384 research outputs found
Pentamidine Dosage: A Base/Salt Confusion
Pentamidine has a long history in the treatment of human African trypanosomiasis (HAT) and leishmaniasis. Early guidelines on the dosage of pentamidine were based on the base-moiety of the two different formulations available. Confusion on the dosage of pentamidine arose from a different labelling of the two available products, either based on the salt or base moiety available in the preparation. We provide an overview of the various guidelines concerning HAT and leishmaniasis over the past decades and show the confusion in the calculation of the dosage of pentamidine in these guidelines and the subsequent published reports on clinical trials and reviews. At present, only pentamidine isethionate is available, but the advised dosage for HAT and leishmaniasis is (historically) based on the amount of pentamidine base. In the treatment of leishmaniasis this is probably resulting in a subtherapeutic treatment. There is thus a need for a new, more transparent and concise guideline concerning the dosage of pentamidine, at least in the treatment of HAT and leishmaniasi
Geometric Exponents, SLE and Logarithmic Minimal Models
In statistical mechanics, observables are usually related to local degrees of
freedom such as the Q < 4 distinct states of the Q-state Potts models or the
heights of the restricted solid-on-solid models. In the continuum scaling
limit, these models are described by rational conformal field theories, namely
the minimal models M(p,p') for suitable p, p'. More generally, as in stochastic
Loewner evolution (SLE_kappa), one can consider observables related to nonlocal
degrees of freedom such as paths or boundaries of clusters. This leads to
fractal dimensions or geometric exponents related to values of conformal
dimensions not found among the finite sets of values allowed by the rational
minimal models. Working in the context of a loop gas with loop fugacity beta =
-2 cos(4 pi/kappa), we use Monte Carlo simulations to measure the fractal
dimensions of various geometric objects such as paths and the generalizations
of cluster mass, cluster hull, external perimeter and red bonds. Specializing
to the case where the SLE parameter kappa = 4p'/p is rational with p < p', we
argue that the geometric exponents are related to conformal dimensions found in
the infinitely extended Kac tables of the logarithmic minimal models LM(p,p').
These theories describe lattice systems with nonlocal degrees of freedom. We
present results for critical dense polymers LM(1,2), critical percolation
LM(2,3), the logarithmic Ising model LM(3,4), the logarithmic tricritical Ising
model LM(4,5) as well as LM(3,5). Our results are compared with rigourous
results from SLE_kappa, with predictions from theoretical physics and with
other numerical experiments. Throughout, we emphasize the relationships between
SLE_kappa, geometric exponents and the conformal dimensions of the underlying
CFTs.Comment: Added reference
Failure of feedback as a putative common mechanism of spreading depolarizations in migraine and stroke
The stability of cortical function depends critically on proper regulation.
Under conditions of migraine and stroke a breakdown of transmembrane chemical
gradients can spread through cortical tissue. A concomitant component of this
emergent spatio-temporal pattern is a depolarization of cells detected as slow
voltage variations. The velocity of ~3 mm/min indicates a contribution of
diffusion. We propose a mechanism for spreading depolarizations (SD) that rests
upon a nonlocal or non-instantaneous feedback in a reaction-diffusion system.
Depending upon the characteristic space and time scales of the feedback, the
propagation of cortical SD can be suppressed by shifting the bifurcation line,
which separates the parameter regime of pulse propagation from the regime where
a local disturbance dies out. The optimisation of this feedback is elaborated
for different control schemes and ranges of control parameters
Astrocytic Ion Dynamics: Implications for Potassium Buffering and Liquid Flow
We review modeling of astrocyte ion dynamics with a specific focus on the
implications of so-called spatial potassium buffering, where excess potassium
in the extracellular space (ECS) is transported away to prevent pathological
neural spiking. The recently introduced Kirchoff-Nernst-Planck (KNP) scheme for
modeling ion dynamics in astrocytes (and brain tissue in general) is outlined
and used to study such spatial buffering. We next describe how the ion dynamics
of astrocytes may regulate microscopic liquid flow by osmotic effects and how
such microscopic flow can be linked to whole-brain macroscopic flow. We thus
include the key elements in a putative multiscale theory with astrocytes
linking neural activity on a microscopic scale to macroscopic fluid flow.Comment: 27 pages, 7 figure
The influence of tumor- and treatment-related factors on the development of local recurrence in osteosarcoma after adequate surgery. An analysis of 1355 patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols
Background: Local recurrence (LR) in osteosarcoma is associated with very poor prognosis. We sought to evaluate which factors correlate with LR in patients who achieved complete surgical remission with adequate margins. Patients and methods: We analyzed 1355 patients with previously untreated high-grade central osteosarcoma of the extremities, the shoulder and the pelvis registered in neoadjuvant Cooperative Osteosarcoma Study Group trials between 1986 and 2005. Seventy-six patients developed LR. Results: Median follow-up was 5.56 years. No participation in a study, pelvic tumor site, limb-sparing surgery, soft tissue infiltration beyond the periosteum, poor response to neoadjuvant chemotherapy, failure to complete the planned chemotherapy protocol and biopsy at a center other than the one performing the tumor resection were significantly associated with a higher LR rate. No differences were found for varying surgical margin widths. Surgical treatment at centers with small patient volume and additional surgery in the primary tumor area, other than biopsy and tumor resection, were significantly associated with a higher rate of ablative surgery. Conclusions: Patient enrollment in clinical trials and performing the biopsy at experienced institutions capable of undertaking the tumor resection without compromising the oncological and functional outcome should be pursued in the futur
Detection and identification of human Plasmodium species with real-time quantitative nucleic acid sequence-based amplification
BACKGROUND: Decisions concerning malaria treatment depend on species identification causing disease. Microscopy is most frequently used, but at low parasitaemia (<20 parasites/μl) the technique becomes less sensitive and time consuming. Rapid diagnostic tests based on Plasmodium antigen detection do often not allow for species discrimination as microscopy does, but also become insensitive at <100 parasites/μl. METHODS: This paper reports the development of a sensitive and specific real-time Quantitative Nucleic Acid Sequence Based Amplification (real-time QT-NASBA) assays, based on the small-subunit 18S rRNA gene, to identify the four human Plasmodium species. RESULTS: The lower detection limit of the assay is 100 – 1000 molecules in vitro RNA for all species, which corresponds to 0.01 – 0.1 parasite per diagnostic sample (i.e. 50 μl of processed blood). The real-time QT-NASBA was further evaluated using 79 clinical samples from malaria patients: i.e. 11 Plasmodium. falciparum, 37 Plasmodium vivax, seven Plasmodium malariae, four Plasmodium ovale and 20 mixed infections. The initial diagnosis of 69 out of the 79 samples was confirmed with the developed real-time QT-NASBA. Re-analysis of seven available original slides resolved five mismatches. Three of those were initially identified as P. malariae mono-infection, but after re-reading the slides P. falciparum was found, confirming the real-time QT-NASBA result. The other two slides were of poor quality not allowing true species identification. The remaining five discordant results could not be explained by microscopy, but may be due to extreme low numbers of parasites present in the samples. In addition, 12 Plasmodium berghei isolates from mice and 20 blood samples from healthy donors did not show any reaction in the assay. CONCLUSION: Real-time QT-NASBA is a very sensitive and specific technique with a detection limit of 0.1 Plasmodium parasite per diagnostic sample (50 μl of blood) and can be used for the detection, identification and quantitative measurement of low parasitaemia of Plasmodium species, thus making it an effective tool for diagnostic purposes and useful for epidemiological and drug studies
Migraine aura: retracting particle-like waves in weakly susceptible cortex
Cortical spreading depression (SD) has been suggested to underlie migraine aura. Despite a precise match in speed, the spatio-temporal patterns of SD and aura symptoms on the cortical surface ordinarily differ in aspects of size and shape. We show that this mismatch is reconciled by utilizing that both pattern types bifurcate from an instability point of generic reaction-diffusion models. To classify these spatio-temporal pattern we suggest a susceptibility scale having the value [sigma]=1 at the instability point. We predict that human cortex is only weakly susceptible to SD ([sigma]<1), and support this prediction by directly matching visual aura symptoms with anatomical landmarks using fMRI retinotopic mapping. We discuss the increased dynamical repertoire of cortical tissue close to [sigma]=1, in particular, the resulting implications on migraine pharmacology that is hitherto tested in the regime ([sigma]>>1), and potentially silent aura occurring below a second bifurcation point at [sigma]=0 on the susceptible scale
Conformal mapping methods for interfacial dynamics
The article provides a pedagogical review aimed at graduate students in
materials science, physics, and applied mathematics, focusing on recent
developments in the subject. Following a brief summary of concepts from complex
analysis, the article begins with an overview of continuous conformal-map
dynamics. This includes problems of interfacial motion driven by harmonic
fields (such as viscous fingering and void electromigration), bi-harmonic
fields (such as viscous sintering and elastic pore evolution), and
non-harmonic, conformally invariant fields (such as growth by
advection-diffusion and electro-deposition). The second part of the article is
devoted to iterated conformal maps for analogous problems in stochastic
interfacial dynamics (such as diffusion-limited aggregation, dielectric
breakdown, brittle fracture, and advection-diffusion-limited aggregation). The
third part notes that all of these models can be extended to curved surfaces by
an auxilliary conformal mapping from the complex plane, such as stereographic
projection to a sphere. The article concludes with an outlook for further
research.Comment: 37 pages, 12 (mostly color) figure
A mathematical model of the metabolic and perfusion effects on cortical spreading depression
Cortical spreading depression (CSD) is a slow-moving ionic and metabolic
disturbance that propagates in cortical brain tissue. In addition to massive
cellular depolarization, CSD also involves significant changes in perfusion and
metabolism -- aspects of CSD that had not been modeled and are important to
traumatic brain injury, subarachnoid hemorrhage, stroke, and migraine.
In this study, we develop a mathematical model for CSD where we focus on
modeling the features essential to understanding the implications of
neurovascular coupling during CSD. In our model, the sodium-potassium--ATPase,
mainly responsible for ionic homeostasis and active during CSD, operates at a
rate that is dependent on the supply of oxygen. The supply of oxygen is
determined by modeling blood flow through a lumped vascular tree with an
effective local vessel radius that is controlled by the extracellular potassium
concentration. We show that during CSD, the metabolic demands of the cortex
exceed the physiological limits placed on oxygen delivery, regardless of
vascular constriction or dilation. However, vasoconstriction and vasodilation
play important roles in the propagation of CSD and its recovery. Our model
replicates the qualitative and quantitative behavior of CSD --
vasoconstriction, oxygen depletion, extracellular potassium elevation,
prolonged depolarization -- found in experimental studies.
We predict faster, longer duration CSD in vivo than in vitro due to the
contribution of the vasculature. Our results also help explain some of the
variability of CSD between species and even within the same animal. These
results have clinical and translational implications, as they allow for more
precise in vitro, in vivo, and in silico exploration of a phenomenon broadly
relevant to neurological disease.Comment: 17 pages including 9 figures, accepted by PLoS On
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