Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to study sensory nerve plasticity after nerve injury and repair, recordings were made from afferent axons innervating the tibialis anterior muscle in rats under several different experimental conditions. In two groups of rats, reinnervation of the denervated tibialis anterior was examined 2.5 months (group A) and 7 months (group B) after section, along with self-anastomosis of the common peroneal nerve. The other rats (group C) were examined 2.5 months after the nerve was cut and ligatured to its stumps to avoid axonal regeneration. No evoked potentials and no activation in response to any test agent were found in group C rats. We found a significant increase in the proportion of group I-II fibers and a significant decrease in group IV fibers in the group B rats when compared with group A (P < 0.05 and P < 0.01) and control animals (P < 0.01 and P < 0.01). A higher conduction velocity was measured in group IV fibers in group B rats when compared with group A (P < 0.01) and the controls (P < 0.01). The proportion of afferent units showing an optimal discharge in response to tendon vibration at 70 Hz (range 0-100 Hz) was higher in groups A and B (72.2 and 80%, respectively) than in the controls (36.8%). The response of muscle afferents to KCl (1-20 mM) and lactic acid (0.5-3 mM) concentrations was markedly depressed in group A rats (P < 0.05), whereas it was restored and even accentuated in group B animals when compared with the controls (P < 0.05). Electrically induced fatigue (3 min, 10 Hz) significantly activated (P < 0.05) muscle afferents only in controls. The present study indicates that after self-anastomosis of a cut hindlimb muscle nerve, sensory innervation was markedly modified in the direction of enhanced mechanosensitivity to high-frequency tendon vibration and depressed metabosensitivity.
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PMID:Changes in afferent activities from tibialis anterior muscle after nerve repair by self-anastomosis. 1115 Sep 67

Patients treated with nucleoside analogue reverse transcriptase inhibitors (NRTIs) develop a varying degree of myopathy or neuropathy after long-term therapy. Zidovudine (AZT) causes myopathy; zalcitabine (ddC), didanosine (ddl) and lamuvidine (3TC) cause neuropathy; stavudine (d4T) and fialuridine (FIAU) cause neuropathy or myopathy and lactic acidosis. The tissue distribution of phosphorylases responsible for phosphorylation of NRTIs relates to their selective tissue toxicity. The myopathy is characterized by muscle wasting, myalgia, fatigue, weakness and elevation of CK. The neuropathy is painful, sensory and axonal. In vitro, NRTIs inhibit the gamma-DNA polymerase, responsible for replication of mtDNA, and cause mtDNA dysfunction. In vivo, patients treated with AZT, the best studied NRTI, develop a mitochondrial myopathy with mtDNA depletion, deficiency of COX (complex IV), intracellular fat accumulation, high lactate production and marked phosphocreatine depletion, as determined with in vivo MRS spectroscopy, due to impaired oxidative phosphorylation. Animals or cultured cells treated with NRTIs develop neuropathy, myopathy, or cell destruction with similar changes in the mitochondria. There is evidence that the NRTI-related neuropathy is also due to mitochondrial toxicity. The NRTIs (AZT, ddC, ddl, d4T, 3TC) contain azido groups that compete with natural thymidine triphosphate as substrates of DNA pol-gamma and terminate mtDNA synthesis. In contrast, FIAU that contains 3'-OH groups serves as an alternate substrate for thymidine triphosphate with DNA pol-gamma and is incorporated into the DNA causing permanent mtDNA dysfunction. The NRTI-induced mitochondrial dysfunction has an influence on the clinical application of these agents, especially at high doses and when combined. They have produced in humans a new category of acquired mitochondrial toxins that cause clinical manifestations resembling the genetic mitochondrial disorders.
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PMID:Peripheral neuropathy and antiretroviral drugs. 1129 2

In amyotrophic lateral sclerosis (ALS), muscles with preserved strength can have fasciculation potentials (FPs) as the only abnormality. The FPs in strong muscles are predominantly simple and stable, and can often be recruited by a slight voluntary contraction. In weak and atrophic muscles, the FPs are generally complex and unstable, tend to have a slower firing rate and are not recruited by voluntary contraction. Macro-electromyography studies suggest that these FPs are part of a more complex motor unit, as opposed to simple FPs which can represent all the motor unit. FPs driven by transcranial magnetic stimulation (TMS) were observed in 13 ALS patients. TMS-driven fasciculations had a simple morphology and were stable. Complex potentials were never cortically driven. These observations strengthen the conviction that fasciculations in ALS can have different origins. Simple, stable FPs arise proximally and are probably related to excitotoxicity phenomena, while complex, unstable FPs are most likely to originate in distal axonal sprouts that are associated with the reinnervation process. Some ALS patients with fatigue and mild weakness can have profuse fasciculations at an early phase in the evolution of the disease. Patients with denervation localized in one region and diffuse FPs should be strongly suspected of having ALS. With this strategy it should be possible to shorten the diagnosis time.
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PMID:Pathophysiological significance of fasciculations in the early diagnosis of ALS. 1146 25

Previous studies suggest that aminopyridine may play a role in the symptomatic treatment of fatigue in multiple sclerosis. Although the mechanism underlying the beneficial effect on fatigue remains unclear, it has been proposed that aminopyridines may help to improve conduction in demyelinated central pathways, implicating both axonal and synaptic mechanisms. The objective of the present study is to determine whether 4-AP decreases daily-living fatigue in progressive multiple sclerosis. The effect of 4-AP on other neurophysiological and neuropsychological parameters was also considered. A 'double-blind', randomized, 'placebo-controlled', crossover trial was conducted on 54 patients with progressive multiple sclerosis. All patients received treatment with placebo and 32 mg per day of 4-AP, each for 6 months. The main outcome measure was the Fatigue Severity Scale. Secondary measures were EDSS, cognitive functions and neurophysiological parameters. Forty-nine patients (91%) completed the study. Changes in fatigue scores, EDSS and cognitive functions were not significantly different between 4-AP and placebo. However, when patients treated with 4-AP were divided into two groups according to the serum level of 4-AP, a significant effect on fatigue compared with placebo was observed in the 'high level' (>30 ng/ml) group (P=0.05). Synchronization of motor evoked potentials improved during 4-AP with respect to placebo (P=0.019) and this correlated positively with fatigue reduction (P=0.010). No relevant side effects were observed.
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PMID:Fatigue in progressive multiple sclerosis: results of a randomized, double-blind, placebo-controlled, crossover trial of oral 4-aminopyridine. 1179 55

To investigate whether there are inter-nerve differences in the extent and pattern of axonal excitability changes produced by voluntary contractions of tibialis anterior (TA) and abductor pollicis brevis (APB), threshold tracking was used to measure axonal excitability parameters [threshold, supernormality and strength-duration time constant (tauSD)] of peroneal and median motor axons in 11 healthy subjects. Maximal contractions for 1 min resulted in an increase in threshold, an increase in supernormality, a decrease in tauSD and an increase in latency, all of which indicate axonal hyperpolarization. The increase in threshold was less in peroneal axons (18 +/- 4%) than median axons (37 +/- 6%, mean +/- SEM, P < 0.001), and was accompanied by smaller absolute changes in latency, supernormality, and tauSD. Peroneal axons had less supernormality at rest but a greater change in supernormality for the change in threshold. There were major contraction-induced changes in the compound muscle action potential of TA but not that of APB. Voluntary contractions depress axonal excitability, but the changes are quantitatively different for motor axons innervating different muscles. There are three clinical implications. First, weakness and fatigue due to activity-dependent conduction block may vary for different muscles, independent of disease severity, and therapeutic strategies to overcome activity-dependent conduction block may not be equally effective for different muscles. Second, in motor control studies using the H reflex to document motoneuron excitability, a constant stimulus will not produce a constant neural volley if the stimulated axons have been activated by, for example, a voluntary contraction. Third, TA is probably not optimal for testing for activity-dependent conduction block.
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PMID:Effects of voluntary activity on the excitability of motor axons in the peroneal nerve. 1187 Jun 83

Chronic denervation syndromes such as the post-polio syndrome are associated with progressive muscle weakness and fatigue after motoneuron death. Neither the etiology nor the management of these syndromes is clear. To address this issue, we partially denervated rat hindlimb muscles for 1 or 12 months and examined whether chronically enlarged motor units (MUs) become destabilized with time and further destabilized by daily running on exercise wheels. MU enlargement, measured electrophysiologically and morphologically was significantly reduced at 12 months in extensively denervated muscles, and to a lesser extent in moderately denervated muscles, as compared to the findings at 1 month. A 1-month period of running exercise further reduced the size of the chronically enlarged MUs in the extensively denervated muscles. We have therefore (1) successfully established a rat model of time-related MU size reduction, in which destabilization of chronically enlarged MUs results in loss of axonal terminals, and (2) demonstrated that nonphysiological activity has small but significant effects of further destabilizing the chronically enlarged MUs.
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PMID:Effect of exercise on stability of chronically enlarged motor units. 1187 Jul 12

Vinorelbine (VNR) is a semi-synthetic vinca alkaloid (5'nor-anhydro-vinblastine) that differs from other vinca alkaloids by a modification of the catharantine moiety of the molecule. VNR binds to tubulin and inhibits tubulin assembly and microtubule formation. It has less activity than other vinca alkaloids against axonal microtubules and this may account for its reduced neurotoxicity in clinical use. In gastrointestinal tumours, VNR did not show significant activity in advanced pancreatic adenocarcinomas. Two phase II studies in metastatic colorectal cancer resulted in conflicting results: no activity in first-line therapy on lung metastases, but encouraging results in 5-fluorouracil (5-FU)-resistant metastases. Conversely, significant antitumoural effect in oesophageal squamous cell carcinoma has been demonstrated. The first study was performed in 46 patients with metastatic disease. Six of 30 patients (20%) without prior chemotherapy achieved a partial response (95% confidence interval (CI), 8-39%). One of 16 (6%) with prior chemotherapy responded. Grade (gr) 3 or 4 granulocytopaenia occurred in 59% of patients and peripheral neurotoxicity was minor (26% gr 1). These results were confirmed by another group. A phase I study was performed using VNR and concurrent radiation (64 Gy) in previously untreated patients with inoperable locally advanced oesophageal cancer ineligible for cisplatin-5-FU-based chemoradiation. Twenty-four patients entered the study. The maximal tolerated dose has been reached at 25 mg/m(2)/week, the dose-limiting toxicities being febrile neutropaenia and infection. Major objective tumour response was observed at each dose level except the first one. Recruitment is ongoing to confirm the recommended dose of VNR (20 mg/m(2)/week). A phase II study of a VNR-cisplatin combination in metastatic oesophageal squamous cell carcinoma was recently completed. Seventy-one eligible patients were included. Main toxicities were haematological (gr 3-4 granulocytopaenia, 41%), infection, vomiting and fatigue. The response rate was 37% (95% CI, 26-49%) with a median duration of response of 7.7 months. This 2-day regimen appears at least as active and less toxic than the standard 5-day 5-FU and cisplatin regimen.
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PMID:Activity of vinorelbine in gastrointestinal cancers. 1200 75

Conduction block is an important functional consequence of demyelination whereby nervous transmission is abolished. Its mechanism has been discussed with respect to the loss of insulation due to disruption of myelin. Recent development of threshold tracking techniques, which enabled noninvasive assessment of axonal membrane potentials and ion channels, has provided evidence that axonal excitability changes significantly and contributes to conduction failure. This view, based upon axo-glial interaction, clarifies the mechanism of muscle fatigue and fasciculation associated with peripheral demyelination and possibly explains selective motor involvement in multifocal motor neuropathy.
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PMID:Physiology of conduction block in multifocal motor neuropathy and other demyelinating neuropathies. 1263 14

A brief period of strong muscle contraction suppresses the amplitude of EMG responses evoked in relaxed muscle by transcranial magnetic stimulation (TMS) of the contralateral motor cortex. Here we investigate this phenomenon in more detail by recording the descending motor volleys evoked by TMS from electrodes in the cervical epidural space of three conscious patients implanted with chronic electrical stimulators for control of pain. We confirm that fatigue suppresses I waves evoked by TMS. In addition, D waves were suppressed in two of the patients, suggesting that axonal excitability might also be compromised by a period of intense muscle contraction.
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PMID:Direct demonstration of reduction of the output of the human motor cortex induced by a fatiguing muscle contraction. 1267 36

Amongst the varied symptomology of multiple sclerosis is to be found the alteration of higher functions (cognitive deficit), which has considerable repercussions on the quality of life of patients. The old descriptions of the disease rarely differentiate cognitive affectation from the more general category of "mental symptoms", which also includes a broad range of affective disorders. Towards 1960 neuropsychological tests began to be employed, and it was from the 1970s onwards that a clear distinction was drawn between deterioration of the higher functions and psycho-affective aspects in the disease. The pattern of cognitive deterioration in patients with multiple sclerosis is not uniform. During the initial phases of the disease it is, in general, light and it has an insidious start, although inter-individual variability is wide, depending on the predominant pathological alterations in the lesions and on their number and localisation. In more severe cases, it is possible to include within the debatable term of subcortical dementia, intellectual slowness, problems of attention, alterations in abstract reasoning, shortcomings in the resolution of problems and memory dysfunction. It is an almost invariable complication of the advanced stages of the disease, since the lesions characterised by axonal loss affect broad areas of white matter, which determines the deafferentation of several areas of cortical association. There does not appear to be any correlation between cognitive deterioration and the variables of the disease considered in an independent way, such as demographic data, clinical course, alterations of mood, consumption of medicines or fatigue. Although, evidently, the disease's progressive secondary forms of greater duration and the accumulation of lesions are what present the greatest deterioration. With present-day techniques of neuroimaging it has been possible to show a correlation between cognitive deterioration and the existence of an increase in ventricular size, periventricular lesions and atrophy of the callous body.
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PMID:[Cognitive deterioration in multiple sclerosis]. 1286 Dec 94


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