Cost comparison of asthma treatments in 12-week study : caution about matching and short observational follow-up

This review was funded by Observational and Pragmatic Research Institute Pte Ltd.Peer reviewedPublisher PD

Hypoglossal motoneurons: a model to investigate physiological and pathophysiological properties of brainstem motoneurons

Hypoglossal motoneurons (HMs) are brainstem neurons that command rhytmic contraction of the tongue muscles during breathing as well as a variety of non-respiratory functions such as sleep, vocalization, suckling and swallowing. Neurodegenerative diseases like amyotrophic lateral sclerosis (ALS; Lou-Gehrig disease) often damage HMs with distressing symptoms like dysarthria, dysphagia and breathing failure..

A repertoire of rhythmic bursting produced by hypoglossal motoneurons in physiological and pathological conditions

The brainstem nucleus hypoglossus contains motoneurons that provide the exclusive motor nerve supply to the tongue. In addition to voluntary tongue movements, tongue muscles rhythmically contract during a wide range of physiological activities, such as respiration, swallowing, chewing and sucking. Hypoglossal motoneurons are destroyed early in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease often associated with a deficit in the transport system of the neurotransmitter glutamate

From bench to patient: model systems in drug discovery

Model systems, including laboratory animals, microorganisms, and cell- and tissue-based systems, are central to the discovery and development of new and better drugs for the treatment of human disease. In this issue, Disease Models & Mechanisms launches a Special Collection that illustrates the contribution of model systems to drug discovery and optimisation across multiple disease areas. This collection includes reviews, Editorials, interviews with leading scientists with a foot in both academia and industry, and original research articles reporting new and important insights into disease therapeutics. This Editorial provides a summary of the collection's current contents, highlighting the impact of multiple model systems in moving new discoveries from the laboratory bench to the patients' bedsides

Translational approach for gene therapy in epilepsy:Model system and unilateral overexpression of neuropeptide Y and Y2 receptors

Although novel treatment strategies based on the gene therapy approach for epilepsy has been encouraging, there is still a gap in demonstrating a proof-of-concept in a clinically relevant animal model and study design. In the present study, a conceptually novel framework reflecting a plausible clinical trial for gene therapy of temporal lobe epilepsy was explored: We investigated (i) whether the post intrahippocampal kainate-induced status epilepticus (SE) model of chronic epilepsy in rats could be clinically relevant; and (ii) whether a translationally designed neuropeptide Y (NPY)/Y2 receptor-based gene therapy approach targeting only the seizure-generating focus unilaterally can decrease seizure frequency in this chronic model of epilepsy. Our data suggest that the intrahippocampal kainate model resembles the disease development of human chronic mesial temporal lobe epilepsy (mTLE): (i) spontaneous seizures originate in the sclerotic hippocampus; (ii) only a part of the animals develops chronic epilepsy; (iii) animals show largely variable seizure frequency that (iv) tends to progressively increase over time. Despite significant hippocampal degeneration caused by kainate injection, the use of MRI allowed targeting the recombinant adeno-associated viral (rAAV) vectors encoding NPY and Y2 receptor genes to the remaining dorsal and ventral hippocampal areas ipsilateral to the kainate injection. Continuous video-EEG monitoring demonstrated not only prevention of the progressive increase in seizure frequency in rAAV-NPY/Y2 treated animals as compared to the controls, but even 45% decrease of seizure frequency in 80% of the epileptic animals. This translationally designed study in a clinically relevant model of epilepsy suggests that simultaneous overexpression of NPY and Y2 receptors unilaterally in the seizure focus is a relevant and promising approach that can be further validated in more extensive preclinical studies to develop a future treatment strategy for severe, often pharmacoresistant focal epilepsy cases that cannot be offered alternative therapeutic options

Flexible use of allocentric and egocentric spatial memories activates differential neural networks in mice

Goal-directed navigation can be based on world-centered (allocentric) or body-centered (egocentric) representations of the environment, mediated by a wide network of interconnected brain regions, including hippocampus, striatum and prefrontal cortex. The relative contribution of these regions to navigation from novel or familiar routes, that demand a different degree of flexibility in the use of the stored spatial representations, has not been completely explored. To address this issue, we trained mice to find a reward relying on allocentric or egocentric information, in a modified version of the cross-maze task. Then we used Zif268 expression to map brain activation when well-trained mice were required to find the goal from a novel or familiar location. Successful navigation was correlated with the activation of CA1, posterior-dorsomedial striatum, nucleus accumbens core and infralimbic cortex when allocentric-trained mice needed to use a novel route. Allocentric navigation from a familiar route activated dorsomedial striatum, nucleus accumbens, prelimbic and infralimbic cortex. None of the structures analyzed was significantly activated in egocentric-trained mice, irrespective of the starting position. These data suggest that a flexible use of stored allocentric information, that allows goal finding even from a location never explored during training, induces a shift from fronto-striatal to hippocampal circuits

Differential Effect of Neuropeptides on Excitatory Synaptic Transmission in Human Epileptic Hippocampus

Development of novel disease-modifying treatment strategies for neurological disorders, which at present have no cure, represents a major challenge for today's neurology. Translation of findings from animal models to humans represents an unresolved gap in most of the preclinical studies. Gene therapy is an evolving innovative approach that may prove useful for clinical applications. In animal models of temporal lobe epilepsy (TLE), gene therapy treatments based on viral vectors encoding NPY or galanin have been shown to effectively suppress seizures. However, how this translates to human TLE remains unknown. A unique possibility to validate these animal studies is provided by a surgical therapeutic approach, whereby resected epileptic tissue from temporal lobes of pharmacoresistant patients are available for neurophysiological studies in vitro. To test whether NPY and galanin have antiepileptic actions in human epileptic tissue as well, we applied these neuropeptides directly to human hippocampal slices in vitro. NPY strongly decreased stimulation-induced EPSPs in dentate gyrus and CA1 (up to 30 and 55%, respectively) via Y2 receptors, while galanin had no significant effect. Receptor autoradiographic binding revealed the presence of both NPY and galanin receptors, while functional receptor binding was only detected for NPY, suggesting that galanin receptor signaling may be impaired. These results underline the importance of validating findings from animal studies in human brain tissue, and advocate for NPY as a more appropriate candidate than galanin for future gene therapy trials in pharmacoresistant TLE patients

Measurement of prompt D+D^+ and Ds+D^+_{s} production in pPbp\mathrm{Pb} collisions at sNN=5.02 \sqrt {s_{\mathrm{NN}}}=5.02\,TeV

International audienceThe production of prompt $D^+$ and $D^+_{s}$ mesons is studied in proton-lead collisions at a centre-of-mass energy of $\sqrt {s_{\mathrm{NN}}}=5.02\,$TeV. The data sample corresponding to an integrated luminosity of $(1.58\pm0.02)\mathrm{nb}^{-1}$ is collected by the LHCb experiment at the LHC. The differential production cross-sections are measured using $D^+$ and $D^+_{s}$ candidates with transverse momentum in the range of $0<p_{\mathrm{T}} <14\,\mathrm{GeV}/c$ and rapidities in the ranges of $1.5<y^*<4.0$ and $-5.0<y^*<-2.5$ in the nucleon-nucleon centre-of-mass system. For both particles, the nuclear modification factor and the forward-backward production ratio are determined. These results are compared with theoretical models that include initial-state nuclear effects. In addition, measurements of the cross-section ratios between $D^+$, $D^+_{s}$ and $D^0$ mesons are presented, providing a baseline for studying the charm hadronization in lead-lead collisions at LHC energies

Measurement of prompt D+D^+ and Ds+D^+_{s} production in pPbp\mathrm{Pb} collisions at sNN=5.02 \sqrt {s_{\mathrm{NN}}}=5.02\,TeV

International audienceThe production of prompt $D^+$ and $D^+_{s}$ mesons is studied in proton-lead collisions at a centre-of-mass energy of $\sqrt {s_{\mathrm{NN}}}=5.02\,$TeV. The data sample corresponding to an integrated luminosity of $(1.58\pm0.02)\mathrm{nb}^{-1}$ is collected by the LHCb experiment at the LHC. The differential production cross-sections are measured using $D^+$ and $D^+_{s}$ candidates with transverse momentum in the range of $0<p_{\mathrm{T}} <14\,\mathrm{GeV}/c$ and rapidities in the ranges of $1.5<y^*<4.0$ and $-5.0<y^*<-2.5$ in the nucleon-nucleon centre-of-mass system. For both particles, the nuclear modification factor and the forward-backward production ratio are determined. These results are compared with theoretical models that include initial-state nuclear effects. In addition, measurements of the cross-section ratios between $D^+$, $D^+_{s}$ and $D^0$ mesons are presented, providing a baseline for studying the charm hadronization in lead-lead collisions at LHC energies