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Biomedical subjects

W E Russell

Publications and source records attributed to W E Russell.

At least 19 recordsLinked to original sources
PubMed1992

Increased production of transforming growth factor alpha following acute gastric injury.

Transforming growth factor alpha (TGF-alpha) production recently has been found in normal mammalian gastric mucosa. Inasmuch as TGF-alpha and epidermal growth factor (EGF) both stimulate epithelial cell migration and proliferation and suppress gastric acid secretion, the authors of the current study proposed that these growth factors may participate in tissue repair after acute gastric mucosal injury. Consequently, TGF-alpha and EGF production were examined after orogastric administration of either acidified taurocholate or 0.6 mol/L HCl to rats. TGF-alpha messenger RNA (mRNA) expression increased in a dose- and time-dependent manner after administration of taurocholate, whereas EGF mRNA expression was not detected. Radioimmunoassay of gastric mucosal scrapings obtained 6 hours after gastric injury induced by 0.6 mol/L HCl showed a 2.1-fold increase in immunoreactive TGF-alpha but no increase in immunoreactive EGF. In addition, there was a 68-fold increase in immunoreactive TGF-alpha in gastric juice within 30 minutes of gastric instillation of HCl and, again, no increase in immunoreactive EGF. There is a rapid appearance of TGF-alpha in the gastric juice within 30 minutes of injury, which is followed by increased expression of TGF-alpha mRNA and protein in the gastric mucosa. These studies suggest that locally produced TGF-alpha may participate in gastric mucosal repair following acute gastric injury to rats.

Animals↗
PubMed1991

Growth hormone secretion in the obese male rat: modulation by the gonadal and thyroid axes.

The present study was designed to determine if either the testes or thyroid plays a role in the blunted GH secretion observed in the obese male rat. Analysis of individual GH secretory profiles in adult lean and obese Zucker rats revealed a severe attenuation of both mean GH levels and individual GH pulse amplitudes in obese rats as well as a significant lowering of circulating testosterone levels. Normalization of the testosterone levels by the use of sc Silastic capsules elevated but did not normalize GH pulse amplitudes in obese animals. Further, the GH response to either rat GH-releasing factor (5 mu/kg) or morphine (1 mg/kg) were reduced in obese male rats. In contrast, the thyroid axis showed minimal change in obese animals. A slight reduction in free T3 levels in serum was observed while free and total T4 and total T3 were normal in obese rats. Further, mean circulating TSH levels and the TSH response to 500 ng/kg TRH were not altered in fat rats. Thus, the reduced GH secretion observed in the obese rat is not paramount to an alteration in either gonadal or thyroid function. This alteration of the GH secretory axis may not be attributable to one factor but more likely caused by a number of concomitant deficits which may act in concert to manifest impaired GH secretion.

Animals↗
PubMed1990

Calorie and protein provision for recovery from severe burns in infants and young children.

Severely burned adults increase their metabolic energy expenditure (MEE) to levels approaching twice the normal resting metabolic rate (RMR). There are no available measurements of MEE for severely burned infants and toddlers, however, and nutritional support relies on published estimates of MEE that range from 200% to 400% of RMR. We determined the actual calories provided to 10 infants and children ages 3-33 mo during acute care for severe burns (59 +/- 5% total-body-surface burn). Our standard protocol emphasizes the delivery of amino acids at 3 g.kg-1.d-1 in conjunction with prompt excision and grafting. An anabolic state characterized by weight maintenance and healing was supported with far fewer calories than predicted by four published formulas for MEE. We conclude that when greater than 2.5 g.kg-1.d-1 protein is provided, efficient protein utilization for recovery is achieved with calorie provision at 120-200% RMR in severely burned infants and toddlers.

Burn Units↗
PubMed1990

Sexual differentiation of growth hormone feedback effects on hypothalamic growth hormone-releasing hormone and somatostatin.

To investigate possible sex differences in the feedback regulation of growth hormone (GH) secretion, concentrations of immunoreactive GH-releasing hormone (GRF) and somatostatin (SS) were measured in the median eminence (ME) and the hypothalamus of male and female rats bearing the MtTW15 tumor, which secretes high amounts of GH and prolactin (PRL). Four weeks after tumor implantation in male rats, the GRF concentration in the whole hypothalamus, including the ME, was decreased by 37% (0.29 +/- 0.02 vs. 0.46 +/- 0.02 ng/mg protein in intact male controls; p less than 0.001) and the concentration of SS was increased by 40% (11.5 +/- 0.7 vs. 8.1 +/- 0.3 ng/mg protein in male controls; p less than 0.01). In female rats, the presence of tumor for 4 weeks caused a smaller (18%) reduction in GRF concentrations (0.27 +/- 0.02 vs. 0.33 +/- 0.03 ng/mg protein in intact female controls; p less than 0.05) and no significant change in SS concentrations (10.2 +/- 0.08 vs. 9.7 +/- 0.8 ng/mg protein in female controls). Tumor-related changes in GRF and SS concentrations were also more pronounced in male rats than in females, when determined separately in the microdissected ME and in the remaining hypothalamus. These differences occurred despite similar increases in serum GH, PRL and insulin-like growth factor I concentrations in male and female tumor-bearing rats. To assess which hormone (GH or PRL) was responsible for these changes, intact male rats were treated for 10 days with 2 daily s.c. injections of rat GH (rGH; 100 and 250 micrograms/day), rat PRL (100 and 250 micrograms/day) or vehicle.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Absence of ultradian rhythm or diurnal variation in insulin-like growth factor-I in rats.

We studied the variation in plasma insulin-like growth factor-I (IGF-I) concentrations in unrestrained, cannulated rats. To detect rapid changes, 6 rats were sampled every 15 min for 6 h. Plasma was assayed for growth hormone (GH), and for IGF-I before and after acid-ethanol (AE) extraction to reduce the masking effect of plasma binding proteins. AE increased the immunoreactivity of freshly collected rat serum and heparinized plasma by 3-fold, but had no effect on serum after 4 weeks of storage at -20 degrees C. In contrast, heparinized plasma maintained its sensitivity to AE for many months after collection. AE-extracted serum was identical in potency to serum that was subjected to acid gel chromatography. GH showed high amplitude, synchronized pulses every 3.3 +/- 0.15 h. Despite variations in IGF-I concentrations that resembled pulsations, when the data from both unextracted and AE-extracted plasma were subjected to 2 computer algorithms designed to detect hormone pulses, no pulses were identified in 8 of the 24 series of analyses. The two programs concurred only 4 times in their identification of a pulse in unextracted plasma, and in only one instance was a pulse identified in both unextracted and AE-extracted plasma from a given sample. Based on repeated measurements of a single serum sample, the program of Santen and Bardin (S&B) had a false-positive rate of 11%, and that of Merriam and Wachter (M&W) less than 10%. There was no positive correlation between summed GH and IGF-I concentrations over the 6 h of sampling, or after a 1- or 2-hour lag period. To detect diurnal variations, a second group of 5 rats was sampled every 2 h for 36 h. These animals showed little fluctuation of IGF-I concentrations and no differences between the light and dark periods. Our studies provide no evidence for episodic release of IGF-I or diurnal variations entrained to light or feeding cycles.

Activity Cycles↗
PubMed1989

A form of basic fibroblast growth factor is secreted into the adluminal fluid of the rat coagulating gland.

Rat coagulating gland and its secreted fluid contain a mitogenic substance that, by numerous criteria, appears to be similar to basic fibroblast growth factor (basic FGF). It is a potent competence factor in the BALB/c3T3 mouse embryo fibroblast assay, elutes from heparin-agarose at concentrations of NaCl greater than 1.0 M, and has an isoelectric point (pI) between 8 and 9. In coagulating gland fluid, its molecular weight was 20,000 +/- 5,000, as indicated by gel filtration on Sephadex G-200. Western blot analysis of purified factor from coagulating gland cytosol and fluid, respectively, revealed immunoreactive bands of 16,000 and 17,000 relative molecular weight similar to that of purified bovine basic FGF.

Animals↗
PubMed1989

Sexual and developmental differences in peptides regulating growth hormone secretion in the rat.

Sex differences in the hypothalamic control of growth hormone (GH) secretion were investigated by measuring rat GH-releasing factor (rGRF) and somatostatin in male and female rats. Rat GRF-like immunoreactivity (rGRF-IR) was higher in the median eminence and hypothalamic tissue outside of the median eminence of adult (90-day-old) male compared to female rats. A similar pattern of rGRF-IR content was found in the median eminence of 35-day-old rats. This sex difference developed between days 25 and 35 of age, during which time serum concentrations of insulin-like growth factor (IGF-1) and body weight increased in both sexes. To a lesser extent, the content of somatostatin-like immunoreactivity (SLI) was higher in the median eminence of adult female rats compared to male rats. Whole hypothalamic rGRF-IR and SLI contents were influenced only moderately by adult gonadectomy or gonadal steroid treatments. For example, estrogen increased rGRF-IR content in castrated rats, but orchidectomy alone or orchidectomy followed by testosterone did not influence rGRF-IR content. Additionally, whole hypothalamic SLI content was unaffected by orchidectomy or orchidectomy followed by testosterone or estrogen. One month after ovariectomy, rGRF-IR and SLI in whole hypothalamic fragments were similar to their respective contents in gonad-intact males. However, ovariectomy followed by estrogen or testosterone did not restore rGRF-IR content and partially restored SLI content to levels seen in gonad-intact females.

Aging↗
PubMed1988

Two Ca2+-dependent ATPases in rat liver plasma membrane. The previously purified (Ca2+-Mg2+)-ATPase is not a Ca2+-pump but an ecto-ATPase.

We have shown that the rat liver plasma membrane has at least two (Ca2+-Mg2+)-ATPases. One of them has the properties of a plasma membrane Ca2+-pump (Lin, S.-H. (1985) J. Biol. Chem. 260, 7850-7856); the other one, which we have purified (Lin, S.-H., and Fain, J.N. (1984) J. Biol. Chem. 259, 3016-3020) and characterized (Lin, S.-H. (1985) J. Biol. Chem. 260, 10976-10980) has no established function. In this study we present evidence that the purified (Ca2+-Mg2+)-ATPase is a plasma membrane ecto-ATPase. In hepatocytes in primary culture, we can detect Ca2+-ATPase and Mg2+-ATPase activities by addition of ATP to the intact cells. The external localization of the active site of the ATPase was confirmed by the observation that the Ca2+-ATPase and Mg2+-ATPase activities were the same for intact cells, saponin-treated cells, and cell homogenates. Less than 14% of total intracellular lactate dehydrogenase, a cytosolic enzyme, was released during a 30-min incubation of the hepatocytes with 2 mM ATP. This indicates that the hepatocytes maintained cytoplasmic membrane integrity during the 30-min incubation with ATP, and the Ca2+-ATPase and Mg2+-ATPase activity measured in the intact cell preparation was due to cell surface ATPase activity. The possibility that the ecto-Ca2+-ATPase and Mg2+-ATPase may be the same protein as the previously purified (Ca2+-Mg2+)-ATPase was tested by comparing the properties of the ecto-ATPase with those of (Ca2+-Mg2+)-ATPase. Both the ecto-ATPase and the (Ca2+-Mg2+)-ATPase have broad nucleotide-hydrolyzing activity, i.e. they both hydrolyze ATP, GTP, UTP, CTP, ADP, and GDP to a similar extent. The effect of Ca2+ and Mg2+ on the ecto-ATPase activity is not additive indicating that both Ca2+- and Mg2+-ATPase activities are part of the same enzyme. The ecto-ATPase activity, like the (Ca2+-Mg2+)-ATPase, is not sensitive to oligomycin, vanadate, N-ethylmaleimide and p-chloromercuribenzoate; and both the ecto-ATPase and purified (Ca2+-Mg2+)-ATPase activities are insensitive to protease treatments. These properties indicate that the previously purified (Ca2+-Mg2+)-ATPase is an ecto-ATPase and may function in regulating the effect of ATP and ADP on hepatocyte Ca2+ mobilization (Charest, R., Blackmore, P.F., and Exton, J.H. (1985) J. Biol. Chem. 260, 15789-15794).

Adenosine Triphosphatases↗
PubMed1988

Transforming growth factor beta (TGF-beta) inhibits hepatocyte DNA synthesis independently of EGF binding and EGF receptor autophosphorylation.

Subpicomolar concentrations of human platelet-derived transforming growth factor beta (TGF-beta) inhibited growth factor-stimulated DNA synthesis in primary cultures of adult rat hepatocytes. This inhibition was not the result of changes in the size of intracellular pools of 3H-thymidine and was not dependent on the state of confluence of the cells. A 24-hr exposure to TGF-beta either before or after insulin/EGF stimulation was as inhibitory on DNA synthesis between 48 and 72 hr of culture as was TGF-beta present throughout 72 hr of culture. From 12 hr in culture to 24 hr, hepatocyte EGF binding sites dropped from about 230,000 to 85,000 per cell with no significant change in Kd, but with a loss in capacity for EGF-induced receptor down-regulation. Maximally inhibitory concentrations of TGF-beta did not compete with EGF for the EGF receptor, and a 4- to 24-hr exposure to TGF-beta did not alter subsequent EGF binding. Coincubation of hepatocytes with TGF-beta and EGF did not influence the 60% reduction in EGF binding sites produced by EGF alone. In addition, TGF-beta did not prevent EGF-induced autophosphorylation of the 170,000 dalton EGF receptor in membranes from whole liver. Our studies suggest that TGF-beta regulates hepatocyte growth independently of changes in EGF receptor number, ligand affinity, or postbinding autophosphorylation.

Animals↗
PubMed1988

Type beta transforming growth factor reversibly inhibits the early proliferative response to partial hepatectomy in the rat.

Type beta transforming growth factor (TGF-beta), a factor produced by many cell types, is a potent inhibitor of hepatocyte DNA synthesis in vitro. To determine whether TGF-beta can influence hepatocyte proliferation in vivo, its effects were examined on the regenerative response of liver to partial hepatectomy (PH) in the rat. Porcine platelet-derived TGF-beta 1 (0.5 micrograms), administered intravenously at the time of PH and 11 hr later, reduced the fraction of hepatocytes engaged in DNA synthesis 22 hr after PH by 67% and inhibited the rate of hepatic [3H]thymidine incorporation by 50%. TGF-beta 2 produced a similar effect. A single dose of 0.5 micrograms of TGF-beta 1 given 11 hr after PH reduced liver [3H]thymidine incorporation by 32%; 4.5 micrograms of TGF-beta 1 or TGF-beta 2 inhibited DNA synthesis by 88% and the labeling index by 86%. Although sensitive to TGF-beta administered 11 hr after PH, late in the G1 phase of the cell cycle, a single dose of 0.5 micrograms given at the time of PH did not significantly influence DNA synthesis 22 hr after PH. The inhibitory effects of TGF-beta were transient; rats treated with two 0.5-microgram doses of TGF-beta at 0 and 11 hr had completely restored their original liver DNA mass 8 days after PH. Administration of 0.5 microgram of either TGF-beta 1 or TGF-beta 2 every 12 hr for 5 days failed to suppress the recovery of hepatic DNA mass. However, the nuclear labeling index of the TGF-beta-treated animals was significantly higher than that of the controls. There was no evidence of cytotoxicity from TGF-beta, as determined by liver histology and plasma concentrations of glucose, insulin-like growth factor I, and two hepatic enzymes. Thus, TGF-beta 1 and TGF-beta 2 reversibly inhibit the proliferative response of liver to PH and may be important in the modulation of normal liver growth and repair.

Alkaline Phosphatase↗
PubMed1987

Liver regeneration during immunosuppression.

As a preface to studies on the feasibility of liver segment transplantation, we studied the course of liver regeneration in immunosuppressed rats. Partial hepatectomies were performed in young adult male rats who were then treated with daily cyclosporine, dexamethasone, the combination of both agents, or vehicle. Body weight, liver weight, and liver DNA content were measured in subgroups of rats studied at various times after partial hepatectomy. All treated animals experienced weight loss, a phenomenon most marked in animals treated with both dexamethasone and cyclosporine. The DNA content of regenerating liver increased initially after partial hepatectomy in all animals. Restoring their original hepatic DNA in a fashion indistinguishable from controls, animals treated with cyclosporine increased liver DNA four fold within the first six days after partial hepatectomy. Animals treated with dexamethasone and both dexamethasone and cyclosporine increased their complement of liver DNA 2.5 fold, to 80% of that originally present. After day 6, the combined cyclosporine and dexamethasone treatment group became extremely catabolic and experienced a sharp decline in liver DNA. We conclude that despite the deleterious effects of cyclosporine and dexamethasone, especially in combination, on weight gain following partial hepatectomy, these agents do not prevent DNA synthesis and the accretion of new liver mass. We are encouraged by these studies to proceed with experimental studies on the normal growth and repair of liver segments transplanted into an immunosuppressed host.

Animals↗
PubMed1986

Fetal alcohol syndrome and DiGeorge anomaly: critical ethanol exposure periods for craniofacial malformations as illustrated in an animal model.

Acute maternal ethanl (alcohol) administration induces different craniofacial anomalies in the offspring of experimental animals, depending on the gestational day of teratogen exposure. Previous studies in our laboratories have illustrated the sequence of developmental changes leading to the "typical" fetal alcohol syndrome (FAS) craniofacial phenotype which results from teratogen exposure during gastrulation. These facial features are accompanied by deficiencies in median forebrain derivatives. Ethanol teratogenesis at this time apparently results in a loss of midline territory of the embryonic disc with little effects on neural crest-dependent laterally derived structures including the visceral arches. Acute ethanol exposure in mice 1 1/2 days later, at a time when neural crest cells are populating the frontonasal prominence and the visceral arches, results in a craniofacial phenotype that is similar to that noted in the DiGeorge anomaly or sequence. Sequential scanning electron microscopic analysis in our laboratory of embryos exposed on day 8 1/2 have illustrated deficiencies in the developing facial prominences and the visceral arches. The developing forebrain and midbrain appear hypoplastic. We have also observed heart, great vessel, and thymus abnormalities in these fetuses. Histologic analyses indicate that a common pathogenetic basis for the above-mentioned (day 8 1/2-induced) fetal alcohol effects appears to be an interference with the integrity of the cranial (including occipital) neural crest. Other discrete cell populations may also be involved since we have observed abnormalities in other regions, including placodal and closing membrane tissues. This animal model provides evidence linking maternal ethanol abuse during the 3rd or 4th weeks of human gestation to the development in the conceptus of FAS or DiGeorge anomally craniofacial characteristics, respectively. As the DiGeorge anomaly has been noted in the offspring of alcoholic women, this animal model indicates that ethanol and/or its metabolites is, in these cases, the causative agent.

Animals↗
PubMed1986

Mitogenic activity of hydroxyapatite: requirement for somatomedin C.

Synovial hyperplasia is a feature of the chronic synovitis associated with basic calcium phosphate crystals [hydroxyapatite (HA), octacalcium phosphate, tricalcium phosphate] and calcium pyrophosphate. Each of these crystals stimulated mitosis of cultured human skin fibroblasts or canine synovial fibroblasts in a concentration-dependent fashion. We examined the effect of pure somatomedin C (Sm-C) on HA crystal induced mitogenesis. Confluent cultures of human fibroblasts were rendered quiescent by incubation in the presence of 1% platelet-poor-Sm-C free plasma (PPSCFP) for 24 hours. HA crystals stimulated thymidine incorporation 2.3-fold over control value. Addition of Sm-C significantly augmented the effect of HA crystals (P less than 0.01). Nearly identical effects were observed in the presence of 100 micrograms/ml HA crystals or 15 ng/ml PDGF. Monoclonal antibodies against Sm-C had little effect on the basal 3H thymidine uptake by control cells incubated in 1% PPSCFP but blocked over 50% of the HA crystal or PDGF-induced 3H thymidine incorporation both in the presence or absence of Sm-C. The incomplete blocking suggested either the presence of other "progression" factors, such as insulin-like growth factor II in the conditioned media or the possibility that HA or PDGF in high enough dosage enabled cells to escape their dependence on Sm-C for DNA synthesis.

Cells, Cultured↗
PubMed1985

Expression of a biologically active analogue of somatomedin-C/insulin-like growth factor I.

A synthetic gene coding for an analogue of somatomedin-C/insulin-like growth factor I (Sm-C/IGF-I) was synthesized by solid support phosphoramidite chemistry and subsequently cloned and expressed in Escherichia coli as a fusion protein. The gene, designed with a threonine codon substituted for a methionine codon at position 59 was expressed fused to an eight-amino acid leader peptide under the direction of the E. coli tryptophan promoter. The fusion protein, termed L0-[Thr59]-Sm-C/IGF-I was purified extensively (greater than 97%) and found to be 60% as active as native Sm-C/IGF-I in a radioimmunoassay and 50% as potent as native Sm-C/IGF-I in a radioreceptor assay. Like native Sm-C/IGF-I it was also mitogenic for Balb/c 3T3 cells. After removal of the eight amino acid leader peptide by cyanogen bromide treatment, the resulting threonine analogue, termed [Thr59]-Sm-C/IGF-I was 80% as potent as native Sm-C/IGF-I in both the RIA and the radioreceptor assays. It was also mitogenic in Balb/c 3T3 cells. These two analogues, therefore, display biological activities similar to human-derived Sm-C/IGF-I.

Animals↗
PubMed1985

Somatomedin C/insulinlike growth factor I during liver regeneration in the rat.

We measured immunoreactive somatomedin C/insulinlike growth factor I (Sm C/IGF I) in blood and tissues of rats following partial hepatectomy (PH) to determine a possible regulatory role for this growth factor in liver regeneration. From a mean value of 0.66 U/ml +/- 0.19 before PH, the serum Sm C/IGF I rose to 1.09 +/- 0.08 1 h after PH [P less than 0.001 vs. sham-hepatectomized (SH) values]. Concurrently there was a twofold rise in serum aspartate aminotransferase, suggesting that the rise in Sm C/IGF I may be the result of hepatocellular injury rather than a specific secretory event. In the subsequent 22 h, serum Sm C/IGF I of PH rats fell to 0.31 +/- 0.06 U/ml, compared with 0.73 +/- 0.03 in SH rats. During this time, liver concentrations of the peptide declined to 30% of basal, whereas lung and kidney fell to only approximately 60% of basal. As the Sm C/IGF I declined, hepatic DNA synthesis increased 10-fold in PH animals. Our results, therefore, do not support a mitogenic role for Sm C/IGF I in the regulation of liver regulation. Food consumption was markedly depressed in the 22 h after PH (20.8 +/- 2.6 vs. 4.33 +/- 2.9 g/day; P less than 0.001). PH and pair-fed SH rats had serum Sm C/IGF I concentrations that were indistinguishable (0.31 +/- 0.06 vs. 0.35 +/- 0.11 U/ml), although liver tissue concentrations were lower in PH rats (0.04 +/- 0.01 U/g vs. 0.07 +/- 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗