A dramatic response to checkpoint inhibitor in a woman with small cell carcinoma of the hypercalcemic type of the ovary.

OBJECTIVE: We present the rare case of a 21 year old woman with small cell carcinoma of the right ovary of the hypercalcemic type with dramatic response to checkpoint inhibitor. METHODS: Case report. RESULTS AND CONCLUSIONS: Our patient, a 22-year old woman with small cell carcinoma of the hypercalcemic type with hepatic metastases, is currently 43 months under treatment with pembrolizumab. Last MRI revealed no viable liver metastases nor other signs of recurrence. This is the longest survival of a patient with small cell carcinoma of the ovary under therapy with checkpoint inhibitors reported in the literature so far. With this report we emphasize the importance of immunohistological testing for PD-L 1. Treating clinicians should keep off-label use of immune checkpoint blockade in mind when treating this highly aggressive tumor if all other treatment options fail.

Lifting the veil of secrecy: maternal and neonatal outcome of oocyte donation pregnancies in Germany.

BACKGROUND: In Germany, performing fertility procedures involving oocyte donation is illegal, as stated by the Embryo Protection Law. Nonetheless, in our clinical routine we attend to a steadily rising number of pregnant women, who have sought oocyte donation abroad. Due to the legal circumstances many women opt to keep the origin of their pregnancy a secret. However, studies have shown, that oocyte donation is an independent risk factor for the development of pregnancy complications, such as preeclampsia. OBJECTIVE: The aim of this study is to evaluate maternal and neonatal outcomes of oocyte donation pregnancies in three large obstetric care units in Berlin, Germany. METHODS: We retrospectively analyzed all available medical data on oocyte donation pregnancies at Charité University hospital, Vivantes Hospital Friedrichshain, and Neukoelln in the German capital. RESULTS: We included 115 oocyte donation (OD) pregnancies in the present study. Our data are based on 62 singleton, 44 twin, 7 triplet, and 2 quadruplet oocyte donation pregnancies. According to our data, oocyte donation pregnancies are associated with a high risk of adverse maternal and fetal outcome, i.e., hypertension in pregnancy, preterm delivery, Cesarean section as mode of delivery, and increased peripartum hemorrhage. CONCLUSION: Although oocyte donation is prohibited by German law, many couples go abroad to seek reproductive measures using oocyte donation after former treatment options have failed. OD pregnancies are associated with a high risk of preeclampsia, C-section as mode of delivery, and peripartum hemorrhage. Detailed knowledge of the associated risks is of utmost importance to both the patient and the treating physician and midwife.

Lab-testing, predicting, and modeling multi-stage activated carbon adsorption of organic micro-pollutants from treated wastewater.

Multi-stage reuse of powdered activated carbon (PAC) is often applied in practice for a more efficient exploitation of the PAC capacity to remove organic micro-pollutants (OMP). However, the adsorption mechanisms in multi-stage PAC reuse are rarely investigated, as large-scale experiments do not allow for systematic tests. In this study, a laboratory method for the separation of PAC/water suspensions and the subsequent reuse of the PAC and the water was developed. The method was tested on wastewater treatment plant (WWTP) effluent in a setup with up to 7 PAC reuse stages. The tests show that the overall OMP removal from WWTP effluent can be increased when reusing PAC. The reason is that a repeated adsorption in multi-stage PAC reuse results in similar equilibrium concentrations as a single-stage adsorption. Thus, a single relationship between solid and liquid phase OMP concentrations appears valid throughout all stages. This also means that the adsorption efficiency of multi-stage PAC reuse setups can be estimated from the data of a single-stage setup. Furthermore, the overall OMP removals in multi-stage setups coincide with the overall UV254 removals, and for each respective OMP one relationship to UV254 removal is valid throughout all stages. The results were modeled by a simple modification of the equivalent background compound model (EBCM) which was also used to simulate the additional OMP removals in multi-stage setups with up to 50 reuse stages.

Rapid small-scale column testing of granular activated carbon for organic micro-pollutant removal in treated domestic wastewater.

This study investigates the applicability of the rapid small-scale column test (RSSCT) concept for testing of granular activated carbon (GAC) for organic micro-pollutants (OMPs) removal from wastewater treatment plant (WWTP) effluent. The chosen experimental setup was checked using pure water, WWTP effluent, different GAC products, and variable hydrodynamic conditions with different flow velocities and differently sized GAC, as well as different empty bed contact times (EBCTs). The setup results in satisfying reproducibility and robustness. RSSCTs in combination with WWTP effluent are effective when comparing the OMP removal potentials of different GAC products and are a useful tool for the estimation of larger filters. Due to the potentially high competition between OMPs and bulk organics, breakthrough curves are likely to have unfavorable shapes when treating WWTP effluent. This effect can be counteracted by extending the EBCT. With respect to the strong competition observed in GAC treatment of WWTP effluent, the small organic acid and neutral substances are retained longer in the RSSCT filters and are likely to cause the majority of the observed adsorption competition with OMPs.

Allele-specific gene expression in a wild nonhuman primate population.

Natural populations hold enormous potential for evolutionary genetic studies, especially when phenotypic, genetic and environmental data are all available on the same individuals. However, untangling the genotype-phenotype relationship in natural populations remains a major challenge. Here, we describe results of an investigation of one class of phenotype, allele-specific gene expression (ASGE), in the well-studied natural population of baboons of the Amboseli basin, Kenya. ASGE measurements identify cases in which one allele of a gene is overexpressed relative to the alternative allele of the same gene, within individuals, thus providing a control for background genetic and environmental effects. Here, we characterize the incidence of ASGE in the Amboseli baboon population, focusing on the genetic and environmental contributions to ASGE in a set of eleven genes involved in immunity and defence. Within this set, we identify evidence for common ASGE in four genes. We also present examples of two relationships between cis-regulatory genetic variants and the ASGE phenotype. Finally, we identify one case in which this relationship is influenced by a novel gene-environment interaction. Specifically, the dominance rank of an individual's mother during its early life (an aspect of that individual's social environment) influences the expression of the gene CCL5 via an interaction with cis-regulatory genetic variation. These results illustrate how environmental and ecological data can be integrated into evolutionary genetic studies of functional variation in natural populations. They also highlight the potential importance of early life environmental variation in shaping the genetic architecture of complex traits in wild mammals.

Age at maturity in wild baboons: genetic, environmental and demographic influences.

The timing of early life-history events, such as sexual maturation and first reproduction, can greatly influence variation in individual fitness. In this study, we analysed possible sources of variation underlying different measures of age at social and physical maturation in wild baboons in the Amboseli basin, Kenya. The Amboseli baboons are a natural population primarily comprised of yellow baboons (Papio cynocephalus) that occasionally hybridize with anubis baboons (Papio anubis) from outside the basin. We found that males and females differed in the extent to which various factors influenced their maturation. Surprisingly, we found that male maturation was most strongly related to the proportion of anubis ancestry revealed by their microsatellite genotypes: hybrid males matured earlier than yellow males. In contrast, although hybrid females reached menarche slightly earlier than yellow females, maternal rank and the presence of maternal relatives had the largest effects on female maturation, followed by more modest effects of group size and rainfall. Our results indicate that a complex combination of demographic, genetic, environmental, and maternal effects contribute to variation in the timing of these life-history milestones.

Genetic evidence reveals temporal change in hybridization patterns in a wild baboon population.

The process and consequences of hybridization are of interest to evolutionary biologists because of the importance of hybridization in understanding reproductive isolation, speciation, and the influence of introgression on population genetic structure. Recent studies of hybridization have been enhanced by the advent of sensitive, genetic marker-based techniques for inferring the degree of admixture occurring within individuals. Here we present a genetic marker-based analysis of hybridization in a large-bodied, long-lived mammal over multiple generations. We analysed patterns of hybridization between yellow baboons (Papio cynocephalus) and anubis baboons (Papio anubis) in a well-studied natural population in Amboseli National Park, Kenya, using genetic samples from 450 individuals born over the last 36 years. We assigned genetic hybrid scores based on genotypes at 14 microsatellite loci using the clustering algorithm implemented in STRUCTURE 2.0, and assessed the robustness of these scores by comparison to pedigree information and through simulation. The genetic hybrid scores showed generally good agreement with previous morphological assessments of hybridity, but suggest that genetic methods may be more sensitive for identification of low levels of hybridity. The results of our analysis indicate that the proportion of hybrids in the Amboseli population has grown over time, but that the average proportion of anubis ancestry within hybrids is gradually decreasing. We argue that these patterns are probably a result of both selective and nonselective processes, including differences in the timing of life-history events for hybrid males relative to yellow baboon males, and stochasticity in long-distance dispersal from the source anubis population into Amboseli.

Paternal effects on offspring fitness in a multimale primate society.

When females mate with multiple males, paternal care is generally expected to be negligible, because it may be difficult or impossible for males to discriminate their own offspring from those of other males, and because engaging in paternal care may reduce male mating opportunities. Consequently, males in multimale societies are not predicted to provide direct benefits to their offspring. We have recently demonstrated, however, that males in a typical multimale primate society (yellow baboons, Papio cynocephalus) discriminate their own offspring from those of other males and provide care to them in the form of repeated support during agonistic encounters. This observation raises the question of whether fathers enhance offspring fitness in this species. Here we use 30 years of data on age at maturity for 118 yellow baboons with known fathers. We show that the father's presence in the offspring's social group during the offspring's immature period accelerated the timing of physiological maturation in daughters. Sons also experienced accelerated maturation if their father was present during their immature period, but only if the father was high ranking at the time of their birth. Because age at reproductive maturity has a large impact on lifetime reproductive success, our results indicate a direct effect of paternal presence on offspring fitness. This relationship in turn suggests that the multiple roles that males play in multimale animal societies have not been sufficiently examined or appreciated and that paternal effects may be more pervasive than previously appreciated.

Concentrations of four fecal steroids in wild baboons: short-term storage conditions and consequences for data interpretation.

One source of both bias and "noise" in fecal steroid analysis is temporal change in steroid concentrations resulting from duration or conditions of fecal sample storage. However, no consensus currently exists regarding correct procedures or precautions necessary for fecal sample storage, and conditions vary widely within field endocrinology literature. This study considered the effects of short-term, weeks-long, storage conditions on quantifiable fecal testosterone (fT), glucocorticoids (fGC), estrogens (fE), and progestagen (fP) metabolite concentrations in wild baboons (Papio cynocephalus). Quadruplicate subsamples of fecal samples (n=29) collected at Amboseli National Park and its environs were subjected to four different storage conditions prior to lyophilization, in order to determine the effects of storage on subsequent steroid concentrations, as assessed by 125I radioimmunoassays. As expected, the best alternative to the "initial condition" of lyophilization at three days after collection was to freeze fecal samples at -20 degrees C for two weeks prior to lyophilization. This storage method resulted in no significant change from initial steroid concentrations for fE, fT, or fP, although fGC showed a slight but significant decline. Storage for two weeks in a charcoal refrigerator caused a mean increase in all four steroid concentrations. However, the results from this storage condition were robust in terms of practical questions asked of the data: fE and fP values still reflected pregnant versus non-pregnant states in baboon females; a fGC profile constructed by age class resembled that created from the samples from the initial condition, although slightly inflated across age classes; and there were only moderate changes in relative fT concentrations across adult males. Knowledge of the effects of storage upon each steroid analyzed within one's study is a necessary component in determining the optimal compromise for storage protocol in a particular research project.

A matter of time: evaluating the storage of fecal samples for steroid analysis.

The extraction and immunoassay of fecal steroids is an increasingly common technique, used in both captive and field studies to provide an approximation of an animal's circulating concentration of hormones through non-invasive methods. Storage of fecal samples is of critical concern because fecal bacteria metabolize fecal steroids within hours after deposit. Ethanol is often used as a preservative for fecal samples stored for several hours at room temperature. We examined the stability of fecal estrogen (fE) and glucocorticoid (fGC) metabolites from baboon (Papio cynocephalus) samples in a 95% ethanol solution at ambient temperature and at -20 degrees C over the course of six months, to determine the effect of storage on steroid concentrations. As measured by radioimmunoassay, fE metabolite concentrations increased by 122% at 90 days and fGC metabolite concentrations increased by 92% at 120 days. After peaking, both hormones declined to near initial concentrations by 180 days in ambient temperature samples. In samples stored at sub-zero temperatures, fGC metabolite concentrations showed a similar but dampened pattern, while fE metabolite concentrations exhibited small and variable changes with no consistent trend. We discuss explanations for the dynamic pattern of changing fecal metabolite concentrations and offer practical and analytical guidance to field workers for situations in which ideal conditions for stabilizing hormones are not available.

Non-lethal weapons technologies--the case for independent scientific analysis.

Various technologies have been proposed for non-lethal weapons (NLW), some of them credible, or at least plausible, but strong claims were made for others without evidence or references. Five such technologies are examined. For the chemical and biological examples, detailed information is lacking but the diminishing number of such claims over time and general scientific knowledge suggest that fulfilment of the promises is improbable. For acoustic weapons, a detailed study found that many of the claims are plainly untrue. In this case, even wrong values for physiological thresholds were presented. Civil and military NLW programmes in the USA put their main emphasis on simple, short-term technologies rather than exotic ones. In order to avoid dangers arising from unrealistic promises, the concept of preventive arms control should be applied to NLW. Its first step is a scientific analysis, investigating the new weapons, the propagation of their effects and the effect on the targets. Such detailed studies are needed for each proposed NLW technology.

Neuroanatomy of magnetoreception: the superior colliculus involved in magnetic orientation in a mammal.

The neural substrate subserving magnetic orientation is largely unknown in vertebrates and unstudied in mammals. We combined a behavioral test for magnetic compass orientation in mole rats and immunocytochemical visualization of the transcription factor c-Fos as a marker of neuronal activity. We found that the superior colliculus of the Zambian mole rat (Cryptomys anselli) contains neurons that are responsive to magnetic stimuli. These neurons are directionally selective and organized within a discrete sublayer. Our results constitute evidence for the involvement of a specific mammalian brain structure in magnetoreception.

Status change during adulthood: life-history by-product or kin selection based on reproductive value?

When dominance status predicts fitness, most adaptive models of dominance relationships among cercopithecine primate females predict lifetime maintenance of status. These models and alternative ones positing rank decline as a non-adaptive by-product have remained largely untested, however, because lifetime status of older adults has been virtually unknown for natural populations. In a 25-year study of adult female savannah baboons (Papio cynocephalus), in each of three social groups, rank losses were common among the 66 females that lived past median adult age. These losses were not accounted for by loss in relative rank from group growth or by loss in absolute rank from reversals in rank between members of different maternal families or between sisters. Rather, females that had mature daughters experienced loss of dominance status to these offspring, a characteristic of all but the top-ranking matriline of each group. Among proposed hypotheses for rank reversals between adults, that of kin selection based on relative reproductive value is most clearly supported by these data. In contrast, observed patterns of rank loss are not consistent with alternative models that postulate that changes during adult lifespan are a product of accumulated risk, physical decline during ageing, or coalitionary support among females within or between matrilines.

Immigration and hybridization patterns of yellow and anubis baboons in and around Amboseli, Kenya.

In 1986, Samuels and Altmann reported evidence for a hybrid zone between Papio anubis and Papio cynocephalus in Amboseli, Kenya, in a baboon population that has been the subject of long-term study since 1971 [Samuels & Altmann, International Journal of Primatology 7:131-138, 1986]. In the current report we document ongoing patterns of hybridization in Amboseli between anubis and yellow baboons. In July 2000, we exhaustively scored living members of study groups for their degree of hybridity, using seven phenotypic characteristics (five in juveniles). We also scored all former members of study groups on the basis of photographic records, field notes, and observer recollections. A total of five anubis males and 11 males with hybrid phenotypes have immigrated into study groups over the course of the long-term study, and immigrations by hybrid males have increased in frequency over time. Further, the increasing frequency of hybrid phenotypes among animals born into study groups indicates that anubis and hybrid males have successfully reproduced in study groups. However, hybrid phenotypes and anubis immigrations were limited to groups in the southwestern portion of the Amboseli basin, with no hybrids occurring in the six eastern groups. Finally, we present evidence that anubis and hybrid males in Amboseli exhibit patterns of natal dispersal that are different from those of yellow males in Amboseli: males with anubis or hybrid phenotypes were significantly more likely to immigrate as juveniles or young subadults than were yellow males.

Cross-species amplification, non-invasive genotyping, and non-Mendelian inheritance of human STRPs in Savannah baboons.

Twenty-nine human microsatellite primer pairs were screened for their utility in the cross-species amplification of baboon DNA derived from both blood and feces as part of a larger study to identify paternal half sisters in a population of wild baboons (Papio cynocephalus). Forty-one percent (12/29) of the human primers successfully amplified baboon DNA. Of these 12 primers, six amplified fragments that were both polymorphic and heterozygous (mean number of alleles = 6, mean heterozygosity = 87%) and yielded repeatable results. However, only five of these six simple tandem repeat polymorphisms (STRPs) showed patterns of Mendelian inheritance (i.e., mothers and offspring shared at least one allele at each locus), and were therefore useful for determining relatedness between individuals. Analysis of the sixth primer revealed non-Mendelian inheritance, i.e., three of the six known mother-daughter pairs had no shared alleles. This failure was probably due to non-specific fragment amplification, and may have resulted from a different STRP locus being amplified in mother and daughter. This finding highlights the importance of sampling DNA from known parent-offspring pairs when screening microsatellite primers for genetic studies. Multiple, independent replications of genotypes and Mendelian checks are both particularly important when using cross-species amplification or when using a low-quality source of DNA.

Impact of injection rate on the Thrombolysis in Myocardial Infarction (TIMI) trial frame count.

A mechanical injection was used to determine the impact of injection rate on the TIMI frame count. The 1.0-ml/s increase in hand injection rates from the 10th to 90th percentiles for angiographers is associated with a minor decrease of <2 frames that is <7% of the corrected TIMI frame count.

Coronary artery injection technique: a quantitative in vivo investigation using modern catheters.

To date, there have been no quantitative in vivo assessments of contrast volumes and injection rates using modern high flow catheters during coronary angiography. Contrast volumes (n = 554), injection durations (n = 563), and injection rates (n = 498) were collected during 88 cardiac catheterizations. With increasing cathetersize (6, 7, and 8 French), injection volume increased (P < 0.0001), duration decreased (P < 0.0001), and rate increased (P < 0.0001). Compared with injections into the right coronary artery, left coronary artery injections were larger (7.1 +/- 0.1 cc vs. 4.8 +/- 0.1 cc, p < 0.0001), longer (3.6 +/- 0.05 sec vs 3.0 +/- 0.07 sec, P < 0.0001) and faster (2.1 +/- 0.04 cc/sec vs. 1.7 +/- 0.06 cc/sec, P < 0.0001). Patients with a significant stenosis in the left main or proximal right coronary artery received less contrast (P < 0.0001) more slowly (P < 0.0001) over a similar duration of injection (P = NS). When collaterals arose from the injected artery, angiographers injected more contrast (P < 0.001) over a longer period (P < 0.0001) more slowly (P < 0.0001). Catheter size and the injected vessel's location and anatomy significantly affect coronary catheterization injection technique.

Hypercortisolism associated with social subordinance or social isolation among wild baboons.

BACKGROUND: The phenomena of basal hypercortisolism and of dexamethasone resistance have long intrigued biological psychiatrists, and much is still unknown as to the causes and consequences of such adrenocortical hyperactivity in various neuropsychiatric disorders. We have analyzed basal cortisol concentrations and adrenocortical responsiveness to dexamethasone in a population of wild baboons living in a national park in Kenya. We tested whether social subordinance in a primate is associated with dexamethasone resistance. Furthermore, we examined whether individual differences in adrenocortical measurements were predicted by the extent of social affiliation in these animals. METHODS: Seventy yellow baboons (Papio cynocephalus) were anesthetized and injected with 5 mg of dexamethasone; the cortisol response was monitored for 6 hours. The animals were of both sexes in a range of ages and had known ranks in the dominance hierarchies within their troops. Extensive behavioral data were available for a subset of 12 adult males who were anesthetized under circumstances that also allowed for the determination of basal cortisol concentrations. RESULTS: The socially subordinate baboons were less responsive to dexamethasone than were the dominant ones; as one manifestation of this, postdexamethasone cortisol values were more than 3 times higher in the dozen lowest-ranking animals compared with the dozen highest. In addition, socially isolated males had elevated basal cortisol concentrations and showed a trend toward relative dexamethasone resistance. CONCLUSIONS: Our findings indicate that social status and degree of social affilitation can influence adrenocortical profiles; specifically, social subordinance or social isolation were associated in our study with hypercortisolism or feedback resistance.

Behavioural risk factors in the reproduction of inbred and outbred oldfield mice

The present study investigated two rarely measured aspects of inbreeding depression: the relationship between inbreeding and behaviour, and the possibility that inbred individuals that survive infancy may still suffer from inbreeding depression by failing to breed or failing to show appropriate mating or parental behaviours. Specifically, the relationship between (1) behaviour at pairing and reproductive success, (2) inbreeding and reproductive success and (3) inbreeding and pairing behaviour, was examined in two subspecies of the oldfield mouse, Peromyscus polionotusEffects of parental and offspring inbreeding were separated through experimental design and analysis. Activity level during the first 25 days after pairing predicted future reproductive success: pairs that remained less active during the nocturnal (active) period were significantly less likely to breed than pairs that remained more active. Inbred females took significantly longer to produce their first litters and were less likely to produce litters than were outbred females, independently of whether females were related to their mates (i.e. whether their offspring would be inbred). Inactive pairs averaged fewer surviving pups than did active pairs. Inbreeding coefficient of female was a significant predictor of activity level in one of the two subspecies, suggesting that inbreeding may affect behaviour. Inbred adult females showed inbreeding depression in the form of lower conception rates and fewer surviving offspring, although the specific traits affected differed for the two subspecies. The implications for captive breeding programs, and likely causes of the subspecific differences, are discussed.