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Biomedical subjects

S C Hughes

Publications and source records attributed to S C Hughes.

At least 37 records · Page 2Linked to original sources
PubMed1995

Tissue IGFBP-3 proteolysis: contrasting pathophysiology to that in the circulation.

Endogenous IGFBP-3 has been examined in the circulation and in four different extravascular fluids in normal healthy adults and in patients with psoriasis or arthritis. In all of these cases there was no apparent increase of IGFBP-3 protease activity in the circulation. In contrast, endogenous IGFBP-3 from normal skin interstititial fluid and synovial fluid from healthy adults was found to be predominantly in the 29 kDa proteolytically modified form. This indicated that in these extravascular fluids in normal healthy adults a protease was active which was similar, if not identical, to that found in the circulation in pregnancy and other conditions. This was confirmed by the fragmentation of recombinant IGFBP-3 when incubated with these fluids. When the skin interstitial fluid or synovial fluid were taken from abnormal tissues (psoriasis in the former and osteoarthritis or rheumatoid arthritis in the latter) there was a considerable reduction in the amount of endogenous IGFBP-3 in the 'clipped' form and a reduction in the protease activity. In psoriatic lesions, this reduction in IGFBP-3 protease activity was shown to be due to the presence of an inhibitor in the interstitial fluid but not in the circulation. In both peritoneal and follicular fluid, the ratio of intact to fragmented IGFBP-3 appeared to relate to the oestrogen status. In peritoneal fluid there was a decrease in intact IGFBP-3 during the late proliferative/early secretory phase of the endometrial cycle. In the ovary there was an increase in the amount of fragmented IGFBP-3 in the follicular fluid from the dominant follicle in comparison with atretic follicles from the same ovary. There is normally little proteo-lysis of IGFBP-3 in the circulation but this increases in many conditions where there is increased metabolic activity. The same enzyme(s) appear to be active in many extravascular fluids but under very different regulation. The activity in these extravascular fluids is normally high but can be decreased with local tissue inflammation; this decrease appears to be mediated by the induction of a local inhibitor.

Adult↗
PubMed1995

Parturients infected with human immunodeficiency virus and regional anesthesia. Clinical and immunologic response.

BACKGROUND: It is estimated that 1.5 million Americans are infected with the human immunodeficiency virus (HIV-1), and the consequences of HIV infection are a leading cause of death in women aged 15-44 yr. Thus, HIV-1 disease, or acquired immunodeficiency syndrome, occurs with increasing frequency in the parturient, and there is little information concerning the risks of regional anesthesia. Fear of spreading infection to the central nervous system or adverse neurologic sequelae have led some clinicians to advise against regional anesthesia. Thus, this study was undertaken to evaluate the possible problems or risks associated with regional anesthesia in parturients infected with HIV-1 and to determine whether anesthesia affected the clinical course of the disease. METHODS: The clinical course and immunologic function of 30 parturients infected with HIV-1 were evaluated prospectively. Extensive medical and laboratory evaluation before delivery and 4-6 months postpartum was undertaken. Medical problems related to HIV-1 disease and use of antiviral drugs also were monitored. The anesthetic management was dictated by the clinical situation and the patient's wishes were careful postpartum follow-up to evaluate possible neurologic changes or infection. RESULTS: Regional anesthesia was administered in 18 parturients, and 12 received small doses of opioids or no analgesia. There were no changes in the immunologic parameters studied (CD4+, p24, beta 2 microglobulins), and HIV-1 disease remained stable in the peripartum period. There were no infections, complications, or neurologic changes in the peripartum period. Sixty-eight percent of the infants were HIV-1-negative and, in 21% of infants, the HIV-1 status was indeterminate (probably negative). CONCLUSIONS: This prospective study of parturients infected with HIV-1 demonstrated that regional anesthesia can be performed without adverse sequelae. There were no neurologic or infectious complications related to the obstetric or anesthetic course. The immune function of the parturient was stable in the peripartum period. Although the number of patients studied was small, with careful medical evaluation, regional anesthesia is an acceptable choice in the parturient infected with HIV-1.

Acquired Immunodeficiency Syndrome↗
PubMed1995

The 'dawn phenomenon' in adolescents with insulin dependent diabetes mellitus: possible contribution of insulin-like growth factor binding protein-1.

OBJECTIVE: Insulin resistance increases during adolescence, and is exaggerated in patients with insulin dependent diabetes mellitus (IDDM). A relative deficiency of insulin-like growth factor-I (IGF-I) may contribute to this increased insulin requirement. Two mechanisms have been proposed: (a) increased GH secretion, caused by failure of IGF feedback control, leading to increased insulin resistance and (b) lack of insulin-like action of the IGFs which is reinforced by high plasma levels of IGFBP-1, an inhibitor of IGF action. The contribution of these two mechanisms to the 'dawn phenomenon' is assessed. DESIGN: The two possible mechanisms were studied during the dawn rise of glucose in pubertal adolescent patients with IDDM. Two overnight studies were performed in each subject. Patients remained on the same insulin regimen throughout. SUBJECTS: Twenty-two diabetic adolescent subjects, aged (mean +/- SEM) 14.0 +/- 0.4 years, duration of IDDM 7.9 +/- 0.8 years, were recruited. Pubertal status was: group 1 (breast stage 1-2; testicular volume < 4-8 ml) 3 male and 4 female, group 2 (breast stage 3; testicular volume 10-12 ml) 0 male 4 female, group 3 (breast stage 4-5; testicular volume 15-25 ml) 4 male and 7 female. Height standard deviation score (mean +/- SD) (-0.02 +/- 0.99) and daily insulin dose (50.4 +/- 3.1 U/day) did not change between studies. There were no differences in HbA1 (study A 11.26 +/- 0.45%, study B 11.09 +/- 0.42%). METHODS: The subjects were admitted for the two studies 0.3 +/- 0.03 years apart. Blood samples were taken via an indwelling cannula every 20 minutes between 1900 and 0700 h. MEASUREMENTS: GH was assayed every 20 minutes, IGFBP-1, glucose and free insulin every hour and IGF-I at 0700 h. GH, IGFBP-1, IGF-I and free insulin were measured by radioimmunoassay. IGFBPs were also analysed by Western ligand blotting techniques. GH profiles were analysed by Pulsar and results compared by paired Student's t-test. The relations between the dawn rise in glucose and the changes in IGFBP-1, GH and free insulin were examined by multiple linear regression analysis. RESULTS: Serum IGFBP-1 levels rose overnight in the two studies (study A, from 9 +/- 1 at 2200 to 59 +/- 9 micrograms/l at 0700 h; study B, from 10 +/- 1 at 2100 to 64 +/- 14 micrograms/l at 0700 h) whilst insulin levels fell from 47 +/- 5 at 2200 to 16 +/- 2 mU/l at 0700 h (study A) and from 45 +/- 5 at 2000 to 14 +/- 2 mU/l at 0700 h (study B). Glucose levels fell from 16.0 +/- 1.0 to 9.3 +/- 0.9 mmol/l at 0400 h, and then rose to 11.9 +/- 1.1 mmol/l at 0700 h during study A, and from 13.4 +/- 1.3 to 10.1 +/- 1.1 mmol/l at 0400 h and then rose to 13.5 +/- 1.0 mmol/l at 0700 h during study B. There were no differences in GH secretion between studies (mean GH levels (mean +/- SD) (study A, 15.7 +/- 6.6 mU/l; study B, 16.2 +/- 7.1 mU/l; correlation within subjects between studies r = 0.77, P < 0.001), sum of GH peaks (study A, 189.9 +/- 90.3 mU/l; study B, 185.8 +/- 100.2 mU/l; r = 0.57, P = 0.006)). Mean GH levels varied with pubertal stage (group 1, 12.1 +/- 1.5 mU/l; group 2, 23.3 +/- 2.1 mU/l; group 3, 15.3 +/- 1.2 mU/l). Serum IGF-I levels were not different (study A, 203 +/- 12 micrograms/l; study B, 218 +/- 13 micrograms/l). REGRESSION ANALYSIS: The change in plasma glucose between 0200 and 0700 h in both studies related to free insulin, IGFBP-1 and the sum of the GH levels over the preceding hour (log glucose = 7.87 + 5.32 log IGFBP-1 (P = 0.0001) - 5.05 log free insulin (P = 0.0001) - 1.44 log GH (P = 0.004); R2 = 72%). Mean overnight GH levels did not predict the morning rise in plasma glucose. CONCLUSION: The morning rise of IGFBP-1 and plasma glucose appear to be related in this group of subjects with IDDM and this was a consistent finding in the two studies. This relation was additive to the effect of insulin deficiency.

Adolescent↗
PubMed1995

Could abnormalities in insulin-like growth factors and their binding proteins during pregnancy result in gestational diabetes?

A number of dramatic changes have been documented in the insulin-like growth factors (IGFs-I and -II) and their binding proteins (IGFBPs) during pregnancy. In this study we have tested the hypothesis that a failure of the normal proteolytic modification of IGFBP-3 is responsible for gestational diabetes by examining serum samples taken in the third trimester from 29 women with uncomplicated pregnancies, 21 women with established Type 1 diabetes and 20 women with gestational diabetes. Analysis of IGFBP-3 by Western immunoblotting revealed that it was present in a modified form, migrating at around 29 kDa, in the circulation of all of the women investigated. Semiquantification of the activity of the protease which modifies the IGFBP-3 demonstrated considerable variation between individuals in their ability to fragment radiolabelled IGFBP-3 following a 45-min co-incubation. Surprisingly, in one individual (with gestational diabetes) there was no detectable protease activity even though her endogenous IGFBP-3 had been modified. However, overall there was no clear-cut difference in protease activity between the different groups. Radioimmunometric analysis of IGF-I revealed significantly higher levels in women with gestational diabetes than either of the other two groups (P < 0.05). Similarly IGFBP-3 levels were also increased in these same women (P < 0.05). In contrast, IGF-II levels did not alter between the three groups. In conclusion, our hypothesis was not supported by these data and gestational diabetes was found not to be associated with any reduction in the activity of the circulating IGFBP-3 protease which could have decreased the availability of the IGF nor with any alteration in IGFs which could explain the onset of diabetes in these women.

Adult↗
PubMed1995

Growth hormone, insulinlike growth factor-1, and insulinlike growth factor binding proteins 1 and 3 in chronic liver disease.

The liver is the major source of circulating insulinlike growth factor-I (IGF-I) and has been suggested as a major source of at least two of the major binding proteins that modify its bioavailability. We aimed to assess the direct effects of liver dysfunction on serum levels of IGF-1 and its major binding proteins by measuring fasting levels of growth hormone, IGF-1, IGFBP-1, IGFBP-3, insulin, C peptide, and glucose in 35 patients with cirrhosis and during an oral glucose tolerance test in 16 of those patients. Serum levels of growth hormone (GH) were high in the patients: median, 12.0 mU/L (range, 1 to 87) compared with normals, 0.95 mU/L (0.1 to 20) (P < .0005) and serum IGF-1 levels were low: 81 ng/mL (38 to 153) versus 193 ng/mL (151 to 235) (P < .0001). Serum IGFBP-3 levels were low in the patients: 1.59 mg/L (0.46 to 4.43) compared with normals, 5.41 (4.34 to 6.11) (P < .0001), and there was a significant negative correlation between IGFBP-3 levels and Childs Pugh score (r = .63 P < .0001). Fasting IGFBP-1 levels were significantly higher in the patients 31 ng/mL (11 to 92) than normals, 14 (7 to 20) (P < .0001). There was no correlation between fasting insulin and IGFBP-1 levels despite high fasting insulin levels. A decrease in IGFBP-1 levels was seen during the glucose tolerance test (GTT) in all patients. In conclusion, there are significant changes in the levels of two of the major IGF-1 binding proteins that may further limit the bioavailability of already low circulating IGF-1 levels. Substrate availability appears to be a stronger influence on fasting IGFBP-1 levels than does insulin, and the close correlation of IGFBP-3 with liver function indicates a dominant regulatory role of the hepatocyte.

Adult↗
PubMed1994

Changes in circulating insulin-like growth factor-binding protein-1 (IGFBP-1) during prolonged exercise: effect of carbohydrate feeding.

Plasma levels of glucose, insulin, the insulin-like growth factor (IGF-I and -II) and IGFBP-1 were determined in four young healthy males performing cycle exercise to fatigue while being fed either placebo (trial C) or glucose polymer solution (trial G). There was a significant decline in glucose and insulin from rest to fatigue in C (P < 0.01 and P < 0.05, respectively), but not in G. IGF-I or IGF-II levels did not change significantly in either of the trials. IGFBP-1 levels increased 12-fold in C (11.4 +/- 1.6 ng/ml at rest to 136.5 +/- 19.7 ng/ml at fatigue P < 0.01), and 5.6-fold in G (11.0 +/- 2.3 ng/ml to 62.2 +/- 15 ng/ml, P < 0.05). In C a significant negative correlation was found between IGFBP-1 and glucose (r = 0.69, P < 0.01) and IGFBP-1 and insulin (r = -0.612, P < 0.05) in C, but not in G. These results suggest that during prolonged exercise factors other than insulin or glucose may regulate IGFBP-1 and that IGFBP-1 may serve a role other than to prevent the hypoglycaemic action of the IGFs.

Adult↗
PubMed1992

Hydralazine does not restore uterine blood flow during cocaine-induced hypertension in the pregnant ewe.

Cocaine abuse is widespread, and its use by the parturient has potential significant adverse effects in both the mother and the newborn. This study was undertaken in gravid ewes to determine the effects of treatment of cocaine-induced hypertension with hydralazine (Apresoline) on the maternal and fetal cardiovascular systems, catecholamine response, blood gas and acid-base status, and uterine blood flow (UBF). Twenty-one experiments were performed in 15 chronically instrumented ewes near term gestation. After a 30-min control period, cocaine was given intravenously to all ewes for 55 min to induce and maintain increased maternal mean arterial pressure (MMAP) and reduced UBF. The sheep were randomly assigned to receive either cocaine alone (n = 11, control group) or hydralazine (n = 10, treatment group), starting 15 min after the cocaine administration. Both drugs were discontinued 55 min after the start of the cocaine administration, followed by a 35-min recovery period. In the control group, cocaine administration resulted in a 31 +/- 13% (SD) increase in MMAP (P less than 0.05) and a 26 +/- 21% reduction in UBF (P less than 0.05). In the treatment group, the initial cocaine administration resulted in a similar increase in MMAP and decrease in UBF. Hydralazine therapy restored MMAP toward baseline after 20 min of administration, but UBF remained reduced (37 +/- 17%) throughout therapy (P less than 0.05) and recovery (18 +/- 13%) (P less than 0.05). The maternal heart rate increased maximally by 121 +/- 33% (P less than 0.05) after the administration of hydralazine, compared with a 14 +/- 21% increase (P less than 0.05) in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Maternal anesthesia and the stressed fetus: effects of isoflurane on the asphyxiated fetal lamb.

The effects of maternal isoflurane-oxygen anesthesia (isoflurane, 1% inspired) were measured in eight pregnant ewes and their asphyxiated singleton fetuses. Stable fetal asphyxia, indicated by a stable fetal arterial pH of 7.1-7.2 units, was produced by maternal uterine artery occlusion. Maternal and fetal heart rates and blood pressures; maternal uterine artery flow; maternal arterial, fetal arterial, and sagittal sinus pH; and blood gas tensions were determined during an awake control period, during fetal asphyxia alone, and during fetal asphyxia plus isoflurane-oxygen. Measurements of representative fetal whole organ blood flows, cardiac output, and cerebral oxygen consumption were also made during each of the three experimental periods. During asphyxia alone regional and total brain, heart, and adrenal flows increased above control while flow to the spleen and carcass decreased. Similar responses were seen during asphyxia plus isoflurane-oxygen. Fetal arterial and sagittal sinus pH, base excess, po2, and oxygen saturation decreased, and hydrogen ion concentrations and pco2 increased during asphyxia alone and asphyxia plus isoflurane-oxygen. Cerebral oxygen consumption decreased significantly from control during asphyxia plus isoflurane-oxygen, whereas no significant changes occurred in cerebral oxygen delivery. These results support the conclusions that in the asphyxiated fetus: 1) acidosis is increased; 2) cardiac output is redistributed to vital organs; and 3) the balance of cerebral oxygen supply-to-demand is maintained during maternal isoflurane-oxygen anesthesia.

Anesthesia, Inhalation↗