Refractory Reduction Research Articles

The Kv7 potassium channel activator flupirtine affects clinical excitability parameters of myelinated axons in isolated rat sural nerve

Flupirtine is an activator of Kv7 (KCNQ/M) potassium channels that has found clinical use as an analgesic with muscle relaxant properties. Kv7 potassium channels are expressed in axonal membranes and pharmacological activation of these channels may restore abnormal nerve excitability. We have examined the effect of flupirtine on the electrical excitability of myelinated axons in isolated segments of rat sural nerve. Axonal excitability was studied in vitro with the same parameters used by clinical neurophysiologists to assess peripheral nerve excitability in situ. Application of flupirtine in low micromolar concentrations resulted in an increase in threshold current, a reduction of refractoriness and an increase in post-spike superexcitability. These effects are consistent with an increase in Kv7 conductance and membrane hyperpolarization. Flupirtine also enhanced and prolonged the late, long-lasting period of axonal subexcitability that follows a short burst of action potentials. This effect was blocked by XE 991 (10 microM), an antagonist of Kv7 channels. In summary, flupirtine affects measures of excitability that are altered in the myelinated axons of patients with peripheral nerve disorders. This indicates that neuropathies with abnormal nerve excitability parameters corresponding to those affected by flupirtine may benefit from activation of axonal Kv7 potassium channels.

Axonal function in a family with episodic ataxia type 2 due to a novel mutation

Episodic ataxia type 2(EA-2) is a rare, autosomal dominant disorder characterised by recurrent episodes of ataxia and dysarthria,due to mutations in the CACNA1A gene on chromosome 19 encoding voltage-dependent Ca2+ channels. The aim of the present study was to explore whether axonal membrane properties, assessed using nerve excitability techniques, were abnormal in patients with EA-2 . Nerve excitability techniques were applied to the median nerve of three individuals from three generations of a single family, all of whom had typical features of EA-2. This family was found to have a novel mutation at codon 1451 of the Ca2+ channel alpha 1A subunit. Nerve excitability testing demonstrated significant abnormalities,with all patients outside the normal 95 % confidence limits in having a high rheobase and reduced early hyperpolarizing threshold electrotonus. On average there were also significant reductions in refractoriness,late sub excitability and early depolarizing threshold electrotonus. Mathematical modelling indicated that a similar pattern of abnormalities may result from a reduced voltage dependence of slow K+ channels (KCNQ channels). There are significant and distinctive changes in peripheral nerve excitability in EA-2 patients,which are presumably induced indirectly. These findings raise the possibility that excitability testing may prove a convenient screening test for patients with this suspected channelopathy.

Altered nerve excitability properties in established diabetic neuropathy

The underlying cause of diabetic neuropathy remains unclear, although pathological studies have suggested an ischaemic basis related to microangiopathy, possibly mediated through effects on the energy-dependent Na+/K+ pump. To investigate the pathophysiology of diabetic neuropathy, axonal excitability techniques were undertaken in 20 diabetic patients with neuropathy severity graded through a combination of quantitative sensory testing (QST) using a vibratory stimulus, assessment of symptom severity using the Total Neuropathy Symptom Score (T-NSS) and measurement of glycosylated haemoglobin as a marker of disease control. To assess axonal excitability, compound muscle action potentials were recorded at rest from abductor pollicis brevis following stimulation of the median nerve, and stimulus-response behaviour, threshold electrotonus, a current-threshold relationship and the recovery of excitability were recorded in each patient. All patients had established neuropathy, with abnormalities of T-NSS present in all patients and QST abnormalities present in 65%. Compared with controls, diabetic neuropathy patients had significant reduction in maximal CMAP amplitude (P < 0.0005), accompanied by a 'fanning in' of threshold electrotonus. In addition, the strength-duration time constant was decreased in diabetic neuropathy patients and recovery cycles were altered with reductions in refractoriness, the duration of the relative refractory period, superexcitability and subexcitability. It is proposed that while the changes in threshold electrotonus with supportive findings in the current-threshold relationship are consistent with axonal depolarization, possibly mediated by a decrease in Na+/K+ pump activity, the alterations in the recovery cycle of excitability could be explained on the basis of a smaller action potential, reflecting a limitation on the nodal driving current imposed by a reduction in Na+ conductances.

ABO and platelet transfusion revisited

Historically, ABO compatibility between donor and recipient has been considered of minor importance for platelet transfusion. However, in a recent randomized trial we showed that provision of only ABO-identical platelets was associated with a significantly higher corrected count increment (CCI) in the early transfusions and with a twofold reduction in refractoriness, as compared with platelets given unmatched for ABO. In older studies this phenomenon was not observed. We wondered whether in these previous studies the use of the conventional term "ABO compatible", whereby ABO-identical platelet transfusions are grouped with those that are merely ABO compatible, might have obscured the advantages of the ABO-identical platelets. In this paper the CCI from our original study are compared with what would have been found had the conventional terminology of "ABO compatible" and "ABO incompatible" been used. In our original study the mean CCI in patients receiving only ABO-identical platelets was 64% higher than that achieved with ABO-unmatched products. However, when the transfusions were reanalyzed according to conventional terminology of ABO "compatible" and "incompatible," the actual benefits of ABO-identical platelets were no longer detected. Thus, had we used the conventional terminology in the original study we would have come to completely different conclusions about the importance of ABO in platelet transfusion. We hypothesize that transfusion of ABO-incompatible plasma leads to the formation of immune complexes that can destroy compatible platelets by indirect mechanisms. This model predicts that the success of a transfusion could be affected by previous incompatible transfusions. When transfusions were classified as to whether they were first, second, or third unmatched transfusion, increasing numbers of transfusions of ABO-incompatible plasma were associated with progressively poorer mean increments. The same was true for platelet ABO-incompatible transfusions. In contrast, increasing numbers of ABO-identical transfusions were not associated with poorer increments. The failure to appreciate that (a) transfusions containing ABO-incompatible plasma yield poor increments and (b) the effects of ABO-nonidentical transfusions are cumulative, and therefore affect the success of subsequent identical transfusions, may have led in the past to the incorrect conclusion that ABO matching was of minor importance in repetitively transfused patients.

Changes in high alumina brick used in hot air stoves

Aluminous brick made by the Semiluks Refractories Plant containing 60% Al2O3 sinters intensely, with sharp changes in properties and reductions in refractoriness from 1810 to 1750°C when used at temperatures of 1500–1600°C. The least-change zone and working zone of the refractory consist mainly of mullite and glassy substance. The amount of mullite increases in the direction from the least-change to the working zone. It is necessary to use high alumina refractories with a higher content of Al2O3 (70–72%), preferably with increased density, in order to increase the life of the linings in hot air stoves.

Highly refractory' material based on magnesia spinel

An increase in the content of commercial alumina in magnesite refractory body to a ratio of MgO∶Al2O3 =1.3, corresponds to an increase in the refractoriness-under-load and 4% compression, increases the spalling resistance with a certain reduction in refractoriness.