45 research outputs found
Long-term efficacy of botulinum toxin A for treatment of blepharospasm,hemifacial spasm, and spastic entropion: a multicentre study using two drug-dose escalation indexes
PURPOSE: To investigate the long-term effectiveness and safety of botulinum
neurotoxin A (BoNT-A) treatment in patients with blepharospasm (BEB), hemifacial
spasm (HFS), and entropion (EN) and to use for the first time two modified indexes, 'botulin toxin escalation index-U' (BEI-U) and 'botulin toxin escalation
index percentage' (BEI-%), in the dose-escalation evaluation. METHODS: All
patients in this multicentre study were followed for at least 10 years and main
outcomes were clinical efficacy, duration of relief, BEI-U and BEI-%, and
frequency of adverse events. RESULTS: BEB, HFS, and EN patients received a mean
BoNT-A dose with a significant inter-group difference (P<0.0005, respectively).
The mean (+/-SD) effect duration was statistically different (P=0.009) among
three patient groups. Regarding the BoNT-A escalation indexes, the mean (+/-SD)
values of BEI-U and BEI-% were statistically different (P=0.035 and 0.047,
respectively) among the three groups. In BEB patients, the BEI-% was
significantly increased in younger compared with older patients (P=0.008). The
most frequent adverse events were upper lid ptosis, diplopia, ecchymosis, and
localized bruising. CONCLUSIONS: This long-term multicentre study supports a high
efficacy and good safety profile of BoNT-A for treatment of BEB, HFS, and EN. The
BEI indexes indicate a significantly greater BoNT-A-dose escalation for BEB
patients compared with HFS or EN patients and a significantly greater BEI-% in
younger vsolder BEB patients. These results confirm a greater efficacy in the
elderly and provide a framework for long-term studies with a more flexible and
reliable evaluation of drug-dose escalation
Biophysical Basis for Three Distinct Dynamical Mechanisms of Action Potential Initiation
Transduction of graded synaptic input into trains of all-or-none action
potentials (spikes) is a crucial step in neural coding. Hodgkin identified three
classes of neurons with qualitatively different analog-to-digital transduction
properties. Despite widespread use of this classification scheme, a
generalizable explanation of its biophysical basis has not been described. We
recorded from spinal sensory neurons representing each class and reproduced
their transduction properties in a minimal model. With phase plane and
bifurcation analysis, each class of excitability was shown to derive from
distinct spike initiating dynamics. Excitability could be converted between all
three classes by varying single parameters; moreover, several parameters, when
varied one at a time, had functionally equivalent effects on excitability. From
this, we conclude that the spike-initiating dynamics associated with each of
Hodgkin's classes represent different outcomes in a nonlinear
competition between oppositely directed, kinetically mismatched currents. Class
1 excitability occurs through a saddle node on invariant circle bifurcation when
net current at perithreshold potentials is inward (depolarizing) at steady
state. Class 2 excitability occurs through a Hopf bifurcation when, despite net
current being outward (hyperpolarizing) at steady state, spike initiation occurs
because inward current activates faster than outward current. Class 3
excitability occurs through a quasi-separatrix crossing when fast-activating
inward current overpowers slow-activating outward current during a stimulus
transient, although slow-activating outward current dominates during constant
stimulation. Experiments confirmed that different classes of spinal lamina I
neurons express the subthreshold currents predicted by our simulations and,
further, that those currents are necessary for the excitability in each cell
class. Thus, our results demonstrate that all three classes of excitability
arise from a continuum in the direction and magnitude of subthreshold currents.
Through detailed analysis of the spike-initiating process, we have explained a
fundamental link between biophysical properties and qualitative differences in
how neurons encode sensory input
Present state and future perspectives of using pluripotent stem cells in toxicology research
The use of novel drugs and chemicals requires reliable data on their potential toxic effects on humans. Current test systems are mainly based on animals or in vitro–cultured animal-derived cells and do not or not sufficiently mirror the situation in humans. Therefore, in vitro models based on human pluripotent stem cells (hPSCs) have become an attractive alternative. The article summarizes the characteristics of pluripotent stem cells, including embryonic carcinoma and embryonic germ cells, and discusses the potential of pluripotent stem cells for safety pharmacology and toxicology. Special attention is directed to the potential application of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) for the assessment of developmental toxicology as well as cardio- and hepatotoxicology. With respect to embryotoxicology, recent achievements of the embryonic stem cell test (EST) are described and current limitations as well as prospects of embryotoxicity studies using pluripotent stem cells are discussed. Furthermore, recent efforts to establish hPSC-based cell models for testing cardio- and hepatotoxicity are presented. In this context, methods for differentiation and selection of cardiac and hepatic cells from hPSCs are summarized, requirements and implications with respect to the use of these cells in safety pharmacology and toxicology are presented, and future challenges and perspectives of using hPSCs are discussed
Persistent Place-Making in Prehistory: the Creation, Maintenance, and Transformation of an Epipalaeolithic Landscape
Most archaeological projects today integrate, at least to some degree, how past people engaged with their surroundings, including both how they strategized resource use, organized technological production, or scheduled movements within a physical environment, as well as how they constructed cosmologies around or created symbolic connections to places in the landscape. However, there are a multitude of ways in which archaeologists approach the creation, maintenance, and transformation of human-landscape interrelationships. This paper explores some of these approaches for reconstructing the Epipalaeolithic (ca. 23,000–11,500 years BP) landscape of Southwest Asia, using macro- and microscale geoarchaeological approaches to examine how everyday practices leave traces of human-landscape interactions in northern and eastern Jordan. The case studies presented here demonstrate that these Epipalaeolithic groups engaged in complex and far-reaching social landscapes. Examination of the Early and Middle Epipalaeolithic (EP) highlights that the notion of “Neolithization” is somewhat misleading as many of the features we use to define this transition were already well-established patterns of behavior by the Neolithic. Instead, these features and practices were enacted within a hunter-gatherer world and worldview
Configuring peer-to-peer software: an empirical study of how users react to the regulatory features of software
Presents a study undertaken to develop an understanding of how regulation takes place in IT and focuses on the regulatory features of software with regard to peer-to-peer software for MP3 file sharing, explaining that, while such software may become obsolete due to the rapidly changing technology, it still makes sense to understand some of the main aspects of the subject and reveal any research methodological issues that might prove fruitful in later applications. Explains that the main purpose of the research was to find important patterns in the process of regulation as opposed to simply generating an empirically justified theory. Describes the gathering of research data through extensive interviews conducted with 13 carefully selected interviewees about their use of seven different types of file sharing peer-to-peer applications (BearShare, AudioGalaxy, KaZaa, I-Mesh, Morpheus, WinMX, LimeWire. Concludes that the evidence suggests that during the interaction process with peer-to-peer technologies, people act in a manner that is deliberate only if they feel that a particular problem affects their own personal goals or interests