Fulminant necrotising enterocolitis immediately following change to low birth weight formula feeds.

INTRODUCTION: The aim of this study was to investigate how low birth weight formula (LBWF) feeds may be implicated in the pathogenesis of a particularly fulminant form of necrotising enterocolitis (NEC). MATERIALS AND METHODS: A retrospective case note review was undertaken of cases of fulminant NEC between 1997 and 2003 with particular regard to the feeding history. RESULTS: Nine preterm infants were stable and already tolerating full enteral feeds for a median of seven days prior to developing fulminant NEC within a median of 24 hours following the introduction of LBWF. CONCLUSIONS: Although fortification of feeds undoubtedly benefits many premature neonates, there may be a tendency for LBWF feeds to preempt the development of fulminant NEC. This possible temporal association between LBWF and fulminant NEC requires further investigation.

Effect of a new oral somatostatin analog (SDZ CO 611) on gastric emptying, mouth to cecum transit time, and pancreatic and gut hormone release in normal male subjects.

Sixteen healthy male volunteers participated in a randomized, double blind, parallel groups study. Subjects received either 1 or 5 mg SDZ CO 611 (a new, orally active somatostatin analog) twice daily over a 14-day period and acted as their own controls. Gastric emptying of 99mTc and mouth to cecum transit time, as measured by the breath hydrogen technique, after a mixed meal containing lactulose and 99mTc-diethylenetriaminepentaacetate, were assessed once before, twice during, and once after the period of study medication. Gastric emptying of 99mTc was significantly accelerated by the higher dose of SDZ CO 611, whereas mouth to cecum transit time was prolonged by the drug in a dose-dependent manner. Both doses of SDZ CO 611 led to suppression of the fasting level and postprandial release of several gastrointestinal and pancreatic hormones. This effect was more marked in those subjects taking 10 mg/day of the study medication. Motilin and pancreatic polypeptide were the most sensitive to the inhibitory actions of the analog. Glucose tolerance was significantly impaired by the 10-mg dose of the drug. We conclude that this new, orally active derivative of somatostatin is as effective on the gastrointestinal tract as the sc somatostatin analog octreotide. It would, therefore, be a useful advance in the treatment of gastroenteropancreatic tumors.

Vasoactive intestinal peptide, but not pituitary adenylate cyclase-activating peptide, modulates the responsiveness of the gonadotroph to LHRH in man.

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) are hypothalamic peptides sharing considerable sequence homology which are postulated to be hypophysiotrophic releasing factors. When infused into man, PACAP has no effect on anterior pituitary hormone levels, while VIP causes a significant increase in circulating prolactin concentrations. However, PACAP has recently been shown to augment the release of LH and FSH in response to LHRH in rat anterior pituitary cell culture. In order to ascertain if either peptide has a similar effect in man, PACAP and VIP were infused at 3.6 pmol/kg per min into six healthy male volunteers, and an LHRH test was performed 30 min after the infusion was commenced. Infusion of PACAP did not alter the gonadotrophin response to LHRH significantly. However, VIP augmented the release of LH significantly, both during the infusion and for 30 min thereafter, although there was no effect on FSH release. Thus VIP, but not PACAP, potentiates the release of LH after LHRH injection in man.

Regulation of anterior pituitary galanin and vasoactive intestinal peptide by oestrogen and prolactin status.

The neuropeptides vasoactive intestinal peptide (VIP) and galanin are synthesized in the anterior pituitary, galanin in the lactotroph and VIP probably in another cell type, and both stimulate prolactin secretion. Oestrogen regulates anterior pituitary VIP and galanin, galanin expression reflecting physiological variation in oestrogen status, whilst VIP is induced by pharmacological concentrations of oestrogen. Implanting anterior pituitaries under the renal capsule to induce hyperprolactinaemia we studied the regulation of anterior pituitary VIP and galanin synthesis and storage by prolactin and its interaction with oestrogen status. Five groups of animals were studied: control, hypophysectomized implanted, implanted, hyperoestrogenized (oestradiol-17 beta; 250 micrograms/day) and hyperoestrogenized implanted. Spontaneously cycling animals were followed through two cycles prior to implanting and were maintained for at least 1 week and then killed once they were in dioestrus. Circulating prolactin levels were significantly elevated in implanted animals but not in hypophysectomized implanted animals compared with controls. There was a more marked increase in prolactin levels in hyperoestrogenized animals and hyperoestrogenized implanted animals, with no significant difference between these two groups. Native anterior pituitary galanin and VIP content was suppressed in implanted animals, and markedly increased in hyperoestrogenized animals. Pituitary implantation only marginally reduced the effect of hyperoestrogenization on galanin content but abolished the effect of hyperoestrogenization on VIP content. Implant peptide content was suppressed to less than 10% of native anterior pituitary content. Galanin was not detected in implants from hypophysectomized-implanted animals but implant VIP content was unaffected by hypophysectomy. VIP content was increased in implants from hyperoestrogenized implanted animals but implant galanin content was unaffected by hyperoestrogenization. Peptide mRNA levels changed in parallel with peptide content except that the implant galanin mRNA levels were increased by hyperoestrogenization. Thus it appears that prolactin negatively regulates anterior pituitary galanin and VIP gene expression and content, probably due to a direct effect on the anterior pituitary and by altered secretion of hypothalamic factors. Oestrogen is a potent stimulus to expression of both peptide genes. Its positive effect on anterior pituitary peptide gene expression and content is greatly diminished by the effect of implant-induced hyperprolactinaemia, suggesting that circulating prolactin levels may be controlled by a negative feedback effect of prolactin on galanin and VIP. A similar effect of hyperoestrogenization is observed in the implants, except that galanin content remains at a low level, suggesting that the combination of hyperoestrogenization and the absence of dopamine may lead to uncontrolled release of high levels of galanin.

Signalling pathways mediating secretory and mitogenic responses to galanin and pituitary adenylate cyclase-activating polypeptide in the 235-1 clonal rat lactotroph cell line.

The neuropeptides galanin and pituitary adenylate cyclase-activating peptide (PACAP) have been implicated in the physiological regulation of lactotroph function. Using the 235-1 clonal lactotroph rat cell line we have studied the signalling pathways mediating the secretory and mitogenic responses to galanin and PACAP. Both peptides stimulated prolactin release to a similar maximal extent. PACAP (100 nM) stimulated an increase in the proliferation rate of 235-1 cells, but was significantly less effective than 100 nM galanin (161.8 +/- 2.3% vs 296.1 +/- 9.1% of control). PACAP stimulated cAMP accumulation with an ED50 of 3.2 nM, and a maximal effect of almost two-fold at a concentration of 100 nM. Galanin depleted cAMP, by 30% at a concentration of 100 nM. The aminosteroid phospholipase C (PLC) inhibitor U-73122 virtually abolished maximal peptide stimulated prolactin release. Depletion of inositol phosphates or downregulation of protein kinase C reduced maximal peptide stimulated prolactin release from about 260% to about 160% of unstimulated release. Both peptides at a concentration of 100 nM caused a sustained increase in intracellular calcium when incubated with cells for 30 min. These results demonstrate that both peptides stimulate prolactin release and the proliferation rate of 235-1 cells. The most important signalling pathway for prolactin release activated by both peptides is via PLC, although they also regulate cAMP levels, which are increased by PACAP and decreased by galanin. Despite maximal peptide stimulated prolactin release being equal, galanin has a greater mitogenic effect on 235-1 cells than PACAP, raising the possibility that it activates an additional mitogenic signalling pathway.

An unlikely role for cyclic AMP in the mediation of the excitatory and inhibitory effects of noradrenaline on transmission in the olfactory cortex.

Simultaneous measurements have been made of the actions of noradrenaline and other agonists, alone and in the presence of appropriate antagonists, on synaptic transmission and cyclic AMP levels in the rat olfactory cortex. The possible role of cyclic AMP as an obligatory mediator of the excitatory and inhibitory actions of noradrenaline is discussed.

Myopericarditis in Churg-Strauss syndrome.

Churg-Strauss syndrome is a disseminated vasculitis with multisystem involvement, characterized by necrotizing arteritis, eosinophilic infiltration, and extravascular granuloma formation. In as many as 60% of all cases, the heart may be affected. We describe a 30-year-old man in whom pericarditis was followed by the development of a large pericardial effusion, with evidence of impaired right and left ventricular function. The patient had a 5-year history of asthma. Early therapy with high-dose prednisolone and azathioprine led to resolution of the pericardial effusion and prevented a further reduction in biventricular function.

Osteomyelitis of the pelvis and proximal femur: diagnostic difficulties.

Osteomyelitis of the pelvis or proximal femur may still be diagnosed late because the infection is deeply placed and investigations may concentrate solely upon the possibility of septic arthritis. Periacetabular infection was diagnosed in 16 children between 1994 and 1998. A high index of suspicion and the use of appropriate imaging will ensure that the condition is not allowed to progress, although in this series one child underwent an unnecessary appendectomy, and a subsequent sepsis of the hip joint was drained in another case. Radiographs of the pelvis were rarely abnormal within 7 days of the onset of symptoms and an ultrasound scan focused on the hip joint may miss the periarticular changes.

Modelling the extraction of soil contaminants with supercritical carbon dioxide.

Extractions of volatile organic compounds (VOC's) in contaminated soil from petroleum site were performed with supercritical carbon dioxide at different temperatures, pressures, extraction times, solvent flow rates, soil moisture contents and soil acidity. Three soil systems were investigated in order to compare the best parameters for extraction. A central composite rotatable design has been used to evaluate the influence of operation conditions on the extraction efficiency to generate model equations representing the types of soil. The results indicate that at least 70-80% of the initial amount of VOC's can be removed at moderate temperatures even at very high moisture content. Supercritical extraction is best suited to silt type soils which have a low adsorption capacity. VOC's recoveries from the artificial contaminated soil samples were higher in comparison with real contaminated soils. At moderate temperatures, the extraction efficiency for real soils is low because pollutants bind strongly to the soil.

The outcome of expectant management of congenital cystic adenomatoid malformations (CCAM) of the lung.

INTRODUCTION: The appropriate management of asymptomatic congenital cystic adenomatoid malformations of the lung (CCAM) remains controversial. The aim of this study is to determine the outcome of expectant management of these lesions and the sensitivity of antenatal ultrasound diagnosis. MATERIAL AND METHODS: A retrospective review was undertaken of all cases identified from prospectively collected databases with an antenatal or postnatal diagnosis of CCAM in the Northern region of England between 1985 and 2006 where such lesions underwent resection only when symptomatic. RESULTS: Thirty-seven cases of confirmed CCAM were identified antenatally or postnatally. Twenty-six (70%) were identified by antenatal ultrasound scans (during a period of near-universal antenatal scanning), of whom 21 (81%) were liveborn. In total, 16 of 29 (55%) liveborn infants with CCAM were symptomatic, and either died within the first postnatal week or underwent resection. Thirteen (45% of livebirths) were managed expectantly and remained asymptomatic. The sensitivity of antenatal ultrasound screening for CCAM increased over the period to 90% in the latter half of the study (p=0.035), although the positive predictive value (66%) did not improve. CONCLUSIONS: Expectant management was a reasonable option for almost half of the babies, but over one third required surgery for CCAM, most becoming symptomatic in infancy. In view of the uncertainty that surrounds decisions regarding expectant or pre-emptive resection in asymptomatic infants, the authors advocate having an open and honest discussion when counselling parents (particularly antenatally) regarding surveillance or expectant management as a reasonable strategy.

Comparison of the effects of continuous subcutaneous insulin infusion (CSII) and NPH-based multiple daily insulin injections (MDI) on glycaemic control and quality of life: results of the 5-nations trial.

AIMS: The goal of the study was to determine whether continuous subcutaneous insulin infusion (CSII) differs from a multiple daily injection (MDI) regimen based on neutral protamine hagedorn (NPH) as basal insulin with respect to glycaemic control and quality of life in people with Type 1 diabetes. METHODS: The 5-Nations trial was a randomized, controlled, crossover trial conducted in 11 European centres. Two hundred and seventy-two patients were treated with CSII or MDI during a 2-month run-in period followed by a 6-month treatment period, respectively. The quality of glycaemic control was assessed by HbA(1c), blood glucose values, and the frequency of hypoglycaemic events. For the evaluation of the quality of life, three different self-report questionnaires have been assessed. RESULTS: CSII treatment resulted in lower HbA(1c) (7.45 vs. 7.67%, P < 0.001), mean blood glucose level (8.6 vs. 9.4 mmol/l, P < 0.001) and less fluctuation in blood glucose levels than MDI (+/- 3.9 vs. +/- 4.3 mmol/l, P < 0.001). There was a marked reduction in the frequency of hypoglycaemic events using CSII compared with MDI, with an incidence ratio of 1.12 [95% confidence interval (CI): 1.08-1.17] and 2.61 (95% CI: 1.59-4.29) for mild and severe hypoglycaemia, respectively. The overall score of the diabetes quality of life questionnaire was higher for CSII (P < 0.001), and an improvement in pump users' perception of mental health was detected when using the SF-12 questionnaire (P < 0.05). CONCLUSION: CSII usage offers significant benefits over NPH-based MDI for individuals with Type 1 diabetes, with improvement in all significant metabolic parameters as well as in patients' quality of life. Additional studies are needed to compare CSII with glargine- and detemir-based MDI.

Consequentialist demographic norms and parenting rights.

"This paper extends the author's recent work on dynamically consistent consequentialist social norms for an unrestricted domain of decision trees with risk to trees in which the population is a variable consequence--i.e., endogenous. Given a form of ethical liberalism and ethical irrelevance of distant ancestors, classical utilitarianism is implied (provided also that a weak continuity condition is met). The 'repugnant conclusion' that having many poor people may be desirable can be avoided by denying that individuals' interests extend to the circumstances of their birth. But it is better avoided by recognizing that potential parents have legitimate interests concerning the sizes of their families."

Elevated serum parathyroid hormone related protein and 1,25-dihydroxycholecalciferol in hypercalcaemia associated with adult T-cell leukaemia-lymphoma.

Hypercalcaemia occurs in up to 80% of patients with adult T-cell leukaemia-lymphoma (ATLL) associated with human T-cell leukaemia virus-1 infection. Elevated serum levels of 1,25-dihydroxycholecalciferol, implicated in the pathogenesis of hypercalcaemia in lymphoma, and of parathyroid hormone-related protein (PTHrP), which is associated with hypercalcaemia of several solid malignancies, were demonstrated in a patient with ATLL hypercalcaemia. Treatment with bisphosphonates reduced the serum calcium but had no significant effect on the serum PTHrP levels. This case supports recent in vitro evidence for enhanced PTHrP expression in ATLL tumour cells and suggests that more than one tumour cell product may be involved in the pathogenesis of ATLL hypercalcaemia.

Galanin regulates basal and oestrogen-stimulated lactotroph function.

Oestrogen, an essential physiological regulator of reproductive function, controls lactotroph proliferation and prolactin release. The neuropeptide galanin co-localizes to the lactotroph, but its physiological function is largely unknown. Pituitary galanin expression is extremely sensitive to the oestrogen status of the animal. A marked elevation occurs during pregnancy and lactation, and exogenous 17 beta-oestradiol can cause a 4,000-fold increase in messenger RNA levels. Here we report that galanin is secreted by a minority of lactotrophs and is essential for the regulation of basal and vasoactive-intestinal-polypeptide-stimulated prolactin release. Hyperoestrogenization increases the number of galanin-secreting cells and the resulting increase in basal prolactin release is completely abolished by treatment with galanin antiserum. Galanin is a potent lactotroph growth factor and galanin-immunoneutralization completely inhibits the previously reported mitogenic effects of oestrogen on the lactotroph. These findings represent direct evidence for paracrine regulation of lactotroph function and demonstrate that the effect of oestrogen on lactotroph proliferation and prolactin release are mediated by locally secreted galanin.

Localization of metastatic gastroenteropancreatic tumours by somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]-octreotide.

Most gastroenteropancreatic tumours express somatostatin receptors, allowing imaging using radiolabelled somatostatin analogues. Octreotide can be modified by coupling a DTPA moiety to the N-terminal D-phenylalanine to allow labelling with In111. We studied the comparative effectiveness of this radiopharmaceutical in identifying tumour extent. Twenty-two patients with metastatic gastroenteropancreatic tumours were scanned using [111In-DTPA-D-Phe1]-octreotide. In 11 patients with the carcinoid syndrome, one of six primary lesions was identified by CT scanning and by [111In-DTPA-D-Phe1]-octreotide scanning. Hepatic metastases were present in all patients, 9 of whom had positive scintigraphy. Two other sites of intra-abdominal uptake and four distant sites, not previously identified, were demonstrated. Five other distant sites were confirmed to be carcinoid metastases. All 11 patients with other gastroenteropancreatic tumours had positive scans, demonstrating 7/9 primary lesions, 12 intra-abdominal lesions, including hepatic metastases in all cases, and one distant lesion, all previously identified. Thus [111In-DTPA-D-Phe1]-octreotide imaging effectively identified the extent of metastatic disease from gastroenteropancreatic tumours, and confirmed lesions whose significance was uncertain following previous imaging procedures.

Amino acid infusion blocks renal tubular uptake of an indium-labelled somatostatin analogue.

The Indium-labelled somatostatin analogue pentetreotide has been successfully developed for imaging of somatostatin receptor positive tumours. However there is significant renal tubular uptake of the radiolabelled peptide, which can obscure upper abdominal tumours and would preclude its use for targeted radiotherapy. The aim of this study was to determine whether amino acid infusion, which has been shown to block renal tubular peptide reabsorption, diminishes renal parenchymal uptake of this radiolabelled analogue. Eight patients being scanned with the 111In-labelled somatostatin analogue, pentetreotide, for localisation of gastroenteropancreatic tumours received an infusion of synthetic amino acids. The ratio of isotope uptake in kidney to that in spleen was assessed, and compared to the ratio for matched control patients, to determine if amino acid infusion reduced renal parenchymal uptake of the radiopharmaceutical. The amount of isotope in the urine was determined to ensure that any effect of the amino acid infusion was unrelated to changes in clearance. Infusion of amino acids significantly reduced renal parenchymal uptake of isotope at 4 h. There was a non-significant increase in urinary clearance of isotope over the 4 h, consistent with reduced reuptake and a lack of effect on glomerular filtration rate. This technique, by preventing renal damage, may allow the use of this somatostatin analogue for local radiotherapy, and could be of wider value in blocking tubular re-uptake of potentially nephrotoxic agents, such as radiolabelled Fab fragments.