Optogenetic and potassium channel gene therapy in a rodent model of focal neocortical epilepsy.

Neocortical epilepsy is frequently drug-resistant. Surgery to remove the epileptogenic zone is only feasible in a minority of cases, leaving many patients without an effective treatment. We report the potential efficacy of gene therapy in focal neocortical epilepsy using a rodent model in which epilepsy is induced by tetanus toxin injection in the motor cortex. By applying several complementary methods that use continuous wireless electroencephalographic monitoring to quantify epileptic activity, we observed increases in high frequency activity and in the occurrence of epileptiform events. Pyramidal neurons in the epileptic focus showed enhanced intrinsic excitability consistent with seizure generation. Optogenetic inhibition of a subset of principal neurons transduced with halorhodopsin targeted to the epileptic focus by lentiviral delivery was sufficient to attenuate electroencephalographic seizures. Local lentiviral overexpression of the potassium channel Kv1.1 reduced the intrinsic excitability of transduced pyramidal neurons. Coinjection of this Kv1.1 lentivirus with tetanus toxin fully prevented the occurrence of electroencephalographic seizures. Finally, administration of the Kv1.1 lentivirus to an established epileptic focus progressively suppressed epileptic activity over several weeks without detectable behavioral side effects. Thus, gene therapy in a rodent model can be used to suppress seizures acutely, prevent their occurrence after an epileptogenic stimulus, and successfully treat established focal epilepsy

Anticonvulsant drug actions on neurons in cell culture

Two actions of clinically used antiepileptic drugs have been studied using mouse neurons in primary dissociated cell culture. The antiepileptic drugs phenytoin, carbamazepine and valproic acid were demonstrated to limit sustained high frequency repetitive firing of action potentials at free serum concentratons that are achieved in patients being treated for epilepsy. Furthermore, an active metabolite of carbamazepine also limited sustained high frequency repetitive firing while inactive metabolites of phenytoin and carbamazepine did not limit sustained high frequency repetitive firing. Phenobarbital and clinically used benzodiazepines limited sustained high frequency repetitive firing of action potentials, but only at concentrations achieved during the treatment of generalized tonic-clonic status epilepticus. Ethosuximide did not limit sustained high frequency repetitive firing even at concentrations four times those achieved in the serum of patients treated for generalized absence seizures. Phenobarbital and clinically used benzodiazepines enhanced postsynaptic GABA responses at concentrations achieved free in the serum during treatment of generalized tonic-clonic or generalized absence seizures. However, phenytoin, carbamazepine, valproic acid and ethosuximide did not modify postsynaptic GABA responses at therapeutic free serum concentrations. These results suggest that the ability of antiepileptic drugs to block generalized tonicclonic seizures and generalized tonic-clonic status epilepticus may be related to their ability to block high frequency repetitive firing of neurons. The mechanism underlying blockade of myoclonic seizures may be related to the ability of antiepileptic drugs to enhance GABAergic synaptic transmission. The mechanism underlying management of generalized absence seizures remains unclear.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41657/1/702_2005_Article_BF01243417.pd

Low back pain education and short term quality of life: a randomized trial

BACKGROUND: Different interventions can reduce the burden of the chronic low back pain. One example is the use of a 'Back School Programme'. This is a brief therapy that uses a health education method to empower participants through a procedure of assessment, education and skill development. This study aimed to evaluate to what extent the programme could improve quality of life in those who suffer from the condition. METHODS: This was a randomized controlled trial. One-hundred and two female patients with low back pain (n = 102) were randomly allocated into two groups, matched in terms of age, weight, education, socioeconomic status, occupation and some aspects of risk behavior. Group 1 (back school group, n = 50) but not group 2 (clinic group, n = 52) received the 'Back School Programme'. Then quality of life using the Short Form Health Survey (SF-36) was assessed at two time points: at baseline and at three months follow-up. The findings were compared both within and between two groups. RESULTS: The 'Back School Programme' was effective in improving patients' quality of life; significant differences were found on all eight subscales of the SF-36 for group 1. In the clinic group (group 2), improvement was observed on three scales (bodily pain, vitality and mental health) but these improvements were less than in group 1. The mean improvement over all eight subscales of the SF-36 was significantly better for the 'Back School Programme' group. CONCLUSION: The 'Back School Programme' is an effective intervention and might improve the quality of life over a period of 3 months in patients who experience chronic low back pain

Orientifolds and the Refined Topological String

We study refined topological string theory in the presence of orientifolds by counting second-quantized BPS states in M-theory. This leads us to propose a new integrality condition for both refined and unrefined topological strings when orientifolds are present. We define the SO(2N) refined Chern-Simons theory which computes refined open string amplitudes for branes wrapping Seifert three-manifolds. We use the SO(2N) refined Chern-Simons theory to compute new invariants of torus knots that generalize the Kauffman polynomials. At large N, the SO(2N) refined Chern-Simons theory on the three-sphere is dual to refined topological strings on an orientifold of the resolved conifold, generalizing the Gopakumar-Sinha-Vafa duality. Finally, we use the (2,0) theory to define and solve refined Chern-Simons theory for all ADE gauge groups

Non-Equilibrium Edge Channel Spectroscopy in the Integer Quantum Hall Regime

Heat transport has large potentialities to unveil new physics in mesoscopic systems. A striking illustration is the integer quantum Hall regime, where the robustness of Hall currents limits information accessible from charge transport. Consequently, the gapless edge excitations are incompletely understood. The effective edge states theory describes them as prototypal one-dimensional chiral fermions - a simple picture that explains a large body of observations and calls for quantum information experiments with quantum point contacts in the role of beam splitters. However, it is in ostensible disagreement with the prevailing theoretical framework that predicts, in most situations, additional gapless edge modes. Here, we present a setup which gives access to the energy distribution, and consequently to the energy current, in an edge channel brought out-of-equilibrium. This provides a stringent test of whether the additional states capture part of the injected energy. Our results show it is not the case and thereby demonstrate regarding energy transport, the quantum optics analogy of quantum point contacts and beam splitters. Beyond the quantum Hall regime, this novel spectroscopy technique opens a new window for heat transport and out-of-equilibrium experiments.Comment: 13 pages including supplementary information, Nature Physics in prin

Contribution of Cystine-Glutamate Antiporters to the Psychotomimetic Effects of Phencyclidine

Altered glutamate signaling contributes to a myriad of neural disorders, including schizophrenia. While synaptic levels are intensely studied, nonvesicular release mechanisms, including cystine–glutamate exchange, maintain high steady-state glutamate levels in the extrasynaptic space. The existence of extrasynaptic receptors, including metabotropic group II glutamate receptors (mGluR), pose nonvesicular release mechanisms as unrecognized targets capable of contributing to pathological glutamate signaling. We tested the hypothesis that activation of cystine–glutamate antiporters using the cysteine prodrug N-acetylcysteine would blunt psychotomimetic effects in the rodent phencyclidine (PCP) model of schizophrenia. First, we demonstrate that PCP elevates extracellular glutamate in the prefrontal cortex, an effect that is blocked by N-acetylcysteine pretreatment. To determine the relevance of the above finding, we assessed social interaction and found that N-acetylcysteine reverses social withdrawal produced by repeated PCP. In a separate paradigm, acute PCP resulted in working memory deficits assessed using a discrete trial t-maze task, and this effect was also reversed by N-acetylcysteine pretreatment. The capacity of N-acetylcysteine to restore working memory was blocked by infusion of the cystine–glutamate antiporter inhibitor (S)-4-carboxyphenylglycine into the prefrontal cortex or systemic administration of the group II mGluR antagonist LY341495 indicating that the effects of N-acetylcysteine requires cystine–glutamate exchange and group II mGluR activation. Finally, protein levels from postmortem tissue obtained from schizophrenic patients revealed significant changes in the level of xCT, the active subunit for cystine–glutamate exchange, in the dorsolateral prefrontal cortex. These data advance cystine–glutamate antiporters as novel targets capable of reversing the psychotomimetic effects of PCP

Long-term exposure of mouse pancreatic islets to oleate or palmitate results in reduced glucose-induced somatostatin and oversecretion of glucagon

AIMS/HYPOTHESIS: Long-term exposure to NEFAs leads to inhibition of glucose-induced insulin secretion. We tested whether the release of somatostatin and glucagon, the two other major islet hormones, is also affected. METHODS: Mouse pancreatic islets were cultured for 72 h at 4.5 or 15 mmol/l glucose with or without 0.5 mmol/l oleate or palmitate. The release of glucagon and somatostatin during subsequent 1 h incubations at 1 or 20 mmol/l glucose as well as the islet content of the two hormones were determined. Lipid-induced changes in islet cell ultrastructure were assessed by electron microscopy. RESULTS: Culture at 15 mmol/l glucose increased islet glucagon content by approximately 50% relative to that observed following culture at 4.5 mmol/l glucose. Inclusion of oleate or palmitate reduced islet glucagon content by 25% (at 4.5 mmol/l glucose) to 50% (at 15 mmol/l glucose). Long-term exposure to the NEFA increased glucagon secretion at 1 mmol/l glucose by 50% (when islets had been cultured at 15 mmol/l glucose) to 100% (with 4.5 mmol/l glucose in the culture medium) and abolished the inhibitory effect of 20 mmol/l glucose on glucagon secretion. Somatostatin content was unaffected by glucose and lipids, but glucose-induced somatostatin secretion was reduced by approximately 50% following long-term exposure to either of the NEFA, regardless of whether the culture medium contained 4.5 or 15 mmol/l glucose. Ultrastructural evidence of lipid deposition was seen in <10% of non-beta cells but in >80% of the beta cells. CONCLUSIONS/INTERPRETATION: Long-term exposure to high glucose and/or NEFA affects the release of somatostatin and glucagon. The effects on glucagon secretion are very pronounced and in type 2 diabetes in vivo may aggravate the hyperglycaemic effects due to lack of insulin

MIS Distal Metatarsal Metaphyseal Osteotomy in the treatment of metatarsalgia: MOXFQ patient reported outcomes

Baer, Gillian - ORCID 0000-0002-1528-2851 https://orcid.org/0000-0002-1528-2851Introduction The aim of this paper is to present validated patient reported outcomes for MIS Distal Metatarsal Metaphyseal Osteotomy (DMMO) in the treatment of metatarsalgia. We aim to evaluate the DMMO procedure, report patient satisfaction with the operated foot and report any complications of this procedure.Patients and Methods Between 2014 and 2016, patients who had failed conservative treatment for metatarsalgia were identified in the orthopaedic outpatient clinic. Twenty four consecutive patients requiring DMMO plus/minus toe straightening were prospectively studied. Patients requiring additional procedures at the time of surgery were excluded. Patients completed the validated Manchester-Oxford Foot Questionnaire (MOXFQ) three weeks pre-operatively and 1 year postoperatively. The MOXFQ results were analysed using Paired t-tests. A supplementary question was asked regarding patient satisfaction with the operated foot.Results There were 20 women and 4 men with a mean age of 64 years (sd 8.6). Statistically significant differences were found between the pre and postoperative MOXFQ. The postoperative MOXFQ score demonstrated a poorer result for two patients, no change for two patients and improvement in 20 patients, with four of these patients recording the lowest possible score. There was a 29.5 point improvement in mean metric MOXFQ Index score. Seventy-nine percent (n=19) of patients were satisfied or very satisfied with the operated foot. The average recoil of the metatarsal heads following DMMO was M2 4.01mm, M3 4.55mm, M4 4.16mm. There was one delayed union and no non-unions. Further reported complications were a gastric bleed, pulmonary embolism (VTE), and one intra operative broken burr.Conclusion Our study demonstrates a clinically important and statistically significant improvement in patient reported outcomes following DMMO, with 79% of patients satisfied or very satisfied with this procedure. The average recoil of the metatarsal heads following DMMO was M2 4.01mm, M3 4.55mm, M4 4.16mm with one delayed union and no non-unions.https://doi.org/10.1016/j.foot.2019.10166143pubpu