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Biomedical subjects

J Norton

Publications and source records attributed to J Norton.

At least 91 records · Page 5Linked to original sources
PubMed1991

Transforming growth factor-beta improves healing of radiation-impaired wounds.

Exogenously applied TGF-beta 1 has been shown to increase wound strength in incisional wounds early in the healing process. An impaired wound healing model was first established in guinea pigs by isolating flaps of skin and irradiating the flaps to 15 Gray in one fraction using a 4-MeV linear accelerator. Incisions made 2 d after irradiation were excised 7 d later, and showed decreased linear wound bursting strength (WBS) as compared to non-irradiated control wounds on the contralateral side of each animal (p = 0.001). The effect of TGF-beta on healing of radiation-impaired wounds was studied using this model. Skin on both left and right sides of guinea pigs was irradiated as above. A linear incision was made in each side. Collagen with either 1, 5, or 20 micrograms of TGF-beta was applied to one side prior to closure with staples, whereas the contralateral side received saline in collagen. Wounds given either 1 or 5 micrograms of TGF-beta were found to be stronger than controls at 7 d (p less than 0.05), whereas those receiving the higher 20-micrograms dose were weaker than controls (p less than 0.05). Thus, TGF-beta in lower doses improved healing at 7 d but very large amounts of the growth factor actually impaired healing. In situ hybridization done on wound samples showed increased type I collagen gene expression by fibroblasts in wounds treated with 1 micrograms TGF-beta over control wounds. These results indicate that TGF-beta improved wound healing as demonstrated by increased WBS. This improvement is accompanied by an up-regulation of collagen gene expression by resident fibroblasts.

Animals↗
PubMed1991

Vessel associated adhesion molecules in normal skin and acute graft-versus-host disease.

Immunohistological staining of skin from normal donors and bone marrow transplant recipients was undertaken using antibodies to two vessel associated adhesion molecules, endothelial leucocyte adhesion molecule-1 (ELAM-1). In normal skin ELAM-1 staining was restricted to a variable but generally small number of endothelial cells which were significantly increased in graft-versus-host disease (GvHD), but only when the fully developed histological picture of epidermal basal damage and leucocytic infiltration was present. All other biopsy specimens from marrow recipients taken before or after transplantation were similar to those of normal controls even in the presence of a clinical rash consistent with early GvHD. Although VCAM-1 positivity was seen on a few endothelial cells in normal skin, staining was mainly observed on dermal dendritic cells surrounding blood vessels and adnexal structures. In specimens with histological evidence of GvHD, positive perivascular dendritic cells were increased and were accompanied by the appearance of large numbers of similar cells dispersed throughout the upper dermis. Biopsy specimens from marrow recipients before and after transplantation resembled those from normal donors except for the presence of a rash after transplantation when some specimens, which lacked the leucocytic infiltrate diagnostic of GvHD, showed an increase in VCAM-1 positive cells, particularly in the upper dermis. The identification of these cells may therefore be useful in diagnosing early GvHD.

Acute Disease↗
PubMed1991

Prolonged reversal of diabetic state in NOD mice by xenografts of microencapsulated rat islets.

Transplantation of the islets of Langerhans could be the most promising approach to the clinical treatment of insulin-dependent (type I) diabetes mellitus. In this study, we report on a modified encapsulation technique that produces small alginate-polylysine capsules (0.25-0.35 mm diam). In an in vitro study, both encapsulated and unencapsulated islets showed comparable responses to glucose challenge in terms of insulin secretion. With the new capsules, 16 spontaneously diabetic NOD mice received transplants of 800 encapsulated rat islets/animal. Nonfasting blood glucose concentration decreased from 24.4 +/- 1.4 to 4.0 +/- 1.3 mM. At 4 and 5 mo posttransplantation, the capsules were removed from 2 recipients. Both animals regressed to a hyperglycemic state after capsule removal. However, after another islet transplantation, normoglycemia was again restored in these 2 animals. In control mice, which received unencapsulated islets, the xenografts remained functional for less than 10 days. A high mortality rate was observed among these animals within 2 mo of the recurrence of the hyperglycemic state. Our results clearly indicate that encapsulation of pancreatic islets in the improved capsules can effectively prolong xenograft survival without immunosuppression in an animal model that mimics human type I diabetes mellitus.

Animals↗
PubMed1991

An immunohistological study of gamma/delta lymphocytes in human cutaneous graft-versus-host disease.

The proportion of T lymphocytes bearing the gamma/delta and alpha/beta T cell antigen receptors was determined in histological sections of skin from normal subjects and patients suffering from acute graft-versus-host disease (GVHD) using antibodies to the delta and beta chains. The proportion of gamma/delta cells in GVHD was very low (4.3% of CD3+ cells) but significantly higher than in skin from normal donors (0.8%) and marrow recipients without GVHD (0%). The significance of this is not clear and we were unable to determine whether it represented selective localization of these cells to the skin or simply reflected peripheral blood values in the early post-transplant period in some patients with GVHD. Localization of gamma/delta cells to the epidermis was not seen; all were identified in the dermis particularly in the perivascular zone. Although it is not possible to exclude a role for gamma/delta cells in initiating GVHD, the present study suggests that they do not play an important role in producing the epidermal damage that characterizes this condition.

Adult↗
PubMed1990

Effect of photodynamic therapy on tumor necrosis factor production by murine macrophages.

Photodynamic therapy (PDT) involves the treatment of tumors in the presence of sensitizer, light, and oxygen, causing energy-dependent cytotoxicity. A vascular effect that causes hemorrhagic tumor necrosis has been described with PDT, but its basis remains undefined. To investigate the possible role of tumor necrosis factor (TNF) production in the generation of such a vascular effect and/or a direct tumor effect, we treated thioglycollate-elicited murine macrophages with PDT, and we measured the possible production of TNF using the L929 assay. An energy-dependent production of TNF by macrophage treated with PDT, stimulated or unstimulated with endotoxin, was demonstrated, and TNF production was inhibited at the highest treatment energy levels. These data represent the first description of cytokine production by PDT-treated macrophages, and may serve as another mechanism of PDT cytotoxicity in vivo, either directly by TNF-mediated tumor necrosis, or indirectly by vascular effects on tumor vessels.

Animals↗
PubMed1990

Intrastriatal implants of mesencephalic cell suspensions in weaver mutant mice: ultrastructural relationships of dopaminergic dendrites and axons issued from the graft.

Dissociated cell suspensions were prepared from the ventral midbrain of normal mouse foetuses and stereotaxically implanted into the neostriatum of 2-3 months old homozygous weaver mutant mice, which are severely deficient in dopamine. In tests of amphetamine-induced turning behaviour 60 days after grafting, recipient animals displayed a rotational bias opposite to the grafted side. Prior to perfusion, which was carried out at 80 days after transplantation surgery, the grafted striata of the weaver recipients were deprived of their intrinsic mesostriatal dopamine input by local injections of 6-hydroxydopamine into the ipsilateral substantia nigra in order to selectively study the innervation derived from the graft. Grafts were found to contain an estimated 100-700 tyrosine hydroxylase immunoreactive neurones. An ultrastructural analysis demonstrated that both axons and dendrites immunoreactive for tyrosine hydroxylase extended from the graft into the recipient striatum. In the host striatum proximal to the graft (i.e. at a distance of 0.0-0.5 mm from the graft) the proportion of dendrites to axons was about 1:2, whereas distal to the graft (i.e. at a distance of 0.5-1.0 mm) it was 1:20. Graft-derived tyrosine hydroxylase immunoreactive axons were primarily found in apposition with unlabelled dendrites or spines of the recipient striatum (greater than 90%). Graft-derived dopaminergic dendrites received synaptic input from unlabelled axon terminals and were opposed to the unlabelled somata of striatal neurones in a few instances. In conclusion, this study shows that mesencephalic cell suspensions survive in the weaver striatum and provide a functional dopamine innervation which comprises both axonal and dendritic processes.

Animals↗
PubMed1990

Age-related changes in striatal dopamine D2 receptor binding in weaver mice and effects of ventral mesencephalic grafts.

Dopamine (DA) D2 receptor binding is increased in the striatum of 5-6 months old weaver mutant mice (Kaseda et al. 1987). This may occur in response to the loss of DA neurons in the midbrain and the decrease in DA content in the striatum of homozygous mutants. One purpose of the present study was to determine if the diminished DA innervation is associated with changes in D2 receptors at earlier ages and if the increase in DA D2 receptor binding seen at 5-6 months is a lasting phenomenon. Specific [3H]spiperone binding was measured in the dorsolateral (DL), dorsomedial (DM) and ventrolateral (VL) striatum and in the nucleus accumbens (AC) of homozygous weaver mutant mice (wv/wv), heterozygous littermates (wv/+) and wild-type controls (+/+). Mice were studied at 20 days and 1, 3, 6, 9 and 12 months of age. The difference in specific [3H]spiperone binding in DL striatum between wv/wv and +/+ mice was significantly greater at 6 months than the difference at 1 month and at 12 months of age. Foetal ventral mesencephalic grafts survive and establish functional innervation in the striatum of weaver mice as shown by the induction of a contralateral turning bias (Low et al. 1987). The second aim of the present studies was to determine if such grafts would also reverse the increase in DA D2 receptor binding in the striatum. Aspiration cavities were prepared in the cortex of weaver mice, and ventral mesencephalic tissue from E14-E15 +/+ foetuses was subsequently placed on the surface of the right dorsal striatum when the recipients were 3 months old.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1990

The role of CD4+ helper T cells in the destruction of microencapsulated islet xenografts in nod mice.

Islet transplants for large numbers of patients with diabetes will require xenografts. Microencapsulation is an appealing method for islet xenografting. However, graft function has been limited by a cellular reaction, particularly intense in spontaneously diabetic, NOD mice. The purpose of this study was to elucidate the mechanism of this reaction. Poly-1-lysine-alginate microcapsules containing 4000-12,000 dog or 1800-2000 rat islets were xenografted intraperitoneally into streptozotocin (SZN)-diabetic C57BL/6J and NOD mice, with or without recipient treatment with GK 1.5 (anti-CD4 monoclonal antibody) (20-30 microliters i.p. every 5 days, begun on day -7. Grafts were considered technically successful if random blood glucose (BG) was normalized (less than 150 mg/dl) within 36 hr. Graft failure was defined as BG greater than 250 mg/dl. Dog and rat islets in microcapsules normalized BG in both SZN and NOD mice within 24 hr routinely. Empty microcapsules and GK 1.5 treatments alone did not affect BG. NODs destroyed both microencapsulated dog and rat islets more rapidly than did SZN-diabetic mice (P less than .01). Graft biopsies showed an intense cellular reaction, composed of lymphocytes, macrophages and giant cells, and no viable islets. GK 1.5 treatment significantly prolonged both dog-to-NOD and rat-to-NOD grafts (P less than 0.01). Biopsies of long-term functioning grafts (on days 65-85) demonstrated viable islets and no cellular reaction around microcapsules; 1/4 rat and 1/8 dog islet xenografts continued to function indefinitely in NOD recipients, even after cessation of GK 1.5 therapy. Prediabetic NODs receiving encapsulated dog or rat islets mounted a moderate cellular reaction to grafts. Empty microcapsules excited no cellular reaction in diabetic or prediabetic NODs. We conclude that the NOD reaction to microencapsulated xenogeneic islets is helper T cell-dependent, and that the target of this reaction is not the microcapsule itself, but the donor cells within.

Animals↗
PubMed1990

Foci of increased T2 signal intensity in MR images of healthy elderly subjects. A follow-up study.

An 18-month follow-up study was conducted on 26 healthy elderly subjects with and without foci of increased T2 signal intensity on MR imaging. The subjects did not differ with respect to health status or cognitive performance as measured by the Cognitive Subscale of the Cambridge Mental Disorders of the Elderly Examination and the Mini Mental State Examination at follow-up. There was a significant decline in performance on the Digit Symbol Substitution Test in subjects who had evidence of T2 foci compared to the performance of subjects without T2 foci. This may indicate that the presence of T2 foci is correlated with subtle difficulties in learning and memory.

Aged↗
PubMed1990

Adenomatoid tumor of the adrenal gland with ultrastructural and immunohistochemical demonstration of a mesothelial origin.

We describe an adenomatoid tumor arising in the left adrenal gland of a patient who underwent bilateral adrenalectomy for the ectopic adrenocorticotropic hormone syndrome. The mesothelial origin of the tumor was confirmed by electron microscopy and positive immunohistochemical staining for keratin. The tumor had a prominent cystic component raising the question whether adrenal cysts are derived from mesothelial inclusions. It is proposed that consideration be given to adding a new category of "mesothelial cysts" to the classification of adrenal gland cysts.

Adrenal Gland Neoplasms↗
PubMed1990

Splenectomy in the management of systemic mast cell disease.

The records of 26 patients with systemic mast cell disease (SMCD) treated during the past decade at the National Institutes of Health were reviewed to determine the role of splenectomy in the management of SMCD. Seventeen (65%) patients had indolent SMCD, manifested primarily by urticaria pigmentosa and mast cell infiltration of the skin, bone marrow, or gastrointestinal tract. None of these patients underwent splenectomy. These patients required only symptomatic therapy. Nine (35%) patients, including those with associated hematologic disorders and those with a lymphoma-like illness termed lymphadenopathic mastocytosis with eosinophilia, had aggressive SMCD. Five of nine patients with aggressive SMCD underwent splenectomy. Of the five patients with splenectomy, three were alive at the time of this report, whereas none of the four who did not have a splenectomy was still alive. Length of survival without splenectomy was 26 months. With splenectomy, length of survival at the time of this report was 34 months. Patients without splenectomy died of bleeding caused by severe thrombocytopenia. Patients with splenectomy appeared better able to tolerate chemotherapy. We thus conclude that while splenectomy is of no value in the management of indolent mastocytosis, it should be considered in patients with aggressive SMCD.

Adult↗
PubMed1989

Characterization of Hodgkin's disease derived cell line HDLM-2.

The cell line HDLM-2 was established from the pleural effusion of a patient with Hodgkin's disease. Here, we describe the morphological, cytochemical, enzymological, immunological, molecular biological, and functional characteristics of the cell line. The results of this multiparameter profile show that HDLM-2 is different from other well-studied leukemia-lymphoma cell lines including other Hodgkin's disease derived cell lines. HDLM-2 cultures contain mainly mono- or binucleated cells, but also prominent giant cells with two to ten nuclei. HDLM-2 cells do not express an immunophenotype characteristic of a given cell lineage. However, the cells are positive for Ki-1, HeFi-1, Leu-M1, Tac, and HLA class II markers. Cytochemical, enzymological, and functional data are equally inconclusive, but are definitely not compatible with a monocyte/macrophage profile. Analysis of the gene status documents that T-cell receptor beta- and gamma-chain genes are rearranged while immunoglobulin heavy chain genes are in germline configuration. The combined results indicate a T-cell origin of HDLM-2 cells. The evidence available from this and other established Hodgkin's disease derived cell lines suggests a lymphoid origin of Hodgkin and Reed-Sternberg cells.

Animals↗
PubMed1988

Effect of prostaglandin F2 alpha on human parathyroid adenomas: evidence for uncoupling of parathyroid hormone secretion and cAMP accumulation.

Human parathyroid adenomas are aberrantly regulated by extracellular calcium. We tested pertussis toxin, which ADP-ribosylates and inactivates several guanine nucleotide regulatory proteins, to test the role of these proteins in the secretory control of adenomatous parathyroid tissue. Pertussis toxin did not affect basal cAMP accumulation in 12 adenomas and enhanced parathyroid hormone (PTH) release in 6 of 10 adenomas. Prostaglandin F2 alpha (PGF2 alpha) inhibited cAMP in three of six adenomas, and pertussis toxin pretreatment did not affect this result. PTH release in 7 of 10 adenomas was inhibited by PGF2 alpha, and pertussis toxin did not significantly alter PTH release. Pertussis toxin catalyzed ADP-ribosylation of a 40-kDa protein in all adenomas tested (n = 8). We conclude that cAMP accumulation was not affected by pertussis toxin but that in 6 of 10 adenomas, the toxin enhanced PTH release. We suggest that cAMP accumulation and PTH release may be uncoupled from negative control by inhibitory ligands in adenomatous tissue or that the G-proteins involved do not couple to regulatory receptors or to effector.

Adenoma↗
PubMed1988

Mesencephalic dopamine cell deficit involves areas A8, A9 and A10 in weaver mutant mice.

The mesencephalic dopamine (DA) cell system was examined in mice homozygous and heterozygous for the weaver (wv) gene and in wild-type controls to estimate the extent of cell losses associated with the genetically determined central DA deficiency observed in weaver homozygotes. Animals of the three genotypes (+/+, wv/+, wv/wv) were studied at postnatal day (P)20 and P90. Serial coronal sections were obtained through the brainstem. Half of the sections were immunolabeled with antiserum to tyrosine hydroxylase (TH). Cell counts were obtained in areas A8 (retrorubral nucleus, RRN), A9 (substantia nigra, SN), and A10 (ventral tegmental area, VTA). The counts were analyzed with repeated measures analysis of variance followed by individual comparisons among group means. In A8, weaver homozygotes did not differ significantly from wild-type controls at P20, whereas there was a significant difference of 56% at P90. In A9, weaver homozygotes differed significantly from wild-type mice by 42% at P20 and by 69% at P90. The decrease in cell number between P20 and P90 in weaver homozygotes was 54%. In A10, weaver homozygotes did not differ significantly from wild-type controls at P20, whereas there was a significant difference of 26% at P90. Cell numbers in all three areas of heterozygotes did not differ significantly from wild-type control values at either age point. These findings demonstrate that by three months of age homozygous weaver mutants exhibit nerve cell losses in all three areas of the mesencephalic DA cell system. Such losses account for the DA deficiency seen in striatal, limbic and cortical projection fields.

Age Factors↗
PubMed1988

Synaptic connectivity of tyrosine hydroxylase immunoreactive nerve terminals in the striatum of normal, heterozygous and homozygous weaver mutant mice.

Striatal dopamine deficiency in weaver mutant mice is associated with loss of mesencephalic dopamine neurons. The maximum dopamine concentration in the striatum of weaver mutants is found on postnatal day 20, when it represents 50% of the control value. By day 180, it declines to 25% of the control value. Correspondingly, the number of nigral dopamine neurons is 58% of the normal number on day 20 and becomes 31% of the normal value by day 90. The aim of the present study was to examine whether dopamine axon terminals in the weaver striatum establish synaptic connections with postsynaptic neurons at the time when striatal dopamine concentration is at its peak value (i.e. on postnatal day 20), and if so, to compare the profile of synaptic connectivity of dopamine axon terminals found in the striatum of normal mice with that of heterozygous and homozygous weaver mutants. To that end, 20-day-old weaver homozygotes, along with age-matched weaver heterozygotes and wild-type mice were studied by electron microscopy after immunocytochemical labelling for tyrosine hydroxylase. A single micrograph of each of 1543 dopamine axon terminals was examined in total in the three genotypes; quantitative analyses of the relations of tyrosine hydroxylase immunoreactive nerve terminals were carried out in the dorsolateral striatum, which receives the dopamine projection from the substantia nigra proper. In all three genotypes, junctional contacts formed by tyrosine hydroxylase immunoreactive nerve terminals in the striatum were predominantly of the symmetrical type. In wild-type and heterozygous mice, the majority of contacts (92% and 91% respectively) were formed with dendrites and spines. In weaver mutant mice, the majority of contacts (87%) were also with dendrites and spines, but the proportion of axosomatic contacts was double that found in normal animals. The proportions of contacts that displayed junctional membrane specializations in single sections were 27% in wild-type mice, 29% in weaver heterozygotes, and 17% in homozygous weaver mutants. Taking into consideration that the plane of the section might not always have included the synaptic specialization, a stereological formula was applied. It was estimated that 85-89% of the contacts may be truly junctional in the striatum of normal and heterozygous mice, whereas only 53% may be junctional in the striatum of weaver homozygotes. The reduced incidence of junctional synapses in weaver homozygotes may suggest either inadequate synaptogenesis, or an early loss of synapses after their formation, or both.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Reinstatement of synaptic connectivity in the striatum of weaver mutant mice following transplantation of ventral mesencephalic anlagen.

Ventral mesencephalic anlagen survive following grafting to the striatum of weaver mutant mice and reinnervate the dopamine-depleted basal ganglia of the recipients. The aim of the present study was to examine the pattern of connectivity established by graft-deriving dopamine afferents in the host striatum. Grafts were obtained from normal embryos at a gestational age of 14-15 days and implanted into a surgical cavity overlying the dorsal striatum of adult weaver recipients. Tissue was processed for electron microscopic immunocytochemistry using a primary antiserum against tyrosine hydroxylase. At the time of examination, recipient weaver mutants were 8.5 months old and the grafts had survived for 4.5 months. Grafts were found to contain an estimated 100-1000 tyrosine hydroxylase immunoreactive neurons. Tyrosine hydroxylase immunoreactive fibres, displaying characteristic varicosities, innervated the dorsal striatum to a depth of 1000 micron. In the non-grafted striatum, 8% of the contacts of tyrosine hydroxylase immunoreactive nerve terminals were junctional. That proportion contrasted with the corresponding value of normal animals, which is 27%. In the grafted striatum, 29% of the contacts were junctional. That percentage approximated the value found in normal animals. By applying a stereological correction, it can be estimated from those numbers that the true proportion of junctional contacts in the non-grafted striatum of 8.5-month-old mutants may be 26%, whereas that in the grafted side may be 91%, which is close to the normal situation. The majority of contacts in the reinnervated striatum (84%) were made with dendrites and spines. However, the proportion of total axosomatic contacts in the reinnervated striatum was twice as high as that found in the striatum of normal animals, and the proportion of junctional synapses was three times higher than that found normally. We conclude that: (1) in spite of a genetically determined degenerative process, the dorsal neostriatum of weaver mutant mice is receptive to synaptic investment by dopamine afferents originating in normal donor tissue. (2) In repopulating the denervated weaver striatum, graft-deriving dopamine afferents display a connectional selectivity, i.e. they establish synaptic relations preferentially with those cellular domains that are normally innervated by dopamine nerve terminals. In this context, it is possible that dopamine fibres originating in the grafts invest postsynaptic sites that had either been vacated from the intrinsic dopamine input or had never received such an input. (3) The striatal connectivity following transplantation may retain features of immaturity as suggested by t

Animals↗