Itzhak Wirguin

miRNA malfunction causes spinal motor neuron disease

Defective RNA metabolism is an emerging mechanism involved in ALS pathogenesis and possibly in other neurodegenerative disorders. Here, we show that microRNA (miRNA) activity is essential for long-term survival of postmitotic spinal motor neurons (SMNs) in vivo. Thus, mice that do not process miRNA in SMNs exhibit hallmarks of spinal muscular atrophy (SMA), including sclerosis of the spinal cord ventral horns, aberrant end plate architecture, and myofiber atrophy with signs of denervation. Furthermore, a neurofilament heavy subunit previously implicated in motor neuron degeneration is specifically up-regulated in miRNA-deficient SMNs. We demonstrate that the heavy neurofilament subunit is a target of miR-9, a miRNA that is specifically down-regulated in a genetic model of SMA. These data provide evidence for miRNA function in SMN diseases and emphasize the potential role of miR-9–based regulatory mechanisms in adult neurons and neurodegenerative states.

Suppression of experimetal autoimmune encephalomyelitis by cannabinoids

The effect of delta 8-THC on experimental autoimmune encephalomyelitis (EAE) was examined. delta 8-THC is an analogue of delta 9-THC, the psychoactive component of marijuana. It is more stable and less psychotropic than delta 9-THC and like the latter it binds to the brain cannabinoid receptor. Two strains of rats were inoculated for EAE, and delta 8-THC (40 mg/kg) was administered for up to 21 days. delta 8-THC significantly reduced the incidence and severity of neurological deficit in both rat strains. The beneficial influence of delta 8-THC only occurred on oral administration and not with parenteral injection. Serum corticosterone levels were twofold elevated in rats with EAE chronically treated with delta 8-THC. These results suggest that suppression of EAE by cannabinoids may be related to their effect on corticosterone secretion.

Efficacy of repeated intravenous immunoglobulin in severe unresponsive Guillain-Barré syndrome.

1 and 4 while the two others had demyelinative features. All four had raised cerebrospinal fluid protein concentrations upon admission and patient 4 had a 25 000 GM1 antibody titre. The patients were retreated with IVIg after 14–21 days and substantial or rapid improvement was noted within days (figure). All four patients began to walk within several weeks. Patient 1 is of special interest because he was in a critical condition for 15 days with flaccid quadriplegia, respiratory failure, and severe autonomic instability, with long asystoles necessitating a pacemaker. Electrophysiological studies at this phase showed inexcitable nerves in all his limbs. During the second course of IVIg he began to improve and to make a remarkable recovery. Unlike the patients reported by Irani et al no relapses occurred in all 12 patients after the onset of motor improvement. As the figure suggests, it appears that the second course of IVIg had a favourable impact on the clinical course of these patients. This favourable response is especially striking as two of the patients had features compatible with an adverse prognosis (severe axonal involvement in both and antecedent diarrhoea and high titres of GM1 antibodies in one). The outcome in these patients suggests that in some GBS cases the standard dose of IVIg is not sufficient and that in such cases it is justified to repeat the treatment. This is true even in cases with adverse prognostic features such as early axonal damage. Now that it has been determined that IVIg and plasma exchange are equally effective and that the combination of therapies offers no advantage, a next logical step might be a controlled study designed to determine optimum doses and regimens of current therapies in GBS.

A high incidence of migraine with aura among morbidly obese women

Introduction.—Nearly two‐thirds of adults in the United States and an increasing percentage of the population worldwide are overweight or obese. The relationship of obesity to headache has received inadequate attention. We evaluated the incidence of headache in a sample of morbidly obese women.

Infection and the etiology and pathogenesis of multiple sclerosis.

Multiple sclerosis (MS) currently defies clinical and scientific definitions, and carries a prognosis that remains practically unchanged despite many years of intensive research. Although the prevailing dogma is that MS is an immune-mediated condition, it fulfills none of the criteria of an autoimmune disease. On the other hand, there is enough significant data to suggest that infectious agents(s) could be involved in either direct damage to the white matter or induce inflammatory responses that secondarily affect the brain. Our goal here is to review the data supporting the possibility that infection has a critical role in the disease, examine the list of potential candidates that have been suggested, and outline an approach regarding the potential role of infectious agents in the etiology and pathogenesis of MS.

Acetylcholinesterase inhibitors and cholinergic modulation in Myasthenia Gravis and neuroinflammation

The cholinergic network affects various cellular functions including neurotransmission, and immune reactions. In Myasthenia Gravis (MG), diagnosis and symptomatic therapy are based on cholinergic modulation by acetylcholinesterase inhibitors (AChEI). In Alzheimers disease (AD) a neurodegenerative disorder associated with inflammatory pathology, cholinergic systems cell loss occurs early. Treatments with special AChEI enhance cholinergic transmission and may act as anti-inflammatory agent via immunocompetent cells expressing alpha-7 acetylcholine receptor (AChR). In Multiple Sclerosis (MS) an inflammatory T-cell-mediated disease, demyelination and neurodegeneration follow neuroinflammation. MS treatment includes anti-inflammatory and immunomodulatory drugs. AChEI can induce cholinergic up-regulation with subsequent effect on neuroinflammation via alpha-7-AChR expressing cells. These effects are additional to the cognitive benefit induced by AChEI.

Thiamine-Responsive Acute Neurological Disorders in Nonalcoholic Patients

Wernicke’s encephalopathy (WE) is most commonly associated with alcoholism, although other causes have also been implicated. In the years 1994–1997, 9 patients with no history of alcohol abuse presented with acute signs of ophthalmoplegia or nystagmus and ataxia which resolved within 48 h after intravenous thiamine. There were 7 women and 2 men aged 17–57 (7 below the age of 30). Precipitating events included vomiting 2, drastic weight-reducing diet 2, renal colic in a postpartum woman 1, colonic surgery 2 and chronic hemodialysis 1. In 2 patients there was no obvious precipitating event but their history was suggestive of a genetic predisposition. Mental changes were slight or absent in all patients and all of them made good functional recovery. These cases suggest that the diagnosis of WE should be considered more often in nonalcoholics in various clinical settings.

Murine typhus presenting as subacute meningoencephalitis

Abstract Murine typhus is a febrile systemic illness, presenting with headache and undulating fever. Neurological involvement is considered a rare complication. During 1994 and 1995, 34 patients admitted to our hospital were diagnosed as having murine typhus. Five of these patients presented with a syndrome of subacute “aseptic” meningitis or meningoencephalitis. Three had bilateral papilloedema and 2 had focal neurological signs. None had a rash or other systemic findings suggestive of rickettsial disease. The diagnosis was based on serum and cerebrospinal fluid serology and on prompt response to doxycycline therapy. These cases suggest that neurological involvement in murine typhus is more common than previously suspected and that murine typhus should be included in the differential diagnosis of subacute meningitis in endemic areas.

Lipopolysaccharides of a Campylobacter coli isolate from a patient with Guillain–Barré syndrome display ganglioside mimicry

Abstract Campylobacter coli was isolated from a patient with severe, axonal type Guillain–Barre syndrome (GBS). The patients serum was tested by ELISA for glycolipid antibodies and showed a high titer of IgG antibodies to asialo-GM1 (GA1) and GD3. Campylobacter coli lipopolysaccharide (LPS) was extracted and analyzed by ELISA, immunoblot binding and blocking studies, and found to avidly bind cholera toxin and peanut agglutinin. The LPS from the patients isolate also induced anti-GA1 antibodies in a rat model. These findings suggest that the LPS from this bacterial isolate contains a ganglioside-like epitope, which most likely resembles GA1. Thus, it appears that ganglioside cross-reactivity is not unique to Campylobacter jejuni and seems to occur in all bacterial isolates from GBS cases so far analyzed.

Changes in cerebral venous sinuses diameter after lumbar puncture in idiopathic intracranial hypertension: a prospective MRI study.

Idiopathic intracranial hypertension (IIH), is characterized by elevated intracranial pressure (ICP) without a clear cause. Recently it was shown that in more than 90% of the IIH patients there is stenosis of the transverse dural sinuses. In this study we assessed the changes in diameter of cerebral veins after lumbar puncture, in order to have some more insight regarding the volume and pressure influence on cerebral veins.