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Biomedical subjects

A Logan

Publications and source records attributed to A Logan.

At least 37 records · Page 2Linked to original sources
PubMed2000

Apoptosis during goitre involution - the role of Bcl-2.

Goitrogenesis is accompanied by hyperplasia and hypertrophy and involves tissue remodelling and angiogenesis. During the involution of the goitre there must be removal of this increased thyroid volume, in addition to further remodelling, which may involve apoptosis. We investigated apoptosis in the involuting rat thyroid using male Fisher rats that were on a goitrogenic regimen for 14 days and then returned to a normal diet. Thyroid weights increased fourfold with the goitrogenic regimen. During involution, the largest decrease in weight was between day 2 and day 4 after withdrawal of treatment. After 34 days of involution, the thyroid weight plateaued, but had not returned to control values. High levels of Bcl-2 immunoreactivity were observed in normal and goitrous rat thyroids. These high levels were significantly reduced at 2 days of involution, after which high levels of Bcl-2 immunoreactivity returned. In situ end-labelling of apoptotic cells showed that there was an increase in the number of cells undergoing DNA fragmentation during goitrogenesis (1.0+/-0.8 cells/100 cells, n=9) compared with controls, in which no positive staining was observed. After 2 days of goitrogen withdrawal, there was a further fourfold increase in the number of in situ end-labelled cells (day 16: 4.1+/-1.7, n=9). Numbers of positive cells returned to low levels after 4 days of involution (day 18: 0.3+/-0.8, n=9). Using antiserum to apoptosis-specific protein, we found increased immunoreactivity during goitrogenesis and after 2 days of involution that was localised predominantly with the stromal and vascular tissue at both time points. The data show that rapid downregulation of Bcl-2 accompanies thyroid involution, which involves increased levels of apoptosis within the stromal compartment.

Animals↗
PubMed1999

Decorin attenuates gliotic scar formation in the rat cerebral hemisphere.

The transforming growth factor-betas (TGF-betas) are potent fibrogenic factors implicated in numerous CNS pathologies in which fibrosis and neural dysfunction are causally associated. In this study, we aimed to demonstrate significant inhibition of fibrogenesis, glial scarring, and inflammation in penetrating incisional wounds of the rat brain using the proteoglycan decorin, which effectively inhibits TGF-beta activity. Adult rats were assigned to two treatment groups each receiving 14 daily intraventricular injections of 10 microliter total volume of: (i) saline plus 0.3% autologous rat serum = 30 microgram protein); or (ii) saline plus 30 microgram recombinant human decorin. On day 0 of the experiment, a stereotactically defined unilateral incisional lesion was placed through the cerebral cortex into the lateral ventricle and, after 14 days, brains were processed for immunohistochemical analysis of the lesion site. Specific antibodies were used to visualize the deposition within the wound of matrix molecules and the extent and nature of reactive astrocytosis and inflammation. Quantitative and qualitative image analysis of the fibrous scar was performed in sections from a defined anatomical plane through the wound to detect the antifibrotic effects of decorin treatment. Treatment of wounds with decorin led to a marked attenuation of all aspects of CNS scarring including matrix deposition, formation of an accessory glial limiting membrane, and inflammation. Our findings suggest that decorin is potentially applicable to a number of human CNS fibrotic diseases to arrest the deposition of excessive extracellular matrix components and maintain and/or restore functional integrity.

Animals↗
PubMed1999

Magnetic Resonance Imaging of Gases: A Single-Point Ramped Imaging with T1 Enhancement (SPRITE) Study.

A pure phase-encoding MRI technique, single-point ramped imaging with T1 enhancement, SPRITE, is introduced for the purpose of gas phase imaging. The technique utilizes broadband RF pulses and stepped phase encode gradients to produce images, substantially free of artifacts, which are sensitive to the gas T1 and T&ast:2 relaxation times. Images may be acquired from gas phase species with transverse relaxation times substantially less than 1 ms. Methane gas images, 1H, were acquired in a phantom study. Sulfur hexafluoride, 19F, images were acquired from a gas-filled porous coral sample. High porosity regions of the coral are observed in both the MRI image and an X-ray image. Sensitivity and resolution effects due to signal modulation during the time-efficient acquisition are discussed. A method to increase the image sensitivity is discussed, and the predicted improvement is shown through 1D images of the methane gas phantom. Copyright 1999 Academic Press.

Journal Article↗
PubMed1999

Pathophysiological Role of Growth Factors in Diabetic Kidney Disease: Focus on Innovative Therapy.

Various growth factors have been proposed to be players in the development of diabetic microvascular complications. In particular, the growth hormone/insulin-like growth factor system and the transforming growth factor beta system have measurable effects on the development of diabetic kidney disease through a complex intrarenal system. Recent findings indicating that these growth factors might be responsible for early renal changes in diabetes have provided insight into processes that might be relevant to the future development of new drugs useful in the treatment of diabetic kidney disease.

Journal Article↗
PubMed1999

Differential characteristics of human 15-lipoxygenase isozymes and a novel splice variant of 15S-lipoxygenase.

The lipoxygenases (LOs) are a family of nonheme iron dioxygenases that catalyse the insertion of molecular oxygen into polyunsaturated fatty acids. Five members of this gene family have been described in man, 5-LO, 12S-LO, 12R-LO, 15-LO and 15S-LO. Using partially purified recombinant 15S-LO enzyme and cells constitutively expressing this protein, we have compared the activity, substrate specificity, kinetic characteristics and regulation of this enzyme to that previously reported for 15-LO. 15S-LO has a threefold higher Km, similar Vmax and increased specificity of oxygenation for arachidonic acid, and a similar Km but decreased Vmax for linoleic acid in comparison to 15-LO. Unlike 15-LO, 15S-LO is not suicide inactivated by the products of fatty acid oxygenation. However, in common with other LOs, 15S-LO activity is regulated through calcium-dependent association of the enzyme with the membrane fraction of cells. In addition, whilst independently cloning the recently described 15S-LO, we identified a splice variant containing an in-frame 87-bp deletion corresponding to amino acids 401-429 inclusive. Modelling of the 15S-LO and subsequent studies with partially purified recombinant protein suggest that the deleted region comprises a complete alpha-helix flanking the active site of the enzyme resulting in decreased specificity of oxygenation and affinity for fatty acid substrates. Alternative splicing of 15S-LO would therefore provide a further level of regulation of fatty acid metabolism. These results demonstrate that there are substantial differences in the enzyme characteristics and regulation of the 15-LO isozymes which may reflect differing roles for the proteins in vivo.

Amino Acid Sequence↗
PubMed1999

Inhibition of glial scarring in the injured rat brain by a recombinant human monoclonal antibody to transforming growth factor-beta2.

The transforming growth factor-betas (TGF-betas) are potent fibrogenic factors implicated in numerous central nervous system (CNS) pathologies in which fibrosis and neural dysfunction are causally associated. In this study, we aim to limit the fibrogenic process in a model of CNS scarring using a recombinant human monoclonal antibody, derived from phage display libraries and specific to the active form of the TGF-beta2 isoform. The implicit inference of the work was that, as such antibodies are potential pharmacological agents for the treatment of human CNS fibrotic diseases, validation of efficacy in a mammalian animal model is a first step towards this end. Treatment of cerebral wounds with the anti-TGF-beta2 antibody led to a marked attenuation of all aspects of CNS scarring, including matrix deposition, formation of an accessory glial-limiting membrane, inflammation and angiogenesis. For example, in the wound, levels of: (i) the connective tissue components fibronectin, laminin and chondroitin sulphate proteoglycan; and (ii) wound-responsive cells including astrocytes and macrophages/microglia, were markedly reduced. Our findings suggest that such synthetic anti-fibrotic TGF-beta antibodies are potentially applicable to a number of human CNS fibrotic diseases to arrest the deposition of excessive extracellular matrix components, and maintain and/or restore functional integrity.

Animals↗
PubMed1999

Distinct sites of insulin-like growth factor (IGF)-II expression and localization in lesioned rat brain: possible roles of IGF binding proteins (IGFBPs) in the mediation of IGF-II activity.

Although expression of the IGF-II has been demonstrated within the central nervous system (CNS), past studies have failed to reveal its precise roles or responses subsequent to a traumatic injury. To demonstrate that IGF-II, IGFBP, and IGF receptor (-R) expression alters in response to a penetrating CNS injury, we used the techniques of ribonuclease protection assay, in situ hybridization, immunohistochemistry, Western blotting, and RIA. Under normal physiology, IGF-II expression is restricted to the mesenchymal support structures of the brain, including the choroid plexus, where its expression is coincident with that of IGFBP-2. Between 1-7 days post lesion (dpl), in the acute phase following a penetrant wound to the CNS, IGF-II and IGF-IIR protein, but not messenger RNA, were colocalized, with IGF-I, IGF-IR, and IGFBP-1, -2, -3, and -6, to neurons, macrophages, astrocytes, and microglia within the damaged tissue. Within the cerebrospinal fluid (CSF), levels of IGF-II peptide increased to peak at 7 dpl. IGFBP-2, -3, and -6 were also observed within the CSF, with IGFBP-2 predominating and exhibiting an increase in binding efficiency from 7-10 dpl. In the chronic phase of injury (7-14 dpl), an increase in both IGF-II, IGF-IIR and IGFBP-5 messenger RNA and protein was observed specifically and focally in the marginal astrocytes forming the limiting glial membrane of the wound. Thus, our evidence suggests that there are two mechanisms of action for IGF-II within the injured rat brain. During the acute phase, the secretion of IGF-II from the choroid plexus into the CSF is up-regulated, resulting in increased transport of the peptide to the wound. In the CSF, transported IGF-II is complexed to IGFBP-2 and essentially demonstrates an endocrine mode of action with a balance of locally produced IGFBPs modulating its bioactivity in the wound. Later in the wounding response, levels of IGF-II decline in the CSF and the wound neuropil, possibly with the aid of increased IGFBP-5 levels that may help to locally sequester and down-regulate IGF-II activity. Hence, in the chronic phase of the injury response, IGF-II reasserts itself to a predominantly autocrine/paracrine role restricted to the mesenchymal support structures, including the glia limitans, which may help reestablish and maintain tissue homeostasis.

Animals↗
PubMed1999

Use of flexible intermediate and intensive care to reduce multiple transfers of patients.

OBJECTIVE: To test an alternative flexible approach to traditional fixed intermediate and intensive care to minimize transfers of patients. METHODS: Patients admitted to a 28-bed nursing unit with intermediate care potential and a 12-bed intensive care unit at a 300-bed teaching community hospital were studied. The group included 524 patients with a discharge diagnosis code for mechanical ventilation. During eight 3-week cycles, 1073 transfers of patients were tabulated. A plan-do-study-act method was used to improve weaning from mechanical ventilation and reduce the number of inappropriate days in intensive care. Admissions and transfers to the 2 units for all patients during the eight 3-week cycles were compared over time. Length of stay and mortality were noted for all patients treated with conventional and noninvasive ventilation. RESULTS: Direct admissions to the flexible intermediate unit increased with no overall change in admissions to the intensive care unit. Fewer patients needed conventional ventilation, and more in both units were treated with noninvasive ventilation. The median number of transfers per patient treated with mechanical ventilation decreased from 1.94 to 1.20. Length of stay and mortality also decreased among such patients. Some cost savings were attributable to the decrease in the number of transfers. Transfers out of the hospital directly from the intensive care unit increased from 2.24% to 4.43%. CONCLUSIONS: In a community teaching hospital, flexible care policies decreased the number of in-hospital transfers of patients treated with mechanical ventilation.

Critical Care↗
PubMed1998

Digital blocks with adrenaline. An old dogma refuted.

In the early part of the century, when adrenaline first became widely available, it was used in an uncontrolled manner and cases of ischaemic necrosis led to it falling into disfavour for hand surgery. Local anaesthesia with adrenaline is currently widely used for palmar and dorsal hand surgery but there remains a very deeply ingrained resistance to its use for digital anaesthesia. It is widely thought that it will cause irreversible digital artery vasospasm. This prospective study reports the effect of 2% lignocaine with 1:80,000 adrenaline digital blocks on various parameters of digital arterial blood flow in 100 consecutive patients. Our findings show that adrenaline only temporarily reduced digital blood flow. Perfusion of the digits persisted in every case.

Adult↗
PubMed1997

Early active mobilization for extensor tendon injuries. The Norwich regime.

Dynamic splinting following extensor tendon repair gives better results than static splinting, but involves cumbersome splints and recommended protocols are often complicated. We prefer controlled active mobilization of extensor tendon repairs without dynamic splinting. Six weeks after repair, excellent or good function was obtained in 22 out of 24 simple extensor tendon injuries and in 11 out of 13 complex injuries. The results of this prospective study are comparable with those reported after dynamic splinting; this regime does not require outrigger splintage and is simple to follow.

Adult↗
PubMed1997

Hormonal control of insulin-like growth factor-binding protein-5 production in the involuting mammary gland of the rat.

We have demonstrated a 50-fold increase in the concentration of insulin-like growth factor-binding protein-5 (IGFBP-5) in milk after 2 days of mammary involution induced by removal of the suckling young. IGFBP-5 was identified by its immunoreactivity with an antiserum to IGFBP-5 and was shown by in situ hybridization to be synthesized by the secretory epithelial cells undergoing apoptosis. Smaller increases in IGFBP-2 and -4 messenger RNAs (mRNAs) were also evident, but neither protein could be detected on Western ligand blots of milk. Preliminary evidence failed to detect mRNAs for IGFBP-1, -3, or -6. The large increase in IGFBP-5 concentrations in milk from involuting mammary glands was inhibited by 90% if the dams received concurrent PRL injections for 2 days, but was unaffected by GH, progesterone, corticosterone, or an antiserum to insulin-like growth factor I (IGF-I). In lactating rats allowed to continue nursing their young, 17beta-estradiol failed to affect IGFBP-5 concentrations, whereas in animals that had half the teats sealed to prevent milk removal, IGFBP-5 concentrations increased 5- to 10-fold in the sealed gland compared with those in the contralateral gland where milk removal continued. The changes in IGFBP-5 concentrations in milk were accompanied by similar changes in steady state mRNA levels of IGFBP-5 in mammary tissue. We have previously shown that PRL inhibits apoptosis and involution of the mammary gland, whereas teat sealing has the opposite effect. We, therefore, propose that IGFBP-5 serves to inhibit IGF-I-mediated cell survival, but that it is normally suppressed by PRL and milk removal. Although IGFBP-5, when bound to extracellular matrix, augments the action of IGF, we believe that in the involuting mammary gland IGFBP-5 inhibits IGF action by interacting with casein micelles, which contain calcium phosphate nanoclusters, thereby preventing IGF interaction with IGF receptors. This is analogous to the interaction of IGFBP-5 with hydroxyapatite, which serves to sequester IGFs in bone. IGFBP-5 may, in fact, play a central role in inducing apoptosis, as it is also up-regulated in involuting prostate and thyroid glands as well as in atretic ovarian follicles.

Animals↗
PubMed1997

Spatial and temporal changes in the insulin-like growth factor (IGF) axis indicate autocrine/paracrine actions of IGF-I within wounds of the rat brain.

A precise role for insulin-like growth factors (IGFs), IGF-binding proteins (IGFBPs), and IGF-receptors (IGF-Rs) in damaged central nervous system (CNS) tissue has not been elucidated, although their expression in the ischemic brain has been demonstrated. However, little is known of IGF responses after CNS trauma. In this study, we have used ribonuclease protection assay, in situ hybridization, and immunohistochemistry to demonstrate that IGF-I, IGFBPs, and IGF-1R expression alters in response to a penetrating CNS injury. Within penetrant cerebral wounds in the acute phase of the response (1-7 days post lesion; dpl), increased levels of IGF-I, IGFBP-1, -2, -3, -6, and IGF-1R protein were localized to injury responsive astrocytes, neurons and cells of the monocyte lineage. IGF-I, IGFBP-2, and 3 showed a congruency in sites of messenger RNA (mRNA) and peptide expression, with IGF-I and IGFBP-2 mRNA expression predominating. IGF-I, IGFBP-1, and IGFBP-3 protein were also associated with the microvascular endothelium, which was accompanied by increased levels of IGFBP-3 mRNA. These early changes in IGFBP expression probably facilitate IGF-I action. Later in the wounding response (7-14 dpl), the expression of IGFBP-4 and IGFBP-5 peaked within astrocytes and neurons, with IGFBP-5 mRNA being specifically localized to the glia limitans within the wound, suggesting an inhibitory role for these proteins, down-regulating the effects of IGF-I chronically. Our evidence suggests that within penetrating CNS wounds, IGF-I acts in an autocrine/paracrine manner to regulate cellular responses, with its spatial and temporal availability being modulated by the differential presence of stimulatory vs. inhibitory IGFBPs.

Animals↗