Open-label study of etanercept treatment in patients with moderate-to-severe plaque psoriasis who lost a satisfactory response to adalimumab.

BACKGROUND: Some patients with plaque psoriasis experience secondary failure of tumour necrosis factor inhibitor therapy. OBJECTIVES: To evaluate efficacy, safety and patient-reported outcomes (PROs) with etanercept in patients with secondary adalimumab failure. METHODS: This phase IV open-label single-arm estimation study (NCT01543204) enrolled patients on adalimumab who had achieved static Physician's Global Assessment (sPGA) score 0/1 (clear/almost clear). Patients subsequently lost response, defined as sPGA ≥ 3 or loss of 50% improvement in Psoriasis Area and Severity Index (PASI 50). At baseline, patients had involved body surface area ≥ 10%, sPGA ≥ 3 and PASI ≥ 10. Antiadalimumab antibodies (ADAs) were measured at screening. Patients received etanercept 50 mg twice weekly for 12 weeks, followed by 50 mg weekly. The primary end point was sPGA 0/1 at week 12 (intention-to-treat analysis; no hypothesis tested). Additional outcomes included rates of sPGA 0/1, PASI responses, safety, PROs of itch, pain and flaking, Dermatology Life Quality Index, treatment satisfaction and Work Productivity and Activity Impairment questionnaire. RESULTS: Sixty-four patients enrolled; 67% had ADAs. sPGA 0/1 rates at week 12 were 39·7% [95% confidence interval (CI) 27·6-52·8; primary end point] and 45% (95% CI 29·3-61·5) for patients positive for ADAs and 35% (95% CI 15·4-59·2) for patients negative for ADAs. PASI 75 response rates at week 12 were 47·5% (95% CI 31·5-63·9) for patients who were positive for ADAs and 50% (95% CI 27·2-72·8) for patients negative for ADAs. No new safety signals were observed. PROs of itch, pain and flaking consistently improved at week 12 and were maintained through week 24. CONCLUSIONS: Patients with psoriasis who experienced secondary failure of adalimumab achieved satisfactory response to etanercept regardless of ADA status.

Simple models of stimulation of neurones in the brain by electric fields.

The excitation of pyramidal cells in the motor cortex, produced by electric fields generated by distant electrodes or by electromagnetic induction, has been modelled. Linear, steady-state models of myelinated axons capture most of the geometrical aspects of neurone activation in electric fields. Some non-linear features can be approximated. Models with a proximal sealed-end and distal infinite axon, or of finite length, are both serviceable. Surface anodal stimulation produces hyperpolarisation of the proximal axon (closest to the anode) and depolarisation in the distal axon. The point of maximum depolarisation can be influenced by the location of the cathode (greater separation of anode and cathode causes more distal depolarisation). Axon bends can produce very localised depolarisation. Cathodal stimulation may be less effective than anodal as a result of anodal block of conduction of action potentials in the distal axon. The latencies of responses to anodal stimulation, recorded in the distal axon, will decrease as the stimulus strength is increased and the point of action potential initiation moves distally node by node. Larger jumps in latency will be produced when the point of action potential initiation moves from one axon bend to another.

Vestibular-evoked muscle responses in patients with spinal cord injury.

The vestibular system was activated by galvanic electrical stimulation in 22 patients with spinal cord injury. Three patients were studied standing and all were studied sitting. Electromyographic responses recorded in soleus (standing patients) and the erectores spinae (all patients) were compared with data from 18 control subjects. The vestibular stimulus polarity and head position were arranged so as to produce excitatory medium latency muscle responses in the controls. Responses in the patient group were present bilaterally, present unilaterally or absent below the level of injury. The amplitude of response recorded in erectores spinae at lumbar levels below the lesion in 21 patients (left and right side responses summed) and five control subjects was positively correlated with American Spinal Injuries Association (ASIA) grade: the smallest amplitudes were found in patients with the most severe impairment (Spearman rank correlation coefficient rs = 0.59; P = 0.002, two-tailed). The latency of response (averaged for both sides) was negatively correlated with ASIA grade in 21 patients: the longest latencies were found in patients with the most severe impairment (rs = -0.57; P < 0.01, two-tailed). Amplitude and latency were negatively correlated (rs = -0.72, P < 0.002, two-tailed). The latencies of responses recorded in the erectores spinae at different vertebral levels were linearly related to the vertical distance from the inion to the recording site in both patient and control groups. The conduction velocities of the spinal pathways activated by vestibular stimulation were 4.6 and 10.4 m/s in patient (recording below lesion) and control groups, respectively. Both clinical status (patients recording below lesion, patients recording above lesion and controls) and distance were significant predictors of latency (general linear model, P < 0.0005). It is concluded that measurement of vestibular-evoked responses could provide information on the level and density of spinal cord lesions.

Vestibular actions on back and lower limb muscles during postural tasks in man.

The vestibular system was activated by galvanic electrical stimulation in 19 normal subjects. With the head turned to one side so that the stimulating anode was on the posterior mastoid process, stimulation caused standing subjects to sway backwards in the sagittal plane. Electromyography showed bilateral activation of erector spinae, gluteus maximus, biceps femoris, soleus and intrinsic foot (toe flexor) muscles. When head direction or electrode polarity was reversed so that the anode was anterior, all those muscles became less active and the subjects swayed forwards. With the head facing forward, stimulation caused sideways sway in the coronal plane, towards the anode, with excitation of the erector spinae on the anode side and reduced activity on the cathode side. The limb muscles were activated on the side opposite the anode and showed complex responses on the anode side. Responses were detectable in the erectores spinae muscles in sitting subjects. No responses in limb muscles were detected in the sitting posture. Subject responses in erector spinae recorded at L3/L4 had latencies from 59 to 110 ms, using a 2 mA stimulus. Latencies in lower limb muscles were longer. The results suggest a role for the vestibular system and descending brain stem motor pathways to the erectores spinae muscles in the control of postural orientation of the back when sitting and standing. The conduction velocity in the motor pathway was estimated to be 13 +/- 10 m s(-1) (mean +/- S.D., n = 12 subjects).

Prior test experience compromises the anxiolytic efficacy of chlordiazepoxide in the mouse light/dark exploration test.

It is now well established that prior test experience can alter behavioural baselines and attenuate/abolish the anxiolytic efficacy of benzodiazepines in the elevated plus-maze paradigm. In view of evidence that different models of anxiety measure qualitatively distinct forms of anxiety-like behaviour, it is important to establish whether the effects of prior experience extend to other widely-used tests. The present study assessed the behavioural and pharmacological sequelae of a single undrugged prior exposure to the light/dark exploration (L/D) test in mice, using ethological scoring methods. One group of adult male Swiss-Webster mice was given a single undrugged exposure to the L/D test 24 h prior to drug testing, while another group was completely naïve to the apparatus. On test day, half the animals in each experiential condition were treated with saline and half with an anxiolytic dose (10 mg/kg) of chlordiazepoxide (CDP). When administered to test-naïve animals, CDP induced a clear reduction in anxiety-like behaviour as evidenced by significant increases in exploration of the light compartment (line crossings, % line crossings, and % time) as well as reductions in stretched attend postures (SAPs) and the proportion of SAPs displayed toward the light compartment. The behavioural specificity of these effects was confirmed by the absence of a drug effect on line crossings in the dark compartment, total rearing and grooming. In complete contrast, with the sole exception of a decrease in total SAPs, CDP was without significant behavioural effect in test-experienced mice. As prior test experience did not significantly alter behavioural baselines in the L/D test, a second experiment was designed to investigate the possibility that handling/intraperitoneal injection may have precluded detection of experientially-induced changes in baseline behaviour. Results showed that handling/injection had no effect upon L/D behavioural profiles in either test-naïve or test-experienced subjects, and confirmed that prior experience itself did not modify the primary indices of anxiety in this test. Present data indicate that prior test experience seriously compromises the anxiolytic efficacy of CDP (10 mg/kg) in the mouse L/D test and, together with recent findings in the four-plate test, appear to confirm that an experientially-induced reduction in sensitivity to the anxiolytic effects of benzodiazepines is by no means unique to the elevated plus-maze.

Task-related changes of transmission in the pathway of heteronymous spinal recurrent inhibition from soleus to quadriceps motor neurones in man.

An H reflex conditioning technique was used to monitor the transmission of heteronymous recurrent inhibition from soleus to quadriceps motor neurones of the human lower limb. Inhibition declined during quadriceps muscle contraction under all conditions examined, falling to zero at around one-third of the maximum voluntary contraction. Inhibition declined during soleus muscle contraction in sitting, standing and bicycling tasks. The level of inhibition assessed at a given (weaker than 30%) level of quadriceps contraction was reduced during postural tasks involving quadriceps and soleus co-contraction (standing and late-stance phase of walking) when compared with sitting and performing matched voluntary muscle contractions. The level of inhibition during the mid-power stroke of a bicycling task, which also involved co-contraction of quadriceps and soleus, was greater than during matched voluntary muscle contractions while sitting. It is concluded that the pathway of heteronymous recurrent inhibition from soleus to quadriceps motor neurones is under at least two types of control: one related to the task, which sets the operating range, and a second which couples inhibition to the level of muscle contraction. Multiple control pathways are consistent with the diverse effects on recurrent inhibition reported in subjects with upper motor neurone lesions.

Visual search performance in dyslexia.

According to the magnocellular theory of dyslexia, otherwise intelligent children may fail to learn to read because of abnormalities in the magnocellular layers of the lateral geniculate nucleus (mLGN). If this were the case, one would predict that dyslexic subjects who show a deficit on low-level psychophysical tasks which tax the magnocellular system would also have deficits on higher-level visual tasks which do not rely on the properties of mLGN cells but depend upon the functioning of areas whose main inputs originate in the mLGN. In other words, magnocellular deficits should be traceable at later stages of visual processing. One area where such later processing is thought to occur is the posterior parietal cortex, damage to which impairs function on some classes of visual search. To test this hypothesis, we tested two groups of dyslexic subjects and a group of non-dyslexic controls on a range of visual search tasks. One group of dyslexic subjects had elevated motion coherence thresholds, a sign of deficits at the early levels (e.g. mLGN) of visual processing, and the other group had normal motion coherence thresholds. If the magnocellular deficits extended to the parietal cortex, it follows that the subjects with elevated motion coherence thresholds should have deficit in visual search, whereas those with normal motion coherence thresholds should not. The dyslexics with a motion coherence deficit were also impaired on serial visual search tasks but not on a parallel search. The dyslexics with normal motion coherence performance were unimpaired on visual search. The deficit was expressed as an elevation in reaction times, but there was no difference between the groups either in error rates or in the way the tasks were ranked according to difficulty. The results suggest that those dyslexics who have visual problems related to magnocellular functions also have visual-attentional problems related to the functions of areas such as the parietal cortex, which are dominated by inputs originating in the magnocellular LGN.

Responses of 11 Fraxinus Cultivars to Ash Yellows Phytoplasma Strains of Differing Aggressiveness.

Five cultivars of Fraxinus americana (white ash) and five of F. pennsylvanica (green ash) were graft-inoculated with three strains of ash yellows phytoplasmas at Ames, IA, and with thrsee other strains at Ithaca, NY. A sixth green ash cultivar was tested only in New York. Trees were allowed to grow in field plots for 3 years. Infection was detected via the DAPI (4', 6-diamidino-2-phenylindole 2HCl) fluorescence test. Incidence of witches'-brooms on infected trees was greater on white ash than green ash and varied significantly among phytoplasma strain treatments at both locations. Volume growth of infected ash, averaged across cultivars over 2 years in Iowa and 3 years in New York, was 49 and 59%, respectively, as great as that of noninfected trees. Foliar greenness was reduced significantly by infection at both locations, and this reduction was positively correlated with growth reduction. Cultivars at each location varied significantly in growth of noninfected trees and in growth of diseased trees relative to that of nonin-fected trees (a measure of phytoplasma tolerance), but cultivar means for these variables in Iowa were not significantly correlated with those in New York. Green ash cvs. Bergeson, Dakota Centennial, and Patmore and white ash cv. Autumn Applause were above average in tolerance at both locations. Phytoplasma strains at each location varied significantly in aggressiveness as indicated by host growth suppression.

Changes in transmission in the pathway of heteronymous spinal recurrent inhibition from soleus to quadriceps motor neurons during movement in man.

H reflexes were induced in the human quadriceps muscle by electrical stimulation of the femoral nerve. The reflexes were conditioned by prior stimulation of the inferior soleus nerve. The conditioning stimulus produced an inhibition of long duration (>20 ms). The threshold of this inhibition was at zero soleus motor discharge and the inhibition scaled with soleus motor discharge. It was concluded that the inhibition was a heteronymous recurrent inhibition of quadriceps motor neurons mediated by Renshaw cells which had been activated by soleus motor neuron discharge. This recurrent inhibition declined during voluntary tonic contraction of the quadriceps, falling to zero at around one-third of maximum voluntary contraction. Antagonist contraction and weak co-contraction of the quadriceps and its antagonists did not lead to any significant change in recurrent inhibition. It is concluded that motor commands descending from the brain reduce heteronymous recurrent inhibition during isolated quadriceps muscle contraction, but to a much lesser extent during co-contraction. No evidence was obtained for any descending facilitation of heteronymous recurrent inhibition.

Fictive locomotion in the adult decerebrate rat.

In adult immobilised, decerebrate rats, administration of L-3,4-dihydroxyphenylalanine, stimulation of the mesencephalic locomotor centre, or a combination of the two elicited fictive locomotor patterns in hindlimb muscle nerves. The patterns correspond closely to those observed in decerebrate animals that were free to move.

Evidence for cutaneous and corticospinal modulation of presynaptic inhibition of Ia afferents from the human lower limb.

1. Presynaptic inhibition of soleus muscle Ia afferent fibres, produced by stimulation of group I afferents in the common peroneal nerve, was assessed from changes in the H reflex at long conditioning intervals, in six normal subjects. 2. Stimulation of the ipsilateral sural nerve at the malleolus, just before stimulation of the common peroneal nerve at the head of the fibula, decreased the presynaptic inhibition. This effect was strongest during voluntary plantar flexion and weaker during dorsiflexion or at rest. 3. Stimulation of other cutaneous nerve branches serving the dorsum of the ipsilateral foot, and also the contralateral sural nerve, decreased presynaptic inhibition. Adequate stimulation of low threshold cutaneous mechanoreceptors by light brushing of both distal dorsal and plantar surfaces of the ipsilateral foot decreased presynaptic inhibition. 4. Stimulation of the ipsilateral plantar nerves increased presynaptic inhibition, but this action is attributed to activation of group I afferents from the intrinsic muscles of the foot. 5. Transcranial magnetic stimulation of the lower limb area of the contralateral motor cortex decreased presynaptic inhibition. This effect was strongest during voluntary plantar flexion and weaker during dorsiflexion or at rest. 6. The actions of cutaneous and corticospinal pathways completely occluded each other. However, when both effects were adjusted to be liminal, a spatial facilitation between them was observed. 7. It is concluded that in man, as in the cat, cutaneous and corticospinal axons converge on interneurones that inhibit the machinery of presynaptic inhibition of group Ia afferents. These actions may be responsible for the modulation of presynaptic inhibition which has been observed to precede and accompany a wide range of human movements.

Tritium isotope effect in high-performance liquid chromatography of eicosanoids.

A significant difference in retention time between unlabeled and the corresponding multi-tritium-labeled eicosanoid has been observed in the high performance liquid chromatography (HPLC) analysis of 11 eicosanoids. Variations in retention time range from 3-7%, depending on the separation conditions as well as the number and position of the tritium substitution. Multi-tritium-labeled eicosanoids were eluted earlier than the corresponding unlabeled eicosanoid in reversed phase HPLC, whereas no isotope effect was seen with 14C- and 3H2-eicosanoids. Considerations must be given to this tritium isotope effect whenever both multi-tritium-labeled and unlabeled eicosanoids are used for HPLC cochromatography or recovery studies.

14(R),15(S)-epoxyeicosatrienoic acid (14(R),15(S)-EET) receptor in guinea pig mononuclear cell membranes.

A high affinity binding site for 14(R),15(S)-EET, one of the major cytochrome P-450 metabolites of arachidonic acid (AA) in blood vessels, liver, kidney and urine of patients with pregnancy-induced hypertension, has been identified in a membrane preparation from guinea pig mononuclear (GPM) cells. Using a radioligand assay, binding of 14(R),15(S)-[3H]EET to its receptor site was saturable, specific and reversible. Scatchard analysis of saturation binding studies yielded a dissociation constant (Kd) of 5.7 x 10(-9) M, and maximum number of binding sites (Bmax) of 2.4 pmol/mg membrane protein. The specificity of the binding site was determined by competition studies. 14(S),15(R)-EET and 8,9-EET had a Ki of 6.3 and 8.8 nM, respectively, followed by 12(R)-HETE and LTD4. 12(S)-HETE and 5,6-EET were even less effective as a competitive inhibitor of radioligand and binding with Ki values from 2 to 20 microM. Receptor antagonists for TxA2, LTB4, LTD4 and PAF failed to displace 14(R),15(S)-[3H]EET from its binding site on GPM cell membranes. The results correlate well with the reported biological functions of 14,15-EET. In view of its potent biological activities, 14,15-EET may exert its cellular function through the binding and activation of its stereo-specific cell surface binding sites or receptor.

Vestibular-evoked postural reactions in man and modulation of transmission in spinal reflex pathways.

1. The effects of galvanic stimulation of the vestibular apparatus (with electrodes on the mastoid processes) have been studied in standing human subjects. With the head turned to one side, subjects swayed towards the anode. 2. Forwards sway was preceded by electromyographic (EMG) activity in quadriceps and tibialis anterior muscles. Backwards sway was preceded by EMG activity in soleus and hamstring muscles. 3. Using the method of H reflex conditioning, forward sway was found to be preceded by inhibition of soleus motoneurones. 4. Interaction between the vestibular-evoked inhibition of soleus motoneurones preceding forwards sway and peripheral reflex inhibition was examined by a spatial facilitation method. 5. Interaction was found between vestibular-evoked inhibition and Ia reciprocal, group I non-reciprocal and group Ia-Ia presynaptic inhibitory pathways. It is concluded that vestibular signals converge on spinal interneurones subserving these inhibitory actions. 6. A 'decoupling' of soleus motoneurons and soleus-coupled Renshaw cells was found in the period of soleus activation preceding backwards sway.

Cortical modulation of transmission in spinal reflex pathways of man.

1. The motor actions in the lower limb of transcranial electrical stimulation of the motor cortex have been studied in sitting human subjects. 2. Cortical stimulation induced a short latency inhibition of H reflexes evoked in soleus motoneurones both at rest and during small voluntary contractions of soleus. 3. Spatial interaction between cortical inhibition of soleus motoneurons and inhibition evoked through identified spinal reflex machinery was investigated. 4. Interactions were found between cortically evoked inhibition and spinal Ia reciprocal inhibition, group I non-reciprocal inhibition and higher threshold components of longer latency reciprocal inhibition (D1 and D2 inhibitions). 5. Interactions were facilitatory when cortical and spinal inhibitory actions were weak and reversed to occlusion when both actions were strong. 6. It is concluded that the corticospinal pathway converges on the interneurones which subserve Ia reciprocal, group I non-reciprocal, D1 and D2 inhibition of soleus motoneurones. 7. No significant interaction was found under the present experimental conditions between cortical stimulation and group Ia-Ia presynaptic inhibition of soleus afferents. 8. The statistical significance of spatial interactions observed with H reflex conditioning was investigated using a control experiment.

Reflex actions of knee joint afferents during contraction of the human quadriceps.

(1) The spinal reflex actions of afferents stimulated by knee joint distension have been investigated in man. (2) Cannulation of the knee and infusion of saline raised intra-articular pressure, especially during quadriceps contraction. High pressures did not induce any sensation of pain. Pressure was taken as an index of joint proprioceptor activation. (3) Increased pressure progressively depressed the quadriceps H-reflex, both at rest and during quadriceps contraction. There was no indication of a threshold pressure for this inhibitory action. (4) It is concluded that joint distension inhibits quadriceps motoneurons through spinal pathways that still operate during voluntary contraction. These pathways could thus contribute to pathological weakness after joint injury. (5) Joint distension produced spatial facilitation of non-reciprocal inhibition of quadriceps H-reflexes from afferents in the tibial nerve.

The effects of lesions on autogenetic inhibition in the decerebrate cat.

1. The effects of spinal and brain lesions on autogenetic inhibition from contraction receptors were studied in the decerebrate cat. Inhibitory feedback gain was estimated by measuring the effect of tension perturbations on reflex contractions of the soleus muscle. Tendon vibration was used to clamp the firing rate of primary spindle afferents, to prevent spindle unloading from disfacilitating the reflex contraction. In addition, secondary spindle afferents could be selectively excited by stimulating fusimotor fibres during muscle vibration. 2. Following an acute contralateral or bilateral dorsal transection of the spinal cord at L3, the vibration reflex tension fell by between 50 and 74% in three decerebrate animals. This was accompanied by a variable increase in inhibitory feedback, ranging between 180 and 360%. 3. In two animals, selective stimulation of fusimotor fibres supplying soleus muscle was without effect in the presence of muscle vibration both before and after the spinal lesion. In the third animal, a small and variable reduction in tension could be obtained only after the lesion, implying that an inhibitory pathway from homonymous secondary spindle afferents to alpha-motoneurones was released. 4. In a separate series of experiments, contralateral cerebral lesions were made 2-12 months prior to the acute inhibitory feedback measurement. Inhibitory feedback gain was increased, on average twofold in decerebrate animals with chronic cerebral lesions, when compared to control decerebrate animals. 5. Selective stimulation of fusimotor fibres to excite spindle secondary afferents was uniformly without effect in decerebrate animals with chronic cerebral lesions. In one animal spinal transection had only a minor effect on extensor tone and on inhibitory feedback gain, in contrast to the control decerebrate cats. 6. The implications of these findings are discussed in relation to the use of animals with spinal and supraspinal lesions as models of spasticity.

The mesencephalic centre controlling locomotion in the rat.

A mesencephalic locomotor region has been located in the rat brain. Electrical stimulation of the mid-brain in decerebrate animals was used to elicit locomotion on a freely mobile treadwheel. The lowest threshold stimulation sites were reconstructed from histology and accumulated from different experiments. An averaging procedure, taking into account the threshold stimulus current used in each experiment, was used to identify the brain region in which neurons would have been activated in most experiments. The mesencephalic locomotor region so defined corresponds closely to nucleus cuneiformis and the immediately surrounding pedunculopontine region.