Prediction and prevention in endocrinology.
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Animals↗
Biomedical subjects
A Logan
Publications and source records attributed to A Logan.
Central action of basic fibroblast growth factor on ingestive behaviour in mice.
Intracerebroventricular (ICV) infusion of basic fibroblast growth factor (FGF-2) at 50 ng/h for 5 days in male BALB/c mice suppressed the daily intakes of water and food (n = 4). Intakes were reduced on the second day, and were suppressed until the second day after stopping the infusion. The same infusion for 4 days had little effect on the high intakes of 0.3 M NaCl solution and water induced by prolonged ICV infusion of angiotensin II, or the daily food intake in these experiments (n = 7). However, the same infusion for 3-4 days reduced the increased intake of NaCl solution in Na-depleted mice (n = 8), reduced the increased water intake of water-restricted mice (n = 6 or n = 7), and reduced daily food intake in both experiments. Ventricular enlargement was noted in mice at the end of these experiments but, for reasons advanced, did not appear to account for the responses. The results indicate that FGF-2 may have an inhibitory role in these ingestive behaviours.
Angiotensin II↗
Effects of sodium status on the venous response to noradrenaline infusion in pre-ascitic cirrhosis.
1. This study assesses the effects of sodium status on venous responsiveness to noradrenaline and the neurohumoral profile in pre-ascitic cirrhotic patients. Eight cirrhotic patients and ten control subjects were studied after both a low (20 mmol/day) and a high (200 mmol/day) sodium diet. Venous responsiveness to increasing doses of noradrenaline in a dorsal hand vein and various plasma hormone levels were measured. Maximal response (Rmax.) and the dose of noradrenaline that yielded 50% of Rmax. (ED50) were then calculated. 2. A significantly smaller dorsal hand vein diameter was observed in the control subjects on a low sodium (2.23 +/- 0.14 mm) compared with a high sodium (2.57 +/- 0.15 mm; P = 0.04) diet, but not in the cirrhotic patients. Rmax. was not significantly different in either group on both diets. With low sodium intake, ED50 was similar in the two groups. However, on high sodium intake, control subjects had a significantly higher ED50 (34.4 +/- 7.4 ng/min) than the cirrhotic patients (5.03 +/- 0.86 ng/min; P < 0.003). Plasma noradrenaline in the control subjects fell significantly with the change from a low (1.29 +/- 0.11 nmol/l) to a high (0.68 +/- 0.09 nmol/l; P < 0.001) sodium diet, but remained elevated in the cirrhotic patients. Cirrhotic patients had significantly higher atrial natriuretic factor levels and lower plasma renin activity than the control subjects on both diets. 3. In conclusion, pre-ascitic cirrhotic patients show no evidence of venodilatation. Their sympathetic nervous activity is not suppressible by volume expansion. Relative hyper-responsiveness of the peripheral venous circulation to adrenergic stimulation with high sodium intake is present.
Adult↗
Speaking on behalf of nurses. Speaking on behalf of AURN.
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Delivery of Health Care↗
Systemic hemodynamic, forearm vascular, renal, and humoral responses to sustained cardiopulmonary baroreceptor deactivation in well-compensated cirrhosis.
The aim of this study was to assess baroreceptor function in well-compensated cirrhosis by determining the forearm vascular, renal, and humoral responses to sustained baroreceptor deactivation. The effect of sodium status on baroreceptor function was also assessed. Eight cirrhotic patients and 10 age- and sex-matched controls were studied twice after a 20 mmol and 200 mmol of sodium/d diet for 7 days. Systemic and renal hemodynamics, renal sodium handling, forearm blood flow, and neurohumoral factors were assessed before, during, and after the application of lower body negative pressure (LBNP) for 1 hour. Controls and cirrhotic patients had similar baseline mean arterial pressure, heart rate, forearm and renal hemodynamics. High-sodium intake resulted in suppression of sympathetic nervous activity in the controls (plasma norepinephrine, 1.06 +/- 0.11 nmol/L on low vs. 0.76 +/- 0.08 nmol/L on high sodium; P = 0.01) but not in the cirrhotic patients (1.35 +/- 0.22 nmol/L on low vs. 1.26 +/- 0.11 nmol/L on high sodium; P > 0.05). Both groups responded to LBNP with significant further increases in plasma norepinephrine, resulting in significant decreases in forearm blood flow on both sodium diets. Controls also responded with a significant worsening of renal hemodynamics on low-sodium diet only, but this was not observed in the cirrhotic patients on either diet. Therefore, in well-compensated cirrhotic patients: (1) sympathetic activation occurs despite an adequate, effective arterial filling, and this may contribute to sodium retention; and (2) baroreceptor function is normal. Apparent end organ unresponsiveness within the renal circulation may account for the lack of renal hemodynamic changes to reflex sympathetic stimulation.
Adult↗
Effects of transforming growth factor beta 1 on scar production in the injured central nervous system of the rat.
In the central nervous system (CNS), nerve regeneration after traumatic injury fails. The formation of a dense fibrous scar is thought to restrict in part the growth of axonal projections, providing one of the many reasons that complete lesions of neural pathways in the adult mammalian CNS are rarely followed by significant functional recovery. In order to determine which mechanisms mediate scar formation in the CNS and to investigate whether they can be modulated in vivo, we have attempted to define the potential role of trophic factors. Our previous studies have shown the focal elevation of transforming growth factor beta 1 (TGF beta 1) expression in lesioned CNS tissue. In the studies described here, we demonstrate that TGF beta 1 participates in the scarring response in the rat brain. First, the elevated protein levels of TGF beta 1 are localized to specific populations of injury-responsive cells in the traumatized CNS. Furthermore, the injection of TGF beta 1 into the brains of injured rats causes a dramatic increase in the scarring response. Conversely, when neutralizing TGF beta 1 antibodies are administered, the deposition of fibrous scar tissue and the formation of a limiting glial membrane that borders the lesion is significantly attenuated, thus establishing a role for the endogenous growth factor in regulation of the non-glial component of the scar. In implicating TGF beta 1 in the scarring response in the CNS, the potential use for TGF beta 1 antagonists as inhibitors of scar formation in the injured mammalian CNS is self-evident.
Animals↗
Growth factors in CNS repair and regeneration.
Traumatic central nervous system (CNS) injury is a significant clinical problem in the developed world. After injuries that penetrate into either the mature brain or spinal cord, damaged neurons initially begin to regrow, but this regeneration is aborted as a fibrotic scar is laid down within the wound. Reconnection of several neuronal pathways does not occur. Functional recovery from such injuries is therefore poor and morbidity severe, particularly for those patients with spinal cord damage. Although palliative measures are available to improve the quality of life, there is no accepted treatment to restore impaired sensory or motor function, so patients remain significantly and permanently debilitated. However, the rapid recent advances that have been made in our understanding of the underlying cellular and trophic pathology of such injuries offer the potential for development of novel therapies to control scarring, enhance neuron survival and stimulate axon regeneration, thereby promoting functional recovery.
Animals↗
Fibroblast growth factor in the hypothalamic-pituitary axis: differential expression of fibroblast growth factor-2 and a high affinity receptor.
In situ hybridization and immunohistochemistry were used to map gene expression and protein distribution of basic fibroblast growth factor (FGF-2) in the hypothalamic-pituitary system. Although the expression of FGF-2 mRNA in the pituitary is low, the protein is widely distributed in both its neural and anterior lobes. In the anterior lobe, immunoreactive (ir-) FGF-2 localizes to basement membranes and select endocrine cells. In the neural lobe, ir-FGF-2 is detected in basement membranes, pituicytes, and Herring bodies. Analyses of FGF high affinity receptor (FGFR) immunoreactivity in the anterior pituitary establishes a distribution of FGFR similar to that of FGF-2. In the neural lobe, ir-FGFR is associated with nerve fibers, pituicytes, and Herring bodies. Unlike FGF-2, the distribution of FGFR1 mRNA correlates well with the presence of the immunoreactive receptor. In the hypothalamus, magnocellular neurons of paraventricular and supraoptic nuclei contain ir-FGF-2 and ir-FGFR. In the median eminence, ir-FGF-2 and ir-FGFR is associated with fibers, glial, and endothelial cells. Ependymal and subependymal cells lining the third ventricle also show high levels of ir-FGF-2 and ir-FGFR and mRNAs. Overall, there is a specific and selective distribution of FGF-2 and its high affinity receptor(s) in the hypothalamo-pituitary axis. This localization lead us to postulate a role in neurohypophyseal functions, possibly water balance.
Animals↗
Coordinated pattern of expression and localization of insulin-like growth factor-II (IGF-II) and IGF-binding protein-2 in the adult rat brain.
Insulin-like growth factors (IGFs) have numerous actions on neuronal and glial cell function in vitro, although their in vivo roles within the central nervous system (CNS) remain undefined. Levels of IGF-II are high in most rat tissues before the third postnatal week, but rapidly decrease thereafter, except in the brain and spinal cord, where elevated titers are present in the adult. This suggests a function of IGF-II within the CNS. IGF-binding proteins (IGFBPs) modify the type 1 IGF receptor-mediated activity of IGFs, thereby regulating the activities of IGF-II in the CNS. In this study, we use a ribonuclease protection assay, in situ hybridization, and immunohistochemistry to demonstrate that IGF-II and one of the major CNS binding proteins, IGFBP-2, show a striking congruency in their anatomical pattern of expression and localization throughout the adult rat brain. Both proteins are synthesized predominantly in the leptomeninges, choroid plexus, and parenchymal microvasculature, but become localized, remote from the site of synthesis, in the myelin sheaths of individual myelinated axons and in all of the myelinated nerve tracts in the brain, which presumably represents the site of IGF-II bioactivity. The spatial disparity between sites of synthesis and sites of bioactivity suggests a key role for IGFBP-2 in the regulation of IGF-II bioavailability within the brain.
Animals↗
Enhanced expression of transforming growth factor-beta 1 during thyroid hyperplasia in rats.
Transforming growth factor-beta 1 (TGF-beta 1) has been reported to influence the growth rate and iodine uptake and organification in vitro by isolated thyrocytes. We have determined changes in the expression and presence of TGF-beta 1 within the rat thyroid during goitre induction, and subsequent involution following goitrogen withdrawal. Hyperplastic goitres were induced in adult rats by administration of methimazole together with a low iodine diet for up to 12 weeks. Goitrogen-treated rats quickly became hypothyroid compared with controls, and exhibited thyroid hyperplasia and hypertrophy assessed by thyroid weight, and DNA and protein content (control: total serum thyroxine (T4) 66 +/- 4 nmol/l, thyroid weight 5 +/- 1 mg/100 g body weight, mean +/- S.D., n = 10; 2 weeks goitrogen: T4 undetectable, thyroid weight 27 +/- 4 mg/100 g, n = 10). Thyroid growth rate slowed subsequently between 2 and 10 weeks. Messenger RNA for TGF-beta 1 was compared in the thyroids and livers of control and goitrous rats by ribonuclease protection assay. Low levels of mRNA for TGF-beta 1 were detected in thyroids from control rats at all time-points, while TGF-beta 1 mRNA was barely detectable in liver. Thyroid TGF-beta 1 mRNA levels substantially and progressively increased at 1 and 2 weeks of goitrogen treatment respectively, and remained above control levels at 4 and 10 weeks. As thyroid involution occurred 4 weeks following goitrogen withdrawal, so thyroid TGF-beta 1 mRNA levels declined. In control animals, the cellular localization of TGF-beta 1 mRNA, determined by in situ hybridization, was found to be a subpopulation of follicular epithelial cells, and immunohistochemical co-localization of TGF-beta 1 and calcitonin identified these tentatively as parafollicular or C-cells. During goitre formation, abundant TGF-beta 1 mRNA and peptide were found to be widely distributed within the entire follicular epithelium. While this ubiquitous distribution had largely disappeared in the involuting gland, TGF-beta 1 peptide was retained within the parafollicular cells, which appeared more abundant than in thyroids from control animals. These results suggest that an increased local expression of TGF-beta 1, a putative growth inhibitor, during thyroid hyperplasia may contribute to the temporal stabilization of goitre size.
Animals↗
Increase of basic fibroblast growth factor (FGF) and FGF receptor messenger RNA during rat thyroid hyperplasia: temporal changes and cellular distribution.
Goitre was induced in adult rats by acute (1 or 2 weeks) or chronic (4 or 10 weeks) administration of methimazole together with a low iodine diet. Involution of thyroid growth was then observed at 16 weeks, 4 weeks after withdrawal of goitrogens and reversion to a normal diet. Experimental animals quickly became hypothyroid compared with controls and exhibited thyroid hyperplasia (control (n = 10): total serum thyroxine (T4) 66 +/- 4 nmol/l, thyroid weight 5 +/- 1 mg/100 g body weight, means +/- S.D.; experimental (n = 10): T4 undetectable, thyroid weight 27 +/- 4 mg/100 g body weight after 2 weeks of treatment). Thyroid growth rate subsequently slowed between 2 and 10 weeks. Messenger RNA for basic fibroblast growth factor (basic FGF) and for the high-affinity FGF receptor, was compared in the thyroids and livers of control and goitrous rats by ribonuclease protection assay. Low levels of mRNA for basic FGF and its receptor were detectable in thyroids from control rats at all times, while none was detected in the livers from any animal. Basic FGF and receptor mRNAs increased, and were detected at greatest abundance in hyperplastic thyroids at 1 and 2 weeks respectively, during goitre formation, but subsequently declined in parallel with thyroid growth rate at 4 and 10 weeks. When quantified by radioimmunoassay, basic FGF extracted from thyroids was fivefold greater than in controls after 1 week of goitrogen treatment (control (n = 4): 24 +/- 9 pmol/micrograms DNA; goitre (n = 4): 100 +/- 16 pmol/micrograms DNA; P < 0.05). Basic FGF and FGF receptor mRNAs localized by in situ hybridization predominantly to the epithelial cell population within follicles. Localization by immunohistochemistry demonstrated that basic FGF was present in the thyroids of control rats, and was largely associated with the basement membrane of follicles. During thyroid hyperplasia, increased basic FGF immunoreactivity appeared over the cytoplasm of follicular epithelial cells and was lost from the extracellular matrix. Thyroid involution following removal of goitrogen/low iodine treatment was associated with a decrease in mRNA for basic FGF or its receptor, and a loss of immunoreactive basic FGF from the cytoplasm of follicular cells. These results suggest that autocrine expression of basic FGF and FGF receptor could contribute to thyroid hyperplasia in rats.
Animals↗
Altered expression of insulin-like growth factor-I (IGF-I) and IGF binding proteins during rat thyroid hyperplasia and involution.
We have investigated changes in the synthesis and localization of insulin-like growth factor (IGF)-I and IGF binding proteins (IGFBPs) in thyroid tissues during the induction of goitre in iodine-deficient rats, and during the subsequent involution of the gland following goitrogen withdrawal. Goitre was induced in adult rats by acute (1 or 2 weeks) or chronic (4 or 10 weeks) administration of methimazole together with a low iodine diet. After twelve weeks the goitrogenic stimuli were removed and thyroids examined 4 weeks later. Circulating T4 levels became undetectable within two weeks of goitrogen administration while thyroid weight had increased five-fold. The thyroids continued to increase in size up to 10 weeks, but at a slower growth rate. IGF-I mRNA, detected by ribonuclease protection assay, was present in the control rat thyroid and increased in abundance after both 1 and 2 weeks of goitrogen administration. Levels of IGF-I mRNA showed a relative decline with prolonged goitrogen administration, and following thyroid involution the hybridization signal was similar to that seen in control glands. Northern blot hybridization showed that IGFBP-2, -3 and -5 mRNAs were all present in growth-quiescent, control thyroids and those encoding IGFBP-2 and -3 were elevated in the goitrous glands and remained so as long as goitrogen was administered, thereafter declining during thyroid involution. IGF-I and IGFBP-2 and -3 mRNAs and synthesized peptides, detected by in situ hybridization and immunohistochemistry respectively, were found to co-localize predominantly in follicular epithelial cells. IGFBP-5 mRNA abundance was unaltered during goitre formation, but was increased in the involuting thyroid. Both IGFBP-5 mRNA and peptide were localized to the parafollicular cells (C-cells) which were increased in number during involution. The results suggest that an increased expression of IGF-1 may contribute to early goitre formation, but that a relative increase in the abundance of IGFBP-2 and -3 may limit IGF availability at later times, and facilitate a slowing of thyroid growth rate. The discrete expression of IGFBP-5 by C-cells suggests that it could contribute indirectly to goitre formation or involution by acting in a paracrine fashion.
Animals↗
Angiogenesis.
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Angiogenesis Inducing Agents↗
Making calcium signals selective.
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Animals↗
Transforming growth factor-beta 1 and basic fibroblast growth factor in the injured CNS.
After injuries that penetrate the mature brain or spinal cord, damaged axons initially show a growth response, but later their regeneration is aborted as a dense permanent scar is laid down within the core of the wound. Functional recovery from such injuries is poor and morbidity is severe, particularly for those patients with spinal cord damage. Clinically, no long term therapeutic treatments have been developed that might inhibit scarring and promote neuronal growth. Consequently, the prevalence of patients permanently disabled from head and spinal cord injury is high, estimated at more than 1:1000 of the population of North America (Office of Technology Assessment USA, 1990). Ann Logan and Martin Berry define the mechanisms that underlie the wound healing response in the CNS and discuss the rationale for the development of novel therapeutic strategies.
Animals↗
The presence of myofibroblasts in the dermis of patients with Dupuytren's contracture. A possible source for recurrence.
Samples of skin and underlying cord obtained at dermofasciectomy for Dupuytren's contracture have been examined for the presence of smooth muscle alpha-actin (SM alpha-actin), a marker for myofibroblasts. 15 of the 20 samples stained positively for SM alpha-actin corresponding with areas of hypercellular Dupuytren's tissue. In 12 of these 15 samples SM alpha-actin-positive hypercellular Dupuytren's tissue extended into the dermis, in three cases reaching the epidermis. In eight samples, diffusely distributed cells positive for SM alpha-actin and resembling fibroblasts were seen in the dermis. These cells appeared to be separate from the Dupuytren's foci. The presence of hypercellular foci and isolated fibroblasts positive for SM alpha-actin within the dermis may explain the high recurrence rate of Dupuytren's disease after fasciectomy.
Actins↗
Correlation of proto-oncogene expression and proliferation and meningiomas.
Proliferation and proto-oncogene expression in 19 meningiomas of typical and atypical histology were analyzed in an attempt to understand the mechanism of growth that characterizes the neoplastic process in these tumors. Proliferation was estimated as the proliferative index by the enumeration of S-phase cells in imprints of tumor tissue exposed to bromodeoxyuridine in vitro, and the gene expression of c-myc, c-fos, c-src, c-H-ras, N-myc, acidic and basic fibroblast growth factor, insulin-like growth factors I and II, platelet-derived growth factor-alpha, and epidermal growth factor was quantified by messenger ribonucleic acid dot-blot hybridization assay. Atypical and malignant tumors had significantly higher proliferative indexes than did their nonmalignant counterparts. Levels of c-myc and c-fos messenger ribonucleic acid were elevated more than fivefold in 72 and 78% of the tumors, respectively, relative to the lowest levels detected in the series. Levels of growth factor messenger ribonucleic acid were sporadically elevated; 37 to 44% of tumors had more than fivefold enhanced levels of acidic and basic fibroblast growth factor. Positive correlations between proliferation and proto-oncogene/growth factor expression were found for c-myc in atypical/malignant tumors and for epidermal growth factor in fibroblastic meningiomas. Deregulated expression of c-myc and c-fos common to both typical and atypical tumors suggests that these are early events in the meningioma tumor process that may disturb the control of cell differentiation and together with fibroblast growth factors are likely to endow the transformed cell with a selective growth advantage by reducing the requirement for exogenous mitogens and by providing a niche for the growth of the tumor clone. Positive correlation of c-myc levels with proliferation in atypical/malignant meningiomas implies that this is a feature of malignancy and indicates continued disruption of the negative regulation of proto-oncogene expression, perhaps by tumor suppressor gene losses, during the course of tumor progression.
Cell Division↗
Enhanced expression of transforming growth factor beta 1 in the rat brain after a localized cerebral injury.
It is becoming clear that transforming growth factor beta (TGF beta) may be a key factor regulating inflammatory and tissue specific wound responses. Because the formation of a glial-collagen scar at CNS lesion sites is thought to contribute to the pathology associated with penetrating CNS injuries, and because in the periphery TGF beta 1 stimulates fibroblast deposition of scar tissue, we used in situ hybridization and immunohistochemistry to investigate the effect of a defined cerebral lesion on the local expression of TGF beta 1. Induction of TGF beta 1 mRNA and protein is relatively diffuse in the neuropile around the margins of the lesion at 1, 2 and 3 days, but becomes localized to the region of the glial scar at 7 and 14 days. The signal intensity for TGF beta 1 mRNA and protein is maximal between 2 and 3 days and decreases between 7 and 14 days after lesion. The predominant cell types in the neuropile localizing TGF beta 1 mRNA and protein have the morphological characteristics of astrocytes, although macrophages are also detected. An induction of TGF beta 1 mRNA was also observed in endothelial cells of the meninges, hippocampal fissure and choroid plexus, at 2 and 3 days. However, this is dramatically reduced by 7 days and has disappeared by 14 days. These results suggest a role for TGF beta 1, not only in inflammation, but also in the tissue-specific glial scar formation that occurs in the CNS. Furthermore, they suggest a potential therapeutic use of TGF beta 1 antagonists in the CNS to help limit the pathogenesis associated with matrix deposition in the wound.
Animals↗