Discovery of a Locally and Orally Active CXCL12 Neutraligand (LIT-927) with Anti-inflammatory Effect in a Murine Model of Allergic Airway Hypereosinophilia.

We previously reported Chalcone-4 (1) that binds the chemokine CXCL12, not its cognate receptors CXCR4 or CXCR7, and neutralizes its biological activity. However, this neutraligand suffers from limitations such as poor chemical stability, solubility, and oral activity. Herein, we report on the discovery of pyrimidinone 57 (LIT-927), a novel neutraligand of CXCL12 which displays a higher solubility than 1 and is no longer a Michael acceptor.

Prodrugs of a CXC Chemokine-12 (CXCL12) Neutraligand Prevent Inflammatory Reactions in an Asthma Model in Vivo.

Chalcone 4 (compound 1) is a small molecule that neutralizes the CXC chemokine CXCL12 and prevents it from acting on the CXCR4 and CXCR7 receptors. To overcome its poor solubility in aqueous buffers, we designed highly soluble analogues of compound 1, phosphate, l-seryl, and sulfate, all inactive by themselves on CXCL12 but when cleaved in vivo into 1, highly active locally at a low dose in a mouse airway hypereosinophilia model.

Small neutralizing molecules to inhibit actions of the chemokine CXCL12.

The chemokine CXCL12 and the receptor CXCR4 play pivotal roles in normal vascular and neuronal development, in inflammatory responses, and in infectious diseases and cancer. For instance, CXCL12 has been shown to mediate human immunodeficiency virus-induced neurotoxicity, proliferative retinopathy and chronic inflammation, whereas its receptor CXCR4 is involved in human immunodeficiency virus infection, cancer metastasis and in the rare disease known as the warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis (WHIM) syndrome. As we screened chemical libraries to find inhibitors of the interaction between CXCL12 and the receptor CXCR4, we identified synthetic compounds from the family of chalcones that reduce binding of CXCL12 to CXCR4, inhibit calcium responses mediated by the receptor, and prevent CXCR4 internalization in response to CXCL12.

Convenient method to access new 4,4-dialkoxy- and 4,4-diaryloxy-diaza-s-indacene dyes: Synthesis and spectroscopic evaluation.

A straightforward method for the synthesis of original 4,4-dialkoxy- or 4,4-diaryloxy-diaza-s-indacenes (BODIPY) derivatives obtained by treatment of BODIPY 1 with various alcohols in the presence of AlCl3 is described. The novel compounds are characterized by spectroscopic properties similar to those of the parent BODIPY 1, absorption and emission spectra with similar band shapes, high molar absorption coefficients (epsilon lambda max approximately 80,000 M(-1) cm(-1)), and for most of them high fluorescence quantum yields (Phi exp from 0.52 to 0.

Gerstmann-Sträussler-Scheinker disease with A117V mutation in a second French-Alsatian family.

We report a kindred of French/Alsatian origin with symptoms of Gerstmann-Sträussler-Scheinker disease over 3 generations. In the propositus, cerebellar signs and memory disturbance were the presenting features, followed by other neurological manifestations. Biopsy of the cerebral cortex showed numerous multicentric and "kuru"-type amyloid plaques that on immuno-light and electron microscopy stained with antibody to prion protein.

A multi-centre, double-blind trial of tizanidine, a new antispastic agent, in spasticity associated with hemiplegia.

A double-blind study was carried out in 105 patients with chronic spasticity associated with hemiplegia in order to compare the efficacy and tolerability of tizanidine with that of diazepam. Dosage was increased progressively, if tolerated, to a maximum of 24 mg tizanidine or 30 mg diazepam per day at the end of 2 weeks. The optimum dosage was then maintained for 6 weeks.

Multi-centre, double-blind trial of a novel antispastic agent, tizanidine, in spasticity associated with multiple sclerosis.

A multi-centre, double-blind study was carried out in 100 patients suffering from chronic spasticity due to multiple sclerosis to compare the effectiveness of tizanidine hydrochloride with that of baclofen. Patients were allocated at random to receive treatment initially with daily doses of either 6 mg tizanidine or 15 mg baclofen and the dose was increased during the first 2 weeks up to a maximum of 24 mg tizanidine or 60 mg baclofen per day. Patients were then treated with the optimum dose for 6 weeks.

[Anomalies in fatty acids distribution and superoxide dismutase activity in lymphocytes of an adult with atypical ceroid lipofuscinosis].

A 27-year-old Algerian patient presented a slowly progressive disease clinically characterized by a cerebellar syndrome, absence of deep reflexes, bilateral sign of Babinski, deep sensory disturbances, ophthalmologic disorders and pes cavus. The diagnosis of ceroid lipofuscinosis resulted from the presence of lipofuscin deposits evidenced as autofluorescent bodies, and a particular type of curvilinear, crystalloid ultrastructural inclusion bodies in muscle, lymphocytes and liver. Biochemical tests showed reduction in levels of linoleic and arachidonic acids, and of superoxide dismutase activity in lymphocytes.

Lymphocytotoxic and monocytotoxic antibodies in the serum and cerebrospinal fluid of multiple sclerosis patients.

Serum cold cytotoxic antibodies (CA), detected at 15 degrees C using a microcytotoxicity technique, were present in 12 of 21 multiple sclerosis (MS) patients, weak or absent in 6 neurological patients without MS and present but weak in 5 out of 32 healthy controls. In MS, these cold CA were directed against 3 distinct cellular populations: total lymphocytes, B lymphocytes and monocytes; certain antibody tests were positive at 37 degrees C; no correlation between CA and clinical disease was observed. Cerebrospinal fluid (CSF) antibody levels were high in both MS and non-MS patients and at 37 degrees C produced lysis of monocytes in the absence of complement.

[Familial presenile dementia: Gerstmann-Sträussler-Scheinker's syndrome (author's transl)].

A similar affection has developed in eight members from four generations of a family living in the Alsace. The disease is characterized by the onset of a pyramidal, pseudobulbar syndrome and dementia during the third or fourth decade of life. The outcome is fatal after a mean period of three years.

[Frequency and semeiological evolution of epileptic seizures occurring between 40 and 65 years of age (author's transl)].

458 patients who had their first epileptic fit between the ages of 40 and 65 are classified into 5 groups according to the seizure symptomatology: when the symptomatology remains unchanged, the frequency of fits is less than 1 per month in 84% of generalized fits and more than 1 per month in 52% of focal fits. When the symptomatology changes, the frequency of fits is less than 1 per month when the inaugural fit is generalized (23 out of 27) and more than 1 per month when the inaugural fit is focal (15 out of 21). Modifications of the symptomatology correlate positively with a prevalence of tumor aetiology.

[Stuporous states during treatment with sodium valproate. Pathogenetic hypotheses].

In 11 patients with complex partial epileptic seizures stuporous states were observed during treatment with valproate (VPA) (2 cases), with VPA and phenobarbitone (PB) (4 cases), or with VPA, PB and a third anti-epileptic drug (5 cases). Based on 3 characteristic cases, an attempt is made to define the role of VPA, the nature of the stuporous states, and the origin of digestive disorders which often herald the onset of behavioural disorders. Several clinical studies have suggested the direct responsibility of VPA even if the adverse effects are potentiated by many other anti-epileptic drugs.

[An autosomal recessive syndrome with myopathy and central and peripheral nervous system involvement (author's transl)].

Three of 11 children, offspring of a consanguineous marriage, presented a progressive myopathy and seizures, associated with symptoms suggesting both central and peripheral nervous system involvement. The ultrastructural muscular lesions were not specific. The association of severe impairment of muscle tissue and of central nervous system is rare, being described in centronuclear myopathy, cerebromuscular dystrophy, Kearns-Sayre syndrome and in a few isolated cases.

[Does posterior internuclear ophthalmoplegia exist? A report on eleven cases and the results of oculography (author's transl)].

Based on the anatomical and clinical findings in the very rare cases reported, recent experimental data, and the results of oculography, the authors consider that this condition merits definition as an individual entity. It is usually associated with other disorders of oculomotility which may mask clinical signs, and oculography is necessary to establish the diagnosis. Terminologically, it would appear logical to retain the terms; abduction internuclear ophthalmoplegia (and not, posterior), and adduction internuclear ophthalmoplegia (and not, anterior).

[Opsoclonia: oculographic study].

Oculographic study of a case of opsoclonus associated with infectious meningoencephalitis was used to determine the criteria of definition of this abnormal ocular movement, distinguishing it from the other abnormal movements of flutter and dysmetria. The authors first discuss, on the basis of these recordings, the possible relationship between opsoclonus and myoclonia, and then the role of the cerebellum. The disturbances noted in the course of study of saccadian movement lead them to suggest the hypothesis of overall involvement of the saccadian oculomotor system.

[Clinical and E.E.G. study of 9 cases of cortical blindness (author's transl)].

The authors report 9 cases of cortical blindness (7 of vascular origin, 2 due to septic embolism). These were characterised by blindness, loss of the blink reflex in response to threat, and of optokinetic nystagmus, conservation of the pupil reflexes, a confusional state with memory disturbances and anosognosia. The accompanying E.