Efficacy and safety of recombinant human C1-inhibitor for the treatment of attacks of hereditary angioedema: European open-label extension study.

BACKGROUND: Hereditary angioedema (HAE) owing to C1 inhibitor deficiency is an autosomal dominant disorder, characterized by recurrent, potentially life-threatening, localized attacks of tissue swelling. Current treatment involves the infusion of C1 inhibitor protein (C1-INH) isolated from human plasma. OBJECTIVES: This open-label extension to a European, Israeli and Argentinean randomized study (NCT00262301) aimed to investigate the efficacy and safety of recombinant human C1 inhibitor (rhC1-INH) as a first-line treatment following an HAE attack, together with its effect on subsequent attacks. METHODS: An HAE-specific visual analogue scale (VAS) 0-100 mm was used by patients to assess the severity of attack at four anatomical locations. Patients were treated with one, single-vial, fixed-dose of rhC1-INH (2100 U), followed by up to two further vials at the investigators discretion. The primary end-point was the time from first rhC1-INH injection to first onset of relief of symptoms (≥ 20 mm decrease on VAS). Response to treatment was defined as the onset of relief within 4 h. RESULTS: A total of 57 patients were treated for 194 HAE attacks. Overall, sustained relief of symptoms was achieved in 87% of rhC1-INH-treated patients within 4 h of treatment, with 57% of attacks requiring only one vial of rhC1-INH. When categorized by successive attacks experienced by individual patients, the response rate to rhC1-INH treatment was 96%, 83%, 87%, 80% and 80% for attacks 1-5 respectively. Treatment with rhC1-INH was well tolerated, with no discontinuations owing to treatment-emergent adverse events and no adverse events relating to immunogenicity. CONCLUSIONS AND CLINICAL RELEVANCE: Treatment with rhC1-INH provides fast-onset relief for an HAE attack, with a high rate of therapeutic response maintained throughout subsequent attacks.

Duplicate publication and 'paper inflation' in the Fractals literature.

The similarity of documents in a large database of published Fractals articles was examined for redundancy. Three different text matching techniques were used on published Abstracts to identify redundancy candidates, and predictions were verified by reading full text versions of the redundancy candidate articles. A small fraction of the total articles in the database was judged to be redundant. This was viewed as a lower limit, because it excluded cases where the concepts remained the same, but the text was altered substantially. Far more pervasive than redundant publications were publications that did not violate the letter of redundancy but rather violated the spirit of redundancy. There appeared to be widespread publication maximization strategies. Studies that resulted in one comprehensive paper decades ago now result in multiple papers that focus on one major problem, but are differentiated by parameter ranges, or other stratifying variables. This 'paper inflation' is due in large part to the increasing use of metrics (publications, patents, citations, etc) to evaluate research performance, and the researchers' motivation to maximize the metrics.

Free-volume dynamics in glasses and supercooled liquids.

A free-volume theory is developed based on the defect diffusion model (DDM). In addition, positronium annihilation lifetime spectroscopy (PALS) ortho-positronium free-volume and intensity data are presented for poly(propylene glycol) with a molecular weight of 4000 (PPG 4000) in both the glassy and liquid states and dielectric relaxation and electrical conductivity data are reported for PPG 4000 in the liquid state. The DDM is used to interpret all of the data for PPG 4000 and previously reported PALS and dielectric relaxation data for glycerol. It is shown that while the PPG 4000 data exhibit a preference for the three-halves power law, the data for glycerol favor the first power (standard Vogel-Fulcher-Tammann) law. Good agreement between the DDM and the experimental results is found for all of the electrical data and the PALS free-volume data. While reasonable agreement is also found for the PALS intensity data for PPG 4000, a discrepancy exists between the experimental PALS intensity data and theory for glycerol. For the electrical conductivity for PPG 4000, a transition is observed at the same temperature (about 1.4 T(g) where T(g) is the glass transition temperature) where the PALS free volume changes from steeply rising with temperature to approximately independent of temperature. The same behavior is observed at about 1.5 T(g) for previously reported dielectric relaxation and PALS data for glycerol. Model parameters are presented that show the dominance of mobile single defects above (1.4-1.5) T(g) and the dominance of immobile clustered single defects below T(g) . Finally, a coherent picture of glasses and glass-forming liquids is presented based on the theory and results of the experiments.

A new vogel-like law: ionic conductivity, dielectric relaxation, and viscosity near the glass transition.

A model is developed that describes temperature and pressure dependence of dielectric relaxation, ionic conductivity, and viscosity of glass-forming liquids near the glass transition temperature. The expressions for ionic conductivity are compared with experimental results for two polymer electrolytes. Those for dielectric relaxation are compared with data for poly(propylene oxide) and poly(vinyl acetate). The theoretical viscosity law is compared with experiment for propylene carbonate.

Hydrophobic free energy eigenfunctions of pore, channel, and transporter proteins contain beta-burst patterns.

Hydropathy plots are often used in place of missing physical data to model transmembrane proteins that are difficult to crystallize. The sequential maxima of their graphs approximate the number and locations of transmembrane segments, but potentially useful additional information about sequential hydrophobic variation is lost in this smoothing procedure. To explore a broader range of hydrophobic variations without loss of the transmembrane segment-relevant sequential maxima, we utilize a sequence of linear decompositions and transformations of the n-length hydrophobic free energy sequences, Hi, i = 1...n, of proteins. Constructions of hydrophobic free energy eigenfunctions, psil, from M-lagged, M x M autocovariance matrices, CM, were followed by their all-poles, maximum entropy power spectral, Somega(psil), and Mexican Hat wavelet, Wa,b(psil), transformations. These procedures yielded graphs indicative of inverse frequencies, omega-1, and sequence locations of hydrophobic modes suggestive of secondary and supersecondary protein structures. The graphs of these computations discriminated between Greek Key, Jelly Role, and Up and Down categories of antiparallel beta-barrel proteins. With these methods, examples of porins, connexins, hexose transporters, nuclear membrane proteins, and potassium but not sodium channels appear to belong to the Up and Down antiparallel beta-barrel variety.

Mode matches in hydrophobic free energy eigenfunctions predict peptide-protein interactions.

The dominant statistical hydrophobic free energy inverse frequencies amino acid wavelengths as hydrophobic modes, of neurotensin (NT), cholescystokinin (CCK), the human dopamine D2 receptor [(DA)D2], and the human dopamine transporter (DAT) were determined using orthogonal decomposition of the autocovariance matrices of their amino acid sequences as hydrophobic free energy equivalents in kcal/mol. The leading eigenvalues-associated eigenvectors were convolved with the original series to construct eigenfunctions. Eigenfunctions were further analyzed using discrete trigonometric wavelet and all poles, maximum entropy power spectral transformations. This yielded clean representations of the dominant hydrophobic free energy modes, most of which are otherwise lost in the smoothing of hydropathy plots or contaminated by end effects and multimodality in conventional Fourier transformations. Mode matches were found between NT and (DA)D2 and between CCK and DAT, but not the converse. These mode matches successfully predicted the nonlinear kinetic interactions of NT-(DA)D2 in contrast with CCK-(DA) D2 on 3H-spiperone binding to (DA) D2, and by CCK-DAT but not NT-DAT on [N-methyl-3H]-WIN 35,428 binding to DAT in (DA)D2 and DAT cDNA stably transfected cell lines without known NT or CCK receptors. Computation of the dominant modes of hydrophobic free energy eigenfunctions may help predict functionally relevant peptide-membrane protein interactions, even across neurotransmitter families.

Mode matches and their locations in the hydrophobic free energy sequences of peptide ligands and their receptor eigenfunctions.

Patterns in sequences of amino acid hydrophobic free energies predict secondary structures in proteins. In protein folding, matches in hydrophobic free energy statistical wavelengths appear to contribute to selective aggregation of secondary structures in "hydrophobic zippers." In a similar setting, the use of Fourier analysis to characterize the dominant statistical wavelengths of peptide ligands' and receptor proteins' hydrophobic modes to predict such matches has been limited by the aliasing and end effects of short peptide lengths, as well as the broad-band, mode multiplicity of many of their frequency (power) spectra. In addition, the sequence locations of the matching modes are lost in this transformation. We make new use of three techniques to address these difficulties: (i) eigenfunction construction from the linear decomposition of the lagged covariance matrices of the ligands and receptors as hydrophobic free energy sequences; (ii) maximum entropy, complex poles power spectra, which select the dominant modes of the hydrophobic free energy sequences or their eigenfunctions; and (iii) discrete, best bases, trigonometric wavelet transformations, which confirm the dominant spectral frequencies of the eigenfunctions and locate them as (absolute valued) moduli in the peptide or receptor sequence. The leading eigenfunction of the covariance matrix of a transmembrane receptor sequence locates the same transmembrane segments seen in n-block-averaged hydropathy plots while leaving the remaining hydrophobic modes unsmoothed and available for further analyses as secondary eigenfunctions. In these receptor eigenfunctions, we find a set of statistical wavelength matches between peptide ligands and their G-protein and tyrosine kinase coupled receptors, ranging across examples from 13.10 amino acids in acid fibroblast growth factor to 2.18 residues in corticotropin releasing factor. We find that the wavelet-located receptor modes in the extracellular loops are compatible with studies of receptor chimeric exchanges and point mutations. A nonbinding corticotropin-releasing factor receptor mutant is shown to have lost the signatory mode common to the normal receptor and its ligand. Hydrophobic free energy eigenfunctions and their transformations offer new quantitative physical homologies in database searches for peptide-receptor matches.

The brain as a dynamic physical system.

The brain is a dynamic system that is non-linear at multiple levels of analysis. Characterization of its non-linear dynamics is fundamental to our understanding of brain function. Identifying families of attractors in phase space analysis, an approach which has proven valuable in describing non-linear mechanical and electrical systems, can prove valuable in describing a range of behaviors and associated neural activity including sensory and motor repertoires. Additionally, transitions between attractors may serve as useful descriptors for analysing state changes in neurons and neural ensembles. Recent observations of synchronous neural activity, and the emerging capability to record the spatiotemporal dynamics of neural activity by voltage-sensitive dyes and electrode arrays, provide opportunities for observing the population dynamics of neural ensembles within a dynamic systems context. New developments in the experimental physics of complex systems, such as the control of chaotic systems, selection of attractors, attractor switching and transient states, can be a source of powerful new analytical tools and insights into the dynamics of neural systems.

On the relationship among three theories of relaxation in disordered systems.

Empirical evidence has accumulated showing the wide occurrence of a stretched-exponential relaxation decay law for many diverse condensed-matter systems. Several theories based on different physical mechanisms have been successful in deriving the stretched-exponential decay law in a natural way. Three of these theories, the direct-transfer model, the hierarchically constrained dynamics model, and the defect-diffusion model are shown here to have an underlying common mathematical structure.

Analysis of the effects of cesium ions on potassium channel currents in biological membranes.

Cesium ions block potassium channels in biological membranes in a voltage dependent manner. For example, external cesium blocks inward current with little or no effect on outward current. Consequently, it produces a characteristic N-shaped current-voltage relationship. We have modeled this result by single file diffusion of ions in a narrow channel spanning the membrane with a special blocking site in the channel for cesium ions. The model enables us to make detailed comparisons of the effects of cesium on potassium channels in different types of biological membranes.

On the Williams-Watts function of dielectric relaxation.

It has been observed over the past 15 years that experimental frequency-dependent dielectric constants of broad classes of materials including polymeric systems and glasses may be interpreted in terms of the Williams-Watts polarization decay function [Formula: see text] The exponent alpha and the time constant T depend on the material and fixed external conditions such as temperature and pressure. We derive this form of varphi(alpha)(t) from the following random-walk model. Suppose that an electric field has been applied for some time to a medium containing many polar molecules (or polar groups in complex molecules) and the direction of their dipole moments remains frozen as the field is removed. Furthermore, suppose that the medium contains mobile defects that on reaching the site of a frozen dipole relax the medium to the degree that the dipole may reorient itself. If the diffusion of defects toward dipoles is executed as a continuous-time random walk composed of an alternation of steps and pauses and the pausing-time distribution function has a long tail of the form psi(t) infinity t(-1-alpha), then the relaxation function has the above fractional exponential form.

Effects of external cesium and rubidium on outward potassium currents in squid axons.

We have studied the effects of external cesium and rubidium on potassium conductance of voltage clamped squid axons over a broad range of concentrations of these ions relative to the external potassium concentration. Our primary novel finding concerning cesium is that relatively large concentrations of this ion are able to block a small, but statistically significant fraction of outward potassium current for potentials less than approximately 50 mV positive to reversal potential. This effect is relieved at more positive potentials. We have also found that external rubidium blocks outward current with a qualitatively similar voltage dependence. This effect is more readily apparent than the cesium blockade, occurring even for concentrations less than that of external potassium. Rubidium also has a blocking effect on inward current, which is relieved for potentials more than 20-40 mV negative to reversal, thereby allowing both potassium and rubidium ions to cross the membrane. We have described these results with a single-file diffusion model of ion permeation through potassium channels. The model analysis suggests that both rubidium and cesium ions exert their blocking effects at the innermost site of a two-site channel, and that rubidium competes with potassium ions for entry into the channel more effectively than does cesium under comparable conditions.

On 1/f noise and other distributions with long tails.

It is shown, following Shockley [Shockley, W. (1957) Proc. IRE 45, 279-290], that, when a population is engaged in tasks whose completion requires the successful conclusion of many independent subtasks, the distribution function for successes in the primary task is log normal. It is also shown that, when the dispersion of the log-normal distribution is large, the distribution is mimicked by a 1/x distribution over a wide range of x. This argument provides a generic set of processes that yields the much observed 1/x distribution, and will also lead to a 1/f noise spectrum. It is commonly found that distributions that seem to be log normal over a broad range (say to the 95th percentile of a population) change to an inverse fractional power (Pareto) distribution for the last few percentile. Annual income distributions are examples with this structure. The very wealthy generally achieve their superwealth through amplification processes that are not available to most. We have introduced a simple amplification model to characterize the transition from a log-normal distribution to an inverse-power Pareto tail.

Delayed kinetics of squid axon potassium channels do not always superpose after time translation.

The activation of potassium ion conductance in squid axons by voltage-clamp depolarization is delayed when the depolarizing step is preceded by a conditioning hyperpolarization of the axonal membrane. Moreover, the control conductance kinetics superpose with the delayed kinetics when they are translated along the time axis by an amount equal to the delay. We have found that the degree of superposition with internally perfused axons depends upon voltage-clamp protocol. The kinetics superpose almost exactly for modest test depolarizations, whereas they clearly fail to superpose completely for more positive levels of membrane depolarization. We have modeled these results by incorporating a time dependence into the rate constant of activation of potassium channel gates in the Hodgkin and Huxley model of potassium ionic conductance.

Random walks with self-similar clusters.

We construct a random walk on a lattice having a hierarchy of self-similar clusters built into the distribution function of allowed jumps. The random walk is a discrete analog of a Lévy flight and coincides with the Lévy flight in the continum limit. The Fourier transform of the jump distribution function is the continuous nondifferentiable function of Weierstrass. We show that, for cluster formation, it is necessary that the mean-squared displacement per jump be infinite and that the random walk be transient. We interpret our random walk as having an effective dimension higher than the spatial dimension available to the walker. The difference in dimensions is related to the fractal (Hausdorff-Besicovitch) dimension of the self-similar clusters.

Successful tumour immunotherapy with cimetidine in mice.

Cimetidine significantly slowed metastatic development and prolonged survival in tumour-bearing mice, in association with inactivation of suppressor cells. Pharmacological blockade of the suppressor cell system may represent a new strategy for successful immunotherapy of human neoplasia.

Random walk analysis of potassium fluxes associated with nerve impulses.

We present a novel recursion method for obtaining theoretical expressions for unidirectional single-file fluxes of ions through narrow membrane channels containing an arbitrary number of ion sites. The theory is applied to experimental tracer fluxes associated with nerve impulses from cephalopod giant axon membranes at various temperatures between 7 degrees and 27 degrees. The comparison between the theoretical and experimental one-way fluxes suggests that the potassium channel in nerve membrane contains three ion sites, which is consistent with the deduction by Hodgkin and Keynes that the potassium channel contains two or three sites on the basis of the ratio of tracer influx to tracer efflux. The analytical results in this paper provide a further test of the single-file model for nerve and other membrane preparations.