Influence of pions and hyperons on stellar black hole formation

We present numerical simulations of stellar core-collapse with spherically symmetric, general relativistic hydrodynamics up to black hole formation. Using the CoCoNuT code, with a newly developed grey leakage scheme for the neutrino treatment, we investigate the effects of including pions and \Lambda-hyperons into the equation of state at high densities and temperatures on the black hole formation process. Results show non-negligible differences between the models with reference equation of state without any additional particles and models with the extended ones. For the latter, the maximum masses supported by the proto-neutron star are smaller and the collapse to a black hole occurs earlier. A phase transition to hyperonic matter is observed when the progenitor allows for a high enough accretion rate onto the proto-neutron star. Rough estimates of neutrino luminosity from these collapses are given, too.Comment: 22 pages, 10 figures. Minor change

Der Mu-Opioidrezeptor-Polymorphismus 118A>G : ein genetischer Modulator von Opioideffekten

The µ-opioid receptor is the primary target structure of most opioid analgesics and thus responsible for the predominant part of their wanted and unwanted effects. Carriers of the frequent genetic µ-opioid receptor variant N40D (allelic frequency 8.2 - 17 %), coded by the single nucleotide polymorphism A>G at position 118 of the µ-opioid receptor coding gene OPRM1 (OPRM1 118A>G SNP), suffer from a decreased opioid potency and from a higher need of opioid analgesics to reach adequate analgesia. The aim of the present work was to identify the mechanism by which the OPRM1 118A>G SNP decreases the opioid potency and to quantify its effects on the analgesic potency and therapeutic range of opioid analgesics. To elucidate the consequences of the OPRM1 118A>G SNP for the effects of opioid analgesics, brain regions of healthy homozygous carriers of the OPRM1 118A>G SNP were identified by means of functional magnetic resonace imaging (fMRI), where the variant alters the response to opioid analgesics after painful stimulation. Afterwards, the µ-opioid receptor function was analyzed on a molecular level in post mortem samples of these brain regions. Finally, the consequences of the OPRM1 118A>G SNP for the analgesic and respiratory depressive effects of opioids were quantified in healthy carriers and non-carriers of OPRM1 118A>G SNP by means of experimental pain- and respiratory depression-models. To identify pain processing brain regions, where the variant alters the response to opioid analgesics after painful stimulation, we investigated the effects of different alfentanil concentration levels (0, 25, 50 and 75 ng/ml) on pain-related brain activation achieved by short pulses (300 msec) of gaseous CO2 (66% v/v) delivered to the nasal mucosa using a 3.0 T magnetic head scanner in 16 non-carriers and nine homozygous carriers of the µ-opioid receptor gene variant OPRM1 118A>G. In brain regions associated with the processing of the sensory dimension of pain (pain intensity), such as the primary and secondary somatosensory cortices and the posterior insular cortex, the activation decreased linearly in relation to alfentanil concentrations, which was significantly less pronounced in OPRM1 118G carriers. In contrast, in brain regions known to process the affective dimension of pain (emotional dimension), such as the parahippocampal gyrus, amygdala and anterior insula, the pain-related activation disappeared already at the lowest alfentanil dose, without genotype differences. Subsequently, we investigated the µ-opioid receptor-expression ([3H]-DAMGO saturation experiments, OPRM1 mRNA analysis by means of RT-PCR), the µ-opioid receptor affinity ([3H]-DAMGO saturation and competition experiments) and µ-opioid receptor signaling ([35S]- GTPγS binding experiments) in post mortem samples of the human SII-region, as a cortical projection region coding for pain intensity, and lateral thalamus, as an important region for nociceptive transmission. Samples of 22 non-carriers, 21 heterozygous and three homozygous carriers of OPRM1 118A>G SNP were included into the analysis. The receptor expression and receptor affinity of both brain regions did not differ between non-carriers and carriers of the variant N40D. In non-carriers, the µ-opioid receptors of the SII-region activated the receptor bound G-protein more efficiently than those of the thalamus (factor 1.55-2.27). This regional difference was missing in heterozygous (factor 0.78-1.66) and homozygous (factor 0.66-1.15) carriers of the N40D variant indicating a reduced receptor-G-protein-coupling in the SII-region. Finally, the consequences of the alteration of µ-opioid receptor function in carriers and noncarriers of the genetic variant was investigated using pain- and respiratory depression-models. Therefore, 10 healthy non-carriers, four heterozygous and six homozygous carriers of the µ- opioid receptor variant N40D received an infusion of four different concentrations of alfentanil (0, 33.33, 66.66 and 100 ng/ml). At each concentration level, analgesia was assessed by means of electrically (5 Hz sinus 0 to 20 mA) and chemically (200 ms gaseous CO2 pulses applied to the nasal mucosa) induced pain, and respiratory depression was quantified by means of hypercapnic challenge according to Read and recording of the breathing frequency. The results showed that depending on the used pain model, both heterozygous and homozygous carriers of the variant N40D needed 2 – 4 times higher alfentanil concentrations to achieve the same analgesia as non-carriers. This increase seems to be at least for homozygous carriers unproblematic, because to reach a comparable respiratory depression as non-carriers, they needed 10-12 times higher alfentanil concentrations. The results of this work demonstrate that the µ-opioid receptor variant N40D causes a regionally limited reduction of the signal transduction efficiency of µ-opioid receptors in brain regions involved in pain processing. Thus, the painful activation of sensory brain regions coding for pain intensity is not sufficiently suppressed by opioid analgesics in carriers of the variant N40D. Due to the insufficient suppression in hetero- and homozygous carriers of the variant N40D, the concentration of opioids has to be increased by a factor 2 - 4, in order to achieve the same analgesia as in non-carriers. At the same time, the respiratory depressive effects are decreased to a greater extent in homozygous carriers of the N40D variant as they need a 10 - 12 times higher opioid concentration to suffer from the same degree of respiratory depression as non-carriers. Due to the increased therapeutic range of opioid analgesics, an increase of the opioid dose seems to be harmless, at least for homozygous carriers of the N40D variant.Opioidanalgetika sind bis heute das adäquate Mittel zur Behandlung schwerer Schmerzzustände. Dabei wird ihre breite Anwendbarkeit durch opioidtypische unerwünschte Nebenwirkungen wie Atemdepression, Benommenheit, Übelkeit bis zum Erbrechen, Obstipation, Miosis und juckende Hautreizung eingeschränkt. Das Ausmaß der auftretenden Opioidwirkungen variiert von Patient zu Patient. Fortschritte in der genetischen Forschung haben gezeigt, dass ein Teil der Variabilität von Opioidwirkungen in der genetischen Variabilität der Bevölkerung begründet liegt. Opioide wirken über G-Protein-gekoppelte Rezeptoren, die Opioidrezeptoren, bestehend aus dem μ-, κ-, δ-Opioidrezeptor. Anhand von μ-Opioidrezeptor-Knockout-Mäusen konnte gezeigt werden, dass vor allem die μ-Opioidrezeptoren für den überwiegenden Teil der erwünschten und unerwünschten Wirkungen von Opioidanalgetika verantwortlich sind. Die μ-Opioidrezeptoren werden vom OPRM1 Gen codiert. Bei einer häufigen genetischen Variante des μ- Opioidrezeptor-Gens OPRM1 (Allelfrequenz ca. 8,2-17%) steht an Position 118 in Exon 1 das Nukleotid Adenin anstatt Guanin (OPRM1-118A>G-Polymorphismus). Als Folge wird anstelle von Asparagin die Aminosäure Aspartat an Position 40 (N40D) der N-terminalen extrazellulä- ren Rezeptorbindungsdomäne eingebaut. Bei Trägern der μ-Opioidrezeptor-Variante N40D wurde wiederholt eine Verminderung der Opioidpotenz und ein erhöhter Bedarf von Opioidanalgetika zur adäquaten Schmerzstillung im Vergleich zu Nichtträgern der Variante beobachtet. Desweiteren weisen einige Studien auf eine Erhöhung der therapeutischen Breite von Opioidanalgetika in Trägern dieser Variante hin. So benötigten Träger der N40D Variante im Vergleich zu Nichtträgern höhere Konzentrationen von Alfentanil (1,3-fach) bzw. Morphin (2-fach), um die gleiche Analgesie bei postoperativen Schmerzen zu erreichen, und dennoch waren sie weniger von opioidtypischen unerwünschten Wirkungen betroffen. Die miotischen Effekte von Morphin, seines aktiven Metaboliten Morphin-6-glucuronid (M6G) und Levomethadon waren in Trägern der N40D Variante verringert und Träger des varianten Allels mussten nach hohen Dosen M6G weniger erbrechen als Nichtträger. Es gibt aber auch eine Studie, deren Ergebnisse gegen eine erhöhte therapeutische Breite von Opioiden in Träger des varianten 118G-Allels sprechen. Diese zeigte, dass in heterozygoten Trägern des 118G Allels die Analgesie nach M6G Gabe zwar verringert war, die atemdepressiven Effekte von M6G aber unverändert waren. Dies deutet auf eine verminderte therapeutische Breite von Opioiden in heterozygoten Trägern hin. Die der verminderten Opioidpotenz zu Grunde liegenden molekularen Mechanismen sind nicht eindeutig geklärt. So wurde in AV-12-Zellen, die mit der 118G Variante des µ-Opioidrezeptor-Gens transfiziert wurden, eine 3-fach höhere Affinität des N40D Rezeptors zu seinem endogenen Liganden β-Endorphin beobachtet, während die Affinität zu Opioiden wie Morphin oder dessen aktiven Metaboliten Morphin-6-glucuronid unverändert waren. Diese Ergebnisse erklären leider nicht die verminderte Opioidpotenz bei Trägern der 118G Variante. Eine mögliche Erklärung für die verminderte Opioidanalgesie wäre eine verminderte Rezeptorexpression in Trägern der 118G Variante. Die Möglichkeit einer verminderten Rezeptorexpression wird durch die Beobachtung gestützt, dass in Hirngewebsproben von Trägern der 118G Variante im Vergleich zu Nichtträgern tendenziell geringere Mengen an OPRM1 mRNA gefunden wurden, was auf eine verminderte Expression des Rezeptorproteins hinweisen könnte. Diese Vermutung wird durch Ergebnisse aus Rezeptorexpressions-Experimenten in mit der 118G Variante des µ-Opioidrezeptor-Gens transfizierten HEK 293-Zellen und CHO-Zellen untermauert. Im Gegensatz dazu gibt es auch Veröffentlichungen, in denen die Rezeptorexpression in mit der 118G Variante transfizierten HEK 293-Zellen und COS-Zellen unverändert war. Daher ist der endgültige Beweis, dass die µ-Opioidrezeptorexpression in Trägern der 118G Variante verringert ist, noch nicht erbracht. ..

Linkage between increased nociception and olfaction via a SCN9A haplotype

Background and Aims: Mutations reducing the function of Nav1.7 sodium channels entail diminished pain perception and olfactory acuity, suggesting a link between nociception and olfaction at ion channel level. We hypothesized that if such link exists, it should work in both directions and gain-of-function Nav1.7 mutations known to be associated with increased pain perception should also increase olfactory acuity. Methods: SCN9A variants were assessed known to enhance pain perception and found more frequently in the average population. Specifically, carriers of SCN9A variants rs41268673C>A (P610T; n = 14) or rs6746030C>T (R1150W; n = 21) were compared with non-carriers (n = 40). Olfactory function was quantified by assessing odor threshold, odor discrimination and odor identification using an established olfactory test. Nociception was assessed by measuring pain thresholds to experimental nociceptive stimuli (punctate and blunt mechanical pressure, heat and electrical stimuli). Results: The number of carried alleles of the non-mutated SCN9A haplotype rs41268673C/rs6746030C was significantly associated with the comparatively highest olfactory threshold (0 alleles: threshold at phenylethylethanol dilution step 12 of 16 (n = 1), 1 allele: 10.6±2.6 (n = 34), 2 alleles: 9.5±2.1 (n = 40)). The same SCN9A haplotype determined the pain threshold to blunt pressure stimuli (0 alleles: 21.1 N/m2, 1 allele: 29.8±10.4 N/m2, 2 alleles: 33.5±10.2 N/m2). Conclusions: The findings established a working link between nociception and olfaction via Nav1.7 in the gain-of-function direction. Hence, together with the known reduced olfaction and pain in loss-of-function mutations, a bidirectional genetic functional association between nociception and olfaction exists at Nav1.7 level

Quick discrimination of A delta and C fiber mediated pain based on three verbal descriptors

Background: A delta and C fibers are the major pain-conducting nerve fibers, activate only partly the same brain areas, and are differently involved in pain syndromes. Whether a stimulus excites predominantly A delta or C fibers is a commonly asked question in basic pain research but a quick test was lacking so far. Methodology/Principal Findings: Of 77 verbal descriptors of pain sensations, "pricking", "dull" and "pressing" distinguished best (95% cases correctly) between A delta fiber mediated (punctate pressure produced by means of von Frey hairs) and C fiber mediated (blunt pressure) pain, applied to healthy volunteers in experiment 1. The sensation was assigned to A delta fibers when "pricking" but neither "dull" nor "pressing" were chosen, and to C fibers when the sum of the selections of "dull" or "pressing" was greater than that of the selection of "pricking". In experiment 2, with an independent cohort, the three-descriptor questionnaire achieved sensitivity and specificity above 0.95 for distinguishing fiber preferential non-mechanical induced pain (laser heat, exciting A delta fibers, and 5-Hz electric stimulation, exciting C fibers). Conclusion: A three-item verbal rating test using the words "pricking", "dull", and "pressing" may provide sufficient information to characterize a pain sensation evoked by a physical stimulus as transmitted via A delta or via C fibers. It meets the criteria of a screening test by being easy to administer, taking little time, being comfortable in handling, and inexpensive while providing high specificity for relevant information

The explosion mechanism of core-collapse supernovae: progress in supernova theory and experiments

The explosion of core-collapse supernova depends on a sequence of events taking place in less than a second in a region of a few hundred kilometers at the center of a supergiant star, after the stellar core approaches the Chandrasekhar mass and collapses into a proto-neutron star, and before a shock wave is launched across the stellar envelope. Theoretical efforts to understand stellar death focus on the mechanism which transforms the collapse into an explosion. Progress in understanding this mechanism is reviewed with particular attention to its asymmetric character. We highlight a series of successful studies connecting observations of supernova remnants and pulsars properties to the theory of core-collapse using numerical simulations. The encouraging results from first principles models in axisymmetric simulations is tempered by new puzzles in 3D. The diversity of explosion paths and the dependence on the pre-collapse stellar structure is stressed, as well as the need to gain a better understanding of hydrodynamical and MHD instabilities such as SASI and neutrino-driven convection. The shallow water analogy of shock dynamics is presented as a comparative system where buoyancy effects are absent. This dynamical system can be studied numerically and also experimentally with a water fountain. The potential of this complementary research tool for supernova theory is analyzed. We also review its potential for public outreach in science museums.Comment: 19 pages, 6 figures, invited review accepted for publication in PAS

The Human Operculo-Insular Cortex Is Pain-Preferentially but Not Pain-Exclusively Activated by Trigeminal and Olfactory Stimuli

Increasing evidence about the central nervous representation of pain in the brain suggests that the operculo-insular cortex is a crucial part of the pain matrix. The pain-specificity of a brain region may be tested by administering nociceptive stimuli while controlling for unspecific activations by administering non-nociceptive stimuli. We applied this paradigm to nasal chemosensation, delivering trigeminal or olfactory stimuli, to verify the pain-specificity of the operculo-insular cortex. In detail, brain activations due to intranasal stimulation induced by non-nociceptive olfactory stimuli of hydrogen sulfide (5 ppm) or vanillin (0.8 ppm) were used to mask brain activations due to somatosensory, clearly nociceptive trigeminal stimulations with gaseous carbon dioxide (75% v/v). Functional magnetic resonance (fMRI) images were recorded from 12 healthy volunteers in a 3T head scanner during stimulus administration using an event-related design. We found that significantly more activations following nociceptive than non-nociceptive stimuli were localized bilaterally in two restricted clusters in the brain containing the primary and secondary somatosensory areas and the insular cortices consistent with the operculo-insular cortex. However, these activations completely disappeared when eliminating activations associated with the administration of olfactory stimuli, which were small but measurable. While the present experiments verify that the operculo-insular cortex plays a role in the processing of nociceptive input, they also show that it is not a pain-exclusive brain region and allow, in the experimental context, for the interpretation that the operculo-insular cortex splay a major role in the detection of and responding to salient events, whether or not these events are nociceptive or painful

16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy

Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected individuals. The present study tested whether six large recurrent copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associated with neurodevelopmental disorders also increase risk of RE. Our association analyses revealed a significant excess of the 600 kb genomic duplication at the 16p11.2 locus (chr16: 29.5-30.1 Mb) in 393 unrelated patients with typical (n = 339) and atypical (ARE; n = 54) RE compared with the prevalence in 65 046 European population controls (5/393 cases versus 32/65 046 controls; Fisher's exact test P = 2.83 × 10−6, odds ratio = 26.2, 95% confidence interval: 7.9-68.2). In contrast, the 16p11.2 duplication was not detected in 1738 European epilepsy patients with either temporal lobe epilepsy (n = 330) and genetic generalized epilepsies (n = 1408), suggesting a selective enrichment of the 16p11.2 duplication in idiopathic focal childhood epilepsies (Fisher's exact test P = 2.1 × 10−4). In a subsequent screen among children carrying the 16p11.2 600 kb rearrangement we identified three patients with RE-spectrum epilepsies in 117 duplication carriers (2.6%) but none in 202 carriers of the reciprocal deletion. Our results suggest that the 16p11.2 duplication represents a significant genetic risk factor for typical and atypical R