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Spindle cell squamous carcinoma of the thyroid: an unusual anaplastic tumor associated with tall cell papillary cancer.

Five cases of spindle cell squamous carcinoma of the thyroid associated with tall cell papillary carcinoma were examined. The unusual spindle cell squamous carcinoma in these cases resembles those previously described in other sites, including the breast and oropharynx. Three patients demonstrated concurrent spindle cell squamous anaplastic carcinoma and tall cell papillary carcinoma at initial diagnosis, whereas two patients developed concurrent tumor morphologies subsequent to initial diagnoses of only papillary carcinoma. The mean age of the patients was 77 yr, with a female:male ratio of 4:1. Thyroglobulin immunoreactivity was demonstrated in the tall cell papillary component of each case but was absent in both the squamous and spindle cell components. Low molecular weight cytokeratin immunoreactivity was strongly and diffusely present in the tall cell papillary and squamous components, whereas the spindle cell areas demonstrated only focal weak to negative reactivity. Only the squamous cell component demonstrated consistent immunoreactivity with high-molecular-weight keratin antibodies. These unusual tumors have not been previously described in the thyroid, and the association of spindle cell squamous anaplastic carcinoma with tall cell papillary carcinoma in five independent cases may indicate a particular relationship.

Aged↗

Effects of zopiclone on sleep spindles studied with an improved waveform recognition method.

The effects of zopiclone on sleep spindles were analyzed in six normal volunteers by using an improved waveform recognition method. The appearance rate of spindles during stage 2 of NREM sleep showed a significant increase on the drug night, which returned to the baseline on the withdrawal night. The mean duration of spindles was significantly prolonged on the drug night. No definite changes were observed in the average spindle frequency. The mean amplitude of spindles had a tendency to decrease on the drug night. On the withdrawal night, the mean amplitude decreased significantly compared with that of the baseline. Our results indicate that zopiclone is one of the spindle enhancing drugs, and that its property resembles that of benzodiazepines.

Adult↗

[Effect of lormetazepam, triazolam and flunitrazepam on rapid eye movements, K-complexes and sleep spindles in normal probands].

"Equipotential" doses of lormetazepam, triazolam and flunitrazepam were tested regarding their influence on K-complexes, sleep spindles and rapid eye movements. The receptor affinity was used to determine the equipotency. In this respect triazolam, lormetazepam and flunitrazepam show a relationship of 1:2:4. Lormetazepam, however, showed only slight changes of the three neurophysiological parameters even when given as double dosage. Triazolam and flunitrazepam reduce K-complexes considerably, increase sleep spindles enormously and reduce REM activity markedly; both substances suppress the first REM period, flunitrazepam even the second one. All three of the benzodiazepines have the same effect on the dissociation of K-complexes and sleep spindles; epochs with K-complexes or sleep spindles are favored compared to epochs with K-complexes and sleep spindles. The general reduction of K-complexes and the increase in sleep spindles can be interpreted as a sleep protective function. When deciding on the dosage, however, REM-suppression should be used as a guide since it has the strongest effect on the cyclic structure of sleep which nowadays is considered to be the safest evidence of well balanced sleep behavior.

Adult↗

Effects of the infraorbital nerve-transection on the formation of Ia fibers in muscle spindles of the masseter muscle in developing mice.

The effect of the transection of the infraorbital nerve on d 20 after birth on the formation of the annulospiral ending of Ia fibers of muscle spindles in the masseter muscle was investigated in developing mice. On the 20th d after the operation, there were significant differences between control and treated animals in the ratio of muscle spindles with non-coiled endings to all muscle spindles, and the ratios of muscle spindles with non-coiled endings in the masseter muscle on the operated and sham-operated sides were about equal to each other. On the 30th d after the operation, the ratio for the masseter muscle on the operated side was approximately twice that for the one on the sham-operated side. The ratio for the operated side was about equal to that for 15-d-old control mice, and about twice that for 20-d-old control animals. Thus, the present results indicate that disorder of sensory inputs following the transection of the infraorbital nerve leads to degeneration and/or inhibition of the formation of annulospiral endings in muscle spindles of the masseter muscle, and suggest that disorder of the masticatory mechanism may be caused by the degeneration and/or inhibition of the formation of the endings in many muscle spindles of the masseter muscle.

Animals↗

Spindle coma in viral encephalitis.

Our patient's EEG evolved from the spindle coma pattern to normality in parallel with his clinical improvement. This clinical and EEG evolution has been described previously, and emphasizes the heterogeneity of the spindle pattern. The initial focal asymmetry implied focal cerebral abnormality, and was one of the clinical findings favoring HSV encephalitis in the absence of radiologic or pathologic support. The ability of partially-damaged cerebral cortex to express spindle activity is well-described with various cerebral lesions, as is the spindle coma pattern after intoxication. We are not aware of a previous report with HSV or other encephalitis, but an infectious etiology could be suspected in two patients of Hansotia et al. and is conceivable in the three comatose patients of Britt in whom no diagnosis could be established. In such cases, the pathophysiology of the spindle coma pattern is likely to involve an aberrant cortical response to normal reticular formation input and thalamic spindle pacemakers.

Adolescent↗

[Formation of "caudate spindles" in the sensomotor cortex of the rabbit during ontogeny].

The electrical activity elicited by electrical stimulation of the caudate nucleus in the sensorimotor and visual cortex was recorded in adult and 3-60-days old rabbits. It was shown that single stimuli applied to the caudate nucleus evoked bursts of synchronized rhythmical cortical waves similar in appearance to the so-called "caudate spindles" described in cats and monkeys. The latency of the "caudate spindles" in adult rabbit was about 200 ms, the duration--1-3 s and the frequency--11-3 c/s. The most prominent area for obtaining "caudate spindles" was the ipsilateral sensorimotor cortex. In spite of repeated efforts we have never recorded "caudate spindles" in rabbits of the youngest group. Beginning from the 15th postnatal day caudate stimulation induced bursts of rhythmical activity in the sensorimotor cortex which was similar to "caudate spindle", but with lower frequency (about 8 c/s), longer latency (350 ms) and high threshold. The definite type of spindles appears by the end of the first month of life, in the period of complication of conditioned reflexes.

Animals↗

Study of sleep spindles in the rat: a new improvement.

The two kinds of sleep spindles, previously described in the rat, were studied in intact animals, cerveau isole preparations and unilaterally neodecorticated rats. The anterior (frontal) spindles reach their maximum during deep slow sleep, when accompanied by theta activity, during the so-called intermediate stage which occurs just before and after paradoxical sleep. This stage is extended by low doses of barbiturate and similar patterns are induced by an intercollicular transection. The anterior spindles are suppressed by unilateral nedecortication and become abortive on contralateral hemisphere. The posterior ones, larger when recorded in the dorsal hippocampus than an the occipital cortex precede the appearance of the theta activity of intermediate stage. They are absent when the theta rhythm is present, during the long-continued intermediate stage under barbiturate ad in the cerveau isole preparation; but an unilateral neodecortication does not prevent the occurrence of posterior spindles on the white matter. Thus, during deep slow sleep, the rat shows both frontal cortex spindles, fully spread out during intermediate stage, and posterior spindles, probably originating from structures implied in the theta genesis and heralding the occurrence of this rhythmic slow activity.

Animals↗

Involvement of the dopaminergic system in the regulation of the caudate spindle in the rat.

In an attempt to study the neural mechanism of the development of the caudate spindle, effects of dopamine agonist or antagonists and baclofen on the spindle were studied in gallamine-immobilized rats. The spindle was significantly enhanced by chlorpromazine, haloperidol and pimozide, and these effects of drugs were completely antagonized by apomorphine. A marked prolongation of the duration of the spindle was observed by the treatment with baclofen, and this side effect was antagonized by apomorphine but not by methysergide, eserine or picrotoxin. These results suggest that the dopaminergic system may play an important role in the development of the caudate spindle in the rat, i.e. as a negative modulatory system in the manifestation of the caudate spindle.

Action Potentials↗

Directionally controlled spindle disassembly after mitosis in the diatom Pinnularia.

Two aspects of late mitosis have been investigated further. First, the two interdigitated half spindles that form the central spindle of this organism appear to separate before their disassembly. This separation is not dependent upon the cleavage furrow breaking the spindle as appears to be the case of observing normal mitosis; it occurs even when cleavage is artificially prevented with cytochalasin D. After separation, the birefringence of each half spindle fades steadily from the overlap end (now, the "free" end) back to the pole. Disassembly commences about 1 1/2 min after the half spindles separate, synchronously in each daughter cell. This observation suggests that the microtubules in each half spindle are of uniform polarity and their disassembly, presumably influenced by this polarity, proceeds from only one end (the "free" end). The other end, however, may be "capped" by polar structures. Because there is this pause between separation and the initiation of disassembly, breakdown of microtubules is probably not initiated merely by their ends becoming free in the cytoplasm.

Cell Division↗

Light microscopic observations of the contacts made between two spindle afferent types and alpha-motoneurons in the cat trigeminal motor nucleus.

Previous studies indicate that cat jaw-muscle spindle afferents can be divided into two types (type I and II) on the basis of their axonal trajectories. The present study examined the relationship between spindle afferent fibers and their target masseter alpha-motoneurons in the cat by using the intracellular horseradish peroxidase (HRP) injection technique, and provided several new findings on the synaptic organization generated between the two. Five type I afferent fiber-motoneuron pairs and nine type II afferent-motoneuron pairs were well stained with HRP. The following conclusions were drawn: 1) A motoneuron received contacts from only one collateral of any given spindle afferent. 2) The number of contacts made between an afferent and a motoneuron ranged from one to three. 3) The contacts made by a spindle afferent were on the same dendrite or dendrites branching from the same primary dendrite. 4) The vast majority of the contacts made by an afferent on a motoneuron were distributed in the dendritic tree within 600 microns from the soma, i.e., in the proximal three fourths of the dendritic tree. The differences observed between the two afferent types were as follows. First, type II afferent terminals made contacts on more distal dendrites of the motoneurons than did type I afferent terminals. Second, the contacts made between a type I afferent and a motoneuron were clustered together, but those made between a type II afferent and a motoneuron were widely dispersed. The present results provided the general rules of synaptic contacts between the spindle afferents and masseter alpha-motoneurons, and demonstrated that the spatial distribution of synaptic contacts on the dendritic tree was different between type I and type II afferents.

Animals↗

Ultrastructural study of a blood-muscle spindle barrier after systemic administration of horseradish peroxidase.

The permeability of the normal muscle spindle capsule to the entrance of an exogenous protein tracer was assessed by the use of horseradish peroxidase (HRP). Adult mice were injected intravenously with a solution of HRP (MW 40,000). After varying intervals, ranging from two to 240 minutes, animals were perfused aortically with fixative, and anterior tibialis muscles were removed, processed, and examined. The results were evaluated by electron microscopic cytochemical techniques, and attention was directed to the movement of tracer and its relationship to the outer and inner capsule of the muscle spindle. HRP was first demonstrated in cytoplasmic vesicles crossing the continuous capillary endothelium supplying the muscle spindle, and was then detected in the interstitial space surrounding the outer capsule. In polar regions, HRP had entered the periaxial space by two minutes, and it was seen in cytoplasmic vesicles of the attenuated outer capsule. Later, HRP abutted the sarcolemma of intrafusal fibers, and by 12.5 minutes there was evidence of tracer in T-tubules of these muscle cells. Whereas at no time was tracer observed traversing any of the numerous intracellular junctions of the capsule, it appeared that polar regions were leaky and open-ended at their distal portions. The sensory equatorial zone was considerably less permeable to the entrance of tracer. Whereas HRP was visible intially in cytoplasmic vesicles of the subjacent capillary endothelium, it was not until 12.5 minutes that racer could be demonstrated within some vesicles of equatorial outer capsule cells. At later times, a small amount of HRP was observed in the equatorial periaxial space, where it was phagocytosed and finally sequestered by cells of the inner capsule as membrane-bound lysosomal deposits. Consequently, at no time was tracer incorported into either intrafusal fibers or their sensory nerve terminals. Thus, in contract to polar regions, the muscle spindle capsule in the equatorial zone appears to be effective in preventing the indiscriminate penetration of HRP from the bloodstream. This suggests dissimilar paths of tracer movement from the microvasculature into sensory and non-sensory regions of the muscle spindle.

Animals↗

Motor innervation of intrafusal fibers in rat muscle spindles: incomplete separation of dynamic and static systems.

Distributions of 53 motor axons to different types of intrafusal fibers were reconstructed from serial 1-micron-thick transverse sections of 13 poles of spindles in the rat soleus muscle. The mean number of motor axons that innervated a spindle pole was 4.1. Approximately 60% of motor axons lost their myelination prior to or shortly after entry into the periaxial fluid space of spindles. Motor innervation to the juxtaequatorial portion of nuclear bag fibers (particularly the bag1) consisted of groups of short, synaptic contacts that were terminations of thin, unmyelinated axons. In contrast, motor endings on both the bag1 and bag2 fibers were platelike in the polar intracapsular region. Chain fibers had a single midpolar platelike ending. The ratio of motor axons that innervated the bag1 fiber exclusively to axons that innervated bag2 and/or chain fibers was 1:1. However, one-fourth of motor axons coinnervated the dynamic bag1 fiber in conjunction with static bag2 and/or chain fibers. Thus the complete separation of motor control of the dynamic bag1 and static bag2 intrafusal systems observed in cat tenuissimus spindles is neither representative of the pattern of motor innervation in all other species of mammals nor essential to normal spindle function.

Animals↗

Attenuated dynamic responses of primary endings of muscle spindles: a basis for depressed tendon responses in acrylamide neuropathy.

Depressed or lost tendon reflexes commonly observed in patients with peripheral neuropathies may result partly from attenuation of the dynamic discharge from the primary endings of muscle spindles. This possibility was investigated in cats with an experimental neuropathy induced with acrylamide (30 mg/kg/day intramuscularly). Achilles tendon reflexes and the dynamic discharge from primary muscle spindles were evaluated after five or ten injections of acrylamide. After five injections the animals were moderately impaired neurologically, the Achilles tendon reflex was difficult to elicit in 2 of 5 animals, and the dynamic responses of primary endings of soleus muscle spindles to stretch were depressed. Following ten injections of acrylamide the cats were severely impaired neurologically; tendon responses were either absent or difficult to elicit, and the dynamic responses of their muscle spindles to stretch were reduced by 50% (p less than 0.01). Additionally, the spindels responded to stretch with only 20 to 30% the normal number of afferent impulses. These data suggest that lost tendon responses in acrylamide neuropathy result in part from inadequate activation of motoneurons by spindle afferent discharge.

Acrylamides↗

Polar ejection forces are operative in crane-fly spermatocytes, but their action is limited to the spindle periphery.

Laser microsurgery was employed to reveal kinetochore-independent forces acting on chromosome arms in crane-fly spermatocytes. When a portion of an arm situated along the interpolar axis between the equator and a pole was cut off, the resultant acentric fragment was transported poleward and outward into the peripheral domain of the spindle. If the fragment was generated well in advance of the onset of anaphase, then at the spindle periphery, it changed direction and moved away from the pole and back toward the equator. That domain-specific movement-poleward in the central spindle and away from the pole at the spindle periphery-not only provides the first evidence for polar ejection forces acting on acentric fragments in a meiotic system, but it is the first example of kinetochore-independent forces in both directions at the same stage of division. Sniglets generated by laser pulses directed at specific sites in the spindle revealed that the mechanism underlying ejection forces was specific to chromosomes. At anaphase onset, polar ejection forces ceased, and pole-directed forces took over. At that time, chromosome fragments that had been ejected to the equator moved poleward again, providing clear evidence for kinetochore-independent forces on chromosome arms during anaphase.

Anaphase↗

Dynamic association of a tumor amplified kinase, Aurora-A, with the centrosome and mitotic spindle.

Aurora-A kinase, also known as STK15/BTAK kinase, is a member of a serine/threonine kinase superfamily that includes the prototypic yeast Ipl1 and Drosophila aurora kinases as well as other mammalian and non-mammalian aurora kinases involved in the regulation of centrosomes and chromosome segregation. The Aurora-A gene is amplified and overexpressed in a wide variety of human tumors. Aurora-A is centrosome-associated during interphase, and binds the poles and half-spindle during mitosis; its over-expression has been associated with centrosome amplification and multipolar spindles. GFP-Aurora-A was used to mark centrosomes and spindles, and monitor their movements in living cells. Centrosome pairs labeled with GFP-Aurora-A are motile throughout interphase undergoing oscillations and tumbling motions requiring intact microtubules and ATP. Fluorescence recovery after photobleaching (FRAP) was used to examine the relative molecular mobility of GFP-Aurora-A, and GFP-labeled alpha-tubulin, gamma-tubulin, and NuMA. GFP-Aurora-A rapidly exchanges in and out of the centrosome and mitotic spindle (t(1/2) approximately 3 sec); in contrast, both tubulins are relatively immobile indicative of a structural role. GFP-NuMA mobility was intermediate in both interphase nuclei and at the mitotic spindle (t(1/2) approximately 23-30 sec). Deletion mapping identifies a central domain of Aurora-A as essential for its centrosomal localization that is augmented by both the amino and the carboxyl terminal ends of the protein. Interestingly, amino or carboxy terminal deletion mutants that maintained centrosomal targeting exhibited significantly slower molecular exchange. Collectively, these studies contrast the relative cellular dynamics of Aurora-A with other cytoskeletal proteins that share its micro-domains, and identify essential regions required for targeting and dynamics.

Antigens, Nuclear↗

Patterns of tubulin isotype synthesis and usage during mitotic spindle morphogenesis in Physarum.

Tubulin synthesis in the naturally synchronous plasmodium of Physarum polycephalum is a markedly periodic event restricted to the late G2 period of the cell cycle. Mitosis in the plasmodium is intranuclear, and there are no cytoplasmic microtubules at any stage of the cell cycle. We have combined a biochemical investigation of the synthesis of the plasmodial tubulin isotypes and their participation in the mitotic spindle with a microscopic study (immunofluorescence) of the development of spindle microtubules throughout the cell cycle. We have shown that all four tubulin isotypes identified in the plasmodium (alpha 1, alpha 2, beta 1 and beta 2) are present in the mitotic spindle. The stoichiometry of isotype usage in the mitotic spindle generally reflects the overall abundance of isotypes in the plasmodium as a whole: beta 2 greater than alpha 1 greater than alpha 2 greater than beta 1. We have also shown that tubulins synthesized in the G2 period of one cell cycle can be incorporated into the spindles of the immediately ensuing mitosis and have sufficient biological longevity to allow participation in the mitotic divisions of future cell cycles. Thus, the phenomenon of periodic tubulin synthesis does not reflect a restricted use of tubulin to the cell cycle in which it was synthesized. The major polymerization of tubulin in the nucleus occurred less than 30 min before metaphase. A novel tubulin-containing structure was, however, present in the nucleus approximately 60 min before metaphase. Polymerized tubulin is rapidly removed from the nucleus following nucleokinesis.

Cell Cycle↗

A component of the interphase cytoskeleton is cyclically recruited into spindle poles during mitosis.

During the transition from interphase to mitosis, proteins are recruited into forming spindle poles [Leslie, Cell Motil. Cytoskeleton 16:225-228, 1990]. Antibodies which recognize these recruited components clearly label spindle poles during mitosis but the location and character of such proteins during interphase remain a mystery. Competition assays using an antibody to a recruited spindle pole protein show that in its disperse form the spindle pole protein is a highly insoluble component of the cytoskeleton which is dispersed to such an extent during interphase that it is difficult to identify by immunolocalization. The function of recruited spindle pole proteins is unknown but the aggregation/dispersion cycle and the antigen are highly conserved, appearing in sea urchin embryos and tissue culture cells.

Animals↗

Projection of jaw-muscle spindle afferents to the caudal brainstem in rats demonstrated using intracellular biotinamide.

Intracellular staining with biotinamide was used to study the axonal projection and synaptic morphology of rat jaw-muscle spindle afferents. Intracellular recordings in the mesencephalic trigeminal nucleus (Vme) were identified as spindle afferent responses by their increased firing during stretching of the jaw-elevator muscles. Biotinamide-stained axon collaterals with boutons were found in the trigeminal motor nucleus (Vmo), Vme, the region dorsal to Vmo including the supratrigeminal region, the dorsomedial portion of the trigeminal principal sensory nucleus, and the dorsomedial part of the rostral spinal trigeminal subnucleus oralis. Additional, previously undescribed projections of jaw-muscle spindle afferents were found to the dorsomedial portion of the caudal spinal trigeminal subnucleus oralis (Vodm), the dorsomedial part of the spinal trigeminal subnucleus interpolaris (Vidm), the caudal parvicellular reticular formation, laminae IV and V of the spinal trigeminal subnucleus caudalis (Vc), and the dorsal division of the medullary reticular field. Labeled spindle boutons in Vodm formed predominately axodendritic synapses. Some of these boutons received presynaptic inputs from unlabeled P-type boutons containing clear, spherical, or flattened vesicles. In Vidm, labeled collaterals and boutons were densely clustered into glomerular-like structures. Labeled boutons in Vidm made axodendritic, axosomatic, and axoaxonic synapses and received synaptic contacts from unlabeled boutons containing clear, spherical, or flat and pleomorphic vesicles. Unlabeled presynaptic boutons in Vidm occasionally contained dense core vesicles. Labeled boutons in Vc mainly formed synaptic contacts with large diameter dendrites. This projection of jaw-muscle spindle afferents to caudal brainstem regions may play a significant role in masticatory-muscle stretch reflexes and in the integration of trigeminal proprioceptive information and its transmission to higher centers.

Afferent Pathways↗