The central nervous system in systemic lupus erythematosus. Part 1. Clinical syndromes: a literature investigation

OBJECTIVES: To establish the central nervous system (CNS) manifestations of systemic lupus erythematosus (SLE) as described in the literature and to compare the results with two previously published classifications. METHODS: Using PUBMED, a systematic search was performed for publications from 1980 onwards on CNS syndromes of patients with SLE. A distinction was made between CNS syndromes induced by SLE and the CNS autoimmune diseases associated with SLE. Criteria were defined for inclusion of CNS syndromes or diseases as SLE-induced or SLE-associated. RESULTS: The literature search yielded names of 30 syndromes and two diseases, but only 16 syndromes and one disease fulfilled the set of predefined criteria. Two syndromes-depression and anxiety-were predominantly psychological in origin in most patients; other syndromes were biological. DISCUSSION: Strengths and weaknesses of two classifications of CNS syndromes are evaluated. The older of the two is long and has not been accepted fully. Brevity is an advantage of the American College of Rheumatology (ACR) nomenclature system. A disadvantage of this system is the concealment of differences in health risks by the pooling of items. Furthermore, the items of the system do not all belong to the same dimension: one is pathological and the others are clinical. To remedy these drawbacks, we suggest the rephrasing and subdivision of items and that the predominantly psychopathological syndromes should be dealt with separately in epidemiological studies. CONCLUSIONS: SLE may induce 16 different clinical syndromes of the CNS and is occasionally associated with one other CNS autoimmune disease. A modification of the ACR nomenclature system is proposed.     

Metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) by human cytochrome P4501B1

Cytochrome P4501B1 (CYP1B1) is the most recently identified member of the dioxin-inducible CYP1 family. CYP1B1 is constitutively expressed in most human tissues, including colon and breast, and can activate numerous chemically diverse carcinogens. We evaluated the metabolism of the dietary heterocyclic amine carcinogen 2-amino-1-methyl-6- phenylimidazo[4,5-b]pyridine (PhIP) by microsomes from yeast expressing the human CYP1B1 protein. PhIP metabolites were analysed by HPLC with fluorescence and absorbance detection. We found that human CYP1B1 metabolizes PhIP to three products: N2-OH-PhIP, a mutagenic activation product; 4'-OH-PhIP, a detoxification product; and 2-OH-PhIP, the mutagenic potential of which is unknown. Metabolite identity was confirmed by co-elution with authentic standards and synchronous fluorescence spectroscopy. The identity of the 2-OH-PhIP standard was additionally confirmed by mass spectrometry. Kinetic studies of the formation of N2-OH-PhIP, 4'-OH-PhIP and 2-OH-PhIP by CYP1B1 indicated apparent Km values of 5.7 +/- 1.3, 2.2 +/- 0.5 and 1.3 +/- 0.2 microM, respectively. Apparent turnover rates were 0.40 +/- 0.03, 0.93 +/- 0.02 and 0.04 +/- 0.00 nmol product/min nmol P450, respectively. At saturating levels of substrate, CYP1B1-mediated formation of the non- mutagenic metabolite 4'-OH-PhIP was favored two-fold over that of the mutagenic metabolite, N2-OH-PhIP and >10-fold over that of 2-OH-PhIP. The formation of N2-OH-PhIP, a potent mutagen implicated in the etiology of human colon and breast cancer, indicates that CYP1B1 may play an important role in PhIP-mediated carcinogenesis.      

Development of innervation of skeletal muscle fibers in man: Relation to acetylcholine receptors

The aim of this study was to establish the time scale of developmental changes in innervation of skeletal muscle fibers in man. Specimens of thigh and intercostal muscle from 19 embryos and 18 infants were examined with histological methods which enabled the discrimination between fetal (gamma) and adult (epsilon) types of acetylcholine receptors (AChRs). At 8 weeks of development, AChRs were distributed diffusely in the myotube membranes. Following onset of innervation in approximately the ninth week the length of the AChR positive area diminished and reached its shortest size at the sixteenth developmental week. At the sixteenth and eighteenth week some nerve terminals opposed the muscle membrane outside the AChR positive area. Decrease in the number of nerve terminals, strongly suggesting elimination of polyneuronal innervation, started in the sixteenth week and was completed in the twenty-fifth week. This fetal (gamma) type of AChR could no longer be demonstrated after the thirty-first week. The length of the end-plates as determined by the presence of AChRs increased again in the last week before birth and reached a plateau size by the end of the first year after birth. It is concluded that in man the transition from poly- to mononeuronal innervation takes place between the sixteenth and twenty-fifth weeks of development. The evidence available suggests that the retraction of nerve terminals is preceded by loss of AChRs from the muscle membrane facing the terminals. There is no relationship between retraction of nerve terminals and the switch from fetal to adult type of AChR. The size of the presynaptic apparatus changes little after the first year of life. © 1993 Wiley-Liss, Inc.     

Perisynaptic satellite cells in human external intercostal muscle: a quantitative and qualitative study

It is not known whether or not satellite cell nuclei are more common in the vicinity of motor endplates than in extrasynaptic regions of human muscle, as in animals. If so, perisynaptic satellite cells may have a role in preserving neuromuscular function. We compared the frequencies of satellite cell nuclei and of myonuclei in perisynaptic and extrasynaptic regions of human external intercostal muscle, and found an absolute as well as a relative increase of perisynaptic satellite cells. The mean frequency of satellite cell nuclei per sarcomere was 0.016 in perisynaptic and 0.00003 in extrasynaptic regions. The mean frequency of myonuclei per sarcomere was 0.098 in perisynaptic and 0.014 in extrasynaptic regions. We could not demonstrate any influence of aging on satellite cell distribution. Perisynaptic satellite cells had many processes, and some features suggested a more active state. These cells might add to the pool of junctional myonuclei for synthesis of acetylcholine-receptor molecules or help in the repair of the postsynaptic membrane. Alternatively, they may synthesize basal lamina substances that are specific for the endplate.     

Chronic idiopathic polyneuropathy presenting in middle or old age: a clinical and electrophysiological study of 75 patients.

The clinical and electrophysiological features were prospectively studied of 75 patients (46 men and 29 women) with chronic polyneuropathy presenting in middle or old age in whom a diagnosis could not be made even after extensive evaluation and a follow up of six months. The mean age at the onset of symptoms was 56.5 years. The clinical features of chronic idiopathic polyneuropathy are heterogeneous. On clinical grounds 44 patients had a sensorimotor, 29 patients a sensory, and two patients a motor polyneuropathy. The overall clinical course in chronic idiopathic polyneuropathy was slowly progressive. None of the patients became severely disabled. Electrophysiological and nerve biopsy studies were compatible with an axonal polyneuropathy. Antibodies against myelin associated glycoprotein, gangliosides, and sulphatides were assessed in 70 patients and found to be negative.     

Age-related changes in human thyroarytenoid muscles: a histological and histochemical study

We examined the thyroarytenoid muscles of 23 larynges in order to assess function-related characteristics and to discover age-related changes. The neonatal thyroarytenoid muscle differed from limb muscles in the slow maturation of fibre types. In adults, we examined the medial part of the thyroarytenoid muscle. It showed a larger variation in fibre size and more endomysial connective tissue than is common for limb muscles. Structural and histochemical evidence of ageing developed from approximately the 6th decade. It comprised a marked increase of endomysial connective tissue and striking myopathic changes of muscle fibres. Up to 20% of the muscle fibres showed at some places of some sections evidence of mitochondrial accumulations and increased mitochondrial enzyme activity (ragged red fibres). The rise of such ragged red fibres is commonly related to the development of mutations in mitochondrial DNA. Significant myopathic changes including mitochondrial abnormalities develop in the thyrovocalis muscle with age and may play a role in the functional deficit of the larynx in old age.     

Autosomal recessive form of hereditary motor and sensory neuropathy type I.

We studied pathologic changes in sural nerve biopsies from four patients with probable autosomal recessive (AR) hereditary motor and sensory neuropathy (HMSN) type I with a median motor nerve conduction velocity greater than 10 m/sec, comparing them with the pathologic features in autosomal dominant (AD) HMSN type I. The four recessive and two sporadic cases showed segmental demyelination. However, the classic onion bulbs of concentric Schwann cell processes, which occur in AD type I, were rare; many axons, also of a smaller size, were surrounded by onion bulbs of basal laminae. Schwann cells of the myelinated and unmyelinated types were involved in these onion bulb formations. Patients with HMSN type I who have many basal lamina onion bulbs should be considered as having AR inheritance.