A preliminary trial of the effect of recombinant human growth hormone on short-term linear growth and glucose homeostasis in children with Crohn's disease.

BACKGROUND: It is unclear whether recombinant human growth hormone (rhGH) improves linear growth in children with Crohn's disease (CD). AIMS: To investigate the effects of rhGH on height velocity (HV) and glucose homeostasis over a 6-month period. DESIGN AND SETTING: Randomized controlled trial in two tertiary children's hospitals in 22 children with inflammatory bowel disease amongst whom 21 had CD. Duration of disease from diagnosis and number of acute relapses requiring either exclusive enteral nutrition or therapeutic dose of oral prednisolone were similar in the treatment and control groups. INTERVENTION: Either rhGH (0·067 mg/kg per day) as daily subcutaneous injections (rhGH group; n, 11) or no rhGH, (Ctrl; n, 11) for 6 months. MAIN OUTCOME MEASURE: Percentage change in HV after 6 months in the two groups. Auxology, puberty, skeletal age, disease factors, treatment and glucose homeostasis were also assessed. RESULTS: Median HV increased from 4·5 (range, 0·6, 8·9) at baseline to 10·8 (6·1, 15·0) cm/year at 6 month (P = 0·003) in the rhGH group, whereas in the Ctrl group, it was 3·8 (1·4, 6·7) and 3·5 cm/year (2·0, 9·6), respectively (P = 0·58). Median percentage increase in HV after 6 months in the rhGH group was 140% (16·7, 916·7) compared with 17·4% (-42·1%, 97·7%) in the Ctrl group (P < 0·001). There were no significant differences in disease activity and proinflammatory cytokines at baseline and 6 months in both groups and change in bone age for chronological age was also similar in the two groups. In the rhGH group, fasting insulin increased from 4·0 (2·0, 11·0) to 7·0 mU/l (2·0, 16·0) (P = 0·02), whereas in the Ctrl group, it was 3·0 (1·2, 12·7) and 3·8 mU/l (2·1, 7·0) (P = 0·72), respectively. CONCLUSIONS: Although this pilot trial shows that rhGH can improve short-term linear growth in children with CD, the clinical efficacy of this therapy needs to be further studied in longer-term studies of growth, glucose homeostasis and disease status.

The growth hormone insulin-like growth factor 1 axis in children and adolescents with inflammatory bowel disease and growth retardation.

CONTEXT: There is scarce knowledge about the growth hormone (GH) insulin-like growth factor-1 (IGF1) axis in children & adolescents with inflammatory bowel disease (IBD) and growth retardation. OBJECTIVE: To describe the pattern of GH and IGF1 secretion in children & adolescents with IBD. DESIGN: A retrospective review of 28 patients (23 M) of IBD (25 Crohn's Disease and three Ulcerative Colitis) and growth retardation who had investigation of the GH/IGF-1 axis. Height velocity (HV) and serum IGF1 were converted to standard deviation score (SDS); to account for delayed puberty in girls over 11 years and boys over 12 years, HV and serum IGF1 SDS were adjusted for bone age. RESULTS: Median (range) age and Ht SDS at the time of endocrine evaluation was 14.3 years (7.7,17.0) and -2.0(-3.6,-0.9), respectively. Median HVSDS over the prior 12 months was -2.2(-7.7,2.8). Median peak serum GH on insulin tolerance test (ITT) was 5.8 mcg/l (1.3, 24.0), and median serum IGF1 SDS was -0.9(-3.1, 0.1). Five of 28 (18%) had a peak serum GH of >12 mcg/l. Overall, four had biochemical evidence of functional GH deficiency (peak GH < 3 mcg/l and IGF1 SDS < 0) and 11 children had biochemical evidence suggesting GH resistance (peak GH > 6 mcg/l and IGF1 SDS < 0). However, only one child had a peak serum GH > 6 mcg/l and a very low IGF1 SDS of <-2.0. There was a negative association between peak serum GH and Ht SDS (r = -0.49, P = 0.008), but there was no association with HV and there was no association between IGF1 SDS and Ht or HV SDS. IGF1 SDS showed a negative association with erythrocyte sedimentation rate (r = -0.41, P = 0.04). CONCLUSION: Growth retardation in children and adolescents with IBD is commonly associated with a range of biochemical abnormalities ranging from functional GH deficiency to GH resistance. In these children, poor relationship between systemic markers of growth and height velocity point to an important role of growth factors at the target organ level in modulating growth in children with IBD. The value of assessing the GH/IGF-1 axis and whether it predicts subsequent response to growth-promoting therapy requires further exploration.

Best practice in primary care pathology: review 6.

This sixth best practice review examines four series of common primary care questions in laboratory medicine: (1) laboratory monitoring in hypertension and heart failure abnormalities; (2) markers of inflammatory joint disease; (3) laboratory investigation of chronic diarrhoea; and (4) mumps and chickenpox. The review is presented in question-answer format, referenced for each question series. The recommendations represent a precis of guidance found using a standardised literature search of national and international guidance notes, consensus statements, health policy documents and evidence-based medicine reviews, supplemented by Medline Embase searches to identify relevant primary research documents. They are not standards but form a guide to be set in the clinical context. Most are consensus based rather than evidence based. They will be updated periodically to take account of new information.

Development of a high pressure liquid chromatography method for the determination of mycophenolic acid and its glucuronide metabolite in small volumes of plasma from paediatric patients.

In order to facilitate the simultaneous determination of the levels of mycophenolic acid (MPA) and mycophenolic acid glucuronide (MPAG) in plasma samples a step wise gradient high performance liquid chromatography (HPLC) method was developed using UV detection system and naproxen as an internal standard. The analytes were extracted from plasma using Strata-X polymeric solid phase extraction (SPE) cartridges. Separation was achieved within a total chromatographic run time of 18 min at 1.0 ml/min flow rate using a Hv PURITY C18 column. The method was found to be linear over the concentration range investigated, 1.0-16 microg/ml (r > 0.99) for MPA and 10-160 microg/ml (r > 0.99) for MPAG. The limit of detection was 0.1 microg/ml for both MPAG and MPA. The intra- and inter-day imprecisions expressed as R.S.D. were 7.8 and 6.6%, respectively, for MPA (1 microg/ml) and 6.2% and 5.6%, respectively, for MPAG (20 microg/ml). The average extraction recovery from plasma was 93.06%, for MPA and 92.41% for MPAG. The method developed was found to be accurate and precise in quantifying the level of MPA and MPAG over a their therapeutic range of concentrations in small volumes of plasma and thus can be effectively used in the routine drug monitoring procedures and pharmacokinetic studies. It was also developed in such a way that it should be easily coupled to an electro-spray ionization mass spectrometer should greater sensitivity be required.

Exercise to exhaustion in the second-wind phase of exercise in a case of McArdle's disease with and without creatine supplementation.

The cardio-pulmonary and biochemical changes observed in a case of McArdle's disease, exercising with increasing work rates to exhaustion in the "second-wind" phase of exercise are reported for the first time. A work rate of 275-325 watts was achieved. Venous blood lactate remained unchanged throughout. The plasma ammonium level reached a plateau of approximately 400 mmol/l at 100 watts. At a work rate of 150-175 watts the ratio of O2 consumption to CO2 production increased, the inverse of an anaerobic threshold. Maximal cardiopulmonary responses were achieved at 200 watts. During the final periods of exercise from 200 to 275/325 watts pulmonary ventilation did not significantly change but there was a decrease in the venous blood H+ concentration, and pO2 and in increase in the pCO2. Creatine supplementation at 25 g/day for five days did not improve exercise performance.

Safety of the insulin tolerance test.

Concerns have been raised about the hazards of the insulin tolerance test (ITT), used to measure growth hormone secretion. In Glasgow, we continue to use this test, adhering to a strict protocol. A review of outcome over a 10 year period (1989-99), during which 550 ITTs were performed, was undertaken. No serious adverse events occurred; in particular, no child fitted or required intravenous glucose. Fewer tests were done during the latter five years, with a higher yield of growth hormone (GH) deficiency, reflecting our increasingly conservative approach to paediatric GH therapy during this period. We conclude that the ITT is safe and reliable in a paediatric setting provided that a strict procedure is followed.

Sex hormone binding globulin concentration as a prepubertal marker for hyperinsulinaemia in obesity.

BACKGROUND: Overweight children become obese adults who are prone to develop the "metabolic syndrome" and premature coronary arterial disease (CAD). AIMS: To assess whether sex hormone binding globulin (SHBG) is a potential marker for hyperinsulinaemia/insulin resistance in prepubertal obese children. METHODS: Twenty five obese children (body mass index (BMI) >2SD) who warranted investigation on clinical grounds were enrolled. Their insulin response to an oral glucose tolerance test was assessed. RESULTS: Fourteen children were hyperinsulinaemic. Despite being matched for age and BMI, SHBG concentrations were below the sex related reference range in the hyperinsulinaemic group. CONCLUSION: Our results indicate that a subnormal SHBG concentration in a prepubertal child is strongly predictive of hyperinsulinaemia. By measuring the circulating SHBG concentration, it might be possible to identify those at most risk of premature CAD, targeting them for lifestyle changes.

Changes in skeletal and cardiac muscle enzymes during the Scottish Coast to Coast Triathlon.

While skeletal muscle injury is common after prolonged exercise, evidence in the literature supporting cardiac muscle injury is conflicting. Creatine kinase and cardiac troponin-I were measured, in 31 amateur athletes (25 male) before, and 12-24 hours after, a 300 km cycling/running/canoe triathlon event. A short questionnaire was used to assess level of fitness, training and previous experience. Creatine kinase levels were greater after the 45 km cross-country run compared with after a 155 km road cycle (60.5 +/- 62.8 iu/L/kg vs 19.3 +/- 9.6 iu/kg, P = 0.03). Individuals performing running and cycling events consecutively had creatine kinase similar to those observed after running alone (50.2 +/- 53.8 iu/L/kg vs 60.5 +/- 62.8 iu/L/kg, P = 0.55). Cardiac troponin-I was elevated above the normal range (0.1 ng/L) in six athletes (four in running and cycling events, one in the running and one in the cycling event). We conclude that running produces significantly more skeletal muscle injury than cycling and that strenuous endurance exercise involving running and cycling in amateur trained athletes is associated with release of cardiac specific enzymes. The functional and longer term consequences of this require further study.

Lipid and lipoprotein concentrations in pregnancies complicated by intrauterine growth restriction.

Previous studies have shown that in preeclampsia, plasma lipids climb substantially above levels seen in normal pregnancies. Such lipid changes may play a role in the endothelial damage characteristic of preeclampsia. Pregnancies complicated by intrauterine growth restriction (IUGR), without preeclampsia, have similar placental pathology to preeclampsia despite the absence of the maternal systemic manifestations of hypertension and proteinuria. The aim of this study was to perform a cross-sectional study of lipid and lipoprotein concentrations in the third trimester, from normal pregnancies, and those complicated by IUGR without preeclampsia. Our hypothesis was that, in contrast to the exaggerated lipid changes seen in preeclampsia, lipid and lipoprotein concentrations in IUGR would be similar to those of matched healthy pregnant controls. Fasting blood samples for lipids and lipoprotein fractions were taken in the third trimester, from eight women with IUGR; and eight women with uncomplicated pregnancies, matched as a group for age, booking weight, parity, and gestational age at sampling. There were no significant differences (P > 0.05) in the median concentrations of triglyceride, high-density lipoprotein, and very-low-density lipoprotein 1 (VLDL1), between cases and controls. However, women with IUGR pregnancies had significantly lower cholesterol [4.95 mmol/L (3.35-7.10) vs. 7.47 (5.75-8.45); median (range) for IUGR patients and controls, respectively; P < 0.01], low-density lipoprotein (LDL)-cholesterol [2.45 mmol/L (0.95-3.60) vs. 4.25 (3.35-5.60); P < 0.01], VLDL2 mass [59.0 mg/dL (37-87) vs. 103.0 (64-168); P < 0.01], intermediate-density lipoprotein mass [56.0 mg/dL (31-110) vs. 125.6 (91-157); P < 0.01], and total LDL mass [221.0 mg/dL (104-237) vs. 380.3 (267-534); P < 0.01]. In addition, it was noteworthy that, with respect to LDL-cholesterol and total LDL mass, there was little or no overlap in the ranges of concentrations measured between cases and controls. Because VLDL2 and intermediate-density lipoprotein are the synthetic precursors to LDL in the circulation, their significantly lower median concentrations imply a failure of appropriate LDL synthesis in IUGR pregnancies. Whatever the mechanism, if our results are confirmed in larger studies and longitudinal investigations, then LDL-cholesterol measurements (when LDL-cholesterol fails to rise appropriately or is low in the third trimester) may be of use in identifying mothers with, or at risk of, a pregnancy complicated by IUGR.

Audit of an emergency biochemistry service.

AIM: To examine a model for the evaluation of appropriateness of testing in an emergency biochemistry laboratory. METHODS: A model was devised in which incoming emergency test requests were categorised as appropriate or inappropriate. Explicit criteria were used to define eight minor categories, which were chosen to reflect accurately current working practice within the hospital and laboratory. Five junior medical staff each undertook a prospective 24 hour assessment, during which time all incoming requests were monitored and categorised according to these criteria. Concordance between monitors was evaluated before and during assessments. RESULTS: Of 509 requests, 384 (75%) were appropriate and 125 (25%) were inappropriate according to the criteria used to define categories. Inappropriate requests fell into three main groups: preoperative samples (43.2% (54/125) of all inappropriate requests), missed routine samples (33.6% (42/125)) and accelerated (priority) analyses (16% (20/125)). Various other reasons accounted for the remaining 7.2% (9/125). CONCLUSION: This model may be used to obtain valid information about current clinical and laboratory practice. Strategies to reduce the number of inappropriate requests have been identified in order to reserve the emergency service for situations of true need.

Laboratory turnround time: closing the loop.

AIMS: To institute recommendations from a laboratory turnround time study; to evaluate audit methods; and to quantify improvements achieved. METHODS: Changes to result report distribution and specimen delivery were affected by posting results directly from the laboratory followed by the introduction of a twice daily courier service. Improvements were evaluated by repeating the turnround time audit described in an earlier report. Pre-, peri- and post-analytical turnround times were compared before and after changes had been instituted. RESULTS: Directly posting general practitioner (GP) results increased the percentage of reports which reached their destination within one and two days after they were generated from 13 to 29% and from 68 to 82%, respectively. Pre- and postanalytical times were superimposable before and after posting was started. Corresponding improvements to the satellite hospital service were from 25 to 78% and from 60 to 82%, respectively. The courier service shortened the median total turnround time from 50 to nine hours for GPs and from 69 to 18 hours for the satellite hospital. Fifty three per cent of GP reports and 21% of satellite hospital reports arrived on the same day as the sample was taken: 99% and 94%, respectively, had arrived by the next day. The number of analytically "old" samples which arrived the day after they had been taken, thus invalidating many results, fell from 25 to 3%. CONCLUSIONS: These audits of laboratory turnround time have been used to present a valid case for changes to laboratory transport and to quantify the improvements achieved. They produce consistent and repeatable results, which may also be used to monitor future performance, to assess further changes and to establish the cost-effectiveness of resources used.

Method for assessment of laboratory turnaround times: comparison before, during, and after analysis.

AIMS: To establish a mechanism to examine the components of turnaround time in a representative cross-section of laboratory users; and to identify potential areas for improvement. METHODS: Information was collected manually from result reports received by eight laboratory users: three wards in the main hospital, four GP practices, and one local psychiatric hospital. This was combined with data from the departmental computer files to create a spreadsheet detailing different time points in the processing of a specimen, from venepuncture to receipt of result report. RESULTS: At the main hospital, 80% of samples arrived within two hours of venesection and 95% by four hours; 75% of samples were analysed within two hours; 85% of results arrived in the wards within six hours of printing, although 12% took more than 18 hours to arrive; median overall time six hours. At the satellite (psychiatric) hospital, all samples arrived within seven hours of venesection; 45% were analysed within two hours--the rest the following morning; there were highly variable post-analytical times, minimum 18 hours, maximum 122 hours; the median overall time was 69 hours. Twenty five per cent of samples from GPs took more than 20 hours to arrive; 75% were analysed within two hours, the rest took over 18 hours--waiting overnight; the post-analytical times were highly variable, minimum 22 hours, maximum 122 hours; the median overall time was 50 hours. CONCLUSIONS: The method is easily repeatable and demonstrates the need for local improvement in the post-analytical period. Although specific to the individual data handling system for one laboratory, this method may be used as a basis for other laboratories in pathology disciplines to undertake a representative assessment of turnaround times for different groups of laboratory users.

Use of Autosuture Surgiport for pleural drain insertion.

The insertion of pleural drains (tube thoracostomy) is associated with serious complications in up to 10 per cent of cases. A safe and efficient technique of tube thoracostomy using the Autosuture Surgiport is described.

Plasma angiotensin-converting enzyme activity in patients with bronchial carcinoma.

Plasma angiotensin-converting enzyme (ACE) activities were measured in 58 consecutive patients presenting with bronchial carcinoma. The mean ACE activity before treatment was significantly lower than that of a control population (P less than 0.005). There was a significant and direct relationship between the initial plasma ACE activity and survival time (P less than 0.01) which could not be explained by further analysis for age, clinical staging, or respiratory function, as judged by % FEV. There was a significant increase in plasma ACE activity (P less than 0.03) in nine patients with three or more plasma samples after treatment with chemotherapy or radiotherapy. These results suggest that low plasma ACE activity is associated with poor prognosis in bronchial carcinoma.