In vivo effects of protease inhibitors on chickens with hereditary muscular dystrophy.

Beginning on day 4 ex ovo, and every 3 d thereafter, genetically dystrophic Line 413 chickens were given intraperitoneal injections (4 mg/kg body wt) of a protease inhibitor, leupeptin, pepstatin, or antipain. Experimental chickens received protease inhibitors dissolved in a water:ethanol:dimethyl sulfoxide solution (50:40:10, vol:vol:vol). Control untreated animals received diluent injections. Untreated dystrophic chickens typically reach around day 30 ex ovo a maximum ability to right from the supine position in a standardized functional test for muscle weakness. After day 30 ex ovo, the dystrophic chickens are found to decline progressively in their ability to right, compared with normal, nondystrophic controls, which have an unimpaired ability to right. Concomitantly, dystrophic chickens exhibit characteristically high levels of plasma creatine phosphokinase enzyme activity. In addition, an increased frequency of degenerating, regenerating, and vacuolated myofibers, and inflammatory cells appear in the affected pectoralis major muscles from the dystrophic chicken. Throughout the duration of the trial, there was no major enhancement in the functional righting ability of dystrophic chickens receiving any one of the protease inhibitors tested. However, there was a significant reduction in the abnormally high levels of plasma creatine phosphokinase in the treated chickens. Also, there was an apparent reduction in the mean number of vacuolated fibers in the pectoralis muscle from the protease inhibitor-treated birds. No significant reductions were observed in the relative frequency of degenerating and regenerating myofibers or inflammatory cells. In addition to the plasma creatine phosphokinase decrease, however, therapeutic benefit was seen in 31.0, 30.5, and 14.8% increases in the wet weight (and total noncollagen protein) of pectoralis muscle from dystrophic chickens receiving leupeptin, pepstatin or antipain, respectively.

Adult central core disease. Clinical, histologic and genetic aspects: case report and review of the literature.

Central core disease (CCD) is mainly a disease of infancy and childhood and represents a member of a group of muscular disorders known as "congenital, benign (non-progressive) myopathies". It is an uncommon disease of infancy and early childhood, and presentation is rare in adulthood. The disease is mainly familial with an autosomal-dominant pattern of inheritance, yet sporadic cases can occur. The diagnosis is based on a muscle biopsy, which documents unique morphological abnormalities of focal loss of oxidative enzyme in type I muscular fibers. The basis for this loss of such activities is represented by a near-total absence of mitochondria and sarcoplasmic reticulum in the cores. We describe a 58-year-old man diagnosed with CCD, who is one of the oldest individuals reported with CCD diagnosed by a muscle biopsy. The clinical, pathological and genetic features of this rare entity are discussed herein.

Morphologic and functional alterations in aging rat muscle.

To understand better the causes of reduced contractile force in aging skeletal muscle, we performed a physiologic and morphologic analysis of plantaris muscle in old rats. The peak twitch tension (Fmax) and rates of force development and relaxation were significantly lower in old (24 months old) rats than in young (six month old) rats. In teased muscle fiber preparations, there was a 5% reduction in the mean number of fibers in the aging plantaris muscle. Histologically, a net loss of fibers occurred only in the muscle belly. Histochemically, fewer Type I fibers were seen in the belly and proximal regions, whereas distally fewer Type IIa fibers were seen. The loss of Types I and IIa oxidative fibers suggested a conservation of fast-twitch Type IIb fibers in a fast-twitch muscle. The relatively small loss of muscle fibers does not explain the large decline in muscle contractile performance which, despite established doctrine, was independent of muscle mass, fiber number or size, or number of fast-twitch fibers. The reduced force production in aging rat muscle appears to be due to a defect in excitation, contraction performance or metabolic activity, rather than a purely anatomical abnormality of muscle.

Correlation of endothelin-1 and transforming growth factor beta 1 with malignancy and vascularity in human gliomas.

Because the prominent neovascularization characteristic of high grade primary brain tumors is composed mostly of vascular smooth muscle cells (VSMC), we studied the expression of the potent smooth muscle mitogen endothelin-1 (ET-1) and one of its secretagogues, transforming growth factor beta 1 (TGF-beta 1) in a series of astrocytic tumors. TGF-beta 1 is also of interest due to its known activity as an angiogenic factor. Using immunohistochemical methods, we examined 30 surgical cases: 10 glioblastoma multiforme, 10 anaplastic astrocytomas, and 10 low-grade astrocytomas. Using a monoclonal antibody to TGF-beta 1 and a polyclonal antibody to ET-1, we detected both growth factors in all cases of glioblastoma examined. In cases of anaplastic astrocytoma, 4 tumors were positive for both factors; 2 contained only ET-1; 2 contained only TGF-beta 1; and 2 exhibited no tumor cell immunoreactivity for either factor. In low-grade astrocytoma, 4 of 10 tumors showed weak ET-1 immunoreactivity; 2 of those contained TGF-beta 1 immunopositive tumor astrocytes: 6 tumors were negative for both factors. In all tumors that expressed both factors, serial sections showed that regions of ET-1 immunopositivity also tended to be positive for TGF-beta 1. Endothelial cells within all tumors were positive for ET-1. ET-1 and TGF-beta 1 are present in human astrocytomas and their expression correlates with tumor vascularity and malignancy. These results suggest roles for both ET-1 and TGF-beta 1 in the growth and progressive angiogenesis of the human glioma.

Continuous muscle fiber activity: a case with unusual clinical features.

A patient with continuous muscle fiber activity is described. From our search of the literature, we believe this is the oldest patient with a reported case of this disorder, and the symptoms and treatment varied from previously reported cases in these respects: symptoms remained confined to the lower extremities after 18 months had elapsed, there was no response to phenytoin sodium or carbamazepine, and the patient required a full dose of tubocurarine chloride to stop the abnormal myoelectric potentials. A site of dysfunction in the unbranched motor axon is suggested as the locus of generation of the stimulus for the abnormal myoelectric activity.

Abnormal spontaneous electrical activity and gross enlargement of muscle.

In a patient with congenital hypertrophy of the right leg, there developed progressive enlargement of the extremity and inflammatory pseudotumor and electrical myotonia within the enlarged muscle. In three other reported cases, progressive muscle enlargement was associated with abnormal spontaneous electrical and mechanical activity of muscle. In all four cases, the muscle enlargement was probably due to a combination of work hypertrophy secondary to the abnormal mechanical activity and stretch-induced hypertrophy of denervated muscle.

Polymyositis beginning as a focal process.

Six patients with polymyositis initially complained of a single, localized, painful mass involving an extremity. The mass enlarged during the course of a two- to six-week period. Biopsy of the lesion revealed myopathic changes with inflammation, and the diagnosis of benign inflammatory pseudotumor was considered. The mass regressed, but during the next three to six months, a rapidly progressive generalized myopathy developed that caused weakness of the trunk and extremities in association with malaise and weight loss. Subsequent muscle biopsy specimens obtained from a site remote from the original mass were again characterized by lymphocytic infiltration, fiber necrosis, and regenerative activity. Our experience indicates that polymyositis may begin as a focal process that mimics a localized inflammatory pseudoneoplastic reaction. An essential clue to the diagnosis of polymyositis at this early stage is the elevation of ESR and serum creatine phosphokinase levels that does not occur in pseudotumor. The muscle biopsy further serves to distinguish polymyositis from pseudotumor.

A familial mitochondrial myopathy with central defect in neural transmission.

A family was found to exhibit progressive external ophthalmoplegia, congenital cataracts, variable somatic weakness, gonadal dysgenesis, and, in one member, an abnormal chromosomal pattern. Muscle biopsy specimens showed "ragged-red" fibers; electron microscopy showed widespread paracrystalline mitochondrial inclusions. Orbicularis oculi reflex testing in the propositus showed bilateral absence of the late response. The family was evaluated in relation to other familial mitochondrial myopathies; a central defect in brain stem neural transmission was suggested as a mechanism for the progressive external ophthalmoplegia.

Subcortical arteriosclerotic encephalopathy (Binswanger's disease). Computed tomographic, nuclear magnetic resonance, and clinical correlations.

Twenty-three elderly patients were found to have a consistent pattern of leukoencephalopathy by computed tomography and nuclear magnetic resonance imaging. Eight patients presented with vague, nonspecific symptoms and had no neurologic deficits. The other 15 patients had neurologic deficits that presented in one of three ways: stroke, seven patients; slowly progressive dementia and gait disturbance, five patients; or slowly progressive dementia alone, three patients. Risk factors for arteriosclerosis (hypertension, diabetes) were present in 18 patients (78%). The necropsy of one patient revealed arteriosclerotic vasculopathy characteristic of subcortical arteriosclerotic encephalopathy (SAE) or Binswanger's disease. Subcortical arteriosclerotic encephalopathy may be a relatively common affliction of elderly patients, most of whom have risk factors for arteriosclerosis. The modes of presentation and associated clinical signs are variable, and more than one third may have no neurologic deficit. In some cases SAE overlaps with normal pressure hydrocephalus by clinical and neuroimaging criteria. Some patients with normal pressure hydrocephalus who do not respond to ventricular shunting may actually have SAE.

A demyelinating disorder associated with cerebrovascular amyloid angiopathy.

Five patients with a demyelinating disorder and associated amyloid angiopathy are presented. The disease affected middle-aged individuals, pursued a fluctuating course, and ended in progressive, fatal deterioration of the central nervous system. Neurologic findings indicated multiple lesions within the neuraxis; profound dementia was prominent in all cases. Pathologically, numerous demyelinated plaques, similar to those in multiple sclerosis, were found in the cerebral white matter, and less consistently in other locations such as optic nerve, brain stem, and spinal cord. Amyloid accumulated massively in and around blood vessels, usually in the immediate vicinity of the plaques. At least one similar case is reported in the literature, but the nosologic status of the condition is uncertain.

Selective paralysis of downward gaze caused by bilateral lesions of the mesencephalic periaqueductal gray matter.

A patient who had selective paralysis of downward gaze caused by bilateral lesions of the dorsolateral mesencephalic periaqueductal gray (PAG) matter is reported. Her necropsy findings differed from all previous reports of the syndrome, in that regions of the mesencephalon that have been considered as critical for executing downward gaze (dorsomedial to red nuclei, rostral interstitial nuclei of the medial longitudinal fasciculus [ri MLF]) were normal. These lesions may have produced the syndrome by involving the caudal portions of the nuclei of the posterior commissure (subcommissural), from which one of the commissural systems used by the ri MLF originates. It is also possible that the syndrome was produced by selective destruction of PAG neurons that generate downward impulses or by interruption of posterior commissure fibers containing downward impulses that travel through the dorsolateral PAG before terminating in the more ventral mesencephalon.

Autopsy correlations of computerized tomography: experience with 6,000 CT scans.

Seventy-nine autopsy correlations of CT scans showed (1) excellent correlations in normal brains, but the size of the lateral ventricles consistently larger during life than after death; (2) a distinctive pattern differentiating obstructive from nonobstructive hydrocephalus; (3) infarctions appearing as areas of decreased densities of parenchyma in vascular distributions; (4) distinctive high density appearances of hemorrhages that differentiated them from infarctions and, in general, all other pathologic processes; (5) supratentorial, intraventricular, and posterior fossa tumors appearing as masses that displaced, distorted, collapsed, and enlarged normal spaces and structures such as ventricles and pineal gland; (6) 11 false-negative CT scans in some cases of brain stem infarction, brain stem hemorrhage, and small metastasis; and (7) an overall accuracy of 86.2 percent of CT scanning in correctly identifying pathology of the brain.

Legionella myositis.

Neuromuscular involvement in patients with legionnaires' disease is common, with serum CK elevations in up to 78% of patients. A few cases have been associated with neuropathy. The mechanism of injury to the neuromuscular system is unknown, but organisms have not previously been found in nerve or muscle. We report the clinical, electrophysiologic, and pathologic findings in a patient with Legionella myositis and motor neuropathy, the first case to demonstrate direct muscle invasion by the Legionella organism.

An eye movement disorder in amyotrophic lateral sclerosis.

Defective pursuit eye movements were recorded by electrooculography (EOG) in 11 of 18 patients (61%) with amyotrophic lateral sclerosis. Pursuit defects consisted of a breakdown of smooth tracking into saccadic motions that were grossly in excess (frequencies and amplitudes) of saccadic interruptions of pursuit in normal subjects. In nine patients, defective pursuits cogwheeling) were obvious by visual inspection as well as by EOG; in two, this abnormality was seen only by EOG. In eight patients, the pursuit defect was the only abnormality of oculomotor function; in three, there were also saccadic defects (optokinetic nystagmus or conjugate gaze) discerned by EOG. Autopsy revealed neuronal degeneration in substantia nigra and demyelination in integral capsule in one patient with the pursuit defect but not in another patient without the defect. The pursuit defect may be a sign of extrapyramidal or supratentorial pyramidal involvement in ALS.

Prognostic factors in brainstem gliomas.

Although brainstem gliomas carry the worst prognosis of any brain tumor in children, with median survivals of 9 to 12 months, there may be a subgroup of long-term survivors. We have identified 12 children with brainstem gliomas, 5 of whom have survived greater than 6 years and 6 less than or equal to 12 months. Another child, alive and well 3 years following diagnosis, was considered in the long-term survivor group. Favorable prognostic factors included neurofibromatosis, symptoms greater than or equal to 12 months before diagnosis, calcification on CT, exophytic location, and pathology suggesting a low-grade tumor. Recognition that certain patients with brainstem gliomas may have prolonged survivals even in the absence of definitive treatment must be taken into consideration when new treatment regimens are being formulated.

Monozygotic female twin carriers discordant for the clinical manifestations of Duchenne muscular dystrophy.

We studied twin sisters, in their sixth decade, who were obligate carriers of Duchenne dystrophy. One had a slowly progressing limb-girdle myopathy since her mid-20s. The other sister showed no evidence of neuromuscular disease by history or on physical examination but had high serum CK values and degeneration and regeneration of fibers in a muscle biopsy. Otherwise, they were phenotypically identical, karyotypically normal females with cytogenetically normal X-chromosomes. Based on red cell and HLA loci antigen determinations, there was a 99.2% probability that they were monozygotic. The mutant gene segregating in the family is probably linked to the Xp21 DNA marker pERT87.

Neuronal-associated tumor necrosis factor (TNF alpha): its role in noradrenergic functioning and modification of its expression following antidepressant drug administration.

Tumor necrosis factor-alpha (TNF alpha) and the alpha 2-adrenergic agonist clonidine regulate norepinephrine (NE) release from noradrenergic nerve terminals in the central nervous system (CNS). In the present study, superfusion and electrical field stimulation were applied to a series of rat hippocampal brain slices in order to investigate the regulation of [3H]-NE release. NE release had been previously determined to be decreased by TNF alpha in a concentration-dependent manner, an effect which was potentiated by the alpha 2-adrenergic antagonist idazoxan. Presently, we demonstrate that similar to alpha 2-adrenergic activation, TNF alpha regulation of NE release in a region of the brain rich in noradrenergic nerve terminals, is dependent upon the frequency of electrical stimulation applied to the hippocampal slice. Furthermore, immunoperoxidase staining has verified our previous findings of constitutive TNF alpha protein in the rat brain. Staining for TNF alpha appears to be largely localized to neurons and neuronal processes, further substantiating the proposal that TNF alpha is either synthesized de novo or is accumulated in and released by neurons. After administration of the tricyclic antidepressant desipramine, tissue sections obtained from the rat hippocampus and locus coeruleus are devoid of neuronal-associated TNF alpha immunoreactivity. TNF alpha localization in neurons and its modification of NE release comparable to alpha 2-adrenergic receptor activation, explains a functional role for the cytokine as a neuromodulator in the CNS.

The early effects of ischemia upon skeletal muscle mitochondria.

The effects of early ischemia were studied in the anterior tibial muscle of Sprague-Dawley rats after 2--24 hr of tourniquet compression at the thigh. Ragged-red fibers, moth-eaten fibers, cores and targets were seen in tissue examined by enzyme histochemistry and electron microscopy. Giant mitochondria, abnormalities of cristal arrangement, crystalloids, osmiophilic inclusion bodies and myeloid figures were dominant features of the mitochondrial reaction. The results of this experiment indicate that early ischemia induces a variety of changes described in other neuromuscular conditions such as dystrophy and the "mitochondrial myopathies". The pathogenesis of these changes and their relationship to human disease of muscle is discussed.

Limited benefit to genetically dystrophic chickens from a synthetic proteinase inhibitor: Ep475.

Chickens with inherited muscular dystrophy (Line 413) were treated in two separate trials with daily intraperitoneal injections of 10% DMSO-water solutions containing the proteinase inhibitors, Ep475 and E64. Drug therapy in each case significantly prolonged the functional ability of the treated chickens. Diluent control chickens around day 35 ex ovo characteristically reached a maximum ability to right from the supine position in a standardized functional test for muscle weakness. Subsequently, the control chickens were found to decline progressively in their ability to right. Treatment with the proteinase inhibitors had no effect on the typically elevated levels of plasma creatine kinase activity. In a histological analysis of the affected pectoralis major muscle, drug treatment had no effect on the relative distribution of degenerating, and vacuolated fibers, inflammatory cells, and abnormal fiber diameters. An exception was seen in decreased necrotic fibers of chickens treated with high doses of Ep475. Moreover, both inhibitors had positive effects on two biochemical abnormalities common to the dystrophic pectoralis muscle: increase in noncollagen protein, and reduction in total calcium.

Primitive neuroectodermal tumors of childhood. An approach to therapy.

Primitive neuroectodermal tumors are found in the cerebrum of children and young adults. The are clinically highly malignant and have rapid course from diagnosis to death. Their microscopic pathology reveals 90% to 95% nondifferentiation, frequent mitoses, and small dark cells with no observable cytoplasm. This paper discusses the treatment of three children with this tumor with a combination of surgery irradiation, and combination chemotherapy. The results of this approach are compared with previous reports in the literature. The average survival in this series is 24 months versus approximately 8 months reported in the literature.