Low density lipoprotein is protected from oxidation and the progression of atherosclerosis is slowed in cholesterol-fed rabbits by the antioxidant N,N'-diphenyl-phenylenediamine.

The oxidative modification of low density lipoprotein (LDL) may play an important role in atherosclerosis. We found that the antioxidant N,N'-diphenyl-1,4-phenylenediamine (DPPD) inhibits in vitro LDL oxidation at concentrations much lower than other reported antioxidants. To test whether DPPD could prevent atherosclerosis, New Zealand White rabbits were fed either a diet containing 0.5% cholesterol and 10% corn oil (control group) or the same diet also containing 1% DPPD (DPPD-fed group) for 10 wk. Plasma total cholesterol levels were not different between the two groups, but DPPD feeding increased the levels of triglyceride (73%, P = 0.007) and HDL cholesterol (26%, P = 0.045). Lipoproteins from DPPD-fed rabbits contained DPPD and were much more resistant to oxidation than control lipoproteins. After 10 wk, the DPPD-fed animals had less severe atherosclerosis than did the control animals: thoracic aorta lesion area was decreased by 71% (P = 0.0007), and aortic cholesterol content was decreased by 51% (P = 0.007). Although DPPD cannot be given to humans because it is a mutagen, our results indicate that orally active antioxidants can have antiatherosclerotic activity. This strongly supports the theory that oxidized LDL plays an important role in the pathogenesis of atherosclerosis.

Role of AMP-activated protein kinase in mechanism of metformin action.

Metformin is a widely used drug for treatment of type 2 diabetes with no defined cellular mechanism of action. Its glucose-lowering effect results from decreased hepatic glucose production and increased glucose utilization. Metformin's beneficial effects on circulating lipids have been linked to reduced fatty liver. AMP-activated protein kinase (AMPK) is a major cellular regulator of lipid and glucose metabolism. Here we report that metformin activates AMPK in hepatocytes; as a result, acetyl-CoA carboxylase (ACC) activity is reduced, fatty acid oxidation is induced, and expression of lipogenic enzymes is suppressed. Activation of AMPK by metformin or an adenosine analogue suppresses expression of SREBP-1, a key lipogenic transcription factor. In metformin-treated rats, hepatic expression of SREBP-1 (and other lipogenic) mRNAs and protein is reduced; activity of the AMPK target, ACC, is also reduced. Using a novel AMPK inhibitor, we find that AMPK activation is required for metformin's inhibitory effect on glucose production by hepatocytes. In isolated rat skeletal muscles, metformin stimulates glucose uptake coincident with AMPK activation. Activation of AMPK provides a unified explanation for the pleiotropic beneficial effects of this drug; these results also suggest that alternative means of modulating AMPK should be useful for the treatment of metabolic disorders.

Targeted disruption of the tumor necrosis factor-alpha gene: metabolic consequences in obese and nonobese mice.

To address the hypothesis that tumor necrosis factor (TNF)-alpha has a role in obesity-associated insulin resistance or the regulation of in vivo lipid metabolism, mice with targeted disruption of the TNF-alpha gene were generated and studied. The absence of TNF-alpha protein in TNF-null (-/-) mice was confirmed. Lean or obese (gold-thioglucose [GTG]-injected) homozygous (-/-) mice were compared with lean or obese age- and sex-matched wild-type (+/+) mice derived from the same line at 13, 19, and 28 weeks of age. The following parameters were significantly affected in lean -/- versus +/+ mice: Body weight was not affected until week 28 (decreased by 14%); epididymal fat pad weight also decreased (25%) at this time, as did percentage body fat (16%), while percentage body protein was increased 13%. Fed plasma insulin levels decreased 47% (28 weeks), triglyceride levels decreased (all three ages; maximum 35% at 19 weeks), and fed plasma leptin decreased 33% (28 weeks). Fasting glucose was slightly (10%) reduced, but the glucose response to an oral glucose tolerance test (OGTT) was not affected. There was a trend (NS) toward increased total adipose tissue lipoprotein lipase in -/- versus +/+ mice. GTG-treatment resulted in obese -/- and +/+ mice with equal mean body weights (42 and 58% increased weight versus lean mice). The following parameters were significantly different in obese -/- mice: fasting plasma glucose decreased 13% (28 weeks), fed plasma insulin decreased 67% (28 weeks), and insulin response to OGTT was decreased by 50%. For both groups of obese mice, glucose levels during the OGTT were substantially increased compared with those in lean mice; however, mean stimulated glucose levels were 20% lower in obese -/- versus +/+ mice. We conclude 1) that TNF-alpha functions to regulate plasma triglycerides and body adiposity and 2) that although TNF-alpha contributes to reduced insulin sensitivity in older or obese mice, the absence of TNF-alpha is not sufficient to substantially protect against insulin resistance in the GTG hyperphagic model of rodent obesity.

An antidiabetic thiazolidinedione potentiates insulin stimulation of glycogen synthase in rat adipose tissues.

Thiazolidinedione derivatives are a novel class of insulin-sensitizing agents that have demonstrated effective antidiabetic activity in vivo. Here, the effects of the potent thiazolidinedione derivative, AD-5075, on the rate-limiting enzyme of glycogen synthesis, glycogen synthase, were investigated in cultured rat adipose tissue. Short term preincubation of adipose tissue with AD-5075 potentiated acute insulin stimulation of I-form glycogen synthase activity in a concentration-dependent (EC50 approximately, 61nM) and time-dependent (t1/2 approximately, 2.3 h) manner. The thiazolidinedione derivative increased the responsiveness of I-form glycogen synthase activity to insulin stimulation at both maximal and submaximal insulin concentrations. In contrast, it had no effect on total glycogen synthase activity. Isoproterenol inhibited acute insulin activation of I-form glycogen synthase activity in a dose-dependent manner; maximal inhibition was attained at a concentration of 3 nM. AD-5075 antagonized isoproterenol inhibition of insulin's action. The concentration of glycogenolytic agent required to attain maximal inhibition was increased an order of magnitude in tissue treated with the antidiabetic agent. Short term preincubation of adipose tissue under hyperglycemic conditions (15 or 25 mM glucose) decreased insulin-stimulated I-form glycogen synthase activity. Concurrent treatment of the tissue with AD-5075 abrogated this glucose toxicity-induced inhibition of insulin action. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase, blocked insulin activation of glycogen synthase in a dose-dependent manner. Half-maximal inhibition was observed at approximately 0.3 microM, and maximal inhibition occurred at 1.0 microM. AD-5075 did not antagonize wortmannin's inhibitory action. These results indicate that thiazolidinediones can act directly on adipose tissues to augment an important metabolic effect of insulin and counteract the inhibitory effects of catecholamines or hyperglycemia. As insulin stimulation of glycogen synthase remains wortmannin inhibitable in the presence of AD-5075, the effects of thiazolidinediones on insulin signal transduction may be phosphatidylinositol 3-kinase-dependent.

Role of skeletal muscle in thiazolidinedione insulin sensitizer (PPARgamma agonist) action.

Thiazolidinedione (TZD) insulin sensitizers are specific agonists of peroxisome proliferator activated receptor (PPAR)gamma. However, their mechanism of action and the in vivo target tissue(s) that mediate insulin sensitization remain poorly defined. Although PPARgamma messenger RNA expression has been reported in skeletal muscle, the expression of PPARgamma within myocytes in intact muscle tissue has not been examined. An antipeptide PPARgamma antibody was generated; immunohistochemistry was then used to demonstrate that PPARgamma is present within nuclei of myocytes [in both skeletal (white and red fibers) and cardiac tissue (rodent and human)]. The effect of insulin sensitizer treatment on muscle insulin action was studied using ob/ob mice after 4 days dosing with a potent (6 nM PPARgamma Kd) TZD (10 mg/kg x day). 2-deoxyglucose (2-DOG) uptake was then assessed in freshly isolated soleus muscles from lean vs. ob/ob vs. TZD-treated ob/ob mice. In lean mouse muscles, 2-DOG uptake was stimulated by 82%, 95%, 165% (with 25, 100, 2000 microU/ml insulin); muscles from ob/ob were severely insulin resistant (<80% stimulation with 2000 microU/ml insulin). Muscles from TZD-treated ob/ob displayed a normal insulin response with 100 (71%) or 2000 (158%) microU/ml insulin. Additional studies were performed using ZDF rats treated with/without TZD for 7 days. In vivo 2-DOG glucose uptake into soleus, gastrocnemius, and diaphragm muscles was measured during euglycemic-hyperinsulinemic clamp. Compared with lean rats, muscle 2-DOG uptake in ZDF was reduced by 52% (soleus) or 71% (diaphragm). Partial (40-60%) normalization of the reduced 2-DOG uptake was evident in TZD-treated ZDF rats. In contrast to the effect of in vivo treatment on muscle insulin action, preincubation of isolated soleus muscles from naive lean or ob/ob mice for 5 h with 100 nM TZD did not affect insulin-stimulated 2-DOG uptake. We conclude: 1) PPARgamma is expressed in myocytes within skeletal and cardiac muscle. 2) In vivo activation of PPARgamma by treatment of insulin-resistant mice/rats with a potent TZD corrects impaired muscle insulin action. 3) The lack of a direct effect on muscle after 5 h in vitro TZD incubation suggests that changes in insulin action may require a longer duration of PPARgamma activation or that improved muscle insulin sensitivity may result from an indirect in vivo effect of PPARgamma activation (e.g. changes in systemic lipid metabolism).

Peroxisome proliferator-activated receptors gamma and alpha mediate in vivo regulation of uncoupling protein (UCP-1, UCP-2, UCP-3) gene expression.

A role for peroxisome proliferator-activated receptors, PPAR gamma and PPAR alpha, as regulators of energy homeostasis and lipid metabolism, has been suggested. Recently, three distinct uncoupling protein isoforms, UCP-1, UCP-2, and UCP-3, have also been identified and implicated as mediators of thermogenesis. Here, we examined whether in vivo PPAR gamma or PPAR alpha activation regulates the expression of all three UCP isoforms. Rats or lean and db/db mice were treated with PPAR gamma [thiazolidinedione (TZD)] or PPAR alpha (WY-14643) agonists, followed by measurement of messenger RNAs (mRNAs) for UCP-1, UCP-2, and UCP-3 in selected tissues where they are expressed. TZD treatment (AD 5075 at 5 mg/kg x day) of rats (14 days) increased brown adipose tissue (BAT) depot size and induced the expression of each UCP mRNA (3x control levels for UCP-1 and UCP-2, 2.5x control for UCP-3). In contrast, UCP-2 and UCP-3 mRNA levels were not affected in white adipose tissue or skeletal muscle. Chronic (30 days) low-dose (0.3 mg/kg x day) TZD treatment induced UCP-1 mRNA and protein in BAT (2.5x control). In contrast, chronic TZD treatment (30 mg/kg x day) suppressed UCP-1 mRNA (>80%) and protein (50%) expression in BAT. This was associated with further induction of UCP-2 expression (>10-fold) and an increase in the size of lipid vacuoles, a decrease in the number of lipid vacuoles in each adipocyte, and an increase in the size of the adipocytes. TZD treatment of db/db mice (BRL 49653 at 10 mg/kg x day for 10 days) also induced UCP-1 and UCP-3 (but not UCP-2) expression in BAT. PPAR alpha is present in BAT, as well as liver. Treatment of rats or db/db mice with WY-14643 did not affect expression of UCP-1, -2, or -3 in BAT. Hepatic UCP-2 mRNA was increased (4x control level) in db/db and lean mice, although this effect was not observed in rats. Thus, in vivo PPAR gamma activation can induce expression of UCP-1, -2, and -3 in BAT; whereas chronic-intense PPAR gamma activation may cause BAT to assume white adipose tissue-like phenotype with increased UCP-2 levels. PPAR alpha activation in mice is sufficient to induce liver UCP-2 expression.

Anatomic connections of inferior parietal cortex (area 7) with subcortical structures related to vestibulo-ocular function in a monkey (Macaca fascicularis).

Connections of the posterior parietal cortex (area 7) with subcortical structures related to the vestibulo-ocular function were studied on four macaque monkeys by using anterograde and retrograde tracer. Wheat germ agglutinin (WGA)-horseradish peroxidase (HRP) or tritiated amino acids were injected into the posterior part of area 7, including the caudal end of the superior bank of both the superior temporal sulcus and the lateral sulcus. The posterior parietal cortex was found to be reciprocally connected with three different ipsilateral thalamic nuclei: the nucleus ventralis posterior inferior, the magnocellular part of the medial geniculate nucleus, and some intralaminar nuclei. Through these connections, area 7 might control the vestibulo-ocular response (VOR) by modulating the ascending vestibular information. This cortical area 7 also projects to the ipsilateral intermediate and deep layers of the superior colliculus and to several ipsilateral pontine nuclei. The dorsolateral pontine nucleus is of particular interest because it is known to be related to smooth pursuit eye movements. Cortical area 7 also was seen to project to the accessory nucleus of Darkschewitsch, to all the vestibular nuclei, and to the nucleus propositus hypoglossi; the last two projections were found to be bilateral with a greater ipsilateral contribution. Efferents from posterior parietal cortex are directed to precise regions within the vestibular nuclei that are specifically involved in vestibulo-ocular reflex, or that are in turn connected with brainstem structures implicated in smooth pursuit eye movements. These connections are consistent with the posterior parietal cortex exerting a multilevel influence on the different systems dealing with eye-head movement coordination.

In search for the egocentric reference. A neurophysiological hypothesis.

Unilateral lesions of the middle suprasylvian gyrus in the cat parietal cortex produce an asymmetrical vestibulo-ocular reflex such that responses to head rotation toward the side opposite to the lesion become weaker. Unilateral lesions of the superior colliculus in the cat also produce the same effect. In either case symmetrical responses are recovered within 2-3 weeks. These results are discussed in terms of displacement, by the unilateral lesion, of an internal reference used for directing behaviour within extrapersonal space. Relevance of this hypothesis to clinical symptoms observed in man after unilateral posterior parietal lesions is discussed, with particular emphasis on the unilateral neglect phenomenon.

Morphometric analysis of envelope glycoprotein gp120 distribution on HIV-1 virions.

The surface of HIV-1, like that of other retroviruses, is studied with virally encoded glycoproteins which appear ultrastructurally as electron-dense spikes or knobs. The glycoprotein that forms the spike structure, gp120, is non-covalently bound to the transmembrane glycoprotein gp41. Mature HIV-1 virions do not have as many spikes as the genetically related retroviruses HIV-2 and SIV. gp120 is lost from HIV-1 during viral morphogenesis and after incubation of the virus with the soluble form of cellular receptor CD4. In this study we used ultrastructural cytochemistry and morphometry to quantitate the distribution of envelope glycoprotein spikes on budding and mature HIV-1 virions and to look for alternatives to the laborious and somewhat subjective spike-counting technique for envelope spike analysis on HIV-1. HIV-1, strain HTLV-IIIB, was examined after staining of envelope glycoproteins with either tannic acid, immunogold staining for gp120 (gp120-immunogold), or lectin-gold staining with concanavalin A for mannose residues (ConA-HRP-gold) and frequency distributions of spikes or gold particles per micron HIV-1 membrane generated. Envelope spikes were normally distributed on membranes of budding and mature HIV-1. However, the density of spikes per micron viral membrane on mature HIV-1 virions was approximately 50% of that observed on budding virions. ConA-HRP-gold and gp120-immunogold did not efficiently label budding virions. The shape of the frequency distribution for ConA-HRP-gold particles on mature virions was similar to that for envelope spikes and could be used to quantitate envelope glycoproteins on HIV-1. In addition, ConA-HRP-gold staining was able to detect the loss of envelope proteins after treatment of virus with soluble CD4. gp120-immunogold labeling was patchy and many virions were unlabeled. ConA-HRP-gold staining proved to be a rapid, reliable, and easily quantifiable method for estimation of envelope glycoprotein density on mature HIV-1. However, the loss of spike structures throughout the life cycle of HIV-1 can effectively be determined only by direct spike counting.

Ultrastructural evidence of an interaction between Env and Gag proteins during assembly of HIV type 1.

Assembly and budding of retroviruses is believed to involve a complex interaction of envelope and capsid proteins at the host cell membrane. The nature of these interactions is, however, incompletely understood. Studies of the topography of the surface of HIV-1 have shown that the envelope glycoprotein projections (knobs) are arranged in a T = 7 levo rotational symmetry. Similarly, an icosahedral structure has been suggested for the p17 matrix of HIV-1. In an effort to investigate whether there is a structural interaction between these molecules, virions whose maturation was blocked by an inhibitor of HIV protease were studied using cytochemistry, morphometry, and 2D fast Fourier transform image enhancement. Analysis of the relationship between core morphology and the topographic distribution of envelope glycoprotein projections on HIV-1 provided structural evidence of an interaction between Env and Gag proteins. Furthermore, image enhancement revealed a periodic substructure in the Pr55gag plaque. Taken together, the data suggest an interaction between Pr55gag and the gp120-gp41 complex during assembly and budding of HIV-1. This interaction may, in part, contribute to determining the amount of Env glycoprotein that will be incorporated into a virion, and therefore play a role in the biology of HIV-1.

Cortical control of oculomotor functions. I. Optokinetic nystagmus.

The cortical control of horizontal optokinetic nystagmus (OKN) has been studied in 13 adult cats with unilateral lesions. OKN was induced by rotating the visual field around the animals in both binocular and monocular conditions. (1) No deficits of OKN appeared following unilateral ablations of visual cortex. (2) Lesions of different parts of suprasylvian cortex were made: the posterior and the middle suprasylvian cortex involving area 7 and the lateral suprasylvian area (LSA). Only the middle suprasylvian cortex damage produced on OKN asymmetry due to a decrease of the slow-phase velocity directed toward the side of the lesion. The deficits were compensated for within about 10 days. We conclude that the middle suprasylvian cortex and particularly LSA regulate the ipsilateral slow phases of OKN.

Cortical control of oculomotor functions. II. Vestibulo-ocular reflex and visual-vestibular interaction.

The cortical control of the vestibulo-ocular reflex (VOR) and visual suppression of VOR was studied in 13 adult cats with unilateral lesions. VOR was tested in the dark by sinusoidal rotations of the animal at different frequencies. Visual suppression of VOR was tested in the light by keeping the visual field stationary with respect to the animal. No deficits of VOR and visual suppression of VOR appeared following unilateral ablations of visual cortex. Unilateral lesions of different parts of the suprasylvian cortex were made in the posterior and middle suprasylvian cortex involving area 7 and the lateral suprasylvian area (LSA). After middle suprasylvian cortex damage (particularly area 7), all the animals exhibited a VOR asymmetry due mainly to a gain decrease of slow phases directed towards the side of the lesion. In two animals, transitory spontaneous nystagmus was present in the dark with the fast phase directed toward the side of the lesion. Only when LSA was destroyed, could an asymmetry of the visual suppression of VOR be observed with a loss of the visual suppression during ipsilateral rotations. The VOR deficit was transient: spontaneous nystagmus disappeared within the first postoperative week, the vestibular asymmetry and the loss of visual suppression of VOR were no longer present after 2-3 weeks. We conclude that the middle suprasylvian cortex, particularly area 7, exerts an ipsilateral control on the VOR.

High fat fed hamster, a unique animal model for treatment of diabetic dyslipidemia with peroxisome proliferator activated receptor alpha selective agonists.

Dyslipidemia, a major risk factor for cardiovascular disease, may be directly linked to diabetic hyperglycemia and insulin resistance. An appropriate dyslipidemic animal model that has diabetes would provide an important tool for research on the treatment of diabetic dyslipidemia. Ten days of high fat feeding in golden Syrian hamsters resulted in a significant increase in insulin resistance and baseline serum lipid levels accompanied by a pronounced dyslipidemia. Thirteen days of treatment with fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARalpha) selective agonist, produced a dose-dependent decrease in serum lipid levels. The pattern observed was characterized by lowered very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) and raised high-density lipoprotein (HDL) cholesterol in a fashion similar to that seen in man. Diabetic conditions were also significantly improved by fenofibrate with a normalization of impaired glucose tolerance and an improvement of insulin sensitivity during an oral glucose tolerance test. These data suggest that fenofibrate may correct not only the dyslipidemia but also the insulin resistance caused by a high fat diet, and the high fat fed hamster may be a good animal model for research on the treatment of diabetic dyslipidemia with PPARalpha selective agonists.

Saccade metrics in multiple sclerosis: versional velocity disconjugacy as the best clue?

We studied the parameters (latency, amplitude, peak velocity) of horizontal saccades in 32 patients with multiple sclerosis (MS) and 20 healthy, age matched control subjects. Saccades were recorded by direct-current electro-oculography technique (EOG). The patients were divided in 2 groups according to the absence or the presence of clinical internuclear ophthalmoplegia (INO). In both groups, we found increased latency, hypometria and reduced velocity. The disconjugacy of saccades was measured by calculating the ratio of abduction and adduction peak velocities (the versional disconjugacy index: VDI). Though the absolute value of this index might be dependent on the recording technique, its variation is not. Interestingly, the VDI was significantly increased in the groups of MS patients without clinical INO, indicating a more severe slowing in adduction. We concluded that VDI may be a very useful index in detecting subtle disorders in saccades conjugacy.

Saccades in internuclear ophthalmoplegia: are abduction disorders related to interocular disconjugacy?

We studied horizontal saccades by direct-current electro-oculography in 18 patients with internuclear ophthalmoplegia (INO), and in 16 healthy, age-matched subjects. The occurrence of abducting signs, i.e. overshoot and dissociated nystagmus, was related to an increase of interocular dissociation (measured by the ratio of abduction and adduction peak velocities). The amplitude of abduction hypermetria was strongly correlated with the intensity of adduction slowing. These findings support the idea of an adaptive mechanism underlying the overshoot and nystagmus of abduction saccades in INO.

The role of smooth pursuit in suppression of post-rotational nystagmus.

Some authors have suggested that the smooth pursuit system (SPS) may be responsible for nystagmus suppression when a small visual target--stationary with respect to a subject receiving vestibular stimulation in the dark--is presented. Under five experimental conditions, post-rotational vestibular stimulations were combined in different ways with the presentation of a small visual target. The oculomotor responses of 15 normal subjects were recorded and analyzed. The characteristics of nystagmus suppression (latency, dynamics, and nonlinear behaviour) seem to be consistent with the hypothesis of SPS participation. A nonlinear mathematical model of the interaction between vestibulo-ocular reflex and SPS is presented. Computer simulation of the experimental conditions considered in this study provides theoretical results which closely approximate the actual experimental data.

[Projections of the parietal cortex on the vestibular complex in Macaca]. / Projections du cortex pariétal sur le complexe vestibulaire du macaque.

Connections of parietal cortex (especially posterior part of area 7) with subcortical structures related with vestibular function were examined in four monkeys (Macaca Fascicularis), by means of anterograde labeling with HRP and tritated amino-acids tracers. Posterior parietal cortex was found to have direct efferent projections onto vestibular nuclei complex and prepositus hypoglossi nucleus. These efferences were distributed bilaterally with an ipsilateral preponderance. The labeled terminals were organized in precise patterns in vestibular nuclei in such a way that two groups of cortical efferences could be distinguished: the first one terminates on vestibular nuclei related with the cervico-spinal motor system and the second one terminates on both prepositus hypoglossi nucleus and vestibular nuclei involved in vestibulo-ocular functions. These latter efferent projections of parietal cortex onto vestibular nuclei complex could account for the role played by the posterior part of area 7 in the modulation of the vestibulo-ocular reflex.

[Study of 213 cases of multiple sclerosis treated with azathioprine from 1967- to 1982]. / Etude de 213 cas de sclérose en plaques traités par l'azathioprine de 1967 à 1982.

Effects of azathioprine, 150 mg per day on average, were studied in 213 patients with multiple sclerosis. Thirty-eight case reports were excluded from the final analysis due to lack of continuous treatment (22 cases) or of complete data (16 cases). The 175 patients followed up regularly for a mean of 10 years had received the drug for from 6 months to 15 years (mean approximately 4 years). The treatment was generally well tolerated and there were no irreversible side effects. Results for the different parameters studied, when compared with those in untreated controls, showed the following features: for patients with the remittent form of MS: a statistically significant increase in cases showing no further progression, a reduced frequency of attacks (increased during spontaneous evolution of the affection), a significantly lower incidence of cases that became progressive in nature, and a general improvement in disability score at the end of follow-up. The course of the disease appeared to be more severe before treatment than in untreated cases. In patients with the progressive form of MS (47 cases) the ratio of total disability scores to number of years of observation was reduced in treated when compared with control patients, whereas this ratio was similar in both groups before treatment. General improvement in scores was therefore definitely related to treatment. These findings are in agreement with those of our 1978 study (Aimard, Confavreux et al.) and of others using the same protocol (Oger et al., and Rosen).(ABSTRACT TRUNCATED AT 250 WORDS)

[Familial paroxysmal ataxia responsive to acetazolamide]. / Ataxie paroxystique familiale sensible à l'acétazolamide.

From their early twenties, a 56 year-old french woman and her 33 year-old son suffered from paroxysmal attacks of gait ataxia, incoordination of both hands, dysarthria and nystagmus. These attacks lasted from one to three hours and occurred at the rate of one to seven per week. On examination between attacks, there was only a bilateral horizontal and upward-beating gaze nystagmus. This was documented by E.O.G. Biological investigations were normal with the exception of a mild elevation of glucose blood level. Treatment with acetazolamide 250 mg daily, completely abolished the attacks in both patients. These cases meet the criteria of familial paroxysmal ataxia, a disorder only described in the United States up to the present. Although rare, this disease should be recognized because of its dramatic response to acetazolamide.

Dual bronchodilatory and pulmonary anti-inflammatory activity of RO5024118, a novel agonist at vasoactive intestinal peptide VPAC2 receptors.

BACKGROUND AND PURPOSE: Vasoactive intestinal peptide is expressed in the respiratory tract and induces its effects via its receptors, VPAC(1) and VPAC(2). RO5024118 is a selective VPAC(2) receptor agonist derived via chemical modification of an earlier VPAC(2) agonist, RO0251553. In the present studies, we characterized the pharmacological activity of RO5024118. EXPERIMENTAL APPROACH: Stability of RO5024118 to human neutrophil elastase was assessed. Bronchodilatory activity of RO5024118 was investigated in guinea pig and human isolated airway smooth muscle preparations and in a guinea pig bronchoconstriction model. Pulmonary anti-inflammatory activity of RO5024118 was investigated in a lipopolysaccharide mouse model and in a porcine pancreatic elastase (PPE) rat model. KEY RESULTS: RO5024118 demonstrated increased stability to neutrophil elastase compared with RO0251553. In human and guinea pig isolated airway preparations, RO5024118 induced bronchodilatory effects comparable with RO0251553 and the long-acting ß-agonist salmeterol and was significantly more potent than native vasoactive intestinal peptide and the short-acting ß-agonist salbutamol. In 5-HT-induced bronchoconstriction in guinea pigs, RO5024118 exhibited inhibitory activity with similar efficacy as, and longer duration than, RO0251553. In a lipopolysaccharide-mouse model, RO5024118 inhibited neutrophil and CD8(+) cells and myeloperoxidase levels. In rats, intratracheal instillation of PPE induced airway neutrophilia that was resistant to dexamethasone. Pretreatment with RO5024118 significantly inhibited PPE-induced neutrophil accumulation. CONCLUSIONS AND IMPLICATIONS: These results demonstrate that RO5024118 induces dual bronchodilatory and pulmonary anti-inflammatory activity and may be beneficial in treating airway obstructive and inflammatory diseases. LINKED ARTICLES: This article is part of a themed section on Analytical Receptor Pharmacology in Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2010.161.issue-6.