Critical illness polyneuropathy.
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Critical Illness↗
Biomedical subjects
A C Breuer
Publications and source records attributed to A C Breuer.
Direct measurement of fast axonal organelle transport in the sciatic nerve of rats treated with acrylamide.
The effects of acrylamide on fast axonal transport have been measured primarily using the indirect methods of isotope or enzyme accumulation. We report the first direct evaluation of the effects of subchronic acrylamide dosing (150, 300, or 500 mg/kg total dose, i.e., 50 mg/kg, 2x/wk, for 1.5, 3, 5 wk, respectively) on the fast axonal transport motility machinery itself using video-enhanced differential interference contrast optics with digital image processing and computer analysis. Four principle observations were made: (1) Rapid anterograde transport was not affected at any dosage level within 1 wk after cessation of dosing. (2) A high cumulative dosage (500 mg/kg total) of acrylamide or bisacrylamide produced approximately 7-18% decrease in the rate of retrograde transport in both myelinated and unmyelinated axons. (3) Lower dosages of acrylamide (150 or 300 mg/kg total) produced an increase in retrograde transport rates in myelinated axons only. (4) During the "recovery" phase for the 500 mg/kg acrylamide animals (i.e., 3 or 5 wk after the last dosage of acrylamide) the rate of anterograde transport in the myelinated axons was decreased at 3 wk but not at 5 wk, and the rate of retrograde transport in the myelinated axons returned to control levels while the retrograde transport in the unmyelinated axons continued at abnormally slow speeds. The application of this new technique to evaluate the neurotoxic effects of acrylamide provides evidence of dynamic changes in the axonal transport motility machinery itself and differential effects on myelinated versus unmyelinated fibers.
Acrylamide↗
Fast axonal transport is modulated by altering trans-axolemmal calcium flux.
Factors involved in fast axonal transport (motor proteins, microtubules, organelles, etc.) have been identified but the molecular mechanism controlling transport is unknown. We used video enhanced microscopy to directly evaluate the effect of calcium on fast axonal transport (FAxT). FAxT alterations included rapid speed decreases (within minutes) in Ca2+ free buffer and rapid speed increases (within seconds) when axons were treated with parathyroid hormone, BAY K 8644, or K+ depolarization. The speed increases were blocked by dihydropyridine Ca2+ channel antagonists. Ryanodine (20 microM), known to block calcium release from subcellular stores, caused a decrease in the rate of retrograde FAxT. Calcium ionophore A23187 (at 1 and 20 micrograms/ml) caused increases in FAxT, an effect also noted only in retrograde moving organelle traffic. Hyper- or hypo-tonic solutions produced no alterations making axoplasmic viscosity changes an unlikely explanation for the speed changes. Reproducible alteration of FAxT by manipulation of Ca2+ levels provides evidence that Ca2+ modulates fast axonal transport. Retrograde transport appears more sensitive to changes in Ca2+ and differential effects on antero- and retro-FAxT mechanisms suggest directional specificity for some of these signals which may be based upon the organelle size. Endogenous substances (e.g. PTH) that trigger axonal Ca2+ changes may rapidly modulate the rate of material delivery in axons. The results are discussed within the context of a Ca2+/calmodulin-dependent modification of the cytoskeletal matrix.
Animals↗
Direct measurement of fast axonal organelle transport in chronic ethanol-fed rats.
While indirect methods have been used, direct evaluation and measurement of the fast axonal transport system itself in chronic ethanol-fed rats have not been carried out previously. We evaluated this system using analog and digital image enhancement of differential interference contrast optical images in real time to assess the effect of ethanol on fast intra-axonal organelle traffic in rat sural nerve. A radiolabeling method for evaluating fast axonal transport was used in similar animals to compare the indirect and direct techniques. Also, the concentration of organelles (mitochondria, large and small clear vesicles, dense vesicles, and membranous whorls) in the annulospiral sensory nerve endings of muscle spindles from a foot muscle (flexor digitorum brevis) of these same animals was quantitated from electron micrographs. Rats were fed an ethanol-containing liquid diet for one to five months. Three observations were made; (1) There was no statistically significant change in the mean organelle speed in the anterograde direction, but the mean organelle speed in the retrograde direction increased 11%, 9%, and 17% (statistically significant) at 3, 4, and 5 months of ethanol exposure, respectively. (2) Significant increases in organelle content of sensory nerve endings were seen at 2 and 3 months of intoxication. (3) Increases in organelle densities in terminals were transitory and returned to normal in the face of on-going ethanol administration. We conclude: (1) There is no permanent impairment of fast axonal organelle transport in this model after 5 months of exposure. (2) Sensory endings on muscle spindles show transitory increases in organelle density. (3) Retrograde speed increases may be a partial compensatory mechanism to help restore normal terminal organelle density.(ABSTRACT TRUNCATED AT 250 WORDS)
Alcoholism↗
Amount and speed of fast axonal transport in diabetes.
Abnormalities in axonal transport have been observed in human and experimental diabetes and may be related to the pathogenesis of diabetic neuropathy. Axonal transport has previously been evaluated by indirect methods. In this study, direct-measurement techniques were applied (with computer-enhanced video-recorded images) for the first time to evaluate intra-axonal organelle speed and frequency (the amount of organelle traffic) in both the anterograde fast component (AFC) and retrograde fast component (RFC) of axonal transport in diabetic nerve. Sciatic nerve and dorsal and ventral nerve roots were studied in the animal model of insulin-dependent diabetes (BB/Wistar rat) and sciatic nerve in the non-insulin-dependent (streptozocin-induced) model of diabetes (STZ-D rat). STZ-D rats were studied at 1 mo, and BB/Wistar rats were studied at 1 and 2 mo of diabetes duration. Statistically significant decreases in peripheral axon organelle speed were found only for RFC at 1 mo of diabetes in both the BB/Wistar (8.1%) and STZ-D (5.4%) rats. The difference was no longer significant in BB/Wistar rats at 2 mo of diabetes. This recovery suggests that the underlying abnormality is reversible. No differences were seen in AFC of any axons, and the only other difference seen was a 5.1% decrement in RFC at 2 mo in the ventral roots. No significant difference was observed in any group for organelle frequencies. Other factors should be considered to explain the decrease in materials transported in accumulation studies. The transient deficits in RFC speed observed remain of undetermined significance in the pathogenesis of diabetic neuropathy.
Animals↗
Fast axonal transport alterations in amyotrophic lateral sclerosis (ALS) and in parathyroid hormone (PTH)-treated axons.
Video-enhanced contrast techniques have been used to study fast axonal transport of organelles in diseased and normal human axons. A broad perspective on the importance of axonal transport in the pathogenesis of human neurological disorders is presented and problems in dealing with human nerve summarized. Results from analysis of organelle traffic in axons from motor nerve in patients with amyotrophic lateral sclerosis (ALS) show: 1) higher mean speed of anterograde organelles, 2) lower mean speed of retrograde organelles, and 3) lower retrograde organelle traffic density. Hyperparathyroidism, another human clinical syndrome, can mimic ALS. The effect of parathyroid hormone (PTH) on axons in vitro is to increase the mean speed of both anterograde and retrograde organelle traffic. The dose response curve and time course of the PTH effect are delineated. Dihydropyridine calcium channel antagonists block the PTH effect, implicating extracellular calcium in the alteration of organelle traffic speed. The results are discussed in relation to neuronal function and the regulation of fast axonal transport.
Amyotrophic Lateral Sclerosis↗
Long-term analysis of organelle translocation in isolated axoplasm of Myxicola infundibulum.
Moving intra-axonal organelles demonstrate frequent variations in speed when viewed over several seconds. To evaluate these and other motion variations, a long-term analysis of organelle motion in isolated axoplasm of Myxicola infundibulum was carried out using differential interference contrast optics and analog and digital image enhancement techniques. Motion characteristics of individual organelles were analyzed for periods of up to 58 minutes. Three principle observations on organelle motion were made: 1) Classes of organelles of the same size demonstrated a 5- to 25-fold variation of speed, with the slowest speeds occurring most frequently; 2) organelle speeds over individual translocations (motion without stopping) are inversely proportional to their size, but the speeds calculated for the long-term analysis of organelle motion (total distance travelled/total observation time, including pauses) did not reflect this observation; and 3) organelles displayed variable trip lengths, durations, mean speeds, and pause durations, and the relationships between these variations showed no repetitive patterns. In contrast to reported observations of uniform velocities of organelles moving on isolated microtubule preparations, these observations suggest that a variety of factors must play a role in organelle translocation in Myxicola axoplasm.
Animals↗
Calcium dependent modulation of fast axonal transport.
The highly differentiated structure of the neuron poses special problems for the intracellular movement of molecules throughout the cell. Molecular transport distances from the synthesizing neuron cell body along the axon (which has no substantial synthetic capabilities) to the axon terminal are very great. The transported substances, transport support structures, translocator motors, and control elements are currently the focus of intense research. Interruption of this flow of molecules could have disastrous effects upon the cell and ultimately the organism resulting in neuropathological conditions. Calcium plays a critical role in modulating fast-axonal transport (FAT) speeds. Before discussing the effect of calcium on FAT, we summarize our broad perspective on the role of axonal transport in neurologic disease.
Amyotrophic Lateral Sclerosis↗
Fast axonal transport in amyotrophic lateral sclerosis: an intra-axonal organelle traffic analysis.
Fast transport of intra-axonal organelles was studied in motor nerve from amyotrophic lateral sclerosis (ALS) patients. Organelle traffic in ALS nerves demonstrated a significant increase in anterograde mean speed, while retrograde mean speed was decreased compared with that of controls. Retrograde traffic density (organelles per unit time) was also significantly decreased in the ALS specimens. Anterograde transport machinery is therefore intact and may be responding to the increased physiologic demand of larger motor units. Diminished retrograde speed and organelle traffic density are consistent with a defect in retrograde transport and could impair communication between axon terminals and perikarya.
Amyotrophic Lateral Sclerosis↗
Influence of translocation track on the motion of intra-axonally transported organelles in human nerve.
The mechanism by which organelles are transported bidirectionally in axoplasm is still unknown; however, evidence of a key role for microtubules in many nonmammalian models has been established. We have observed common or shared tracks within the axoplasm of human nerves along which multiple organelles of varying size and shape are bidirectionally transported. Organelles traveling anterogradely and retrogradely were visualized by video-enhanced differential interference contrast optics and analyzed with the aid of computer-image-processing techniques. Speeds of translocating organelles were determined at eight to 16 translocation points along a path or "track." Each translocation speed was plotted against its corresponding position on the track to develop a "speed/position diagram." Regardless of mean organelle speed or direction of motion, organelles sharing a common track exhibited similar patterns of "speeding up" and "slowing down" relative to position along the track. Speed position data for organelles translocating the local axonal region of a common track showed no unique patterns (not different from a uniform distribution, p less than 0.05). The unique speed/position patterns exhibited by common tracks were not necessarily related to the patterns of other tracks in the immediate vicinity (distance between tracks of less than 0.50 micron). These findings suggest that there are "common tracks" shared by organelles moving retrogradely and anterogradely; both the organelles and the "track" associated with its translocation play a role in the resultant motion of that organelle; the influence exerted by a common track on the motion of an organelle results in a pattern of speed changes related to position along the track.
Afferent Pathways↗
Rapid vesicle formation and aggregation in abnormal human biles. A time-lapse video-enhanced contrast microscopy study.
Rapid nucleation of cholesterol crystals has previously been shown to provide a sharp discrimination between abnormal (cholesterol gallstone-associated) and normal human gallbladder bile. In the present study, we sought to further clarify the crystal nucleation process by time-lapse microscopy using a novel high-resolution video-enhanced microscopy technique. Using a previously described method for removal of particles from abnormal biles, we found a strikingly rapid rate of de novo formation of unilamellar vesicles, soon followed by massive vesicular aggregation, culminating in crystal formation. In normal biles, by contrast, this rapid aggregation process was not observed and the isolated unilamellar vesicles showed prolonged stability. Morphometric analysis of interval particle counts showed statistically significant differences. The process of cholesterol monohydrate crystal nucleation in supersaturated human bile is characterized by a sequential combination of vesicle formation, vesicle aggregation, and subsequent crystal formation. The primary distinction between abnormal and normal biles resides only in the consistent rapidity of onset and completion of these events in the abnormal biles.
Bile↗
Amyotrophic lateral sclerosis: effects of acute intravenous and chronic subcutaneous administration of thyrotropin-releasing hormone in controlled trials.
We performed double-blind crossover trials to assess the effects of thyrotropin-releasing hormone (TRH) on amyotrophic lateral sclerosis patients. For acute intravenous trials, 500 mg TRH or placebo with norepinephrine was given at 1-week intervals (16 patients). CSF TRH concentration increased, and clinical side effects appeared with TRH. For chronic studies, 25 mg TRH and a saline placebo were given subcutaneously every day for 3 months (25 patients). CSF TRH level increased 29-fold after a single TRH injection, and mild transient side effects occurred. Vital signs, respiratory function, semiquantitative and quantitative neurologic function, muscle strength by manual and dynamometer testing, and EMG were studied. With daily TRH, 10 patients noted subjective improvement without objective evidence, and 10 patients complained of worsening of the disease with objective decline after TRH was stopped. Statistical analysis, however, showed no beneficial effects from either acute or chronic TRH trials.
Adult↗
Vesicle aggregation in model systems of supersaturated bile: relation to crystal nucleation and lipid composition of the vesicular phase.
The presence of small vesicles composed of phospholipid and cholesterol has recently been demonstrated in super-saturated model and in dilute native human biles by several groups using differing methods. Among compositional factors shown to favor spontaneous vesicle formation and prolong the cholesterol monohydrate nucleation time in model bile systems are dilution, a raised cholesterol saturation index (CSI), and a low bile salt/phospholipid ratio. Time-lapse video-enhanced microscopy of a series of model bile systems representing systematically designed variations in the above factors revealed strong evidence for an essential linkage between antecedent vesicle aggregation and subsequent crystal nucleation. Stability of vesicles was inversely related to their degree of cholesterol saturation, i.e., the greater the degree of vesicular cholesterol saturation, the less their stability (metastability). Instability of vesicles was reflected by their early aggregation followed by rapid cholesterol crystal nucleation. The lowest degree of vesicular cholesterol saturation was found in dilute systems which also exhibited the greatest metastability despite a high degree of cholesterol solubility (raised CSI). Conversely, the more concentrated and least metastable systems exhibited both rapid vesicle aggregation and rapid onset of crystal nucleation. These systems, while influenced by the other compositional factors, were found to have a high degree of vesicular cholesterol saturation, i.e., cholesterol/phospholipid molar ratio = 2.0. An additional finding was the extreme variability in the proportionate distribution of total solution cholesterol distributed to the vesicular phase, i.e., from zero to as high as 37%. Higher solute concentration, raised bile salt/lecithin ratio, and raised CSI were interactive and almost equally capable of increasing the proportionate amount of cholesterol in the vesicular phase. In conclusion, lipid compositional differences in model bile systems drastically affect the cholesterol saturation of spontaneously formed phospholipid-cholesterol vesicles. This effect, in turn, exerts a potent influence upon the metastability of vesicles, subsequently affecting the cholesterol crystal nucleation time.
Bile↗
Flow visualization of blood at the wall of a porous fiber.
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Blood↗
Factors affecting cholesterol monohydrate crystal nucleation time in model systems of supersaturated bile.
We explored the influence of several compositional factors considered capable of influencing the nucleation time of model biles supersaturated in cholesterol. In addition to the classical techniques, e.g., electron microscopy and quasielastic light scattering, employed for size measurement and structural assessment, we employed a novel technique, i.e., video-enhanced microscopy, for particle evaluation in these polydisperse systems which often may simultaneously contain isolated small vesicles, their complex aggregates, and small cholesterol monohydrate crystals. The factors we studied included dilution, degree of cholesterol supersaturation, bile salt/lecithin molar ratio, and Ca2+ concentration. Dilution markedly raised the degree of cholesterol saturation, prolonged nucleation time for cholesterol monohydrate crystals, and favored formation of metastable small unilamellar vesicles. Increasing the degree of cholesterol supersaturation as an independent variable in more concentrated systems both shortened the nucleation time and favored spontaneous formation of a relatively small number of isolated vesicles. A decrease in bile salt/lecithin molar ratio within the physiologically relevant range was accompanied by a prolonged nucleation time and favored spontaneous vesicle formation. Large numbers of small unilamellar vesicles were observed even in concentrated model bile solutions (total lipids: 20 g/dl) when the bile salt/lecithin molar ratio was 1.9 or less. At physiological concentrations, Ca2+ promoted nucleation of cholesterol monohydrate crystals only in vesicle-containing solutions. Taken together, the following conclusions can be drawn. First, spontaneous vesicle formation in dilute systems prolongs solid cholesterol crystal nucleation. It can thus provide a supplementary non-micellar mode of cholesterol transport in micellar systems of supersaturated human bile. Second, dilution, degree of cholesterol supersaturation, and a decrease in bile salt/lecithin ratio prolong cholesterol crystal nucleation time and favor spontaneous vesicle formation. With increasing calcium concentrations, opposite effects are observed. Third, the presence of vesicles may help to account for the frequently observed and otherwise unexplained remarkable degree of metastable supersaturation and prolonged metastability (delayed nucleation time) for cholesterol in human bile.
Bile↗
Mechanism and frequency of brachial plexus injury in open-heart surgery: a prospective analysis.
A computer-assisted prospective analysis of 531 patients undergoing open-heart operations revealed that 26 patients (5%) sustained brachial plexus injury. In 22 of the 26 patients (85%), the lesion involved the lower trunk or C8-T1 nerve roots. Electromyograms confirmed the clinical impression in 13 patients. In 19 of the 26 patients (73%), the side on which the plexus lesion was found correlated with the side of internal jugular vein cannulation. Because of the anatomical proximity of the lower trunk to the internal jugular vein and the preponderance of lower trunk lesions, we postulate that traumatic cannulation may be a major mechanism of plexus injury. Thus, the resulting syndrome of pain, dysesthesias, and hand weakness may sometimes be preventable.
Adult↗
Radicular vessels are the most probable source of needle-induced blood in lumbar puncture: significance for the thrombocytopenic cancer patient.
Despite knowledge of the bleeding hazard to thrombocytopenic cancer patients undergoing lumbar puncture (LP), a retrospective analysis of physician behavior at one hospital revealed no consistent use of platelet transfusions in patients with less than 20,000 platelets/mm3 on the day of LP. A review of the literature and laboratory cerebrospinal fluid (CSF) data in two institutions, and the performance of an LP experiment revealed that: (1) Batson's epidural venous plexus is an unlikely source and spinal radicular vessels are the most probable source of needle-induced blood in lumbar puncture; (2) the frequency of encountering needle-induced blood at LP is high, 73% (3) the frequency of brushing a nerve root, with the associated risk of lacerating the radicular artery or vein on its surface with the bevel of the LP needle, is high and may be on the order of 26%; and (4) while the passage of an LP needle, obturator in place, through a blood filled vein may carry red cells into a red cell-free medium, this does not always occur. These new considerations argue for more consistent adherence to the already published recommendation of platelet transfusion immediately prior to LP in patients with low platelets. This issue is of particular relevance to the rapidly growing population of thrombocytopenic cancer patients with extended survival on multiple chemotherapeutic regimens requiring lumbar puncture.
Adult↗
Thoracic root pain in diabetes: the spectrum of clinical and electromyographic findings.
Diabetic thoracic radiculopathy has been reported rarely. Fifteen new cases, seen in an equal number of patients over a 3-year period and confirmed by electromyographic findings, have been analyzed. All patients presented with severe abdominal or chest pain, which often was not radicular in character. The presence of dysesthesias and an abnormal sensory examination of the trunk aided diagnosis. The pain was frequently associated with marked weight loss but carried a good prognosis for recovery. Six additional patients with negative electromyographic examinations were considered to have the disorder. Diabetic thoracic radiculopathy produces a distinct syndrome and may be more common than is generally recognized.
Adult↗