Correction to: EUROCAT: an update on its functions and activities.

The published online version contains the following errors: On the cover page "JRC Management Committee" - should be corrected to JRC-EUROCAT Management Committee. In the authors list under the title, same as above, "JRC Management Committee" should be corrected to JRC-EUROCAT Management Committee.

EUROCAT: an update on its functions and activities.

This paper provides an outline of the development and growth of EUROCAT, the European network of congenital anomaly registers. In recent years the network has been through a period of transition and change. The Central Register of data has transferred from the Ulster University to the EU Joint-Research-Centre, Ispra, Italy.The benefits of combining data from across Europe, from different populations and countries are described by the uses to which these data can be put. These uses include:. surveillance of anomalies at a local, regional or pan-European level. pharmacovigilance. registration of rare diseasesNew studies and projects are underway, including EUROlinkCAT (a Horizon 2020 funded data-linkage project), promising a fruitful future in further research of congenital anomalies.

Characterization of rat gastric inhibitory peptide cDNA.

Gastric inhibitory peptide (GIP) is a 42 amino acid gastrointestinal peptide which inhibits gastric acid secretion and stimulates pancreatic insulin secretion in the presence of glucose. Here we report the sequence of the cDNA encoding the rat GIP precursor. PreproGIP was 144 amino acids in length and comprised the GIP peptide itself, N- and C-terminal flanking peptides of 22 and 59 amino acids respectively and a typical hydrophobic signal peptide. The sequence indicated that GIP is released from its precursor by cleavage at single arginine residues. The C-terminal flanking peptide may have an important function since it was well conserved and contained a region of 16 amino acids with only a single, conservative replacement. Rat GIP mRNA was found in the duodenum and jejunum. Levels of GIP mRNA in the duodenum were increased twofold after a period of 2 days of starvation. There was no detectable expression of the GIP gene in other parts of the gastrointestinal tract or in other endocrine tissues. However, in pancreatic mRNA preparations, a larger mRNA was detected after low stringency hybridization. This could represent a further member of this gene family.

Extra-pancreatic expression of the rat islet amyloid polypeptide (amylin) gene.

Messenger RNA for rat islet amyloid polypeptide (IAPP) has been identified not only in the pancreas but also, in lesser amounts, in preparations from the stomach and dorsal root ganglia. In the stomach, insulin mRNA was not detectable, ruling out possible contamination by pancreatic tissue. Because IAPP and calcitonin gene-related peptide (CGRP) are related and CGRP is present in both stomach and dorsal root ganglia, it was possible that 'IAPP' signals were in fact due to cross-hybridization with CGRP mRNA. A second IAPP probe was constructed which does not cross-react. This probe also detected mRNA in both tissues, confirming the expression of IAPP in both tissues. The regional distribution of IAPP mRNA in the stomach did not parallel that of gastrin mRNA. IAPP mRNA was present in the antrum, centrum and pylorus and, like gastrin, the highest amounts were in the pylorus. However, the ratio between the pylorus and centrum was 3.6:1 for IAPP and 156:1 for gastrin. The effects of dietary manipulation were determined; a period of 48 h of starvation reduced pancreatic IAPP mRNA by approximately 60%, whereas in the stomach there was no significant reduction. If the action of IAPP was hormonal, pancreas and stomach would not be acting in concert. A paracrine role for gastric IAPP therefore seems more likely.

The interaction of CGRP and adrenomedullin with a receptor expressed in the rat pulmonary vascular endothelium.

An abundant, seven trans-membrane domain receptor related to the calcitonin receptor has been studied by a number of groups without identification of its ligand. A recent report claimed that the receptor was a type 1 CGRP receptor (Aiyar et al J. Biol. Chem. 271 11325-11329 (1996)). We have studied the equivalent rat sequence in transfected cells. When expressed in 293 cells the receptor interacts with CGRP and adrenomedullin with KD values of 1.2 nM for CGRP and 11 nM for adrenomedullin. Both ligands cause an elevation of intracellular cAMP with EC50 values of 4 nM and 20 nM respectively and these effects are inhibited by the antagonist CGRP8-37. The receptor is expressed at high levels in the pulmonary vascular endothelium. Both the pharmacological data and the localisation are consistent with the conclusion that the orphan receptor is a type J CGRP receptor. However, when expressed in COS-7 cells, no receptor activity could be demonstrated suggesting that 293 cells contain a factor necessary for functional receptor expression.

Pharmacokinetics of iodine-123-IMBA for melanoma imaging.

UNLABELLED: The development of an effective radiopharmaceutical with affinity for malignant melanoma has been a research goal for some time. The early detection of melanoma metastases would greatly improve the therapy outcome for this disease. This article describes the synthesis of radioiodinated IMBA, N-(2-diethylaminoethyl)-3-[123I/131I]iodo-4-methoxybenzamide 8, its organ distribution, its comparison with BZA and other benzamides, and demonstrates the scintigraphic efficacy of the title compound with three melanoma patients. METHODS: The syntheses and radioiodination of eight benzamide derivatives are described. After intravenous injection into C57B16-mice subcutaneously transplanted with B16 melanoma, the organ distribution of the respective benzamides were investigated at 1 and 6 hr. n-octanol/phosphate buffer partition coefficients. The wholebody retention, erythrocyte and serum protein bound fractions of radioiodinated benzamides were measured. RESULTS: While structural changes in the amide substituents of N-(2-dialkylaminoalkyl)-4-iodobenzamides 2-7 resulted in no improvement in organ distribution compared with BZA, the 3-iodo-4-methoxyphenyl form of IMBA showed high melanoma uptake with significantly higher melanoma/nontarget tissue ratios. Compared with BZA the average ratio improved after 1 hr by a factor of eight and was still four times better after 6 hr. BZA and IMBA exhibit almost identical n-octanol/ phosphate buffer partition coefficients, however, IMBA has a faster urinary excretion facilitated by a lower affinity to erythrocytes and serum proteins; this could explain the improved tissue partinioning observed. Scintigraphy of patients with melanoma metastases confirmed the promising characteristics derived from the animal studies. CONCLUSION: Due to rapid background clearance and high melanoma affinity, IMBA showed high tumor contrast already at 4 hr after injection which makes it a promising new radiopharmaceutical for the scintigraphic detection of melanoma metastases.

alpha-Adrenoceptors in the mouse vas deferens and their effects on its response to electrical stimulation.

1 Noradrenaline (ID50, 0.75 micrometer) and clonidine (ID50, 2.8 nM) produced a dose-related inhibition of the twitch response of the isolated vas deferens of the mouse to electrical stimulation, their effectiveness decreasing as frequency of stimulation increased from 0.2 to 16 hertz. 2 Phenylephrine (1.0--2.0 micrometer) produced a dose-related contraction of the mouse isolated vas deferens and potentiated the responses to field stimulation. 3 Yohimbine (10 nM) antagonized the inhibitory effects of noradrenaline and clonidine, but had no effect on the motor activity of phenylephrine. At a concentration of 128 nM yohimbine potentiated the twitch response by 110% at 1 Hz, but its effectiveness decreased with increasing frequency of stimulation up to 16 hertz. 4 Thymoxamine (0.3 micrometer) antagonized the effects of phenylephrine, but not those of clonidine. 5 From a consideration of the known characteristics of pre- and postsynaptic alpha-adrenoceptors, it is concluded that the inhibitory effect of noradrenaline is produced by stimulation of the former and the effects of phenylephrine by stimulation of the latter.

CGRP and adrenomedullin binding correlates with transcript levels for calcitonin receptor-like receptor (CRLR) and receptor activity modifying proteins (RAMPs) in rat tissues.

1. Putative receptors for CGRP and adrenomedullin have been investigated in the rat. Calcitonin Receptor-Like Receptor (CRLR), in combination with Receptor Activity Modifying Proteins (RAMPs) is hypothesized to bind either CGRP or adrenomedullin. The receptors known as RDC1 and L1 have also been shown to bind CGRP and adrenomedullin respectively. 2. In this study it is shown that rat CRLR cDNA specifies a CGRP receptor when co-transfected with RAMP-1 cDNA and an adrenomedullin receptor when co-transfected with either RAMP-2 or RAMP-3 cDNA in human embryonic kidney 293 cells. 3. CRLR, RAMP, RCD1 and L1 mRNA levels and CGRP and adrenomedullin receptor densities have been measured and correlated with each other in eight rat tissues selected for their distinctive patterns of CGRP and adrenomedullin binding. 4. The data are consistent with the predictions of the CRLR/RAMP model. CGRP binding correlates well with RAMP-1 mRNA levels (R=1.0, P=0.007), adrenomedullin binding shows a tendency to vary with RAMP-2 mRNA levels (R=0.85, P=0.14) and total binding is correlated with CRLR mRNA levels (R=0.94, P=0.03). The data do not support the hypothesis that RDC1 and L1 account for the majority of CGRP and adrenomedullin binding respectively.

Use of surrogate respondents in studies of stroke and dementia.

A study was performed to determine the misclassification of information on exposure when surrogate informants are interviewed. Information from nondementia patients admitted to a geriatric ward was compared with that obtained from the patients' family members or friends (informants). Thirty-seven patients were recruited (17 with current or previous stroke, and 20 no history of stroke). Information on past medical and family history, cigarette smoking and alcohol consumption was collected using a questionnaire that was administered independently to patients and informants. For nonstroke patients, agreement on smoking and alcohol consumption at different ages was generally good. Informants reported slightly lower smoking and alcohol intake than patients: 1.3 fewer total pack-years (95% CI, -3.8, +6.5) and 2.7 fewer units/week (95% CI, -1.5, +6.9), respectively. For stroke patients, informants tended to report a greater smoking consumption at all ages, and a slightly higher alcohol consumption. Informants reported an excess of 7.4 total pack-years (95% CI, -1.2, + 16.0) and 2.19 units/week (95% CI, -1.0, +5.3). Agreement for medical history was good, except for hypertension. There was poor agreement for family medical history. The impact of misclassification is discussed.

Implantable artificial lung. Preliminary report.

The ultimate treatment of chronic respiratory insufficiency is pulmonary replacement by an artificial organ, homologous lung transplantation, or chronic paracorporeal respiratory supplementation. The woven capillary membrane oxygenator appears to be a major development toward implantable artificial organs. The four units tested are made up of screens 3.5 by 4.0 cm. of capillary tubing 0.3 mm. I.D. by 0.64 mm. O.D. assembled into rectangular blocks. Units made up by five, ten, twenty, and forty screens have been assembled and tested according to the protocol suggested by Galletti. The maximum oxygen transfer rate with blood was 48 ml. per minute per square meter. Water carbon dioxide transfer rate was 23.1 ml. per minute per square meter. The pressure drops in the liquid phase were 8.5, 15.3, 13.8, 17.6 mm. Hg at 1 L. per minute flow. These results indicate that the woven capillary membrane lung is an acceptably efficient oxygenator. The characteristics of design and performance suggest that this oxygenator can be made to be implanted into the chest or used as a paracorporeal respiratory assistance device.

Gastrin-releasing peptide-like immunoreactivity in medullary thyroid carcinoma.

Gastrin-releasing peptide, the mammalian counterpart of amphibian bombesin, has been found to be present in high concentration by radioimmunoassay in eight histologically confirmed medullary thyroid carcinomas and to be undetectable in postmortem normal thyroid tissue. Chromatographic analysis of the tumor extracts by gel permeation revealed two major peaks of gastrin-releasing peptide-like immunoreactivity (GRP-LI). However, reverse-phase high-pressure liquid chromatography demonstrated three immunoreactive peaks of GRP-LI. None of these immunoreactive peaks was coeluted with synthetic porcine GRP or amphibian bombesin, but one of the peaks exactly emerged in the position of neuromedin C (C-terminal decapeptide of GRP). Sections from nine primary or secondary tumours were immunostained for GRP using a peroxidase/anti-peroxidase technic. All the medullary thyroid carcinomas were shown to contain GRP-LI, specifically localized to the tumor cells. This immunoreactivity is elevated in plasma from some patients with this malignancy, raising the possibility that it may be used as an additional tumor marker.

Lack of correlation of free deoxypyridinoline excretion with Taq1 restriction length polymorphisms in the vitamin D receptor gene in males.

An association between allelic variants in the vitamin D receptor gene and bone mineral density has been previously described. A bimodal variation in the rate of bone resorption (as measured by urinary deoxypyridinoline excretion rate) has also been reported. We have recruited male volunteers, to minimise variation associated with ovarian function, to investigate a possible connection between these observations. Allelic variants in the vitamin D receptor gene were identified as Taq1 restriction fragment length polymorphisms. The ratio of variants TT:Tt:tt occurred with a frequency of 34%:47%:17%. Excretion rates of urinary free deoxypyridinoline, measured by immunoassay, were compared in age-matched males from each genetic group. There were no significant differences based on the paired Student's t-test. Excretion rates declined with age (P = 0.04) and the best fit model fits the same regression line to each group. Genetic variation in the vitamin D receptor is not linked with differences in bone resorption rates.

Radioiodinated N-(alkylaminoalkyl)-substituted 4-methoxy-, 4-hydroxy-, and 4-aminobenzamides: biological investigations for the improvement of melanoma-imaging agents.

The syntheses and radiolabelling of 27 new N-(alkylaminoalkyl)-4-methoxy-, -4-hydroxy-, and -4-aminobenzamides are described and evaluated in C57B1/6 mice with subcutaneously transplanted B16 melanoma in order to screen the optimal chemical structure for melanoma scintigraphy. Using T1(TFA)3 for 131I- labelling, a series of radioiodinated 4-methoxy benzamide derivatives proved to exhibit superior melanoma uptake with outstanding melanoma/non-target-tissue ratios. From the benzamide derivatives tested, N-(2-(1'-piperidinyl)ethyl-3-[131I]iodo-4-methoxybenzamide and N-(2-diethylaminoethyl)-3-[131I]iodo-4-methoxybenzamide demonstrated best results. The introduction of 4-hydroxy and 4-amino groups led to less favourable benzamides. While the former compounds showed little melanoma uptake, the latter revealed unfavourable melanoma/non-target-tissue ratios. Additionally, it could be shown that an amino group was inevitably necessary for melanoma uptake, and that dialkylation of the amide nitrogen and replacing CONH by CH2NH revealed less advantageous results.

Assessing quality of life in people with multiple sclerosis.

PURPOSE: The quality of life of multiple sclerosis (MS) patients was assessed using two MS specific quality of life measures (FAMS and SF-54) and a short generic measure (EuroQol) in order to make recommendations for routine assessment. Factors contributing to quality of life within this population were also considered. METHOD: Questionnaires were either sent by post or completed at interview. Ninety-six MS patients known to a consultant in rehabilitation medicine completed the questionnaires. RESULTS: Patients scored very low on subscales related to physical health. Correlations were high between the FAMS and SF-54 but low with the EuroQoL. Stepwise multiple linear regressions showed mood measures to account for the most variance on all quality of life composite scores. The MS patients within the study had much lower SF-36 quality of life scores than the general population and other illness groups. CONCLUSIONS: The EuroQol did not measure the same aspects of quality of life as the FAMS and SF-54 and was not found to be a sensitive measure within this sample. The SF-54 suffered from floor effects on physical health subscales and therefore the FAMS was recommended.

Measurement of 90Sr in bone ash.

Bone is a critical organ for the accumulation of many radionuclides, including 90Sr. A bone ash has been prepared by NIST to become a standard reference material and the assaying of the 90Sr activity concentration is reported. A radiochemical procedure, based on extraction chromatography using a crown ether, has been developed to separate Sr from the bone ash. The natural Sr content of the bone ash has been determined by isotope dilution inductively coupled plasma mass spectrometry. The 90Sr activity concentration has been measured by low-level liquid scintillation counting.