition, sperm defence and sperm offence, showed nonsignificant heritability across several offspring cohorts. Instead, our analysis revealed, for the first time, the existence of phenotypic plasticity in SCS across an extreme environment (5% CO2 ), and an influence of sperm ageing. Evolvability of SCS was substantial for sperm defence but weak for sperm offence. Our results suggest that the paradigm of explaining evolution by sperm competition is more complex and will benefit from further experimental work on the heritability or evolvability of SCS, measuring phenotypic plasticity, and separating the effects of sperm competition and sperm ageing.

Multiple sclerosis in children and adolescents: incidence and clinical picture - new insights from the nationwide German surveillance (2009-2011).

BACKGROUND AND PURPOSE: Pediatric multiple sclerosis (MS) clinical and incidence data have been reported for several countries but valid age dependent incidence data are not yet available. The true incidence of pediatric MS in Germany was estimated and the clinical characteristics at diagnosis according to the 2005 McDonald criteria are described. METHODS: Between 2009 and 2011 active prospective nationwide surveillance for MS in children and adolescents ≤15 years included all pediatric hospitals, MS centers and private practices specialized in MS. Data were adjusted for under-reporting by capture-recapture from an independent second source. RESULTS: The estimated incidence of pediatric MS was 0.64 per 100,000 person-years with clear increase from age group ≤10 (0.09/100,000) to 2.64 per 100,000 in age group 14-15 years. All had relapsing-remitting disease with polysymptomatic onset in half of the cases. Spinal MRI with positive findings in two-thirds of patients contributed to diagnosis. CONCLUSION: Using an active prospective surveillance system and the McDonald criteria for first MS diagnosis the age-related incidence of pediatric MS in Germany was uncovered and is more common than in previous estimates. Thorough application of McDonald criteria and inclusion of spinal MRI data allowed for early diagnosis in almost 90% of cases.

GATA1s induces hyperproliferation of eosinophil precursors in Down syndrome transient leukemia.

Transient leukemia (TL) is evident in 5-10% of all neonates with Down syndrome (DS) and associated with N-terminal truncating GATA1 mutations (GATA1s). Here we report that TL-cell clones generate abundant eosinophils in a substantial fraction of patients. Sorted eosinophils from patients with TL and eosinophilia carried the same GATA1s mutations as sorted TL blasts, consistent with their clonal origin. TL blasts exhibited a genetic program characteristic of eosinophils and differentiated along the eosinophil lineage in vitro. Similarly, ectopic expression of Gata1s, but not Gata1, in wild-type CD34(+)-hematopoietic stem and progenitor cells induced hyperproliferation of eosinophil promyelocytes in vitro. Although GATA1s retained the function of GATA1 to induce eosinophil genes by occupying their promoter regions, GATA1s was impaired in its ability to repress oncogenic MYC and the pro-proliferative E2F transcription network. Chromatin Immunoprecipitation Sequencing (ChIP-seq) indicated reduced GATA1s occupancy at the MYC promoter. Knockdown of MYC, or the obligate E2F-cooperation partner DP1, rescued the GATA1s-induced hyperproliferative phenotype. In agreement, terminal eosinophil maturation was blocked in Gata1(Δe2) knockin mice, exclusively expressing Gata1s, leading to accumulation of eosinophil precursors in blood and bone marrow. These data suggest a direct relationship between the N-terminal truncating mutations of GATA1 and clonal eosinophilia in DS patients.

Reducing blood loss after total knee replacement: a fibrin solution.

Blood loss during total knee replacement (TKR) remains a significant concern. In this study, 114 patients underwent TKR, and were divided into two groups based on whether they received a new generation fibrin sealant intra-operatively, or a local infiltration containing adrenaline. Groups were then compared for mean calculated total blood volume (TBV) loss, transfusion rates, and knee range of movement. Mean TBV loss was similar between groups: fibrin sealant mean was 705 ml (281 to 1744), local adrenaline mean was 712 ml (261 to 2308) (p = 0.929). Overall, significantly fewer units of blood were transfused in the fibrin sealant group (seven units) compared with the local adrenaline group (15 units) (p = 0.0479). Per patient transfused, significantly fewer units of blood were transfused in the fibrin sealant group (1.0 units) compared with the local adrenaline group (1.67 units) (p = 0.027), suggesting that the fibrin sealant may reduce the need for multiple unit transfusions. Knee range of movement was similar between groups. From our results, it appears that application of this newer fibrin sealant results in blood loss and transfusion rates that are low and similar to previously applied fibrin sealants.

[GATA1-mutation associated leukemia in children with trisomy 21 mosaic]. / GATA1-Mutations-assoziierte Leukämien bei Kindern mit Trisomie 21-Mosaik.

Mutations of the hematopoietic transcription factor GATA1 (GATA1s) are pathognomonic in newborn with transient leukemia and children with Down syndrome and myeloid leukemia (ML-DS). Both TL and ML-DS can also occur in children with trisomy 21 mosaic.Between 2002 and 2011, 15 newborns and infants were diagnosed with DS mosaic. 9 of them presented with TL and 8 children suffered from ML-DS; 2 of them with a history of TL. In children without stigmata the special morphology and immunophenotype of blasts triggered the screening for GATA1 mutation and trisomy 21 mosaic.All newborns with TL achieved complete remission (CR). Due to clinical symptoms caused by the leukemic blasts, in 3 children low-dose cytarabine was applied. 1 patient died due to cardiac defect. In all patients GATA 1 s was confirmed. 6 children with ML-DS were initially treated according the AML-BFM protocol. After ML-DS was confirmed, therapy was continued with the intensity reduced schedule according to the ML-DS 2006 protocol. All children are still in CR (follow-up 1.8-7 years, median 2.7 yrs). 2 children with unknown trisomy 21 mosaic were diagnosed as acute megakaryoblastic leukemia (AMKL) and treated according the high risk arm of the AML-BFM 2004 including allogeneic stem cell transplantation in one child). GATA1 mutation was identified retrospectively. Both children are alive in CR.GATA1s associated leukemia has to be excluded in all young children with AMKL (<5 years old) to prevent overtreatment. Treatment with reduced intensity seems sufficient in children trisomy 21 mosaic and ML-DS.

[Interhospital transport of intensive care patients in Lower Saxony : statewide need-based and effective management]. / Intensivverlegung in Niedersachsen : Landesweite bedarfsgerechte und effektive Sicherstellung.

BACKGROUND: Since 2007 interhospital transport of intensive care patients in Lower Saxony appertains to the performance requirements of emergency medical services. Against this background the Working Group for Evaluation of Intensive Care Transport (Arbeitsgemeinschaft Evaluation Intensivverlegung) was established. This group formulated standardized definitions for the requirements of intensive care transport vehicles and a federal statewide monitoring of intensive care transport was implemented to analyze if simultaneously on-call intensive care transport systems (intensive care helicopter and ground based mobile intensive care units) can be deployed need-based and efficiently. METHODS: A prospective follow-up study and evaluation of intensive care transport in Lower Saxony between April 1(st) 2008 and July 31(st) 2010 was carried out. RESULTS: A total of 6,779 data records were evaluated in this study of which 4,941 (72.9%) missions were located in Lower Saxony, 2,928 (43.2%) missions were carried out by helicopters and 3,851 (56.8%) by ground based mobile intensive care units. The mean duration of a mission was 3 h 59min±2 h 25 min, 4 h 39 min±2 h 23 min by ground based mobile intensive care units and 2 h 21 in±30 min by helicopter units. All systems proved to be feasible for intensive care transport. The degree of urgency was estimated correctly in 94.8% of the evaluated missions and 58.0% of the transfers could not be deployed. In 76.8% patients were transferred to hospitals with a higher level of medical care, 51.7% of patients were transferred for intensive care therapy and 40.4% for an operation/intervention. Of the patients 38.2% required mechanical ventilation and in 48.3% invasive monitoring was carried out. CONCLUSION: Interhospital transfer of intensive care patients can be carried out need-based with a limited number of intensive care transport vehicles if the missions are deployed effectively by standardized disposition in accordance with performance requirements.

Prevalence and prognostic value of IDH1 and IDH2 mutations in childhood AML: a study of the AML-BFM and DCOG study groups.

Mutations in the NADP(+)-dependent isocitrate dehydrogenase genes 1 and 2 (IDH1 and IDH2) have recently been found in adult acute myeloid leukemia (AML) patients with a prevalence rising up to 33%. To investigate the frequency of IDH1/2 mutations in pediatric AML, we characterized the mutational hotspot (exon 4) of these genes in diagnostic samples from 460 pediatric AML patients. Our analysis identified somatic IDH1/2 mutations in 4% of cases (IDH1 R132 n=8; IDH2 R140 n=10) and the minor allele of single-nucleotide polymorphism (SNP) rs11554137 in 47 children (10.2%). IDH mutations were associated with an intermediate age (P=0.008), FAB M1/M2 (P=0.013) and nucleophosmin1 mutations (P=0.001). In univariate analysis, IDH(mutated) compared with IDH(wildtype) patients showed a significantly improved overall survival (OS; P=0.032) but not event-free survival (EFS; P=0.14). However, multivariate analysis did not show independent prognostic significance. Children with at least one minor allele of IDH1 SNP rs11554137 had similar EFS (P=0.27) and OS (P=0.62) compared with major allele patients. Gene expression profiles of 12 IDH(mutated) were compared with 201 IDH(wildtype) patients to identify differentially expressed genes and pathways. Although only a small number of discriminating genes were identified, analysis revealed a deregulated tryptophan metabolism, and a significant downregulation of KYNU expression in IDH(mutated) cases.

Neuromyelitis optica and NMO-IgG in European pediatric patients.

OBJECTIVE: Neuromyelitis optica (NMO) is currently considered a severe relapsing CNS demyelinating disorder that is associated with aquaporin-4 immunoglobulin G (NMO-IgG) while in earlier reports of NMO in childhood it has been described as a benign and monophasic disorder. This study was performed to analyze the prevalence and the clinical course of NMO in a European pediatric cohort of patients with demyelinating CNS disorders. METHODS: A cohort study was performed evaluating 118 pediatric patients presenting at the Center for Multiple Sclerosis in Childhood and Adolescents, Göttingen, Germany, with demyelinating CNS disorders between 2000 and 2009. In all patients, NMO-IgG status was determined. RESULTS: The majority of patients (94%) were diagnosed with remitting recurrent multiple sclerosis. Six patients fulfilled the clinical criteria for NMO but only 1 was seropositive for NMO-IgG. This patient had a severe relapsing course in contrast to the seronegative patients who showed a mild and in the majority of cases monophasic course. CONCLUSIONS: The diagnostic criteria clearly distinguished the patients with NMO from patients with other demyelinating CNS disorders. In the European pediatric population, NMO is very rare and in the majority of patients not associated with NMO-IgG. These seronegative cases have a benign and predominantly monophasic course and therefore do not need the immunosuppressant therapy that is recommended for NMO in the recent literature.

Estimating the feeding rate of the bedbug Cimex lectularius in an infested room: an inexpensive method and a case study.

The common bedbug, Cimex lectularius L. (Hemiptera: Cimicidae), is a globally re-emerging pest that is playing an increasing role in legal disputes and compensation claims as a result of its unpleasant feeding activity. However, there is little information about the feeding frequency of bedbugs outside controlled laboratory cultures. Here, we present a simple method of estimating the average time since the last bloodmeal of individual female bedbugs in a single sampling event, applicable to a single bedbug harbourage or an entire room. Using the temperature-dependent rate of decrease in the abdomen size of the bedbug after a bloodmeal, we found that, in a highly infested room kept at a constant temperature of 26 degrees C, females fed every 2.5 days on average. Our method corrects for variations in body size across different populations and determines the shrinkage that occurs when individuals are preserved in ethanol. This method should, therefore, be widely applicable. It is cheap, rapid and, if coupled with information on the total number of bedbugs present in a room, allows for the estimation of the minimum number of times persons lodging in a room have been bitten by bedbugs. This method can also be used to calculate the feeding rate of other blood-sucking insects on their hosts. The sex ratio in the infestation was female-biased. Finally, our case study suggests that individual female bedbugs within a harbourage do not seem to feed at a regular rate, but tend to synchronize feeding patterns.

Novel CLN8 mutations confirm the clinical and ethnic diversity of late infantile neuronal ceroid lipofuscinosis.

The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited lysosomal storage diseases and the prototype of childhood onset neurodegenerative disorders. To date, 10 NCL entities (CLN1-CLN10) are known and characterized by accumulation of autofluorescent storage material, age of onset and clinical symptoms. CLN8 was first identified as the causative gene for a late-onset form with progressive epilepsy and mental retardation in Finnish patients. In addition, CLN8 phenotypes were described in Turkish, Israeli and Italian patients with a more rapid progression of visual loss, epilepsy, ataxia and mental decline. Here, we report the first mutations in German (c.611G>T) and Pakistani (c.709G>A) patients. Our findings confirm previous assumptions that the CLN8 variant can occur in many ethnic groups. So far, large CLN gene deletions are only known for the CLN3 gene. Here, we also describe a novel, large CLN8 gene deletion c.544-2566_590del2613 in a Turkish family with a slightly more severe phenotype. Our data indicate that patients with clinical signs of late infantile NCL and characteristic ultrastructural inclusions should also be screened for CLN8 mutations independent of their ethnic origin.

Antifungal compounds redirect metabolic pathways in yeasts: metabolites as indicators of modes of action.

AIMS: Metabolic pathways, e.g. biosynthesis of ergosterol or carbohydrate metabolism including respiration, are well-known targets of several fungicides. With our study we wanted to prove that metabolite profiles can be used to classify fungicides according to their mode of action and that concentrations of key metabolites are changed even without detectable reduced growth rates. METHODS AND RESULTS: We exposed the yeasts Candida albicans and Saccharomyces cerevisiae to inhibitors of the electron transport chain and to compounds known to interact with osmotic stress defence pathways. Glycerol and ethanol were chosen as key metabolites of branches of glucose catabolism. Increased glycerol concentrations were observed not only when the osmotic stress response was activated, but also as response to the inhibition of the electron transfer chain, whereas elevated ethanol levels were observed only when the respiratory pathways were blocked. CONCLUSIONS: The treatment of the yeasts Candida albicans and Saccharomyces cerevisiae with antimycotic compounds led to a redirection of metabolic pathways, which could be followed by the quantification of both the metabolites ethanol and glycerol. Only the combination of both concentration profiles allowed the clear distinction between inhibitors of the respiratory chain and effects on the osmotic stress response pathway. IMPACT OF STUDY: The extension of the number of metabolites to a comprehensive quantitative metabolic profile of compound-treated test organisms can be an additional tool in fungicide research allowing the detection of compounds which act on fungi and, moreover, the elucidation of modes of action.

Sensitivity to bites by the bedbug, Cimex lectularius.

Bedbugs are a public health problem and can cause significant economic losses, but little is known about the effects of bites on humans. We reviewed case reports and published papers on bedbug bites to assess the empirical basis of the commonly cited figure that only approximately 80% of the population are sensitive to bedbug bites. We found the sensitivity estimate to be based on only one study carried out 80 years ago. However, this study did not account for the now well-established fact that only repeated exposure to external allergens leads to skin reactions. In our sample, 18 of 19 persons showed a skin reaction after bedbug exposure, but in most cases only after repeated controlled exposure. With repeated exposure, the latency between bite and skin reactions decreased from approximately 10 days to a few seconds. Our results are relevant for the hospitality industry, where apparently increasing infestation rates are likely to lead to an increase in the number of tourists and hotel employees exposed to bedbugs. Medical and public health professionals may expect to see an increase in the prevalence of people with bedbug bite sensitivity. The significance of the delayed reaction time of skin to bites may also have implications in litigation cases where people seek compensation.

Detection of seminal fluid proteins in the bed bug, Cimex lectularius, using two-dimensional gel electrophoresis and mass spectrometry.

The global increase of the human parasite, the common bed bug Cimex lectularius, calls for specific pest control target sites. The bed bug is also a model species for sexual conflict theory which suggests that seminal fluids may be highly diverse. The species has a highly unusual sperm biology and seminal proteins may have unique functions. One-dimensional PAGE gels showed 40-50% band sharing between C. lectularius and another cimicid species, Afrocimex constrictus. However, adult, sexually rested C. lectularius males were found to store 5-7 microg of seminal protein and with only 60 microg of protein we obtained informative 2-D PAGE gels. These showed 79% shared protein spots between 2 laboratory populations, and more than half of the shared protein spots were detected in the mated female. Further analysis using liquid chromatography electrospray ionization tandem mass spectrometry revealed that 26.5% of the proteins had matches among arthropods in databases and 14.5% matched Drosophila proteins. These included ubiquitous proteins but also those more closely associated with reproduction such as moj 29, ubiquitin, the stress-related elongation factor EF-1 alpha, a protein disulfide isomerase and an antioxidant, Peroxiredoxin 6.