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Biomedical subjects

T J Sims

Publications and source records attributed to T J Sims.

At least 91 records · Page 5Linked to original sources
PubMed1985

Lipoid proteinosis: an inherited disorder of collagen metabolism?

The dermal collagen of a patient with lipoid proteinosis was investigated by immunohistochemistry and biochemical analysis. The affected skin was found to contain significantly less collagen per unit dry weight than normal dermis but showed elevated levels of type 3 collagen with respect to type I. Purification of collagen types from affected skin after pepsin digestion showed no novel forms, but a doubling in the yield of type 5 collagen. These results correlated well with those of immunohistochemistry which showed a patchy, diffuse, widely distributed type 3 collagen and an increase in types 4 and 5 collagens associated with 'onion skin' endothelial basement membrane thickening. Estimation of collagen cross-links showed an abnormal pattern with a preponderance of the keto-imine form not normally associated with skin. These results strongly suggest that lipoid proteinosis involves a primary perturbation of collagen metabolism.

Adolescent↗
PubMed1985

Enzymatic regulation of glycoprotein synthesis in peripheral nervous system myelin.

The enzyme UDP-N-acetylglucosamine: dolichyl phosphate, N-acetylglucosamine-1-phosphate transferase initiates the synthesis of the oligosaccharide chain of complex-type glycoproteins. In view of the high content of glycoprotein in peripheral nerve myelin, the properties of this enzyme, its changes with age, and the effect of the specific inhibitor tunicamycin were investigated. The enzyme activity in rat peripheral nerve homogenate was completely dependent on the presence of exogenous dolichyl phosphate as well as Mg2+ and a detergent (Triton X-100) and was also greatly stimulated by a high salt concentration (0.4 M KCl) and AMP. The highest specific activity was present in the postmitochondrial membranes. The specific activity in postmitochondrial membranes in the presence of exogenous dolichyl phosphate reached a maximum at 17 days and remained relatively high throughout development, up to 2 years of age, but the activity was much lower when dolichyl phosphate was not added. This indicates that the enzyme level does not decrease with age, but that the content of the lipid cofactor may limit glycoprotein synthesis in vivo. Tunicamycin (5 micrograms) was injected intraneurally into 24-day-old rat sciatic nerve, and the enzyme was assayed from 1 to 24 days after injection. The specific activity of the transferase remained at low levels (5-40% of the level in control nerve) in most injected nerves assayed throughout this postinjection period. A protein previously identified as the unglycosylated P0 protein was synthesized in vitro by the tunicamycin-injected nerve and could be demonstrated to be incorporated into myelin in large amounts at 2 days and in small amounts at 6 days after injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylglucosamine↗
PubMed1985

Defective neutrophil and monocyte motility in patients with early onset periodontitis.

Several studies have documented suppressed polymorphonuclear neutrophil (PMN) chemotaxis in most patients with juvenile periodontitis. In contrast, data regarding PMN chemotaxis in patients with rapidly progressive periodontitis are very limited, and monocyte (MN) chemotaxis and random migration of PMNs or MNs from these patients have not been studied previously. Accordingly, we examined cell motility of PMNs and MNs from 27 patients with rapidly progressive periodontitis, 5 patients with juvenile periodontitis, and 37 normal control subjects by using a microchamber technique and the synthetic peptide N-formylmethionyl-leucyl-phenylalanine (FMLP) as the chemoattractant. As a group, PMNs and MNs from patients with rapidly progressive periodontitis manifested significantly enhanced random migration relative to control cells (P less than 0.001), suppressed directed migration (chemotaxis) at FMLP doses of 10(-9) and 10(-8) M (P less than 0.05), and enhanced directed migration at a dose of 10(-6) M FMLP (P less than 0.01). In contrast, PMNs from patients with juvenile periodontitis exhibited normal random migration, and directed migration was significantly suppressed at all doses of FMLP tested (P less than 0.05). An abnormality of either PMN or MN motility was observed in 26 of 27 patients with rapidly progressive periodontitis. Enhanced random migration was seen in PMNs in 63%, MNs in 39%, and both cell types in 26% of the patients. Suppressed chemotaxis was seen in PMNs in 85%, in MNs in 74%, and in both cell types in 69% of the patients. The prevalence and magnitude of abnormalities in motility were somewhat lower in treated than in untreated patients. Thus, most, if not all, of this subgroup of patients with early onset, highly destructive periodontitis have abnormalities in PMN or MN motility, and these defects may differ from those seen in cells from patients with the juvenile form of the disease.

Adolescent↗
PubMed1984

An improved method for assessing the incorporation of labeled precursors into DNA by human mononuclear cells.

The blastogenic responsiveness of activated lymphoid cells is usually assessed in vitro by measuring the incorporation of radioactive thymidine or iododeoxyuridine, a thymidine analog, into DNA. The accuracy of this method is compromised by the presence in activated and unactivated lymphocytes and in some of the substances used to activate them, of degradative enzymes which compete with DNA synthetase, the incorporation efficiency of exogenous precursor is inherently low. We have done studies aimed at improving both the efficiency and the accuracy of the assay system by selectively inhibiting the enzymes responsible for thymidylate synthesis de novo and DNA precursor degradation. Culture conditions were investigated and potential inhibitors were tested using human peripheral blood mononuclear cells activated with phytohemagglutinin. Nucleoside-degrading activity of mammalian and bacterial cells is due largely to nucleoside phosphorylases, enzymes that require orthophosphate for activity. We partly inhibited DNA precursor degradation by lowering the phosphate concentration in the culture medium and lowering the pH, thereby reducing the orthophosphate concentration. To reduce precursor degradation further, we tested several potential nucleoside phosphorylase and thymidylate synthetase inhibitors at various concentrations. Our data show that the addition of 1 mM fluorouracil and 1 mM deoxyuridine to the culture medium largely prevents degradation of radioactive thymidine and iododeoxyuridine without unduly compromising the DNA-labeling efficiency of cells activated with mitogens or bacterial homogenates. Under these conditions, label incorporation increases linearly as the number of blast cells or the labeling time increases.

Adolescent↗
PubMed1984

Cross-linking in type IV collagen.

Type IV collagen could not be extracted from human placenta using 6M-urea containing 10mM-dithiothreitol, indicating that the type IV molecule is stabilized within the basement membrane by covalent cross-links. However, various forms of type IV collagen molecule were extractable by means of increasingly severe proteolytic conditions. Type IV collagen tetramers ('spiders') lacking only the C-terminal globular region (NC1) were further digested to the 'long-form' 7S fragment and an assortment of helical rod-like molecules derived from the 'leg' region. These molecules were separated by salt fractionation and examined by rotary-shadowing electron microscopy. Isolation of these fractions from placenta which had been reduced with NaB3H4 revealed that both the 7S (N-terminal) and C-terminal regions contained significant proportions of reducible lysine-derived cross-links. These cross-links were shown to be exclusively the stable oxo-imine hydroxylysino-5-oxonorleucine. The number of the cross-links per molecule was significantly lower than might be expected in order to fully stabilize the molecule. These results suggest that the keto-imine cross-links in type IV collagen have been stabilized in part by conversion into an unknown non-reducible form, although a sensitive immunoassay failed to show the presence of any pyridinoline. Comparison with the fibrous collagen from placenta suggested that the rate of this conversion is much greater in basement-membrane collagen.

Basement Membrane↗
PubMed1984

Specificity in central myelination: evidence for local regulation of myelin thickness.

The ventral funiculi of normal and X-irradiated 13-day-old rats were studied by electron microscopy. In both tissues, oligodendrocytes form myelin sheaths around multiple axons, with a single oligodendrocyte associated with several axons of different sizes. Despite their origin from the same glial cell, the myelin sheaths are thicker for larger axons. Polyribosomes and rough endoplasmic reticulum are observed in distal oligodendrocyte processes, in proximity to the forming myelin sheaths. These results indicate that myelin sheath thickness is matched to axon size via local mechanisms, and suggest a role of polyribosomes and/or rough endoplasmic reticulum in myelin formation.

Animals↗
PubMed1984

Congenital dislocation of the hip: a possible inborn error of collagen metabolism.

Significant changes in the type of collagen, the fibril diameter and the nature of the crosslinks have been demonstrated in the joint capsules of subjects with congenital displacement of the hip (CDH). These changes are probably tissue specific since no detectable change could be observed in the skin of these subjects compared to controls. These preliminary biochemical studies clearly demonstrate that CDH involves an error in collagen metabolism.

Child, Preschool↗
PubMed1984

Central canal area in the early postnatal rat: normal development and radiation-induced changes.

The spinal central canal area in the early postnatal rat differs markedly in appearance from that in the adult. Dorsally and ventrally, the walls of the canal lack nuclei and appear to be composed of processes from cell bodies at some distance from the lumen. Additionally, a densely packed cluster of cells similar to those in the lateral walls is situated ventral to the canal area. Preliminary data indicated that the cells in this cluster were extremely susceptible to ionizing radiation; the present study: (1) characterizes these cells ultrastructurally in the normal animal; and (2) examines radiation-induced changes. Ultrastructurally, the cells forming this cluster in the normal 3-day-old rat were tightly packed, and their outlines followed the contours of adjacent cells. The cytoplasm, which contained an abundance of organelles, including distinct, wide-bore endoplasmic reticulum with darkly stained cisternae, occasionally surrounded bundles of axons. Synapses and junctional complexes were absent. Both nuclear and cytoplasmic characteristics are those of immature astrocytes. By 6 h following irradiation of the 3-day-old, many cells in this cluster were pyknotic, and by 24 h the cluster had essentially disappeared. The number of cells surrounding the lumen decreased less rapidly than in the cluster. By 10 days post-irradiation (P-I) this number was approximately 39% less than in the control. These changes indicated a differential sensitivity to ionizing radiation between the cells of the ventral cluster and those elsewhere in the central canal area.

Animals↗
PubMed1983

Interactions between intraspinal Schwann cells and the cellular constituents normally occurring in the spinal cord: an ultrastructural study in the irradiated rat.

Relationships between intraspinal Schwann cells and neuroglia, particularly, astrocytes, were studied following X-irradiation of the spinal cord in 3-day-old rats. Initially, this exposure results in a depletion of the neuroglial population. By 10 days post-irradiation (P-I), gaps occur in the glia limitans, although the overlying basal lamina remains intact. Development of and myelination by intraspinal Schwann cells is well underway by 15 days P-I. These Schwann cell-occupied regions have a paucity of astrocyte processes, a finding which persists throughout the study (60 days P-I), and several types of Schwann cell-neuroglial interfaces are observed, including: (1) astrocyte separation of Schwann cells from oligodendrocyte-myelinated regions; (2) intermingling of Schwann cell-myelinated axons and oligodendrocyte-myelinated axons in the absence of astrocyte processes; and (3) ensheathment of unmyelinated axons by astrocyte processes which separate these axons from the Schwann cells. The gaps in the glia limitans widen as the P-I interval increases. At 45 and 60 days P-I, the basal lamina no longer forms a singular, continuous covering over the spinal cord surface, but follows instead a rather tortuous course over the disrupted glia limitans and the intraspinal Schwann cells. Although the mode of initial occurrence of Schwann cells within the spinal cord is not yet understood, the data indicate that the astrocyte population is involved in that process, as well as in limiting the further development of Schwann cells within the substance of the spinal cord.

Aging↗
PubMed1983

An investigation of the biochemical and histological changes in the collagen of the kidney and skeletal muscle in systemic sclerosis.

Changes in the distribution and quantity of different collagen types in some internal organs was determined in tissues from patients with systemic sclerosis. In addition, sera from patients with systemic sclerosis were assayed for circulating anti-collagen antibodies and were compared with normal sera. The results of a specific immunohistological survey of skeletal muscle and kidney showed a general increase in type I and III collagens in the fibrotic lesions when compared with age matched normal tissue. A thickening of basement membranes was also observed. Biochemical quantitation of the ratio of types I and III collagens in normal and affected kidney showed up to a three-fold increase in type III compared to type I collagen, consistent with the immunohistological data. Finally, quantitation, by the ELISA technique, of circulating anticollagen antibodies in sera from patients with systemic sclerosis demonstrated positive results for types I, III and IV collagens when compared with normal controls. These results are discussed in relation to the clinical progression and possible mechanisms of pathogenesis of the disease.

Adult↗
PubMed1983

Effect of factors other than pathologic status on responsiveness of peripheral blood mononuclear cells from patients with chronic periodontitis.

Studies were designed to assess factors other than pathologic status of the cell donor which affect the blastogenic responsiveness in vitro of peripheral blood mononuclear cells (PBMs) from normal donors and patients with periodontitis. Cultures were established and activated using phytohemagglutinin-P (PHA) or homogenates of Actinomyces viscosus (AVIS), a gram-positive plaque microorganism, and Fusobacterium nucleatum (FUSO), a gram-negative plaque microorganism. Activation was assessed by measuring the incorporation of labeled precursor into DNA. The effects of incubation time, vessel shape, cell concentration, prostaglandin E2 and indomethacin on blastogenic responsiveness were studied. Blastogenic responsiveness became maximal after 5 to 8 days' activation with the bacterial substances, and after 3 days' activation with PHA. Radioactivity incorporated by cultures in microtest wells with flat, round and conical bottoms was 5.9, 7.8 and 10.6 X 10(3) cpm, respectively. Cultures of cells from all of the patients and normal subjects were activated by PHA, AVIS and FUSO, and cell concentration was a major determinant of the magnitude of the blastogenic response. Responsiveness of cultures from all patients and control subjects activated with AVIS and FUSO was inhibited significantly by prostaglandin E-2 (PGE2) at a concentration of 10 microM. Inhibition was generally 50% or greater. Indomethacin, an inhibitor of prostaglandin production, at a concentration of 0.5 micrograms/ml significantly enhanced responsiveness of AVIS- and FUSO-activated cultures from control donors and patients, indicating that prostaglandins are produced endogenously, and that they affect cell responsiveness. The effect of PGE2 and indomethacin on PHA-activated cultures was more variable and, where present, of a lesser magnitude than that observed for cultures activated with bacterial homogenates. In most cultures the effects were not statistically significant. Our data show that in studies of lymphocyte activation, the incubation time, culture-vessel shape, cell concentration and presence of endogenous inhibitors need to be taken into account.

Adult↗
PubMed1982

Autoradiographic and ultrastructural studies of areas of spinal cord occupied by Schwann cells and Schwann cell myelin.

Schwann cells, peripheral-type myelin and connective tissue elements develop within the dorsal portion of the X-irradiated spinal cord in immature rats. Factors controlling the distribution of these elements within the irradiated site are not fully understood. In the present study [3H]thymidine autoradiography was used to examine proliferative activities of cells in these areas occupied by peripheral nervous system components, and correlative ultrastructural evaluations were made. At 15 and 20 days post-irradiation (P-I), the Schwann cells occupied the dorsolateral portions of the dorsal funiculi, and heavily labeled cells occurred throughout these areas. By 25 days P-I the Schwann cells extended ventrally into the depths of the dorsal funiculi and into the dorsal gray matter, and labeled cells were concentrated in the deeper portions of these areas. Ultrastructurally, the Schwann cells and peripheral-type myelin were more mature in the superficial portions where proliferative activity was diminished. In contrast, much less mature, peripheral-type myelin occurred in the depths where the labeled cells were concentrated. At 30 and 45 days P-I, labeled cells were much less frequent but usually occurred in the depths when observed. Similarly, a dorsal-ventral gradient in maturity of peripheral-type myelin was evident ultrastructurally. By 60 and 90 days P-I, labeling was rare, and mature Schwann cell myelin was present throughout the areas. Astrocytes and their processes were less numerous in regions invaded by Schwann cells, as compared to controls, and studies are in progress to evaluate the relationships between these glial elements and intraspinal peripheral nervous system components.

Animals↗
PubMed1982

Effects of endogenous and exogenous inhibitors on the incorporation of labeled precursors into DNA by human mononuclear cells.

The degree of responsiveness of lymphoid cells to activation by mitogens and antigens is commonly assessed in vitro by measuring radioactive DNA precursor incorporation. Several lines of evidence indicate that artifacts affect the results and that these measurements may not be an accurate reflection of cell activation. Cultures of blastogenically activated lymphocytes contain soluble, noncytotoxic factors that inhibit the incorporation of radioactive nucleosides into DNA by dividing cells without affecting their rate of DNA synthesis. Inhibitors were found in the serum component of the medium and in the bacterial homogenates used to activate the cells, and they were produced by the activated cells. Inhibitor activity in serum has properties expected of a nucleoside such as thymidine, including a molecular weight of less than 10(3). The inhibitor activity present in some bacterial homogenates and that produced by activated cells enzymically degrade labeled DNA precursors, thereby preventing their availability for incorporation. Other bacterial preparations contain DNA precursors, which compete with labeled nucleosides for incorporation, and additional low-molecular-weight inhibitor is produced when the preparations are incubated. Preparations of various bacteria differ greatly with regard to the potency of their inhibitor activity. In some cases incorporation of label in activated cultures is reduced to background levels. Inhibition by these substances leads to erroneous conclusions regarding the proliferative activity of cultured lymphocytes, since the amount of label incorporated does not accurately indicate the true rate of DNA synthesis of the cells.

Actinomyces↗
PubMed1981

Genetically associated similarities and differences in the generation of neurons comprising an early developing reflex pathway in mouse spinal cord.

Tritiated thymidine autoradiography has been used to study the generation of lateral motor neurons (LMNs), association interneurons (ANs) and dorsal root ganglion cells (DRGNs) in the spinal cords of genetically diverse strains of mice. The neuronal populations analyzed in this study form an early developing reflex pathway and the ontogeny of this circuit exhibits genetically associated variability. The strains of mice used in this investigation have been shown to differ in the embryonic age at which forelimb reflex movements are first manifest and in the timing of synapse formation within the reflex pathway. A precocious development of these reflex traits occurs in strain C57BL/6J in comparison to embryos of intermediate (CBA/CaJ) and late developing (LP/J) strains. All three inbred strains show the same basic generation sequence for the neuronal populations comprising the forelimb reflex pathway. The generation of LMNs precedes that of ANs, and the generation of ANs, in turn, precedes that of DRGNs. Since this is the same sequence as that observed for the formation of synaptic junctions in all three strains, it is suggested that synaptogenic sequences in reflex circuits may be determined by the generation sequence of the component neuronal populations. Although the strains all exhibit the same basic sequence of neuronal generation, the temporal relationships of the generation of each cell population within this sequence show significant strain dependent variations. C57BL/6J displays a larger temporal separation between the generation of each cell type than LP/J, and CBA/CaJ is intermediate to the other two strains in this respect. The fact that this strain order is identical to that observed for the development of reflex traits suggests that genetically associated differences in the timing of neuronal birthdays within a common generation sequence may have a substantial influence on the timing of synaptogenesis within the reflex pathway.

Animals↗
PubMed1980

Biochemistry and histology of the connective tissue of Dupuytren's disease lesions.

When compared to age-matched control aponeurosis, lesions of Dupuytren's disease contain higher contents of water, collagen and chondroitin-sulphate, as well as increased proportions of soluble collagens and of reducible cross-links; these indicate synthesis of new collagen. The lesions show also increased amounts of type III collagen and an increased hydroxylation and glycosylation of the reducible cross-links. All these parameters are characteristic of granulation and scar tissues. Type III collagen was located by means of immunofluorescence on thin argyrophilic fibres and also within the large fibre bundles which appeared to be disrupted into microbundles. The increase of type III collagen and the presence of myofibroblasts in the apparently unaffected aponeurosis show that the disease is widespread and suggest that it is initiated within the aponeurosis and propagated by the cells migrating along the collagen bundles.

Adult↗