Catecholamine-induced muscle weakness

Infusions of epinephrine or levarterenol bitartrate into a rabbit nerve-muscle preparation decreased the force of the evoked twitch of anterior tibial and gastrocnemius-soleus muscles. The adverse effect of the catecholamines was not directly on skeletal muscle. The alpha-receptor blocking drug phenoxybenzamine hydrochloride prevented the adverse effect of the catecholamines if it was given prior to catecholamine infusions and unmasked a weak augmentation of twitch tension. Taken with the finding of abnormal accumulation of catecholamine in human dystrophic muscles, the production of an experimental myopathy resembling human dystrophy by the monoamine oxidase inhibitor pargyline hydrochloride, and the finding of excessive levels of catecholamines in the tissues and urine of dystrophic animals, these experiments support the hypothesis that catecholamines could play a pathogenetic role in some dystrophic diseases of muscle.     

Severe hypophosphatemia in children with kwashiorkor is associated with increased mortality

Severe hypophosphatemia, serum phosphate concentration <0.32 mmol/L (<1.0 mg/dL), occurred in 8 of 68 (12%) of children with kwashiorkor within 48 hours of admission; 5 of 8 (63%) of these children died, compared with 13 of 60 (22%) children without severe hypophosphatemia (P <.02). Dermatosis and dehydration were significantly correlated with severe hypophosphatemia, but these clinical signs could not reliably predict fatal cases. Severe hypophosphatemia seems to be common and life-threatening in children with kwashiorkor in Malawi.     

Disturbances of neuromuscular interaction may contribute to muscle weakness in spinal muscular atrophy

During a critical period of development, motoneurones and muscles are dependent on functional interaction with each other for their survival. In certain neuromuscular disorders such as spinal muscular atrophy (SMA), motoneurones die and muscle development is seriously affected. Recently advances have been made towards understanding the genetic basis of this disease, and a particular gene, i.e. the survival motoneurone gene (SMN), has been identified and found missing in SMA patients. Nevertheless the function of this gene is not clear, it may be involved in the control of the development of either the motoneurone or the muscle. Here we report that disrupting neuromuscular interaction during the early postnatal period has similar consequences on the development of muscles and motoneurones to those seen in patients with SMA, in that there is a loss of motoneurones and muscle function is severely impaired. In view of this, we discuss the possibility that these symptoms in SMA patients may be due to a disturbance of neuromuscular interaction during a critical stage of development.     

Immobilizing muscle weakness accentuated in leg and proximal muscles

A 54 year old waiter was referred to the hospital because of proximal muscle weakness, most pronounced in his legs, which progressed to an inability to stand or walk within weeks. Myopathy was diagnosed based on the muscle biopsy findings and myositis was ruled out by laboratory and biopsy results. Further investigations led us to exclude an endocrine cause, hypovitaminosis D, infectious myopathy or a paraneoplastic syndrome. Heteroanamnesis revealed severe alcoholism, lasting for more than 30 years. The presumed alcohol induced hepatopathy was confirmed by liver biopsy. There were no signs of an acute alcoholic myopathy, as the weakness had developed rather insidiously, there was no elevation of the CK serum level nor myoglobinuria and a type 2 fibre atrophy was found by muscle biopsy. As expected the weakness improved under abstention. Thus the final diagnosis of a chronic alcohol induced myopathy was established.     

A case of respiratory muscle weakness due to cytochrome c oxidase enzyme deficiency

BACKGROUND: Cytologic evaluation of abnormal nipple secretion is a well-established method for the rapid diagnosis of breast carcinoma in females. However, less attention has been focused on male patients presenting with nipple discharge. CASE: A case of intraductal carcinoma of the male breast was diagnosed by nipple discharge cytology alone. CONCLUSION: This report illustrates the usefulness of nipple discharge cytology in the diagnosis of early breast carcinoma in males.     

Distribution of muscle weakness of central and peripheral origin

According to the established clinical tradition about the distribution of weakness, the ratios of flexor/extensor strength of patients with upper motor neuron lesions are expected to be relatively high for the elbow and wrist and low for the knee. To assess the diagnostic value of these patterns of weakness, muscle strength of 70 patients with limb weakness of central or peripheral origin was measured with a hand held dynamometer. The ratios of flexor/extensor strength at the knee, elbow, and wrist did not differ significantly between patients with central or peripheral origin of muscle weakness. The examination of tendon jerks proved to be of more value as a localising feature. The traditional notion about the distribution of weakness in upper motor neuron lesions may be explained by an intrinsically greater strength in antigravity muscles, together with the effects of hypertonia.     

Prolonged muscle weakness after neuromuscular blockade in the intensive care unit

As noted, quadriparesis with reduced reflexes and difficulty with ventilator weaning may be seen as a result of a number of neuromuscular disorders. The clinical approach relies on exclusion of a central cause first, followed by careful examination of peripheral nerve and muscle function. Persistent neuromuscular blockade should be excluded initially because it is a readily reversible condition. Use of a train of four stimulation with a peripheral twitch monitor can quickly establish integrity of conduction across the neuromuscular junction. If necessary, further electrophysiologic studies allow differentiation among the relevant diagnostic possibilities. CIP is characterized by nerve conduction and EMG findings consistent with axonal degeneration of sensory and motor fibers. GBS is distinguished by evidence of demyelination on nerve conduction studies, in addition to elevated spinal fluid protein. Persistent neuromuscular blockade is identified by a decremental response on repetitive stimulation studies of neuromuscular transmission. The acute myopathy following neuromuscular blockage does not involve sensory responses. Needle EMG examination reflects a myopathic pattern, rather than a neurogenic one as seen in CIP or GBS. In myopathic patients who are unable to move their limbs at all (precluding a full EMG examination), a muscle biopsy identifies muscle as the site of involvement.     

Transient weakness and compound muscle action potential decrement in myotonia congenita

Twenty-five Turkish patients with recessive myotonia congenita (RMC), 16 of whom had genetic confirmation, were studied. Nineteen had transient weakness. In the upper extremities, onset age of transient weakness was usually in the early teens. All untreated RMC patients had a compound muscle action potential decrement of > or =25%, usually above 50%, with repetitive nerve stimulation at 10/s for 5 s. Patients with other nondystrophic diseases with myotonia, except 1 patient with dominant myotonia congenita, had no transient weakness and a CMAP decrement below 25%.     

Segmental distribution of muscle weakness in SMA III: implications for deterioration in muscle strength with time

Systemic and topical administration of non-steroidal anti-inflammatory drugs (NSAIDs) has been shown to reduce periodontal disease progression in both animal models and human subjects. Our present research focuses on single enantiomers of these agents to examine whether enantiospecific therapy will be efficacious in slowing periodontitis. The purpose of this study was to evaluate the inhibitory effects of (S)-ketoprofen on experimentally induced alveolar bone loss in beagle dogs. 16, 18-month-old, female beagles were brought to optimal periodontal health over a 2-week pretreatment period. Experimental periodontitis was then induced by placing silk ligatures around premolar and molar teeth and by instituting a soft, plaque-promoting diet. At baseline, animals were randomized to 1 of 4 groups, consisting of 2x daily administration of (1) placebo dentifrice, (2) 0.3% (S)-ketoprofen dentifrice, (3) 3.0% (S)-ketoprofen dentifrice, or (4) 10.0 mg (S)-ketoprofen capsules (p.o.) over a 60 day treatment period. Standardized, periapical radiographs exposed at days 1 and 60 were analyzed by computer-assisted digital radiography in order to assess the rate of alveolar bone loss. Secondary outcomes included technetium 99m-tin-diphosphonate (99mTc-Sn-MDP) uptake and the gingival index. At baseline, no differences were observed among the groups for linear bone height or 99mTc-Sn-MDP uptake ratios. From days 1 to 60, cohorts differed significantly in terms of bone loss rates (p < 0.001). In particular, beagles treated with systemic or topical (S)-ketoprofen (0.3% or 3.0% dentifrices) exhibited significantly lower mean rates of bone loss compared to placebo treated beagles (p < 0.05). Group differences in mean radiopharmaceutical uptake ratio changes approached significance (ANOVA, p = 0.07), where animals treated with topical 0.3% (S)-ketoprofen demonstrated a reduction and other groups demonstrated elevations over the 60-day dosing period. Treatment cohorts did differ significantly with respect to changes in mean gingival indices (p < 0.05). Animals treated with 0.3% or 3.0% (S)-ketoprofen dentifrice exhibited significantly reduced elevations in gingival index scores as compared to placebo treated animals. These data provide evidence that enantiospecific therapy with (S)-ketoprofen, topically or systemically delivered, may alter the progression of periodontal disease in the beagle dog model.     

Periodic muscle weakness and cervical ventroflexion caused by hypokalemia in a Burmese cat

A 2-year-old female Burmese cat was referred to the University Hospital of Companion Animals of Utrecht University because of periodic muscle weakness and cervical ventroflexion. Laboratory examinations revealed hypokalemia. The combination of breed, clinical signs and hypokalemia warranted the diagnosis of 'periodic hypokalemic myopathy', a homozygote recessive hereditary disease in Burmese cats. Potassium supplementation resulted in complete disappearance of the signs. Possible causes of hypokalemia in the cat are discussed.     

Acetylcholine receptor epsilon-subunit deletion causes muscle weakness and atrophy in juvenile and adult mice

In mammalian muscle a postnatal switch in functional properties of neuromuscular transmission occurs when miniature end plate currents become shorter and the conductance and Ca2+ permeability of end plate channels increases. These changes are due to replacement during early neonatal development of the gamma-subunit of the fetal acetylcholine receptor (AChR) by the epsilon-subunit. The long-term functional consequences of this switch for neuromuscular transmission and motor behavior of the animal remained elusive. We report that deletion of the epsilon-subunit gene caused in homozygous mutant mice the persistence of gamma-subunit gene expression in juvenile and adult animals. Neuromuscular transmission in these animals is based on fetal type AChRs present in the end plate at reduced density. Impaired neuromuscular transmission, progressive muscle weakness, and atrophy caused premature death 2 to 3 months after birth. The results demonstrate that postnatal incorporation into the end plate of epsilon-subunit containing AChRs is essential for normal development of skeletal muscle.     

Oxygen transport to muscle during exercise in chronic congestive heart failure secondary to idiopathic dilated cardiomyopathy

In chronic heart failure, oxygen delivery during exercise is impaired mainly because of failure of cardiac output to increase normally. Compensatory mechanisms are hemoglobin concentration increase, right-ward shift in the oxyhemoglobin dissociation curve, and blood flow redistribution from the nonexercising organs to the exercising muscles.     

Mutational analysis of PHEX gene in X-linked hypophosphatemia

Hypophosphatemic rickets is commonly an X-linked dominant disorder (XLH or HYP) associated with a renal tubular defect in phosphate transport and bone deformities. The XLH gene, referred to as PHEX, or formerly as PEX (phosphate regulating gene with homologies to endopeptidases on the X-chromosome), encodes a 749-amino acid protein that putatively consists of an intracellular, transmembrane, and extracellular domain. PHEX mutations have been observed in XLH patients, and we have undertaken studies to characterize such mutations in 46 unrelated XLH kindreds and 22 unrelated patients with nonfamilial XLH by single stranded conformational polymorphism and DNA sequence analysis. We identified 31 mutations (7 nonsense, 6 deletions, 2 deletional insertions, 1 duplication, 2 insertions, 4 splice site, 8 missense, and 1 within the 5' untranslated region), of which 30 were scattered throughout the putative extracellular domain, together with 6 polymorphisms that had heterozygosity frequencies ranging from less than 1% to 43%. Single stranded conformational polymorphism was found to detect more than 60% of these mutations. Over 20% of the mutations were observed in nonfamilial XLH patients, who represented de novo occurrences of PHEX mutations. The unique point mutation (a-->g) of the 5'untranslated region together with the other mutations indicates that the dominant XLH phenotype is unlikely to be explained by haplo-insufficiency or a dominant negative effect.     

The responses of secondary endings of cat soleus muscle spindles to succinyl choline

In this report we examine biochemical and genetic alterations in DNA topoisomerase II (topoisomerase II) in K562 cells selected for resistance in the presence of etoposide (VP-16). Previously, we have demonstrated that the 30-fold VP-16-resistant K/VP.5 cell line exhibits decreased stability of drug-induced topoisomerase II/DNA covalent complexes, requires greater ATP concentrations to stimulate VP-16-induced topoisomerase II/DNA complex formation, and contains reduced mRNA and protein levels of the M(r) 170,000 isoform of topoisomerase II, compared with parental K562 cells. K/VP.5 cells grown in the absence of VP-16 for 2 years maintained resistance to VP-16, decreased levels of topoisomerase II, and attenuated ATP stimulation of VP-16-induced topoisomerase II/DNA binding, compared with K562 cells. Sequencing of cDNA coding for two consensus ATP binding sites and the active site tyrosine in the K/VP.5 topoisomerase II gene indicated that no mutations were present in these domains. In addition, single-strand conformational polymorphism analysis of restriction fragments encompassing the entire topoisomerase II cDNA revealed no evidence of mutations in the gene for this enzyme in K/VP.5 cells. Nuclear extracts from K562 (but not K/VP.5) cells contained a heat-labile factor that potentiated VP-16-induced topoisomerase II/DNA covalent complex formation in isolated nuclei from K/VP.5 cells. Immunoprecipitated topoisomerase II from K/VP.5 cells was 2.5-fold less phosphorylated, compared with enzyme from K562 cells. Collectively, our data suggest that acquired VP-16 resistance is mediated, at least in part, by altered levels or activity of a kinase that regulates topoisomerase II phosphorylation and hence drug-induced topoisomerase II/DNA covalent complex formation and stability.