Identification of the upward movement of human CSF in vivo and its relation to the brain venous system.

CSF flux is involved in the pathophysiology of neurodegenerative diseases and cognitive impairment after traumatic brain injury, all hallmarked by the accumulation of cellular metabolic waste. Its effective disposal via various CSF routes has been demonstrated in animal models. In contrast, the CSF dynamics in humans are still poorly understood. Using novel real-time MRI, forced inspiration has been identified recently as a main driving force of CSF flow in the human brain. Exploiting technical advances toward real-time phase-contrast MRI, the current work analyzed directions, velocities, and volumes of human CSF flow within the brain aqueduct as part of the internal ventricular system and in the spinal canal during respiratory cycles. A consistent upward CSF movement toward the brain in response to forced inspiration was seen in all subjects at the aqueduct, in 11/12 subjects at thoracic level 2, and in 4/12 subjects at thoracic level 5. Concomitant analyses of CSF dynamics and cerebral venous blood flow, that is, in epidural veins at cervical level 3, uniquely demonstrated CSF and venous flow to be closely communicating cerebral fluid systems in which inspiration-induced downward flow of venous blood due to reduced intrathoracic pressure is counterbalanced by an upward movement of CSF. The results extend our understanding of human CSF flux and open important clinical implications, including concepts for drug delivery and new classifications and therapeutic options for various forms of hydrocephalus and idiopathic intracranial hypertension

Inspiration is the major regulator of human CSF flow.

The mechanisms behind CSF flow in humans are still not fully known. CSF circulates from its primary production sites at the choroid plexus through the brain ventricles to reach the outer surface of the brain in the subarachnoid spaces from where it drains into venous bloodstream and cervical lymphatics. According to a recent concept of brain fluid transport, established in rodents, CSF from the brain surface also enters the brain tissue along para-arterial routes and exits through paravenous spaces again into subarachnoid compartments. This unidirectional flow is mainly driven by arterial pulsation. To investigate how CSF flow is regulated in humans, we applied a novel real-time magnetic resonance imaging technique at high spatial (0.75 mm) and temporal (50 ms) resolution in healthy human subjects. We observed significant CSF flow exclusively with inspiration. In particular, during forced breathing, high CSF flow was elicited during every inspiration, whereas breath holding suppressed it. Only a minor flow component could be ascribed to cardiac pulsation. The present results unambiguously identify inspiration as the most important driving force for CSF flow in humans. Inspiratory thoracic pressure reduction is expected to directly modulate the hydrostatic pressure conditions for the low-resistance paravenous, venous, and lymphatic clearance routes of CSF. Furthermore, the experimental approach opens new clinical opportunities to study the pathophysiology of various forms of hydrocephalus and to design therapeutic strategies in relation to CSF flow alterations

Therapie der blanden Struma: Erfahrungen mit einer Kombination von 100 µg L-Thyroxin und 10 µg L-Trijodthyronin

Dtsch med Wochenschr 1981; 106: 579-583 DOI: 10.1055/s-2008-1070359 © Georg Thieme Verlag KG Stuttgart · New York Therapie der blanden Struma: Erfahrungen mit einer Kombination von 100 µg L-Thyroxin und 10 µg L-Trijodthyronin Treatment of non-toxic goitre: results of combined treatment with 100 µg L-thyroxine and 10 µg L-triiodothyronine C. R. Pickardt, R. Gärtner, J. Habermann, K. Horn, P. C. Scriba, F. A. Horster, H. Wagner, K. Hengst Medizinische Klinik Innenstadt der Universität München, Klinik für Innere Medizin, Medizinische Hochschule Lübeck, Medizinische Klinik C und Poliklinik der Universität Düsseldorf sowie Medizinische Klinik und Poliklinik der Universität Münster Zusammenfassung Bei 96 Patienten mit blander Struma wurde eine offene Prüfung mit einem neuen Schilddrüsenhormonpräparat durchgeführt, das 100 µg L-Thyroxin (T4) und 10 µg L-Trijodthyronin (T3) pro Tablette enthält. Als Parameter für die therapeutisch wirksame Tagesdosis wurde die Suppression des TRH-stimulierten Thyreotropinspiegels im Serum gewählt. Hierbei war eine Tagesdosis von 50 µg T4 und 5 µg T3 bei 16 Patienten unwirksam; 75 µg T4 und 7,5 µg T3waren bei nur 4 von 12 Patienten suppressiv wirksam, während 100 µg T4 und 10 µg T3 bei allen Düsseldorfer und Münsteraner Patienten, aber nur bei 17 von 31 Patienten in München den TRH-stimulierten TSH-Anstieg supprimierte. Während der gesamten Therapiedauer blieben Thyroxin- und Trijodthyroninspiegel im Serum im Normbereich; bei einigen Patienten erhöhte sich der Quotient aus Thyroxin und thyroxinbindendem Globulin über die Norm. Zeichen einer Überdosierung oder Unverträglichkeit wurden nicht beobachtet. In pharmakokinetischen Untersuchungen an acht freiwilligen schilddrüsengesunden Probanden erreichte der mittlere Thyroxin- und Trijodthyroninspiegel etwa 2 Stunden nach Applikation sein Maximum und näherte sich nach sechs Stunden wieder der Norm. Es zeigten sich deutliche individuelle Schwankungen in den ersten Stunden nach Applikation. Wir empfehlen deshalb, Schilddrüsenhormonspiegel erst 12 oder 24 Stunden nach Applikation eines Schilddrüsenhormonpräparates zu bestimmen; zu dieser Zeit sollte auch der TRH-Test durchgeführt werden. Die Untersuchungen bestätigen die Notwendigkeit, bei der Strumatherapie mit einem Schilddrüsenhormonpräparat die suppressiv wirksame Dosis individuell zu ermitteln; diese Dosis beträgt vorzugsweise 100 µg Thyroxin und 10 µg Trijodthyronin oder 150 µg Thyroxin oder 100 µg Thyroxin und 20 µg Trijodthyronin pro Tag.A new thyroid hormone preparation (100 µg L-thyroxine [T4] and 10 µg L-triiodothyronine [T3] per tablet) was given to 96 patients with non-toxic goitre. Suppression of the TRH-stimulated thyrotropin level in serum was chosen as a measure of therapeutic effectiveness. Daily dose of 50 µg T4 and 5 µg T3 was ineffective in 16 patients; 75 µg T4 and 7.5 µg T3 was effective in only four of twelve patients, while 100 µg T4and 10 µg T3 was effective in all patients from clinics in Düsseldorf and Münster, but in only 17 of 31 patients from Munich, in suppressing the TRH-stimulated TSH rise. During the entire period of treatment serum thyroxine and triiodothyronine levels remained normal. In some patients the ratio of thyroxine to thyroxine-binding globulin was above normal. Signs of overdosage or intolerance were not observed. Pharmacokinetic studies on eight volunteers with normal thyroid function demonstrated that the mean thyroxine and triiodothyronine levels reached maximum about two hours after administration, returning towards normal after six hours. There were marked individual variations in the first hours after administration. It is therefore recommended that the thyroid hormone level be determined no earlier than 12 or 24 hours after the thyroid hormone preparation has been administered; TRH test should also be performed at this time. These results indicate the need for determining individually the effective suppressive dose of a thyroid hormone preparation in the treatment of goitre. Preferably the dose should be 100 µg thyroxine and 10 µg triiodothyronine, or 150 µg thyroxine or 100 µg thyroxine and 20 µg triiodothyronine per day

Crossover to the KPZ equation

We characterize the crossover regime to the KPZ equation for a class of one-dimensional weakly asymmetric exclusion processes. The crossover depends on the strength asymmetry $an^{2-\gamma}$ ($a,\gamma>0$) and it occurs at $\gamma=1/2$. We show that the density field is a solution of an Ornstein-Uhlenbeck equation if $\gamma\in(1/2,1]$, while for $\gamma=1/2$ it is an energy solution of the KPZ equation. The corresponding crossover for the current of particles is readily obtained.Comment: Published by Annales Henri Poincare Volume 13, Number 4 (2012), 813-82

Dynamical aspects of mean field plane rotators and the Kuramoto model

The Kuramoto model has been introduced in order to describe synchronization phenomena observed in groups of cells, individuals, circuits, etc... We look at the Kuramoto model with white noise forces: in mathematical terms it is a set of N oscillators, each driven by an independent Brownian motion with a constant drift, that is each oscillator has its own frequency, which, in general, changes from one oscillator to another (these frequencies are usually taken to be random and they may be viewed as a quenched disorder). The interactions between oscillators are of long range type (mean field). We review some results on the Kuramoto model from a statistical mechanics standpoint: we give in particular necessary and sufficient conditions for reversibility and we point out a formal analogy, in the N to infinity limit, with local mean field models with conservative dynamics (an analogy that is exploited to identify in particular a Lyapunov functional in the reversible set-up). We then focus on the reversible Kuramoto model with sinusoidal interactions in the N to infinity limit and analyze the stability of the non-trivial stationary profiles arising when the interaction parameter K is larger than its critical value K_c. We provide an analysis of the linear operator describing the time evolution in a neighborhood of the synchronized profile: we exhibit a Hilbert space in which this operator has a self-adjoint extension and we establish, as our main result, a spectral gap inequality for every K>K_c.Comment: 18 pages, 1 figur

Evidence for structural and electronic instabilities at intermediate temperatures in κ\kappa-(BEDT-TTF)2_{2}X for X=Cu[N(CN)2_{2}]Cl, Cu[N(CN)2_{2}]Br and Cu(NCS)2_{2}: Implications for the phase diagram of these quasi-2D organic superconductors

We present high-resolution measurements of the coefficient of thermal expansion $\alpha (T)=\partial \ln l(T)/\partial T$ of the quasi-twodimensional (quasi-2D) salts $\kappa$-(BEDT-TTF)$_2$X with X = Cu(NCS)$_2$, Cu[N(CN)$_2$]Br and Cu[N(CN)$_2$]Cl. At intermediate temperatures (B), distinct anomalies reminiscent of second-order phase transitions have been found at $T^\ast = 38$ K and 45 K for the superconducting X = Cu(NCS)$_2$ and Cu[N(CN)$_2$]Br salts, respectively. Most interestingly, we find that the signs of the uniaxial pressure coefficients of $T^\ast$ are strictly anticorrelated with those of $T_c$. We propose that $T^\ast$ marks the transition to a spin-density-wave (SDW) state forming on minor, quasi-1D parts of the Fermi surface. Our results are compatible with two competing order parameters that form on disjunct portions of the Fermi surface. At elevated temperatures (C), all compounds show $\alpha (T)$ anomalies that can be identified with a kinetic, glass-like transition where, below a characteristic temperature $T_g$, disorder in the orientational degrees of freedom of the terminal ethylene groups becomes frozen in. We argue that the degree of disorder increases on going from the X = Cu(NCS)$_2$ to Cu[N(CN)$_2$]Br and the Cu[N(CN)$_2$]Cl salt. Our results provide a natural explanation for the unusual time- and cooling-rate dependencies of the ground-state properties in the hydrogenated and deuterated Cu[N(CN)$_2$]Br salts reported in the literature.Comment: 22 pages, 7 figure

Evolutionary trajectories in rugged fitness landscapes

We consider the evolutionary trajectories traced out by an infinite population undergoing mutation-selection dynamics in static, uncorrelated random fitness landscapes. Starting from the population that consists of a single genotype, the most populated genotype \textit{jumps} from a local fitness maximum to another and eventually reaches the global maximum. We use a strong selection limit, which reduces the dynamics beyond the first time step to the competition between independent mutant subpopulations, to study the dynamics of this model and of a simpler one-dimensional model which ignores the geometry of the sequence space. We find that the fit genotypes that appear along a trajectory are a subset of suitably defined fitness \textit{records}, and exploit several results from the record theory for non-identically distributed random variables. The genotypes that contribute to the trajectory are those records that are not \textit{bypassed} by superior records arising further away from the initial population. Several conjectures concerning the statistics of bypassing are extracted from numerical simulations. In particular, for the one-dimensional model, we propose a simple relation between the bypassing probability and the dynamic exponent which describes the scaling of the typical evolution time with genome size. The latter can be determined exactly in terms of the extremal properties of the fitness distribution.Comment: Figures in color; minor revisions in tex

Spotting Trees with Few Leaves

We show two results related to the Hamiltonicity and $k$-Path algorithms in undirected graphs by Bj\"orklund [FOCS'10], and Bj\"orklund et al., [arXiv'10]. First, we demonstrate that the technique used can be generalized to finding some $k$-vertex tree with $l$ leaves in an $n$-vertex undirected graph in $O^*(1.657^k2^{l/2})$ time. It can be applied as a subroutine to solve the $k$-Internal Spanning Tree ($k$-IST) problem in $O^*(\min(3.455^k, 1.946^n))$ time using polynomial space, improving upon previous algorithms for this problem. In particular, for the first time we break the natural barrier of $O^*(2^n)$. Second, we show that the iterated random bipartition employed by the algorithm can be improved whenever the host graph admits a vertex coloring with few colors; it can be an ordinary proper vertex coloring, a fractional vertex coloring, or a vector coloring. In effect, we show improved bounds for $k$-Path and Hamiltonicity in any graph of maximum degree $\Delta=4,\ldots,12$ or with vector chromatic number at most 8

From Vicious Walkers to TASEP

We propose a model of semi-vicious walkers, which interpolates between the totally asymmetric simple exclusion process and the vicious walkers model, having the two as limiting cases. For this model we calculate the asymptotics of the survival probability for $m$ particles and obtain a scaling function, which describes the transition from one limiting case to another. Then, we use a fluctuation-dissipation relation allowing us to reinterpret the result as the particle current generating function in the totally asymmetric simple exclusion process. Thus we obtain the particle current distribution asymptotically in the large time limit as the number of particles is fixed. The results apply to the large deviation scale as well as to the diffusive scale. In the latter we obtain a new universal distribution, which has a skew non-Gaussian form. For $m$ particles its asymptotic behavior is shown to be $e^{-\frac{y^{2}}{2m^{2}}}$ as $y\to -\infty$ and $e^{-\frac{y^{2}}{2m}}y^{-\frac{m(m-1)}{2}}$ as $y\to \infty$.Comment: 37 pages, 4 figures, Corrected reference