Activation of the receptor tyrosine kinase RET improves long-term hematopoietic stem cell outgrowth and potency.

Expansion of human hematopoietic stem cells (HSCs) is a rapidly advancing field showing great promise for clinical applications. Recent evidence has implicated the nervous system and glial family ligands (GFLs) as potential drivers of hematopoietic survival and self-renewal in the bone marrow niche; how to apply this process to HSC maintenance and expansion has yet to be explored. We show a role for the GFL receptor, RET, at the cell surface of HSCs in mediating sustained cellular growth, resistance to stress, and improved cell survival throughout in vitro expansion. HSCs treated with the key RET ligand/coreceptor complex, glial-derived neurotrophic factor and its coreceptor, exhibit improved progenitor function at primary transplantation and improved long-term HSC function at secondary transplantation. Finally, we show that RET drives a multifaceted intracellular signaling pathway, including key signaling intermediates protein kinase B, extracellular signal-regulated kinase 1/2, NF-κB, and p53, responsible for a wide range of cellular and genetic responses that improve cell growth and survival under culture conditions.

Periodic limb movements in syringomyelia and syringobulbia.

Twenty-six patients with syringomyelia were studied with polysomnography to determine the frequency of periodic limb movements (PLM) and its relationship to the presence of a Chiari anomaly, the severity of corticospinal tract involvement, and localization of the syrinx. Sixteen patients showed PLM in stages I and II of non-REM sleep and three PLM also while awake. There were no statistically significant differences in overall disability, corticospinal signs, presence of an associated Chiari anomaly, and disease duration between patients with and without PLM, although there was a trend for patients with PLM to have more severe disease. There was preservation of the lumbosacral enlargement of the spinal cord by the syrinx in all patients with PLM. The latency delay between lower and upper limb muscles was suggestive of conduction along propriospinal pathways. Syringomyelia may lead to an abnormal state of spinal hyperexcitability favoring the appearance of PLM. Detailed magnetic resonance image studies of patients with different localizations of the syrinx cavities may help to determine which tracts are involved in the production of PLM.

Respiratory disturbances during sleep in syringomyelia and syringobulbia.

OBJECTIVE: To determine the frequency and types of abnormalities of respiratory control during sleep in syringomyelia and syringobulbia and to provide a basis to predict patients at risk of sudden death. METHODS: Thirty patients (15 male and 15 female; mean age 39.0 +/- 12.6 years) with communicating syringomyelia were divided into two groups: those with evidence of syringobulbia (17 patients) and those without compromise of the medulla or syringomyelia (13 patients). Patients were studied with pulmonary function studies and polysomnography. Respiratory center sensitivity to CO2 (rebreathing technique) was measured in 9 patients. RESULTS: Severely affected patients had mild-to-moderate restriction and individual patients had bilateral diaphragmatic or vocal cord palsy, abnormal respiratory rhythm, prolonged inspiratory time, or an abnormal respiratory response to CO2. Very prolonged central, obstructive, and mixed sleep apneas with low O2 saturation values and a fixed heart rate were recorded in most patients with syringobulbia. Five patients developed severe respiratory complications and died during a follow-up period of 10 years. Respiratory abnormalities failed to correlate with syrinx size. CONCLUSIONS: Severe abnormalities in respiratory rhythm generation during sleep occur in patients with syringobulbia. The respiratory disturbances are not due to muscle weakness and they are not correlated with the size of the cavity. The combination of dysphagia and dysphonia in patients with longstanding syringomyelia and syringobulbia predicted likelihood of respiratory disturbances during sleep.

Risk of sudden death during sleep in syringomyelia and syringobulbia.

Clinical, respiratory, and polysomnographic findings in three patients with syringomyelia and syringobulbia who developed severe respiratory complications are described. Neurological examination showed evidence of IXth and Xth cranial nerve involvement with dysphagia and dysphonia, but there were no complaints of serious sleep difficulties. Two patients died during sleep and the other was resuscitated during a nap. All patients showed moderate restrictive ventilatory defects with reduced maximal buccal pressures and one also showed a low ventilatory response to CO2 rebreathing. Protracted central, obstructive, and mixed apnoeas and hypopnoeas were commonly observed during sleep. There were no changes in heart rate during these events. A combination of respiratory and cardiovascular mechanisms might have been responsible for the severe complications described.

Recurrent hypersomnia in two adolescent males with Asperger's syndrome.

Two individuals with Asperger's syndrome, a rare pervasive developmental disorder, developed recurrent episodes of hypersomnia and abnormal behavior (Kleine-Levin syndrome) during adolescence. The possible etiological role of developmental structural brain anomalies and the differential diagnosis of recurrent hypersomnia and abnormal behavior in patients with pervasive developmental disorders are discussed.

[Transcortical reflexes of proprioceptive origin and motor epilepsy (author's transl)]. / Reflexes transcorticaux d'origine proprioceptive et epilepsie motrice.

The long-loop reflex involved in the triggering of paroxysmal activities by proprioceptive afferents is examined in monkeys with a chronic alumina focus and in cats with an acute penicillin focus. Electrical stimulation of a tibial nerve in monkeys as well as muscle stretch in cats elicit a cortical 'evoked spike', i.e., an evoked potential followed by an epileptic spike, accompanied by one or two motor bursts in the muscles concerned. With a very small acute focus, this transcortical reflex is shown to be quite topical: muscles in the vicinity are not affected. Relationships between evoked spike and myoclonic jerk are examined and it is shown that motor efferents usually follow the pyramidal tract. The concept of a transcortical reflex of proprioceptive origin is discussed on the basis of data collected from these models.

Modulation of proprioceptive transcortical reflexes in the cat with a penicillin epileptic motor focus.

Mechanisms responsible for the triggering of paroxysmal events by proprioceptive afferents, previously described in the monkey with a chronic epileptic focus, were studied in more detail in the cat with a penicillin focus. To analyse the topical organization of this reflex triggering, the focus was restricted to very small areas of the motor cortex; in this study only pericruciate areas were considered in which stimulation elicited a motor response in one of the several forelimb muscles tested, and which received afferents from that muscle. When the focus was located in the post-sigmoid gyrus, stimulation (usually by stretch) of the given (target) muscle first elicited a cortical spike following the evoked response, and secondly a late phasic EMG response (about 40 msec latency) quite distinct from purely spinal reflexes. Cortical spikes and late EMG responses were closely correlated, especially considering their probability of occurrence or their parallel latency fluctuations. In most cases, this effect was limited to the muscle whose motor area had been treated with penicillin: stretching muscles in the vicinity was ineffective, nor were these muscles activated when the target muscle was stimulated. Evidence is given for the participation of a transcortical reflex in the generation of the late phasic response and for the involvement of the pyramidal tract in this reflex.

Cortical control of the unit activity in nucleus medialis dorsalis thalami of the cat.

Effects of electrical stimulation of OFC (gyrus proreus, gyrus orbitalis, gyrus sigmoideus anterior) on MD unitary activity were studied. Acute preparations, curarized and unanesthetized or anesthetized with chloralose or barbiturates, were used. Steel microelectrodes were used for recording. Single rectangular pulses (0.5 msec and 0.1-0.5 ma) or short duration trains of stimuli were delivered. 479 neurons were tested and 244 (50.9 percent) responsive cells were revealed. Responses patterns: Type I, excitatory in nature. The discharge was composed of one or more spikes (latencies below 100 msec). Type II, characterized by the suppression or diminution of spontaneous activity during variable periods of time. Type III, defined by the appearance of burst activity (latencies above 150 msec). Values up to 1500-2000 msec were not rare. Type II and III responses have clearly prevailed. The g. proreus stimulation gave the higher MD responsive values. Successive stimulations of the five cortical areas were made to study convergence phenomena. The largest degree of convergence was found with stimulation interplay at the two zones of g. proreus. In a small group of neurons, the convergence of cortical and peripheral natural stimulation was also observed. A hypothesis has been proposed for long latency response generation and the inhibitory effect of cortical stimulation on the nuclear activity has been emphasized.