Arthur J. Hudson

Pain perception and response: central nervous system mechanisms.

Although several decades of studies have detailed peripheral and ascending nociceptive pathways to the thalamus and cerebral cortex, pain is a symptom that has remained difficult to characterize anatomically and physiologically. Positron emission tomography (PET) and functional magnetic imaging (fMRI) have recently demonstrated a number of cerebral and brain stem loci responding to cutaneous noxious stimuli. However, intersubject variability, both in the frequency and increased or decreased intensity of the responses, has caused uncertainty as to their significance. Nevertheless, the large number of available imaging studies have shown that many areas with recognized functions are frequently affected by painful stimuli. With this evidence and recent developments in tracing central nervous system connections between areas responding to noxious stimuli, it is possible to identify nociceptive pathways that are within, or contribute to, afferent spino-thalamo-cortical sensory and efferent skeletomotor and autonomic motor systems. In this study it is proposed that cortical and nuclear mechanisms for pain perception and response are hierarchically arranged with the prefrontal cortex at its highest level. Nevertheless, all components make particular contributions without which certain nociceptive failures can occur, as in pathological pain arising in some cases of nervous system injury.

Clinicopathological features of primary lateral sclerosis are different from amyotrophic lateral sclerosis

Primary lateral sclerosis (PLS) bears close resemblance to cases of amyotrophic lateral sclerosis (ALS) presenting with spasticity, but histopathological studies have shown significant difference between the two conditions. When the lower motor neurons in cases of ALS and PLS are compared with the equivalent cells of control subjects, morphometric studies indicate significantly decreased size and increased convexity (rounding) of the cell bodies only in ALS. In both disorders there is loss or shrinkage of the largest cortical motor neurons (Betz cells) in the primary motor cortex, though this change is not conspicuous in all cases of ALS. Morphometry reveals in both diseases a general reduction in the sizes of pyramidal cells in the precentral gyrus, indicating that smaller neurons are involved. The cortical motor neurons shrink more in PLS than in ALS. It is concluded that there is clear difference between ALS and PLS. In PLS, quantitative histopathological data show that the neuronal degeneration is confined to long descending pathways, notably the corticospinal system, with no concomitant involvement of lower motor neurons. In ALS, lower motor neuron degeneration occurs in all cases, whereas involvement of the motor cortex is variable.

Myopathy in primary familial hyperparathyroidism: Clinical and morphologic studies

Two female siblings with myopathy associated with primary hyperparathyroidism are described. Clinical features were similar in both, with fatigue, wasting and weakness of the quadriceps muscles, intact deep tendon reflexes (including the patellar reflex) and skeletal pain. Following removal of a parathyroid adenoma, both patients showed recovery of muscle bulk and strength except for minimal residual weakness of the quadriceps muscles in one. Light and electron microscopic studies of muscle showed a moderate atrophy of some muscle fibers, degenerative and regenerative muscle changes, and thickening of arterioles and of the basement membrane of the smallest endomysial vessels, particularly capillaries. The factors that may be relevant to the pathogenesis of these thickenings and myopathy are discussed. It is emphasized that the morphologic changes are nonspecific, and therefore further studies are required to determine the etiology and pathogenesis of the myopathy in hyperparathyroidism.

Fatty acid oxidation by skeletal muscle mithochondria in duchenne dystrophy

Abstract In a study of palmitate oxidation by skeletal muscle mitochondria in Duchenne muscular dystrophy, it was found that in cases with a family history of sex-linked recessive inheritance palmitate oxidation was markedly reduced whereas in isolated cases the values were essentially normal. Reduced values of palmitate oxidation were also observed in the definite female carriers o the sex-linked dystrophic gene. These findings suggest that isolated cases may have a different disorder from the cases of familial Duchenne muscular dytrophy.

Similarities of Guamanian ALS/PD to Post-Encephalitic Parkinsonism/ALS: Possible Viral Cause

Guamanian amyotrophic lateral sclerosis with parkinsonism-dementia (ALS/PD) has been the subject of intensive study since its discovery in 1947 because of its extraordinarily high incidence in a small ethnic group (Chamorros) whose dietary lack and customs have suggested possible causes. As yet, these and other suspected causes have eluded proof. Because of marked similarities between Guamanian ALS/PD and late onset post-encephalitic (encephalitis lethargica) parkinsonism and ALS it is suggested that they have a common cause. The parkinsonism and ALS in the two disorders are clinically very similar and neuropathological studies have shown a very similar distribution of neurofibrillary tangles in neurons. Some clinical differences, such as ocular features in the post-encephalitic cases and dementia in Guamanian ALS/PD, can be explained by differences in the severity of infection and the interval between the encephalitis and onset of sequelae. Although unproven, influenza A (HswilN1 strain) has long been suspected as the cause of encephalitis lethargica because of simultaneous pandemics of the two diseases in the 1920s. Because influenza A can persistently infect cells and has a marked propensity to mutate it is an optimal candidate among other RNA viruses for delayed nervous system infection as a possible cause of ALS/PD.

Gerstmann-Sträussler-Scheinker disease with coincidental familial onset

A family with Gerstmann-Straussler-Scheinker disease had coincidental clinical onset in three members of two generations, a phenomenon suggesting a common source of a transmissible agent. A regular dietary supplement in this family was home-bred rabbit. The clinical picture, although generally similar to that in previous accounts, included the unusual findings of visual loss (one patient) and sensory loss (one patient), and dementia was not apparent until late in the illness in two patients. Pathological examination of a cerebellar cortical biopsy specimen from one patient and postmortem tissue from two patients revealed multicentric amyloid plaques located in cerebral and cerebellar cortex, basal ganglia, and white matter with degeneration of corticospinal, dorsal spinocerebellar, dentatorubral, and geniculocalcarine tracts and dorsal columns. Spongiform change was focal and confined to the superficial cerebral cortical layers.

Amyotrophic Lateral Sclerosis/Parkinsonism/Dementia: Clinico-Pathological Correlations Relevant to Guamanian ALS/PD

In a recent report on the clinical and pathological features of Guamanian ALS/PD and post-encephalitic parkinsonism/ALS a number of similarities were described, notably in the distribution of neurofibrillary tangles throughout the nervous system. In this account additional pathological features which these disorders share (and which differ from classical ALS, Parkinsons and Alzheimers diseases) are described. These include atrophy of the globus pallidus and the entire substantia nigra, viz. pars compacta and pars reticulata. Moreover, neither Lewy bodies nor senile plaques are features of the Guamanian and post-encephalitic disorders. The significance of these observations and their relationship, more generally, to parkinsonism, ALS and dementia are discussed.

Triglyceride metabolism in skeletal muscle from normal and dystrophic mice.

Abstract 1. 1. Optimal conditions were established and measurements were made of the capacity of homogenates of skeletal muscle from normal and dystrophic mice (Strain 129) to incorporate [1- 14 C]palmitate or sn -[1- 14 C ]glycerol-3- P into triglycerides and phospholipids. 2. 2. sn -[1- 14 C ]Glycerol-3- P was incorporated into the triglycerides and phospholipids to about the same extent in both normal and dystrophic muscle. Similarly no difference was observed in the incorporation of [1- 14 C]palmitate into the phospholipids. The incorporation of [l- 14 C]palmitate into the triglycerides showed a slight increase in the muscle of dystrophic mice. The data obtained were consistent with the view that no quantitative differences appear to exist in the de novo synthesis of triglycerides and phospholipids in normal and dystrophic muscle. Suggestive evidence was obtained of an increased exchange of free fatty acid with the fatty acid of triglycerides in dystrophic muscle. 3. 3. The capacity of skeletal muscle homogenates from normal and dystrophic mice (Strain 129) to carry out the hydrolysis of tributyrin and tripalmitin has been studied. 4. 4. Evidence based on studies with inhibitors suggested the possible existence of two different lipases which are responsible for the hydrolysis of these two substrates. One is termed a “short-chain triglyceride lipase” which catalyses the hydrolysis of tributyrin and the second, a “long-chain triglyceride lipase” which catalyses the hydrolysis of tripalmitin. 5. 5. The long-chain triglyceride lipase (“tripalmitinase”) had an optimal pH of 6.5. Previous treatment of muscle preparation with the non-ionic detergent, Cutscum, was necessary. The addition of albumin had no effect. The enzyme activity was shown to sediment in the 90000 × g pellet. 6. 6. Skeletal muscle from dystrophic mice was found to have significantly elevated short-chain (125 %) and long-chain (minimal value of 52 %) triglyceride lipase activities compared to the activities of the corresponding littermate controls.

Insulin binding to myotonic dystrophy fibroblasts.

Insulin receptor binding was examined in cultured skin fibroblasts from 10 myotonic dystrophy patients and 10 age- and sex-matched control subjects. The conditions for insulin binding to fibroblasts were optimal and employed HEPES binding buffer, pH 8.0 at 15 degrees C for 5 h. These conditions correspond to those previously employed with monocytes from MyD subjects. The normalized initial insulin binding capacity showed a decrease of 62% from 5.04 +/- 0.28% of the total labeled insulin added/mg protein in the control to 1.93 +/- 0.13% in the myotonic dystrophy group (P less than 0.01) due mainly to a marked reduction in high affinity receptors or in receptor affinity. The addition of 1.0 ng/ml of unlabeled insulin produced significant decreases to 3.80 +/- 0.25% in the control group and 1.24 +/- 0.09% in the MyD group. The results are similar to previously reported findings with monocytes from myotonic dystrophy patients and suggest that a surface membrane defect exists in this disease. However, the conditions that have been employed in the binding procedures in all of the studies, while optimal, are performed at a high pH and low temperature and could have an important bearing on the interpretation of a membrane disorder.

Anti-neurone antibodies are not characteristic of amyotrophic lateral sclerosis

AUTOANTIBODIES, a suggested cause of motor neurone degeneration in amyotrophic lateral sclerosis (ALS), were sought immunohistochemically after applying diluted sera to sections of normal human spinal cord. Serum from a case of paraneoplastic motor neurone disease provided a positive control, giving strong staining of motor neurones for IgG but not IgM. The sera of 11 of 21 ALS patients contained IgG that could bind to motor neurones, but similar antibodies occurred also in 5 of 8 subjects with other nervous system disorders and in 3 of 9 neurologically normal controls. Bound IgM was more weakly stained than IgG, and was seen as often with control as with ALS sera. These findings do not support the notion that humoral autoantibodies mediate neuronal destruction in ALS.