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SummaryAims Hyponatraemia (HN) is the most common electrolyte balance disorder in clinical practice. Since the 1970s, demeclocycline has been used in some countries to treat chronic HN secondary to syndrome of inappropriate antidiuretic hormone secretion (SIADH). The precise mechanism of action of demeclocycline is unclear, but has been linked to the induction of nephrogenic diabetes insipidus. Furthermore, the safety profile of demeclocycline is variable with an inconsistent time to onset, and a potential for complications. There has been no systematic evaluation of the use of demeclocycline for the treatment of HN secondary to SIADH to date. A systematic literature review was performed to obtain an insight into the clinical safety and efficacy of demeclocycline for this condition. Methods Embase™, MEDLINE®, MEDLINE® In-Process, and The Cochrane Library were searched on two occasions using MeSH terms combined with free-text terms. References were screened by two independent reviewers. Relevant publications were then extracted by two independent reviewers, with a third reviewer collating and finalising extractions. Results The searches returned a total of 705 hits. 632 abstracts were screened after the removal of duplicates. Following screening, 35 full-length publications were reviewed. Of these, 17 were excluded, resulting in 18 studies deemed relevant for data extraction. Two were randomised controlled trials (RCTs), 16 were non-RCTs, and 10 were case reports. Discussion Although most reports suggest that demeclocycline can address serum sodium levels in specific patients with HN, efficacy is variable, and may depend upon the underlying aetiology. Demeclocycline dose adjustments can be complex, and as its use in clinical practice is not well defined, it can differ between healthcare professionals. Conclusion There is a lack of clinical and economic evidence supporting the use of demeclocycline for HN secondary to SIADH. Patients receiving demeclocycline for HN secondary to SIADH must be closely monitored.

Background: Severe hypertriglyceridaemia is a recognized complication of Type 2 diabetes mellitus (T2DM); however, there is no consensus on acute management despite the significant risk of developing associated complications such as acute pancreatitis and hyperviscosity syndrome. Aim: To identify the association between hyperglycaemia and severe hypertriglyceridaemia in patients with T2DM and assess the effect of continuous insulin infusion therapy on serum triglyceride (TG) concentrations and report any adverse events associated with this therapeutic approach. Design: Retrospective review of case records. Methods: Patients with uncontrolled hyperglycaemia and severe hypertriglyceridaemia (serum TG > 15 mmol/l) treated with continuous intravenous insulin infusion between October 2008 and September 2009 were retrospectively evaluated ( n = 15). Details recorded included demographics, admission details, lipid profiles, glycaemic control, serum amylase and adverse events. Patients receiving treatment-dose unfractionated heparin infusion were excluded. Results: Severe hypertriglyceridaemia is associated with hyperglycaemia in our heterogeneous group of patients with T2DM presenting with new-onset diabetes or established disease on pre-existing insulin or oral hypoglycaemic agents. Administration of continuous exogenous insulin not only achieved normoglycaemia but also dramatically corrected severe hypertriglyceridaemia in all patients ( P = 0.001). Conclusions: The administration of continuous insulin in patients with T2DM with severe hypertriglyceridaemia is a simple and safe method of significantly reducing the immediate risk associated with this metabolic complication and should be considered in any T2DM patient presenting with severe hypertriglyceridaemia and hyperglycaemia.

Uterine fibroids are benign tumours, which are associated with subfertility and early pregnancy loss. This study was carried out to examine the effect of submucous fibroids on concentrations of glycodelin, insulin-like growth factor binding protein-1 (IGFBP-1), interleukin-6 (IL-6), interleukin-10 (IL-10), tumour necrosis factor α (TNFα) and osteopontin in uterine flushings. Premenopausal women with a certain diagnosis of submucous fibroid confirmed on three-dimensional saline infusion sonohysterography were recruited into the study. The control group included women without ultrasonic evidence of any uterine or endometrial pathology. All women had uterine flushings performed 7days post LH surge. Enzyme linked immunoassays were performed to analyse glycodelin, IL-6, IL-10, TNFα and osteopontin, whilst immunoradiometric assay was used to analyse IGFBP-1. In 23 women with submucous fibroids, the concentrations of glycodelin and IL-10 in uterine flushings were significantly lower compared with 17 women in the control group (P=0.002; P=0.007, respectively). There were no significant differences between the two groups in concentrations of IGFBP-1, IL-6, TNFα and osteopontin. Women with submucous fibroids had significantly lower concentrations of glycodelin and IL-10 in mid-luteal phase uterine flushings. This finding may explain the association with submucous fibroids and adverse reproductive outcomes. Uterine fibroids are small growths from the muscle of the uterus (womb). Submucous fibroids protrude into the cavity of the womb. We do not know what causes fibroids to form and grow. In most women, fibroids cause no symptoms and they are sometimes detected on routine gynaecological examination. In some women, however, fibroids can cause heavier and longer menstrual periods. Another problem associated with fibroids is bleeding between periods. The effect of fibroids on fertility is not clear, but some doctors believe that they may also cause infertility and early miscarriage. This study tried to see whether presence of submucous fibroids has any effect on various substances produced by the lining of the womb to facilitate development of early pregnancy. Women with a confirmed diagnosis of submucous fibroids were asked to attend the clinic and have the uterine cavity flushed with a special solution 7days after ovulation. The fluid, which was taken back from the womb, was then analysed to measure the amounts of substances that favour pregnancy development. Women with a normal uterine cavity were also asked to have the uterine cavity flushed to act as a comparison. The study showed that the uterine cavities of women with submucous fibroids were producing decreasing amount of substances favourable to early pregnancy development. We speculate that this may explain why some women with submucous fibroids have difficulties falling pregnant. Our findings should be helpful to doctors advising women with submucous fibroids who wish to start a family.

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. 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. 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

Fibroblast growth factor-2 (FGF-2) is expressed in human fetal tissues and placenta. We, therefore, determined whether FGF-2 appeared in either fetal or maternal circulations during normal pregnancies [fetuses appropriate for gestational age (AGA)] or those complicated by fetal growth restriction (small for gestational age). Cordocentesis was performed, and matched maternal blood was collected between 19-39 weeks gestation, whereas maternal and cord blood and amniotic fluid (AF) were collected at term. FGF-2 was extracted from maternal serum (MS), cord serum (CS), and AF by heparin-Sepharose affinity chromatography and subjected to Western blot analysis or quantified by specific RIA. Western blot analysis of MS, CS, and AF revealed, in each case, a single immunoreactive FGF-2 species of 18 kilodaltons (kDa), although this was not present in nonpregnant serum. In AGA pregnancies, immunoreactive FGF-2 was present in MS from at least 18 weeks gestation and rose to maximum values at the end of second trimester (weeks 28-31; mean +/- SEM, 342 +/- 62 pmol/L), but by term had declined (weeks 40-42; 104 +/- 24 pmol/L). In CS, FGF-2 immunoreactivity was highest at weeks 18-20 of gestation (662 +/- 144 pmol/L), but thereafter, slowly declined to term (weeks 40-42; 119 +/- 28 pmol/L). Immunoreactive FGF-2 levels in MS and CS of small for gestational age pregnancies in the second trimester tended to be lower than those in AGA pregnancies, but differences were not statistically significant. AF also contained immunoreactive FGF-2 at term (91 +/- 35 pmol/L). Neutral gel chromatography on Sephadex G-200 revealed that FGF-2 immunoreactivity eluted as a broad peak with an apparent molecular size of 55-160 kDa. These same fractions contained peptides of 55-60, 90-95, and 120-130 kDa, which were recognized by antisera against the extracellular domain of the high affinity FGF receptor, FGFR1, after Western blot. Ligand blot analysis of the same nitrocellulose filters using 125I-labeled FGF-2 revealed that the 55- to 60-kDa species specifically bound FGF-2. This binding species was not recognized during Western blot analysis using an antiserum raised against the intracellular tyrosine kinase domain of FGFR1, suggesting that it represents a truncated receptor form. Similar FGFR1 immunoreactive species were present in nonpregnant female and male sera, but were barely detectable in term CS or AF.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

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 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 ±0·033mmol/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.

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.(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.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.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.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.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.

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 μg human GHRH(1–29) were evaluated during pentobarbitone anaesthesia. Compared with saline-treated controls (peak GH concentration of 506·0±68·5 μg/l), peak GH levels were enhanced by the low dose (704·4±47·8 μg/l, PPP 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 μg human GHRH(1–29) with samples taken at 5, 10, 20 and 40 min following stimulation. During the initial sampling period, mean GH levels were significantly (PP < 0·01). Administration of GHRHab to saline-pretreated animals did not alter mean GH levels when compared with animals receiving control NSIgG (saline plus NSIgG, 9·3±1·1; saline plus GHRHab, 8±1·1 μg/l, P = NS). In contrast, the raised mean GH levels seen in betamethasone-pretreated rats receiving NSIgG (12·3 ±1·1 μg/l) were reduced by GHRHab administration (7·6±1·1 μg/l); these levels were not different from those of the saline-pretreated group suggesting that the observed permissive effect of glucocorticoids on GH secretion is mediated through enhanced GHRH activity. SRIHab increased mean basal GH levels to a similar extent in both saline- and betamethasone-pretreated groups (17·4±1·2 μg/l and 19·3 ±1·1 μg/l respectively, PP These results imply that glucocorticoid treatment increases basal GH levels through a GHRH-dependent mechanism and also increases pituitary sensitivity to exogenous GHRH when inhibitory somatostatin tone is blocked. Journal of Endocrinology (1991) 131, 75–86