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Autoimmune diseases are characterized by a breakdown of immune tolerance partly due to environmental factors. The short-chain fatty acid acetate, derived mostly from gut microbial fermentation of dietary fiber, promotes antiinflammatory Tregs and protects mice from type 1 diabetes, colitis, and allergies. Here, we show that the effects of acetate extend to another important immune subset involved in tolerance, the IL-10–producing regulatory B cells (B10 cells). Acetate directly promoted B10 cell differentiation from mouse B1a cells both in vivo and in vitro. These effects were linked to metabolic changes through the increased production of acetyl-coenzyme A, which fueled the TCA cycle and promoted posttranslational lysine acetylation. Acetate also promoted B10 cells from human blood cells through similar mechanisms. Finally, we identified that dietary fiber supplementation in healthy individuals was associated with increased blood-derived B10 cells. Direct delivery of acetate or indirect delivery via diets or bacteria that produce acetate might be a promising approach to restore B10 cells in noncommunicable diseases.

The NBOMe series is an emerging class of synthetic hallucinogens with limited data available on their use and effects. Whilst toxicity to related substances exist in the literature, no such cases exist for 25G-NBOMe. This case describes a 17-year old male who presented to the Emergency Department with seizures having ingested 25G-NBOMe that had been purchased over the Internet. He was tachycardic, hypotensive and hyperthermic on arrival and required admission to the Intensive Care Unit (ICU) due a persistently low Glasgow Coma Scale (GCS) and profound metabolic derangement. His inpatient stay was prolonged by a persistently high creatine kinase with associated transient acute kidney injury. In contrast, an accompanying friend who had ingested the same drug developed no adverse effects. Our patient's clinical presentation was consistent with reports of adverse outcomes associated with other drugs in the series and demonstrates that acute toxicity can also be seen with 25G-NBOMe with potentially life threatening outcomes., (Copyright © 2017 by Taiwan Society of Emergency Medicine & Ainosco Press. All Rights Reserved.)

Background: Parathyroid cancer has a poor mid-term prognosis, often because of local recurrence, observed in half of all patients. Modern diagnostic workup increasingly enables a preoperative diagnosis of parathyroid cancer. There is limited evidence that more comprehensive oncologic surgery can reduce the risk of local recurrence. This study aims to identify the best specific surgical approach in parathyroid cancer., Methods: This observational cohort study comprises 19 consecutive patients who had undergone oncologic or nononcologic resection for parathyroid cancer. Baseline parameters were compared by using univariate analysis; outcomes were assessed by χ (2) testing and Kaplan-Meier statistics., Results: Fifteen of 19 patients were primarily operated on in our tertiary center between 1996 and 2013, and four were referred for follow-up because of their cancer diagnosis. Patient cohorts defined by histologic R-status were comparable for established risk factors: sex, calcium levels, low-risk/high-risk status, and presence of vascular invasion. Oncologic resections were performed in 13 of 15 patients primarily treated in the center and 0 of 4 treated elsewhere (χ (2) = 5.6; p < 0.01). R0 margins were achieved in 11 of 13 (85 %) undergoing oncologic resection and 1 of 6 (17 %) undergoing local excision (χ (2) = 8.1; p < 0.01). R0 margins and primary oncologic resection were associated with higher disease-free survival rates (χ (2) = 7.9; p = 0.005 and χ (2) = 4.7; p = 0.03, respectively). Revision surgery achieved R0 margins in only 2 of 4 (50 %) of patients., Conclusions: In parathyroid cancer, a more comprehensive surgery (primary oncologic resection) provides significantly better outcomes than local excision as a result of reduction of R1 margins and locoregional recurrence.

Background: The best surgical approach to parathyroid cancer is disputed. Recommendations vary and are built on incoherent evidence. High rates of recurrence and death require an in-depth review of underlying findings., Methods: This retrospective study includes 11 patients with parathyroid cancer who underwent surgery with central and/or lateral neck dissection by a single surgeon between 2005 and 2010. The diagnosis was based on histopathological criteria in all patients. Patterns of lymph node and soft tissue involvement of these and formerly reported patients were analysed based on full-text review of all published cases of parathyroid cancer., Results: In this series only 1 of 11 patients (9.1%) manifested lymph node metastasis. In the literature, lymph node metastases have been reported in only 6.5% of 972 published patients, or in 32.1% of the 196 in whom lymph node involvement was assessed by the authors. They were, with few exceptions, localised in the central compartment. Recurrence in soft tissue is more frequent than in locoregional lymph nodes., Conclusion: Oncological en bloc clearance of the central compartment with meticulous removal of all possibly involved soft tissues, including a systematic central lymph node resection, may improve outcomes and should be included in the routine approach to the suspicious parathyroid lesion. There is no need for a prophylactic lateral neck dissection.

Endometrial polyps have been associated with infertility and early pregnancy loss. The aim of this study was to investigate the effect of hysteroscopic polypectomy on the concentrations of endometrial implantation factors in uterine flushings. Pre-menopausal women with a certain diagnosis of endometrial polyp on contrast-enhanced transvaginal ultrasound scan were recruited into this prospective study. In all women, paired samples of uterine flushings were obtained on the same day of the menstrual cycle prior to and post hysteroscopic polypectomy. Enzyme-linked immunoassays were performed to analyse glycodelin, interleukin-6 (IL-6), interleukin-10 (IL-10), tumour necrosis factor alpha (TNFalpha) and osteopontin, whilst immunoradiometric assay was used to analyse insulin-like growth factor binding protein-1 (IGFBP-1). Concentrations of IGFBP-1, TNFalpha and osteopontin in uterine flushings were significantly lower in the mid-secretory phase prior to polypectomy in comparison to the measurements obtained after complete surgical removal of the polyp (P < 0.05). There were no differences in the concentrations of glycodelin, IL-6 and IL-10 in paired samples prior to and post-polypectomy. The presence of endometrial polyps is associated with decreased mid-secretory concentrations of IGFBP-1, TNFalpha and osteopontin, which are reversed following surgical polypectomy.

Objective: Increased mortality with severe hyponatraemia is well known. What is less clear is the mortality risk according to the pattern of the developing hyponatraemia and whether this may be affected by the intervention of the clinician., Methods: From our laboratory database, we retrospectively collected data of a 12-month period of adult patients with severe hyponatraemia (< or = 120 mmol/l). One hundred and thirteen patients were identified. Normonatraemic controls (n = 113) were identified by plasma sodium of 135 mmol/l over the same period, and whose nadir during hospitalisation was > or = 130 mmol/l. Results are mean +/- SD unless stated otherwise. Duration of hospitalisation and clinical outcomes was confirmed from hospital records., Results: The mean nadir plasma sodium of the hyponatraemic group was 116.0 +/- 4.4 mmol/l and 134.0 +/- 2.8 mmol/l in controls. Although the hyponatraemic patients were younger than controls (65.8 +/- 18.4 vs. 72.3 +/- 14.9 years; p = 0.004), they had higher mortality (24 vs. 7, p = 0.002) and longer hospitalisation than controls: median (IQR), 12 (7-22) vs. 7 (3-16.5) days (p < 0.001). A total of 55 patients developed severe hyponatraemia following admission. This subgroup comprised a higher proportion of surgical patients (23.6% vs. 1.7%, p < 0.001) than those with severe hyponatraemia on admission. Furthermore, both mortality (n = 17 vs. n = 7; p = 0.02) and duration of hospitalisation, median 19 days (IQR 10-35) vs. 9.5 (5-15) days (p < 0.001), were greater. Failure to measure plasma and urinary osmolalities was associated with increased mortality., Conclusions: Severe hyponatraemia is associated with prolonged admission and increased mortality compared with normonatraemic patients. Progressive hyponatraemia following admission incurs a higher risk of death. This may represent illness-severity, inappropriate management or inadequate investigation.

We describe a case of infective endocarditis due to Neisseria elongata, and review the literature. N. elongata is a constituent of the normal oral flora and a rare cause of infective endocarditis. Unfamiliarity with the organism and its rod-shaped morphology may lead to a delay in microbiological diagnosis. Although the organism is relatively sensitive to antibiotics, our experience in the management of the described case and a review of previous reports suggest that antibiotic therapy alone may not be sufficient. It is likely that patients with N. elongata endocarditis will require surgery.

Background: Serum sialic acid (TSA) has been shown to be a cardiovascular risk factor and an acute phase reactant, with elevated concentrations associated with increased cardiovascular mortality and to precede the onset of type 2 diabetes., Aim: The purpose of this present study was to test the hypothesis that serum TSA may be related to serum leptin concentrations in healthy individuals., Methods: Thirty Fijian individuals were studied (8 males and 22 females). They were urban Melanesians living in Raiwaga, a suburb of Suva in Fiji., Results: Serum TSA significantly correlated with subject body mass index (BMI, rho 0.39, P<0.05) and serum leptin concentration (rho 0.44, P<0.05). In stepwise multiple regression analysis serum TSA independently correlated with subject waist/hip ratio (r(2)=0.167, P<0.02) and diastolic blood pressure (r(2)=0.300, P<0.01) but not with age, BMI, serum insulin-like growth factor binding protein (IGFBP-1), fasting plasma glucose or systolic or diastolic blood pressure., Conclusions: Serum TSA is related to markers of obesity and adipose tissue metabolism which may help to explain why it is a reputed cardiovascular risk factor and why elevated serum TSA concentrations precede the development of type 2 diabetes mellitus.

Background: Serum total sialic acid (TSA) has been shown to be a strong cardiovascular risk factor with increased concentrations being associated with increased mortality. Serum TSA is also elevated in patients with type 2 diabetes including those with micro- and macrovascular complications. We wished, therefore, to test the hypothesis that serum TSA may be abnormal in individuals with impaired glucose tolerance (IGT) and impaired fasting glucose (IFG), in Fijian Melanesians., Method: Twenty-one subjects with IGT (17 women and four men) were recruited along with 20 subjects with IFG (14 women and six men) and 22 normal subjects (12 women and 10 men). Serum TSA was 2.18 +/- 0.027 mmol//L, 2.19 +/- 0.033 mmol/L and 2.24 +/- 0-042 mmol/L in the three groups, respectively, which was not statistically different. Both systolic and diastolic blood pressure were, however, higher in the IGT group compared with the IFG and normal groups (P<0.04)., Conclusion: Serum TSA is not elevated in Fijian Melanesians with IGT and IFG although it is reported to be elevated in type 2 diabetes mellitus in other populations. Further research is needed to establish why serum TSA is a potent independent cardiovascular risk factor and is elevated in type 2 diabetes mellitus in some populations.

These neuroendocrine studies were part of a series of studies testing the hypotheses that 1) there may be reduced activity of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome and 2) low-dose augmentation with hydrocortisone therapy would improve the core symptoms. We measured ACTH and cortisol responses to human CRH, the insulin stress test, and D-fenfluramine in 37 medication-free patients with CDC-defined chronic fatigue syndrome but no comorbid psychiatric disorders and 28 healthy controls. We also measured 24-h urinary free cortisol in both groups. All patients (n = 37) had a pituitary challenge test (human CRH) and a hypothalamic challenge test [either the insulin stress test (n = 16) or D-fenfluramine (n = 21)]. Baseline cortisol concentrations were significantly raised in the chronic fatigue syndrome group for the human CRH test only. Baseline ACTH concentrations did not differ between groups for any test. ACTH responses to human CRH, the insulin stress test, and D- fenfluramine were similar for patient and control groups. Cortisol responses to the insulin stress test did not differ between groups, but there was a trend for cortisol responses both to human CRH and D-fenfluramine to be lower in the chronic fatigue syndrome group. These differences were significant when ACTH responses were controlled. Urinary free cortisol levels were lower in the chronic fatigue syndrome group compared with the healthy group. These results indicate that ACTH responses to pituitary and hypothalamic challenges are intact in chronic fatigue syndrome and do not support previous findings of reduced central responses in hypothalamic-pituitary-adrenal axis function or the hypothesis of abnormal CRH secretion in chronic fatigue syndrome. These data further suggest that the hypocortisolism found in chronic fatigue syndrome may be secondary to reduced adrenal gland output. Thirty-two patients were treated with a low-dose hydrocortisone regime in a double-blind, placebo-controlled cross-over design, with 28 days on each treatment. They underwent repeated 24-h urinary free cortisol collections, a human CRH test, and an insulin stress test after both active and placebo arms of treatment. Looking at all subjects, 24-h urinary free cortisol was higher after active compared with placebo treatments, but 0900-h cortisol levels and the ACTH and cortisol responses to human CRH and the insulin stress test did not differ. However, a differential effect was seen in those patients who responded to active treatment (defined as a reduction in fatigue score to the median population level or less). In this group, there was a significant increase in the cortisol response to human CRH, which reversed the previously observed blunted responses seen in these patients. We conclude that the improvement in fatigue seen in some patients with chronic fatigue syndrome during hydrocortisone treatment is accompanied by a reversal of the blunted cortisol responses to human CRH.

Objective: Previous studies have suggested that chronic fatigue syndrome (CFS) is associated with changes in appetite and weight, and also with mild hypocortisolism. Because both of these features may be related to leptin metabolism, we undertook a study of leptin in CFS., Design: (i) A comparison of morning leptin concentration in patients with CFS and controls and (ii) a randomized, placebo-controlled crossover study of the effects of hydrocortisone on leptin levels in CFS., Patients: Thirty-two medication free patients with CFS but not comorbid depression or anxiety. Thirty-two age, gender, weight, body mass index and menstrual cycle matched volunteer subjects acted as controls., Measurements: We measured basal 0900 h plasma leptin levels in patients and controls. All 32 patients were taking part in a randomized, placebo-controlled crossover trial of low dose (5 or 10 mg) hydrocortisone as a potential therapy for CFS. We measured plasma leptin after 28 days treatment with hydrocortisone and after 28 days treatment with placebo., Results: At baseline, there was no significant difference in plasma leptin between patients [mean 13.8, median 7.4, interquartile range (IQR) 18.0 ng/ml] and controls (mean 10.2, median 5.5, IQR 11.3 ng/ml). Hydrocortisone treatment, for both doses combined, caused a significant increase in leptin levels compared to placebo. When the two doses were analysed separately, only 10 mg was associated with a significant effect on leptin levels. We also compared the hydrocortisone induced increase in leptin between those who were deemed treatment-responders and those deemed nonresponders. Responders showed a significantly greater hydrocortisone-induced rise in leptin than nonresponders. This association between a clinical response to hydrocortisone and a greater rise in leptin levels may indicate a greater biological effect of hydrocortisone in these subjects, perhaps due to increased glucocorticoid receptor sensitivity, which may be present in some patients with CFS., Conclusions: We conclude that, while we found no evidence of alterations in leptin levels in CFS, low dose hydrocortisone therapy caused increases in plasma leptin levels, with this biological response being more marked in those CFS subjects who showed a positive therapeutic response to hydrocortisone therapy. Increases in plasma leptin levels following low dose hydrocortisone therapy may be a marker of pretreatment physiological hypocortisolism and of response to therapy.

Insulin resistance in chronic liver disease (CLD) is well documented. This study investigated whether similar changes occur in acute liver failure (ALF). Patients with ALF (n = 10) were recruited within 72 hours of their peak prothrombin time (range 42-120 seconds). All patients were ventilated for encephalopathy (grade III-IV). Peripheral and endogenous insulin sensitivity were assessed by a hyperinsulinemic euglycemic clamp (Human Actrapid 1.5 mU/min/kg) with an infusion of D-[6,6-(2)H(2)] glucose. The clamp was performed on day 0 and then on day 7 and day 14. During the insulin infusion, the mean total peripheral glucose uptake (area under the curve [AUC]) was 1,422 (SD, 1,253), 2,244 (SD, 1,392), and 4,500 (SD, 1,120) micromol/kg on days 0, 7, and 14, respectively. Significant changes occurred from day 0 to 14 (day 14-day 0: 3,078 [95% CI, 1,798 to 4,359]; P =.001) and day 7 to 14 (day 14-day 7: 2,256 [95% CI, 923 to 3,589]; P =.001). No significant difference in endogenous glucose production was demonstrated over time. Mean peripheral insulin sensitivity altered over time, increasing from 0.09 (SD, 0.09) micromol/kg/min/mU/L on day 0 to 0.24 (SD, 0.16) on day 7 and 0.5 (SD, 0.1) on day 14. Significant changes occurred between days 0, 7, and 14 (day 7-day 0: 0.15 [95% CI, 0.04 to 0.26], P =.006; day 14-day 0: 0.4 [95% CI, 0.28 to 0.5], P =.001; day 14-day 7: 0.2 [95% CI, 0.12 to 0.38], P =.001). This study demonstrates that in ALF, impaired peripheral uptake of glucose occurs, peripheral insulin sensitivity being restored at 2 weeks in subjects who survived.

This study was performed to investigate the hypothesis that insulin-like growth factor binding protein-1 (IGFBP-1) is involved in the pathogenesis of trophoblast invasion and impaired placentation in human pregnancy. The role of total and non-phosphorylated IGFBP-1 in women with fetal growth restriction and in high risk pregnancies identified by uterine artery Doppler ultrasound screening was examined. This was a prospective study of women booked for antenatal care having second trimester anomaly scans and Doppler screening between 22-26 weeks gestation. Women were divided into three groups and compared: normal uterine artery Doppler and normal fetal growth (control group, n = 10); abnormal Doppler and normal fetal growth [bilateral uterine artery notches (BN; n = 16); abnormal Doppler and intrauterine growth restriction (IUGR; n = 8)]. Maternal serum was collected, stored and assayed simultaneously for total and non-phosphorylated IGFBP-1. There was elevated total and non-phosphorylated IGFBP-1 (mean 44.99 +/- 12.19 and 29.61 +/- 10.38 microg/l respectively) in the IUGR group compared with controls (mean 17.96 +/- 3.24 and 12.18 +/- 1.55 microg/l, P < 0.05). This finding suggests that the various IGFBP-1 isoforms, the degree of phosphorylation and the ratios of these different forms locally may be important during trophoblast invasion and may be implicated in clinical manifestations of impaired placentation later in the second trimester.

Background: Reports of mild hypocortisolism in chronic fatigue syndrome led us to postulate that low-dose hydrocortisone therapy may be an effective treatment., Methods: In a randomised crossover trial, we screened 218 patients with chronic fatigue. 32 patients met our strict criteria for chronic fatigue syndrome without co-morbid psychiatric disorder. The eligible patients received consecutive treatment with low-dose hydrocortisone (5 mg or 10 mg daily) for 1 month and placebo for 1 month; the order of treatment was randomly assigned. Analysis was by intention to treat., Findings: None of the patients dropped out. Compared with the baseline self-reported fatigue scores (mean 25.1 points), the score fell by 7.2 points for patients on hydrocortisone and by 3.3 points for those on placebo (paired difference in mean scores 4.5 points [95% CI 1.2-7.7], p=0.009). In nine (28%) of the 32 patients on hydrocortisone, fatigue scores reached a predefined cut-off value similar to the normal population score, compared with three (9%) of the 32 on placebo (Fisher's exact test p=0.05). The degree of disability was reduced with hydrocortisone treatment, but not with placebo. Insulin stress tests showed that endogenous adrenal function was not suppressed by hydrocortisone. Minor side-effects were reported by three patients after hydrocortisone treatment and by one patient after placebo., Interpretation: In some patients with chronic fatigue syndrome, low-dose hydrocortisone reduces fatigue levels in the short term. Treatment for a longer time and follow-up studies are needed to find out whether this effect could be clinically useful.

Sepsis is characterized by a severe shift in metabolism, characterized by low IGF-I levels. We have studied the influence of caecal ligation and puncture (CLP) on the levels of circulating IGF-I and hepatic IGF-I and IGF-binding protein (IGFBP)-1, -2 and -3 mRNA in adult male Wistar rats (n = 12) and compared it with sham-operated rats (n = 6). In order to exclude anorexia-induced changes we also studied animals pair-fed to both groups. IGF-I levels were measured by RIA. Steady-state hepatic IGF-I, IGFBP-1, IGFBP-2 and IGFBP-3 mRNA levels were measured by Northern blot analysis using specific rat cDNA probes. Food intake averaged 13.0 +/- 2.0 g/day in the sham-operated rats fed ad libitum during the study period, with a sharp decline in food intake in the CLP animals (2.3 +/- 1.3 g/day). After CLP, there was a significant reduction in circulating IGF-I levels (467.2 +/- 50.9 micrograms/l) compared with sham-operated animals (924.0 +/- 75.3 micrograms/l; P = 0.04) or those pair-fed to the CLP rats (612.5 +/- 52.9 micrograms/l; P = 0.04). Total hepatic IGF-I mRNA levels were significantly reduced (2.57 +/- 0.05 densitometric units (DU) after CLP compared with the sham-operated group (2.71 +/- 0.04); P = 0.04), or their pair-fed controls (2.75 +/- 0.08 DU; P < 0.05). Hepatic IGFBP-3 mRNA levels were lower after CLP (0.37 +/- 0.04 DU) than in the sham-operated animals (0.66 +/- 0.09 DU; P = 0.04) or their pair-fed controls (0.61 +/- 0.05 DU; P = 0.04). On the other hand, hepatic IGFBP-2 mRNA levels were increased after CLP (0.91 +/- 0.11 DU) compared with sham-operated animals (0.28 +/- 0.06 DU; P = 0.01) or with their pair-fed controls (0.22 +/- 0.02; P = 0.01), as were hepatic IGFBP-1 mRNA levels (CLP animals 0.95 +/- 0.11 DU; sham-operated 0.30 +/- 0.04 DU, P = 0.01; pair-fed 0.30 +/- 0.02 DU, P = 0.01). No significant difference between sham-operated animals and their pair-fed controls was observed in circulating IGF-I levels (888.0 +/- 109.3 micrograms/l; P = not significant (N.S.)), hepatic mRNA levels for IGF-I (2.72 +/- 0.06 DU; P = N.S), IGFBP-3 (0.71 +/- 0.07 DU; P = N.S.), IGFBP-2 (0.25 +/- 0.07 DU; P = N.S.) or IGFBP-1 (0.27 +/- 0.06 DU; P = N.S.). In summary, after CLP there was a reduction in both circulating and hepatic IGF-I mRNA levels associated with a specific and differential regulation of hepatic IGFBP-1, -2 and -3 mRNA levels. Although we cannot eliminate a possible effect of surgical stress combined with malnutrition, our results suggest that these changes are a specific effect of sepsis rather than simply a result of surgical stress or poor nutrition alone.

Recent evidence suggests that a number of adulthood conditions, including non-insulin dependent diabetes mellitus (NIDDM) and lipid and cardiovascular abnormalities are associated with intra-uterine growth retardation (IUGR). It is possible that this arises from programming of endocrine axes during development as a result of an adverse intra-uterine environment. Insulin-like growth factors (IGFs) are mitogenic polypeptides which stimulate cellular proliferation and differentiation and are important in human fetal development. The functions of IGFs are modulated by specific high affinity binding proteins (IGFBPs). IGFBP-1 is antagonistic to the insulin-like and growth promoting effects of IGF-I, and IGFBP-3 holds IGFs in the circulation by associating with IGFs and an acid labile subunit to form a ternary complex. Using specific radioimmunoassays and fetal serum obtained during diagnostic cordocentesis we have investigated the role of the IGF/IGFBP axis in human fetal development. In a study of 130 singleton pregnancies we have examined levels of immunoreactive IGFs and IGFBPs in normally grown fetuses (AGA), starved small fetuses affected by uteroplacental insufficiency (UPI), and non-starved small fetuses (SGA). IGF-I was significantly lower in the UPI group (n = 14, 7.8 +/- 0.6 micrograms l-1), than in either the SGA group (n = 22, 31.4 +/- 3.5 micrograms l-1, P = 0.0001) or the AGA group (n = 94, 36.3 +/- 1.9 micrograms l-1, P = 0.0001). IGFBP-3 showed similar changes (UPI: 682.6 +/- 50.0 micrograms l-1; SGA: 831.9 +/- 55.5 micrograms l-1; AGA: 847.7 +/- 19.8 micrograms l-1).(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in thyroid status have a major effect on the GH/insulin-like growth factor (IGF) axis. The majority of IGF in the circulation is bound to specific IGF-binding proteins (IGFBPs) of which six have been cloned and sequenced. We have studied changes in hepatic gene expression of IGFBP-1, -2 and -3, in male Wistar rats rendered hyperthyroid (thyroxine, 200 micrograms/kg per day) or hypothyroid (propylthiouracil, 0.1% daily). Littermates of the same age were used as controls (n = 6 in each group). Thyroxine was measured by radioimmunoassay, and hepatic IGFBP-1, -2 and -3 mRNA levels by Northern blot analysis using specific rat cDNA probes with a 28S ribosomal probe as a loading control. Mean +/- S.E.M. thyroxine levels were 247.0 +/- 44.5 (hyperthyroid group), < 9.0 (hypothyroid group) and 76.0 +/- 4.5 nmol/l (control group). IGFBP-1 and -2 mRNA levels in the hypothyroid animals compared with the controls were significantly increased, but similar levels of expression were found in thyrotoxic and control rats. IGFBP-3 mRNA levels in hypothyroid animals were decreased, and increased in thyrotoxic animals. Thus, in the adult rat, hypothyroidism is associated with increased hepatic IGFBP-1 and -2 gene expression, but decreased IGFBP-3 gene expression, while in thyrotoxicosis there are normal IGFBP-1 and -2 mRNA levels but increased IGFBP-3 gene expression. These results suggest that there is specific and different transcriptional regulation for IGFBP-1, -2 and -3 in hypo- and hyperthyroid rats.

The development of gallstones is a well recognized complication of therapy with the long-acting somatostatin analogue, octreotide in patients with acromegaly. A group of nine acromegalic patients was treated with octreotide at doses of 300-600 micrograms daily for 8 months and the changes in fasting and post-prandial cholecystokinin release, and gall bladder motor function (determined by a radiosotopic technique) were assessed at regular intervals. In addition the development of any gallstones was determined by serial ultrasonography. Fasting cholecystokinin levels showed no significant change over 6 months, whereas the post-prandial levels demonstrated a significant decrease (p less than 0.01) during therapy, yet remained significantly higher than fasting levels. Twenty-four hours after commencing therapy gall bladder ejection fraction was decreased by 57 +/- 23 per cent and gall bladder ejection rate decreased by 63 +/- 19 per cent compared to the pretreatment values, whereas after 6 months' therapy a marked reduction in gall bladder ejection fraction (greater than 35 per cent) and gall bladder ejection rate (greater than 40 per cent) persisted in only four of nine patients. Three of these four patients with persistently impaired gall bladder motor function were subsequently shown to have developed either gallstones or biliary sludge during the course of therapy. We conclude that treatment with octreotide is associated with an impaired post-prandial release of cholecystokinin in all acromegalic patients, but gallstones only develop in those patients who, in addition, have evidence of a persistently impaired gall bladder motor response to cholecystokinin.

Despite causing marked inhibition of somatic growth, glucocorticoids enhance both the response to GH-releasing hormone (GHRH) and the amplitude of naturally occurring GH secretory pulses in the male rat. The relative contribution of the two major hypothalamic regulatory factors for GH (somatostatin and GHRH) to these observed effects remains speculative. In the present studies, we have investigated endogenous and stimulated GH release in rats pretreated with glucocorticoid or vehicle, and the effects of passive immunoneutralization of somatostatin or GHRH. In an initial study, four groups of eight rats were treated with either saline or various doses of a depot preparation of betamethasone: low dose, 0.85 mg; medium dose, 1.7 mg; high dose, 3.4 mg. All doses significantly suppressed body weight gain, total adrenal weight and concentrations of both plasma corticosterone and pituitary ACTH. Seven days after betamethasone treatment, GH responses to an i.v. injection of 1 microgram human GHRH(1-29) were evaluated during pentobarbitone anaesthesia. Compared with saline-treated controls (peak GH concentration of 506.0 +/- 68.5 micrograms/l), peak GH levels were enhanced by the low dose (704.4 +/- 47.8 micrograms/l, P less than 0.05), unaltered by the medium dose (543 +/- 65.8 micrograms/l) and suppressed by the high dose (312.7 +/- 55.2 micrograms/l, P less than 0.05) of betamethasone. Similarly, the area under the secretory curves was increased by 46% following the low dose (P less than 0.01), unaltered by the medium dose and reduced by 33% after the high dose of betamethasone. In a second study, rats were pretreated for 7 days before blood sampling with either the medium dose of betamethasone or saline. On day 5, 48 h before blood sampling, an indwelling venous catheter was fitted enabling sampling of conscious rats. On the day of study, blood samples were taken at 30-min intervals over an initial 2-h period (10.00-12.00 h). Following the sample at 12.00 h, rats were given the reconstituted and dialysed immunoglobulin fraction from either control sheep serum (NSIgG), sheep anti-rat GHRH serum (GHRHab) or sheep anti-somatostatin serum (SRIHab), and samples were taken for a further 90 min (12.30-14.00 h). Directly after the sample at 14.00 h, GH stimulation was effected in all rats using 1 microgram human GHRH(1-29) with samples taken at 5, 10, 20 and 40 min following stimulation.(ABSTRACT TRUNCATED AT 400 WORDS)

A 35 year old woman was admitted with acute radial artery occlusion necessitating two operations and thrombolytic therapy. Subsequently a diagnosis of primary hypothyroidism was made and she was commenced on thyroxine replacement therapy. Her condition, however, continued to deteriorate with the development of an Addisonian crisis heralded by, and complicated by, severe, life-threatening hypercalcaemia. This case highlights the importance of considering Addison's disease in any patient whose condition deteriorates after the introduction of thyroxine replacement, and illustrates the often forgotten association of hypercalcaemia and hypoadrenalism.

Objective: The aim was to study the relationship between growth hormone (GH) and insulin-like growth factor-I (IGF-I) in critically ill patients., Design: Case-control study of critically ill patients admitted to the intensive care unit was carried out., Patients: Six critically ill patients (51-78 years) who required ventilation and parenteral nutrition and six age, weight, height, and sex-matched healthy adults were studied., Measurements: The patients and controls were studied for two 24-hour periods; the patients before and after starting parenteral feeding, and the controls during a 36-hour fast and when taking meals equivalent in calories and protein to the patients' parenteral feed. Serum GH was measured at 20-minute intervals and analysed by a pulse detection algorithm (Pulsar) and Fourier transformation. IGF-I was measured at 0, 12, and 24 hours., Results: Patients had low serum IGF-I levels compared with controls, whether fasted or fed, despite having mean GH levels similar to fasted controls. For fasted patients vs fasted controls the mean (+/- 1 SD) GH levels were 4.5 +/- 2.0 vs 4.0 +/- 2.4 mU/l respectively, and IGF-I levels at the end of the fast were 0.17 +/- 0.11 vs 0.78 +/- 0.29 U/ml (P = 0.003). Patients showed elevated baseline GH levels compared with controls when fasted and during parenteral feeding (patients vs controls fasted 3.1 +/- 1.9 vs 0.8 +/- 0.5 mU/l, P = 0.01; patients vs controls fed 4.2 +/- 4.5 vs 0.5 +/- 0.04 mU/l, P = 0.028). Fourier transformation confirmed oscillatory GH levels in the controls, fasted or fed, but this activity was attenuated in the patients. Parenteral feeding had no effect on the GH profiles or IGF-I levels of patients, but controls showed greater mean GH levels during their fast than when fed., Conclusions: We have demonstrated that critically ill patients have low IGF-I levels associated with augmented baseline GH levels which show reduced oscillatory activity. The results would be compatible with the hypothesis that there is an adaptive change in critically ill patients away from the indirect effects of GH (stimulation of IGF-I production and anabolism) and toward the direct effects (lipolysis and insulin antagonism) which increase the availability of energy substrates. The pattern of GH levels seen in our patients may be important in this adaptation.