Temporal changes in bile acid levels and 12α-hydroxylation after Roux-en-Y gastric bypass surgery in type 2 diabetes.

Since the publication of the above article it has been noted that the author S O'Brien should have been listed as CS O'Brien. The authors should therefore appear as follows: R Dutia, M Embrey, CS O'Brien, RA Haeusler, KK Agénor, P Homel, J McGinty, RP Vincent, J Alaghband-Zadeh, B Staels, CW le Roux, J Yu and B Laferrère The corrected article html and online pdf versions have been amended. The authors wish to apologise for any inconvenience caused.

Temporal changes in bile acid levels and 12α-hydroxylation after Roux-en-Y gastric bypass surgery in type 2 diabetes.

INTRODUCTION: Gastric bypass surgery (GBP) leads to sustained weight loss and significant improvement in type 2 diabetes (T2DM). Bile acids (BAs), signaling molecules which influence glucose metabolism, are a potential mediator for the improvement in T2DM after GBP. This study sought to investigate the effect of GBP on BA levels and composition in individuals with T2DM. METHODS: Plasma BA levels and composition and fibroblast growth factor (FGF)-19 levels were measured during fasting and in response to an oral glucose load before and at 1 month and 2 years post GBP in 13 severely obese women with T2DM. RESULTS: A striking temporal change in BA levels and composition was observed after GBP. During the fasted state, BA concentrations were generally reduced at 1 month, but increased 2 years post GBP. Postprandial BA levels were unchanged 1 month post GBP, but an exaggerated postprandial peak was observed 2 years after the surgery. A significant increase in the 12α-hydroxylated/non12α-hydroxylated BA ratio during fasting and postprandially at 2 years, but not 1 month, post GBP was observed. Significant correlations between BAs vs FGF-19, body weight, the incretin effect and peptide YY (PYY) were also found. CONCLUSIONS: This study provides evidence that GBP temporally modifies the concentration and composition of circulating BAs in individuals with T2DM, and suggests that BAs may be linked to the improvement in T2DM after GBP.

Bone mineral density and expression of vitamin D receptor-dependent calcium uptake mechanisms in the proximal small intestine after bariatric surgery.

BACKGROUND: Roux-en-Y gastric bypass may lead to impaired calcium uptake. Therefore, operation-specific effects of gastric bypass and vertical banded gastroplasty on bone mineral density (BMD) were examined in a randomized clinical trial. Bone resorption markers and mechanisms of decreased calcium uptake after gastric bypass were investigated using blood and endoscopic samples from two additional patient cohorts. METHODS: Total BMD and non-weight-bearing skull BMD were measured by dual-energy X-ray absorptiometry at baseline, and 1 and 6 years after gastric bypass or vertical banded gastroplasty in patients who were not receiving calcium supplements. Bone resorption markers in serum and calcium uptake mechanisms in jejunal mucosa biopsies were analysed after gastric bypass by proteomics including radioimmunoassay, gel electrophoresis and mass spectrometry. RESULTS: One year after surgery, weight loss was similar after gastric bypass and vertical banded gastroplasty. There was a moderate decrease in skull BMD after gastric bypass, but not after vertical banded gastroplasty (P < 0·001). Between 1 and 6 years after gastric bypass, skull BMD and total BMD continued to decrease (P = 0·001). C-terminal telopeptide levels in serum had increased twofold by 18 months after gastric bypass. Proteomic analysis of the jejunal mucosa revealed decreased levels of heat-shock protein 90ß, a co-activator of the vitamin D receptor, after gastric bypass. Despite increased vitamin D receptor levels, expression of the vitamin D receptor-regulated calcium transporter protein TRPV6 decreased. CONCLUSION: BMD decreases independently of weight after gastric bypass. Bone loss might be attributed to impaired calcium absorption caused by decreased activation of vitamin D-dependent calcium absorption mechanisms mediated by heat-shock protein 90ß and TRPV6.

An association between post-meal bile acid response and bone resorption in normal subjects.

BACKGROUND: The mechanism surrounding bone suppression after a meal may involve several mediators, but is yet to be clarified. Bile acids (BA) function as signalling molecules in response to feeding, and may be directly involved in bone suppression acutely after a meal. The aim of this study was to test the hypothesis that BA are involved in the acute bone suppression observed after a meal. METHODS: A prospective study in which samples collected from volunteers fed a 400 Kcal test meal after an overnight fast were analysed for parathyroid hormone (PTH), BA, and carboxyterminal of type 1 collagen telopeptide (CTX). The study was carried out in 10 healthy male volunteers. Ethical approval was obtained from the Local Research and Ethics Committee at King's College Hospital. RESULTS: Total BA, glycine conjugated bile acids (GCBA), PTH and CTX showed a response to meal ingestion. There was a negative correlation between percentage change in PTH and CTX (R (2 )= -0.82, P = 0.004), and between PTH and GCBA (R (2 )= -0.39, P = 0.005). CONCLUSION: This study demonstrated an association between GCBA and PTH suppression after a meal. The drop in PTH concentration after a meal may be responsible for the suppression of bone resorption as observed by the decrease in CTX concentration.

Improved blood pressure, nitric oxide and asymmetric dimethylarginine are independent after bariatric surgery.

BACKGROUND: Obesity is associated with hypertension, but the exact mechanism is not fully understood. Bariatric surgery significantly decreases weight and blood pressure (BP). Low plasma nitric oxide (NO) and raised asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO, concentrations are associated with both obesity and hypertension. Correlations between the changes in these parameters were studied after bariatric surgery. METHODS: Weight, BP, plasma ADMA and NO were measured in 29 obese patients (24 female, 5 male) before and six weeks after bariatric surgery. RESULTS: Patients were 39.2 ± 1.2 (mean ± SEM) years old and weighed 126 ± 3 kg. Six weeks after the surgery, patients had lost 10 ± 0.7 kg (P < 0.0001) and mean arterial pressure (MAP) decreased by 11 ± 1.0 mmHg (P < 0.0001). The plasma ADMA concentration decreased by 24 ± 2% from 5 ± 0.4 to 4.0 ± 0.3 µmol/L (P < 0.0001). The plasma total nitrite concentration increased by 15 ± 1% from 51.4 ± 2.6 to 60 ± 3 µmol/L (P < 0.0001). The correlation between the decrease of ADMA and increase of NO subsequent to weight loss was significant (P < 0.0001). However, MAP was not correlated to the changes in ADMA or NO. CONCLUSIONS: After bariatric surgery, beneficial changes in BP, NO and ADMA occur, but our findings suggest that these BP changes are independent of changes in the NO-ADMA axis. Other causes for the changes in BP should therefore be considered.

Leptin/adiponectin ratio in patients with coronary heart disease: comparing subjects with and without metabolic syndrome.

BACKGROUND: Adiponectin and leptin are adipose tissue-derived hormones, shown to have opposing associations with the metabolic syndrome and coronary heart disease (CHD). This study evaluated the association between the leptin/adiponectin ratio and the components of the metabolic syndrome in a cohort with CHD. Methods and results This cross-sectional study included data from 105 subjects (men = 91), undergoing first-time elective coronary artery bypass grafting (CABG). Leptin and adiponectin concentrations were determined by enzyme-linked immunosorbent assay (ELISA). Association was found between the leptin/adiponectin ratio and homeostatic model assessment (HOMA) (r(s) = 0.34, P = 0.0006), fasting insulin concentrations (r(s) = 0.37, P = 0.0001), fasting glucose concentrations (r(s) = 0.24, P = 0.01), systolic blood pressure (r(s) = 0.20, P = 0.05), diastolic blood pressure (r(s) = 0.24, P = 0.02), waist circumference (r(s) = 0.55, P < 0.0001), body mass index (BMI) (r(s) = 0.55, P < 0.0001) and waist/hip ratio (r(s) = 0.38, P = 0.0001). A significant difference was found in ratios between those with and without insulin resistance (HOMA > 3 and HOMA ≤ 3) (P = 0.029) and those with and without metabolic syndrome, defined by the International Diabetes Federation, (P < 0.001). However, using receiver operating characteristic (ROC) analysis and assessment of area under curve (AUC), the leptin/adiponectin ratio did not perform significantly better than its components. CONCLUSION: In patients with severe CHD, the leptin/adiponectin ratio was not found to be a robust tool to distinguish patients with and without insulin resistance and those with and without the metabolic syndrome.

The relationship between postprandial bile acid concentration, GLP-1, PYY and ghrelin.

BACKGROUND: Gut hormones peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) play an integral role in appetite control and energy homeostasis. Entero-endocrine L-cells can be stimulated by nutrients and or bile acids to co-secrete PYY and GLP-1. The aim of this study was to determine the response of bile acids, PYY, GLP-1 and ghrelin after a test meal. DESIGN: Twelve subjects with a BMI of 22·8 (0·52) kg/m² [mean (SEM)] received a 400 kcal test meal after which blood samples were taken every 30 min from 0 to 180 min. PYY, GLP-1 and ghrelin were measured by radioimmunoassays. Fractionated bile acids were measured by HPLC-MSMS. RESULTS: PYY positively correlated with glycochenodeoxycholic acid (GCDCA) (rs = 0·23, P = 0·03) and taurochenodeoxycholic acid (TCDCA) (rs = 0·26, P = 0·02). GLP-1 positively correlated with GCDCA (rs = 0·22, P = 0·047) and glycodeoxycholic acid (GDCA) (rs = 0·3, P = 0·005). Ghrelin negatively correlated with GDCA (rs = -0·45, P≤ 0·0001), TCDCA (rs = -0·23, P = 0·034) and taurodeoxycholic acid (TDCA) (rs = -0·44, P≤ 0·0001). CONCLUSION: PYY and GLP-1 responses correlated with chenodeoxycholic acid (CDCA) counterparts, whereas ghrelin negatively correlated with deoxycholic acid (DCA) counterparts. Specific bile acids may thus differentially affect entero-endocrine cells.

Postprandial plasma bile acid responses in normal weight and obese subjects.

BACKGROUND: Bile acids can act as signalling molecules via various receptors including the nuclear farnesoid X receptor (FXR) and pregnane X receptor (PXR), and the cell surface G-protein-coupled receptor TGR5. The signalling has been implicated in the release of peptide YY (PYY) and glucagon-like peptide 1 (GLP-1), which improves glycaemic control and energy expenditure. We investigated whether morbidly obese subjects have altered postprandial bile acid responses in comparison to normal weight subjects. METHOD: Blood samples were taken every 30 min from 0 to 180 min following a 400 kcal test meal. Samples were taken from 12 normal weight subjects with a body mass index (BMI) of 23.2 (2.8) kg/m(2) (median [interquartile range (IQR)]) and seven obese patients with a BMI of 47.2 (7.2) kg/m(2). Fractionated bile acids were measured on these samples using high-performance liquid chromatography tandem mass spectrometry. RESULTS: The obese subjects showed a lower postprandial response in total bile acids compared with the normal weight subjects. An increase of 6.4 (5.0) and 2.6 (3.3) micromol/L (median [IQR]) in normal weight and obese subjects was observed, respectively (P = 0.02). The difference was predominantly due to the glycine-conjugated fraction (P = 0.03). There was no difference in the increase of the unconjugated or taurine-conjugated fractions. CONCLUSIONS: The decreased postprandial bile acid response in obese subjects compared with normal weight subjects may partly explain the suboptimal GLP-1 and PYY responses and could affect appetite, glycaemic control and energy expenditure.

Insulin resistance and pre-eclampsia: a role for tumor necrosis factor-alpha?

Insulin resistance occurs in pre-eclampsia, but the cause is unknown. Furthermore, it is uncertain whether women destined to develop pre-eclampsia have a pre-existing insulin resistance or whether it is acquired with the development of the disease. We carried out this study to test the hypotheses that the increase in insulin resistance associated with pre-eclampsia is related to higher levels of tumor necrosis factor (TNF)-alpha, and that the increase in insulin resistance precedes the clinical onset of the disease. Fasting plasma samples were obtained from ten women who subsequently developed pre-eclampsia and ten normal pregnant controls at 16, 20, 24, 28, 32 and 36 weeks' gestation to measure circulating levels of insulin, glucose and TNF-alpha. Fasting insulin resistance index (FIRI) was calculated from insulin and glucose concentrations. In the normal controls, fasting insulin and TNF-alpha levels, and FIRI increased with gestation, and these were significantly greater than baseline values from 24, 28 and 28 weeks, respectively. In the group of women who developed pre-eclampsia, plasma levels of insulin and the FIRI were significantly higher than baseline from 20 and 24 weeks, respectively, but both were significantly higher than in the control group at 32 and 36 weeks. The increase in TNF-alpha in the pre-eclampsia group was significantly greater than in normal pregnant controls (p < 0.001). However, there was no significant association between TNF-alpha levels and FIRI in either normal pregnancy or pregnancies developing pre-eclampsia. These data suggest that insulin resistance in pre-eclampsia precedes the clinical onset of the disease, but that it is not related to elevated levels of TNF-alpha.

A new antiglycolytic agent.

BACKGROUND: Glycolysis is not completely or predictably inhibited by the glucose preservative currently in use, with glucose values falling by as much as 0.5 mmol/L during a 2-4-h period after sample collection. Immediate centrifugation of all samples is also impractical and therefore misdiagnosis of disease can occur, especially if more emphasis is being placed on fasting glucose for the diagnosis of diabetes. METHODS: Glycolysis at room temperature was evaluated over time using glyceraldehyde alone as well as in conjunction with standard antiglycolytic agents. RESULTS: Glyceraldehyde alone does not inhibit glycolysis completely. The combination of 11 mmol/L glyceraldehyde, 119 mmol/L sodium fluoride and 21.7 mmol/L potassium oxalate gave the best antiglycolytic results. The glucose values measured in samples stored at room temperature for 48 h was no different from those measured in samples centrifuged immediately after venepuncture and this is clinically superior to conventionally used sodium fluoride and potassium oxalate. CONCLUSION: Plasma glucose concentrations obtained from blood collected into tubes containing glyceraldehyde, sodium fluoride and potassium oxalate will more closely reflect those of the patient at venepuncture.

Free cortisol index is better than serum total cortisol in determining hypothalamic-pituitary-adrenal status in patients undergoing surgery.

Serum total cortisol has traditionally been used for the interpretation of tests of the hypothalamic-pituitary-adrenal axis. Approximately 80% of total cortisol is bound to cortisol-binding globulin (CBG), and variation in CBG significantly affects serum total cortisol levels. Reliable assessment of hypothalamic-pituitary-adrenal axis reserve is difficult in severely ill patients, because CBG falls substantially during the acute phase response. The free cortisol index (FCI), defined as the ratio of total cortisol/CBG, correlates well with serum free cortisol. We evaluated the FCI in the context of severe stress and the acute phase response by measuring total cortisol and CBG pre- and postoperatively in 31 patients undergoing major elective surgery. Serum total cortisol increased by 55% from 453 +/- 35.2 (mean +/- SEM) nmol/liter (range, 88-882) to 700 +/- 47.2 (range, 294-1631) nmol/liter. Serum CBG decreased by 30% from 45 +/- 1.7 (range, 26.6-64.1) to 31.4 +/- 1.62 (range, 16.1-51.9) mg/liter, but FCI increased by 130% from 10 +/- 0.8 (range, 2-18) to 23 +/- 1.7 (range, 13-58) nmol/mg. In seven patients (23%), postoperative serum total cortisol was less than 500 nmol/liter, but their postoperative CBG levels were significantly lower than levels in the rest of the group (P < 0.01). However, there was no difference in the FCI between this subgroup and the rest of the group. This study demonstrates the importance of CBG measurement and the calculation of FCI for the interpretation of serum total cortisol in situations where CBG changes significantly.

Effect of fluticasone on the elastase:antielastase profile of the normal lung.

BACKGROUND: Excessive elastolytic activity contributes to the pathogenesis of several inflammatory respiratory diseases. The effect of glucocorticoids, which are potent anti-inflammatory agents, on the elastase:antielastase balance of the human respiratory tract is unclear, as studies on patients and in vitro have yielded inconsistent results. DESIGN: To clarify this, bronchoalveolar lavage and lavage fluids from the upper and central airways were collected from 10 healthy, nonsmoking volunteers before and after a 2-week course of inhaled fluticasone propionate (2 x 500 micrograms day-1). Concentrations of two neutrophil elastase inhibitors, alpha-1-proteinase inhibitor (PI) and secretory leukoproteinase inhibitor (SLPI), as well as neutrophil elastase (NE) activity and NE inhibitory capacity (NEIC) were quantified in all lavage fluids. RESULTS: Concentrations of SLPI were highest in the proximal airways and decreased distally. Neutrophil elastase inhibitory capacity activity followed the same gradient and correlated positively and consistently with SLPI, suggesting that this inhibitor makes an important contribution to the regulation of elastolytic activity in the healthy human respiratory tract. Inhaled fluticasone propionate had no effect on any component of the elastase:antielastase balance at any level of the respiratory tract, even though circulating cortisol levels were reduced in all subjects, confirming subject compliance and adequate pulmonary delivery of the drug. CONCLUSION: This lack of action in the respiratory tract may contribute to the ineffectiveness of inhaled glucocorticoids in respiratory conditions characterised by excessive elastolytic activity.

Low dose 25 mg oestradiol implants and 1 mg norethisterone as continuous combined hormone therapy: a prospective study.

The anxiety regarding no-bleed regimens is that breakthrough bleeding and endometrial hyperplasia may occur. We aimed to demonstrate that 25 mg oestradiol implants can be adequately opposed by a low dose of progestogen protecting against osteoporosis. Twenty-two patients were recruited to the study. The mean age was 62 years and body mass index of 26.5. Median oestradiol rose from 77 pmol/L at baseline to 275 pmol/L at one year. Median endometrial thickness remained unchanged at 4 mm and only two women withdrew with bleeding problems. There was one case of proliferative endometrium at one year--all others samples were either atrophic or secretory. Lumbar bone density (L2-L4) rose significantly from 0.939 to 0.992 g/cm2 (6%, P = 0.005) and the total femoral density rose from 0.872 to 0.890 g/cm2 (+2.1%). Bone formation markers increased significantly (serum type 1 procollagen C terminal peptide, P1CP = 112-114, P = 0.0376) and bone resorption fell (serum type 1 collagen C terminal telopeptide, 1CTP = 3.0-2.9, P = 0.2863). E25 implants and low dose progestogen appear to avoid endometrial hyperplasia and bleeding problems while increasing bone density.

A longitudinal study of biochemical markers of bone turnover during normal pregnancy and pregnancies complicated by pre-eclampsia.

OBJECTIVES: To test the hypothesis that the increased bone turnover observed in established pre-eclampsia is present earlier in pregnancy prior to the diagnosis of pre-eclampsia. DESIGN: A prospective longitudinal study. SETTING: Obstetric Unit at Chelsea and Westminster Hospital, London. POPULATION: Nine women who subsequently developed pre-eclampsia and 17 normal pregnant controls. METHODS: Maternal plasma levels of the cross-linked carboxyl terminal telopeptide of the type I collagen (ICTP), a marker of bone resorption, and of the carboxy-terminal propeptide of type I collagen (PICP), a marker of bone formation, were measured longitudinally in nine women who developed pre-eclampsia and 17 women with normal pregnancy. Serial blood samples were obtained at 16, 20, 24, 28, 32 and 36 weeks of gestation and the levels of ICTP and PICP were measured by radio-immunoassay. RESULTS: ICTP and PICP increased progressively in the normal pregnant and pre-eclampsia groups, but the rate of increase was significantly greater in the latter (P = 0.00002 and 0.0008, unpaired t test, for ICTP and PICP summary measures, respectively). In the pre-eclampsia group, positive correlation were observed between ICTP levels at 36 weeks of gestation and plasma uric acid (r = 0.9, P = 0.001) and degree of proteinuria (r = 0.78, P = 0.04). No correlation was observed between the two bone markers and other variables during normal pregnant group. CONCLUSION: These data show that biochemical markers of bone turnover are greater in pregnancies complicated by pre-eclampsia compared with normal pregnancy but only when the disease is clinically evident.

Is a 0900-h serum cortisol useful prior to a short synacthen test in outpatient assessment?

BACKGROUND: The short synacthen test (SST) is the gold standard investigation for the evaluation of adrenal insufficiency and is also frequently used for the evaluation of the hypothalamic-pituitary-adrenal (HPA) axis. The 0900-h serum cortisol concentration has also been evaluated as an indication of cortisol reserve, and a result > 450 nmol/L is highly suggestive of a normal serum cortisol response to the insulin tolerance test, while no patient with a 0900-h serum cortisol < 100 nmol/L had a sufficient response. The aim of this study was to determine if the number of inappropriate SSTs could be reduced if a 0900-h serum total cortisol was done prior to the dynamic function test. METHOD: Two hundred and ten SSTs were performed at 0900 h and the response at 30 min evaluated. RESULTS: Of the 210 SST, 151 (71%) demonstrated a maximum response at 30 min of serum cortisol > 550 nmol/L. All the patients with a 0900-h serum cortisol > 500 nmol/L had an adequate response ( > 550 nmol/L), while no patient with a 0900-h serum cortisol of < 100 nmol/L had an adequate SST response. Twenty one per cent of patients were shown to have had an unnecessary invasive procedure. CONCLUSION: We conclude that the SST is of little added value in patients with a 0900-h serum cortisol of less than 100 nmol/L or more than 500 nmol/L and it should be included in the appropriate protocols for endocrine investigation.

Cortisol-binding globulin is important in the interpretation of dynamic tests of the hypothalamic--pituitary--adrenal axis.

OBJECTIVE: Assessment of the hypothalamic--pituitary--adrenal (HPA) axis relies on the interpretation of serum (total) cortisol in response to dynamic tests of the HPA axis. Most cortisol is bound to cortisol-binding globulin (CBG) and serum total cortisol levels are significantly affected by variation in CBG. We hypothesised that CBG variation significantly affects interpretation of dynamic tests of the HPA axis. DESIGN: We investigated the effect of CBG variation on the outcome of the 250 microg short Synacthen test (SST) in 30 healthy adults. METHODS: Blood was sampled at time -30, 0 (at which point Synacthen was given) and +30 min. CBG and total cortisol were measured at each time-point. Integrity of the HPA axis was confirmed by measurement of urine cortisol. RESULTS: We found that CBG varied significantly within individuals, falling from 51+/-3.4 to 43 +/-3.2 microg/ml (P<0.0001) on changing from standing to lying. Total cortisol levels strongly correlated with CBG (r=0.88, P<0.0001). Thirteen subjects had a +30 min total cortisol <550 nmol/l. In these subjects, the CBG levels at each time-point were significantly lower compared with subjects who had a +30 min total cortisol of >550 nmol/l (P<0.05). To correct for variation in CBG we calculated the total cortisol:CBG ratio and found no significant difference in the +30 min ratio between these two groups. CONCLUSION: CBG varies significantly within and between individuals. This is accompanied by changes in serum total cortisol large enough to affect the outcome of an SST and, by implication, other tests of the HPA axis.

The natural substrate for nitric oxide synthase activity.

There has been little evidence to indicate that arginine is the natural substrate for generating nitric oxide synthase (NOS) activity. It is now shown that carnosine, which is widely distributed in tissues, is likely to be the true substrate. In tissue sections it gives a stronger NOS reaction than does arginine.

Plasma insulin-like growth factor-1 elevated in mild-to-moderate but not severe heart failure.

BACKGROUND: Insulin-like growth factor 1 (IGF-1) promotes favorable cardiac remodeling in heart failure. However, the relation of plasma IGF-1 in patients with various degrees of heart failure is not known. METHODS: Venous plasma samples were collected from patients with clinically documented heart failure (n = 24) and from control subjects (n = 21) for measurements of IGF-1 levels. In the heart failure group, functional assessment of the physical capacity was determined by means of the New York Heart Association (NYHA) score. Objective determination of ventricular performance was made by transthoracic echocardiographic measurement of left ventricular fractional shortening (FS). RESULTS: IGF-1 levels were higher in patients with heart failure (mean age, 67 +/- 2 years; 17 men) than in control subjects (age, 71 +/- 2 years; 9 men) (20.2 +/- 2 mU/L, 14.1 +/- 2 mU/L, respectively, P <.05). However, the elevated IGF-1 levels were demonstrated only in patients with mild-to-moderate symptoms (NYHA classes I and II) of heart failure (24.7 +/- 3.3 mU/L, n = 12, P =.005 vs control subjects) but not in patients with severe symptoms (NYHA classes III and IV) (15.7 +/- 2.3 mU/L, n = 12). There was a strong positive correlation between IGF-1 levels and left ventricular FS (%) (r = 0.58, P =.003, n = 24). Adjustments for other potential confounders including age, sex, treatment received, and underlying cause of heart failure did not alter the relation between IGF-1 and left ventricular FS (odds ratio, 2.01; 95% confidence interval, 1.26 to 6.24; P =.01). CONCLUSIONS: Plasma levels of IGF-1 show distinct variations with the severity of heart failure and may play a vital role in compensated heart failure.

Fetal bone metabolism in normal and rhesus isoimmunised pregnancies.

OBJECTIVE: To construct gestation-specific reference intervals for fetal concentrations of biochemical markers of bone metabolism and assess the effect of rhesus isoimmunisation on these. METHODS: Fetal blood samples were obtained by cordocentesis from 175 pregnancies (43 complicated by rhesus isoimmunisation) and assayed for carboxy terminal pro-peptide of type I pro-collagen (PICP) and cross-linked carboxyterminal telopeptide of type I collagen (ICTP) which directly monitor the rate of bone formation and resorption respectively. RESULTS: Both plasma PICP and ICTP were negatively correlated with gestational age (r = -0.351 and -0.472 for PICP and ICTP, respectively, and P < 0.001 for both). In fetuses affected by rhesus isoimmunisation PICP levels were lower (P=0.030) and more variable (P <0.001) than expected, compared with normal unaffected fetuses. However, no such differences were found in the ICTP levels. In the fetuses affected by rhesus isoimmunisation there was a significant correlation between haemoglobin concentration and both PICP (r = 0.504, P = 0.001) and ICTP (r = 0.343, P = 0.030). CONCLUSIONS: Fetal bone turnover declines from early second trimester to term, and may be deranged in fetuses affected by rhesus isoimmunisation.

Anabolic effect of long-term estrogen replacement on bone collagen in elderly postmenopausal women with osteoporosis.

Estrogen has been shown to stimulate osteoblasts in cell culture and increase bone formation in animal models. Such an anabolic effect of estrogen replacement therapy (ERT) would be beneficial to postmenopausal women with osteoporosis. Hence, we assessed the total collagen content and collagen crosslink maturity in iliac crest bone biopsy from 18 such women before and after 6 years of higher-dose ERT. These results were compared with the serum estradiol level and bone mineral density (BMD). Total collagen content of both cortical and cancellous bone increased, showing a median (95% CI) percent change of 6.7 (0.3-14.2) and 25.6 (13.5-33.8), respectively. Increase in collagen synthesis was supported by a rise in intermediate crosslinks in both cortical and cancellous bone, and mature crosslinks in cortical bone only. At the same time, BMD showed a substantial rise both at the lumbar spine and proximal femur with a median (95% CI) percent change of 28.6 (19.8-37.3) and 14.5 (8.4-20.7), respectively. Serum estradiol and BMD results correlated with cortical bone collagen levels. Our results suggest that long-term higher-dose ERT has a therapeutic role due to its anabolic effect on bone in postmenopausal women with osteoporosis.