Biomedical subjects

C Hildebrand

Publications and source records attributed to C Hildebrand.

At least 73 records · Page 4Linked to original sources

PubMed1993

Functional projection of regenerated rat sural nerve axons to the hindpaw skin after sciatic nerve lesions.

The functional regeneration of polymodal C-fibers and low-threshold mechanoreceptive axons in the rat sural nerve was evaluated 3 months after a sciatic nerve crush lesion or neurotomy and suture. The distribution of polymodal C-fibers was tested through stimulation-induced extravasation of Evans blue albumin in the foot skin. As judged from the area of stained skin, the polymodal sural C-fibers regenerated efficiently after both lesion types. In regenerates, though, the borders of the stained domain were less clearly defined than in controls, and there were minor territorial abnormalities. The Evans blue-stained area on the unoperated side in neurotomy/suture cases was significantly smaller than in normal control animals. The area covered by low-threshold mechanoreceptors in the foot skin was tested through gentle mechanical stimulation with a blunt probe and electrophysiological recording from the sural nerve. In regenerates the foot skin area covered by functional low-threshold mechanoreceptors turned out to be reduced on the operated side compared to controls, particularly after neurotomy/suture. We conclude that sural nerve regeneration is accompanied by a spatially more complete reestablishment of functional C-fiber-related cutaneous polymodal nociceptors than of functional cutaneous low-threshold mechanoreceptors.

Animals↗

PubMed1993

Myelinated nerve fibres in the CNS.

(1) Lamellated glial sheaths surrounding axons, and electrogenetically active axolemmal foci have evolved independently in widely different phyla. In addition to endowing the axons to conduct trains of impulses at a high speed, myelination and node formation results in a remarkable saving of space and energy. This is particularly important in the CNS, where space is restricted. Unlike the PNS, most CNS axons are myelinated, and several axons may be myelinated by a single cell. This adds further economy of space and energy. On the other hand the high level of complexity of the CNS white matter makes it vulnerable. There are several different kinds of disease affecting myelinated fibre tracts, particularly with respect to CNS white matter. (2) The CNS node of Ranvier presents a more complex structure the larger the fibre. The constricted nodal axon is encircled by perinodal astrocytic processes which contain large gliosomes and emit delicate processes towards the nodal axolemma. One astrocyte may project to several nodes. The node gap contains a polyanionic extracellular material. (3) Lamellated myelinoid bodies are frequent along paranodes of large myelinated CNS fibres. These bodies probably form through budding off from the paranodal myelin sheath. Similar bodies are seen inside astrocytes and microglia. The observation that these bodies are Marchi-positive and argyrophilic, and the presence of acid phosphatase activity around myelinoid bodies inside microglia suggests that they might represent degenerating myelin quanta, involved in the turnover of large myelin sheaths. This putative quantal release and breakdown of myelin material must be compensated for by a production of new myelin at other sites. Therefore, myelination may be viewed as a process that continues throughout life. (4) Biochemical analysis of a sub-cellular fraction enriched in myelinoid bodies shows that these bodies have a composition basically similar to that of myelin. However, breakdown products of myelin constituents, as well as exotic high molecular substances, not present in conventional myelin, can also be found. In addition, the myelinoid body fraction contains proteolytic activity. Studies using isotope labelling of myelin proteins show a source-product relation between myelin and myelinoid bodies. Altogether these data strongly support the hypothesis that myelinoid bodies reflect the catabolic side of myelin turnover. (5) Axons in the nerve fibre layer of the adult rat retina are all unmyelinated, although their diameters range up to over 2 microns. These axons exhibit focally differentiated axolemmal areas. At these sites the axolemma presents a dense undercoating with externally associated Müller cell processes or astrocytic processes.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1992

Quantitative structure-activity relationships of N2-phenylguanines as inhibitors of herpes simplex virus thymidine kinases.

Quantitative structure-activity relationships of the Hansch-type were developed to account for inhibition of thymidine kinases from Herpes simplex viruses types 1 and 2 (HSV1,2) by N2-phenylguanines. Derivatives with meta and/or para substituents on the phenyl ring display a wide range of overlapping, but not identical, potencies as inhibitors of the enzymes. IC50 values for 36 (HSV1) and 35 inhibitors (HSV2) were used to develop equations using hydrophobic (pi), electronic (sigma, R), and group size (MR) parameters. Equations 1 and 2 with correlation coefficients of 0.797 and 0.805, respectively, were obtained for inhibitors of the types 1 and 2 enzymes. Potencies were correlated positively with pi values of meta substituents but negatively with pi values of para substituents in the phenyl ring. Positive correlations were also obtained with the resonance parameter R of para substituents and with sigma constants of meta substituents. The most potent inhibitor of both enzymes was N2-[m-(trifluoromethyl)phenyl]guanine, although HSV2 thymidine kinase was more sensitive to certain compounds than the HSV1 enzyme.

Antiviral Agents↗

PubMed1992

Anatomy and developmental chronology of the rat inferior alveolar nerve.

This report describes the anatomy of the inferior alveolar neurovascular bundle in the adult rat and provides a quantitative analysis of the developing inferior alveolar nerve (IAN). Soon after its entrance in the mandibular canal, the IAN splits into a mental nerve (MN) and an inferior dental nerve (IDN), which course in separate bony compartments. The MN passes unbranched through the mandibular canal. The IDN sends branches to the incisor, the first molar, and the second molar. The third molar (M3) is supplied by a separate IAN branch. The adult rat IAN contains 8,000-10,000 axons, 70% of which are myelinated. The MN accounts for 70% of all IAN axons, the IDN 26%, and 4% form the M3 branch. The proportion of large myelinated axons is lower in the MN than in the IDN. Following chemical sympathectomy, the IAN axon number does not change in a statistically significant way. The total number of IAN axons, which is high prenatally and neonatally, has decreased to the adult level about 1 week after birth. De novo myelination commences at birth and is complete 3-4 weeks later. The size spectrum of the myelinated fibres is narrow and unimodal during the first postnatal weeks. By 1 month, the largest fibres reach diameters of approximately 6 microns, and a bimodal pattern is emerging. From 3 months and on, the size range reaches up to 10-12 microns, and the distribution is bimodal. These data provide a basis for further studies on developmental tooth-nerve interactions.

Animals↗

PubMed1992

Nodes of Ranvier and myelin sheath dimensions along exceptionally thin myelinated vertebrate PNS axons.

The trigeminal alveolar branch in the lower jaw of the cichlid Tilapia mariae was examined by light and electron microscopy on single and serial sections, and by light microscopy on teased fibre preparations. The principal purpose was to find out if the exceptionally thin myelinated axons (d < 1 micron) present in this nerve possess true nodes of Ranvier, and to determine the dimensions of their myelin sheaths. This necessitated analysis of the whole size range of myelinated fibres, with respect to nodal and internodal morphology. The results show that the exceptionally thin myelinated fibres exhibit primitive nodal regions, with patches of axolemmal undercoating, and few Schwann cell processes in the node gap. This contrasts with the more complex nodal organization seen in larger trigeminal alveolar branch fibres. For the whole population of myelinated fibres the number of myelin lamellae increases rectilinearly with axon diameter, and sheath length increases with fibre diameter according to a logarithmic expression. The myelin sheaths of the exceptionally thin trigeminal alveolar branch fibres are composed of 10-20 lamellae, and extend 35-50 microns along the axon. These results show that the structural complexity of nodal regions in the trigeminal alveolar branch decreases with decreasing fibre size, that the exceptionally thin myelinated trigeminal alveolar branch fibres possess primitive nodes and that they have very short myelin sheaths. Our crude theoretical calculations suggest that these fibres might be capable of saltatory conduction.

Animals↗

PubMed1991

Nodal spacing in the developing, young adult and aging rat inferior alveolar nerve.

This study examines the nodal spacing (L) in teased preparations of developing, young adult and aging rat inferior alveolar nerves. In nerves from rats aged 1-2 weeks, most internodes show L-values, which increase from 150 microns to 400 microns, as fiber diameter (D) increases. Other internodes are very short (L = 20-150 microns), and exhibit distorted or fragmented myelin sheaths. In nerves from 2-3 week old rats such very short internodes are rare. By 3-4 weeks, and in young adult animals, very short internodes are lacking. The young adult relation L/D is regular and rectilinear. While D ranges from 2 microns to 10 microns, L ranges from 200 microns to 700-800 microns. In nerves from 1-2.5 year old adult rats some internodes are greater than 1000 microns long. These old nerves show signs of of nodal widening and segmental de- and remyelination. Some newly formed internodes are very short. We suggest that the occurrence of very short internodes in the developing rat inferior alveolar nerve reflects a myelin sheath remodelling, that allows the growing sheaths to elongate more than the nerve. Similarly, a scattered segmental de- and remyelination or a contraction of some internodes might enable other internodes in the old adult IAN to elongate, although the animal is fully grown.

Aging↗

PubMed1991

Anatomy of the rat knee joint and fibre composition of a major articular nerve.

Several recent reports discuss the role of joint nerves in arthritis. Many of these are based on studies in the rat. The aim of this study is to examine the anatomy of the rat knee joint, in search for a primary articular nerve, and to analyze the fibre composition of that nerve. The results show that the structure of the joint differs in some respects from the human knee. At the upper end of the bony patella a cartilaginous patella extends proximally, forming the anterior wall of the suprapatellar bursa. Distinct collateral ligaments are integrated in the joint capsule. The extensor digitorum longus muscle bridges the knee joint, originating from the lateral femoral epicondyle. The well-developed menisci contain pyramid-shaped ossicles. The cruciate ligaments are arranged like in the human knee. A large posterior (PAN) and a small medial (MAN) articular nerve can be identified. The PAN is composed of some 400 axons, about 80% of which are unmyelinated. All myelinated fibres are sensory. They present a unimodal size spectrum with a size range of 1-8 microns, and a predominance of small fibres. Specific denervations indicate that about 1/3 of the unmyelinated axons represent afferents, and some 2/3 are sympathetic efferents. Interestingly, neonatal capsaicin treatment did not influence the number of unmyelinated PAN axons. The functional significance of the numerous unmyelinated sympathetic and sensory PAN axons in the normal knee joint remains to be elucidated.

Animals↗

PubMed1991

Fibre composition of the ventral roots L7 and S1 in the owl monkey (Aotus trivirgatus).

The ventral roots L7 and S1 of the owl monkey Aotus trivirgatus, were examined by electron microscopy. On average, these roots contain 2950 and 1837 myelinated axons respectively. In both roots the myelinated axons have bimodal size distributions, but the S1 root contains more small myelinated axons. Both roots contain a substantial proportion of unmyelinated axon profiles (UAP). In the L7 root the proportion of UAP decreases as the spinal cord is approached, from 19% distally to 5% in the juxtamedullary rootlets. Unmyelinated and very small myelinated CNS-type axons have not been observed in the L7 transitional region. The average S1 root contains some 40% unmyelinated axons at all examined proximo-distal levels. Unmyelinated/very small myelinated axons are easily found on the CNS side of the S1 transitional region, in direct relation to motoraxon bundles. Bundles of unmyelinated and small myelinated axons occur in the ventral pia mater of both segments. The unmyelinated axons in the L7 root of the owl monkey appear to be arranged like those in the feline L7 ventral root, possibly representing afferents. It is likely that most unmyelinated and small myelinated axons in the ventral root S1 are autonomic efferents.

Animals↗

PubMed1990

Relations between axons and oligodendroglial cells during initial myelination. II. The individual axon.

Axo-glial relations in the ventral funiculus of the spinal cord (SC) and in the corpus callosum (CC) of the cat were examined by electron microscopy during initial myelination. In addition to random transverse and longitudinal sections from several stages, two series of sections were studied. As a first step in myelination the axons become ensheathed by one to three uncompacted glial lamellae (E-sheaths). E-sheaths present a length range from less than 5 microns to 149 microns (SC) or to 93 microns (CC). E-sheaths are more frequent along SC-axons than CC-axons, and the mean E-sheath is 3.3-fold longer in the former compared to the latter. In both areas naked axon portions occur between successive E-sheaths, but these gaps are insufficient to allow elongation of all short E-sheaths into long ones. Sheaths composed of mixed compacted (M-sheaths) and uncompacted segments have a length range of 66-212 microns in the SC and 66-171 microns in the CC. In relation to the undifferentiated terminations of E-sheaths or mixed E/M-sheaths, undercoated axolemmal domains are always lacking. Fully compacted sheaths were not found in the series from the SC. In the CC, 141-212 microns long compact sheaths were found, with tight axoglial junctions at their terminations. Axolemmal domains with a 'nodal' undercoating occur in relation to some of these terminations. In both areas, individual developing axons present a chaotic mixture of naked, ensheathed and myelinated portions; bulges with clusters of vesiculotubular profiles are frequent along naked and ensheathed axonal portions, particularly in the SC. The axon diameter is clearly larger in myelinated than in naked portions of the same axon. On the basis of these results, we propose that the early glial sheaths of developing CNS axons actively elongate and undergo extensive remodelling before compaction. The maximal length of uncompacted E-sheaths, and the sheath length at which axoglial junctions and nodes of Ranvier form, are markedly different in the two areas.

Animals↗

PubMed1990

Structure-activity relationships of N2-substituted guanines as inhibitors of HSV1 and HSV2 thymidine kinases.

A series of N2-phenylguanines was synthesized and tested for inhibition of the thymidine kinases encoded by Herpes simplex viruses type 1 and type 2. Compounds with hydrophobic, electron-attracting groups in the meta position of the phenyl ring such as m-trifluoromethyl (m-CF3PG, IC50 = 0.1 microM) were the most potent inhibitors of both enzymes. Many derivatives were significantly more potent against the type 2 thymidine kinase, and can effectively discriminate between the two enzymes. Among other N2-substituted guanines, alkyl and benzyl derivatives were moderately potent inhibitors, and the type 2 enzyme was again more sensitive than the type 1 enzyme. None of the compounds inhibited the thymidine kinase isolated from the host HeLa cell line, suggesting that members of this class of compounds may be useful nonsubstrate, antiviral compounds for latent herpesvirus infections.

Chemical Phenomena↗

PubMed1990

Synthesis and cytotoxicity of deoxyadenosine analogues: isomer distribution in the sodium salt glycosylation of 2,6-disubstituted purines.

Several 2-substituted deoxyadenosine derivatives were synthesized and screened for cytotoxicity toward hematopoietic cells in culture. To prepare intermediates for these syntheses, the sodium salts of 2,6-dibromopurine and 2,6-bis(methylthio)purine were reacted with 1-chloro-3,5-di-p-toluyl-alpha-D-erythro-pentofuranose in acetonitrile. Similar reactions using 6-chloropurines have been reported to give only 9-beta and 7-beta nucleosides as major and minor products, respectively. 2,6-Dibromopurine, however, gave 9-beta and 9-alpha isomers as major and minor products, along with a lesser amount of the 7-beta isomer. 2,6-Bis(methylthio)purine, in contrast, produced 9-beta and 7-beta isomers as major and minor products. These results are discussed in terms of sugar anomerization and possible steric and kinetic effects of base substituents in the sodium salt glycosylation reaction. Reactions of the 9-beta nucleoside isomers with ammonia and alkylamines produced several 2-bromo, 2-methylthio, and 2-amino deoxyadenosines. All of the compounds showed weaker cytotoxic activity than 2-bromodeoxyadenosine against hematopoietic cells in culture, when [14C]leucine incorporation into cellular proteins was measured.

Animals↗

PubMed1990

Specific inhibitors of herpes simplex virus thymidine kinase diminish reactivation of latent virus from explanted murine ganglia.

Two specific inhibitors of herpes simplex virus thymidine kinase, N2-phenyl-2'-deoxyguanosine and N2-(m-trifluoromethylphenyl)guanine, were tested for their ability to inhibit the reactivation of virus from explant cultures of latently infected murine trigeminal ganglia. Both compounds significantly diminished the frequency of reactivation compared with that of untreated controls.

Animals↗

PubMed1989

Influence of an experimental hindlimb maldevelopment on axon number and nodal spacing in the rat sciatic nerve.

In neonatal rat pups the femoral and tibial epiphyseal cartilages on the left side were coagulated with a microcautery device. The subsequent femoral and tibial growth in length was markedly restricted on the left side, but the foot and the pelvic region exhibited normal longitudinal growth. After 6 months the sciatic nerves were removed from both sides. Electron microscopic analysis of nerve specimens from the stunted side revealed that the number of axons was 20% less compared to control specimens. Light microscopic examination of teased preparations showed a normal nodal spacing in the pelvic segment but abnormally short internodes in the femoral segment of the left sciatic nerve. These results suggest that the number of axons in the rat sciatic nerve adapts to a target maldevelopment that sets in neonatally, and that internodal elongation during development proceeds according to the local growth in length of the nerve rather than to the length growth of the whole nerve.

Animals↗

PubMed1989

[The Magendie law on spinal ventral and dorsal roots is still of current value].

The law of Magendie--that the spinal ventral roots are motor and the dorsal roots sensory--was recently questioned. It turned out that ventral roots contain a substantial proportion of unmyelinated sensory axons. This and other observations promoted theories that ventral roots might constitute an additional pain pathway. However, it has now become clear that sensory ventral root axons do not enter the CNS via the ventral roots. Instead, they either leave the ventral root at the PNS/CNS interface and either continue to the pia mater, or loop and return to the periphery. The law of Magendie seems still to be valid.

Animals↗

PubMed1989

Myelin sheath remodelling in remyelinated rat sciatic nerve.

In order to elicit de- and remyelination adult rat sciatic nerves were injected with diphtheria toxin dissolved in phosphate buffered saline (PBS). Control nerves were injected with PBS alone. After survival times of 1-10 weeks, the animals were perfused with glutaraldehyde. Specimens from the injected nerves were processed for light microscopic (LM) examination of teased fibres or for electron microscopic (EM) examination of longitudinal thin sections. LM examination of teased fibres after survival times of 6-10 weeks, showed that most remyelinated internodes are 150-300 microns long. In addition, some exceptionally short Schwann cell sheaths, with lengths of 15-150 microns, occur intercalated between conventional remyelinated internodes. EM analysis of thin sections showed that axonal evaginations penetrate in between the terminating myelin lamellae in fibres with nodal widening and/or paranodal demyelination, at early stages of demyelination. Such alterations are not present in relation to myelin sheaths formed during remyelination, which commences about 3 weeks after injection. In addition, some scattered contracted Schwann cell sheaths, which may be as short as 5-10 microns, occur at all stages. These are more frequent shortly after onset of remyelination than at later stages, and they are either composed of a cytoplasmic investment bordered by heminodes, or a more or less distorted myelin sheath bordered by nodes of Ranvier. This picture is very similar to the myelin sheath remodelling observed in regenerated rat sciatic nerves, and in some developing nerves with a mismatch between nerve growth and internodal elongation. It is concluded that a myelin sheath remodelling occurs in de- and remyelinated rat sciatic nerve, presumably as a result of the lack of longitudinal growth.

Animals↗

PubMed1989

Morphological and physiological properties of neurons after long-term axonal regeneration: observations on chronic and delayed sequelae of peripheral nerve injury.

Axonal regeneration has been the focus of extensive investigation of mechanisms which mediate structural and functional recovery after injury to mammalian peripheral nerves and has proven to be a valuable model for development and plasticity in the nervous system. Although details of the acute morphological and physiological responses to nerve injury are well-described, less information is available to nerve injury are well-described, less information is available about long-term alterations which persist or develop after regenerated axons have established connections with their targets. The present paper briefly discusses the mammalian neuron's initial response to peripheral nerve injury and subsequent events which occur during regeneration. Morphological and physiological alterations observed in neurons after long-term axonal regeneration are described and are considered in the context of their potential implications for clinical recovery after nerve injury, as well as their potential contribution to the appearance of delayed neurological dysfunction. Selective responses to neuronal injury during development and in different fiber populations are discussed.

Action Potentials↗

PubMed1989

Nucleoside analogs as non-substrate inhibitors of herpes simplex viruses thymidine kinase.

We have examined the capacity of a series of 6-substituted pyrimidine and 2-substituted purine derivatives to inhibit mammalian thymidine kinase and the thymidine kinases encoded by type 1 and type 2 herpes simplex viruses. Several N2-substituted guanine and deoxy guanosine derivatives displayed selective inhibitory activity against the HSV-1 and HSV-2 thymidine kinases by competing with the phosphorylation of thymidine, suggesting a possible novel pharmacological approach to herpes viruses infections.

Cells, Cultured↗

PubMed1988

Proportion of unmyelinated axons in rat molar and incisor tooth pulps following neonatal capsaicin treatment and/or sympathectomy.

The occurrence of unmyelinated axons was examined ultrastructurally in rat molar and incisor root pulps of normal rats, of neonatally capsaicin-treated rats, of rats subjected to neonatal capsaicin treatment followed by resection of the superior cervical ganglion and of sympathectomized but otherwise normal rats. Following capsaicin treatment the occurrence of unmyelinated pulpal axons was slightly subnormal. Sympathectomy was largely without effect on the population of unmyelinated axons in tooth pulps of capsaicin-treated rats. In normal rats the proportion of unmyelinated axons in molar pulps was not altered by sympathectomy but it caused a slight decrease in the number of unmyelinated incisor pulpal axons. These findings support the view that most of the unmyelinated axons in rat molar and incisor pulps are sensory, that the parent neurons of these axons differ from nociceptive neurons at other sites by being largely resistant to neonatal capsaicin treatment and that very few unmyelinated tooth pulp axons represent postganglionic efferents.

Adrenergic Fibers↗