Biomedical subjects
Publications and source records attributed to M C Brown.
Macrophages are not only phagocytic cells but also secrete a plethora of growth factors that are potentially important for regeneration. This review will examine the emerging evidence of a likely contribution by macrophages to axonal regeneration.
The rate of Wallerian degeneration is unusually slow in severed axons of mice of the C57BL/Ola strain. Within mice of that strain we have now found that the rate of degeneration increases with the age of the animal. In 4-week-old mice nerve stimulation evokes muscle contractions even 5 days after sciatic nerve section and compound action potentials can be recorded in the distal nerve stump up to 3 weeks after section. In 1-year-old animals no action potentials can be excited 5 days after nerve section. Heterozygous mice carrying only one copy of the dominant gene show the same age-related decline in viability of the distal nerve stump after axotomy, and the rate of decline is no greater than for homozygous mice. The more rapid rate of degeneration of severed axons of mice of the C57BL/6J strain was affected in the opposite way by age, degeneration occurring more slowly in older animals.
Wistar rats maintained on a 12-hr daily photoperiod (LD 12:12 cycle) exhibited a diurnal rhythm in urinary 6-sulphatoxymelatonin (aMT6s) concentrations with peak levels in the scotophase. Light-induced functional pinealectomy (FPX) abolished the nocturnal rise in aMT6s, lowering it to photophase levels. The objective of the study was to formulate an oral melatonin replacement regimen that would restore a normal rhythmic output of urinary aMT6s in functionally pinealectomised rats. Three regimens of sequential doses of melatonin were tested. Of these, the regimen with melatonin concentrations of 4 ng, 12 ng, 65 ng, and 4 ng per ml of drinking water given to rats during the 1st, 2nd, 3rd, and 4th 3-hr periods, respectively, of the 12-hr FPX phase, was found to generate a urinary aMT6s level that closely resembled the natural level and rhythm exhibited under an LD 12:12 cycle. This dose is considered appropriate to restore certain melatonin-mediated physiological functions in Wistar rats subjected to FPX.
Stress is a significant threat to the physical and emotional health of contemporary American women. Primary health care providers are an excellent resource for women in need of education about the seriousness of stress. Clinicians can work with women to prevent unnecessary exposure to stressors and to help them learn adaptive coping skills. This article offers a practical, step-by-step approach to stress management for women. Assessment processes, planning concepts and relevant intervention strategies are discussed.
Membrane cofactor protein (MCP) (CD46) of the C system binds to C3b and C4b, functions as a cofactor for their cleavage, and protects autologous cells from C-mediated injury. The predominant structural motif of MCP is the short consensus repeat (SCR), a repeating domain involved in ligand binding of other related C regulatory proteins. SCR deletion mutants were constructed to determine which of the four SCR of MCP contribute to ligand binding and cofactor activity. ELISA were developed to evaluate binding efficiency of mutants to ligand. Analysis of the deletion mutants indicated that the third and fourth SCR were important for both ligand binding and cofactor activity of C3b (iC3) and C4b. In addition, the same SCR were required for efficient binding of an mAb known to inhibit MCP function. The mutant deleted of SCR-2 bound but lacked cofactor activity for iC3. It did not bind or possess cofactor activity for C4b. Deletion of the first (amino-terminal) SCR had a minimal effect on iC3 binding and cofactor activity but reduced the efficiency of C4b binding. The results identify the SCR of MCP that contribute to ligand binding and cofactor activity. The data also suggest the presence of distinguishable iC3 and C4b binding sites and provide evidence that iC3 binding is not always sufficient for cofactor activity.
Erythrocytes (E) lacking high incidence blood group antigens were screened by an antiglobulin test with a monoclonal antibody to human complement receptor type 1 (CR1; C3b/C4b receptor; CD35). Some examples of E lacking Knops, McCoy, Swain-Langley, and York antigens, a serologically related group, were not agglutinated. Moreover, E of the null phenotype for these same antigens were nonreactive. To further explore this relationship, E expressing these antigens were surface labeled, solubilized, and incubated with the corresponding blood group-specific antisera. CR1 was immunoprecipitated, indicating that the epitopes recognized by each of these antisera are expressed on CR1. E of two individuals, putative null phenotypes for the Knops, McCoy, and Swain-Langley blood group antigens, expressed a very low number of CR1 (less than 30/E; approximately 10% of the normal mean). This observation accounts for their lack of reactivity in the antiglobulin test and their prior designation as null phenotypes. Also, the previously reported low as well as variable expression of CR1 on E explains prior difficulties in the serologic analyses of these blood group antigens.
Olivocochlear neurons have somata in the superior olivary complex and provide an efferent innervation to the cochlea. One subgroup of olivocochlear neurons, medial olivocochlear neurons, sends fibers to innervate the cochlear outer hair cells. En route to the cochlea, medial olivocochlear fibers give off branches to the ventral cochlear nucleus, the first auditory center of the brain. This study examines the cochlear-nucleus branches of medial olivocochlear fibers, comparing those from fibers that innervate the cochlear base with those from fibers that innervate the cochlear apex. Basal fibers give off dorsal branches to the granule cell lamina and ventral branches to the auditory nerve root. Apical fibers give off few dorsal branches but many ventral branches that terminate rostrally to the nerve root. This cochleotopic mapping of medial olivocochlear branches corresponds in a general way to that of afferent fibers. Unlike afferent fibers, however, the branches terminate primarily along the edges of the cochlear nucleus. In the mouse, the particular edges of termination are (1) the medial border of the ventral cochlear nucleus where it meets the underlying vestibular nerve root, and (2) the border between the ventral cochlear nucleus and the granule cell lamina. Neurons and dendrites of these border regions may thus integrate efferent and afferent information in a frequency-specific manner.
The ability of actinomycin D, a known antineoplastic agent, to affect NK1 NK2 and NK3 tachykinin (TK) receptor types was assessed on several in vitro bioassays. Actinomycin D was completely ineffective as a TK antagonist in the guinea-pig ileum longitudinal muscle (GPI) and on the rat portal vein (RPV) (two issues containing NK1, and NK3 TK receptors, respectively) while it was a weak competitive antagonist in the endothelium-denuded rabbit pulmonary artery (RPA) and in the hamster trachea (HT) (tissues containing the NK2A and NK2B receptor subtypes, respectively). Furthermore actinomycin D was able to displace [125I]-His-NKA from NK2 receptor sites of the rat small intestine smooth muscle membranes. Although actinomycin D is about 3 orders of magnitude weaker as an NK2 antagonist as compared to the most effective ligands available, it could represent a starting point in the development of non-peptidic NK2 receptor antagonists.
Muscle fibre areas and numbers, tetanic force, resident macrophage numbers and acetylcholine sensitivity were measured in normal and denervated soleus muscles of C57BL/Ola mice for comparison with data from outbred and other inbred strains. Serum creatine kinase levels were also measured. The muscles of normal C57BL/Ola mice had more fibres, generated more tension, had fewer resident macrophages and had a lower acetylcholine sensitivity than muscles of other strains. The normal level of serum creatine kinase was lower in C57BL/Ola mice than in Balb/c mice. Following denervation, the mean cross-sectional area of muscle fibres in Balb/c mice started to fall from day 1 but a fall was not seen in muscles from C57BL/Ola mice until day 5. The development of increased acetylcholine sensitivity was slower in the C57BL/Ola mice although the values in all mouse strains had converged by five days. The levels of serum creatine kinase also rose more slowly following denervation in C57BL/Ola mice. The differences between the data from C57BL/Ola mice and others are ascribed to the slow rate of Wallerian degeneration in that strain. The results support the view that the effects of denervation on muscle are due to both inactivity and an inflammatory effect contributed by nerve degeneration. The mutation that causes slow nerve degeneration may, however, also affect muscle directly, making it more resistant to catabolism.
The levels of NGF and NGF receptor mRNA, the degree of macrophage recruitment, and the ability of sensory and motor axons to regenerate were measured in C57BL/Ola mice, in which Wallerian degeneration following a nerve lesion is very slow. Results were compared with those from C57BL/6J and BALB/c mice, in which degeneration is normal. We found that in C57BL/Ola mice, apart from the actual lesion site, recruitment of macrophages was much lower, levels of mRNA for both NGF and its receptor were raised only slightly above normal, and sensory axon regeneration was much impaired. Motor axons regenerated quite well. These results provide in vivo evidence that macrophage recruitment is an important component of NGF synthesis and of sensory (but not motor) axon maintenance and regrowth.
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Wallerian degeneration is very slow in the mouse strain now known as C57BL/Ola. Sensory axon regrowth following peripheral nerve lesions is very poor in these animals but motor axons succeed in reinnervating the distal nerve stump even while the majority of severed axons are still intact (Lunn et al., Eur. J. Neurosci., 1, 27 - 33, 1989). To see if motor axons could grow into a completely undegenerated portion of nerve, the proximal stumps of the peroneal and tibial nerves were sutured together in six BALB/c mice and the ability of large motor and sensory fibres from the tibial nerve to grow into the peroneal nerve was examined electrophysiologically in four of them. For the acute experiment the peroneal nerve was cut approximately 7 mm central to the point of suture to the tibial nerve. Both at 2 weeks and 7 weeks after surgery the size of the potential recorded in the ventral roots on stimulating the portion of peroneal nerve into which tibial axons were directed to grow was only approximately 8% of the potential recorded when the tibial nerve was itself stimulated. The potential recorded in the dorsal roots was only approximately 2%. Counts of axon numbers in electron micrographs showed a small but non-significant increase over normal in the number of unmyelinated axons in the peroneal nerves which had been connected to the tibial nerve in this way. It is concluded, in agreement with Langley and Anderson (J. Physiol., 31, 365 - 391, 1904), that axon growth into intact nerves is extremely limited in mammals and that the distal nerve stump of C57BL/Ola mice, although it degenerates very slowly, is not therefore equivalent to an intact peripheral nerve.
Wallerian degeneration following peripheral nerve transection in C57BL/Ola mice is very slow in comparison to other strains of mice. We show that following optic nerve transection, the axons of retinal ganglion cells in C57BL/Ola mice undergo very slow Wallerian degeneration and that retrograde degeneration of the ganglion cell bodies is much slower than in other strains of mice. The results suggest that the gene product affecting Wallerian degeneration in the peripheral nervous system (PNS) also confers a greater resistance to degeneration on central nervous system (CNS) neurons.
We examined the effects of anticholinergic medication on memory function in 113 patients with idiopathic Parkinson's disease (PD). Subjects were divided into three disease duration groups: early, middle, and advanced. The battery consisted of three tasks assessing memory of logical discourse, semantically related words, and figural material. We found no evidence of anticholinergic-induced memory dysfunction in any of the three groups. Analysis of covariance indicated that age was not a significant variable; however, dementia may have influenced the relationship between anticholinergic medication and memory scores. Our results indicate that anticholinergic medication does not uniformly compromise memory function in PD patients.
We explored the nature of the visuospatial deficit in Parkinson's disease (PD) and its progression as a function of disease duration. We compared the performance of 183 patients with idiopathic PD and 90 control subjects matched for age and education on six visuospatial measures. We divided patients into three groups according to the disease duration: early (1 to 4 years), middle (5 to 10 years), and advanced (greater than 10 years). Performance deteriorated in five of the six visuospatial measures, as a function of disease duration. However, the pattern of visuospatial decline depended on whether dementia was present. The results were not influenced by age or anticholinergic medication. These findings support the presence of visuospatial deficits in PD patients, with a changing pattern of impairment related to dementia and progression of the disease.
Cochlear nucleus branches of thick olivocochlear axons were labeled by injections of horseradish peroxidase into the spiral ganglion of the cochlear basal turn in mice. Six labeled axons were traced by light microscopy, and selected portions of seven branches were sectioned serially for electron microscopic examination. Axonal branches most frequently terminated near certain granule cell regions of the ventral cochlear nucleus. This article describes terminals, synapses, and postsynaptic elements of these olivocochlear branches. The olivocochlear branches had both terminal and en passant boutons that contained round vesicles and made asymmetric synapses with other neuronal processes. About a quarter of the synapses also possessed additional specializations, postsynaptic, or subjunctional bodies. Mossy terminals, a multisynaptic type of terminal commonly found in granule cell regions, were not found arising from any of the labeled branches. No somatic synapses were found, although contacts with cell bodies were occasionally observed. The predominant synaptic target of olivocochlear branches were what appeared to be dendrites of large diameter. At least some of these large dendrites received multiple synapses from a single labeled olivocochlear branch. The morphological characteristics of reconstructed dendrites suggest that multipolar cells might be predominant targets for the medial olivocochlear system in the cochlear nucleus. This was demonstrated in one case in which a large dendrite was followed to its cell body of origin.
Soluble interleukin-2 receptor (sIL-2R) levels were quantitated in the serum and synovial fluid (SF) of patients with rheumatoid arthritis (RA) and degenerative joint disease (DJD). A sandwich immunoassay, employing two monoclonal antibodies against distinct epitopes on the IL-2R, was utilized for measurement. We found a striking elevation of sIL-2R in RA SF as compared with DJD SF (RA, 1319 +/- 135; DJD, 416 +/- 59; p less than 0.001). RA serum sIL-2R levels were also significantly elevated over DJD levels. There was no interaction between rheumatoid factor (RF) and sIL-2R. RA patients with elevated sIL-2R levels had significantly longer disease duration, higher c-reactive protein (CRP) levels in serum and SF, and higher RF levels in serum and SF. The groups were similar in regard to other laboratory variables. The presence of elevated levels of sIL-2R in RA serum and SF confirms the presence of a heightened immune reactivity and in vivo activation of lymphocytes in RA.