Synthesis of ether analogues derived from HUN-7293 and evaluation as inhibitors of VCAM-1 expression.

The cyclic depsipeptide HUN-7293 (1) and its D-lactate analogue 2 are highly potent inhibitors of inducible cell adhesion molecule expression. We report the synthesis of ether analogues varying in stereochemistry and side chain at the former hydroxyl acid position by employing a 'cut and paste chemistry' methodology starting from 1. As an additional fruit of this synthetic effort, a cyclodepsipeptide featuring a tertiary amine instead of a tertiary amide between PrLEU and MALA was obtained.

Sustained remission of CIDP associated with Evans syndrome.

A patient with chronic inflammatory demyelinating polyneuropathy (CIDP) developed Evans syndrome (hemolytic anemia/thrombocytopenia) 17 months after onset of symptoms despite different immunomodulatory treatments. A therapeutic approach with the chimeric monoclonal anti-CD20 antibody rituximab induced substantial improvement of CIDP and hematologic recovery. The patient remains in sustained remission 17 months after completion of therapy.

Clinical features and pathophysiological basis of sensory neuronopathies (ganglionopathies).

Sensory ganglionopathies have a frequent association with neoplastic disorders (paraneoplastic subacute sensory neuronopathy, or SSN) or dysimmune disorders (Sjögren's syndrome, SS; Miller Fisher syndrome; and Bickerstaff's brainstem encephalitis, BBE), with drugs, such as cisplatin or pyridoxine, and with inherited disorders with degeneration of dorsal root ganglion cells. Unsteady gait and pseudoathetoid movements of the hand are the distinctive signs encountered in these disorders. The chronic disorders are characterized by non-length-dependent abnormalities of sensory nerve action potentials (SNAPs) and differ from other sensory neuropathies in showing a global, rather than distal, decrease in SNAP amplitudes.

Flail arm syndrome: a clinical variant of amyotrophic lateral sclerosis.

We describe a case of a 65-year old patient diagnosed with amyotrophic lateral sclerosis. The clinical findings, with symmetric, predominantly proximal wasting and weakness of both arms (especially of the infra-, supraspinatus and deltoideus) leading to severe functional disability and contrasting with preserved independent ambulation and sparing of bulbar muscles, were consistent with the proposed criteria of the so-called flail arm syndrome. Based on our case we characterize the clinical features of flail arm syndrome and review the literature.

Immune mediated neuropathies--an update on therapeutic strategies.

This paper reviews recent treatment strategies of immune mediated neuropathies, in particular it includes data regarding Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), neuropathy with IgM monoclonal gammopathy and other dysglobulinemic neuropathies. In the treatment of Guillain- Barré syndrome, there is no significant difference between IVIg, plasma exchange or plasma exchange followed by IVIg. However, for reasons of convenience and safety, IVIg is used as standard treatment in most centers.

The clinical significance of diffusion-weighted MR imaging in infratentorial strokes.

Objective: To study the association between diffusion-weighted imaging (DWI) characteristics and stroke etiology, stroke severity, and functional outcome in patients with infratentorial strokes.

Methods: The authors prospectively studied 22 consecutive patients with acute infratentorial strokes. They used a blinded comparison of DWI features (number, distribution, and volume of lesions) with clinical characteristics, namely, stroke etiology (Trial of ORG 10172 in Acute Stroke Treatment [TOAST] classification), severity (NIH Stroke Scale [NIHSS]), length of stay (LOS), and functional 3-month outcome using modified Rankin Scale, Barthel Index, and a dichotomized outcome status (living at home vs institutionalization or death).

Molecular changes in normal appearing white matter in multiple sclerosis are characteristic of neuroprotective mechanisms against hypoxic insult.

Multiple sclerosis is a chronic inflammatory disease of the CNS leading to focal destruction of myelin, still the earliest changes that lead to lesion formation are not known. We have studied the gene-expression pattern of 12 samples of normal appearing white matter from 10 post-mortem MS brains. Microarray analysis revealed upregulation of genes involved in maintenance of cellular homeostasis, and in neural protective mechanisms known to be induced upon ischemic preconditioning.

Distal motor latency and residual latency as sensitive markers of anti-MAG polyneuropathy.

There is debate whether the terminal latency index (TLI) is a sensitive marker for polyneuropathy with anti-myelin-associated-glycoprotein antibodies (anti-MAGP). We examined 6 patients with an anti-MAGP and 6 patients with a chronic inflammatory demyelinating polyneuropathy (CIDP). The electroneurographic features studied were: distal compound motor action potential (CMAP), distal motor latency (DML), motor conduction velocity (MCV) elbow to wrist (distal MCV), MCV axilla to elbow (proximal MCV), MCV distal/proximal, terminal latency index (TLI), residual latency (RL), F-wave, and modified F ratio.

[Actual aspects of myasthenia gravis treatment].

This paper reviews treatment strategies of myasthenia gravis (MG) that are currently in use: 1. enhancement of neuromuscular transmission with acetylcholinesterase inhibitors; 2. short-term immunotherapies, including plasma exchange and intravenous immunoglobulin therapy; 3.

Respiratory failure due to bilateral diaphragm palsy as an early manifestation of ALS.

Background: Diaphragm palsy is common in the advanced stages of motor neuron disease and is a primary cause of fatal outcome However, respiratory failure is a presenting symptom of motor neuron disease in only a small number of patients.

Case Report: We present the case of a patient with dyspnea and orthopnea followed by subacute respiratory failure due to bilateral diaphragm paralysis as the first manifestation of amyotrophic lateral sclerosis.

Conclusions: Failure of respiratory muscle function can be the first symptom of motor neuron disease, and may precede clinical manifestation in voluntary motor units in ALS.

Rituximab in the treatment of polyneuropathy associated with anti-MAG antibodies.

No causative or curative therapy exists for the polyneuropathy associated with antibodies to myelin-associated glycoprotein (anti-MAG). Rituximab is a mouse-human chimeric antibody that specifically eliminates B-cells and B-cell precursors. Preliminary results suggest a beneficial effect on antibody-dependent autoimmune diseases.

Immune-mediated neuropathies: etiology and pathogenic relationship to aging processes.

Immune-mediated peripheral neuropathies are more frequent in aged populations. Equally, underlying diseases such as vasculitis and paraproteinemia are more prevalent in the elderly. Accumulating evidence is linking the aging process of the immune system, immunosenescence, to the susceptibility of older individuals for paraproteinemic, vasculitic and inflammatory demyelinating neuropathies.

Characterization of human nerve basal lamina for their binding properties of anti-MAG antibodies.

The functional importance of the basal lamina in Schwann cell development and in adult peripheral nerve fibers is well known. We have demonstrated previously by confocal microscopy that IgM deposits are present on the basal lamina of myelinating Schwann cells of nerve biopsies from patients with an anti-MAG IgM neuropathy. Therefore, the basal lamina was postulated to represent an early target for the uptake of autoantibodies on the surface of myelinated nerve fibers.

Microheterogeneity of anti-myelin-associated glycoprotein antibodies.

Antibodies to the myelin-associated glycoprotein (MAG) are implicated in the pathogenesis of an acquired demyelinating polyneuropathy. We studied IgM affinity to MAG in 18 patients with anti-MAG antibodies. Binding of sera was tested for anti-MAG immunoreactivity in central nervous system (CNS) by ELISA and in CNS and peripheral nervous system (PNS) by Western blot analysis.

Bilateral vertebral artery occlusion resulting from giant cell arteritis: report of 3 cases and review of the literature.

Giant cell arteritis (GCA) is known to affect the extracranial part of the vertebral arteries. Bilateral vertebral artery occlusion (BVAO) is a rare but serious neurologic condition. We report 3 patients with autopsy-proven (2 patients) or clinically diagnosed (1 patient) GCA causing BVAO.

Differential expression of L- and S-MAG upon cAMP stimulated differentiation in oligodendroglial cells.

Myelin-associated glycoprotein (MAG), an immunoglobulin-like cell signaling protein involved in axon-glial interactions, displays two intracellular C-termini as a result of alternative mRNA splicing. During brain development, the two MAG mRNAs that encode L-MAG and S-MAG differ in their relative abundance. We have investigated the differential expression of L- and S-MAG upon cAMP treatment in the oligodendroglial cell line Oli-neu, a cell line able to differentiate in vitro.

Matrix metalloproteinases-9 and -2 in secondary vasculitic neuropathies.

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endoproteinases that play an important role in inflammation and tissue degradation. MMP-9 and MMP-2 are gelatinases that have been implicated in the degradation of the blood-brain or blood-nerve barrier. We present an immunohistochemical study on 11 nerve biopsy samples of inflammatory and non-inflammatory polyneuropathies.

A convenient protocol for selective cleavage of 2-hydroxy acid amides. Application to semisynthesis of the cyclic heptapeptide aza HUN-7293.

A two-step protocol for the first chemoselective cleavage of 2-hydroxy acid amides has been developed. Mesylation of the model substrate 2-(hydroxypropionylamino)-4-methylpentanoic acid methyl ester (11) followed by treatment with N-ethylthiourea (13) allows cleavage of 2-hydroxy acid amides under smooth conditions. Successful application of this methodology to the open-chain transesterification product 15 (methylester) of the cyclic heptadepsipeptide HUN-7293, a potent inhibitor of inducible cell adhesion molecule expression, delivered the corresponding hexapeptide 18 with unprotected N-terminus in 70-75% yield.

[Neurological manifestations of IgM dysglobulinemia].

Disturbancies in neurological functions associated with paraproteinaemic states are well documented. In recent years increasing attention has been given to paraproteinemia in the absence of evidence of malignancy. In this article we review the main clinical and pathological features associated with IgM paraproteins.

CADASIL mimicking primary angiitis of the central nervous system.

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and primary angiitis of the central nervous system (PACNS) share several clinical and radiological features. However, digital subtraction angiogram (DSA) is generally reported as normal in CADASIL, whereas lumen irregularities in distal cerebral arteries indicate PACNS.

Objective: To describe a potential pitfall of DSA interpretation, which led to the tentative diagnosis of PACNS in a CADASIL patient.