High-Order Phase-Dependent Asymmetry in the Above-Threshold Ionization Plateau.

Above-threshold ionization spectra from cesium are measured as a function of the carrier-envelope phase (CEP) using laser pulses centered at 3.1 µm wavelength. The directional asymmetry in the energy spectra of backscattered electrons oscillates three times, rather than once, as the CEP is changed from 0 to 2π. Using the improved strong-field approximation, we show that the unusual behavior arises from the interference of few quantum orbits. We discuss the conditions for observing the high-order CEP dependence, and draw an analogy with time-domain holography with electron wave packets.

Quantum Optical Signatures in a Strong Laser Pulse after Interaction with Semiconductors.

Electrodynamical processes induced in complex systems like semiconductors by strong electromagnetic fields have traditionally been described using semiclassical approaches. Although these approaches allowed the investigation of ultrafast dynamics in solids culminating in multipetahertz electronics, they do not provide any access to the quantum-optical nature of the interaction, as they treat the driving field classically and unaffected by the interaction. Here, using a full quantum-optical approach, we demonstrate that the subcycle electronic response in a strongly driven semiconductor crystal is imprinted in the quantum state of the driving field resulting in nonclassical light states carrying the information of the interaction. This vital step towards strong-field ultrafast quantum electrodynamics unravels information inaccessible by conventional approaches and leads to the development of a new class of nonclassical light sources.

Organ-specific model of simulated ischemia/reperfusion and hyperglycemia based on engineered heart tissue.

Here we aimed to establish an in vitro engineered heart tissue (EHT) co-morbidity mimicking model of ischemia-reperfusion injury and diabetes. EHTs were generated from primary neonatal rat cardiomyocytes. Hyperglycemic conditions or hyperosmolar controls were applied for one day to model acute hyperglycemia and for seven days to model chronic hyperglycemia. 120 min' simulated ischemia (SI) was followed by 120 min' reperfusion (R) and 1-day follow-up reperfusion (FR). Normoxic controls (N) were not subjected to SI/R. Half of the EHTs was paced, the other half was left unpaced. To assess cell injury, lactate-dehydrogenase (LDH) concentration was measured. Beating force and activity (frequency) were monitored as cardiomyocyte functional parameters. LDH-release indicated relevant cell injury after SI/N in each experimental condition, with much higher effects in the chronically hyperglycemic/hyperosmolar groups. SI stopped beating of EHTs in each condition, which returned during reperfusion, with weaker recovery in chronic conditions than in acute conditions. Acutely treated EHTs showed small LDH-release and âˆ¼80% recovery of force during reperfusion and follow-up, while chronically treated EHTs showed a marked LDH-release, only ∼30% recovery with reperfusion and complete loss of beating activity during 24 h follow-up reperfusion. We conclude that EHTs respond differently to SI/R injury in acute and chronic hyperglycemia/hyperosmolarity, and that our EHT model is a novel in vitro combination of diabetes and ischemia-reperfusion.

Differentiating sepsis from similar groups of symptoms at triage level in emergency care.

OBJECTIVES: Conditions that have similar initial presentations as sepsis may make early recognition of sepsis in an emergency room (ER) difficult. We investigated whether selected physiologic and metabolic parameters can be reliably used in the emergency department to differentiate sepsis from other disease states that mimic it, such as dehydration and stroke. METHODS: Loess regression on retrospective follow-up chart data of patients with sepsis-like symptoms (N = 664) aged 18+ in a large ER in Hungary was used to visualize/identify cutoff points for sepsis risk. A multivariate logistic regression model based on standard triage data was constructed with its corresponding receiver operating characteristic (ROC) curve and compared with another model constructed based on current sepsis guidelines. RESULTS: Age, bicarbonate, HR, lactate, pH, and body temperature had U, V, W, or reverse U-shaped associations with identifiable inflexion points, but the cutoff values we identified were slightly different from guideline cutoff values. In contrast to the guidelines, no inflexion points could be observed for the association of sepsis with SBP, DPB, MAP, and RR and therefore were treated as continuous variables. Compared to the guidelines-based model, the triage data-driven final model contained additional variables (age, pH, bicarbonate) and did not include lactate. The data-driven model identified about 85% of sepsis cases correctly, while the guidelines-based model identified only about 70% of sepsis cases correctly. CONCLUSION: Our findings contribute to the growing body of evidence for the necessity of finding improved tools to identify sepsis at early time points, such as in the ER.

Systematic analysis of different pluripotent stem cell-derived cardiac myocytes as potential testing model for cardiocytoprotection.

INTRODUCTION: Stem cell-derived cardiac myocytes are potential sources for testing cardiocytoprotective molecules against ischemia/reperfusion injury in vitro. MATERIALS AND METHODS: Here we performed a systematic analysis of two different induced pluripotent stem cell lines (iPSC 3.4 and 4.1) and an embryonic stem cell (ESC) line-derived cardiac myocytes at two different developmental stages. Cell viability in simulated ischemia/reperfusion (SI/R)-induced injury and a known cardiocytoprotective NO-donor, S-nitroso-n-acetylpenicillamine (SNAP) was tested. RESULTS: After analysis of full embryoid bodies (EBs) and cardiac marker (VCAM and cardiac troponin I) positive cells of three lines at 6 conditions (32 different conditions altogether), we found significant SI/R injury-induced cell death in both full EBs and VCAM+ cardiac cells at later stage of their differentiation. Moreover, full EBs of the iPS 4.1 cell line after oxidative stress induction by SNAP was protected at day-8 samples. CONCLUSION: We have shown that 4.1 iPS-derived cardiomyocyte line could serve as a testing platform for cardiocytoprotection.

Fecal expression of Escherichia coli lysine decarboxylase (LdcC) is downregulated in E-cadherin negative lobular breast carcinoma.

Breast cancer is characterized by oncobiosis, the abnormal composition of the microbiome in neoplastic diseases. The biosynthetic capacity of the oncobiotic flora in breast cancer is suppressed, as suggested by metagenomic studies. The microbiome synthesizes a set of cytostatic and antimetastatic metabolites that are downregulated in breast cancer, including cadaverine, a microbiome metabolite with cytostatic properties. We set out to assess how the protein expression of constitutive lysine decarboxylase (LdcC), a key enzyme for cadaverine production, changes in the feces of human breast cancer patients (n = 35). We found that the fecal expression of Escherichia coli LdcC is downregulated in lobular cases as compared to invasive carcinoma of no special type (NST) cases. Lobular breast carcinoma is characterized by low or absent expression of E-cadherin. Fecal E. coli LdcC protein expression is downregulated in E-cadherin negative breast cancer cases as compared to positive ones. Receiver operating characteristic (ROC) analysis of LdcC expression in lobular and NST cases revealed that fecal E. coli LdcC protein expression might have predictive values. These data suggest that the oncobiotic transformation of the microbiome indeed leads to the downregulation of the production of cytostatic and antimetastatic metabolites. In E-cadherin negative lobular carcinoma that has a higher potential for metastasis formation, the protein levels of enzymes producing antimetastatic metabolites are downregulated. This finding represents a new route that renders lobular cases permissive for metastasis formation. Furthermore, our findings underline the role of oncobiosis in regulating metastasis formation in breast cancer.

Application of water framework directive in Hungary: development of biological classification systems.

The classification according to the Water Framework Directive (WFD) includes numerous challenges in contrast with the previously applied water qualification standards. The most important element of the ecological status, the biological one, is based on five groups of living organisms: phytoplankton, phytobenthon, macrophytes, macro-invertebrates and fish. The results of a three-year research project financed by the Ministry of Environment and Water (MoEW) and the Hungarian Academy of Sciences (HAS) are reported in this work. The objective of the project was the elaboration of a proposal for biological classification according to the WFD for the related groups of living organisms. In the course of the project the biological characteristics to be measured were selected for each of the above listed groups which served as the basic data for Biological Quality Elements (BQEs). In the BQEs we estimated the type-specific reference values for most of the Hungarian surface water types. Then we created the structure of the qualification system for these groups, including specification of class boundaries between the five classes for the Environmental Quality Ratio (EQR) values on the basis of expert estimation. A Non-Taxonomic Periphyton Index (NTPI, not included in the WFD) was also developed and tested for qualification. The elaborated classification systems were tested on the basis of existing scarce data for numerous Hungarian water types.

Effect of trabeculectomy on ocular blood flow.

BACKGROUND/AIM: Current evidence suggests that vascular insufficiencies in the optic nerve head play an important part in the pathogenesis of glaucomatous optic neuropathy. Trabeculectomy is the most common operative procedure for the treatment of medically uncontrolled glaucoma. This study was conducted to investigate whether trabeculectomy may improve ocular haemodynamics. METHODS: 30 patients with primary open angle glaucoma about to undergo trabeculectomy were included in the study. Patients were evaluated before surgery and at 2 and 10 weeks after trabeculectomy. Optic nerve head blood flow (OnhBF) was assessed with scanning laser Doppler flowmetry. Fundus pulsation amplitude (FPA) measurements were obtained with laser interferometry. RESULTS: Because of the decrease in intraocular pressure there was a significant increase in ocular perfusion pressure (OPP) following trabeculectomy (18.5% (SD 12.0%) and 19.0% (17.1%) at 2 and 10 weeks postoperatively; p <0.001). A significant increase in OnhBF was observed after trabeculectomy (11.6% (16.4%) and 16.2% (20.2%) for each postoperative visit, respectively; p <0.001). FPA was also significantly higher compared with baseline values (17.2% (17.3%) and 17.4% (16.3%), respectively; p <0.001). A significant association between the increase in OPP and the increase in OnhBF and FPA was observed 10 weeks after surgery (r = 0.47; p = 0.009, and r = 0.50; p = 0.005, respectively). CONCLUSION: The results of this study suggest that trabeculectomy improves ocular blood flow in patients with chronic open angle glaucoma.

Short-term effect of stress on tyrosine hydroxylase activity.

The short-term influences of stress on the activities of tyrosine hydroxylase in vivo and in vitro were examined in mice. The in vivo tyrosine hydroxylase activity was estimated by the rate of dopa accumulation which was measured at 30 min after the injection of NSD-1015 (100 mg kg), an aromatic l-amino acid decarboxylase inhibitor, intraperitoneally and was compared with tyrosine hydroxylase activity measured in vitro. For the in vivo assay, both the accumulation of dopa (tyrosine hydroxylase activity) and that of 5-hydroxytryptophan (tryptophan hydroxylase activity) and the levels of monoamines and the metabolites (noradrenalin, adrenalin, dopamine, normetanephrine, 3-methoxytyramine and serotonin) and those of precursor amino acids, tyrosine and tryptophan, were investigated in ten different brain regions and in adrenals. The amount of dopa accumulation in the brain as a consequence of decarboxylase inhibition, in vivo tyrosine hydroxylase activity, was significantly increased by stress, in nerve terminals (striatum, limbic brain, hypothalamus, cerebral cortex and cerebellum) and also in adrenals. The effect of stress on tyrosine hydroxylase activity in vitro at a subsaturating concentration of 6-methyltetrahydropterin cofactor was also observed in nerve terminals (striatum, limbic brain, hypothalamus, and cerebral cortex). The amount of 5-hydroxytryptophan accumulation, the in vivo tryptophan hydroxylase activity, was also significantly increased in bulbus olfactorius, limbic brain, cerebral cortex, septum and lower brain stem. The influence of stress was also observed on the levels of precursor amino acids, tyrosine and tryptophan and monoamines in specific brain parts. These results suggest that the stress influences both catecholaminergic neurons and serotonergic neurons in nerve terminals in the brain. This effect was also observed on tyrosine hydroxylase activity in vitro in nerve terminals. However, in adrenals, the influence by stress was not observed on the in vitro activity, although dopa accumulation was increased.

Effect of salbutamol on the cerebral levels, uptake and turnover of serotonin.

The effect of salbutamol (SB) on the cerebral levels of serotonin (5-HT) and 5-hydroxyindolacetic acid (5-HIAA) was determined as well as the effect on the uptake and turnover of 5-HT in rat brain. SB failed to inhibit the cerebral uptake of 5-HT and did not change 5-HT and 5-HIAA levels in the brain; however, it significantly increased the cerebral turnover of 5-HT. The latter effect may partly be responsible for the antidepressant properties of the compounds.

Vinpocetine preferentially antagonizes quisqualate/AMPA receptor responses: evidence from release and ligand binding studies.

The effect of vinpocetine on excitatory amino acid receptors was examined in the rat brain by two different biochemical approaches. In release experiments with striatal slices, vinpocetine reduced the efflux of dopamine and acetylcholine evoked by glutamate, quisqualate and N-methyl-D-aspartate (NMDA), but not that evoked by kainate. In binding experiments with cortical membranes, vinpocetine reduced the binding of [3H]2-amino-3-3-hydroxy-s-methylisoxasole-4-yl-propionic acid ([3H]AMPA), a quisqualate partial agonist, in an incomplete manner, but failed to influence the binding of [3H]kainate and [3H]3-(2-carboxypyperazine-4-yl)-propyl-1-phosphonic acid ([3H]CPP), an NMDA agonist. These findings suggest that vinpocetine is a quisqualate/AMPA antagonist of some specificity and selectivity.

Stimulus-evoked efflux of GABA from preloaded slices of the rabbit oviduct.

The effect of electrical and chemical stimulation on the efflux of [3H]gamma-aminobutyric acid (GABA) from preloaded slices of the rabbit oviduct was examined. Electrical field stimulation significantly increased the outflow of [3H]GABA. This effect could not be prevented by tetrodotoxin or by the removal of Ca2+ from the medium. High K+ concentrations, veratrine and ethylenediamine also evoked a remarkable elevation in the efflux. The release induced by veratrine was completely abolished in a Ca2+-free medium or in the presence of tetrodotoxin, while the release evoked by high K+ or ethylenediamine was resistant to both conditions. These findings indicate that GABA can be released from the oviduct under the effect of depolarizing stimuli, raising the possibility of a physiological interaction between oviductual GABA and its receptors. The characteristics of oviductal GABA efflux differ from those of neuronal and glial GABA release.

Vinpocetin protects against excitotoxic cell death in primary cultures of rat cerebral cortex.

The protective effect of vinpocetin, a drug clinically useful in brain hypoxia/ischemia, was examined in vitro on cerebrocortical cultures treated with glutamate and related excitotoxins. The extent of cell death was quantified by measuring lactic dehydrogenase activity released from damaged cells into the culture medium. Vinpocetin partially protected the cortical cells against cell death induced by N-methyl-D-aspartate, quisqualate and kainate, indicating that the drug exerts a direct protective action on cerebrocortical cells bearing excitatory amino acid receptors.

Effects of peribulbar anesthesia on ocular blood flow in patients undergoing cataract surgery.

PURPOSE: The effects of extraconal, peribulbar anesthesia on ocular blood flow may be caused by concomitant elevations in intraocular pressure or direct pharmacologic alteration of vascular tone. We quantified the effect on ocular circulation with a new technique for assessment of ocular hemodynamics. METHODS: In a prospective study, ocular hemodynamics were measured before and 1 and 5 minutes after peribulbar anesthesia in 22 eyes with age-related cataract. Measurements included fundus pulsation amplitude with a laser interferometric method assessing the pulsatile choroidal blood flow and mean blood flow velocity as well as resistive index in the ophthalmic and central retinal artery with Doppler sonography. Systemic blood pressure and pulse were monitored throughout the period of ocular hemodynamic measurements. RESULTS: Fundus pulsation amplitude decreased significantly after peribulbar anesthesia (after 1 minute and 5 minutes: -13% and -8%; P < .001). In the central retinal artery, mean blood flow velocity dropped (-15%; P < .001) and resistive index increased (+3%; P = .02) 1 minute after peribulbar anesthesia compared with baseline. There were no changes in ophthalmic artery hemodynamics. Intraocular pressure was elevated 1 minute after peribulbar anesthesia (+29%; P = .003) but reached baseline values after 5 minutes. CONCLUSION: Pulsatile choroidal blood flow and retinal blood flow velocities were reduced after peribulbar anesthesia. These reductions were still present 5 minutes after peribulbar anesthesia, when intraocular pressure had returned to baseline values. This supports the theory of drug-induced vasoconstriction after peribulbar anesthesia. A loss of vision may be a risk of peribulbar anesthesia in patients who have compromised ocular blood flow before surgery.

Assessment of optic disk blood flow in patients with open-angle glaucoma.

PURPOSE: To characterize optic disk blood flow in patients with open-angle glaucoma compared with age-matched healthy control subjects. METHODS: In this prospective cross-sectional study, 90 eyes of 90 patients with open-angle glaucoma and 61 eyes of 61 age-matched healthy control subjects were evaluated. Flow in the optic disk cup and the neuroretinal rim were assessed with scanning laser Doppler flowmetry. Fundus pulsation amplitude in the cup and the macula were assessed with laser interferometry. Visual field mean deviation was measured with the Humphrey 30 to 2 program. RESULTS: Flow in the neuroretinal rim (-18%, P =.002), and in the cup (-46%, P <.001) and fundus pulsation amplitude in the cup (-33%, P <.001) and in the macula (-24%, P <.001) were significantly lower in patients with open-angle glaucoma compared with healthy control subjects. A significant association between blood flow measurements in the cup and fundus pulsation amplitudes in the cup was observed in both study cohorts. A significant association was also observed between the mean defect from visual field testing and ocular hemodynamic parameters. CONCLUSIONS: Reduced optic disk perfusion in patients with open-angle glaucoma is evidenced from two independent methods in the present study. Moreover, our data indicate that reduced ocular blood flow in these patients is linked to visual field changes. It remains to be established whether compromised optic disk and choroidal blood flow contributes to optic disk damage in glaucomatous eyes or is a secondary functional phenomenon.

Ocular blood flow in patients infected with human immunodeficiency virus.

PURPOSE: Alterations of ocular blood flow may play a role in the pathophysiology of human immunodeficiency virus (HIV) related retinal microvasculopathy. In this study ocular blood flow was investigated in patients with HIV infection. DESIGN: In a prospective, cross-sectional study ocular blood flow was measured in 37 eyes of consecutive HIV- infected persons and compared with the data of age-matched healthy controls. This sample size was calculated based on an alpha-error of 0.5 and a beta-error of 0.8. METHODS: Macular white blood cell flow, fundus pulsation amplitude, and blood flow velocities in the retrobulbar vessels were measured with blue field entoptic technique, laser interferometry, and Doppler sonography, respectively. Immunologic and ophthalmologic status was evaluated from each patient. RESULTS: Mean CD4+ cell count of the HIV-infected persons was 206.8 +/- 145.6 cells/mm(3). In five patients HIV-related retinopathy was observed. A significant reduction in leukocyte density was seen in HIV infected persons (82.2 +/- 23.4) as compared with the control group (102.0 +/- 28.4; P =.019). The resistive index in the central retinal artery was higher in HIV infected patients (0.77 +/- 0.05) as compared with the controls (0.74 +/- 0.04; P =.04). The other hemodynamic parameters were not different between groups. No correlation of flow parameters and CD4+ cell count or HIV-related retinopathy was observed. CONCLUSIONS: Decreased macular leukocyte density was detected in HIV infected persons. Our study suggests that abnormal retinal hemodynamics in individuals infected with HIV may be involved in the pathogenesis of HIV-related microvasculopathy.

Effect of RGH-2716 on learning and memory deficits of young and aged rats in water-labyrinth.

RGH-2716 is a novel 1-oxa-3,8-diazaspiro[4.5] decan 2-one, which was published to have potent inhibitory effect on neuronal Na and Ca movement and stimulatory action on nerve growth factor (NGF)-production, as well as to show significant antiamnesic activity in experimental amnesia models. The aim of the present experiments was to study the effect of the compound on the learning process and on the different stages of memory using water-labyrinth in normal and memory impaired young animals, as well as to study cognitive effect of RGH-2716 on aged animals. At the doses of 0.5 mg/kg i.p. or 3 mg/kg p.o. given before daily swimming, this compound improved the learning process of young animals impaired by either diazepam (DIA) or scopolamine (SCOP). In retrograde amnesia model RGH-2716 (3 mg/kg p.o.) significantly ameliorated consolidation process and retrieval of information impaired by SCOP or DIA. Nimodipine and vinpocetine (10 mg/kg p.o.) showed moderate effect compared to RGH-2716. Aged rats pretreated with daily i.p. RGH-2716 performed the tasks with significantly fewer errors and shorter swimming time than untreated aged rats. When aged animals had to solve a new labyrinth problem, treated aged rats showed significantly better learning ability than aged controls. One month of oral treatment of aged rats with 3 mg/kg dose of RGH-2716 two times daily resulted in a "tendency-like" improvement in learning of aged Fischer 344 and spontaneously hypertensive (SH) rats. The present results make RGH-2716 an interesting compound for the treatment of cognitive disorders.

Inhibitory effect of hypoxic condition on acetylcholine release is partly due to the effect of adenosine released from the tissue.

Isolated longitudinal muscle strip with Auerbach's plexus attached was used to study the stimulation-evoked release of 3H-acetylcholine (3H-ACh) under normoxic and hypoxic conditions. Hypoxia reduced the release of ACh. Theophylline, a purinoceptor P1 antagonist and vinpocetine, an antiischemic compound partly reversed the effect of hypoxia. Unlike theophylline, the effect of vinpocetine was not mediated via adenosine action, since it failed to affect the presynaptic action of adenosine, and the effect of theophylline and vinpocetine was additive. When they were added together the effect of hypoxia was almost completely antagonized. Dipyridamole, an adenosine uptake inhibitor, potentiated the effect of hypoxia and the presynaptic inhibitory action of adenosine on ACh release. Evidence was obtained that the effect of hypoxia is at least partly due to adenosine formed from purine nucleotides.

Role of sodium channel inhibition in neuroprotection: effect of vinpocetine.

Vinpocetine (ethyl apovincaminate) discovered during the late 1960s has successfully been used in the treatment of central nervous system disorders of cerebrovascular origin for decades. The increase in the regional cerebral blood flow in response to vinpocetine administration is well established and strengthened by new diagnostical techniques (transcranial Doppler, near infrared spectroscopy, positron emission tomography). The latest in vitro studies have revealed the effect of the compound on Ca(2+)/calmodulin dependent cyclic guanosine monophosphate-phosphodiesterase 1, voltage-operated Ca(2+) channels, glutamate receptors and voltage dependent Na(+)-channels; the latest being especially relevant to the neuroprotective action of vinpocetine. The good brain penetration profile and heterogenous brain distribution pattern (mainly in the thalamus, basal ganglia and visual cortex) of labelled vinpocetin were demonstrated by positron emission tomography in primates and man. Multicentric, randomized, placebo-controlled clinical studies proved the efficacy of orally administered vinpocetin in patients with organic psychosyndrome. Recently positron emission tomography studies have proved that vinpocetine is able to redistribute regional cerebral blood flow and enhance glucose supply of brain tissue in ischemic post-stroke patients.

Intraocular pressure rise after small incision cataract surgery: a randomised intraindividual comparison of two dispersive viscoelastic agents.

AIM: To evaluate the effects of the dispersive viscoelastic agents Ocucoat (hydroxypropyl methylcellulose 2%) and Viscoat (sodium chondroitin sulphate 4%-sodium hyaluronate 3%) on postoperative intraocular pressure (IOP) after bilateral small incision cataract surgery. METHODS: This prospective, randomised study comprised 80 eyes of 40 consecutive patients with age related cataract in both eyes scheduled for bilateral small incision cataract surgery. The patients were randomly assigned to receive Ocucoat or Viscoat during cataract surgery of the first eye. The second eye was operated later and received the other viscoelastic agent. Cataract surgery was performed with a temporal 3.2 mm sutureless posterior limbal incision, phacoemulsification, and implantation of a foldable silicone intraocular lens. The IOP was measured preoperatively as well as 6 hours, 20-24 hours, and 1 week postoperatively. RESULTS: At 6 hours after surgery the mean IOP increased by 4.6 (SD 5.1) mm Hg in the Ocucoat group (p<0.001) and by 8.6 (8.1) mm Hg in the Viscoat group (p<0.001). The increase was significantly higher in the Viscoat group than in the Ocucoat group (p=0.004). Intraocular pressure spikes of 30 mm Hg or more occurred in two eyes in the Ocucoat and in nine eyes in the Viscoat group (p=0.023); 20-24 hours and 1 week postoperatively the mean IOP was not statistically different. CONCLUSION: These findings indicate that Viscoat causes a significantly higher IOP increase and significantly more IOP spikes than Ocucoat in the early period after small incision cataract surgery.