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Biomedical subjects

S M Donovan

Publications and source records attributed to S M Donovan.

At least 37 records · Page 2Linked to original sources
PubMed1998

A cartilage matrix deficiency experimentally induced by vitamin B6 deficiency.

A vitamin B6-deficiency-induced disorder in avian articular cartilage resembling osteoarthritis has been further characterized. We measured several parameters of proteoglycan (PG) metabolism, i.e., fixed charge density and sulfated glycosaminoglycans (S-GAG) content in PN-deficient versus control articular cartilage and synovial fluid from the knee joint. Statistically significant changes were: 1) decreased content and increased extractability of total sulfated PGs from articular cartilage with guanidine HCl; 2) elevation of S-GAG concentration in synovial fluid; 3) increased plasma cystathionine (sulfur amino acid) levels. PG synthesis as assessed by 35SO4 incorporation into S-GAGs was not impaired. A lack of cartilage swelling in 0.15 M saline and the normal water content indicated that although disturbed, the collagen network was not disrupted. This finding was in agreement with a previous microscopic study that revealed no fissures in the articular cartilage. Previous findings of a normal aggregating PG size-distribution and absence of elevated metalloproteases made a disturbance of aggregating PG metabolism unlikely. Escape into the synovial fluid of small PGs, normally bound to articular collagen, was believed to result from an alteration in collagen molecular organization that could be secondary to elevated circulating SH-compounds.

Animals↗
PubMed1998

The influence of manganese deficiency on serum IGF-1 and IGF binding proteins in the male rat.

Young male rats subjected to a dietary manganese (Mn) deficiency respond to the deficiency by reducing their growth rate. The growth hormone (GH)/insulin-like growth factor (IGF) axis is critical for linear growth; this system is exquisitely sensitive to the nutritional state of the animal. In this study, we examined circulating GH, IGF-1, and insulin levels in Mn-deficient (-Mn; fed a 0.5 microg Mn/g diet) and sufficient (+Mn; fed a 45 microg Mn/g diet) male Sprague-Dawley rats. Additionally, we examined the distribution of circulating IGF binding proteins (IGFBPs) in animals of both dietary groups as these proteins modulate IGF-1 action in vivo and in vitro, and have been demonstrated to be altered in a number of nutritional and physiological states. Body weight was significantly reduced in -Mn relative to +Mn rats. Consistent with other studies, daily food intake was not altered. However, cumulative food intake (over 3 months) was marginally lower in -Mn versus +Mn animals. -Mn animals displayed lower circulating concentrations of IGF-1 (66% of control levels) and insulin (60% of control levels) despite having significant elevations in circulating GH levels relative to +Mn animals (140% of control levels). The IGFBP profile of -Mn animals reflected their elevated GH status, as we observed increased binding of tracer (125I-IGF-1) to the circulating IGFBP-3 complex (120% of control binding) using native chromatography techniques. Interestingly, the lower circulating insulin concentrations of -Mn animals did not result in dramatic elevations in lower-molecular-weight binding proteins. In summary, we demonstrate that in young male rats, Mn deficiency is associated with alterations in IGF metabolism. These alterations may contribute to the growth and bone abnormalities observed in -Mn animals.

Animals↗
PubMed1997

Evaluation of hexamethylphosphoramide for gene mutations in Salmonella typhimurium using plate incorporation, preincubation, and suspension assays.

Hexamethylphosphoramide (HMPA), a potent rat nasal carcinogen by inhalation, and three of its metabolites, pentamethylphosphoramide (PMPA), trimethylphosphoramide (TriMPA), and formaldehyde (HCHO), were assessed in Salmonella typhimurium gene mutation assays using various protocols, including plate incorporation, preincubation and suspension assays. HMPA (tested up to 15,000 micrograms/plate) was not mutagenic in plate incorporation or preincubation assays with or without metabolic activation. HCHO was mutagenic in the plate incorporation and preincubation assays (tested up to 150 micrograms/plate). In suspension assays, however, HMPA (tested up to 40 mg/ml), PMPA (up to 44 mg/ml) and HCHO (up to 45 micrograms/ml), but not TriMPA (up to 29 mg/ml), were mutagenic. HMPA and PMPA were positive only with activation. HMPA's mutagenicity was optimized using a relatively high level of rat liver S9 protein (3.5 mg/plate) in the metabolic activation mixture. Semicarbazide, an HCHO trapping agent, added at concentrations up to 167 micrograms/ml, markedly inhibited the mutagenic activities of HMPA and PMPA suggesting that HCHO generation may play a role in their mutagenicity. These studies show that HMPA is mutagenic in a modified Salmonella typhimurium reverse mutation assay with metabolic activation. Successive N-demethylation of HMPA eventually eliminates the mutagenic activity which further suggests that HMPA's mutagenic activity is related to the release of HCHO.

Biotransformation↗
PubMed1997

Protein-energy malnutrition delays small-intestinal recovery in neonatal pigs infected with rotavirus.

Infectious diarrheal diseases and protein-energy malnutrition (PEM) are major causes of child morbidity and mortality worldwide. In the present study, PEM was superimposed on rotavirus infection in neonatal pigs to simulate chronic small intestinal stress in malnourished infants with viral gastroenteritis. Two-day-old cesarean-derived pigs (n = 39) were allotted to three treatment groups: 1) noninfected, full-fed; 2) infected, full-fed; and 3) infected, malnourished. Two days postinfection, severe diarrhea and weight loss (11%) were accompanied by reductions in villus height (60%) and lactase activity (78%) and increased crypt depth (32%) in infected full-fed compared with noninfected pigs (P < 0.05). Malnutrition blunted (P < 0.05) increases in crypt depth elicited by rotavirus. By 9 d postinfection, body weight was 59% less, villus height and lactase activity remained lower (50%), and crypt depth remained greater (62%) in infected full-fed compared with noninfected pigs (P < 0.05). However, diarrhea began to clear in infected full-fed, but not in infected malnourished pigs. Plasma insulin-like growth factor-I (IGF-I) was reduced 68% and crypt depth was reduced 19% in infected-malnourished compared with infected full-fed pigs (P < 0.05). Sixteen days postinfection, full-fed pigs had recovered from rotaviral infection; however, in infected-malnourished pigs, diarrhea and growth stasis persisted, and plasma IGF-I, villus height and alkaline phosphatase activity remained reduced compared with infected full-fed pigs (P < 0.05). Overall, PEM prolonged diarrhea and delayed small-intestinal recovery, indicating that nutritional status during diarrhea is essential for recovery from rotaviral enteritis.

Animals↗
PubMed1997

Orally administered iodinated recombinant human insulin-like growth factor-I (125I-rhIGF-I) is poorly absorbed by the newborn piglet.

BACKGROUND: The purpose of the current study was to determine the degree to which milk-borne insulin-like growth factor-I (IGF-I) is absorbed. METHODS: Cesarean-derived piglets were fitted with umbilical arterial and venous catheters within 2 h of birth and were administered formula containing 21.7 +/- 1.8 microCi of iodinated recombinant human IGF-1 (125I-rhIGF-I) by orgogastric gavage. Blood samples were taken before administration of the 125I-rhIGF-I (t0) and for 4 h postgavage. Plasma was obtained by centrifugation and total and trichloroacetic acid precipitable radioactivity were determined. Immunoreactive 125I-rhIGF-I was assessed using a polyclonal antibody to human IGF-I. Four hours after feeding, intestines were removed, divided into 13 segments, and flushed with saline. Radioactivity within the small intestinal lumen and wall were measured. RESULTS: Radioactivity in portal blood was higher than t0 at all times points (p < 0.05), whereas arterial radioactivity did not differ from t0 until 30 min postgavage. On average 18-20% of total radioactivity in both portal and arterial blood was acid-precipitable, with the proportion decreasing over time (p < 0.001). Immunoprecipitable radioactivity averaged 3-5% of the total radioactivity and was higher in portal than arterial blood (p < 0.05). Based on a plasma volume of 0.062 +/- 0.005 L and a baseline plasma IGF-I concentration of 1.81 +/- 0.56 nmol/L, absorbed 125I-rhIGF-I represented 0.205% of the total plasma IFG-I pool, whereas 14% of the dose was associated with the lining of the intestine. CONCLUSIONS: Absorption of orally administered IGF-I does not contribute significantly to circulating IGF-I.

Administration, Oral↗
PubMed1997

Small intestinal disaccharidase activity and ileal villus height are increased in piglets consuming formula containing recombinant human insulin-like growth factor-I.

The effect of orally administered IGF-I on intestinal development was assessed in piglets. Cesarean-derived, colostrum-deprived piglets received formula alone or formula containing 65 nM (500 microg/L) of recombinant human IGF-I. IGF-I intake averaged 200 microg/kg/d. On d 7 and 14 postpartum, piglets were killed, organs were removed and weighed, and tissue and blood samples were collected. The small intestine was divided into 13 segments that were weighed and measured. A sample of each segment was fixed in formalin, and the mucosa was scraped for enzyme analyses. Food intake, body and organ weights, intestinal weight, length, protein, DNA and RNA content did not differ between the treatment groups. Serum IGF-I, IGF-II, and IGF-binding protein profiles and tissue IGF-binding protein mRNA expression were also comparable between the treatment groups. In contrast, intestinal enzymes and villus height were increased by oral IGF-I. Lactase was approximately 2-fold higher (p < or = 0.05) in the jejunum and proximal ileum, and sucrase was approximately 50% higher (p < or = 0.05) in the jejunum of IGF-I-treated animals than in controls. Villus height in the terminal ileum was approximately 50% greater in IGF-I-treated animals than in controls (p = 0.03). In conclusion, orally administered IGF-I at 200 microg/kg did not affect whole body or organ growth or serum IGF-I concentrations; however, intestinal disaccharidase activity and ileal villus growth were responsive to orally administered IGF-I, supporting a potential role for milk-borne IGF-I in neonatal intestinal development.

Animals↗
PubMed1997

Moderate food restriction reduces serum IGF-I and alters circulating IGF-binding protein profiles in lactating rats.

The role of somatogenic and lactogenic hormones in the adaptative mechanisms which occur in response to nutrient restriction during lactation is unknown. To characterize the effect of food restriction during lactation on serum IGF-I, GH and prolactin concentrations and serum IGF-binding protein (IGFBP) profiles, lactating dams had free access to food (control) or were restricted to 60% of control intake during pregnancy and lactation (RPL) or only during lactation (RL). Serum, milk and mammary gland samples were collected throughout lactation. RL dams lost body weight, control dams gained weight, while RPL dams maintained body weight during lactation. By day 20, body and mammary gland weights of RL and RPL dams did not differ and were lower than control (P < 0.05). Serum IGF-I concentrations in restricted groups were lower than control (P < 0.05), however, hepatic expression of IGF-I mRNA did not differ between groups in early (day 1) or mid-lactation (day 8) and was increased on day 20 in RL dams compared with RPL or control. These data suggest that serum IGF-I and hepatic IGF-I mRNA expression are not co-ordinately regulated in the food-restricted lactating rat. In early lactation, serum IGFBP-3 was lower in RPL dams than control (P < 0.05), whereas IGFBP-1 and -2 were increased in RL and RPL dams in late lactation compared with control. The decrease in IGFBP-3 and increase in lower molecular weight IGFBP may have contributed to the reduction in serum IGF-I by increasing IGF-I clearance from the circulation. Serum GH and prolactin were measured in samples obtained between 0900 and 1200 h. Serum GH did not differ with the exception of an increase on day 1 in control relative to RPL dams and on day 20 in RL dams relative to RPL and control. Serum prolactin was higher in the RL dams than controls on day 4. In summary, food restriction during pregnancy and lactation or solely during lactation results in similar reductions in serum IGF-I and alterations in serum IGFBP despite differences in body weight responses to food restriction during lactation.

Animals↗
PubMed1996

Macrophages synthesize and secrete a 25-kilodalton protein that binds insulin-like growth factor-I.

Primary (thymus) and secondary (spleen) murine lymphoid tissues express a 25-kDa protein that binds IGF-I. To determine the cellular source of this insulin-like growth factor binding protein (IGFBP), 11 murine or human cell lines representing T, B, and myeloid cells at various stages of differentiation were characterized by IGF-I affinity cross-linkage and Western ligand blotting. Mature myeloid cells, but not T or B cells, secrete a 25-kDa protein that is capable of binding IGF-I. CSF-1-derived bone marrow macrophages also synthesize this 25-kDa IGFBP. Thymic macrophages, which were estimated to secrete 2 ng of binding protein/10(6) cells-h, were used in conjunction with [125I] IGF-I affinity cross-linking to develop a protein binding immunomobility-shift assay to identify which IGFBP is produced by these cells. An anti-IGFBP-4Ab, but not an anti-IGFBP-2 Ab or normal rabbit serum, shifted the [125I] IGF-IGFBP complex to a higher m.w. position, indicating that the single 25-kDa IGFBP is IGFBP-4. Northern blotting confirmed that transcripts for IGFBP-4 as well as IGF-I are expressed in thymic macrophages. A putative 278-bp IGFBP-4 cDNA fragment (residues 341-618) of rat) that contains two unique cysteine residues found only in IGFBP-4 was cloned and sequenced from thymic macrophages. These clones differed from the rat sequence at only six residues (97% homology), and the deduced amino acid sequence from the murine cDNA was identical with that of the rat sequence. Subsequent studies revealed that IGF-I stimulates DNA synthesis in thymic macrophages. However, two different IGF-I analogues differing in the amino-terminus that bind equally well to the IGF-I receptor but poorly to IGFBPs are as effective as IGF-I at 100-fold lower concentrations. These data demonstrate that murine macrophages are a source of a single 25-kDa secreted protein that binds IGF-, that the molecular identity of this protein is IGFBP-4, and that this binding protein may antagonize the extracellular effects of IGF-I.

Amino Acid Sequence↗
PubMed1996

Moderate food restriction abolishes the pregnancy-associated rise in serum growth hormone and decreases serum insulin-like growth factor-I (IGF-I) concentrations without altering IGF-I mRNA expression in rats.

Pregnancy-associated growth of maternal and fetal tissues is likely mediated by insulin-like growth factors (IGF). To study the effect of food restriction during pregnancy on the IGF system, pregnant rats either had free access to food (control) or were fed 60% of control food intake. Serum and liver samples were obtained throughout gestation. Serum IGF-I and growth hormone (GH) concentrations were measured by RIA, and IGF binding proteins (IGFBP) were characterized by Western ligand blotting and gel filtration chromatography. Weight gain of control dams was nearly twice that of restricted dams. Litter size was not significantly different; however, fetuses and placentas of restricted dams were 20% smaller than those of controls. Serum IGF-I concentrations on d 20 were 35 and 23% of d 5 concentrations in control and restricted pregnant rats, respectively. However, hepatic IGF-I mRNA did not differ between the treatment groups. A pregnancy-associated rise in serum GH was observed in control but not food-restricted dams. Insulin-like growth factor binding protein with apparent molecular retention of 38-42 kDa (IGFBP-3), 29-31 kDa and 24 kDa were apparent in serum of pregnant dams in early gestation; however, IGFBP-3 was no longer detected by Western ligand blot by d 15 of gestation. The decline in IGFBP-3 was accompanied by an increase in IGFBP-1 and -2, particularly in the serum of food-restricted dams. These data suggest that in food-restricted pregnant rats, serum IGF-I and IGF-I mRNA are insensitive to serum GH concentrations and are not regulated at the level of transcription.

Animals↗
PubMed1996

Short-term metabolic responses do not differ between neonatal piglets fed formulas containing hydrolyzed or intact soy proteins.

Hydrolyzed soy protein (SH) could be used as a protein source in formulas for infants with intolerance to cow's milk protein and may be preferable to intact soy protein (SI). However, metabolic responses to SH are poorly defined. Because of their partially hydrolyzed nature, nonphysiological elevations in either plasma amino acids or regulatory hormones may occur. Therefore, we evaluated effects of SH on plasma nutrient and pancreatic hormone (insulin, glucagon) concentrations. In Experiment 1, 24 newborn pigs were fitted with umbilical arterial and portal catheters, fed formula for 36 h and food deprived for 12 h. Pigs were then fed formula including either SH or SI with glucose polymers or casein-whey proteins (CW) containing lactose, and serial blood samples were taken for 2 h postprandially. Peak portal exceeded peak arterial amino acid concentrations within each treatment, and peak amino acid concentrations in CW-fed pigs exceeded those of SH- and SI-fed pigs. However, only SH formula-fed piglets had higher postprandial portal minus arterial amino acid concentrations (P < 0.05) throughout Experiment 1, suggesting that SH was well digested and absorbed. In Experiment 2, arterial catheters were inserted in 24 piglets. Previous procedures were followed except dietary carbohydrate was standardized to glucose polymers for all three diets, and sampling was extended to 3 h. Overall, portal or arterial nutrient and hormone concentrations were not different in the SI and SH groups (P > 0.05), indicating that hydrolyzed soy protein did not cause abnormal plasma concentrations. In conclusion, hydrolyzed soy protein did not result in elevated nutrient concentrations or hormone responses compared with intact soy or cow's milk protein.

Amino Acids↗
PubMed1996

Intestinal effects of milkborne growth factors in neonates of agricultural importance.

Reduction of postnatal morbidity and mortality of mammalian neonates poses a significant challenge to agricultural and medical sciences. Because nutritional insufficiency and diarrhea represent major stressors, an understanding of factors mediating postnatal growth and development of the gastrointestinal tract is essential. This review explores the role that milkborne growth factors may play in stimulating functional development of the neonatal intestine, with emphasis on the porcine, bovine, and ovine species. Studies reporting milk concentrations and intestinal effects are reviewed, with emphasis on epidermal growth factor, insulin, and the insulin-like growth factors. Collectively, these studies suggest that milkborne growth factors may provide important regulatory signals to the neonatal intestine under both normal and pathophysiological states.

Animals↗
PubMed1995

Zinc deficiency-induced anorexia influences the distribution of serum insulin-like growth factor-binding proteins in the rat.

Zinc (Zn) deficiency can result in severe growth retardation in mammals, and in a number of animal model systems it leads to low circulating insulin-like growth factor-I (IGF-I) concentrations. Using a weanling male rat model and a number of feeding schemes, we show that in addition to lower circulating IGF-I concentrations, Zn deficiency leads to alterations in the distribution of serum IGF-binding proteins (IGFBPs). Serum from Zn-deficient animals labeled in vitro with [125I]IGF-I displayed three peaks of tracer activity: 150 kd (IGFBP-3), 37 kd (IGFBP-2 and -1), and 8 kd (free [125I]IGF-I). Relative to controls, Zn-deficient animals demonstrated more tracer binding in the 37-kd region, whereas less was found in the 150- and 8-kd peaks. Serum from chronically calorie-restricted fed animals displayed [125I]IGF-I binding profiles similar to Zn-deficient serum, implicating Zn deficiency-induced anorexia as the principle factor underlying both the lower circulating IGF-I and the alterations in IGFBP profiles. Concentrations of IGFBP-4 were unaffected by diet manipulation based on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE)/Western ligand blot (WLB) analysis.

Animals↗
PubMed1995

Combined growth hormone (GH) and insulin-like growth factor-I (IGF-I) treatment is more effective than GH or IGF-I alone at enhancing recovery from neonatal malnutrition in rats.

The effect of hormonal therapy on enhancing recovery from neonatal malnutrition was assessed in rats. Malnutrition was induced by maternal food restriction (60% control intake) during lactation. On d 16 postpartum, restricted pups were refed by cross-fostering to control dams and were subcutaneously administered growth hormone (GH), insulin-like growth factor-I (IGF-I), GH + IGF-I or saline. At d 21, pups were weaned and continued hormonal treatments until d 39 postpartum. By d 39, body weight of GH (96% control) and GH + IGF-I- (98%) treated animals were normal, whereas IGF-I (88%) and saline- (85%) treated animals were still stunted. Hormone effectiveness was age dependent, with growth rates of GH + IGF-I-, IGF-I- and GH-treated pups being greatest between d 16 and 30, d 16 and 21 and after d 30, respectively. Protein accretion by d 39 was higher (P < 0.01) in GH and GH + IGF-I groups than saline- or IGF-I-treated groups. On d 39, serum IGF-I concentrations were as follows: GH + IGF-I > IGF-I > GH = saline (placebo), indicating that an elevated serum IGF-I was not required for GH-stimulated growth. Of the three hormonal treatments, GH + IGF-I therapy was most efficacious at promoting rapid and complete body weight recovery and supporting lean body mass accretion.

Animals↗
PubMed1995

Human growth hormone but not human insulin-like growth factor-I enhances recovery from neonatal malnutrition in rats.

The ability of hormonal therapy to enhance recovery from neonatal malnutrition was assessed in rats. Pups were malnourished via maternal food restriction (60% control intake). On d 16, restricted pups (n = 50) (62% control body wt) were refed until d 20 and were given growth hormone, insulin-like growth factor-I, destripeptide [1,3] insulin-like growth factor-I, or saline (placebo). Refed-placebo pups attained 80% of control body weight by d 20. Growth hormone treatment caused a greater weight gain than refeeding alone (P < or = 0.05). Treatment with insulin-like growth factor-I and destripeptide [1,3] insulin-like growth factor-I did not affect body weight. All three hormones increased spleen and kidney weights (P < or = 0.05) compared with the refed-placebo group, whereas only growth hormone increased muscle weight (P < or = 0.05). Malnourished pups had lower serum insulin-like growth factor-I (P < or = 0.05) and insulin-like growth factor binding protein-3 (P < or = 0.05), and higher serum insulin-like growth factor binding protein-2 (P < or = 0.05) and hepatic insulin-like growth factor binding protein-2 mRNA (P < or = 0.05) than controls. Refeeding increased serum insulin-like growth factor-I compared with restricted pups (P < or = 0.05), and insulin-like growth factor-I treatment caused a further increase in serum insulin-like growth factor-I compared with the refed-placebo group (P < or = 0.05). These results show that growth hormone was moderately effective at increasing body weight gain and muscle growth during recovery from malnutrition.

Animals↗
PubMed1995

Investigation into the potential physiological sources of rat milk IGF-I and IGF-binding proteins.

We have previously reported the presence of IGF-I and IGF-binding proteins (IGFBP-2, -3 and -4) in rat milk. Herein, the potential sources of rat milk IGF-I and IGFBPs were investigated. Lactating dams (day 14 postpartum) were separated from their pups and injected intraperitoneally with 0.45 microCi 125I-IGF-I or 125I-IGFBP-3. After 3 h, serum and milk of rats receiving 125I-IGF-I contained 7642 +/- 3121 and 14,455 +/- 7837 c.p.m./ml respectively. Serum and milk of rats given 125I-IGFBP-3 contained 7232 +/- 1366 and 10,371 +/- 4091 c.p.m./ml respectively. Sephacryl S-200 gel filtration chromatography demonstrated that the 125I-IGF-I in both serum and milk was primarily in the 150 kDa IGF-binding complex, whereas the distribution of 125I-IGFBP-3 differed between serum and milk. In serum, most of the 125I-IGFBP-3 was in the 150 kDa fraction, while most 125I-IGFBP-3 in milk was in the 40 kDa fraction. Northern analysis of liver showed IGFBP-1 and -3 mRNA expression, with variable expression of IGFBP-2 and -4 mRNA. In contrast, mammary tissue expressed only IGFBP-2 and -4 mRNA, suggesting that these IGFBPs in milk may arise from de novo synthesis within the mammary gland. The lack of detectable IGFBP-3 mRNA in mammary tissue and the translocation of 125I-IGFBP-3 from the serum suggest that milk IGFBP-3 arises from the maternal circulation.

Animals↗
PubMed1995

Imported echinococcosis in southern California.

A retrospective chart review conducted at two teaching hospitals in Los Angeles County identified 28 patients with infection due to Echinococcus granulosus diagnosed by positive echinococcal serology and/or tissue biopsy between January 1981 and December 1990. Of these patients, 25 (89%) were foreign born and 19 (68%) were immigrants from the Middle East or central Asia. Only 12 of 22 immigrants questioned about epidemiologic risk factors described a history of rural residence or direct exposure to dogs in their native country. Single cysts of liver, lung, and soft tissue were present in six of 28 patients; multiple cysts in the 22 remaining patients were exclusively hepatic in 13 patients, exclusively pulmonary in two patients, and involved mixed sites including liver, lung, abdomen, central nervous system, and bone in seven patients. Natives of middle eastern countries currently constitute a major risk group for imported infection due to E. granulosus in the United States. Since their epidemiologic risk factors may be absent and clinical presentations varied, a high index of suspicion for echinococcosis is warranted in this population based solely on the presence of a cystic mass in liver, lung, or another organ site.

Adult↗