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Biomedical subjects

R I Holt

Publications and source records attributed to R I Holt.

18 recordsLinked to original sources
PubMed2001

Computer assisted learning is an effective way of teaching endocrinology.

OBJECTIVES: Computers are a part of everyday life and offer an exciting way of learning. The aim of our study was to determine the effectiveness of teaching undergraduate endocrinology using a Computer Assisted Learning (CAL) programme. DESIGN AND SUBJECTS: One hundred and eighty-five first year clinical medical students were randomly assigned either to attend a series of conventional lectures (n = 77) or to have the same material available through a CAL programme. MEASUREMENTS: A multiple choice question examination was performed before and after the course. Lecture attendance and individual usage of the computer system were recorded. Students were asked to fill in an evaluation form at the end of the study. RESULTS: There was no significant difference in the first examination scores between the groups. Both groups improved their scores after the course. Students spent longer performing CAL than attending lectures. Those who scored lowest in the first examination spent the most time on the CAL course. Those who spent the most time on the CAL course showed the largest improvement in examination score. Thirty-six out of the 42 students, who completed an evaluation of the CAL programme, rated it better than the standard lectures. CONCLUSIONS: Computer assisted learning is an effective way of increasing knowledge in teaching undergraduate endocrinology. The course was easy to run and was valued more highly than conventional lectures. The module is now running routinely in the year 3 clinical firms at St Thomas' and has resulted in an increase in knowledge in the end of firm assessment.

Computer-Assisted Instruction↗
PubMed2001

Aging and physical fitness are more important than obesity in determining exercise-induced generation of GH.

Exercise is a potent stimulus for GH secretion. Aging and obesity are associated with a diminution of GH secretion. We wanted to determine whether age or fat mass is more important in regulating the GH response to exercise. Four groups of healthy men were studied: seven lean young men [age, <40 yr; body mass index (BMI), <25 kg/m(2)], six overweight young men (age, <40 yr; BMI, >27.5), seven lean older men (age, >60 yr; BMI, <25), and 6 overweight older men (age, 60 yr; BMI, >27.5). The men performed a maximal exercise test. GH secretion was higher in the younger men than in the older men. Peak GH was higher in the older lean men than in the older overweight men. There was no difference between the young groups. Fitness correlated negatively with age and positively with peak GH. In young men, there was no relation between BMI, bioimpedance, or leptin and GH secretion. In contrast, in older men there was an inverse correlation between measures of fat mass and GH secretion. Age and physical fitness are more important than body fat in regulating exercise-induced GH secretion. These findings have important clinical implications if we are to prevent the frailty and morbidity associated with aging.

Adult↗
PubMed2000

Nasogastric feeding enhances nutritional status in paediatric liver disease but does not alter circulating levels of IGF-I and IGF binding proteins.

OBJECTIVE: Complications of childhood cirrhosis include abnormal growth and malnutrition, associated with abnormalities in circulating IGFs and IGFBPs. Controlled studies suggest that intensive enteral feeding enhances nutritional status. The aim was to ascertain whether nasogastric feeding improves nutritional status in clinical practice and to assess the effect of feeding on serum IGF-I and IGFBPs. PATIENTS: Thirty-three children (median age 0.6 years) with biliary atresia and failure to thrive who were treated with nasogastric feeding. MEASUREMENTS: Height, weight and triceps skin fold thickness were measured prior to feeding and regularly for 1 year or until feeding was stopped. Serum IGF-I and IGFBPs were measured by immunoassay at the same intervals. RESULTS: The median duration of feeding was 3.7 months. Twenty-two stopped feeding after liver transplantation, while 10 stopped electively and 1 boy died. Before feeding, the children were losing weight and height centile. Triceps skin fold thickness, weight and height SD scores improved with feeding. Baseline serum IGF-I and IGFBP-3 were low, while IGFBP-1 and IGFBP-2 were raised. IGF-I and IGFBP-1 did not change with feeding. IGFBP-2 fell and reached a nadir by 3 months, while IGFBP-3 rose temporarily for 4-6 weeks. CONCLUSIONS: Nasogastric feeding improves body composition in paediatric liver disease but circulating IGF-I and IGFBPs remain abnormal and do not play a major role in mediating these changes. This does not exclude a paracrine or autocrine effect of IGF-I.

Biliary Atresia↗
PubMed1999

The effect of short stature, portal hypertension, and cholestasis on growth hormone resistance in children with liver disease.

Chronic liver disease is associated with GH resistance, which is characterized by high circulating GH and low insulin-like growth factor I (IGF-I) concentrations. Standard GH replacement has no effect on serum IGF-I in pediatric liver disease. The aims were to examine whether GH resistance can be overcome by supraphysiological GH and to determine whether GH resistance worsens with the progression of liver disease. Thirty children, divided into five groups whose liver disease was at clinically different stages, were studied. They were given 0.2 IU/kg x day GH for 4 days and then 0.4 IU/kg x day for the next 4 days. Serum IGF-I and binding proteins (IGFBPs) were measured by immunoassay. IGF-I was lower in all study groups than in normal controls. IGF-I, IGFBP-3, and acid-labile subunit rose in response to GH. The magnitude of the response reflected nutritional status and liver dysfunction; in particular, portal hypertension was associated with a poor IGF-I response. There was no change in IGFBP-2. GH resistance begins early in the natural history of childhood liver disease and develops with the progression of liver disease, particularly with portal hypertension. It may be partially overcome by supraphysiological GH administration, but the effect becomes smaller with worsening liver disease.

Body Height↗
PubMed1998

Gene expression and serum levels of insulin-like growth factors (IGFs) and IGF-binding proteins in a case of non-islet cell tumour hypoglycaemia.

We describe a case of non-islet cell tumour hypoglycaemia (NICTH) associated with a renal cell carcinoma. Serum insulin-like growth factors (IGFs) (including IGF-II E peptide), IGF-binding proteins (IGFBPs), insulin and C-peptide were measured before and after surgical removal of the tumour. IGFBPs were visualized by Western ligand blotting. Preoperatively 'big' IGF-II and IGFBP-2 levels were raised. IGF-I, IGFBP-1 and IGFBP-3 were low, while insulin, C-peptide and GH were undetectable. These changes were reversed by 2 days postoperatively. Protease assays showed little IGFBP-3 protease activity preoperatively. Preoperatively, neutral chromatography demonstrated most of the immunoassayable IGFBP-3 in a high molecular weight form with a small amount of IGF-II. Most of the IGF-II and big IGF-II eluted in lower molecular weight forms. Postoperative samples showed a shift in IGF-II which became increasingly associated with IGFBP-3 in both low and high molecular weight complexes. By Northern blotting, expression of all species of IGF-II mRNA in the tumour was 10-fold greater than in normal human liver. The tumour did not express IGFBP-1 or IGFBP-2. IGFBP-3 was expressed in small amounts, while the expression of IGFBP-4 was two-fold higher than in liver. In conclusion, we have confirmed high levels of big IGF-II and IGFBP-2 in NICTH, changes which are reversed postoperatively. The IGF-II is derived from the tumour which overexpresses these genes but IGFBP-2 probably arises from extratumour upregulation.

Aged↗
PubMed1998

Serum leptin and insulin in paediatric end-stage liver disease and following successful orthotopic liver transplantation.

OBJECTIVE: Leptin, the product of the ob gene, is a postulated feedback regulator of adiposity with appetite suppressant and catabolic effects. Catabolic states are associated with decreased body fat mass as a result of both nutritional and metabolic perturbation. Low serum leptin has been described previously in a number of catabolic states. It has been unclear whether the observed changes in leptin are a cause or consequence of changes in adiposity. Paediatric end-stage liver disease (ESLD) is characterized by decreased body fat mass and poor linear growth. Successful treatment by orthotopic liver transplantation (OLT) is accompanied by increase in fat mass. We investigated the hypothesis that serum leptin would be low in paediatric ESLD and that increase in body fat mass post-OLT would result in increased serum leptin. DESIGN: Serum leptin and insulin were measured by radioimmunoassay in children with ESLD before and after successful OLT and in age-matched controls. PATIENTS: Twenty-four children with ESLD attending the outpatient department of King's College Hospital, London and 10 age-matched controls. MEASUREMENTS: Anthropometric measurements were performed according to standard techniques and standard deviation (SDS) derived from population standards. Serum leptin and insulin were measured by radioimmunoassay. RESULTS: Serum leptin pre-OLT, leptin (4.06 micrograms/l, [3.45, 5.68] median, with 25th and 75th interquartile ranges) was significantly lower than controls (6.62 micrograms/l, [4.33, 8.05], P = 0.02). Following OLT, serum leptin fell to levels which were significantly lower than pre-OLT values (3.32 micrograms/l, [2.30, 3.99], P = 0.01). There was no significant difference between boys and girls either pre-OLT (boys; 3.64 micrograms/l, [2.45, 5.57], girls; 4.14 micrograms/l, [3.18, 5.65]) or post-OLT (boys; 3.32 micrograms/l, [2.93, 3.62], girls; 3.69 micrograms/l, [2.23, 4.63]. Neither the age at OLT nor the age at the time of blood sampling was correlated with serum leptin pre-OLT or post-OLT. Pre-OLT the children were significantly malnourished with low measures of body fat mass (mid-arm circumference (MAC) SDS -1.90 [-4.67, -1.07]; triceps skinfold thickness (TSF) SDS -1.53, [-2.23, -0.23]; body mass index (BMI) 16.2, [15.5, 16.9]). Three months post-OLT, there were significant improvements in MAC SDS (-0.77, [-1.08, -0.20], P = 0.02) and TSF SDS (-0.41, [-1.95, -0.38], P = 0.003), but no significant change in BMI (15.9 [15.3, 16.7], P = 0.41. Pre-OLT, log serum leptin did not correlate with BMI, MAC SDS or TSF SDS. In contrast, post-OLT, there was a positive correlation between log serum leptin and BMI (r = 0.59, P = 0.003), MAC SDS (r = 0.49, P = 0.01) and TSF SDS (r = 0.41, P = 0.05). BMI also correlated with log serum leptin in the control children (r = 0.64, P = 0.04). CONCLUSIONS: Serum leptin is low in children with end-stage liver disease but does not show the expected correlation with measures of body fat mass. Surprisingly, following orthotopic liver transplantation serum leptin falls significantly despite significant increases in measures of body fat mass (triceps skinfold thickness standard deviation scores, mid-arm circumference standard deviation scores). Orthotopic liver transplantation restores the expected correlation of serum leptin with measures of body fat mass within the treatment group. The elevation of serum leptin above predicted levels in paediatric end-stage liver disease offers a mechanism for the anorexia and cachexia characteristic of this disease.

Anthropometry↗
PubMed1998

Cirrhotic liver expresses low levels of the full-length and truncated growth hormone receptors.

In cirrhosis, as in other conditions of protein catabolism, there is a state of acquired GH resistance, as defined by high circulating GH levels with low insulin-like growth factor I levels. However, patients with end-stage liver failure respond to supraphysiological doses of GH with an increase in circulating insulin-like growth factor I levels. The present study represents a detailed analysis of GH receptor (GHR) expression in cirrhotic liver from 17 patients with end-stage liver disease. Specific binding of labeled GH was identified in all cirrhotic livers studied. The binding affinity for the GHR was similar in cirrhotic and normal livers, but the number of binding sites per mg protein of liver membrane was variable in both normal and cirrhotic liver, although it were generally lower in cirrhotic liver. GHR expression was identified in cirrhotic liver by Northern blotting, RT-PCR, and ribonuclease protection assay. On Northern blotting, a single transcript of 4.8 kb was identified in normal and cirrhotic tissues. RT-PCR identified expression of both full-length GHR and a truncated form of the GHR; this was confirmed by ribonuclease protection assay. In situ hybridization and immunohistochemistry confirmed the expression of GHR in regenerating hepatocytes and isolated cells in fibrous tissue. In conclusion, 1) the low level of GHR in cirrhotic liver may contribute to the acquired GH resistance found in cirrhotic patients; 2) the reduced expression of both full-length and truncated GHR is compatible with the low level of GH-binding protein found in cirrhosis, as this truncated receptor has previously been reported to generate large amounts of GH-binding protein; and 3) the demonstration of GH binding to cirrhotic liver explains why these patients with GH resistance may still respond to supraphysiological doses of GH.

Adult↗
PubMed1998

The insulin-like growth factor and binding protein axis in children with end-stage liver disease before and after orthotopic liver transplantation.

Over 50% of children with established cirrhosis have evidence of growth failure and malnutrition. Orthotopic liver transplantation (OLT) is a successful treatment for many children and leads to improved growth and nutrition. Most of the anabolic actions of GH are mediated through the generation of the mitogenic polypeptide insulin-like growth factor-I (IGF-I). Although this is synthesised ubiquitously, the bulk of circulating IGF-I is derived from the liver. The actions of IGF-I are modulated by a family of at least six high-affinity binding proteins (IGFBPs). Growth failure in end-stage liver disease, both before and after OLT, may result from abnormalities in the IGF-IGFBP axis. Children who had undergone successful OLT were studied before and after OLT. Anthropometry was measured by standard techniques. Serum IGFs, IGFBPs and acid labile subunit (ALS) were measured by RIA, IRMA, ELISA, Western ligand and immunoblotting. The most severely affected anthropometric parameters were skin fold thickness and mid-arm circumference. After OLT there was a marked improvement in these parameters. Chronic liver disease was characterised by low serum IGF-I, IGF-II, IGFBP-3 and ALS levels with raised IGFBP-1 and -2 levels. Serum IGFBP-1 and -2 were negatively correlated with pre-OLT anthropometric parameters. After OLT, there was a rapid normalisation of serum IGF-I, while IGF-II and IGFBP-3 overshot to supranormal levels. ALS levels post-OLT remained below control levels. By 3 years post-OLT, IGFBP-3 had fallen to levels which were insignificantly different from controls. IGFBP-1 fell but remained above normal, while there was no significant change in IGFBP-2. Growth post-OLT correlated positively with serum IGF-I and negatively with IGFBP-1. In conclusion, chronic liver disease is associated with marked changes in body composition. These changes are associated with and may be caused by an impaired generation of IGF-I and altered production of IGFBPs. After OLT there is a marked improvement in growth associated with partial normalisation of the IGF-IGFBP axis. However, there are persistent abnormalities in this axis which may explain growth failure post-OLT.

Adolescent↗
PubMed1997

Hepatic growth hormone receptor, insulin-like growth factor I, and insulin-like growth factor-binding protein messenger RNA expression in pediatric liver disease.

Major changes in serum levels of insulin-like growth factor I (IGF-I) and IGF-binding proteins (IGFBPs) occur in children with end-stage liver disease in association with changes in body composition. We hypothesized that these changes would be associated with changes in hepatic messenger RNA (mRNA) expression. Eleven children with end-stage extrahepatic biliary atresia and 11 controls (liver donors) were studied. Serum samples were obtained from the children with biliary atresia immediately before orthotopic liver transplantation. Serum IGF-I, IGFBP-1, and IGFBP-2 levels were measured by radioimmunoassay, and IGFBP-3 by immunoradiometric assay. In both groups, growth hormone receptor mRNA expression was examined by quantitative reverse transcription-polymerase chain reaction, IGF-I mRNA expression by ribonuclease protection assay, and IGFBP-1 to -4 mRNA expression by Northern analysis. Growth hormone receptor and IGF-I mRNA levels were reduced 1.7-fold (P = .003) and 9.6-fold (P = .0001) in biliary atresia compared with levels in controls. Despite increased serum IGFBP-1 levels and reduced IGFBP-3 levels in biliary atresia, there was no change in either IGFBP-1 or IGFBP-3 mRNA expression. In contrast, serum levels and mRNA expression of IGFBP-2 were increased 1.6-fold (P = .003) and twofold (P = .0001), respectively, compared with controls. Gene expression did not correlate with liver dysfunction or body composition. Changes in growth hormone receptor and IGF-I mRNA expression may account for the reduction in serum IGF-I found in pediatric liver disease. In contrast, the marked alteration in circulating IGFBP levels was not accompanied by changes in hepatic IGFBP gene expression, suggesting that posttranslational mechanisms may be important.

Adolescent↗
PubMed1997

Orthotopic liver transplantation reverses the adverse nutritional changes of end-stage liver disease in children.

The changes in growth and body composition after orthotopic liver transplantation (OLT) were studied in 61 children [median age at OLT 3.49 y (range: 0.04-14.5 y), 26 boys and 35 girls] who had survived > or = 1 y post-OLT. Height, weight, midarm circumference (MAC), triceps skinfold thickness (TSF), and subscapular skinfold thickness (SSF) were measured at OLT, 3 and 6 mo later, then annually up to 5 y. SD scores (SDS) were derived from population standards. Results are reported as mean SDS +/- SEM. At OLT the children were short and malnourished (height: -0.98 +/- 0.22; weight -0.82 +/- 0.18; MAC: -1.77 +/- 0.21; TSF: -1.27 +/- 0.17; SSF: -1.49 +/- 0.17). By 3 mo post-OLT, there was a sustained improvement in MAC (-0.73 +/- 0.22), TSF (-0.48 +/- 0.18), and SSF (-0.50 +/- 0.18). Weight SDS (-0.48 +/- 0.20) improved by 6 mo without significant change in height SDS. The three children with Alagille syndrome were smaller (height, weight, and MAC) than children with other diagnoses but did show catch-up growth. Fulminant hepatic failure was not associated with growth failure before or after OLT. Infants (n = 14) were smaller and more malnourished at OLT (smaller skinfold thicknesses and lower weight SDS) than those who received transplants at an older age. By 1 y post-OLT, the only persisting difference was in TSF. Abnormal liver function at 1 y post-OLT (n = 8) and repeated episodes of steroid-treated rejection (n = 13) were associated with worsening height and weight SDS. The use of tacrolimus for graft salvage from rejection (n = 6) was not associated with growth failure. In conclusion, end-stage liver disease has a more adverse effect on MAC, TSF, and SSF than on height and weight, but a marked and rapid improvement occurred post-OLT. Children who were most severely malnourished and growth restricted at the time of OLT showed the greatest catch-up growth after OLT.

Adolescent↗
PubMed1996

Sequential changes in insulin-like growth factor I (IGF-I) and IGF-binding proteins in children with end-stage liver disease before and after successful orthotopic liver transplantation.

Pediatric end-stage liver disease (ESLD) leads to poor linear growth and wasting. After orthotopic liver transplantation (OLT), catch-up growth occurs unpredictably and with a delay. The bulk of circulating insulin-like growth factor I (IGF-I) and its major circulating binding protein, IGF-binding protein-3 (IGFBP-3), is derived from the liver. We hypothesized that growth failure in ESLD, both before and after OLT, may result from abnormalities in the IGF-IGFBP axis. Serum IGF-I, IGFBP-1, and insulin were measured by RIA, and IGFBP-3 was determined by immunoradiometric assay in 26 children with ESLD (mean of 3.7 samples pre-OLT and 4.2 samples post-OLT per patient) and 30 age-matched controls. In addition, serum IGFBPs were visualized by Western ligand blotting. IGFBP-3 and IGFBP-2 were also observed by immunoblotting with specific antisera. IGFBP-3 protease activity was determined by protease gels using recombinant human IGFBP-3 label as substrate. Anthropometric measurements were performed according to standard techniques. Pre-OLT, IGF-I (32.7 +/- 4.8 micrograms/L), and IGFBP-3 (1.11 +/- 0.10 mg/L) were significantly lower than control values [IGF-I, 168.3 +/- 16.5 micrograms/L (P = 0.0001); IGFBP-3, 2.57 +/- 0.17 mg/L (P = 0.0001)]. Post-OLT, IGF-I (179.2 +/- 19.7 micrograms/L; P = NS) rose to control levels, whereas IGFBP-3 (3.49 +/- 0.14 mg/L; P = 0.002) became significantly greater than the control value. IGFBP-1 was significantly higher pre-OLT (78.9 +/- 9.6 micrograms/L; P = 0.0001) than post-OLT (45.7 +/- 6.9 micrograms/L), and both were significantly higher than control values (18.5 +/- 2.5 micrograms/L; P = 0.0001 vs. pre-OLT and P = 0.0002 vs. post-OLT). There was a trend toward higher insulin levels both pre-OLT (15.5 +/- 1.8 mU/L) and post-OLT (12.5 +/- 1.4 mU/L) compared with control values (9.7 +/- 1.1 mU/L; P = 0.06 vs. pre-OLT). IGFBP-1 was negatively correlated with serum insulin post-OLT (P = 0.008), but there was no correlation pre-OLT. Western ligand blotting confirmed the changes in IGFBP-3 pre- and post-OLT. Immunoblotting demonstrated a reduction in all mol wt forms of IGFVBP-3 pre-OLT. Protease assays demonstrated the appearance of IGFBP-3 proteolysis only at a time coincidental with the operative stress of OLT; overall, there was no difference in protease activity pre- and post-OLT. IGFBP-2 was unchanged post-OLT compared with pre-OLT, although levels were higher than control values. Mid-upper arm circumference and triceps skin fold thickness SD score 3 months post-OLT and weight SD score 1 yr post-OLT were significantly higher than those at OLT. In conclusion, IGF-I and IGFBP-3 are reduced, and IGFBP-1 and IGFBP-2 are increased in children with ESLD. After OLT, IGF-I levels return to normal, but marked abnormalities in IGFBPs remain. These changes may help to explain at least in part the growth failure seen in pediatric ESLD both before and after successful OLT.

Adolescent↗
PubMed1996

Differential effects of malnutrition, bile duct ligation and galactosamine injection in young rats on serum levels and gene expression of IGF-binding proteins.

Hepatic gene expression and circulating levels of IGF-binding proteins (IGFBP)-1 to -4 were examined in two rat models of liver disease employing acute hepatitis or chronic structural damage. The study comprised four groups: group 1 (n = 6) was injected intraperitoneally with saline and food was available ad libitum (AL), group 2 (n = 6) underwent bile duct ligation (BDL), group 3 (n = 6) was injected with 400 mg galactosamine (GAL), group 4 (n = 6) was sham-operated and pair-fed to group 2 (PF). All were killed by decapitation at day 7. Serum IGF-I, by RIA, was significantly (P < 0.05) lower in the BDL group (458 +/- 37 micrograms/l) and PF group (451 +/- 51 micrograms/l) compared with the AL group (643 +/- 77 micrograms/l) and GAL group (720 +/- 67 micrograms/l). Immunoblotting showed raised IGFBP-2 levels in all groups compared with AL (BDL, 167 +/- 14% of AL; GAL, 173 +/- 13%; PF, 149 +/- 9%). IGFBP-3 was decreased in the GAL (56 +/- 11%) and PF groups (66 +/- 5%) but increased in the BDL group (154 +/- 29%). IGFBP-4 was decreased in the GAL (76 +/- 11%) and PF groups (47 +/- 5%) but unchanged in the BDL group (90 +/- 10%). By Northern analysis, IGFBP-1 mRNA expression was increased in the GAL (321 +/- 51%) and PF groups (263 +/- 12%) but reduced in the BDL group (68 +/- 8%). IGFBP-2 expression increased in all groups (PF, 836 +/- 19%; BDL, 683 +/- 121%; GAL, 372 +/- 68%) and was highest in the BDL and PF groups. IGFBP-3 expression was reduced in all groups (BDL, 57 +/- 16%; GAL, 52 +/- 12% PF, 51 +/- 13%). IGFBP-4 expression was reduced in the GAL (30 +/- 4%) and PF (28 +/- 5%) groups but unchanged in the BDL group (76 +/- 9%). Marked changes in gene expression of IGFBPs occurred in both models of liver disease, together with serum changes, which were different from each other and from malnutrition alone.

Animals↗