Tunable non-integer high-harmonic generation in a topological insulator.

When intense lightwaves accelerate electrons through a solid, the emerging high-order harmonic (HH) radiation offers key insights into the material1-11. Sub-optical-cycle dynamics-such as dynamical Bloch oscillations2-5, quasiparticle collisions6,12, valley pseudospin switching13 and heating of Dirac gases10-leave fingerprints in the HH spectra of conventional solids. Topologically non-trivial matter14,15 with invariants that are robust against imperfections has been predicted to support unconventional HH generation16-20. Here we experimentally demonstrate HH generation in a three-dimensional topological insulator-bismuth telluride. The frequency of the terahertz driving field sharply discriminates between HH generation from the bulk and from the topological surface, where the unique combination of long scattering times owing to spin-momentum locking17 and the quasi-relativistic dispersion enables unusually efficient HH generation. Intriguingly, all observed orders can be continuously shifted to arbitrary non-integer multiples of the driving frequency by varying the carrier-envelope phase of the driving field-in line with quantum theory. The anomalous Berry curvature warranted by the non-trivial topology enforces meandering ballistic trajectories of the Dirac fermions, causing a hallmark polarization pattern of the HH emission. Our study provides a platform to explore topology and relativistic quantum physics in strong-field control, and could lead to non-dissipative topological electronics at infrared frequencies.

Prenatal nicotine exposure enhances the trigeminocardiac reflex via serotonin receptor facilitation in brainstem pathways.

In this study we used a rat model for prenatal nicotine exposure to test whether clinically relevant concentrations of brain nicotine and cotinine are passed from dams exposed to nicotine to her pups, whether this changes the trigeminocardiac reflex (TCR), and whether serotonergic function in the TCR brainstem circuitry is altered. Pregnant Sprague-Dawley dams were exposed to 6 mg·kg(-1)·day(-1) of nicotine via osmotic minipumps for the duration of pregnancy. Following birth dams and pups were killed, blood was collected, and brain nicotine and cotinine levels were measured. A separate group of prenatal nicotine-exposed pups was used for electrophysiological recordings. A horizontal brainstem slice was obtained by carefully preserving the trigeminal nerve with fluorescent identification of cardiac vagal neurons (CVNs) in the nucleus ambiguus. Stimulation of the trigeminal nerve evoked excitatory postsynaptic current in CVNs. Our data demonstrate that prenatal nicotine exposure significantly exaggerates both the TCR-evoked changes in heart rate in conscious unrestrained pups, and the excitatory neurotransmission to CVNs upon trigeminal afferent nerve stimulation within this brainstem reflex circuit. Application of the 5-HT1A receptor antagonist WAY 100635 (100 µM) and 5-HT2A/C receptor antagonist ketanserin (10 µM)significantly decreased neurotransmission, indicating an increased facilitation of 5-HT function in prenatal nicotine-exposed animals. Prenatal nicotine exposure enhances activation of 5-HT receptors and exaggerates the trigeminocardiac reflex.

Onsager relations in a two-dimensional electron gas with spin-orbit coupling.

Theory predicts for the two-dimensional electron gas with only a Rashba spin-orbit interaction a vanishing spin Hall conductivity and at the same time a finite inverse spin Hall effect. We show how these seemingly contradictory results are compatible with the Onsager relations: The latter do hold for spin and particle (charge) currents in the two-dimensional electron gas, although (i) their form depends on the experimental setup and (ii) a vanishing bulk spin Hall conductivity does not necessarily imply a vanishing spin Hall effect. We also discuss the situation in which extrinsic spin orbit from impurities is present and the bulk spin Hall conductivity can be different from zero.

Endogenous inhibition of the trigeminally evoked neurotransmission to cardiac vagal neurons by muscarinic acetylcholine receptors.

Stimulation of the nasal mucosa by airborne irritants or water evokes a pronounced bradycardia accompanied by peripheral vasoconstriction and apnea. The dive response, which includes the trigeminocardiac reflex, is among the most powerful autonomic responses. These responses slow the heart rate and reduce myocardial oxygen consumption. Although normally cardioprotective, exaggeration of this reflex can be detrimental and has been implicated in cardiorespiratory diseases, including sudden infant death syndrome (SIDS). An essential component of the diving response and trigeminocardiac reflex is activation of the parasympathetic cardiac vagal neurons (CVNs) in the nucleus ambiguus that control heart rate. This study examined the involvement of cholinergic receptors in trigeminally evoked excitatory postsynaptic currents in CVNs in an in vitro preparation from rats. CVNs were identified using a retrograde tracer injected into the fat pads at the base of the heart. Application of the acetylcholinesterase inhibitor neostigmine significantly decreased the amplitude of glutamatergic neurotransmission to CVNs on stimulation of trigeminal fibers. Whereas nicotine did not have any effect on the glutamatergic responses, the muscarinic acetylcholine receptor (mAChR) agonist bethanechol significantly decreased the excitatory neurotransmission. Atropine, an mAChR antagonist, facilitated these responses indicating this trigeminally evoked brain stem pathway in vitro is endogenously inhibited by mAChRs. Tropicamide, an m4 mAChR antagonist, prevented the inhibitory action of the muscarinic agonist bethanechol. These results indicate that the glutamatergic synaptic neurotransmission in the trigeminally evoked pathway to CVNs is endogenously inhibited in vitro by m4 mAChRs.

Catastrophic flood of the Mediterranean after the Messinian salinity crisis.

The Mediterranean Sea became disconnected from the world's oceans and mostly desiccated by evaporation about 5.6 million years ago during the Messinian salinity crisis. The Atlantic waters found a way through the present Gibraltar Strait and rapidly refilled the Mediterranean 5.33 million years ago in an event known as the Zanclean flood. The nature, abruptness and evolution of this flood remain poorly constrained. Borehole and seismic data show incisions over 250 m deep on both sides of the Gibraltar Strait that have previously been attributed to fluvial erosion during the desiccation. Here we show the continuity of this 200-km-long channel across the strait and explain its morphology as the result of erosion by the flooding waters, adopting an incision model validated in mountain rivers. This model in turn allows us to estimate the duration of the flood. Although the available data are limited, our findings suggest that the feedback between water flow and incision in the early stages of flooding imply discharges of about 10(8) m(3) s(-1) (three orders of magnitude larger than the present Amazon River) and incision rates above 0.4 m per day. Although the flood started at low water discharges that may have lasted for up to several thousand years, our results suggest that 90 per cent of the water was transferred in a short period ranging from a few months to two years. This extremely abrupt flood may have involved peak rates of sea level rise in the Mediterranean of more than ten metres per day.

5-HT2 receptors modulate excitatory neurotransmission to cardiac vagal neurons within the nucleus ambiguus evoked during and after hypoxia.

To examine the role of 5-HT2 receptors in the central cardiorespiratory network, and in particular the respiratory modulation of parasympathetic activity to the heart, we used an in vitro medullary slice that allowed simultaneous examination of rhythmic inspiratory-related activity recorded from hypoglossal rootlet and excitatory inspiratory-related neurotransmission to cardioinhibitory vagal neurons (CVNs) within the nucleus ambiguus (NA). Focal application of ketanserin, a 5-HT2 receptor antagonist, did not significantly alter the frequency of spontaneous excitatory postsynaptic excitatory currents (EPSCs) in CVNs in control conditions. However, ketanserin diminished spontaneous excitatory neurotransmission to CVNs during hypoxia. The inhibitory action of ketanserin was on 5-HT3 mediated EPSCs during hypoxia since these responses were blocked by the 5-HT3 receptor antagonist ondansetron. In addition, a robust inspiratory-related excitatory neurotransmission was recruited during recovery from hypoxia. Focal application of ketanserin during this posthypoxia period evoked a significant augmentation of the frequency of inspiratory-related, but not spontaneous EPSCs in CVNs. This excitatory effect of ketanserin was prevented by application of the purinergic receptor blocker pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS). These results demonstrate 5-HT2 receptors differentially modulate excitatory neurotransmission to CVNs during and after hypoxia. Activation of 5-HT2 receptors acts to maintain excitatory neurotransmission to CVNs during hypoxia, likely via presynaptic facilitation of 5-HT3 receptor-mediated neurotransmission to CVNs. However, activation of 5HT2 receptors diminishes the subsequent inspiratory-related excitatory neurotransmission to CVNs that is recruited during the recovery from hypoxia likely exerting an inhibitory action on inspiratory-related purinergic signaling.

Serotonergic modulation of the trigeminocardiac reflex neurotransmission to cardiac vagal neurons in the nucleus ambiguus.

Stimulation of the trigeminal nerve evokes a dramatic decrease in heart rate and blood pressure, and this reflex has generally been termed the trigeminocardiac reflex. A subset of the trigeminocardiac reflex is the diving reflex in which the nasal mucosa is stimulated with water or air-borne chemical irritants. Activation of the diving reflex evokes a pronounced bradycardia, mediated by increased parasympathetic cardiac activity, and is the most powerful autonomic reflex. However, exaggeration of this protective response could be detrimental and has been implicated in Sudden Infant Death Syndrome (SIDS). Despite the importance and strength of the trigeminocardiac reflex, there is little information about the cellular mechanisms and brain stem pathways that constitute this reflex. To address these issues, stimulation of trigeminal afferent fibers and the evoked excitatory postsynaptic currents were recorded in cardiac vagal neurons (CVNs) in an in vitro brain stem slice preparation. This synaptic pathway is robust and activation of the trigeminal pathway often evoked action potentials in CVNs. Application of the serotonin (5-HT) reuptake inhibitor citalopram significantly enhanced these responses. Consistent with the hypothesis this pathway is endogenously modulated by 5-HT receptors the 5-HT1A receptor antagonist, WAY 100635 inhibited, whereas the 5-HT2A/C receptor antagonist, ketanserin facilitated the excitatory neurotransmission to CVNs. The 5-HT1A receptor agonist 8-hydroxy-2-(dipropylamino)tetralin hydrobromide increased, whereas the 5-HT2 receptor agonist, alpha-methylserotonin maleate salt inhibited this reflex pathway. These results indicate stimulation of trigeminal fibers evokes a powerful excitatory and polysynaptic pathway to CVNs, and this pathway is endogenously modulated and differentially enhanced and depressed, by 5-HT1A and 5-HT2 receptors, respectively.

Mapping and identification of GABAergic neurons in transgenic mice projecting to cardiac vagal neurons in the nucleus ambiguus using photo-uncaging.

The neural control of heart rate is determined primarily by the activity of preganglionic parasympathetic cardiac vagal neurons (CVNs) originating in the nucleus ambiguus (NA) in the brain stem. GABAergic inputs to CVNs play an essential role in determining the activity of these neurons including a robust inhibition during each inspiratory burst. The origin of GABAergic innervation has yet to be determined however. A transgenic mouse line expressing green florescent protein (GFP) in GABAergic cells was used in conjunction with caged glutamate to identify both clusters and individual GABAergic neurons that evoke inhibitory GABAergic synaptic responses in CVNs. Transverse slices were taken with CVNs patch-clamped in the whole cell configuration. Sections containing both the pre-Botzinger complex as well as the calamus scriptorius were divided into approximately 90 quadrants, each 200 x 200 microm and were sequentially photostimulated. Inhibitory post synaptic currents (IPSCs) were recorded in CVNs after a 5-ms photostimulation of 50 microM caged glutamate. The four areas that contained GABAergic cells projecting to CVNs were 200 microm medial, 400 microm medial, 200 microm ventral, and 1,200 microm dorsal and 1,000 microm medial to patched CVNs. Once foci of GABAergic cells projecting to CVNs were determined, photostimulation of individual GABAergic neurons was conducted. The results from this study suggest that GABAergic cells located in four specific areas project to CVNs, and that these cells can be individually identified and stimulated using photouncaging to recruit GABAergic neurotransmission to CVNs.

Abolishment of serotonergic neurotransmission to cardiac vagal neurons during and after hypoxia and hypercapnia with prenatal nicotine exposure.

Cardioinhibitory cardiac vagal neurons (CVNs) do not receive inspiratory-related excitatory inputs under normal conditions. However, excitatory purinergic and serotonergic pathways are recruited during inspiratory activity after episodes of hypoxia and hypercapnia (H/H). Prenatal nicotine (PNN) exposure is known to dramatically change cardiorespiratory responses and decrease the ability to resuscitate from H/H. This study tested whether PNN exposure alters excitatory neurotransmission to CVNs in the nucleus ambiguus during and after H/H. Spontaneous and inspiratory evoked excitatory postsynaptic currents were recorded in CVNs from rats that were exposed to nicotine (6 mg x kg(-1) x d(-1)) throughout the prenatal period. In contrast to unexposed animals, in PNN animals H/H recruited excitatory neurotransmission to CVNs during inspiratory-related activity that was blocked by the alpha3beta4 nicotinic acetylcholine receptor (nAChR) blocker alpha-conotoxin AuIB (alpha-CTX AuIB, 100 microM) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 50 microM) and d(-)-2-amino-5-phosphonopentanoic acid (AP5, 50 microM), selective AMPA/kainate and N-methyl-d-aspartate receptor blockers, respectively. Following H/H, there was a significant increase in inspiratory-related excitatory postsynaptic currents that were unaltered by alpha-CTX AuIB or ondansetron, a 5-HT3 receptor blocker, but were subsequently inhibited by pyridoxalphosphate-6-azophenyl-2', 4'-disulphonic acid (100 microM), a purinergic receptor blocker and CNQX and AP5. The results from this study demonstrate that with PNN exposure, an excitatory neurotransmission to CVNs is recruited during H/H that is glutamatergic and dependent on activation of alpha3beta4-containing nAChRs. Furthermore, exposure to PNN abolishes a serotonergic long-lasting inspiratory-related excitation of CVNs that is replaced by recruitment of a glutamatergic pathway to CVNs post H/H.

Recruitment of excitatory serotonergic neurotransmission to cardiac vagal neurons in the nucleus ambiguus post hypoxia and hypercapnia.

Inhibitory GABAergic and glycinergic neurotransmission to cardioinhibitory cardiac vagal neurons (CVNs) increase during inspiratory activity and likely mediate respiratory sinus arrhythmia, while the frequency of excitatory postsynaptic currents (EPSCs) in CVNs are unaltered during the different phases of respiration. However, following hypoxia and hypercapnia (H/H), the parasympathetic activity to the heart increases and thus far, identification of the pathways and neurotransmitters that are responsible for exciting CVNs post H/H are unclear. This study identifies different excitatory pathways to CVNs recruited post H/H. Spontaneous and inspiratory-related EPSCs were recorded in CVNs before, during, and after 10 min of H/H in an in vitro slice preparation that retains rhythmic respiratory activity. Before and during H/H, EPSCs in CVNs were completely blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and d(-)-2-amino-5-phosphonopentanoic acid (AP5), selective AMPA/kainate and N-methyl-d-apartate (NMDA) receptor blockers, respectively. However, after H/H, there was a significant increase in EPSCs during each inspiratory burst. While some of the inspiratory-related EPSCs were blocked by the broad purinergic receptor antagonist pyridoxalphosphate-6-azophenyl-2', 4'-disulphonic acid (PPADS) and the specific P2X receptor antagonist 2',3'-O-(2,4,6-trinitrophenyl) adenosine 5'-triphosphate monolithium trisodium salt (TNP-ATP) a P2X receptor blocker, most of the recruited excitatory neurotransmission to CVNs is serotonergic because odansetron, a selective 5-HT3 antagonist, abolished the majority of the spontaneous and inspiratory-related EPSCs evoked during recovery from H/H. The results from this study suggest that following episodes of H/H, two nonglutamatergic excitatory pathways, purinergic and serotonergic, activating P2X and 5-HT3 receptors, respectively, are recruited to excite CVNs in the post H/H recovery period.

5-HT(2) receptor subtypes mediate different long-term changes in GABAergic activity to parasympathetic cardiac vagal neurons in the nucleus ambiguus.

Serotonin (5-HT), and in particular 5-HT(2) receptors, play an important role in cardiorespiratory function within the brainstem. In addition, abnormalities in the 5-HT system have been implicated in many cardiorespiratory disorders, including sudden infant death syndrome. However, little is known about the mechanisms of action of 5-HT(2) receptors in altering the activity of parasympathetic cardiac neurons in the brainstem. In this study we examined the effects of activation of different subtypes of 5-HT(2) receptors on spontaneous and respiratory-evoked GABAergic neurotransmission to cardioinhibitory vagal neurons within the nucleus ambiguus as well as rhythmic fictive inspiratory-related activity in rats. A single application of alpha-Me-5-hydroxytryptamine maleate (alpha-Me-5-HT), a 5-HT(2) receptor agonist, did not significantly alter the frequency of spontaneous or respiratory-evoked GABAergic inhibitory postsynaptic currents (IPSCs) in cardiac vagal neurons. However, repetitive successive applications of alpha-Me-5-HT elicited a long-lasting (>/=1 h) decrease in the frequency of spontaneous as well as inspiratory-related GABAergic IPSCs to cardiac vagal neurons. This study demonstrates multiple, but not single applications of the 5-HT(2) receptor agonist alpha-Me-5-HT caused a long-lasting inhibition of both spontaneous and fictive inspiratory-related GABAergic neurotransmission to CVNs, which can be prevented by the 5-HT(2B) receptor antagonist SB204741, but persisted with the 5-HT(2A/2C) receptor antagonist ketanserin. The 5-HT(2) receptor agonist alpha-Me-5-HT also reversibly and transiently excited central fictive inspiratory activity, which was abolished by ketanserin, but was unaffected by the 5-HT(2B) receptor antagonist SB204741.

Nicotinic receptor activation occludes purinergic control of central cardiorespiratory network responses to hypoxia/hypercapnia.

Prenatal nicotine exposure alters the cardiorespiratory network responses to hypoxia/hypercapnia; however the mechanism(s) responsible for these cardiorespiratory network responses and their alteration by prenatal nicotine exposure are unknown. We used an in vitro medullary slice that allows simultaneous examination of rhythmic respiratory-related activity and excitatory synaptic neurotransmission to cardioinhibitory vagal neurons (CVNs). Respiratory related increases in glutamatergic neurotransmission only occurred on recovery from hypoxia/hypercapnia in unexposed animals. These responses were not altered by nicotinic antagonists but were mediated in part by activation of P2 purinergic receptors. Prenatal nicotine exposure transformed central cardiorespiratory responses to hypoxia/hypercapnia; CVNs received a respiratory related glutamatergic neurotransmission during periods of hypoxia and hypercapnia, whereas increases in glutamatergic neurotransmission during recovery were absent. The excitatory neurotransmission to CVNs during hypoxia/hypercapnia in prenatal nicotine-exposed animals were wholly dependent on nicotinic receptor activation. In the presence of nicotinic antagonists, the responses in prenatal nicotine animals reverted to the pattern of responses in unexposed animals in which an increase in glutamatergic neurotransmission occurred not during but only on recovery from hypoxia/hypercapnia, and this recruited excitatory pathway was blocked by P2 receptor antagonists. These data identify a new functional role for purinergic receptors in the cardiorespiratory responses to hypoxia/hypercapnia and their role in occluding nicotinic receptor activation with prenatal nicotine exposure.

A phase I trial of cisplatin plus decitabine, a new DNA-hypomethylating agent, in patients with advanced solid tumors and a follow-up early phase II evaluation in patients with inoperable non-small cell lung cancer.

The authors describe a phase I trial of cisplatin plus decitabine, a novel DNA-hypomethylating agent, in patients with advanced solid tumors, which was followed by an early phase II evaluation of the combination in patients with inoperable non-small cell lung cancer (NSCLC). In the phase I trial, cisplatin was studied at a fixed dose of 33 mg/m2, while decitabine was escalated in four (I-IV) dose escalation levels (45, 67, 90 to 120 mg/m2, respectively) in consecutive groups of at least 3 patients per dose level. Decytabine was administered to the patients as a two-hour intravenous infusion, while cisplatin was given intravenously immediately after the end of decitabine infusion. Both agents were given on days 1-3 every 21 days. Twenty-one patients were included in the phase I trial. Dose level IV (120 mg/m2 decitabine) was considered the maximum tolerated dose (MTD), while the dose-limiting toxicities were neutropenia, thrombocytopenia and mucositis. The recommended doses for phase II trials in good- and poor-risk patients were 90 (level III) and 67 mg/m2 (level II), respectively. One short-lasting partial response was observed in a patient with cervical cancer, while two minor regression were documented in a patients with NSCLC and cervical cancer, respectively. Dose level II was selected for the phase II trial in patients with inoperable NSCLC. Fourteen consecutive patients were included in this part of the study. The median age of the patients was 57 years (range, 39-75), male/female ratio of 11/3 and a median WHO performance status 1 (0-2). The stage of disease were IIIB (5) and IV (9). Prior irradiation to the chest was given in one case. A total of 30 treatment courses were evaluable for toxicity and response, with a median of 2 courses per patient (1-4). Grade 3-4 neutropenia and thrombocytopenia were observed in about half of the cases. Mucositis, diarrhea, nausea and vomiting, and skin rash were also observed in some patients. Three minor responses were documented, which lasted for 4, 16 and 36 weeks. Median survival of patients was 15 weeks (4-38). In conclusion, the cisplatin plus decitabine combination did not exhibit significant antitumor activity in patients with NSCLC at the dose and schedule applied in this trial to justify its further evaluation in this patient population.

A phase II study of recombinant interleukin-2 (IL-2) plus interferon-alfa-2A (IFN-ALFA) given subcutaneously in patients with metastatic malignant melanoma (MMM)

O objetivo deste estudo foi avaliar o perfil de toxicidade, índices de respostas objetivas e sobrevida de pacientes portadores de melanoma maligno metastático tratados com a combinação de Interleucina-2 (IL-2)e Interferon-alfa (IFN-alfa) administrados por via subcutânea (SC). Vinte e cinco pacientes com diagnóstico histopatológico de melanoma maligno metastático e doença mensurável foram tratados com IL-2 na dose de 18 milhões de unidades/m2 e IFN-alfa na dose de 3 milhões de unidades/m2 por via SC diariamente nos dias 1-5 e 8-12 de ciclos com 21 dias. Os pacientes foram todos avaliáveis quanto a toxicidade de acordo com o Common Toxicity Criteria do Instituto Nacional do Câncer dos EUA (CTC-NCI), enquanto que as respostas foram codificadas segundo os critérios da OMS. Os pacientes não haviam recebido tratamento químico, rádio ou imunoterápico prévio. Uma mediana de 3 (2-4) ciclos foram administrados. A toxicidade consistiu sobretudo de fadiga, artralgia, mialgias, febre e calafrios e retenção líquida. Não foram observadas toxicidades com risco severo de óbito. Quatro dos 25 pacientes (17 por cento) apresentaram respostas objetivas. Em 2 destes casos foi possível a ressecção completa de massas residuais pós-tratamento imunoterápico, com remissões mantidas por 6 e 24+ meses, respectivamente. Nos outros 2 casos com resposta parcial, progressão clínica foi observada após 7 e 8 meses, respectivamente. Os pacientes que não responderam inicialmente ou apresentaram progressão posterior foram ao óbito após um seguimento mediano de 3 (1-7) meses. Em conclusão, a combinação de IL-2 e IFN-alfa por via SC produziu respostas limitadas em pacientes com melanoma maligno metastático. Ainda que a toxicidade tenha sido manejável, os resultados acima descritos não recomendam esta abordagem para uso clínico de rotina.

Pneumonia por Mycoplasma pneumoniae: relato de um caso com insuficiencia respiratoria aguda. / Mycoplasma pneumoniae infection associated with acute pulmonary insufficiency. Report of a case

Um homem de 29 anos de idade, previamente higido, apresentou severa pneumonia com insufuciencia respiratoria aguda. Estudos sorologicos indicaram infeccao por Mycoplasma pneumoniae. O tratamento com doxiciclina foi bem sucedido