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The fine structure of muscle capillaries was analyzed morphometrically in 5 normal controls (41 capillaries), 5 cases of scleroderma (23 capillaries), 4 cases of polymyositis (30 capillaries), 6 cases of dermatomyositis (40 capillaries) and 5 cases of systemic lupus erythematosus (SLE) (50 capillaries). In all 4 connective tissue disorders there was hypertrophy of the endothelial cells and the pericytes. The mean capillary area was also significantly increased in scleroderma, dermatomyositis and SLE but not in polymyositis. In all 4 diseases the number of pinocytotic vesicles per unit endothelial cell area was significantly reduced while the mitochondrial and endoplasmic reticulum fractions of the endothelial area were significantly increased. Replication of the basal lamina around muscle capillaries was observed in 24–74% of the capillaries in inflammatory muscle diseases and in none of the control capillaries. Similar abnormalities of the basement membrane can also occur in other myopathies and in neurogenic atrophies. It is postulated that in the inflammatory myopathies the change is indicative of repeated cycles of capillary degeneration and regeneration and is a primary event rather than being the consequence of muscle fiber necrosis. Endothelial microtubular inclusions were observed in 2 of 6 cases of dermatomyositis and in 2 of 5 cases of SLE. While the inclusions appear to be highly specific for these diseases, their nature and pathogenetic significance remains undetermined.

Muscle blood flow (MBF) was measured using the local (133)Xenon injection method in patients with Duchenne type muscular dystrophy (six), limb-girdle dystrophy (four), polymyositis (seven), and in normal controls (11). Measurements were made at rest and during hyperaemia induced by ischaemic exercise and by histamine injection. Capillary diffusion capacity was measured with the (51)Cr-EDTA method in three patients with Duchenne dystrophy and in six normal controls. Patients with Duchenne dystrophy had normal MBF during rest and during hyperaemia after exercise and significantly increased MBF after histamine injection. The capillary diffusion capacity was higher than normal, but not significantly. In limb-girdle dystrophy MBF was normal, while in polymyositis it was significantly decreased in all three circulatory states. The relevance of the findings to the proposed ischaemic aetiology of Duchenne dystrophy is considered.

The “cytoplasmic body”, herein described, represents another basic pathological reaction of the Z disk. It is characterized by (1) its origin in the Z disk, (2) a dense filamentous core, (3) a surrounding lighter halo, (4) randomly orientated thin and finer filaments in the halo, (5) lack of a tetragonal filamentous array regardless of the plane of the section, (6) an accompanying focal decrease of mitochrondria from the affected fibre regions, and (7) its restriction to white (type 2) fibres. These features are compared with those of other anomalies of the Z disk.

A 19-year-old girl had had slight muscle weakness before age 18. In her 19th year, she became progressively weaker and eventually bedfast; she then needed respiratory support. Results of liver function and blood coagulation studies were abnormal when the patient was at her weakest. An almost complete remission occurred after seven weeks of prednisone therapy (60 to 27.5 mg/ day); there was relapse 21 months later with lower dosages (10 to 20 mg/day). With higher dosages, the patient again improved but did not regain her strength fully. In three muscle biopsy specimens, there were myriads of abnormal spaces, especially in type I fibers, containing neutral fat and fatty acids. The histologic abnormalities were less marked during remission than just before the start of therapy or during relapse. The metabolic defect in the present case remains unidentified.

This is a report on a study of a family with familial periodic paralysis in an attempt to clarify the underlying pathogenesis of the disorder. It was found in this particular family that no marked cationic ingress into muscle fibers could be demonstrated. Large dilatations containing granules of material staining with a positive periodic Schiff reaction were demonstrated with the paralysis. That such cisterns contained also water was confirmed. Intracellular recordings demonstrated no hyperpolarization of the membrane potential. During paralysis no propagated impulse could be recorded from intracellular electrodes by indirect or direct stimulation of the muscle fiber. This was indirectly confirmed by the presence of large quiescent areas in the electromyograph. Direct measurement of aldosterone excretion showed no increase of this hormone preceding or during the paralysis. Injection of aldosterone did not precipitate paralysis. No change in blood volume was noted during paralysis. Pitressin would not precipitate an attack. Thus aldosterone seems unlikely to be an etiological agent in this disorder. The action of thyroidal and thyrotropic hormones in the familial form of this disorder appears to be opposite to that described in the sporadic form. Electron microscopic studies suggest that fluid is accumulated in the endoplasmic reticulum and that there is a characteristic change in the mitochrondria during the paralysis. Such changes are reversible. Limited studies in carbohydrate metabolism with these patients suggest an abnormality in which intermediaty metabolites in the formation of glycogen may be responsible for the intracellular shift of water into the fiber to maintain osmotic, electric, and Donnan's equilibriums. Enzymatic studies of muscle homogenates would be the next logical study. In these patients as in others reported, paralysis may be precipitated in the presence of normal serum potassium values.

Introduction Hyperthyroidism in combination with myasthenia gravis, thyrotoxic myopathy, periodic paralysis, exophthalmic ophthalmoplegia, and acute thyrotoxic encephalomyopathy have been recognized as separate clinical entities. 1,2 Thyrotoxic myopathy and periodic paralysis remit upon treatment of the hyperthyroidism. Exophthalmic ophthalmoplegias may pursue a course independent of thyroid secreting activity. Acute thyrotoxic encephalomyopathy may be but a form of fulminating myasthenia gravis appearing in a thyroid crisis. 3,4 The relationship between hyperthyroidism and myasthenia gravis remains undefined. Estimates of the frequency of the occurrence of hyperthyroidism in patients with myasthenia gravis vary from 3% to 8.8%. 2,5-7 The higher percentage in the more recent series of Silver and Osserman 7 is perhaps the more accurate one. An inverse relationship between levels of thyroid activity and the severity of the myasthenia gravis has been endorsed by Thorner, McEachern, and Parnell, and Maclean and Wilson: either therapeutic or spontaneous abatement of the hyperthyroid state

A patient with severe primary hypokalemic periodic paralysis improved significantly on a regimen low in carbohydrate, restricted in sodium and high in potassium. Moderate weakness persisted in the proximal muscles and was associated with persistent vacuolation of muscle fibers. Enlargement of the motor end-plate zone is described in this case of primary hypokalemic periodic paralysis. Considerable weakness occurred even when serum potassium values were within the normal range. On an isocaloric nonreducing diet, the patient lost weight when the carbohydrate intake was reduced. Most of the weight loss could be accounted for by a loss of body water that was not associated with a negative sodium balance. Data obtained in the course of an acute attack are compatible with an increase in the total body water content and a shift of fluid from the extracellular into the intracellular compartment. Renal retention of potassium, sodium and chloride preceded changes in the patient's strength and the decrease in serum potassium. Not more than 10 mEq. of potassium could have been lost from the patient's erythrocytes during the attack despite the decreasing serum potassium levels. A fully paralyzed muscle and a muscle only somewhat weak were similar in their electrolyte and water content, except for the higher calcium and magnesium contents of the weaker muscle. Both muscles had chloride space and water levels which were higher than most normal values; sodium, chloride and magnesium levels higher than normal; and a potassium level which was lower than most normal values. The chloride space values were too high to be a measure of the extracellular space and could not be used for calculating intracellular electrolyte concentrations. Small doses of epinephrine, administered intra-arterially, had a direct adverse effect on the muscles of the perfused forearm. These effects were not mediated by systemic hypokalemia or hyperglycemia but may have been related to an acceleration of glycogenolysis and glycolysis in muscles. An increased uptake of sodium by the forearm tissues followed rather than preceded the decrease in action potential and twitch tension. Maximal voluntary exercise followed by rest caused a transient potentiation and then a depression of the action potential and of the twitch tension in the patient and in healthy subjects, but the patient's response was at times quantitatively greater. The deviation from normal tended to be greatest when the patient was weakest. Excessive accumulation of lactic and pyruvic acids in the blood occurred after a standard work load. This may indicate a greater than normal release of these metabolites from muscle or an impaired metabolism by muscle, or both. There appears to be no impairment in glycogenolysis or glycolysis in muscle during exercise. A close relationship was again observed between carbohydrate metabolism and primary hypokalemic periodic paralysis. The present study points to a possible metabolic lesion, or a contributing mechanism, that can be activated by rapidly induced glycolysis.

A 61-year-old woman had proximal muscle weakness since 38 years of age. Eventually, her distal muscles became affected and she showed widespread muscle wasting, absent tendon reflexes, and electromyographic findings of a neuropathy. On biopsy, there was a lipid storage myopathy, lipid-containing vacuoles in leukocytes, and vacuoles in Schwann cells. The muscle carnitine level was abnormally low, but the serum carnitine level was normal. The findings are consistent with a generalized disorder of carnitine metabolism that may involve carnitine transport across cell membranes.

The subcellular distribution of acid (pH 4.0) and neutral (pH 6.5) α-glucosidases was investigated in biopsy specimens of human skeletal muscle obtained from six normal subjects, four adult cases of acid maltase deficiency, and a case of myophosphorylase deficiency. The highest relative specific activity of acid glucosidase, as well as of other acid hydrolases, was observed in the light mitochondrial fraction. Relatively high acid phosphatase activity was also found in the microsomal fraction. In all muscles the highest relative specific activity of neutral glucosidase was in the microsomal fraction. In acid glucosidase deficient muscle no neutral glucosidase could be detected in the light and heavy mitochondrial fractions but in normal and myophosphorylase deficient muscle neutral glucosidase activity was also detectable in these fractions. The final supernatant of all muscles contained neutral glucoamylase activity. The relevance of these data to the pathogenesis of the different forms of type II glycogenosis is considered.

Maltase (α-1,4-glucosidase) activity was determined at various pH values in tissues in infantile (heart, liver, skeletal muscle), childhood (heart, liver, skeletal muscle), and adult (liver, skeletal muscle, leukocytes) types of acid maltase deficiency (AMD) and in control tissues. In an infantile case of AMD, only traces of neutral maltase were present in heart, and this activity was significantly decreased in skeletal muscle and liver. In a childhood case of AMD, neutral maltase activity was decreased only in liver. No decreases of neutral maltase occurred in adult AMD tissues. An absolute decrease of leukocyte acid maltase was found in four and a relative decrease in one of five adults with AMD. A decrease in the pH 4.0/pH 6.5 ratio of leukocyte maltase activity may aid in the diagnosis of adult AMD.

Acid maltase (AM) deficiency carriers can be detected by muscle enzyme assay. The assay indicates that, just as in infantile and childhood cases, adult cases of the disease are transmitted by autosomal recessive inheritance. With the maltose hydrolysis assay, in some neuromuscular diseases, muscle AM activity can be as low as in heterozygous AM deficiency. A relatively low muscle AM activity in myxoedema myopathy is confirmed. In human muscle, the K(m) of the enzyme for maltose hydrolysis is 7·2 to 9 × 10(-3)M. A modification of the enzyme assay based on this fact is recommended.

Nucleotides and Adenosine Monophosphate Deaminase Activity of Muscle in Primary Hypokalaemic Periodic Paralysis

The effects of 1-triiodothyronine and thyrotropin were investigated in a case of familial periodic paralysis. Hypermetabolism, first induced by the administration of 1-triiodothyronine then by thyrotropin, had no immediate adverse effects on the periodic paralysis. Exacerbations of the disease occurred twice, each time with return of the basal metabolic rate to normal. The increased weakness following withdrawal of l-triiodothyronine was promptly reversed by the administration of thyrotropin. The increased weakness following thyrotropin withdrawal disappeared gradually over twentyfive days. Thyroid hormones rather than pituitary thyrotropin secretion determined the effects on the periodic paralysis. Exacerbations of the disease were not associated with depression of the serum potassium levels. Decreased urinary excretion of potassium was noted during the first exacerbation, and decreased excretion of potassium and sodium were noted preceding the second one. No support could be found for the assumption that the two exacerbations were caused by temporary hyperaldosteronism. The present study points to a difference in the basic abnormality between the thyrotoxic and the familial forms of periodic paralysis.

A deficiency of acid maltase but not neutral maltase was observed in cultured fibroblasts obtained from six adults with glycogen-storage myopathy associated with acid maltase deficiency (A...

Current concepts of Z-disk fine structure are based on studies by Knappeis and Carlsen (1), FranziniArmstrong and Porter (2), Reedy (3), and Kelly (4) . Knappeis and Carlsen found that I filaments terminated adjacent to the disk and, in cross-section, were positioned in corners of I squares with 220 f 35 A sides . Each I filament from one side of the disk faced the geometric center of the space between four I filaments from the opposite side and was joined to these four filaments by four Z filaments. Within the disk, Z filaments formed the sides of tetragons (Z squares) rotated 45 ° to, and measuring half the diagonal length of, I squares . Reedy later noted that Z filaments were not straight but were curved, imparting a woven pattern to the disk . This is the classic appearance of the transversely sectioned Z disk, forming what can be called a Z-1 pattern . Published pictures demonstrating this pattern have been of osmium tetroxide-fixed material from a variety of animal muscles. In normal skeletal muscle, we consistently encountered a different Z-disk image-a Z-2 pattern . Because our specimens were examined after aldehyde-osmium tetroxide fixation, it seemed possible that the difference resulted from different chemical properties of the fixatives . That the Z disk fixed in glutaraldehyde (G) plus osmium tetroxide (O) differs in morphology from that fixed in O alone has been reported recently also by Fardeau (5) and by Landon (6) . We are reporting results of a comparative study of Z-disk morphology in frog, rat, and human muscle after fixation in O, in aldehyde + O, and in aldehyde alone, and after low-ionic-strength extraction (LISE) prior to fixation. Parallel studies on a proliferative anomaly of the Z disk-rodlike structures arising from the organelle (7)-also are presented . Finally, possible ways in which divergent Z-disk images could arise are considered .

Extensor digitorum longus end-plate ultrastructure was quantitatively analyzed in rats fed 300 ppm acrylamide in their diet for 10 to 90 days and in control animals. After 20 days of treatment the mean nerve terminal area was markedly enlarged due to distention by neurofilaments. Subsequently more than half of all nerve terminals disappeared, leaving behind denuded or Schwann-cell-covered postsynaptic regions. Denervation of the end-plates was subtotal; at least one nerve terminal persisted at each junction. Nerve terminals surviving after 30 days had a normal mean size and a reduced content of mitochondria and synaptic vesicles. Postsynaptic atrophy developed only after the presynaptic abnormalities were fully established. After cessation of treatment nerve terminals returned to the end-plates within 30 days but the synaptic vesicle and mitochondrial content of the terminals remained depressed even after 60 days of recovery.

The evolution of one myeloproliferative disorder into another is not unusual.1,2Thus, polycythemia vera, myeloid metaplasia, and myelocytic leukemia may follow, or imperceptibly merge into, one another. Pernicious anemia may also be followed by myelocytic leukemia, and the incidence of myelocytic leukemia in the relatives of patients with pernicious anemia has been reported to be higher than it is in the general population.3On the other hand, myeloid metaplasia or polycythemia vera occurring in proved cases of pernicious anemia is distinctly uncommon. The present report concerns a patient who developed polycythemia vera following therapy for pernicious anemia, relapsed into pernicious anemia 6 years after the onset of polycythemia vera, and again became polycythemic after 9 months of vitamin B12therapy. Report of Case A 62-year-old white woman who was first seen at the Mayo Clinic in January, 1960, complained of severe fatigue, loss of appetite, and a loss

Muscle biopsies of a 7-week-old girl with profound weakness of all but the ocular muscles, combined with hypotonia, hyporeflexia, hepatomegaly, macroglossia, myopathic electromyogram, and slight elevation of serum enzyme levels revealed mild glycogen and marked lipid and mitochondrial excess. Glycogen structure and anaerobic glycolysis were normal. Aldolase and pyruvate kinase levels were relatively low and the lactic dehydrogenase isoenzyme pattern resembled that of heart muscle. Subsequently the patient had normal intellectual and delayed motor development and her macroglossia disappeared. At 22 months pathologic alterations in muscle were strikingly improved and glycolytic enzyme levels and oxidation of labeled oleic acid and Krebs cycle intermediates were normal. Although still unidentified, the basic metabolic lesion is one that (1) affects mitochondria! morphology, (2) alters lipid and glycogen metabolism, (3) may improve with age, and (4) is compatible with a benign clinical course after early infancy.