ABSTRACT
Near-nerve needle sensory nerve conduction of plantar nerves in 100 patients with distal sensory neuropathy with normal routine nerve conduction (DSN-NNC) found the definite neuropathy pattern (abnormality in more than three of six tested nerves) in 65%, axonal neuropathy in 35%, and the known cause in 37% of patients. Absent or diminished reflexes were a reliable indicator for large fiber neuropathy (LFN). This near-nerve needle plantar nerve study provides useful and unequivocal evidence of its value in identifying neuropathy in DSN-NNC by finding LFN in 65% of patients.
Subject(s)
Neural Conduction , Neuritis/diagnosis , Neuritis/physiopathology , Tibial Neuropathy/diagnosis , Tibial Neuropathy/physiopathology , Action Potentials , Adult , Aged , Electromyography , Female , Humans , Male , Middle Aged , Proprioception , Prospective Studies , Retrospective StudiesABSTRACT
The involuntary movements of choreoathetotic type are commonly regarded as a sign of basal ganglia lesion. However, such movements can also occur in pathological processes involving the cervical spinal cord. This condition is referred to as pseudochoreoathetosis. Involuntary movements can be related to lack of proper coordination between agonist and antagonist muscles, their simultaneous activation due to impairment of reciprocal inhibition. The characteristic feature of pseudochoreoathetosis is proprioceptive sensory loss. In this paper we present 4 patients who developed various involuntary limb movements in early stage of the disease. Lesions in the cervical spinal cord were confirmed by MRI. In case 1 the cause was astrocytoma, in cases 2 and 3--demyelination, in case 4 the precise character of the lesion could not be established. Pseudochoreoathetosis is a rare condition which often remains unrecognized. The presented cases emphasise the importance of early and correct diagnosis leading to proper therapeutical procedure.
Subject(s)
Athetosis/etiology , Chorea/etiology , Spinal Cord Diseases/complications , Spinal Cord Diseases/diagnosis , Adult , Basal Ganglia Diseases/diagnosis , Diagnosis, Differential , Female , Humans , Magnetic Resonance Imaging , Radiography , Spinal Cord Diseases/diagnostic imagingABSTRACT
Highly related insulin response sequences (IRSs) mediate effects of insulin on the expression of multiple genes in the liver, including insulin-like growth factor binding protein-1 (IGFBP-1) and phosphoenolpyruvate carboxykinase (PEPCK). Gel shift studies reveal that oligonucleotide probes containing an IRS from the IGFBP-1 or PEPCK gene form a similar complex with hepatic nuclear proteins. Unlabeled competitors containing the IGFBP-1 or PEPCK IRS or a binding site for C/EBP proteins inhibit the formation of this complex. Antibody against C/EBPbeta (but not other C/EBP proteins) supershifts this complex, and Western blotting of affinity purified proteins confirms that C/EBPbeta is present in this complex. Studies with affinity purified and recombinant protein indicate that C/EBPbeta does not interact directly with the IRS, but that other factors are required. Gel shift assays and reporter gene studies with constructs containing point mutations within the IRS reveal that the ability to interact with factors required for the formation of this complex correlates well with the ability of insulin to regulate promoter activity via this IRS (r = 0.849, p < 0.01). Replacing the IRS in reporter gene constructs with a C/EBP-binding site (but not an HNF-3/forkhead site or cAMP response element) maintains the effect of insulin on promoter activity. Together, these findings indicate that a nucleoprotein complex containing C/EBPbeta interacts with IRSs from the IGFBP-1 and PEPCK genes in a sequence-specific fashion and may contribute to the ability of insulin to regulate gene expression.
Subject(s)
CCAAT-Enhancer-Binding Protein-alpha/physiology , Gene Expression Regulation/drug effects , Insulin-Like Growth Factor Binding Protein 1/genetics , Insulin/pharmacology , Response Elements , Binding Sites , Cell Line , Humans , Phosphoenolpyruvate Carboxykinase (ATP)/genetics , Promoter Regions, GeneticABSTRACT
CAAT/enhancer-binding proteins (C/EBPs) play an important role in the regulation of gene expression in insulin-responsive tissues. We have found that a complex containing C/EBPbeta interacts with an insulin response sequence in the insulin-like growth factor-binding protein-1 (IGFBP-1) gene and that a C/EBP-binding site can mediate effects of insulin on promoter activity. Here, we examined mechanisms mediating this effect of insulin. The ability of insulin to suppress promoter activity via a C/EBP-binding site is blocked by LY294002, a phosphatidylinositol 3-kinase inhibitor, but not by rapamycin, which blocks activation of p70(S6 kinase). Dominant negative phosphatidylinositol 3-kinase and protein kinase B (PKB) block the effect of insulin, while activated PKB suppresses promoter function via a C/EBP-binding site, mimicking the effect of insulin. Coexpression studies indicate that insulin and PKB suppress transactivation by C/EBPbeta, but not C/EBPalpha, and that N-terminal transactivation domains in C/EBPbeta are required. Studies with Gal4 fusion proteins reveal that insulin and PKB suppress transactivation by the major activation domain in C/EBPbeta (AD II), located between amino acids 31 and 83. Studies with E1A protein indicate that interaction with p300/CBP is required for transactivation by AD II and the effect of insulin and PKB. Based on a consensus sequence, we identified a PKB phosphorylation site (Ser(1834)) within the region of p300/CBP known to bind C/EBPbeta. Mammalian two-hybrid studies indicate that insulin and PKB disrupt interactions between this region of p300 and AD II and that Ser(1834) is critical for this effect. Signaling by PKB and phosphorylation of Ser(1834) may play an important role in modulating interactions between p300/CBP and transcription factors and mediate effects of insulin and related growth factors on gene expression.
Subject(s)
CCAAT-Enhancer-Binding Protein-beta/physiology , Insulin/pharmacology , Nuclear Proteins/physiology , Protein Serine-Threonine Kinases , Proto-Oncogene Proteins/physiology , Trans-Activators/physiology , Transcriptional Activation/drug effects , Amino Acid Sequence , CCAAT-Enhancer-Binding Proteins/physiology , Leucine Zippers , Molecular Sequence Data , Phosphoenolpyruvate Carboxykinase (ATP)/genetics , Promoter Regions, Genetic , Proto-Oncogene Proteins c-akt , Structure-Activity Relationship , Transcription Factor CHOP , Transcription Factors/physiologyABSTRACT
OBJECTIVES: The clinical manifestations of Wilson's disease (WD) take the form of hepatic, neurological, renal as well as hormonal disturbances. Infertility and amenorrhea are reported in women and hypogonadism in men with WD. Our study was designed to analyse the procreation abilities of patients with WD. MATERIAL AND METHODS: We investigated by a questionnaire the course of pregnancy and delivery in 31 untreated women (mean age 22.5 years, 82 pregnancies) and 15 women (mean age 26.2, 25 pregnancies,) treated with D-penicillamine (D-p) or zinc sulphate (ZnS). We studied also procreation ability of 27 men (mean age 27.2 years). We analysed the congenital abnormalities and frequency of WD in children of our patients. RESULTS: One of 10 untreated women had difficulties with conception. The number and type of pathology (imminent abortions, gestosis, stillbirth, preterm births) were similar in treated and untreated patients. In both mentioned groups the most frequent pathology were spontaneous abortions, which were found in 26% of untreated and in 26.6% of treated women. This percentage is higher than in general population. Most of deliveries in patients with WD were spontaneous. Neither developmental malformations nor serious disorders were noticed in the offspring of our treated patients, 3 children of untreated patients were born with congenital heart disease. In 78 of the 110 children of our patients we examined the copper metabolism and we diagnosed WD in 5 cases (from 3 families). Among 27 investigated men only 1 was impotent. CONCLUSION: The risk of complications during pregnancy in asymptomatic and treated patients is higher than in general population, but it does not make the procreation impossible.
Subject(s)
Fertility/physiology , Gonadal Disorders/etiology , Hepatolenticular Degeneration/complications , Adolescent , Adult , Erectile Dysfunction/etiology , Erectile Dysfunction/physiopathology , Female , Gonadal Disorders/physiopathology , Hepatolenticular Degeneration/physiopathology , Humans , Male , Middle Aged , Pregnancy , Pregnancy Complications/etiology , Pregnancy Complications/physiopathologyABSTRACT
Case fatality rates for stroke were ascertained prospectively in two regional catchment hospitals in Poland and 36 teaching hospitals in the US University Hospital Consortium. Case fatality rates in Poland (23.9%) were higher than in the United States (7.5%). Angina, atrial fibrillation, and congestive heart failure were more frequent in Polish stroke patients (40%, 26%, and 25%, respectively) than in US patients (17%, 12%, and 10%). Stroke severity as indicated by higher frequencies of hemiplegia, disordered consciousness, dysphagia, and aphasia was greater in Poland (19%, 39%, 28%, and 42%, respectively) than the United States (11%, 13%, 14%, and 26%).
Subject(s)
Brain Ischemia/mortality , Stroke/mortality , Adolescent , Aged , Cardiovascular Diseases/mortality , Female , Hospitalization , Humans , Male , Middle Aged , Muscle Weakness/mortality , Poland/epidemiology , Prospective Studies , Severity of Illness Index , United States/epidemiologyABSTRACT
Protein kinase B lies "downstream" of phosphatidylinositide (PtdIns) 3-kinase and is thought to mediate many of the intracellular actions of insulin and other growth factors. Here we show that FKHR, a human homologue of the DAF16 transcription factor in Caenorhabditis elegans, is rapidly phosphorylated by human protein kinase Balpha (PKBalpha) at Thr-24, Ser-256, and Ser-319 in vitro and at a much faster rate than BAD, which is thought to be a physiological substrate for PKB. The same three sites, which all lie in the canonical PKB consensus sequences (Arg-Xaa-Arg-Xaa-Xaa-(Ser/Thr)), became phosphorylated when FKHR was cotransfected with either PKB or PDK1 (an upstream activator of PKB). All three residues became phosphorylated when 293 cells were stimulated with insulin-like growth factor 1 (IGF-1). The IGF-1-induced phosphorylation was abolished by the PtdIns 3-kinase inhibitor wortmannin but not by PD 98059 (an inhibitor of the mitogen-activated protein kinase cascade) or by rapamycin. These results indicate that FKHR is a physiological substrate of PKB and that it may mediate some of the physiological effects of PKB on gene expression. DAF16 is known to be a component of a signaling pathway that has been partially dissected genetically and includes homologues of the insulin/IGF-1 receptor, PtdIns 3-kinase and PKB. The conservation of Thr-24, Ser-256, and Ser-319 and the sequences surrounding them in DAF16 therefore suggests that DAF16 is also a direct substrate for PKB in C. elegans.
Subject(s)
DNA-Binding Proteins/metabolism , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins , Transcription Factors/metabolism , 3-Phosphoinositide-Dependent Protein Kinases , Amino Acid Sequence , Androstadienes/pharmacology , Antibody Specificity , Caenorhabditis elegans Proteins , Carrier Proteins/metabolism , Consensus Sequence , DNA-Binding Proteins/genetics , DNA-Binding Proteins/immunology , Enzyme Activation , Forkhead Box Protein O1 , Forkhead Transcription Factors , Humans , Insulin-Like Growth Factor I/pharmacology , Molecular Sequence Data , Phosphoinositide-3 Kinase Inhibitors , Phosphorylation , Phosphoserine/immunology , Phosphothreonine/immunology , Protein Processing, Post-Translational , Protein Serine-Threonine Kinases/genetics , Proto-Oncogene Proteins c-akt , Recombinant Proteins/metabolism , Serine/metabolism , Signal Transduction , Sirolimus/pharmacology , Threonine/metabolism , Transcription Factors/genetics , Transcription Factors/immunology , Wortmannin , bcl-Associated Death ProteinABSTRACT
Insulin inhibits the expression of multiple genes in the liver containing an insulin response sequence (IRS) (CAAAA(C/T)AA), and we have reported that protein kinase B (PKB) mediates this effect of insulin. Genetic studies in Caenorhabditis elegans indicate that daf-16, a forkhead/winged-helix transcription factor, is a major target of the insulin receptor-PKB signaling pathway. FKHR, a human homologue of daf-16, contains three PKB sites and is expressed in the liver. Reporter gene studies in HepG2 hepatoma cells show that FKHR stimulates insulin-like growth factor-binding protein-1 promoter activity through an IRS, and introduction of IRSs confers this effect on a heterologous promoter. Insulin disrupts IRS-dependent transactivation by FKHR, and phosphorylation of Ser-256 by PKB is necessary and sufficient to mediate this effect. Antisense studies indicate that FKHR contributes to basal promoter function and is required to mediate effects of insulin and PKB on promoter activity via an IRS. To our knowledge, these results provide the first report that FKHR stimulates promoter activity through an IRS and that phosphorylation of FKHR by PKB mediates effects of insulin on gene expression. Signaling to FKHR-related forkhead proteins via PKB may provide an evolutionarily conserved mechanism by which insulin and related factors regulate gene expression.
Subject(s)
DNA-Binding Proteins/metabolism , Insulin-Like Growth Factor Binding Protein 1/biosynthesis , Insulin/pharmacology , Liver/metabolism , Protein Serine-Threonine Kinases , Proto-Oncogene Proteins/metabolism , Response Elements , Transcription Factors/metabolism , Amino Acid Sequence , Base Sequence , Conserved Sequence , DNA-Binding Proteins/genetics , Forkhead Box Protein O1 , Forkhead Transcription Factors , Humans , Insulin-Like Growth Factor Binding Protein 1/genetics , Liver/cytology , Nuclear Proteins/genetics , Phosphorylation , Promoter Regions, Genetic , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins c-akt , Recombinant Proteins/metabolism , Sequence Homology, Amino Acid , Signal Transduction , Transcription Factors/genetics , Transcriptional Activation , Tumor Cells, CulturedABSTRACT
TNF alpha and IL-1 alpha are thought to contribute to impaired anabolism in a variety of clinical states, including sepsis, cancer cachexia and the AIDS wasting syndrome. We asked whether cytokines exert direct effects on hepatic production of IGFBP-1, an important modulator of IGF bioavailability. C57BL/6 mice were treated with 100 micrograms/kg of recombinant IL-1 alpha or TNF alpha by intraperitoneal injection. Western ligand blotting and immunoprecipitation with specific antisera revealed that serum levels of IGFBP-1 (but not IGFBP-2, -3, -4, -5 or -6) are increased approximately 4 fold 2 h after treatment and then decline. Northern blotting confirms that hepatic IGFBP-1 mRNA abundance also is increased acutely in both IL-1 alpha- and TNF alpha-treated animals. Similar results obtained in adrenalectomized mice indicate that adrenal activation is not required for this effect. Cell culture studies show that cytokines exert direct effects on the production of IGFBP-1 by HepG2 hepatoma cells, increasing IGFBP-1 levels in conditioned medium and the abundance of IGFBP-1 mRNA approximately 3-fold. In contrast, transient transfection studies with IGFBP-1 promoter/luciferase reporter gene constructs show that IGFBP-1 promoter activity is reduced after 18 hr cytokine treatment. We conclude that IL-1 alpha and TNF alpha increase circulating levels of IGFBP-1, reflecting direct effects on hepatic IGFBP-1 mRNA abundance. Stimulation of hepatic IGFBP-1 production may contribute to alterations in IGF bioactivity and impaired anabolism in clinical conditions where cytokine production is high. Additional studies are required to identify specific mechanisms mediating effects of cytokines on hepatic production of IGFBP-1.
Subject(s)
Insulin-Like Growth Factor Binding Protein 1/blood , Insulin-Like Growth Factor Binding Protein 1/genetics , Interleukin-1/pharmacology , Tumor Necrosis Factor-alpha/pharmacology , Animals , Blotting, Northern , Carcinoma, Hepatocellular , Gene Expression/physiology , Hypoglycemic Agents/pharmacology , In Vitro Techniques , Insulin/pharmacology , Insulin-Like Growth Factor Binding Protein 2/blood , Insulin-Like Growth Factor Binding Protein 2/genetics , Insulin-Like Growth Factor Binding Protein 3/blood , Insulin-Like Growth Factor Binding Protein 3/genetics , Insulin-Like Growth Factor Binding Protein 4/blood , Insulin-Like Growth Factor Binding Protein 4/genetics , Insulin-Like Growth Factor Binding Protein 5/blood , Insulin-Like Growth Factor Binding Protein 5/genetics , Insulin-Like Growth Factor Binding Protein 6/blood , Insulin-Like Growth Factor Binding Protein 6/genetics , Liver/chemistry , Liver/metabolism , Male , Mice , Mice, Inbred C57BL , Promoter Regions, Genetic/physiology , RNA, Messenger/analysis , Tumor Cells, CulturedABSTRACT
In the paper authors gathered hitherto existing opinions concerning endothelin, its structure, biological role and mechanisms of action. A special attention was paid to children and the activity of endothelin in physiology and pathology in various stages of development.
Subject(s)
Endothelin-1/physiology , Adolescent , Burns/blood , Child , Child, Preschool , Endothelin-1/blood , Health Status , Humans , Infant , Tumor Necrosis Factor-alpha/physiologyABSTRACT
Insulin regulates the expression of multiple hepatic genes through a conserved insulin response sequence (IRS) (CAAAAC/TAA) by an as yet undetermined mechanism. Protein kinase B/Akt (PKB/Akt), a member of the PKA/PKC serine/threonine kinase family, functions downstream from phosphatidylinositol 3'-kinase (PI3K) in mediating effects of insulin on glucose transport and glycogen synthesis. We asked whether PKB/Akt mediates sequence-specific effects of insulin on hepatic gene expression using the model of the insulin-like growth factor binding protein-1 (IGFBP-1) promoter. Insulin lowers IGFBP-1 mRNA levels, inhibits IGFBP-1 promoter activity, and activates PKB/Akt in HepG2 hepatoma cells through a PI3K-dependent, rapamycin-insensitive mechanism. Constitutively active PI3K and PKB/Akt are each sufficient to mediate effects of insulin on the IGFBP-1 promoter in a nonadditive fashion. Dominant negative K179 PKB/Akt disrupts the ability of insulin and PI3K to activate PKB/Akt and to inhibit promoter activity. The IGFBP-1 promoter contains two IRSs each of which is sufficient to mediate sequence-specific effects of insulin, PI3K, and PKB/Akt on promoter activity. Highly related IRSs from the phosphoenolpyruvate carboxykinase and apolipoprotein CIII genes also are effective in this setting. These results indicate that PKB/Akt functions downstream from PI3K in mediating sequence-specific effects of insulin on the expression of IGFBP-1 and perhaps multiple hepatic genes through a conserved IRS.
Subject(s)
Insulin-Like Growth Factor Binding Protein 1/biosynthesis , Insulin/pharmacology , Liver/drug effects , Promoter Regions, Genetic , Protein Serine-Threonine Kinases , Proto-Oncogene Proteins/metabolism , Base Sequence , Conserved Sequence , Gene Expression Regulation , Humans , Insulin-Like Growth Factor Binding Protein 1/genetics , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt , RNA, Messenger/analysisABSTRACT
Somatosensory evoked potentials from median nerve (SEP-M) were examined bilaterally in 43 patients with a well delimited vascular foci in central somatosensory pathways. Scalp, far field, cervical, Erb potentials and conduction times were recorded in each patients. Five subgroups based on localization of foci (parietal cortex, corona radiata, internal capsule, thalamus and extensive subcortical--cortical hemispheric focus) were distinguished. The results from the unimpaired (n-38) and impaired (n-48) sides, focus subgroups and control healthy group were statistically compared. The attempt to establish a specific relationship between the SEP-M picture and site of the lesion gave a negative result. SEP-M changes were more pronounced in cases of very extensive axons run in a compact bundle (internal capsule). The SEP-M examination indicates only the degree of the central sensory system damage. Correlations between intensity SEP-M pathology and clinical sensory disturbances were found. SEP-M parameters on the unimpaired side differed significantly from those of the control group. Therefore the impaired side should not be used as a reference for evaluation of impaired side pathology. The diagnostic validity of far field potentials recordings in such investigations is stressed.
Subject(s)
Brain/physiopathology , Cerebrovascular Disorders/diagnosis , Evoked Potentials, Somatosensory , Adult , Aged , Axons , Cerebrovascular Disorders/physiopathology , Female , Humans , Male , Median Nerve , Middle Aged , Severity of Illness IndexABSTRACT
The influence of age and height on somatosensory evoked potentials (SEP) following median and tibial nerve stimulation was studied. Age correlated with increase of latencies and decrease of amplitudes; exceptionally the amplitude of cortical N20 component increased with age. The central conduction time P31-P40 (tibial nerve stimulation) was longer in elderly subjects, whereas the time N13-N20 (median nerve stimulation) was independent of age. Height showed a positive correlation with latencies and peripheral conduction times; central conduction times (N13-N20 and P31-P40) were independent on height. The correlations of SEP parameters with age and height were expressed quantitatively by regression equations. The presented equations should be treated as a valuable complement to normative data in interpretation of SEP testing results.
Subject(s)
Aging/physiology , Body Height/physiology , Evoked Potentials, Somatosensory/physiology , Median Nerve/physiology , Models, Neurological , Tibial Nerve/physiology , Adult , Electric Stimulation , Female , Humans , Male , Middle Aged , Neural Conduction/physiologyABSTRACT
The study was performed on 62 healthy volunteers (123 nerves) using standard technical parameters. In every case the median nerve was stimulated at the level of II + III fingers and at the wrist. This enabled us to compare potentials evoked by sensory versus mixed nerve stimulation. It has been shown that a reliable evaluation of the somatosensory system is provided by stimulation of mixed nerve. The following montage seems to be the most useful in routine diagnosis. Erb's point - Erb's point, C VII - Fz, Fz - Shoulder, C3,4 - Fz. Additionally, according to clinical situation. C VII - Shoulder and C II - Fz derivations may be used. The Fz - Shoulder derivation enables to record far-field potentials and to control the effect of Fz reference on the waveform of potentials in order derivations. In the study normal values of the main median nerve SEP parameters are presented.
Subject(s)
Evoked Potentials, Somatosensory/physiology , Median Nerve/physiology , Models, Neurological , Synaptic Transmission/physiology , Adolescent , Adult , Aged , Arm/innervation , Female , Humans , Male , Middle Aged , Shoulder/innervationABSTRACT
60 healthy volunteers ranging in age from 15 to 75 years participated in the study. Tibial nerve was stimulated unilaterally or bilaterally at the ankle and SEPs were recorded along the somatosensory pathway. Determination and readability of the potentials were evaluated according to the stimulating and recording method. After unilateral stimulation, the following derivation system was regarded as most useful in routine testing: L4 - Ic (iliac crest), Th12 - Ic, Cz' - Fz, Fz - Shoulder (and, if possible C7 - Fz). When more detailed spinal cord diagnosis is indicated, bilateral stimulation and recording in montage: Th6 - Shoulder, C7 - Shoulder, C7 - Fz, Fz - Shoulder may be helpful. In the study normal values of parameters of the potentials from certain derivations were presented: latencies, amplitudes, peripheral conduction velocities and central conduction times were taken into account. According to our own results (correlative analysis of SEP parameters) and the results of other authors, interpretation of the potentials on various levels of the ascending somatosensory pathway was discussed.
Subject(s)
Evoked Potentials, Somatosensory/physiology , Models, Biological , Synaptic Transmission/physiology , Tibial Nerve/physiology , Adolescent , Adult , Aged , Female , Humans , Leg/innervation , Male , Middle Aged , Spine/innervationABSTRACT
The here presented case was a woman 82 years old suffering for many years of arteriosclerotic Parkinson syndrome. During the last 8 months of her life she exhibited excessive talk flow and states of delirium. Twelve days before death she had a generalized attack of convulsions and the consciousness disorder increased. Moreover, meningeal symptoms were observed, a right side reflex syndrome with Babinski sign and temperature up to 38 degrees C were noted. Death occurred on the 9th day of hospitalization with symptoms of increasing circulatory-respiratory insufficiency. Pathomorphological examination revealed in the myocardium, lungs, liver, kidneys and thyroid multiple purulent foci containing actinomycotic granules. Neuropathological examination revealed both in the cortex and white matter the presence of numerous disseminate bodies staining intensively with HE, PAS- and Gram-Weigert positive and negative in the Ziehl-Nielsen method. Their structure, compact or fine-powdered corresponded to actinomyces colonies. They either showed no reaction or were surrounded by a wall of inflammatory cells such as: neutrophilic leucocytes, lymphocytes, plasmatic cells and histiocytes. The microabscesses were not encapsulated. The case was classified to a diffuse form of brain actinomycosis. The etiopathogenesis of the changes and the clinical-morphological correlations of this very rare infectious disease of the central nervous system are discussed.