Pharmacophysiological study on muscle treated with calcium ionophore A23187

Muscle treated with A23187, which raises intracellular free Ca2+ concentration, was studied to elucidate effects on membrane properties. The mean resting membrane potential was reduced; it was normally depolarized by ouabain but not significantly hyperpolarized by epinephrine and insulin. In the presence of ouabain, membrane depolarization was not provoked by insulin. The results imply a defect of active Na+-transport of the membrane after exposure to a calcium ionophore.     

Therapeutic approach to experimental autoimmune myasthenia gravis by dantrolene sodium

Experimental autoimmune myasthenia gravis in rats was treated with dantrolene sodium (20 mg/kg/day) from 18th to 34th postinoculation day. At the end of the experimental period, day 35 postinoculation, the drug was shown to improve the disease as suggested by clinical observation and by larger MEPP amplitude and lower curare sensitivity without significant change in titers of anti-acetylcholine receptor antibody. Possible mechanisms by which the disease could be affected by the dantrolene-induced accumulation of free calcium in the subcellular store were discussed in relation to roles of calcium in regulation of the receptor protein and related immunity.     

Morphological abnormalities of erythrocyte membrane in the hereditary neurological disease with chorea, areflexia and acanthocytosis

A study with freeze-fracture electron microscopy was made on erythrocyte membrane in 5 patients with the hereditary neurological disease with chorea, areflexia, and acanthocytosis (Levine et al. 1968). Fixed or unfixed specimens from circulating blood were processed by the freeze-fracture technique, and the distribution of the intramembranous particles was studied. A significant increase in areas without intramembraneous particles (IMP-free areas) was found in all cases with the disease as compared to normal subjects. The group mean value of IMP-free areas was 0.11 +/- 0.01 X 10-2 micrometer2/micrometer2 fracture face in the normal P face and 0.10 +/- 0.04 in the normal E face, compared with 1.77 +/- 0.49 in the P face and 1.33 +/- 0.17 in the E face in material from patients. Although abnormalities in lipid metabolism or membrane properties of erythrocytes have not been revealed in this condition hitherto, the present data suggest an abnormality of membrane fluidity due to abnormal lipid metabolism in this unique disease with neurological disorders and acanthocytosis.     

Immunoglobulins in cerebrospinal fluid: Enzyme-immunoassay

Using an enzyme-immunoassay (EIA) technique we established control values for IgA and IgM in cerebrospinal fluid (CSF). These values, together with IgG values determined by single radial immunodiffusion (SRID) technique, showed significant positive correlations with CSF total protein values. The CSF IgA and IgM levels were related to corresponding levels determined in serum. In addition, the values for all 3 immunoglobulin classes in CSF as well as CSF total protein values showed positive correlation with age of subjects, and IgG% and IgA% increased with age. This new EIA procedure can be completed within 24 h and is sensitive enough for determining all 3 immunoglobulin classes using a small amount (100 μl or less) of native CSF.     

Injuries to the major branches of peripheral nerves of the forearm: By Morton Spinner,x + 141 pages, 63 illustrations,Saunders, Philadelphia,London, Toronto, 1972, £ 5.35

We report the case of a patient who suffered from RSSE, and about 13 years later, developed slowly progressive impairment of mental, visual and auditory function, oculomotor involvement, dysphagia, pyramidal and cerebellar signs.Increases of γ-globulin, IgG and IgA were noted in the cerebrospinal fluid. A diffuse atrophy of the cerebrum and cerebellum was observed on pneumoencephalography.Serological tests indicated unusually high antibody titres (HI) against RSSE virus and the Negishi strain of RSSE virus both in the serum and in the cerebrospinal fluid.Histological studies of a brain biopsy specimen indicated active chronic inflammation of the meninges, cortex and white matter. From these findings, we consider that this case demonstrates a chronic progressive encephalitis due to a slow, latent infection by RSSE virus.     

Occurrence of myasthenia gravis in a patient with congenital myotonia

Myasthenia gravis developed acutely in a 32-year-old woman, who incidentally was found to have myotonia congenita of the autosomal dominant mode of inheritance. The simultaneous occurrence of myasthenia gravis and myotonia congenita was established clinically, pharmacologically and electromyographically. There was no immunologic abnormality, whereas the thymus was detected by pneumomediastinographic tomograms. About 2 months after the onset of myasthenia gravis, thymectomy was performed resulting in progressive improvement of myasthenia without apparent change in the myotonia.     

Mood changes in stroke patients: Relationship to lesion location

During the past several years we have been studying mood changes in stroke patients.^1–9 We have reported recently in a follow-up study of 103 outpatients that the duration of untreated post-stroke depression was at least 7–8 mo in two-thirds of the patients.¹ We also found that during the period from 6 mo to 2 yr post-stroke, there was a significant increase in the prevalence and severity of depression as compared to other post-stroke time periods.¹ In addition, we are presently conducting a 2 yr longitudinal study on a separate group of 103 stroke patients and have reported during the acute stroke period that severity of depression was significantly correlated with the severity of the patient's intellectual and functional physical impairment as well as their age and the quality of their social supports.²However, the most consistent finding from our studies is the importance of lesion location.^1–5,9 For instance, we have shown that patients with left hemisphere lesions have higher depression scores than those with right hemisphere lesions. However, intrahemispheric lesion location seems to have as great an impact as interhemisphere lesion location. Patients with left anterior lesions were significantly more depressed than patients with left posterior lesions^2–4 even if the patient had bilateral lesions.⁹ In addition, we have shown that the closer the lesion was to the left frontal pole the greater the depression score^3,4 even in the presence of bilateral hemisphere strokes.⁹ Thus, although multiple factors including severity of impairment and quality of social supports contribute to the development of post-stroke depression,² lesion location seems to be one of the most important variables. Therefore, in the present study we wanted to examine the role of lesion location by selecting a group of stroke patients with single stroke lesions and no prior history of psychiatric disorder to determine what clinical symptoms develop in the acute post-stroke period, and we wanted to analyze what relationship these symptoms might have to size or location of the brain lesion.     

Myotonic muscle in mouse: A light and electron microscopic study in serial sections

The EDL muscle of the Bar Harbor Strain mouse was studied in serial section by light and electron microscopy. Phase contrast microscopy of 15 μm epon sections revealed fiber abnormalities such as central nucleation, atypical fiber diameter and regions of focal fiber necrosis; fiber splitting detected in such sections was a prominent feature of the myotonic muscle. Ultrathin resectioning of selected 15 μm sections showed additional alterations such as dilation of the sarcoplasmic reticulum, mitochondrial conglomerations and disruptions, sarcolemmal infolding and breakdown, and myofibrillar degeneration. The most notable neuropathic changes included distortion in shape and decrease in numbers of synaptic vesicles as well as axonal retraction, reduplication of the basement membrane, and the presence of dense bodies between axon and junctional sarcolemma. These data indicate the involvement of both muscle fiber and motor end plate in mouse myotonic dystrophy.     

Morphometric quantification of the cervical limb motor cells in controls and in amyotrophic lateral sclerosis.

The limb motor cells of the C6 segment of the spinal cord were counted and correlated with quantified histological findings of biceps brachii muscles in controls and in cases of amyotrophic lateral sclerosis (ALS). In 12 controls the motor cells were divided into larger ones with a minimum diameter greater than 20 micron, and smaller cells. Total numbers of the larger motor cells decreased significantly in 11 of 12 cases of ALS and of the smaller cells in 4 cases. In 4 controls most of the constituents of the biceps brachii muscle were normal-sized fibers, while in ALS smaller fibers and interstitial connective tissue increased and hypertrophic fibers decreased in association with a decrease of normal-sized fibers. The correlation coefficients between total numbers of the larger or smaller motor cells and normal-sized fibers in ALS were 0.92 and 0.65 respectively, and the larger motor cells, correlating with muscular atrophy of the upper arm, were considered to be alpha motor cells. Although in ALS the larger motor cells decreased almost diffusely, there were segmental variations, similar to controls, in numbers of the motor cells per 500 micron thickness.     

Paraoxon-induced myopathy: muscle specificity and acetylcholine involvement.

Treatment of rats with Paraoxon, an organophosphorous cholinesterase (ChE) inhibitor, produces a progressive myopathy in skeletal muscle. The earliest stage of lesion development is characterized histologically by heavy trichrome staining of central nuclei with splitting fibers. This progresses to enlargement of central nuclei, more intense splitting, and breakdown of fiber architecture. Final stages are characterized by total fiber necrosis and phagocytosis. The myopathy is more severe in the diaphragm, with 60% tonic, slow fibers, than it is in the soleus, with a majority of intermediate fibers, or the gastrocnemius, a fast white muscle. Maximal inhibition of ChE activity in the muscles occurred during the first 30 min after the initial Paraoxon treatment. Within 24 hr, there was significant recovery of enzyme activity. Evidence suggests there may be a critical period of inhibition of ChE activity to initiate the myopathic process. Results are discussed in terms of a possible nerve-mediated muscle necrosis.     

Retrograde and transganglionic degeneration of sensory neurons after a peripheral nerve lesion at birth

The sciatic nerve of newborn rats (less than or equal to 16 h old) was crushed with a watchmaker forceps. During the first 4 weeks after the injury, examination of ipsilateral L4 through L6 dorsal root ganglia, their dorsal nerve roots, and the dorsal funiculus revealed the presence of degenerating myelin and axons. Chromatolysis was not observed. In the spinal cord, the degenerating argyrophilia was restricted to the medial part of the dorsal funiculus (fasciculus gracilis). This is interpreted as transganglionic degeneration of the central processes of the pseudounipolar cells. Twelve weeks after nerve crush, there was a noticeable reduction in the size of the leg, foot, and muscles innervated by the sciatic nerve as well as a substantial loss (P less than 0.001) of neurons and myelinated axons in ipsilateral spinal ganglia and their dorsal nerve roots. The reduction was most prominent among the larger sensory neurons (greater than 40 microns) and the larger myelinated axons. A total loss of about 60% of sensory neurons was found in the L4 through L6 spinal ganglia. About 58 and 64% of the myelinated axons were lost in L4 and L5 dorsal roots, respectively. The remaining perikarya and dorsal root axons were hypoplastic.     

The myopathology of the Kocher-Debré-Sémélaigne syndrome: Electromyography,light- and electron-microscopic study

Clinical features as well as light and electron microscopy of muscle are described in 7 children with the Kocher-Debré-Sémélaigne syndrome (KDS) and in 3 children with cretinism but no muscular hypertrophy. Electromyography revealed a myopathic pattern in all 6 tested children with the KDS and was normal in the 1 tested child with cretinism and no muscle hypertrophy. Conventional light microscopy revealed central nucleation, variation in muscle fibre size and shape and abortive spiral annulets. No abnormalities were seen at this level of resolution in the 3 cretins with no clinical evidence of muscular hypertrophy. High resolution light microscopy and electron microscopy revealed abnormalities in muscle of KDS children as well as those without muscular hypertrophy. Electron-microscopic alterations included glycogen and mitocondrial aggregates, dilated sarcoplasmic reticulum profiles, honeycomb configurations of membrane profiles, ringbinden, Z-line irregularities as well as varying degrees of myofilamentous loss and disarray. Neuromuscular junctions were normal. Our findings are contrasted with those in the literature. Experimental evidence, possibly relating some of the observed alterations to the hypothyroid state, are cited from the literature. It is concluded that the myopathology of KDS is variable and nonspecific and that pathological alterations do occur in muscles of cretins without concomitant clinical muscular hypertrophy.     

HLA antigens and myasthenia gravis in Japan

Recent studies have noted an increased association of the histocompatibility antigen HLA-B8 with myasthenia gravis in Caucasian patients.The HLA types of 63 Japanese patients with myasthenia were compared to those of 271 controls. The present study was designed to assess correlations between HLA antigens, sex, age at onset, the presence of autoantibodies and thymic morphology.HLA-B12 was increased in Japanese patients, especially females with early age at onset, and in addition it was significantly correlated with thymic hyperplasia. HLA-B5 was frequently found in the patients with thymoma. Statistically the most frequent haplotype found in this disease was HLA-A10–HLA-B12.     

Disulfiram neuropathy. A morphometric study of sural nerve

This report describes peripheral nerve morphology in 3 patients whose acute polyneuropathy followed disulfiram therapy. In all patients a combination of axonal degeneration with segmental demyelination and remyelination was seen, suggesting a varying degree of toxicity to both cytons and Schwann cells. The observed randomness of abnormal internodes argued against primary axonal atrophy and secondary demyelination. While large myelinated fibres were preferentially lost, ultrastructural studies also suggested degeneration of unmyelinated fibres. Because of high chloral consumption at the onset of peripheral nerve disease in 2 patients, the possibility of disulfiram-chloral interaction was considered. Present evidence suggests that the combined use of chloral or its derivatives with disulfiram is best avoided.     

Amyloid neuropathy in multiple myeloma and other plasma cell dyscrasias: A hypothesis of the pathogenesis of amyloid neuropathies

The development of amyloid neuropathy is an uncommon complication of multiple myeloma. The clinical, electrophysiological and pathological features of 3 such patients are described. The small fiber neuropathy in these 3 cases was similar to that in patients with primary amyloidosis and with the Andrade-type of familial neuropathy, and differed from the large fiber neuropathy which more commonly develops in patients with multiple myeloma. We advance the hypothesis that the absence of the blood-nerve barrier in the dorsal root and sympathetic ganglia allows the access of amyloidogenic proteins to these ganglia, and that these ganglia are the primary site of damage to the peripheral nervous system in the amyloid neuropathies.