Efficacy and safety of xaliproden in amyotrophic lateral sclerosis: results of two phase III trials.

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal motor neuron disease. We carried out two randomized, double-blind, placebo-controlled, multi-centre, multi-national studies with xaliproden (a drug with neurotrophic effect) to assess drug efficacy and safety at two doses. Patients with clinically probable or definite ALS of more than 6 months and less than 5 years duration were randomly assigned to placebo, 1 mg or 2 mg xaliproden orally once daily as monotherapy in Study 1 (n=867); or to the same regimen with addition of riluzole 50 mg bid background therapy in Study 2 (n=1210 patients). The two primary endpoints were defined as: 1. Time to death, tracheostomy, or permanent assisted ventilation (DTP), and 2. Time to vital capacity (VC)<50% or DTP before (log-rank test) and after adjustment using a Cox proportional hazard model for prespecified prognostic factors. Secondary endpoints were rates of change of various functional measures. In Study 1, primary outcome measures did not reach statistical significance. For the 2 mg group, for time to VC<50% analysis (without DTP) a significant 30% RRR was obtained (95% confidence interval [CI]: 8.46, P=0.009). In Study 2, no significant results were obtained. However, there was a trend in favour of add-on 1 mg dose xaliproden vs. placebo (RRR 15% [-6.31, ns] for time to VC<50%; RRR 12% [CI: -6.27, ns] for time to VC<50% or DTP). Adjusted RR ratios were consistently more favourable for the xaliproden groups. Tolerability was good, and dose-dependent side effects were largely associated with the serotonergic properties of xaliproden. An effect of xaliproden on functional parameters, especially VC, was noted. Although this effect did not reach statistical significance, xaliproden had a small effect on clinically noteworthy aspects of disease progression in ALS.     

The incidence of error in young children's Wh-questions.

Many current generativist theorists suggest that young children possess the grammatical principles of inversion required for question formation but make errors because they find it difficult to learn language-specific rules about how inversion applies. The present study analyzed longitudinal spontaneous sampled data from twelve 2-3-year-old English speaking children and the intensive diary data of 1 child (age 2;7 [years;months] to 2;11) in order to test some of these theories. The results indicated significantly different rates of error use across different auxiliaries. In particular, error rates differed across 2 forms of the same auxiliary subtype (e.g., auxiliary is vs. are), and auxiliary DO and modal auxiliaries attracted significantly higher rates of errors of inversion than other auxiliaries. The authors concluded that current generativist theories might have problems explaining the patterning of errors seen in children's questions, which might be more consistent with a constructivist account of development. However, constructivists need to devise more precise predictions in order to fully explain the acquisition of questions.     

Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS

Neurotrophin treatment has so far failed to prolong the survival of individuals affected with amyotrophic lateral sclerosis (ALS), an incurable motoneuron degenerative disorder. Here we show that intracerebroventricular (i.c.v.) delivery of recombinant vascular endothelial growth factor (Vegf) in a SOD1(G93A) rat model of ALS delays onset of paralysis by 17 d, improves motor performance and prolongs survival by 22 d, representing the largest effects in animal models of ALS achieved by protein delivery. By protecting cervical motoneurons, i.c.v. delivery of Vegf is particularly effective in rats with the most severe form of ALS with forelimb onset. Vegf has direct neuroprotective effects on motoneurons in vivo, because neuronal expression of a transgene expressing the Vegf receptor prolongs the survival of SOD1(G93A) mice. On i.c.v. delivery, Vegf is anterogradely transported and preserves neuromuscular junctions in SOD1(G93A) rats. Our findings in preclinical rodent models of ALS may have implications for treatment of neurodegenerative disease in general.     

Secretin and VIP-stimulated adenylate cyclase from rat heart

The exact positions of microelectrodes used to measure thePO₂ in the cerebral cortex of the rat were determined by staining the tissue with Alcian Blue. The measurement sites were subsequently located under a light microscope and correlated with the capillary and cellular arrangement of the cortex. The microelectrodes used for thePO₂ measurements were made of gold glass fibers; the Alcian Blue was injected hydrostatically through a micropipette attached to thePO₂ microelectrode. The sites where dye had been deposited were seen under a light microscope as green blue spots about 100 m in diameter. The capillaries were visualized by silver nitrate perfusion. Differences between the localPO₂ values in the neo- and the archeocortex were found. In the neocortex the meanPO₂ was 31 mm Hg, capillary volume 1.6%, capillary surface area 980/mm², capillary length 13.5/mm; whereas in the archeocortex these values where 21 mm Hg, 0.9%, 820/mm² and 9.4/mm respectively. These data indicate a relationship between the microcirculatory transport system and the local oxygen tension and provide further evidence that the meanPO₂ level tends to decrease when moving from the surface into the archeocortex.Supported by the Deutsche ForschungsgemeinschaftReported in part at the 3rd Symposium of ISOTT, Cambridge, GB, 1977; and at the 27th International Congress of Physiological Sciences, Paris, France, 1977     

The topical organization of the afferents to the caudatoputamen of the rat. A horseradish peroxidase study

The aim of the present study was to assess (1) whether the various brain areas known to send projections to the neostriatum of the rat (neocortex, thalamus, substantia nigra, ventral tegmental area and dorsal raphe nucleus) project to all parts of this structure, and (2) whether the subcortical projections show a topical organization. For these purposes, small deposits of horseradish peroxidase were delivered by iontophoretic application, so that the whole extent of the caudatoputamen could be covered in a total of 40 rats.Labeled cortical cells were present mainly in lamina V, and showed a roughly topographical organization. Small numbers of labelled cells were observed in the basal nucleus of the amygdala after injections into the dorsal and central parts of the caudatoputamen. The cells of origin of thalamic afferents to the neostriatum were found not only in the intralaminar nuclei, but also in various other anterior, ‘midline’, and posterior nuclei (e.g. the medial part of the medial geniculate body). In the thalamostriatal projection a topical organization was demonstrated, consisting of oblique thalamic zones, which cross the borders of several thalamic nuclei and project to different parts of the neostriatum. In the substantia nigra and ventral tegmental area many retrogradely labelled cells were present. This nigrostriatal projection appears to be organized along an oblique longitudinal neostriatal axis. The nucleus raphes dorsalis was labelled most abundantly after caudal and ventrolateral injections into the caudatoputamen.It is concluded that, despite the homogeneous cytoarchitectonic structure of the caudatoputamen in the rat, this brain area is rather heterogeneous as regards its afferent connections. In fact each part of the neostriatum receives a specific and unique combination of afferents. The main changes in the input of the neostriatum appear to occur along an oblique longitudinal axis, from the most rostromedial and dorsal part to the caudolateral and ventral part. Such a topographical organization suggests that the neostriatum is likely to be involved in very complex integrative functions involving several brain areas.     

Uncoupling between beta-adrenoceptors and adenylate cyclase in dog ischemic myocardium

Summary We evaluated the effects of ischemic injury on the myocardial adenylate cyclase system, 5 h after ligation of the left anterior descending coronary in 5 anesthetized dogs. Crude cardiac membrane preparations were isolated from control and ischemic areas of ventricular myocardium and tested for: 1. L-(¹²⁵I)iodocyanopindolol binding, in the absence and presence of ±-isoprenaline and GTP, and 2. adenylate cyclase activity. The density of beta-adrenoceptors increased by 35% in membranes from ischemic areas while the proportion of receptors in a high affinity state for ±-isoprenaline decreased from 43% to 20%. Adenylate cyclase activities in the basal state and under stimulation with NaF, forskolin, Gpp(NH)p, ±-isoprenaline and VIP were all markedly and similarly reduced, being only about 30% of comparable activities in membranes from control areas. The ±-isoprenaline subsensitivity of cardiac adenylate cyclase can, thus, be attributed to a defective enzymatic system and not to a reduction in the number of beta-adrenoceptors implying that the internal components of the system were more sensitive to acute ischemia than the outward oriented hormone receptors. It is tempting to ascribe this uncoupling to a functional depletion in the guanine nucleotide-binding regulatory protein Ns that might reflect a loss of high energy phosphate stores including GTP.Abbreviations CYP cyanopindolol - Gpp(NH)p 5-guanyl imidodiphosphate - VIP vasoactive intestinal peptide - Ns guanine nucleotide-binding regulatory protein     

A comparison between muscarinic receptor occupancy,adenylate cyclase inhibition,and inotropic response in human heart

Summary Binding to muscarinic receptors was compared with adenylate cyclase inhibition in membranes derived from human heart auricles, and with inhibition of the contraction of auricular muscle fibers.In the absence of GTP, agonists recognized two classes of receptors both of which bound antagonists with the same affinity. In the presence of GTP, both classes of receptors for agonists were converted into a single low affinity state.Carbachol and oxotremorine inhibited adenylate cyclase activity by 43%, pilocarpine being less efficient (–28%). The 3 agonists exerted similar inhibitory effects on the inotropic response, in 7 out of 9 preparations of electrically- and norepinephrine-stimulated fibers. Dose-effect curves suggested that spareness (or an amplification mechanism) was implicated in the occupancy of low affinity binding sites by carbachol and oxotremorine (but not by the partial agonist pilocarpine) and the resulting inhibition of both adenylate cyclase activity and contractile force.Abbreviations [³H] NMS, [N-methyl-³H] scopolamine methyl chloride - Gpp(NH)p guanosine 5-0-(2-3 imido) triphosphate - EGTA ethylene glycol bis (2-aminoethyl ether)-N,N,N,N-tetraacetic acid     

A retrospective study of Creutzfeldt–Jakob disease in Belgium

Using data from Belgian neuropathological archives, completed with the results of a comprehensive study of available medical records, we found 100 patients who fulfilled diagnostic criteria for probable or definite Creutzfeldt–Jakob disease (CJD). Mean age at death was 63 years. The median disease duration was 9 months. Progressive mental deterioration was present in all cases, whereas signs of cerebellar dysfunction and myoclonus were found in approximately 80% of the patients. In 50% of the population, the EEG revealed characteristic abnormalities. Ninety-six patients suffered from the sporadic type of CJD, while 4 suffered from a hereditary form. In our series, we could find no evidence for the new variant, neither for an iatrogenic cause.     

Influence of the punch diameter and curvature on the yield pressure of MCC-compacts during Heckel analysis.

The volume reduction behaviour of powders has been quantified by means of the 'in-die' yield pressure (YP) using Heckel analysis. However, because different YPs are reported for the same material, the experimental conditions influencing this material-constant were investigated. Silicified microcrystalline cellulose was compressed into flat-faced and convex tablets using a compaction simulator instrumented with load and displacement transducers. During compression, upper and lower punch force and displacement data were recorded and corrected for punch deformation. A symmetrical triangle wave compression profile was used and the instantaneous punch velocity was kept constant (5mm/s). Individual tablet height and weight were used for Heckel analysis. The influence of the 'effective compression pressure' (P(EFF)) (ranging from 10 to 350 MPa), punch diameter (PD) (4, 9.5 and 12 mm) and filling depth (FD) (4.5, 7.5 and 10.5mm) on YP was statistically evaluated using Response Surface Modelling software. A quadratic surface response equation, describing the relationship between P(EFF), PD, FD and YP, was proposed for concave (Adj R(2): 0.8424; S.D.: 14.60 MPa) and flat-faced (Adj R(2): 0.8409; S.D.: 4.49 MPa) punches. YP and tensile strength were mainly determined by P(EFF), irrespective of punch curvature. FD and PD had only a minor influence on the YP, although more pronounced for the concave punches. The method used resulted in reproducible P(EFF) and tensile strength values and the flat-faced tablets showed less weight variation. Flat-faced punches are preferred over punches with a concave surface when investigating the volume reduction behaviour of a powder by means of Heckel analysis and the experimental parameters should be reported.