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Biomedical subjects

M E Atkinson

Publications and source records attributed to M E Atkinson.

At least 19 recordsLinked to original sources
PubMed2004

A novel preparative regimen for autologous transplant in non-Hodgkin's lymphoma: long-term experience with etoposide and thiotepa.

The purpose of this study was to evaluate the efficacy and toxicity of the preparative regimen of thiotepa and etoposide in patients undergoing autologous transplantation for relapsed non-Hodgkin's lymphoma. The study involved 65 consecutive patients who underwent autologous transplantation using the thiotepa/etoposide regimen for relapsed intermediate-grade NHL at the University of Wisconsin Hospital and Clinics (UWHC) between 1987 and 2001. The regimen consisted of thiotepa 300 mg/m(2)/day and etoposide 700 mg/m(2)/day on days -6, -5, and -4. The median age at the time of transplant was 49 years. A total of 50 patients (76%) had diffuse large-cell lymphoma. A total of 50 (77%) patients had chemosensitive disease, and 15 (23%) were chemoresistant. With a median follow-up of 34 months (range, 3-163), 28 patients (43%) remain in CR and 33 (51%) have developed recurrent or progressive disease. The overall survival and event-free survival at 3 years are 40% (95% CI 26-53%) and 32% (95% CI 20-45%), respectively. There was one death attributed to regimen-related toxicity (RRT). Reversible gastrointestinal toxicity was the major RRT, and there was minimal pulmonary and cardiac toxicity. We conclude that the combination of thiotepa and etoposide is an effective preparative regimen with acceptable RRT.

Adult↗
PubMed1999

Addition of high-dose Ara-C to the BMT conditioning regimen reduces leukemia relapse without an increase in toxicity.

The optimal conditioning regimen for allogeneic BMT for hematological malignancies is still to be determined. We used a conditioning regimen including high-dose Ara-C (HDAC)/CY/TBI for patients at high risk for leukemic relapse (regimen A, Ara-C 3 g/m2 every 12 h for six doses followed by CY 45 mg/kg for 2 days and TBI 13.2 Gy in eight fractions) and a standard CY/TBI conditioning regimen for patients at low risk (regimen B, CY 60 mg/kg for 2 days and TBI 13.2 Gy in eight fractions). We analyzed 55 patients treated with regimen A (group A) and 36 patients with regimen B (group B). Relapse rates (10.9% in group A, 2.9% in group B, P = 0.23), 5-year overall (53.2% in group A and 60.8% in group B, P = 0.26) and disease-free (47.7% in group A and 60.8% in group B, P = 0.11) survival rates were not significantly different between these groups, although group A consisted of high-risk patients. Regimen-related toxicities were not significantly different between the two groups. This result suggests that adding HDAC to CY/TBI conditioning regimen may reduce leukemic relapse and improve survival without increasing regimen-related toxicities.

Adolescent↗
PubMed1999

Compartmentalisation of the developing trigeminal ganglion into maxillary and mandibular divisions does not depend on target contact.

During development axons contact their target tissues with phenomenal accuracy but the mechanisms that control this homing behaviour remain largely elusive. A prerequisite to the study of the factors involved in hard-wiring the nervous system during neurogenesis is an accurate calendar of developmental events. We have studied the maxillary and mandibular components of the trigeminal system to determine the stages during embryogenesis when a gross somatotopic order is first established within the trigeminal ganglion and the axons projecting to the brainstem. The retrograde transganglionic fluorescent tracers DiO and DiI were injected into the maxillary and mandibular arches or their derivatives in fixed mouse embryos staged between 13 and 40 somites (E9-E11). After 1-4 wk, the distribution of the 2 tracers was determined using confocal laser scanning microscopy. The first maxillary nerve cell bodies and their developing axons were labelled at the 30 somite stage (E10). This was 2 somite stages earlier than the mesencephalic nucleus and the ganglion cell bodies of the mandibular nerve. The gross somatotopic division of cells within the trigeminal ganglion projecting to the maxillary and mandibular targets was established by the 32 somite stage (E10). This arrangement was evident as 2 groups of cell bodies occupying adjacent but separate regions of the trigeminal ganglion. The central branches of the maxillary and mandibular cell bodies entered the metencephalon as 2 distinct bundles at the same stage. The trigeminal motor nucleus was first detected at the 38 somite stage (E10.5). Gross somatotopy in the major divisions of the trigeminal ganglion is established before outgrowing axons have contacted their peripheral target tissue at E10.5. This suggests that target tissues do not induce somatotopy.

Animals↗
PubMed1998

Target pioneering and early morphology of the murine chorda tympani.

Many studies demonstrate that differentiation of certain sensory receptors during development is induced by their nerve supply. Thus the navigational accuracy of pioneering fibres to their targets is crucial to this process. The special gustatory elements of the facial and glossopharyngeal nerves are used extensively as model systems in this field. We examined the chorda tympani, the gustatory component of the facial nerve, to determine the precise time course of its development in mice. The transganglionic fluorescent tracer DiI was injected into the anterior aspect of the mandibular arch of fixed embryos aged between 30 and 50 somites (E10-E12). It was allowed to diffuse retrogradely via the geniculate ganglion to the brainstem for 4 wk, before the distribution of DiI was determined using confocal laser scanning microscopy. Geniculate ganglion cells were first labelled at the 34 somite stage (E10). Pioneering chorda tympani fibres that arise from these cells passed peripherally and followed an oblique course as they grew towards the mandibular arch. At the 36 somite stage (E10.5), the peripheral component followed an intricate postspiracular course and passed anteriorly to arch over the primitive tympanic cavity, en route to the lingual epithelium. From the 36 to 50 somite stages (E10.5-E12), it consistently traced in the fashion of a 'U' bend. The central fascicle also traced at the 36 somite stage (E10.5) and just made contact with the brainstem. At the 40 somite stage (E11), the central fibres clearly chose a route of descent into the spinal trigeminal tract and branched into the solitary tract. Pioneering chorda tympani fibres contact the lingual epithelium when the target is primordial. The lingual epithelium may be a source of a neurotropic factor that attracts peripheral chorda tympani fibres to the sites of putative papillae. However, the chorda tympani is probably not a vital influence on the subsequent differentiation of gustatory papillae, since the papillae are elaborated 5 d later at E15 in murine embryos. The early morphology of the nerve is true to the amniote vertebrate phenotype.

Animals↗
PubMed1991

A quantitative study of neuropeptide immunoreactive cell bodies of primary afferent sensory neurons following rat sciatic nerve peripheral axotomy.

Following peripheral axotomy, fluoride resistant acid phosphatase (FRAP) and most neuropeptides are depleted in the central terminals of axotomised nerves and reduced in their corresponding cell bodies (DRG) but vasoactive intestinal polypeptide (VIP) increases. The increase in VIP probably results from a change in gene expression in other ganglion cells which do not normally express VIP. A quantitative study was performed to investigate the proportion of DRG cells immunoreactive for different peptides at increasing times after sciatic nerve section. Retrograde fluorescent neuronal labelling of sciatic nerve cell bodies by injection of fast blue into the proximal stump was combined with unlabelled antibody immunohistochemistry for CGRP and VIP. The proportion of cells immunoreactive for these peptides was quantified between two and fourteen days post-axotomy. The number of VIP immunoreactive profiles increased significantly in the first 4 days post-axotomy, followed by a slight decrease before rising again. In contrast, the number of and CGRP-immunoreactive cell profiles declined to zero by 14 days post-axotomy. 4 days post-axotomy 50% of VIP positive cells were also immunoreactive for CGRP. There was neither colocalisation between VIP and FRAP nor between CGRP and FRAP. It is concluded that many peptidergic DRG cell bodies switch their expression of peptide to VIP after injury, whereas non-peptide-containing subpopulations do not.

Acid Phosphatase↗
PubMed1990

Collateral branching innervation of rat molar teeth from trigeminal ganglion cells shown by double labelling with fluorescent retrograde tracers.

Somatotopic projections of each maxillary molar tooth were defined by injecting individual teeth with True blue and plotting the location of fluorescent cells in sections of the trigeminal ganglia. Collateral branching was investigated by injecting True blue and Diamidino yellow into pairs of maxillary molar teeth and examining the ganglia for double labelled cells. Maxillary molar teeth project to the lateral ophthalmomaxillary region of the ipsilateral ganglion with extensive overlap of the projections from individual teeth. Double labelling with both dyes demonstrated considerable collateral branching from single trigeminal ganglion cells to the molar teeth.

Animals↗
PubMed1986

Peripheral axotomy of the rat mandibular trigeminal nerve leads to an increase in VIP and decrease of other primary afferent neuropeptides in the spinal trigeminal nucleus.

In the vasoactive intestinal polypeptide (VIP)-rich lumbosacral spinal cord, VIP increases at the expense of other neuropeptides after primary sensory nerve axotomy. This study was undertaken to ascertain whether similar changes occur in peripherally axotomised cranial sensory nerves. VIP immunoreactivity increased in the terminal region of the mandibular nerve in the trigeminal nucleus caudalis following unilateral section of the sensory root of the mandibular trigeminal nerve at the foramen orale. Other primary afferent neuropeptides (substance P, cholecystokinin and somatostatin) were depleted and fluoride-resistant acid phosphatase activity was abolished in the same circumscribed areas of the nucleus caudalis. The rise in VIP and depletion of other markers began 4 days postoperatively and was maximal by 10 days, these levels remaining unchanged up to 1 year postoperatively. VIP-immunoreactive cell bodies were absent from trigeminal ganglia from the unoperated side but small and medium cells stained intensely in the ganglia of the operated side after axotomy. These observations indicate that increase of VIP in sensory nerve terminals is a general phenomenon occurring in both cranial and spinal sensory terminal areas. The intense VIP immunoreactivity in axotomised trigeminal ganglia suggests that the increased levels of VIP in the nucleus caudalis are of peripheral origin, indicating a change in expression of neuropeptides within primary afferent neurons following peripheral axotomy.

Acid Phosphatase↗
PubMed1986

The origins of the sciatic nerve and changes in neuropeptides after axotomy: a double labelling study using retrograde transport of true blue and vasoactive intestinal polypeptide immunohistochemistry.

One month after sciatic nerve section, only dorsal root ganglion cells which take up True blue applied to the cut end of the nerve show vasoactive intestinal polypeptide immunoreactivity. This indicates that VIP expression is only in cells with damaged axons. Motor axons with True blue-positive perikarya in the ventral horn originate from the fourth to sixth lumbar segments whereas unmyelinated and small myelinated sensory nerves terminate in the third to fifth lumbar segments of the spinal cord.

Animals↗
PubMed1986

Vasoactive intestinal polypeptide (VIP) increases in the spinal cord after peripheral axotomy of the sciatic nerve originate from primary afferent neurons.

Following sciatic nerve axotomy, vasoactive intestinal polypeptide (VIP) immunoreactivity increases dramatically in the central terminal areas of the nerve whereas other primary afferent neuropeptides are depleted. The contribution of the peripheral nerve to VIP increases in the spinal cord was investigated by performing sciatic nerve section alone, dorsal rhizotomy of the lumbar roots, axotomy and rhizotomy in combination or section of other peripheral nerves terminating in the same segments as the sciatic nerve. VIP, and for comparison, substance P (SP), cholecystokinin (CCK), somatostatin (SOM), were localized in the lumbar spinal cord and corresponding sensory ganglia using unlabeled antibody immunohistochemistry. After sciatic nerve section, SP, CCK and SOM were depleted in the lumbar dorsal horn whereas VIP increased. After rhizotomy alone all neuropeptide staining including VIP was depleted; axotomy followed by rhizotomy produced the same result. Axotomy of other peripheral nerves terminating in the lumbar cord increased the area of neuropeptide depletion but correspondingly increased the area of VIP staining. A large proportion of small and medium diameter dorsal root ganglion cells were stained for VIP after nerve section or axotomy but not after rhizotomy alone. A radical change in neuropeptide metabolism of dorsal root ganglion cells occurs after peripheral axotomy, in the form of a marked increase in VIP synthesis. An intact dorsal root is necessary for increases in VIP in the spinal cord indicating the primary afferent origin of the response.

Animals↗
PubMed1986

Vasoactive intestinal polypeptide increases in areas of the dorsal horn of the spinal cord from which other neuropeptides are depleted following peripheral axotomy.

Peripheral nerve section or local capsaicin application produces depletion of substance P and an enzymatic marker, fluoride-resistant acid phosphatase (FRAP), from circumscribed regions of the terminal areas in the spinal cord. We have made use of this phenomenon to map the extent of central termination of subpopulations of primary afferent neurons containing substance P (SP), somatostatin (SOM), cholecystokinin (CCK), vasoactive intestinal polypeptide (VIP) and FRAP in the rat lumbar spinal cord following sciatic nerve section at midthigh level under ether anaesthesia. Between 2 days and 1 year postoperatively, the animals were perfused transcardially and SP, CCK, VIP and SOM were localised in frozen transverse sections of spinal cord segments L1 to S2 and their corresponding ganglia using unlabelled antibody immunohistochemistry. FRAP was localised using a modified Gomori method. SP, SOM, CCK and FRAP were maximally depleted from identical restricted areas of the dorsal horn of the third, fourth and fifth lumbar segments fifteen days after nerve section and remained so for a year. In contrast, VIP staining increased dramatically in the areas from which the other markers were depleted and showed the same time course. Moreover, a large number of neurons in the corresponding ganglia showed positive VIP immunoreactivity after axotomy but were absent from the unoperated side.

Acid Phosphatase↗
PubMed1984

Quantitative ultrastructure of cytolytic lymphocytes mediating allograft rejection in the mouse. I. Cellular alterations in T lymphocytes during specific target cell lysis.

A quantitative ultrastructural analysis of cytolytic T lymphocytes (CTL) is presented which allows both the distinction of these cells from normal T lymphocytes and permits the demonstration of ultrastructural alterations of putative CTL following interaction with target cells (TC). Alloreactive CTL were generated in C57BL/10 mice receiving intraperitoneal fibroblastic allografts and target-binding splenic lymphocytes (TBSL) were concentrated by specific immunoadsorption on fibroblast monolayers. TBSL were subjected to ultrastructural quantification either at the onset of TC interaction or following 30 or 60 min incubation at 37 degrees C. By means of simple stereological relationships it was shown that, in comparison with normal, non-cytolytic splenic T lymphocytes, TBSL were slightly larger cells, displaying around 60% more cytoplasm, a similarly-sized nucleus and approximately triple the volume of Golgi apparatus. During the first 30 min of interaction with TC, the target binding surface of the TBSL plasma membrane decreased in area. This change was accompanied by a polarization of the TBSL towards the target. Incubation of lymphocytes with TC for a further 30 min resulted in a general polarization of lymphocytic cellular constituents away from the TC. These results were only attainable by objective quantitative analysis and are discussed in relation to possible mechanisms of CTL-mediated lysis.

Animals↗
PubMed1984

Large agranular lymphocytes: early non-specific effector cells in allograft rejection in the mouse.

The cytolytic reactivity and ultrastructure of centrally-reactive and allograft-infiltrating lymphocyte populations was investigated in a murine peritoneal allograft system. Animals sensitized with a single intraperitoneal dose of allogeneic L929 fibroblasts generated a population of splenic cytolytic T cells maximally reactive 10 days after immunization. Sensitized splenic lymphocytes, isolated by immunoadsorption on L929 monolayers, were ultrastructurally classified as mature small lymphocytes. At the graft site, cytolytic non-T lymphoid cells displaying the ability to kill K562 target cells, were demonstrable between 4 and 6 days after sensitization. Six-day peritoneal lymphocyte populations were found to contain both cytolytic T cells (L929 killers) and highly reactive K562 killers. Immunoadsorption and cold target competition studies indicated that the K562 killer cells were able to recognize both K562 and L929 targets. K562 target-binding cells appeared to be ultrastructurally immature and were designated 'large agranular lymphocytes'. The role of cytolytic non-T cells in rejecting allografts is discussed.

Animals↗
PubMed1983

The effects of prenatal capsaicin on the distribution of substance P in developing primary afferent neurons.

Capsaicin was injected subcutaneously into 15-day pregnant mice and by transuterine injection into foetuses of the same age. Indirect immunofluorescence was used to assess its effects on the distribution of substance P. Capsaicin administered to either the mother or the foetus crossed the placenta and depleted substance P from the primary afferent terminal field in the spinal cord and abolished reactivity in the dorsal root ganglia and peripheral terminals of spinal nerves. Subcutaneous capsaicin administration to the pregnant female is, operationally, the easiest method providing low doses are used; otherwise pregnant females seem highly susceptible to respiratory failure. These results suggest the use of capsaicin to study prenatal ontogeny of sensory nerves.

Animals↗
PubMed1983

A histochemical study of the cholinergic and adrenergic innervation of the developing teeth and oral tissues in the mouse.

The dental follicle and papilla are innervated at different stages of tooth development. The type of nerves innervating these structures at different stages was investigated using an enzymic method for acetylcholinesterase (AChE) and direct visualization for noradrenaline on fetal and neonatal stages up to 7 days after birth. Glandular and muscular tissue were positive for AChE in 17-day fetuses but no reaction was observed in the teeth or supporting tissues up to 7 days after birth. Noradrenaline was detected in blood vessels at 18 days and in glandular tissue at birth but was not observed in the teeth within the period covered. It is unlikely that AChE plays any role in the innervation of teeth; the adrenergic nerve supply probably develops later.

Acetylcholinesterase↗
PubMed1983

A histological study of the innervation of developing mouse teeth.

The innervation of developing mouse teeth between initial formation and crown formation was investigated using silver-stained serial sections. The developing innervation correlated with the stage of development of individual teeth rather than the chronological age of the mice. Nerves approached the developing dental papilla during the bud stage and formed a basal plexus below the dental papilla in the early cap stage. Nerve fibres from this plexus spread into the dental follicle as it began to develop. However, nerves did not enter the dental papilla until crown formation commenced, when the innervation was fairly rapid. Innervation commenced in the incisor teeth as soon as dentinogenesis started but not until a thin layer of enamel had been formed in the molar teeth. Although some of the early fibres were associated with blood vessels, many nerves lay free in the pulp. The absence of nerves in intimate relationship to the presumptive dental regions during the inductive phase of tooth development suggests that neural induction plays no part in the initiation of odontogenesis. However, it is not possible, from a purely histological study such as this, to attribute any function to the nerves at other stages of tooth development until the neurotransmitter content, and hence the type and likely function of the nerves, is established.

Amelogenesis↗
PubMed1982

The ontogeny of substance P--containing nerve fibres in the developing mouse dentition.

The putative neurotransmitter, substance P, was localised in the developing teeth and periodontium of mice by indirect immunofluorescence. Substance P-containing fibres were visible in the incisor dental follicle eighteen days post-conception and entered the pulp two days after birth. The first molar pulp was innervated four days after birth and the second molar six days after birth. Innervation of the teeth by substance P fibres was delayed compared with the mucous and cutaneous innervation of adjacent areas and correlated with the stage of development of the teeth rather than the chronological age of the animal. The innervation of developing dental structures by substance P probably represents the establishment of a sensory supply prior to function of the tooth.

Animals↗
PubMed1982

The ontogeny of substance P fibers in the mouse trigeminal nerve.

The putative neurotransmitter substance P was localized in the embryonic and neonatal mouse trigeminal nerve by indirect immunofluorescence. Central terminals in the nucleus caudalis gave a positive substance P-like immunofluorescence (SPLI) reaction of E13-E14. SPLI subsequently appeared in the peripheral mucous and cutaneous nerves at E16-17 at which time trigeminal nucleus cell bodies were also positive. These findings indicate the early development of primary afferent nociceptive pathways.

Aging↗