Instability of Insulators near Quantum Phase Transitions.

Thin films of amorphous indium oxide undergo a magnetic field driven superconducting to insulator quantum phase transition. In the insulating phase, the current-voltage characteristics show large current discontinuities due to overheating of electrons. We show that the onset voltage for the discontinuities vanishes as we approach the quantum critical point. As a result, the insulating phase becomes unstable with respect to any applied voltage making it, at least experimentally, immeasurable. We emphasize that unlike previous reports of the absence of linear response near quantum phase transitions, in our system, the departure from equilibrium is discontinuous. Because the conditions for these discontinuities are satisfied in most insulators at low temperatures, and due to the decay of all characteristic energy scales near quantum phase transitions, we believe that this instability is general and should occur in various systems while approaching their quantum critical point. Accounting for this instability is crucial for determining the critical behavior of systems near the transition.

Nonequilibrium Second-Order Phase Transition in a Cooper-Pair Insulator.

In certain disordered superconductors, upon increasing the magnetic field, superconductivity terminates with a direct transition into an insulating phase. This phase is comprised of localized Cooper pairs and is termed a Cooper-pair insulator. The current-voltage characteristics measured in this insulating phase are highly nonlinear and, at low temperatures, exhibit abrupt current jumps. Increasing the temperature diminishes the jumps until the current-voltage characteristics become continuous. We show that a direct correspondence exists between our system and systems that undergo an equilibrium, second-order, phase transition. We illustrate this correspondence by comparing our results to the van der Waals equation of state for the liquid-gas mixture. We use the similarities to identify a critical point where an out of equilibrium second-order-like phase transition occurs in our system. Approaching the critical point, we find a power-law behavior with critical exponents that characterizes the transition.

Evidence for a Finite-Temperature Insulator.

In superconductors the zero-resistance current-flow is protected from dissipation at finite temperatures (T) by virtue of the short-circuit condition maintained by the electrons that remain in the condensed state. The recently suggested finite-T insulator and the "superinsulating" phase are different because any residual mechanism of conduction will eventually become dominant as the finite-T insulator sets-in. If the residual conduction is small it may be possible to observe the transition to these intriguing states. We show that the conductivity of the high magnetic-field insulator terminating superconductivity in amorphous indium-oxide exhibits an abrupt drop, and seem to approach a zero conductance at T < 0.04 K. We discuss our results in the light of theories that lead to a finite-T insulator.

Little-Parks oscillations in an insulator.

We present the results of a magnetoresistance study of the disorder-induced superconductor-insulator transition in an amorphous indium-oxide thin film patterned by a nanoscale periodic array of holes. We observed Little-Parks-like oscillations over our entire range of disorder spanning the transition. The period of oscillations was unchanged and corresponded to the superconducting flux quantum in the superconducting as well as in the insulating phases. Our results provide direct evidence for electron pairing in the insulator bordering with superconductivity.

Electron-phonon decoupling in disordered insulators.

The current-voltage characteristics measured in the insulating state terminating the superconducting phase in disordered superconductors exhibit sharp threshold voltages, where the current abruptly changes by as much as 5 orders of magnitude. We analyze the current-voltage characteristics of an amorphous indium oxide film in the field-tuned insulating state, and show that they are consistent with a bistability of the electron temperature, and with a significant overheating of the electron system above the lattice temperature. An analysis of these current jumps indicates that, in the insulating state, the electrons are thermally decoupled from the phonon bath.

Ventricular preexcitation sensitive to flecainide in late stage chick embryo ECGs: 2,3,7,8-tetrachlorodibenzo-p-dioxin impairs inotropic but not chronotropic or dromotropic responses to isoproterenol and confers resistance to flecainide.

ECGs free of movement artefacts were obtained without anesthesia in 16- to 18-day-old chick embryos close to hatching and used to study the effect of the environmental toxin 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) on cardiac rhythm and conduction. The ECGs of normal late stage chick embryos exhibited short PR intervals, frequent nonisoelectric PR segments, delta waves, and inverted T waves. Those ECG characteristics are found in patients with the Wolff-Parkinson-White syndrome (WPW) in which they reflect ventricular preexcitation associated with the use of accessory conduction pathways and arrhythmias. Isoproterenol (30 microg/egg) did not alter the ECG preexcitation characteristics. Flecainide, a sodium channel blocker used clinically to suppress WPW accessory pathway activity, at 0.5 to 5 mg per egg diminished the preexcitation and caused atrioventricular (AV) block, supporting the use of accessory pathways together with AV-nodal conduction in normal late stage chick embryos. The findings challenge the dogma that accessory pathways are entirely replaced by AV conduction pathways in late fetal development. TCDD, at 1-2 nmol per egg for 48 h, did not affect heart rate, the increase in heart rate by isoproterenol, or the ECG characteristics, suggesting that short-term TCDD treatment did not affect sinus node function or cardiac conduction. The latter results taken together with prior findings indicate that TCDD differentially impairs the inotropic and lusitropic effects but not the chronotropic or dromotropic effects of isoproterenol. In TCDD-treated embryos, flecainide, tested at 5 mg per egg, caused much less inhibition of preexcitation or production of AV block than in the untreated or solvent-treated controls. The resistance to flecainide represents a new TCDD effect consistent with the reported increase of cardiac myocyte [Ca(2+)](i) by TCDD treatment.

Covalent surface chemical modification of electrodes for cardiac pacing applications.

We report the covalent surface modification of active-fixation pacemaker electrodes with butanethiol or dodecanethiol self-assembled monolayers (SAMs) using a platinum or gold metal-thiolate bond (i.e., changing the chemical identity of the exposed metal electrode from metal to organic) in such fashion that (a) the surface is organic in functionality with lipophilic physicochemical characteristics, (b) a possible degradation product is gold (I)-alkanethiolate with putative anti-inflammatory actions, and (c) current density/electric field strength is increased. Superior acute and chronic pacing performance with dodecanethiol-modified, gold-coated, platinum-iridium alloy pacemaker electrodes was observed with inferential evidence of reduced inflammation and scar. This approach may have applicability in other areas of bioelectrodes with practical applications in clinical cardiology, surgery, neuroscience, and subcutaneous sensors.

In vivo potentiostatic studies at the electrode tissue interface: filter properties of the monophasic action potential (Ag/AgCl) electrode in living rat heart.

The monophasic action potential (Franz) catheter is regarded as the criterion standard for high fidelity recording of a class of physiological signals. However, its signal modulation characteristics have never been reported. Broadband impedance spectroscopy was performed in perfused living rat heart in a three-electrode potentiostatic configuration to determine the filtering characteristics of the MAP and model Ag/AgCl electrode-tissue interfaces. The filter transfer function H(f) (attenuation [dB] vs log(f) [log(Hz)]) was derived for the frequency range 10 Hz-10(6) Hz. As a filter, the MAP interface is characterized by two ranges of filtering behavior. At high frequency the MAP interface is a high-pass filter with passband frequency 54 kHz-549 kHz (median 321 kHz) and with -3 dB cutoff points ranging from 10 kHz to 302 kHz. In this high frequency range the transfer function is characterized by decreasing attenuation per decade. However, in the lower frequency range relevant to physiological signals (the monophasic action potential, 0.1-40 Hz), it is a severely attenuating nondiodic high-pass filter element with an average attenuation of 16.87 dB relative to passband. In this physiological range, rolloff is nonlinear with increasing attenuation per decade. While the MAP electrode and model Ag/AgCl electrodes are high-pass filters with robust transfer functions for high frequency signals in the living heart, the attenuation of signals in a frequency range relevant to in vivo physiological recording imparts extreme attenuation that may distort physiological signals unpredictably. This disadvantage may be mitigated by amplitude scaling to a calibrated pure tone signal within the physiological frequency band to recover a reproducible signal.

Transvenous pacemaker insertion ipsilateral to chronic subclavian vein obstruction: an operative technique for children and adults.

Subclavian vein occlusion limits insertion of pacing electrodes in children and adults. The concern is greatest in children with a long-term need for pacing systems necessitating use of the contralateral vein and potential bilateral loss of access in the future. We describe an operative technique to provide ipsilateral access in chronic subclavian vein occlusion in five consecutive pediatric (n = 4, mean age 6.5 years) and adult (n = 1, age 70 with bilateral subclavian vein occlusion) patients in whom this condition was noted at the time of pacemaker or ICD implant. Occlusion was documented by venography. Pediatric cardiac diagnoses included complete heart block in all patients, tetralogy of Fallot in three, and L-transposition of the great vessels in one. Percutaneous brachiocephalic (innominate) or deep subclavian venous access was achieved by a supraclavicular approach using an 18-gauge Deseret angiocath, a Terumo Glidewire, and dilation to permit one or two 9-11 Fr sheaths. Electrode(s) were positioned in the heart and tunneled (pre- or retroclavicularly) to a pre- or retropectoral pocket. Pacemaker and ICD implants were successful in all without any complication of pneumothorax, arterial or nerve injury, or need for transfusion. Inadvertent arterial access did not occur as compared with prior infraclavicular attempts. One preclavicularly tunneled electrode dislodged with extreme exertion and was revised. Ipsilateral transvenous access for pacemaker or ICD is possible via a deep supraclavicular percutaneous approach when the subclavian venous obstruction is discovered at the time of implant. In children, it avoids the use of the contralateral vein that may be needed for future pacing systems in adulthood. This venous approach provides access large enough to allow even dual chamber pacing in children and can be accomplished safely.

Inhibition of local hemorrhage and dermonecrosis induced by Bothrops asper snake venom: effectiveness of early in situ administration of the peptidomimetic metalloproteinase inhibitor batimastat and the chelating agent CaNa2EDTA.

The effectiveness of the chelating agent CaNa2EDTA and the peptidomimetic matrix metalloproteinase inhibitor batimastat (BB-94) to inhibit local tissue damage induced by Bothrops asper snake venom was studied in mice. Both compounds totally inhibited proteolytic, hemorrhagic, and dermonecrotic effects, and partially reduced edema-forming activity, when incubated with venom prior to injection. Much lower concentrations of batimastat than of CaNa2EDTA were required to inhibit these effects. In addition, batimastat, but not CaNa2EDTA, partially reduced myotoxic activity of the venom. When the inhibitors were administered at various time intervals after envenomation at the same site of venom injection, both compounds were effective in neutralizing local hemorrhage and dermonecrosis if administered rapidly after venom. Inhibition was not as effective as the time lapse between venom and inhibitor injections increased. Owing to the relevance of metalloproteinases in the pathogenesis of local tissue damage induced by B. asper and other pit viper venoms, it is suggested that administration of peptidomimetic metalloproteinase inhibitors or CaNa2EDTA at the site of venom injection may represent a useful alternative to complement antivenoms in the neutralization of venom-induced local tissue damage.

Selective lysis of virus-infected cells by cobra snake cytotoxins: A sendai virus, human erythrocytes, and cytotoxin model.

By using a Sendai virus-human erythrocyte model, this work found that virus-infected cells were 10-fold more susceptible to lysis in two of five examined cobra venoms. Four cytotoxins were isolated from the venom of the cobra Naja nigricollis that also showed 10-fold higher cytotoxicity toward virus-infected cells than to untreated cells. As selective destruction of virus-infected cells is of immense importance in clinical practice, this work demonstrates the potential of cobra cytotoxins to serve as leading compounds for the generation of derivatives or fractions with high cytotoxic specificity toward virus-infected cells.

Structure-function study of a heptad repeat positioned near the transmembrane domain of Sendai virus fusion protein which blocks virus-cell fusion.

A synthetic heptad repeat, SV-473, derived from Sendai virus fusion protein is a potent inhibitor of virus-cell fusion. In order to understand the mechanism of the inhibitory effect, we synthesized and fluorescently labeled SV-465, an extended version of SV-473 by one more heptad, its mutant peptide A17,24-SV-465, in which two heptadic leucines were substituted with two alanines, and its enatiomer D-SV-465, composed entirely of Damino acids. Similar mutations in the homologous fusion protein of the Newcastle disease virus drastically reduced its activity. The data revealed that SV-465, but not A17,24-SV-465 or its enantiomer, is highly active in inhibiting Sendai virus-induced hemolysis of red blood cells. None of the peptides interfere with the binding of virions to the target red blood cells as demonstrated by hemagglutinin assay. Fluorescence and circular dichroism (CD) spectroscopy indicated that: (i) only SV-465 could self-assemble in aqueous environment; (ii) only SV-465 could co-assemble with two other biologically active heptad repeats derived from Sendai virus fusion protein; (iii) SV-465 has a higher helical content than A17,24-SV-465 in solution, and (iv) all the peptides bind strongly to zwitterionic and negatively charged phospholipids. Polarized attenuated total reflection infrared spectroscopy revealed that they bound as monomers onto the surface of zwitterionic membranes with predominantly alpha-helical structures. The functional role of the amino acid 465-497 domain in Sendai virus-mediated membrane fusion is discussed in light of these findings.

Inhibition by CaNa2EDTA of local tissue damage induced by Bothrops asper (terciopelo) venom: application in horse immunization for antivenom production.

The ability of the chelating agent CaNa2EDTA to inhibit local tissue damage induced by Bothrops asper venom was studied in mice and in horses used for polyvalent (Crotalinae) antivenom production. CaNa2EDTA was devoid of toxicity when injected i.m. or s.c. inducing only a mild edema. Preincubation of B. asper venom with CaNa2EDTA inhibited hemorrhagic and dermonecrotic activities, but did not reduce edema-forming and myotoxic effects. A group of horses initially immunized with native venoms developed less severe local tissue reactions when injected with booster doses of venom and CaNa2EDTA than when receiving booster injections of venom alone, although they showed a similar antivenom response. Moreover, antivenoms produced from plasmas of horses that received booster injections of either venom alone or venom plus CaNa2EDTA had similar neutralizing activity against lethal, hemorrhagic and coagulant effects induced by B. asper venom. The similar antibody response was corroborated by Western blotting using crude venom and by an ELISA that estimates anti-myotoxin titer. It is concluded that the chelating agent CaNa2EDTA reduces the extent of local tissue damage induced by B. asper venom, without affecting the immune response of horses against pharmacologically-relevant venom components.

Resistance of the Egyptian mongoose to sarafotoxins.

The Egyptian mongoose (Herpestes ichneumon) is known for its resistance to viperid and elapid venoms. The current work demonstrates that it is also resistant to the venom of Atractaspis and its most toxic component, sarafotoxin-b. Intravenous administration of this toxin, at a dose of about 13 times LD100 for mice, resulted in disturbance in electrocardiograms in the mongoose, which returned to normal after several hours. Sarafotoxin-b failed to induce contraction of mongoose aortal preparations. Endothelin-1, which was demonstrated in tissue extracts of the mongoose by immunological methods, induced contraction of the isolated mongoose aorta. This contraction, however, was greatly reduced when endothelin-1 was applied on top of sarafotoxin-b. Binding studies revealed endothelin/sarafotoxin-specific binding sites in brain and cardiovascular preparations of the mongoose. It is suggested that some structural features of endothelin/sarafotoxin receptors in the mongoose enable them to differentiate between the two peptides.

Inhibitory properties of the antibothropic complex from the South American opossum (Didelphis marsupialis) serum.

The South American opossum Didelphis marsupialis is known to be highly resistant to snake envenomation. In this paper it is shown that the opossum serum inhibits haemorrhage induced by both Crotalinae and Viperinae venoms. Tested against Bothrops jararaca (jararaca) venom, the antibothropic complex (ABC) isolated from the opossum serum was at least six times more antihaemorrhagic than the commercial antivenom. ABC showed no proteolytic activity by itself and was not hydrolysed by the venom. It inhibited the hydrolysis of casein by B. jararaca venom, but did not inhibit its hydrolytic activities upon N alpha-benzoyl-L-arginine ethyl ester (BAEE) and N alpha-benzoyl-DL-arginine p-nitroanilide (BAPNA). The inhibitor did not interfere with trypsin and bacterial collagenase activities on BAPNA and N-(3-[2-furyl]acryloyl)-Leu-Gly-Pro-Ala (FALGPA), respectively. It reduced chymotrypsin hydrolysis of N-acetyl-L-tyrosine ethyl ester (ATEE) because ABC is also a substrate for this enzyme. By sodium dodecyl sulfate-polyacrylamide gel electrophoresis, B. jararaca venom preferentially degraded fibrinogen A alpha-chain and fibrin alpha-chain. Tested on extracellular matrix proteins, the venom hydrolysed collagen IV, gelatins I and V, laminin and fibronectin, besides depolimerizing collagen I alpha-chain dimers. Fibrillar collagen V was not digested. These hydrolyses were inhibited by ABC and by EDTA. Our results show that the antibothropic complex is a venom metalloproteinase inhibitor, which could, at least partially, account for its antihaemorrhagic activity. Electrophoretic evidence indicated non-covalent complex formation between the antihaemorrhagic factor and component(s) of B. jararaca venom.

Inhibition of the hemorrhagic activity of Bothrops asper venom by a novel neutralizing mixture.

This study screened 25 sera, 19 synthetic products and five antivenoms obtained after immunization for their ability to neutralize the hemorrhagic activity of venom from the snake Bothrops asper. Among the sera screened, the homologous serum of B. asper itself was found to possess the highest neutralizing capacity, abolishing the hemorrhagic effect of the venom at weight ratio of 3:1. It was more efficient than the antisera obtained by immunization. Among the synthetic compounds tested, only O-phenanthroline and EDTA salts inhibited the hemorrhagic activity at concentrations of 0.5-10 mM; however, only CaNa2EDTA was non-toxic at the concentrations studied. Intravenous injections and in situ administration of the non-toxic inhibitors revealed that a fraction of B. asper serum, the horse polyvalent antivenom and CaNa2EDTA were the most potent antihemorrhagic materials against B. asper venom, especially when administered in situ as a mixture. This work suggests that this neutralizing mixture could be highly useful in the neutralization of local and systemic hemorrhage developing after B. asper envenomation.

Activity of cytotoxin P4 from the venom of the cobra snake Naja nigricollis on gram-positive bacteria and eukaryotic cell lines.

The cytotoxin P4 from the venom of the cobra snake Naja nigricollis was examined for activity against aerobic gram-positive and gram-negative bacteria, yeasts, fungi and eucaryotic cell lines by determination of minimal inhibitory concentrations (MIC) and IC50 values, respectively. Cytotoxin P4 exhibits antimicrobial activity against Bacillus subtilis, Micrococcus flavus and Sarcina lutea. Targets in gram-negative bacteria and fungi apparently were not reached. Toxicity against eucaryotic cells is in a narrow range between lethal and tolerable concentrations.