Inflammatory signals from fatty bone marrow support DNMT3A driven clonal hematopoiesis.

Both fatty bone marrow (FBM) and somatic mutations in hematopoietic stem cells (HSCs), also termed clonal hematopoiesis (CH) accumulate with human aging. However it remains unclear whether FBM can modify the evolution of CH. To address this question, we herein present the interaction between CH and FBM in two preclinical male mouse models: after sub-lethal irradiation or after castration. An adipogenesis inhibitor (PPARγ inhibitor) is used in both models as a control. A significant increase in self-renewal can be detected in both human and rodent DNMT3AMut-HSCs when exposed to FBM. DNMT3AMut-HSCs derived from older mice interacting with FBM have even higher self-renewal in comparison to DNMT3AMut-HSCs derived from younger mice. Single cell RNA-sequencing on rodent HSCs after exposing them to FBM reveal a 6-10 fold increase in DNMT3AMut-HSCs and an activated inflammatory signaling. Cytokine analysis of BM fluid and BM derived adipocytes grown in vitro demonstrates an increased IL-6 levels under FBM conditions. Anti-IL-6 neutralizing antibodies significantly reduce the selective advantage of DNMT3AMut-HSCs exposed to FBM. Overall, paracrine FBM inflammatory signals promote DNMT3A-driven clonal hematopoiesis, which can be inhibited by blocking the IL-6 pathway.

[Gender-inclusive care of victims of violence : The model project "Gender Gewaltkonzept" at the University Hospital Aachen]. / Gendergerechte Versorgung von Gewaltopfern : Das Modellprojekt "Gender Gewaltkonzept" an der Uniklinik Aachen.

Violence is a topic of great social relevance, frequently causing tremendous health consequences for those affected and high consequential costs for health care and the national economy. The established consulting and assistance services are usually restricted to offers for ambulant supply, mainly from private agencies or societies. As a result, there is no identification and care for patients who have experienced violence and who are treated in hospital. Another deficiency is the identification and care of male victims of violence. Despite wide-ranging offers of assistance, only very few gender-specific consulting and support services have been available to date.Therefore, the model project "Gender Gewaltkonzept" was initiated at Aachen University Hospital to assess the prevalence of violence and the potential consequences of the violence experienced on the patients' health. In addition, we investigated whether males and females are in need of different supply requirements.Based on the results of the project "Gender Gewaltkonzept" so far, and on prevalence estimates proving that there is a high rate of violent experiences in both males and females, this overview is aimed at presenting the aid and protection concepts available for victims of violence, in addition to the existing deficiencies of the care system. We present approaches to resolving these deficiencies to be able to establish all-encompassing gender-appropriate support for victims of violence.

Cost-efficient delay generator for fast terahertz imaging.

We present a fast and low-cost delay generator for terahertz (THz) waves that transfers a rotational motion of a transparent dielectric cube into an effective THz delay. The device is easily implemented in the THz beam path and allows for coherent sampling over 40 ps with a scan rate of hundreds of hertz. Furthermore, we show that our approach is particularly suitable for fast THz imaging.

Nonequilibrium and thermal effects in mode-locked VECSELs.

Ultrafast femtosecond timescale dynamics in Vertical External Cavity Surface Emitting Lasers (VECSELs) have recently been employed to achieve record average power and duration mode-locked pulses by employing different types of saturable absorbers and Kerr Lens elements. Microscopic many-body dynamics are expected to dominate when attempting to push pulse durations below 100 fs. We present a preliminary microscopic simulation of ultrafast mode-locking in order to expose the role of hot carrier distributions in establishing ultrafast mode-locking.

Neural network of cognitive emotion regulation--an ALE meta-analysis and MACM analysis.

Cognitive regulation of emotions is a fundamental prerequisite for intact social functioning which impacts on both well being and psychopathology. The neural underpinnings of this process have been studied intensively in recent years, without, however, a general consensus. We here quantitatively summarize the published literature on cognitive emotion regulation using activation likelihood estimation in fMRI and PET (23 studies/479 subjects). In addition, we assessed the particular functional contribution of identified regions and their interactions using quantitative functional inference and meta-analytic connectivity modeling, respectively. In doing so, we developed a model for the core brain network involved in emotion regulation of emotional reactivity. According to this, the superior temporal gyrus, angular gyrus and (pre) supplementary motor area should be involved in execution of regulation initiated by frontal areas. The dorsolateral prefrontal cortex may be related to regulation of cognitive processes such as attention, while the ventrolateral prefrontal cortex may not necessarily reflect the regulatory process per se, but signals salience and therefore the need to regulate. We also identified a cluster in the anterior middle cingulate cortex as a region, which is anatomically and functionally in an ideal position to influence behavior and subcortical structures related to affect generation. Hence this area may play a central, integrative role in emotion regulation. By focusing on regions commonly active across multiple studies, this proposed model should provide important a priori information for the assessment of dysregulated emotion regulation in psychiatric disorders.

Quantum theory of terahertz emission due to ultrashort pulse ionization of gases.

A microscopic model is developed to analyze terahertz (THz) emission after ultrashort one- and two-color laser-pulse excitations of an atomic gas. Optical Bloch equations are derived to describe the pulse-induced ionization in the many-atom system including the Coulombic scattering of the ionized electrons. The model captures the continuous transition between the tunneling and the multiphoton ionization regimes. Numerical evaluations for a wide range of pulse configurations identify optimized excitation conditions for strong THz emission.

Comparative analysis of an intestinal strain of Bifidobacterium longum and a strain of Bifidobacterium animalis subspecies lactis in Cheddar cheese.

Bifidobacteria cultures were incorporated into Cheddar cheeses to conduct a comparative analysis between the commercially available strain Bifidobacterium animalis ssp. lactis Bb-12 and the wild-type intestinal isolate, Bifidobacterium longum DJO10A. They were incorporated as starter adjuncts in separate vats and as a mixed culture, and survival through manufacturing and cheese ripening was assessed. For cheese using only Bb-12, the cells may have grown during cheese manufacture as 133% of the inoculum was incorporated into the cheese, resulting in 8.00 log cfu/g. Counts remained high during ripening showing less than 1 log decrease over a 12-mo period. For cheese using a mixed culture of Bb-12 and DJO10A, both strains were incorporated at much lower levels: 3.02 and 1.11%, respectively. This resulted in cheese with 6.00 and 5.04 log cfu/g for Bb-12 and DJO10A, respectively. Bifidobacteria survival rates were low, most likely due to the moisture of the cheese being below 38%. The Bb-12 demonstrated almost 100% viability during ripening. Numbers of DJO10A started to decline after 2 mo of ripening and dropped below the level of detection (2 log cfu/g) after 4.5 mo of ripening. Neither DJO10A nor Bb-12 fortified cheeses produced detectable amounts of organic acids during ripening other than lactic acid, indicating the lack of detectable metabolic contribution from bifidobacteria during cheese production and ripening such as production of acetic acid. To determine if sublethal stresses could improve the viability of DJO10A, 2 more vats were made, 1 with DJO10A exposed to sublethal acid, cold, and centrifugation stresses, and 1 exposed to none of these stresses. Although stress-primed DJO10A survived cheese manufacture better, as 72.8% were incorporated into the cheese compared with 41.1% of the unprimed, the statistical significance of this difference is unknown. In addition, the difference in moisture levels in the cheese cannot be excluded as influencing this difference. However, the rate of decline during ripening was similar for both. After 6 mo of ripening, cell counts in cheese were 4.68 and 4.24 log cfu/g for primed and unprimed cultures, respectively. These results suggest that whereas priming bifidobacteria with sublethal stresses before incorporation in a cheese fermentation may improve the number of viable cells that get incorporated into the cheese, it does not affect viability during cheese ripening.

Evaluation of leaf water status by means of permittivity at terahertz frequencies.

We present an electromagnetic model of plant leaves which describes their permittivity at terahertz frequencies. The complex permittivity is investigated as a function of the water content of the leaf. Our measurements on coffee leaves (Coffea arabica L.) demonstrate that the dielectric material parameters can be employed to determine the leaf water status and, therefore, to monitor drought stress in plant leaves. The electromagnetic model consists of an effective medium theory, which is implemented by a third order extension of the Landau, Lifshitz, Looyenga model. The influence of scattering becomes important at higher frequencies and is modeled by a Rayleigh roughness factor.

Impact of the contact metallization on the performance of photoconductive THz antennas.

Both AuGe based alloys and Ti/Au metal layer stacks are widely used as ohmic metal contacts for photoconductive THz antennas made of low temperature grown GaAs. Here, we present the first systematic comparison between these two metallization types. A series of antennas of both kinds is excited by femtosecond laser pulses and by the emission from two diode lasers, i.e. we test the structures as pulsed THz emitters and as photomixers. In both cases, coherent and incoherent detection schemes are employed. We find that the power emitted from the antennas with AuGe metallization is 50% higher than that of antennas with a Ti/Au metal layer. From a comparison with a photomixer model we conclude that the higher output power results from a lower contact resistance of the AuGe contacts leading to an increased current flow. However, Ti/Au contacts have a higher thermal stability which might be advantageous if high system stability is called for.

Sex ratios in mule duck embryos at various stages of incubation.

Mule duck hatcheries have long reported varying degrees of unbalance in the sex ratio, with a preponderance of male mules at hatching. The aim of the present study was to assess the distributions of sex ratios at various stages of development in embryos originating from intra- and intergeneric crosses between parental lineages (Muscovy male x Muscovy female, Pekin male x Pekin female, Muscovy male x Pekin female or Mule, and Pekin male x Muscovy female or Hinny). In Experiment I, embryo sexing was performed on Days 1 and 5 of incubation (by multiplex PCR) and at hatching (by vent observation). The sex ratio was not significantly modified during the early stages of embryo development whatever the genetic origin (P>0.05, Days 1 and Day 5) but our results in mule and hinny ducklings confirmed the preponderance of males among normally hatched ducklings originating from the intergeneric lineage (58.9 and 55.4% males in mules and hinnies, respectively; P<0.05 in both cases). Sex ratio (vent sexing) in second grade (cull) ducklings revealed that 68% of these ducklings were females (P<0.05). In Experiment II, the distribution of sex ratio was also performed in mule duck eggs from 6 batches (400,000 eggs/batch) first examined for fertility (candling) on Day 18 of incubation. These results indicate that the percentage of males present in the population of normally hatched ducklings increases when fertility decreases. In addition, this experiment also revealed that 83.7-90.5% of viable male mule embryos develop up to hatching, compared to only 43.0-51.0% of female mule embryos. Given that a deviation in sex ratio during the first stages of incubation is unlikely (Experiment I), it is concluded that the skewed sex ratio of mule ducks at hatching is primarily due to increased late mortality in female mule embryos occurring between egg transfer and hatching. This mortality originated, at least in part, from the intergeneric origin of female mules, and was marked to a greater or lesser extent depending on the initial success of fertilization in a given batch, a possible indication that the initial quality of gametes may selectively exert its influence at the later stages of embryo development.

Nonhalogenated alkane anesthetics fail to potentiate agonist actions on two ligand-gated ion channels.

BACKGROUND: Although ether, alcohol, and halogenated alkane anesthetics potentiate agonist actions or increase the apparent agonist affinity of ligand-gated ion channels at clinically relevant concentrations, the effects of nonhalogenated alkane anesthetics on ligand-gated ion channels have not been studied. The current study assessed the abilities of two representative nonhalogenated alkane anesthetics (cyclopropane and butane) to potentiate agonist actions or increase the apparent agonist affinity of two representative ligand-gated ion channels: the nicotinic acetylcholine receptor and y-aminobutyric acid type A (GABA(A)) receptor. METHODS: Nicotinic acetylcholine receptors were obtained from the electroplax organ of Torpedo nobiliana, and human GABA(A) receptors (alpha1beta2gamma2L) were expressed in human embryonic kidney 293 cells. The Torpedo nicotinic acetylcholine receptors apparent agonist affinity in the presence and absence of anesthetic was assessed by measuring the apparent rates of desensitization induced by a range of acetylcholine concentrations. The GABA(A) receptor's apparent agonist affinity in the presence and absence of anesthetic was assessed by measuring the peak currents induced by a range of GABA concentrations. RESULTS: Neither cyclopropane nor butane potentiated agonist actions or increased the apparent agonist affinity (reduced the apparent agonist dissociation constant) of the Torpedo nicotinic acetylcholine receptor or GABA(A) receptor. At clinically relevant concentrations, cyclopropane and butane reduced the apparent rate of Torpedo nicotinic acetylcholine receptor desensitization induced by low concentrations of agonist. CONCLUSIONS: Our results suggest that the in vivo central nervous system depressant effects of nonhalogenated alkane anesthetics do not result from their abilities to potentiate agonist actions on ligand-gated ion channels. Other targets or mechanisms more likely account for the anesthetic activities of nonhalogenated alkane anesthetics.

The gamma subunit determines whether anesthetic-induced leftward shift is altered by a mutation at alpha1S270 in alpha1beta2gamma2L GABA(A) receptors.

BACKGROUND: A major action of volatile anesthetics is enhancement of gamma-aminobutyric acid receptor type A (GABA(A)R) currents. In recombinant GABA(A)Rs consisting of several subunit mixtures, mutating the alpha1 subunit serine at position 270 to isoleucine [alpha1(S270I)] was reported to eliminate anesthetic-induced enhancement at low GABA concentrations. In the absence of studies at high GABA concentrations, it remains unclear whether alpha1(S270I) affects enhancement versus inhibition by volatile anesthetics. Furthermore, the majority of GABA(A)Rs in mammalian brain are thought to consist of alpha1, beta2, and gamma2 subunits, and the alpha1(S270I) mutation has not been studied in the context of this combination. METHODS: Recombinant GABA(A)Rs composed of alpha1beta2 or alpha1beta2gamma2L subunit mixtures were studied electrophysiologically in whole Xenopus oocytes in the voltage clamp configuration. Currents elicited by GABA (0.03 microM to 1 mM) were measured in the absence and presence of isoflurane or halothane. Anesthetic effects on GABA concentration responses were evaluated for individual oocytes. RESULTS: In wild-type alpha1beta2gamma2L GABA(A), anesthetics at approximately 2 minimum alveolar concentration (MAC) shifted GABA concentration response curves to the left approximately threefold, decreased the Hill coefficient, and enhanced currents at all GABA concentrations. The alpha1(S270I) mutation itself rendered the GABA(A)R more sensitive to GABA and reduced the Hill coefficient. At low GABA concentrations (EC5), anesthetic enhancement of peak current was much smaller in alpha1(S270I)beta2gamma2L versus wild-type channels. Paradoxically, the leftward shift of the whole GABA concentration-response relation by anesthetics was the same in both mutant and wild-type channels. At high GABA concentrations, volatile anesthetics reduced currents in alpha1(S270I)beta2gammaL GABA(A)Rs. In parallel studies on alpha1beta2 (gamma-less) GABA(A)Rs, anesthetic-induced leftward shifts in wild-type receptors were more than eightfold at 2 MAC, and the alpha1(S270I) mutation nearly eliminated anesthetic-induced leftward shift. CONCLUSIONS: The results support a role for alpha1S270 in alpha1beta2gamma2L GABA(A)R gating and sensitivity to inhibition by volatile anesthetics. The alpha1S270 locus also modulates anesthetic enhancement in alpha1beta2 GABA(A)R. The presence of the gamma2L subunit reduces anesthetic-induced left shift of wild-type GABA(A)R and nullifies the impact of the alpha1(S2701) mutation on anesthetic modulation. Thus, the gamma2L subunit plays a significant role in GABA(A)R modulation by volatile anesthetic compounds.

Butanol effects on gamma-amino butyric acid concentration-responses in human alpha1beta2gamma2L gamma-amino butyric acid type A receptors with a mutation at alpha1S270.

Alcohol enhancement of gamma-amino butyric acid type A receptor (GABA(A)R) gating at low GABA is reduced by a serine-to-isoleucine mutation at residue alphaS270, suggesting that alphaS270 forms an enhancement site. However, whether the alphaS270I mutation strengthens alcohol inhibition of GABA(A)Rs remains unexplored. Furthermore, alphaS270 mutations have not been studied in the most prevalent form of mammalian GABA(A)Rs consisting of alpha1, beta2, and gamma2 subunits. In voltage-clamped Xenopus oocytes expressing recombinant alpha1beta2gamma2L GABA(A)Rs, electrophysiological analysis of GABA concentration-responses demonstrates that the alpha1(S270I) mutation increases apparent GABA affinity and significantly reduces the Hill coefficient of GABA(A)R activation. Butanol-induced leftward-shifts in GABA concentration-responses for both wild-type alpha1beta2gamma2L and alpha1(S270I)beta2gamma2L GABA(A)Rs are equal. At high GABA, butanol neither enhances nor inhibits alpha1(S270I)beta2gamma2L responses. Thus, in the dominant mammalian GABA(A)R isoform, the alphaS270I mutation affects neither enhancement nor inhibition by butanol, but alters the gating mechanism by reducing cooperativity, producing an apparent reduction in alcohol enhancement at low GABA.

Hospital admissions for malaria in Basel, Switzerland: an epidemiological review of 150 cases.

The increase in international travel and immigration from tropical countries has led to a growing number of imported malaria cases in industrialized countries. We analyzed the charts of every patient hospitalized for malaria from 1970-1992 in Basel, Switzerland. A period lasting from 1970-1986 was compared to 1987-1992. There were 150 malaria-episodes recorded. Over time, the number of immigrants increased from 12 to 27% (p <.05). More patients were admitted with Plasmodium falciparum-infection (49 vs. 75%, p <.005). The number of untypable malaria decreased from 30 to 9% (p <.005). In the more recent period, more diagnosis were done within a week (66 vs. 50%, p <.05). Twenty-three (15%) patients were admitted to the ICU, four (2. 6%) patients died of cerebral malaria. Twenty-seven (18%) patients developed malaria while taking correct prophylaxis. Despite some progress, malaria is still causing considerable morbidity and mortality. Non adherence to chemoprophylaxis was a major risk factor for acquiring malaria in hospitalized patients.

Dual action of isoflurane on the gamma-aminobutyric acid (GABA)-mediated currents through recombinant alpha(1)beta(2)gamma(2L)-GABA(A)-receptor channels.

Isoflurane (ISO) increased the agonist-induced chloride flux through the gamma-aminobutyric acid A receptor (GABA(A)R). This may reflect an anesthetic-induced increase in the apparent agonist affinity. A dual effect of anesthetics was postulated for both the nicotinic acetylcholine receptor (nAChR) and the GABA(A)R. We tested the hypothesis that, in addition to a blocking effect, ISO increases gamma-aminobutyric acid (GABA)-gated currents through recombinant GABA(A)R channels. HEK293 cells were transfected with rat cDNA for alpha(1),beta(2),gamma(2L) subunits. Currents elicited by 1 mM or 0. 01 mM GABA, respectively, alone, or with increasing concentrations of ISO, were recorded by using standard patch clamp techniques. ISO reduced the peak current elicited by 1 mM GABA. Currents induced by 0.01 mM GABA were potentiated by small ISO (twofold at 0.5 mM ISO) and inhibited by larger concentrations. Withdrawal of ISO and GABA induced rebound currents, suggesting an open-channel block by ISO. These currents increased with increasing concentrations of ISO. At large concentrations of ISO, the inhibitory effect predominated and was caused by, at least partly, an open-channel block. At small concentrations of ISO, potentiation of the GABA-gated currents was more prominent. This dual action of ISO indicates different binding sites at the GABA(A)R. The balance between potentiation and block depends on the concentrations of both ISO and GABA.

Acid aspiration prophylaxis and caesarean section.

Acid aspiration syndrome still contributes to the few anaesthesia-related deaths in caesarean section. Although none of the numerous measures intended to prevent such fatalities is based on clear evidence, many different regimens are being used. As obstetric acid aspiration syndrome occurs mainly in general anaesthesia, using regional techniques wherever possible may be the most effective prophylactic measure.

Altered development and cytokine responses of myeloid progenitors in the absence of transcription factor, interferon consensus sequence binding protein.

Mice deficient for the transcription factor, interferon consensus sequence binding protein (ICSBP), are immunodeficient and develop disease symptoms similar to human chronic myeloid leukemia (CML). To elucidate the hematopoietic disorder of ICSBP(-/-) mice, we investigated the growth, differentiation, and leukemogenic potential of ICSBP(-/-) myeloid progenitor cells in vitro, as well as by cell-transfers in vivo. We report that adult bone marrow, as well as fetal liver of ICSBP-deficient mice harbor increased numbers of progenitor cells, which are hyperresponsive to both granulocyte macrophage colony-stimulating factor (GM-CSF) and G-CSF in vitro. In contrast, their response to M-CSF is strongly reduced and, surprisingly, ICSBP(-/-) colonies formed in the presence of M-CSF are mostly of granulocytic morphology. This disproportional differentiation toward cells of the granulocytic lineage in vitro parallels the expansion of granulocytes in ICSBP(-/-) mice and correlates with a 4-fold reduction of M-CSF receptor expressing cells in bone marrow. Cell transfer studies showed an intrinsic leukemogenic potential and long-term reconstitution capability of ICSBP(-/-) progenitors. Further experiments demonstrated strongly reduced adhesion of colony-forming cells from ICSBP(-/-) bone marrow to fibronectin. In summary, ICSBP(-/-) myeloid progenitor cells share several abnormal features with CML progenitors, suggesting that the distal parts of signaling pathways of these two disorders are overlapping.

[Fatal child neglect in West Germany 1 January 1985 to 2 October 1990. Results of a multicenter study]. / Tödliche Kindesvernachlässigung in der Bundesrepublik Deutschland im Zeitraum 1.1.1985 bis 2.10.1990. Ergebnisse einer multizentrischen Studie.

UNLABELLED: Up to now reliable data were available on cases of lethal child neglect in the area of the Federal Republic of Germany prior to reunification (the former West Germany). In a multicenter study we therefore examined the police and court records for such cases occurring in the period from 1 January 1985 to 2 October 1990 in nearly the entire area of Federal Republic of Germany. RESULTS: The study center received information on 19 cases of lethal child neglect. Extrapolated to all institutes of legal medicine, this corresponds to 20 cases and thus 3.5 cases a year in the whole of West Germany in the period studied. There is to be added a dark-field which cannot be limited more precisely. However, the cases of fatal child neglect might have occurred much more seldom than fatal child abuse caused by use of physical violence. Slightly more than half the victims were younger than 1 year, the oldest one was 7 10/12 years old. Most frequently the children died of starvation and thirst. Mostly the mothers/nursing mothers killed the child alone or together with the victim's father/stepfather. In the majority of the cases there was not a close affection between parents and child. Nearly 30% female/male perpetrators suffered from chronic alcohol abuse. Only 15 (= 56%) of 27 female/male perpetrators were sentenced to imprisonment (period between 7 months on probation and 10 years). Mitigation circumstances existed for nearly half the persons sentenced to imprisonment. It is true that child neglect is a rarer crime, but the experts of legal medicine always have to indicate errors made during the external inspection of the corpse (among others failures to see indications of neglect).

[Prophylaxis against obstetric acid aspiration syndrome in the German Federal Republic in 1997. A review based on results of a federal survey]. / Prophylaxe des geburtshilflichen Säureaspirationssyndroms in der Bundesrepublik Deutschland 1997. Eine Bestandsaufnahme anhand der Ergebnisse einer bundesweiten Umfrage.

A survey of all German hospitals providing obstetric anesthesia was performed in 1997 (n = 1061, recovery rate 82%; comprising about 700,000 deliveries and 115,000 cesareans, resp.) concerning the routine prophylactic measures for acid aspiration syndrome (AAS) in pregnant patients and before obstetric procedures (i.e., prevention of aspiration by positioning, Sellick's manoeuvre, reduction of intragastric volume, or reduction of gastric content acidity). In pregnant patients, any prophylaxis of AAS is performed in 36%. Of the patients expecting delivery in the labour ward, only 7% receive pharmacological AAS treatment. Before scheduled (urgent, non-emergency) cesarean section in general anesthesia, 93% (94%) of patients receive prophylactic treatment, either pharmacological or non-pharmacological. Before regional anesthesia, the corresponding numbers are 52% for both scheduled or urgent CS.