Jeffrey A. Cohen

Glatiramer acetate (Copaxone) treatment in relapsing–remitting MS: Quantitative MR assessment

Objective: To evaluate the efficacy of glatiramer acetate (GA, Copaxone; Teva Pharmaceutical Industries, Ltd., Petah Tiqva, Israel) by MRI-based measures in patients with relapsing–remitting (RR) MS. Methods: Twenty-seven patients with clinically definite RR-MS were treated with either 20 mg of GA by daily subcutaneous self-injection (n = 14) or placebo (n = 13) for approximately 24 months. Axial dual-echo fast-spin-echo T2-weighted images and T1-weighted images before and after gadolinium (Gd) were acquired at 1.5 tesla and transferred into an image processing computer system. The main outcome measures were the number of Gd-enhanced T1 and T2 lesions and their volume as well as brain parenchyma volume. Results: The values of age, disease duration, Expanded Disability Status Scale (EDSS) score, the number of T1- and T2-weighted lesions, and their volume were similar between GA- and placebo-receiving groups at the entry of this study. There was a decrease in the number of T1-enhanced lesions (p = 0.03) and a significant percent annual decrease of their volume in GA recipients compared with those of placebo recipients. There were no significant differences between changes in the two groups in the number of T2 lesions and their volume. The loss of brain tissue was significantly smaller in the GA group compared with that of the placebo group. Conclusions: These results show that GA treatment may decrease both lesion inflammation and the rate of brain atrophy in RR-MS.

Limiting dilution analysis of the frequency of antigen-reactive lymphocytes isolated from the central nervous system of Lewis rats with experimental allergic encephalomyelitis

Lymphocytes were isolated from the spinal cord and draining lymph nodes of Lewis rats with acute experimental allergic encephalomyelitis (EAE) 12 days after immunization with myelin basic protein (MBP) and tetanus toxoid (TT). An average of 8.0 +/- 2.0 X 10(6) cells was obtained from the spinal cord. Of these 71.1 +/- 8.6% expressed the helper-T-cell marker W3/25 and 14.8 +/- 6.2% expressed the killer/suppressor-T-cell marker OX8. By limiting dilution analysis of cells exhibiting an antigen-specific proliferative response, the average frequencies of cells reactive to MBP and TT were 3.36 +/- 2.4 and 7.60 +/- 4.1 per 10(4), respectively. In the draining lymph nodes, the frequencies of cells reactive to MBP and TT were 2.24 +/- 1.7 and 2.69 +/- 2.5 per 10(4). At a relatively early stage of clinical EAE, MBP-reactive T cells comprise only a small minority of the cells which can be isolated from the spinal cord; lymphocytes reactive to a protein antigen irrelevant to EAE pathogenesis are present in comparable numbers. This finding suggests that most of these cells accumulate as a result of mechanisms not specific for MBP-reactive lymphocytes.

A quantitative immunohistochemical comparison of actively versus adoptively induced experimental allergic encephalomyelitis in the Lewis rat

A quantitative immunohistochemical comparison of actively and adoptively induced experimental allergic encephalomyelitis (EAE) in the Lewis rat was performed. Since the methods of EAE induction of these two systems and the kinetics of disease appearance are different, while the histopathology, disease manifestations, duration, and severity are similar, this study sought to identify any differences which exist at the level of the target organ. The number of cells expressing the T helper (W3/25) or suppressor/cytotoxic (OX-8) phenotypes and the number of Ia-positive cells found in the spinal cord of animals given EAE by one of the two methods were compared at two time points at which maximal similarities should exist. The results show that during acute adoptively induced EAE the inflammatory infiltrate contains a larger number of T helper (TH) cells per unit area than in acute active EAE. With the resolution of clinical signs of EAE, the disappearance of cells from the spinal cord is more rapid in adoptive EAE. In contrast, the inflammatory infiltrate and Ia-positive parenchymal cells persist in active EAE following recovery. These results suggest that actively and adoptively induced EAE may differ with respect to the effector mechanisms and/or the mechanisms of recovery at the level of the target organ.

Olfactory disturbances as the initial or most prominent symptom of multiple sclerosis.

two day history of headache, nausea, vomiting, and urinary and faecal incontinence. She had a fever of 39 2°C, a blood pressure of 92/48 mmHg, and a pulse of 98 beats/min. General examination showed mild diffuse lower abdominal tenderness. She was drowsy, but obeyed first order commands, and was localising pain, with mild nuchal rigidity, photophobia, and a pale right disc with a right afferent pupillary defect. Eye movements were normal other than a partial right sixth nerve palsy. She showed left sided hyperreflexia and a left extensor plantar response. CT of the brain showed a small anterior collection in the sphenoid sinus and a small area of low attenuation in the right medial frontal region unchanged from the previous scan. The pituitary was normal in size and position. Her CSF had a protein concentration of 47 mg/l, a glucose concentration of 3-5 mM (blood sugar 3-8 mM), and 10 lymphocytes/mm.3 Serum electrolytes were mildly abnormal (sodium 142 mM, potassi-

7-Aryl 1,5-dihydro-benzo[e][1,4]oxazepin-2-ones and analogs as non-steroidal progesterone receptor antagonists

Novel 7-aryl benzo[1,4]oxazepin-2-ones were synthesized and evaluated as non-steroidal progesterone receptor (PR) modulators. The structure activity relationship of 7-aryl benzo[1,4]oxazepinones was examined using the T47D cell alkaline phosphatase assay. A number of 7-aryl benzo[1,4]oxazepinones such as 10j and 10v demonstrated good in vitro potency (IC(50) of 10-30 nM) and selectivity (over 100-fold) at PR over other steroidal receptors such as glucocorticoid and androgen receptors (GR and AR). Several 7-aryl benzo[1,4]oxazepinones were active in the rat uterine decidualization model. In this in vivo model, compounds 10j and 10u were active at 3 mg/kg when dosed orally.

5-Aryl indanones and derivatives as non-steroidal progesterone receptor modulators.

Novel 5-aryl indanones, inden-1-one oximes, and inden-1-ols were synthesized and evaluated as progesterone receptor (PR) modulators using the T47D cell alkaline phosphatase assay. Both PR agonists and antagonists were achieved with appropriate 3- and 5-substitution from indanones and inden-1-ols while inden-1-one oximes provided only PR antagonists. Several compounds such as 10 and 11 demonstrated potent in vitro PR agonist potency similar to that of steroidal progesterone (1). In addition, a number of compounds (e.g., 12, 13, 17, 18) showed potent PR antagonist activity indicating the indanones and derivatives are promising PR modulator templates.

Receptor systems in tissues of the nervous system

A variety of receptor families mediate excitatory and growth-related functions in tissues of the nervous system. This review will focus on two members of distinct families that appear to be involved in fundamental aspects of growth and differentiation. We will describe several surface proteins known to exist on cells of the nervous system to illustrate common structural and developmental features. An in-depth analysis of the neu gene and its product and the reovirus receptor should aid in providing some insight into the diversity of elements likely to be involved in the development of complex multicellular organ systems exemplified by the central nervous system. In this review we will consider several multigene families and certain of their members which are predominantly associated with cells of the nervous system. Although little is known of the development of the complex mammalian nervous system, we will describe our recent studies analyzing developmental patterns of expression of the neu and reovirus receptor proteins. These receptors represent reasonably well-studied proteins and appear to be associated with growth and differentiation of neuronal elements.

In vivo Modulation of Oligodendrocyte Function by an Anti-Receptor Antibody

The receptor for reovirus serotype 3 (Reo3R) is biochemically, pharmacologically, and antigenically related to the adrenergic receptors. Previous studies have demonstrated that anti-Reo3R antibodies and Reo3R-binding peptides alter oligodendrocyte differentiation in culture. In the present studies, antibodies and peptides that bind the Reo3R were found to alter myelin morphology in vivo. Microinjection of purified anti-Reo3R antibody into guinea pig optic nerves produced expansion of the adaxonal oligodendrocyte cytoplasm, separation of myelin lamellae, widening of Schmidt-Lanterman clefts, myelin vesiculation, and demyelination. A divalent Reo3R-binding peptide reproduced some of these changes. Anti-Reo3R antibodies and Reo3R-binding peptides alter oligodendrocyte function in vivo resulting in myelin changes. These effects appear to be mediated directly by Reo3R perturbation, at least in part, rather than through activation of additional effector mechanisms.

Anti-idiotype Modeled Peptides with Biologic Activity

We have developed synthetic peptides modeled after the hypervariable region of an anti-idiotypic/anti-receptor antibody. These peptides exhibit biologic properties identical to those of the antibody, including inhibition of DNA synthesis.