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Convulsive-like movements in brainstem stroke.

BACKGROUND: Involuntary convulsive-like movements sometimes occur in patients with brainstem strokes. These movements vary in nature, frequency, and trigger, including fasciculation-like, shivering, jerky, tonic-clonic, and intermittent shaking movements. Some are interpreted as decerebrate postures or seizures. It is important to recognize this type of motor phenomenon since it may be a diagnostic clue for early diagnosis and treatment of brainstem strokes. DESIGN: Case report and review of the literature OBSERVATION: A 72-year-old-man presented with impaired consciousness and jerks of the upper limbs mimicking seizures. These episodes consisted of brief clonic contractions of the proximal and distal upper extremities. They were observed in paroxysms lasting for 3 to 5 seconds. Magnetic resonance imaging showed large midpontine infarction. Magnetic resonance angiography revealed the absence of basilar artery blood flow. No seizure discharges were observed in the electroencephalogram. Anticoagulation with intravenous heparin was started. Two days after admission, the patient had a cardiac arrest and died. We review the frequency and nature of convulsive-like movements in brainstem stroke in the literature. CONCLUSIONS: Movements associated with brainstem lesions are not easily differentiated from convulsions. Unexpected onset and inexperience of the observers limit the characterization of this phenomenon. Convulsive-like movements in brainstem stroke may occur more frequently than reported. Early detection of this motor phenomenon may have practical implications.

Aged↗

Expansion of rat oligodendrocyte progenitors into proliferative "oligospheres" that retain differentiation potential.

The limited availability of enriched populations of oligodendroglial progenitors has impeded the exploration of the complex spatio-temporal mechanisms which dictate the chemical "language" of their biology. We have developed a technique to prepare homotypic aggregates of oligodendrocyte progenitors called "oligospheres." These were obtained using various approaches (sieving, Percoll gradient separation and differential adhesion) to purify oligodendroglial progenitors from newborn rat brain. Culturing cells in a mixture of N1 defined medium and conditioned medium from the B104 neuronal cell line in the absence of adhesive substrate allowed to expand routinely and extensively for several months, the oligodendrocyte progenitor population. Under these conditions, the resulting population consisted of 98% GD3-positive/GFAP-negative cells. After dissociation and plating on polyornithine coated substrates, in the presence of low (2%) or high (20%) serum, oligosphere-derived oligodendrocyte progenitors were induced to differentiate into GalC-positive oligodendrocytes or GFAP-positive astrocytes, respectively. When transplanted into the newborn shiverer mouse brain, oligospheres were able to provide a focal reservoir of migrating and myelinating cells. Oligospheres are thus ideal tools for exploring the biological and molecular events of the oligodendrocyte lineage both in vitro and in vivo.

Animals↗

Nuclear transport of myelin basic protein.

The multiple myelin basic protein (MBP) isoforms expressed by myelinating cells are now known to have different expression patterns. The relative abundance of the isoforms containing exon II is greater early in myelinogenesis, whereas in compact myelin the isoforms lacking this exon are more abundant. Further, the individual MBPs exhibit different intracellular localizations, indicating that the isoforms may not be functionally equivalent in myelinating cells. The major MBPs (14 kD and 18.5 kD) have strong affinity for membranes, while on the other hand, the less abundant isoforms (17 kD and 21.5 kD) localize to the nucleus of young oligodendrocytes, suggesting a regulatory role in the myelination program. The same intracellular distribution patterns have been observed when the MBPs are expressed in Hela cells and in shiverer oligodendrocytes. Thus, the intracellular fate of these proteins seems to be generally directed through alternative expression of exon II. Furthermore, the extent of MBPexII entry into the nucleus was found to be directly related to the growth state of host cells. In this paper, we demonstrate that nuclear proteins constitutively expressed by Hela cells also exhibit an apparently growth-related nucleo-cytoplasmic distribution revealing that MBPexII exhibits the same behavior as bona fide nuclear proteins. Also, to further characterize MBP nuclear transport, we explored various parameters of the translocation of MBP into the nucleus using an in vitro system. This experimental paradigm permits the uncoupling of synthesis and translocation events; thus, the transport of MBP into cell nuclei can be studied as a function of time. We also evaluated how changes in temperature as well as energy depletion affect the in vitro nuclear transport of MBP.

Biological Transport↗

Golli-MBP proteins mark the earliest stages of fiber extension and terminal arboration in the mouse peripheral nervous system.

The Golli-myelin basic protein (MBP) transcription unit gives rise to two sets of products. One set (i.e., the MBPs) is expressed exclusively in myelin forming cells and the other set (i.e., the golli isoforms) is expressed in both oligodendrocytes and neurons in the CNS. The two major golli proteins, generated from RNAs transcribed from the most upstream promoter of the gene, contain MBP peptide sequences in their C-terminal halves and are, therefore, structurally and immunologically related to the MBPs. We have examined the distribution and localization of golli proteins in the mouse peripheral nervous system (PNS) using immunocytochemistry with a golli-specific antibody. Golli immunoreactivity was first observed in sensory and motor fibers of the mouse at E11 during fiber tract extension, but prior to the maturation of terminal connections. Once neuromuscular junctions had formed, golli immunoreactivity appeared in motor endplates and persisted to the latest age examined, P60. Golli immunoreactivity was also observed in the cell bodies and processes of the dorsal root ganglia throughout development. Strong staining in the PNS of the dysmyelinating mutant shiverer suggested that the major golli protein in peripheral fibers was the BG21 isoform. Interestingly, golli immunoreactivity was also found in adrenal chromaffin cells, which share a common neural crest derivation with other postganglionic neurons that express golli protein. These results suggest that in addition to its role in early forming neuronal systems of the CNS, golli protein also plays a role in the early development and maintenance of neurons in the PNS.

Animals↗

The new architectonics: an invitation to structural biology.

The philosophy of art might offer an epistemological basis for talking about the complexity of biological molecules in a meaningful way. The analysis of artistic compositions requires the resolution of intrinsic tensions between disparate sensory categories-color, line and form-not unlike those encountered in looking at the surfaces of protein molecules, where charge, polarity, hydrophobicity, and shape compete for our attentions. Complex living systems exhibit behaviors such as contraction waves moving along muscle fibers, or shivers passing through the growth cones of migrating neurons, that are easy to describe with common words, but difficult to explain in terms of the language of chemistry. The problem follows from a lack of everyday experience with processes that move towards equilibrium by switching between crystalline order and chain-like disorder, a commonplace occurrence in the submicroscopic world of proteins. Since most of what is understood about protein function comes from studies of isolated macromolecules in solution, a serious gap exists between what we know and what we would like to know about organized biological systems. Closing this gap can be achieved by recognizing that protein molecules reside in gradients of Gibbs free energy, where local forces and movements can be large compared with Brownian motion. Architectonics, a term borrowed from the philosophical literature, symbolizes the eventual union of the structure of theories-how our minds construct the world-with the theory of structures-or how stability is maintained in the chaotic world of microsystems.

History, 20th Century↗

Physical methods for treating fever in children.

BACKGROUND: Health workers recommend bathing, sponging and other physical methods to treat fever in children and to avoid febrile convulsions. We know little about the most effective methods, or how these methods compare with commonly used drugs. OBJECTIVES: To evaluate the benefits and harms of physical cooling methods used for managing fever in children. SEARCH STRATEGY: We searched the Cochrane Infectious Diseases Group specialized trials register (February 2003), the Cochrane Central Register of Controlled Trials (Issue 1, 2003), MEDLINE (1966 to February 2003), EMBASE (1988 to November 2002), CINHAL (1982 to February 2003), LILACS (February 2003), Science Citation Index (1981 to February 2003), and reference lists of articles. We also contacted researchers in the field. SELECTION CRITERIA: Randomized and quasi-randomized trials comparing physical methods with a drug placebo or no treatment in children with fever of presumed infectious origin. Studies where children in both groups were given an antipyretic drug were included. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial methodological quality. One reviewer extracted data and the other checked the data for accuracy. Results were expressed as Relative Risk (RR) with 95% confidence intervals (CI) for discrete variables, and weighted mean differences for continuous outcomes. MAIN RESULTS: Seven trials, involving 467 participants, met the inclusion criteria. One small trial (n = 30), comparing physical methods with drug placebo, did not demonstrate a difference in the proportion of children without fever by one hour after treatment in a comparison between physical methods alone and drug placebo. In 2 studies, where all children received an anti-pyretic drug, physical methods resulted in a higher proportion of children without fever at one hour (n=125, RR 11.8, CI 3.39 to 40.8). I; in a third study (n=130), which only reported mean change in temperature, no differences wereas detected. Mild adverse events (shivering and goose pimples) were more common in the physical methods group (3 trials, RR 5.09; CI 1.56 to 16.60). REVIEWER'S CONCLUSIONS: A few small studies demonstrate that tepid sponging helps to reduce fever in children.

Acetaminophen↗

Allergic reaction with immune hemolytic anemia resulting from chlorambucil.

In a 73-year-old female with chronic lymphocytic leukemia we observed an acute illness with shivering, high fever, and hemolytic anemia following chlorambucil administration. Reexposure in a controlled clinical situation suggested an allergic drug reaction. In an in vitro assay, we were able to demonstrate chlorambucil as the causative agent of immune hemolysis.

Aged↗

Physiology of hot flashes.

Hot flashes are the most common symptom of the climacteric, although prevalence estimates are lower in some rural and non-Western areas. The symptoms are characteristic of a heat-dissipation response and consist of sweating on the face, neck, and chest, as well as peripheral vasodilation. Although hot flashes clearly accompany the estrogen withdrawal at menopause, estrogen alone is not responsible since levels do not differ between symptomatic and asymptomatic women. Until recently it was thought that hot flashes were triggered by a sudden, downward resetting of the hypothalamic setpoint, since there was no evidence of increased core body temperature. Evidence obtained using a rapidly responding ingested telemetry pill indicates that the thermoneutral zone, within which sweating, peripheral vasodilation, and shivering do not occur, is virtually nonexistent in symptomatic women but normal (about 0.4 degrees C) in asymptomatic women. The results suggest that small temperature elevations preceding hot flashes acting within a reduced thermoneutral zone constitute the triggering mechanism. Central sympathetic activation is also elevated in symptomatic women which, in animal studies, reduces the thermoneutral zone. Clonidine reduces central sympathetic activation, widens the thermoneutral zone, and ameliorates hot flashes. Estrogen virtually eliminates hot flashes but its mechanism of action is not known.

Body Temperature Regulation↗

Geographical distribution of hot flash frequencies: considering climatic influences.

Laboratory studies suggest that hot flashes are triggered by small elevations in core body temperature acting within a reduced thermoneutral zone, i.e., the temperature range in which a woman neither shivers nor sweats. In the present study, it was hypothesized that women in different populations develop climate-specific thermoneutral zones, and ultimately, population-specific frequencies of hot flashes at menopause. Correlations were predicted between hot flash frequencies and latitude, elevation, and annual temperatures. Data on hot flash frequencies were drawn from 54 studies. Pearson correlation analyses and simple linear regressions were applied, first using all studies, and second using a subset of studies that included participants only to age 60 (n = 36). Regressions were repeated with all studies, controlling for method of hot flash assessment. When analyses were restricted to studies that included women up to age 60, average temperature of the coldest month was a significant predictor of hot flash frequency (P < 0.01), explaining 29.2% of the variation in hot flash frequency. In a separate equation, the difference between hottest and coldest temperatures was also a significant predictor (P < 0.01), explaining 26.4% of the variation in hot flash frequency. When regressions used all studies but controlled for method of hot flash assessment, average temperature of the coldest month, difference between hottest and coldest temperatures, and mean annual temperature were significant predictors of hot flash frequency. Women reported fewer hot flashes in warmer temperatures, and more hot flashes with increasing seasonality. These results suggest that acclimatization to coldest temperatures or sensitivity to seasonality may explain part of the population variation in hot flash frequency.

Body Temperature Regulation↗

Body temperature after accidental injury.

Core and mean skin temperatures have been measured in 82 patients shortly after accidental injuries of different severity in order to study the effects of injury on thermoregulation. Skin temperature fell after injury and core temperature also when the injury was severe. After severe injuries both core and mean body temperatures were negatively related to the severity of the injury, measured by the Injury Severity Score. The fall in skin temperature was attributed to vasoconstriction and that in core temperature to decreased heat production due to reduced oxygen transport to the tissues. These changes in temperature should have stimulated shivering which was not observed in the severely injured. This suggests that thermoregulation is affected after injury, and possible mechanisms are discussed.

Accidents↗

Whole gut irrigation and Prepacol laxative preparation for colonoscopy: a comparison.

Two techniques for preparation of the colon for colonoscopy were compared in a controlled trial. Fifty patients given a low residue diet and the laxative Prepacol were compared with 50 patients given whole gut irrigation. Significantly more patients suffered from vomiting (P = 0.0005), shivering (P = 0.0062) and nausea (P = 0.031) following irrigation; in two cases the procedure had to be abandoned because of profuse vomiting. Irrigation was less well tolerated by the patients (P = 0.00002) than preparation with Prepacol. On the other hand, the quality of bowel preparation was found to be better (P = 0.0005) after irrigation. On two occasions colonoscopy was not possible following Prepacol preparation because of faecal residue. Patients with a previous colorectal resection showed a similar quality of cleansing to those patients prepared with irrigation. We conclude that Prepacol is as efficient as irrigation for patients who have had a previous colorectal resection because the quality of bowel preparation is as good and the associated patient discomfort is small.

Adolescent↗

Development of tonic immobility in the rabbit: relation to body temperature.

Tonic immobility was studied in rabbit pups varying in age from 1 to 30 days. During the 1st 2 postnatal weeks the rabbits were active in an open field, had difficulty walking and executing a righting response, lost body temperature rapidly, and had no, or only short durations of, tonic immobility. After this age they were less active, hopped and righted well, maintained core temperature, and showed increased durations of tonic immobility. Within the 1st 2 postnatal weeks cooling and warming potentiated; thereafter, cooling disrupted and only warming potentiated tonic immobility. The results suggest that rate of heat loss can act as a stimulus to block tonic immobility and increase activity in neonatal rabbits. With development, cooling produces shivering which can disrupt tonic immobility, whereas warming may raise movement initiation thresholds which can potentiate tonic immobility.

Age Factors↗

Human embryonic stem cells differentiate into oligodendrocytes in high purity and myelinate after spinal cord transplantation.

Human embryonic stem cells (hESCs) demonstrate remarkable proliferative and developmental capacity. Clinical interest arises from their ability to provide an apparently unlimited cell supply for transplantation, and from the hope that they can be directed to desirable phenotypes in high purity. Here we present for the first time a method for obtaining oligodendrocytes and their progenitors in high yield from hESCs. We expanded hESCs, promoted their differentiation into oligodendroglial progenitors, amplified those progenitors, and then promoted oligodendroglial differentiation using positive selection and mechanical enrichment. Transplantation into the shiverer model of dysmyelination resulted in integration, differentiation into oligodendrocytes, and compact myelin formation, demonstrating that these cells display a functional phenotype. This differentiation protocol provides a means of generating human oligodendroglial lineage cells in high purity, for use in studies of lineage development, screening assays of oligodendroglial-specific compounds, and treating neurodegenerative diseases and traumatic injuries to the adult CNS.

Animals↗

Oligodendrocyte precursor cells generate pituicytes in vivo during neurohypophysis development.

In the vertebrate brain, much remains to be understood concerning the origin of glial cell diversity and the potential lineage relationships between the various types of glia. Besides astrocytes and myelin-forming oligodendrocytes, other macroglial cell populations are found in discrete areas of the central nervous system (CNS). They share functional features with astrocytes and oligodendrocytes but also display specific characteristics. Such specialized cells, called pituicytes, are located in the neurohypophysis (NH). Our work focuses on the lineage of the pituicytes during rodent development. First, we show that cells identified with a combination of oligodendrocyte precursor cell (OPC) markers are present in the developing rat NH. In culture, neonatal NH progenitors also share major functional characteristics with OPCs, being both migratory and bipotential, i.e. able to give rise to type 2 astrocytes and oligodendrocytes. We then observe that, either in vitro or after transplantation into myelin-deficient Shiverer brain, pieces of NH generate myelinating oligodendrocytes, confirming the oligodendrogenic potentiality of NH cells. However, no mature oligodendrocyte can be found in the NH. This led us to hypothesize that the OPCs present in the developing NH might be generating other glial cells, especially the pituicytes. Consistent with this hypothesis, the OPCs appear during NH development before pituicytes differentiate. Finally, we establish a lineage relationship between olig1+ cells, most likely OPCs, and the pituicytes by fate-mapping experiments using genetically engineered mice. This constitutes the first demonstration that OPCs generate glial cells other than oligodendrocytes in vivo.

Animals↗

Myelination by mature ovine oligodendrocytes in vivo and in vitro: evidence that different steps in the myelination process are independently controlled.

The ability of isolated mature post-myelination ovine oligodendrocytes to myelinate was investigated in tissue culture and in vivo. In culture, although the cells adhered preferentially to rat dorsal root ganglia (DRG) axons, sent out processes that encircled and wrapped them, proliferated, and synthesised myelin proteins (MBP), no myelination was found. This failure to find myelination occurred despite the fact that the oligodendrocytes both in the present experiments and in previous studies elaborated membranous structures that have been shown chemically and structurally to be similar to normal central nervous system myelin. These findings contrasted with those seen when neonatal rodent glial cells were added to similar DRG neuron cultures, in which myelination readily occurred. When the same adult ovine oligodendrocytes were transplanted into the brains of Shiverer mice, normal compact myelin was formed, proving that the cells were capable of myelination and suggesting that cross-species incompatibility was probably not a major factor in the lack of myelination in vitro. It is possible that the failure of ovine oligodendrocytes to myelinate DRG axons is due either to the relatively low number of supporting glial cells, such as astrocytes or microglia which may be necessary for satisfactory myelination, or that some other factor in the microenvironment is lacking; in any event, these results point to the complexity of oligodendrocyte-axon interactions. It is clear that each of the events, from adherence to proliferation to wrapping and the myelin compaction may be under the control of a different signal and may operate through a distinct mechanism, even though each process is dependent on the other. The results also point to the potential usefulness of this model system for deciphering such signals and mechanisms.

Animals↗

Dysmyelination in class I MHC transgenic mice.

Why is it that oligodendrocytes do not normally express major histocompatibility complex (MHC) molecules? To examine the effect of aberrant MHC expression in oligodendrocytes, transgenic mice have been produced which expressed the class I MHC gene, H-2Kb, under direction of the MBP promoter [Turnley et al. (1991b) Nature, 353:566-569; Yoshioka et al. (1991) Mol. Cell. Biol., 11:5479-5486]. A proportion of these mice exhibited a shivering phenotype, with tonic seizures and early death. Oligodendrocyte function and viability was shown to be affected, resulting in severe dysmyelination of the CNS. Is this phenomenon of cell damage due to aberrant expression of MHC molecules restricted to oligodendrocytes, and could other, non-MHC molecules, when aberrantly expressed, result in similar cell damage? This paper discusses these questions and examines possible mechanisms for the oligodendrocyte damage and hypomyelination observed in these transgenic mice. Finally, the implications of aberrant MHC expression in oligodendrocytes for demyelinating diseases such as multiple sclerosis are discussed.

Animals↗

Myelin basic protein functions as a microtubule stabilizing protein in differentiated oligodendrocytes.

Myelin basic protein (MBP) is an oligodendrocyte-specific protein essential for oligodendrocyte morphogenesis at late stages of cell differentiation. There is evidence that the morphogenetic function of MBP is mediated by MBP interaction with the cytoskeleton. Thus, an MBP/cytoplasmic microtubule association has been reported, and MBP has Ca(2+)/calmodulin-regulated microtubule cold-stabilizing activity in vitro. However, the unambiguous demonstration of a microtubule-stabilizing activity for MBP in cells has been difficult because oligodendrocytes contain variants of STOP (stable tubule only polypeptide) proteins, which are responsible for microtubule cold stability in different cell types. Herein, we have used genetic mouse models and RNA interference to assay independently the microtubule cold-stabilizing activities of MBP and of STOP in developing oligodendrocytes. In wild-type oligodendrocytes, microtubules were cold stable throughout maturation, which is consistent with the presence of STOP proteins from early stages of differentiation. In contrast, in oligodendrocytes from STOP-deficient mice, microtubules were cold labile in the absence of MBP expression or when MBP expression was restricted to the cell body and became stable in fully differentiated oligodendrocytes, where MBP is expressed in cell extensions. The suppression of MBP by RNA interference in STOP-deficient oligodendrocytes suppressed microtubule cold stability. Additionally, STOP suppression in oligodendrocytes derived from shiverer mice that lack MBP led to the complete suppression of microtubule cold stability at all stages of cell differentiation. These results demonstrate that both STOP and MBP function as microtubule-stabilizing proteins in differentiating oligodendrocytes and could be important for the morphogenetic function of MBP.

Animals↗

Oligodendrocytes of the jimpy phenotype can be partially restored by environmental factors in vivo.

Cross-transplantations of neural tissue between jimpy (jp) shiverer (shi) and normal mice have been performed under heterochronic conditions. In all series, fragments of E14-E15 embryonic neural tissue from the different donors have been transplanted into newborn host brain in order to study environmental influences by differentiated tissue on transplanted embryonic cell lines. Large patches of proteolipid protein (PLP)-positive myelin have been observed in the jp brain after transplantation of shi or normal embryonic tissue into the newborn jp brain, suggesting that the jp parenchyma did not inhibit the differentiation of other oligodendrocytes (ODCs). Jp embryonic tissue had the same mitotic potential as normal tissue, as demonstrated by the larger size of myelin patches observed when jp embryonic tissue was used instead of newborn jp tissue. By contrast, whatever the conditions, jp myelin patches were always obviously smaller than normal or shi myelin patches, suggesting that the myelinating capacity of jp ODCs was not enhanced by environmental factors. Finally, comparison of the ratio of successful outcomes observed following embryonic vs. newborn jp donor tissue, strongly suggests a partial or total normalization of jp embryonic ODCs survival by a more mature shi environment.

Animals↗