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The development of clinical diagnostic procedures comprises early-phase and late-phase studies to elucidate diagnostic accuracy and patient outcome. Economic assessments of new diagnostic procedures compared with established work-ups indicate additional cost for 1 additional unit of effectiveness measure by means of incremental cost-effectiveness ratios when considering the replacement of the standard regimen by a new diagnostic procedure. This article discusses economic assessments of PET and PET/computed tomography reported until mid-July 2014. Forty-seven studies on cancer and noncancer indications were identified but, because of the widely varying scope of the analyses, a substantial amount of work remains to be done.

Prolonged Q-T interval (QT) has been reported in patients with cirrhosis who also exhibit profound abnormalities in vasoactive peptides and often present with elevated heart rate (HR). The aim of this study was to relate QT to the circulating level of endothelins (ET-1 and ET-3) and calcitonin gene-related peptide (CGRP) in patients with cirrhosis. In addition, we studied problems with HR correction of QT.Forty-eight patients with cirrhosis and portal hypertension were studied during a haemodynamic investigation. Circulating levels of ETs and CGRP were determined by radioimmunoassays. Correction of QT for HR above 60 beats per min was performed using the methods described by Bazett (QT(C)) and Fridericia (QT(F)).Prolonged QT(C) (above 440 ms), found in 56% of the patients, was related to the presence of significant portal hypertension and liver dysfunction (p0.05 to 0.001), but not to elevated ET-1, ET-3 or CGRP. When corrected according to Bazett, QT(C) showed no significant relation to differences in HR between patients (r = 0.07, ns). QTF showed some undercorrection of HR (r = -0.36; p0.02). During HR variation in the individual patient, QT(C) revealed a small but significant overcorrection (2.6 ms per heartbeat per min; p0.001). This value was significantly (p0.02) smaller with QTF (1.2 ms per heartbeat per min).The prolonged QT(C) in cirrhosis is related to liver dysfunction and the presence of portal hypertension, but not to the elevated powerful vasoconstrictor (ET-1) or vasodilator (CGRP, ET-3) peptides. The problems with correction of the QT for elevated HR in cirrhosis are complex, and the lowest HR should be applied for determination of the QT.

PURPOSE: The purpose of the study was to define reference ranges for quantitative parameters in [(99m)Tc]mercaptoacetyltriglycerine ([(99m)Tc]MAG3) renography to assist interpretation in a semi-automated (Xeleris, GE) compared to a manual (Picker, Odyssey) software package.PROCEDURES: Forty-eight subjects approved for renal donation were evaluated with [(99m)Tc]MAG3 renography using both the Xeleris and the Picker software.RESULTS: Reference ranges for the two software were comparable regarding the relative function of the two kidneys (the split function, SF) and the residual activities (RA). The time to peak whole-kidney activities (T max whole-kidney) was more dependent on the type of software. Using Bland-Altman limits, we found good and acceptable agreement between the two methods.CONCLUSIONS: We found good correlation between renography results using the Xeleris and Picker software packages. However, software-specific reference ranges are needed.

1. This study describes the effects of hypoxia on relaxing responses and cAMP production induced by the known vasodilator peptides: alphaCGRP, amylin (AMY) and adrenomedullin (AM) on isolated pig coronary arteries in vitro. 2. Hypoxic incubation increased the vasorelaxant effect of alphaCGRP (four-fold; P

Calcitonin gene-related peptide (CGRP), adrenomedullin (AM), and amylin are structurally related peptides mediating vasorelaxation in the coronary circulation possibly via CGRP receptors (subtypes 1 or 2). Functional CGRP1 receptors appear to consist of at least three different kinds of proteins: the calcitonin receptor-like receptor (CRLR), receptor-activity-modifying proteins (RAMPs) and the receptor component protein (RCP). No CGRP2 receptor has yet been cloned. Using reverse transcriptase - polymerase chain reaction, the presence of mRNA sequences encoding CRLR, RCP and RAMPs was demonstrated in human coronary arteries. Relaxant responses were studied on isolated segments of coronary arteries after precontraction with U46619 (9,11-dideoxy-11alpha,9alpha-epoxymethano-prostaglandin F(2alpha)). The human peptides alphaCGRP, AM, and amylin induced relaxation with mean pEC50 values of 8.6, 6.8, and 6.3 M, respectively. Preincubation with alphaCGRP(8-37) (10(-7) -10(-5) M) and a novel nonpeptide CGRP antagonist "Compound 1" (WO98/11128) (10(-7)-10(-5) M) caused a dose-dependent rightward shift of the concentration-response curves for alphaCGRP with pA(2) values of 7.0 and 7.1, respectively. Preincubation with alphaCGRP(8-37) (10(-6) M) and Compound 1 (10(-6) M) caused significant rightward shift of the concentration-response curves for AM and amylin as well with pK B values between 6.6 and 7.5. Preincubation with AM(22-52) had no antagonistic effect on the AM and amylin response, neither did diacetoamidomethyl cysteine CGRP cause any concentration dependent (10(-11)-10(-6) M) dilatation. In conclusion, mRNA for the components forming CGRP1 and AM receptors was detected in the human left anterior descending coronary arteries. alphaCGRP, AM, and amylin mediated vasorelaxation via the CGRP1 receptor. Compound 1 acted as a nonpeptide antagonist at the CGRP1 receptor and could thus become a tool for the study of CGRP-mediated functional responses in human tissue.

Calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) are potent vasorelaxant peptides. This study examined exercise-induced changes in CGRP and AM levels in 12 healthy sea level natives at sea level (SL) and subsequently after 24 h (HA1) and 5 days (HA5) in high altitude hypoxia (4559 m). Plasma values of CGRP, AM, calcitonin, noradrenaline, adrenaline, lactate and heart rate were measured at rest and during maximal exercise (W(max)). On each study day, the dopamine D(2)-receptor antagonist, domperidone (30 mg; n=6), or no medication (n=6) was given 1 h before exercise. W(max) at SL, HA1 and HA5 increased CGRP and AM along with heart rate, lactate and catecholamines, whereas, calcitonin remained unchanged. The maximal CGRP levels at W(max) were significantly decreased at HA1 (74.3+/-6.1 pmol/l; p=0.002) and HA5 (69.6+/-6.0 pmol/l; p

The development of clinical diagnostic procedures comprises early-phase and late-phase studies to elucidate diagnostic accuracy and patient outcome. Economic assessments of new diagnostic procedures compared with established work-ups indicate additional cost for 1 additional unit of effectiveness measure by means of incremental cost-effectiveness ratios when considering the replacement of the standard regimen by a new diagnostic procedure. This article discusses economic assessments of PET and PET/computed tomography reported until mid-July 2014. Forty-seven studies on cancer and noncancer indications were identified but, because of the widely varying scope of the analyses, a substantial amount of work remains to be done.

Calcitonin gene-related peptide (CGRP), amylin and adrenomedullin (AM) belong to the same family of peptides. Accumulating evidence indicate that the calcitonin (CT) receptor, the CT receptor-like receptor (CRLR) and receptor-activity-modifying proteins (RAMPs) form the basis of all the receptors in this family of peptides. Using reverse transcriptase–polymerase chain reaction the presence of mRNA sequences encoding the CRLR, RAMP1 and RAMP2 were demonstrated in porcine left anterior descending (LAD) coronary arteries, whereas porcine calcitonin (CT) receptor mRNA was not present. The partial porcine mRNA sequences shared 82–92% nucleotide identity with human sequences. The human peptides αCGRP, βCGRP, AM and amylin induced relaxation with pEC50 values of 8.1, 8.1, 6.7 and 6.1 M respectively. The antagonistic properties of a novel non-peptide CGRP antagonist ‘Compound 1’ (WO98/11128), βCGRP8–37 and the proposed AM receptor antagonist AM22–52 were compared to the well-known CGRP1 receptor antagonist αCGRP8–37. The αCGRP8–37 and βCGRP8–37 induced concentration-dependent (10−7–10−5 M) rightward shift of both the αCGRP and βCGRP concentration-response curves. βCGRP8–37 (10−6 M) had the same effect as αCGRP8–37 (10−6 M), but with less potent rightward shift of the concentration-response curves for αCGRP, AM and amylin. Preincubation with ‘Compound 1’ (10−7–10−5 M) and AM22–52 (10−6 M) had no significant antagonistic effect. In conclusion, the building blocks forming CGRP and AM receptors were present in the porcine LAD, whereas those of the amylin receptor were not. αCGRP, βCGRP, AM and amylin mediated vasorelaxation via the CGRP receptors. No functional response was detected to adrenomedullin via the adrenomedullin receptor. British Journal of Pharmacology (2001) 133, 1405–1413; doi:10.1038/sj.bjp.0704210

Exercise-induced increases in cardiac output (CO) and oxygen uptake (VO2) are tightly coupled, as also in absence of central motor activity and neural feedback from skeletal muscle. Neuromodulators of vascular tone and cardiac function - such as calcitonin gene related peptide (CGRP) - may be of importance. Spinal cord injured individuals (six tetraplegic and four paraplegic) performed electrically induced cycling (FES) with their paralyzed lower limbs for 29 +/- 2 min to fatigue. Voluntary cycling performed both at VO2 similar to FES and at maximal exercise in six healthy subjects served as control. In healthy subjects, CGRP in plasma increased only during maximal exercise (33.8 +/- 3.1 pmol l(-1) (rest) to 39.5 +/- 4.3 (14%, P

This study describes the effect of variable oxygen supply on relaxing responses induced by α-calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) on isolated pig coronary arteries in vitro. Organ culture during normoxia (21% of O₂) and hypoxia (5% of O₂) induced a significant leftward shift of the AM concentration-response curves compared with fresh vessels altering the pEC₅₀ values from 6.9 ± 0.04 to 8.0 ± 0.04, whereas the potency (pEC₅₀) of αCGRP was attenuated from 8.8 ± 0.04 to 7.6 ± 0.04. AM₂₂₋₅₂ exerted significant antagonistic effect on AM-induced vasorelaxation in hypoxic and normoxic conditions (apparent pK(B) = 6.8-7.2), whereas no antagonistic effect was observed in fresh and hyperoxic (95%) organ cultured vessels. The antagonistic effect exerted by αCGRP₈₋₃₇ (10⁻⁶·⁵-10⁻⁵·⁵ M) on αCGRP-induced vasodilatation in fresh vessels (derived from Schild plot pA₂ = 7.4 ± 0.1) was unaltered during organ culture. The antagonistic effect exerted by αCGRP₈₋₃₇ (10⁻⁶ M) on AM-induced vasorelaxation in fresh vessels (apparent pK(B) = 7.4 ± 0.1) was absent during hypoxic organ culture. The receptor activity-modifying proteins 1 (RAMP1)/calcitonin-like receptor (CLR) messenger RNA ratio was reduced and RAMP2/CLR messenger RNA ratio was increased during hypoxic and normoxic organ culture compared with fresh vessels. Hypoxic organ culture for 24-72 hours potentiated the AM-induced vasorelaxation through an AM₂₂₋₅₂-sensitive receptor but attenuated the vasorelaxant effect of CGRP through the CGRP receptors. This could possibly be explained by relatively decreased levels of RAMP1, thus favoring RAMP2 + CLR complex (=AM receptor) formation during hypoxic organ culture.

The aetiology of the reduced systemic vascular resistance and abnormal 'filling' of the vascular bed in cirrhosis is still obscure. As increased concentrations of the potent vasodilator calcitonin gene-related peptide (CGRP) have recently been reported in cirrhosis, we related CGRP to central and peripheral haemodynamics in patients with cirrhosis.Thirty-one cirrhotic patients and six control subjects underwent an investigation with determination of systemic haemodynamics and circulating CGRP.Circulating CGRP was significantly increased in patients with cirrhosis (P0.02) and covaried directly with the severity of cirrhosis (P0.02). The increased CGRP covaried negatively with the reduced systemic vascular resistance (P0.02), the reduced central blood volume (P0.01), and reduced central circulation time (P0.002) and positively with the non-central blood volume (P0.05).These results suggest that increased CGRP may play a role in the systemic vasodilatation in cirrhosis and may contribute to the abnormal distribution of the blood volume, which may lead to abnormal sodium and water handling.

OBJECTIVE: Our purpose was to determine the concentration of calcitonin gene-related peptide, a potent vasodilator, in maternal plasma, fetal plasma, and placental tissue from pregnancies complicated by severe preeclampsia. STUDY DESIGN: The following groups were studied: severe preelcmapsia (group 1, n = 21), normal pregnancies matched for mode of delivery (group 2, n = 21), and nonpregnant women (group 3, n = 17). Maternal venous blood samples were drawn before labor, and fetal venous samples were drawn from the chorionic plate immediately after delivery. Calcitonin gene-relted peptide was also quantified in placental tissue samples from 15 patients in group 1 and 15 patients in group 2. Calcitonin gene-related peptide was measured with a sensitive and specific radioimmunoassay. RESULTS: No differences were found between maternal plasma calcitonin gene-related peptide concentrations in groups 1 and 2 (29.8 ± 4.2 and 30.4 ± 4.3 pmol/L, respectively). Both had levels similar to those in group 3 (28.5 ± 5.4 pmol/L). Maternal plasma concentrations in the preeclamptic group were unchanged 3 days post partum (29.1 ± 3.6 pmol/L). Fetal plasma calcitonin gene-related peptide concentrations were similar in groups 1 and 2 (30.2 ± 3.9 and 32.2 ± 8.8 pmol/L, respectively). A significant correlation was found between maternal and fetal calcitonin gene-related peptide concentrations (r = 0.43, p < 0.01). Like plasma levels, calcitonin gene-related peptide levels in the supernatants of placental extracts were not different in preeclamptic and normal pregnancies (108.0 ± 70.4 and 100.9 ± 56.1 fmol/gm, respectively). CONCLUSION: On the basis of plasma and placental concentrations, calcitonin gene-related peptide does not seem to play an important role in the pathophysiologic mechanisms of preeclampsia.

In lumbar cerebrospinal fluid (CSF) obtained from patients with chronic tension-type headache (CTH), the concentrations of beta-endorphin, met-enkephalin, dynorphin, cholecystokinin (CCK), calcitonin gene-related peptide (CGRP), and somatostatin were measured before and after 8 weeks of treatment with sulpiride or paroxetine. We previously reported higher than normal met-enkephalin concentrations in CTH. The present study reveals normal basal concentrations of CCK, CGRP and somatostatin and slightly decreased dynorphin in the same patients. Treatment with sulpiride or paroxetine did not change the concentration of any of the neuropeptides measured. These data suggest central changes in opioid systems but not in other peptide systems (CCK, CGRP, somatostatin) involved in nociceptive processing at the level of the spinal cord dorsal horn/nucleus caudalis of the trigeminal nerve in CTH. Such central changes might be pathophysiologically important or merely secondary to other more important occurrences. The lack of changes in neuropeptide concentrations during drug treatment makes planning of studies involving CSF analysis easier, but also limits the probability of obtaining information on specific neuropeptide systems through CSF analysis.

CGRP was extracted from three familial and four sporadic medullary thyroid carcinomas (MTC) and was measured by an assay specific for the amidated C- terminus . The antibody showed equal affinity for α- and β-CGRP. All tumors contained high concentrations of CGRP (range: 63–7889 pmol/g) compared to spinal cord (86 pmol/g), thyroid gland (4 pmol/g), and two small-cell lung carcinomas (4 and 1 pmol/g, respectively). The concentration of calcitonin (CT) was determined with an assay specific for an epitope involving the midportion and C- terminal end of the molecule. In six of the seven tumors investigated, concentrations of CT were found to be higher than for CGRP. Gel chromatography showed heterogeneity with respect to CGRP immunoreactivity. Thus, in all seven extracts, three peaks were seen with K d values 0.37, 0.63, and 0.80, respectively. This profile of immunoreactive CGRP was similar to that obtained from human medulla spinalis, thereby indicating normal posttranslational processing of pro-CGRP in MTC tumors. Further characterization of the three main peaks identified by gel chromatography was performed on pooled fractions from one of the tumors using HPLC, sequencing, and mass spectrometry. The immunoreactive peak with K d 0.37 was identified as human β-CGRP, the peak with K d 0.63 as 19–37 β-CGRP, and the peak with K d 0.80 as 25–37 β-CGRP. No α-CGRP was identified in this tumor. This indicates selective expression of β-CGRP, at least in the tumor investigated.

Summary OBJECTIVE Calcitonin gene-related peptide (CGRP) is a regulatory peptide encoded by the calcitonin gene. CGRP is expressed in increased amounts by the cells of medullary thyroid carcinomas and has been demonstrated by immunohistochemistry to occur in neuroendocrine cells and nerve fibres of lung tissue. MEASUREMENTS Serum CGRP levels were measured in patients with small cell lung carcinomas before treatment (n= 74) and immediately before the second course of chemotherapy (n= 30). In-situ hybridization and immunohistochemistry were performed on tumour tissue and CGRP was extracted from two tumours and characterized by gel chromatography and high pressure liquid chromatography. RESULTS Serum CGRP levels were elevated in small cell lung carcinomas when compared with healthy controls of similar age and sex (median values 55.0 vs 36.6 pmol/l, P

Nine male marathon runners were investigated during habitual training (week 0), after 3 weeks of training break (week 3), and after 2 weeks (week 5) and 4 weeks (week 7) of retraining. Maximal oxygen uptake, body fat (BF), and plasma levels of 25(OH)D3, 1,25(OH)2D3, parathyroid hormone (PTH), calcitonin (CT), albumin, and albumincorrected calcium were determined throughout weeks 0–7. The maximal oxygen uptake decreased after training break and increased during retraining (P=0.002). BF did not change significantly. Plasma 1,25(OH)2D3 was elevated after training break and decreased after 2 and 4 weeks of retraining [week 0: 44.0±3.7 (SEM) pg×1-1; week 3: 52.4±6.0 pg×1-1; week 5: 42.0±2.8 pg×1-1; week 7: 36.9±2.3 pg×1-1; P=0.03]. Plasma 25(OH)D3 did not change significantly. Plasma PTH increased throughout the training break and retraining (week 0: 1.36±0.25 pmol×1-1; week 3: 2.02±0.43 pmol×1-1; week 5: 2.23±0.60 pmol×1-1; week 7: 2.63±0.34 pmol×1-1; P=0.03). Albumincorrected calcium values were transiently decreased during retraining (week 3: 2.77±0.08 mM; week 5: 2.47±0.05 mM; week 7: 2.66±0.07 mM; P=0.01). Plasma CT did not change during training break, but was transiently decreased during retraining (week 0: 9.97±0.39 pmol×1-1; week 3: 9.91±0.37 pmol×1-1; week 5: 8.19±0.50 pmol×1-1; week 7: 9.02±0.45 pmol×1-1; P=0.01). Plasma CT was correlated to albumin (r=0.46, P=0.005), albumin-corrected calcium (r=0.34, P=0.04), and maximal oxygen uptake (r=0.45, P=0.006). Plasma 1,25(OH)2D3 was correlated to 25(OH)D3 (r=0.04, P=0.02), and BF (r=0.50, P=0.002). The described endurance training induced significant changes of plasma 1,25(OH)2D3 and PTH despite only transient changes of albumin-corrected calcium and CT.

The lack of a nocturnal decrease in blood pressure in cyclosporine-treated cardiac transplant recipients may indicate abnormalities in the mechanism(s) responsible for circadian variability in other physiologic parameters such as in circulating hormones. This possibility was addressed through repeated determinations of circulating catecholamines, neuropeptide Y, pancreatic polypeptide, calcitonin gene-related peptide, plasma renin activity, aldosterone, atrial natriuretic factor and cortisol. The results from 10 patients with heart transplants were compared with those of 12 age-matched, healthy control subjects. Both groups were studied during 24-hour supine rest. There was no difference between patients and control subjects in mean levels of catecholamines, neuropeptide Y, pancreatic polypeptide and aldosterone. Patients had higher levels (+/- SD) of plasma renin activity (6.4 +/- 1.3 vs 2.6 +/- 0.4 ng/ml/hour, p less than 0.001), calcitonin gene-related peptide (47.7 +/- 9.9 vs 33.3 +/- 5.7 pmol/liter, p less than 0.01) and atrial natriuretic factor (93.0 +/- 56.7 vs 20.7 +/- 8.9 pg/ml, p less than 0.001) than control subjects, respectively. Cortisol was not detected in patients. Abnormal diurnal profiles in patients were found for calcitonin gene-related peptide, aldosterone and atrial natriuretic factor, and for pancreatic polypeptide, together with decreased levels, in patients with greater than 6 months follow-up. Except for hormones reflecting sympathetic nervous activity, all hormonal systems studied showed abnormalities in level or circadian rhythmicity, or both. The pancreatic polypeptide results suggest that parasympathetic neuropathy could develop in cyclosporine-treated heart transplant recipients.

Circulating levels of calciotropic hormones were measured during one year of treatment with either 200 IU of salmon calcitonin daily or placebo as a nasal spray in 20 postmenopausal women with a former Colles' fracture. A supplement of 0.5 gram elemental calcium was given to all participants. Serum levels of parathyroid hormone and human calcitonin were determined with radioimmunoassays, and serum levels of vitamin D metabolites were determined with protein binding assays. We did not find any significant differences between the two groups with respect to serum levels of calciotropic hormones. In the salmon calcitonin treated group there was a tendency towards a small decrease in serum levels of human calcitonin and an increase in serum levels of calcitriol. Our results suggest that treatment with 200 IU of salmon calcitonin daily as a nasal spray does not markedly affect fasting serum levels of parathyroid hormone, human calcitonin, and vitamin D metabolitis.

Increased calcitonin gene-related peptide (CGRP) in external jugular venous blood during migraine attack is one of the most cited findings in the headache literature. The finding has not been convincingly reproduced and is based on comparison with historic control subjects. The validity of this finding is important for the understanding of migraine. We therefore investigated the issue using an intrapatient comparison design and two different CGRP assays. We sampled blood from the external jugular and cubital vein during, as well as outside of, an attack of migraine without aura. We succeeded in 17 patients, whereas only cubital fossa blood could be sampled in an additional 4 patients. CGRP was measured with the same assay as most previous studies (assay I) and furthermore with a more sensitive and validated assay (assay II). For assay I, mean CGRP concentration in external jugular venous blood during attack was 17.18 pmol/L compared with 15.88 pmol/L outside of attack. Mean difference was 1.81 pmol/L (95% confidence interval [CI]: -2.88, 6.41; p = 0.44). In peripheral blood during attack, CGRP was 16.86 pmol/L compared with 17.57 pmol/L outside of attack. Mean difference was -0.79 pmol/L (95% CI: -4.64, 3.06; p = 0.69). For assay II, external jugular venous blood concentration of CGRP during attack was 32.59 pmol/L compared with 30.59 pmol/L outside of attack; mean difference was 2.00 pmol/L (standard error, 2.39; 95% CI: -3.07, 7.07; p = 0.416). In peripheral blood during attack, CGRP was 33.37 pmol/L compared with 31.84 pmol/L outside of attack; mean difference was 1.53 pmol/L (standard error, 1.90; 95% CI: -2.46, 5.51; p = 0.431). Thus, no difference between CGRP level in external jugular or cubital fossa blood during and outside of attack was found. No difference was found between external jugular and peripheral venous blood. Thus, previous findings of increased CGRP level in external jugular or cubital fossa venous blood could not be confirmed. Our finding strongly suggests that CGRP is not increased in jugular venous blood during migraine without aura. CGRP cannot be used as a biomarker to validate human or animal models of migraine.

1. This study describes the effects of hypoxia on relaxing responses and cAMP production induced by the known vasodilator peptides: alphaCGRP, amylin (AMY) and adrenomedullin (AM) on isolated pig coronary arteries in vitro. 2. Hypoxic incubation increased the vasorelaxant effect of alphaCGRP (four-fold; P0.05), AMY (3.2-fold; P0.05), but not significantly for AM (two-fold; NS). 3. Whereas hypoxia had no effect on arterial cAMP levels, it significantly potentiated the production of cAMP stimulated of alphaCGRP and AMY, but not of AM. 4. The antagonist alphaCGRP(8-37) also exerted an increased effect in hypoxia. The Schild plot-derived pK(B) values revealed an increase in the apparent affinity of the antagonist for the CGRP(1) receptor from 7.0 to 7.2 under control conditions versus 8.0 in hypoxia. 5. Removal of endothelium, peptidase inhibitors, preincubation with the adenosine A(2A) receptor antagonist CSC (10(-3) M), the ATP-sensitive K-channel inhibitor glibenclamide (10(-5) M), the cyclooxygenase inhibitor indomethacin (10(-3) M) or NG-monomethyl-L-arginine (10(-4) M) had no effect on the alphaCGRP-induced vasorelaxation in hypoxia; neither did hypoxia influence the levels of CGRP and AM receptor mRNA. 6. We conclude that hypoxic incubation increases the relaxation and cAMP production induced by alphaCGRP and AMY in rings of porcine coronary arteries in vitro. A concomitant release of adenosine, a cyclooxygenase product, an endothelium-derived substance, activation of vascular ATP-sensitive K-channels, peptidase inhibitors or changes in CGRP and AM receptor mRNA cannot account for the changes observed in hypoxia. Moreover, alphaCGRP(8-37) showed increased affinity at the CGRP(1) receptor during hypoxia, possibly due to a conformational change at the CGRP(1) receptor site.

Sildenafil, a selective inhibitor of the cyclic guanosine monophosphate (cGMP) degrading phosphodiestrase 5 (PDE5), induced migraine without aura in 10 of 12 migraine patients and in healthy subjects it induced significantly more headache than placebo. The aim of the present study was to determine whether the pain-inducing effects of sildenafil would be reflected in plasma levels of important signalling molecules in migraine: cGMP, cyclic adenosine monophosphate (cAMP) and calcitonin gene-related peptide (CGRP). Ten healthy subjects (four women, six men) and 12 patients (12 women) suffering from migraine without aura were included in two separate double-blind, placebo-controlled, cross-over studies in which placebo or sildenafil 100 mg was administered orally. Plasma levels of CGRP, cAMP and cGMP were determined in blood from the antecubital vein. Despite the ability of sildenafil to induce headache and migraine, no significant differences in plasma levels of CGRP, cGMP and cAMP were detected after sildenafil compared with placebo. In conclusion, plasma levels of CGRP, cGMP and cAMP remain normal during sildenafil-induced headache or migraine. However, since previous studies indicate an important role of these signalling molecules, the present study questions whether cAMP and cGMP in peripheral blood can be used for monitoring pathophysiological events in headache and migraine mechanisms.

Summary: Hypertension after craniotomy is frequent. To establish an association between vasoactive modulators and postoperative hypertension, we followed the arterial blood pressure and plasma concentrations of selected substances in patients undergoing craniotomy. Twelve consecutive patients scheduled for operation of a supratentorial brain tumor were anesthetized with thiopental, fentanyl, isoflurane, and pancuronium. None of the patients had a history of arterial hypertension or were hypertensive before the operation. Arterial blood pressure and heart rate measurements were obtained preoperatively, after incision, during closure, and four times in the 50-minute interval after stopping isoflurane. At the same time, plasma concentrations of norepinephrine, epinephrine, renin, aldosterone, atrial natriuretic peptide, endothelin, and cortisol were measured. Data are given as mean ± SD (range). The postoperative concentrations of these substances were significantly higher than the baseline concentrations measured preoperatively. Six of the patients developed postoperative hypertension defined as a mean arterial pressure (MAP) > 20% more than the baseline MAP (group H), and six had normal blood pressure postoperatively (group N). The mean value of the maximal postoperative MAPs measured in groups H and N, respectively, was 118 ± 16 mm Hg (range: 96–132) and 103 ± 9 mm Hg (range: 92–115) (P = .01). Only renin levels were higher intraoperatively in group H when compared to group N. However, postoperative levels of catecholamines, aldosterone, renin, and endothelin levels were higher in group H patients. The results suggest that in addition to an increased discharge of the sympathetic system, activation of the renin-angiotensin aldosterone system may also play an important role in the development of postoperative hypertension after craniotomy.

BACKGROUND AND AIMS—Static and dynamic functions of the wall of large arteries are largely unknown in cirrhosis in vivo. The present study was undertaken to determine arterial compliance (COMPart) in relation to vasodilator and vasoconstrictor systems in patients with cirrhosis. In addition, vasoactivity was manipulated by inhalation of oxygen. STUDY POPULATION AND METHODS—In 20 patients with alcoholic cirrhosis and 12 controls we determined COMPart (stroke volume relative to pulse pressure), cardiac output, plasma volume, systemic vascular resistance, central circulation time, plasma catecholamines, renin activity, endothelin-1, and calcitonin gene related peptide (CGRP) at baseline and during oxygen inhalation. RESULTS—COMPart was significantly increased in cirrhotic patients compared with controls (1.32 v 1.06 ml/mm Hg; p< 0.05) and inversely related to plasma adrenaline levels (r=−0.53; p

Background: Calcitonin gene-related peptide (CGRP) is involved in the pathophysiology of migraine and cluster headache. Whether CGRP has any role in chronic tension-type headache is unknown. Objectives: To compare interictal plasma levels of CGRP between patients with chronic tension-type headache and healthy control subjects, to investigate plasma CGRP in relation to headache state, and to compare plasma CGRP between the peripheral and the cranial circulation. Methods: Blood from the antecubital vein was drawn from 30 patients with chronic tension-type headache and 34 healthy control subjects. In addition, blood samples from the consecutive first 15 patients and from the consecutive first 20 healthy control subjects were also collected from the external jugular vein. Results: CGRP levels measured in the peripheral circulation in patients on days without headache, 63 ± 5 pmol/L, tended to be higher than CGRP levels in control subjects, 53 ± 3 pmol/L ( p = 0.06). In patients, no differences were found between CGRP levels assessed ictally and interictally in either the cranial ( p = 0.91) or the peripheral ( p = 0.62) circulation. Plasma CGRP level was higher in the external jugular vein than in the antecubital vein on days without headache ( p = 0.03) but not on days with headache ( p = 0.82). In control subjects, CGRP levels in the cranial circulation did not differ from CGRP levels in the peripheral circulation ( p = 0.92). Exploratory analyses showed that 8 patients whose usual headache quality was throbbing had a higher interictal plasma CGRP level than control subjects ( p = 0.002), whereas plasma CGRP level was normal in 22 patients with pressing headaches ( p = 0.36). Conclusions: Plasma levels of CGRP are normal in patients with chronic tension-type headache and are unrelated to headache state. Interictal plasma CGRP was increased in patients with a pulsating pain quality. Because the authors have previously shown a similar increase of interictal CGRP levels in migraine, this study suggests that headaches with symptoms that fulfill International Headache Society criteria for tension-type headache may be pathophysiologically related to migraine, if the headache has a pulsating quality.

Increased circulating levels of the neuropeptide calcitonin gene-related peptide (CGRP) have recently been described in cirrhosis. CGRP is formed by alternative transcription of the calcitonin/alpha-CGRP gene, which also gives rise to calcitonin (CT). This study was undertaken to determine circulating plasma concentrations of CT in patients with cirrhosis in relation to the severity of disease and the plasma level of CGRP. Moreover, the kinetics of CT was evaluated for different organ systems by determination of arteriovenous extraction. Thirty-nine patients with cirrhosis (Child-Turcotte classes A/B/C, n = 10/22/7) were studied under a hemodynamic investigation and compared with 13 control subjects without liver disease. CT and CGRP in arterial and organ venous plasma were determined by radioimmunoassays. In patients with cirrhosis, circulating CT was significantly increased versus control (12.1 v 6.9 pmol/L, P.001) and a direct relation to the Child-Turcotte score was found (P.005). The increased circulating CT was directly correlated with increased CGRP (r = .29, P.05). No significant arteriovenous extraction of circulating CT was observed in the kidneys, hepatosplanchnic system, lower extremities, or peripheral circulation, but there was a substantial rate of pulmonary disposal and clearance (P.005). It is concluded that in addition to thyroid production, increased circulating CT in cirrhosis is most likely due to overexpression of the calcitonin/alpha-CGRP gene, with relation to the severity of disease and possibly to an accompanying pulmonary dysfunction.

In patients with cirrhosis, the systemic circulation is hyperdynamic with low arterial blood pressure and reduced systemic vascular resistance. The present study was undertaken to estimate the compliance of the arterial tree in relation to severity of cirrhosis, circulating level of the vasodilator, calcitonin gene-related peptide (CGRP) and mean arterial blood pressure (MAP).Arterial compliance (COMPart=deltaV/deltaP) was determined as the stroke volume relative to pulse pressure (i.e. systolic minus diastolic blood pressure) during a haemodynamic evaluation of portal hypertension in patients with biopsy-verified cirrhosis (Child-Turcotte classes A/B/C=10/15/6).COMPart was significantly higher in cirrhotic patients (n=31) than in controls (n=10) (1.44 vs 1.00 x 10(-3) l/mmHg, p0.01). It increased significantly through the Child-Turcotte classes A, B, and C (1.02, 1.47, and 2.1 x 10(-3) l/mmHg, respectively, p=0.03). The stroke volume did not change significantly with the severity of the disease, but pulse pressure decreased through class A, B, and C (79, 65, and 50 mmHg, respectively, p0.01). COMPart was slightly, but significantly correlated to the circulating level of CGRP (r=0.34, p0.05), and a substantial but inverse correlation was present to MAP (r= -0.63, p0.002).Elevated arterial compliance in cirrhosis is directly related to the severity of the disease and to the elevated level of circulating vasodilator peptide CGRP, and inversely related to the level of arterial blood pressure. The altered static and dynamic functions of the arterial wall in cirrhosis may have implications for the circulatory and homoeostatic derangement, and potentially for therapy with vasoactive drugs.

The regulatory peptide calcitonin was discovered in 1962. During the last decade it has been demonstrated to be part of a gene family. Calcitonin is synthesized in the parafollicular cells (C cells) of the thyroid gland. These cells give rise to an endocrine tumor, medullary thyroid carcinoma (MTC), which is found in a sporadic and an inherited form. Calcitonin is used as a tumor marker for MTC. The calcitonin gene was demonstrated in 1981 to give rise to an alternative peptide product, alpha-CGRP, and a second gene encoding a very similar peptide, beta-CGRP, has also been identified. A third CGRP-like peptide, amylin, was identified in 1986. This article summarizes the present knowledge about gene structure, regulation of gene expression, and expression of the calcitonin gene family in MTC and in MTC-derived cell lines. The methods employed for detection of gene expression and for measurement and characterized of peptide products are described, and finally the relevance of biochemical tumor markers is discussed in relation to the new diagnostic methods for inherited MTC based on molecular biological techniques.

Patients with cirrhosis exhibit a hyperdynamic circulation with increased cardiac output and low arterial blood pressure. The aim of the present study was to assess the effects of oxygen inhalation on systemic, central, and splanchnic haemodynamics and vasoactive systems in patients with cirrhosis (n = 19).Spirometry was normal, but the carbon monoxide diffusing capacity (transfer factor) was significantly decreased, 18.8 ml.min-1.mmHg-1 (-32% of that predicted, p0.0001), and correlated significantly with the cardiac output (r = 0.78, p0.0005), plasma volume (r = 0.72, p0.001) and the central and arterial blood volume (r = 0.67, p0.005). After inhalation of 100% oxygen over a period of 20 min, the cardiac output decreased from 7.4 to 6.6 l/min (p0.0005), and the systemic vascular resistance increased from 980 to 1124 dyn.s.cm-5 (p0.005). The change in systemic vascular resistance was significantly greater in patients with mild liver dysfunction than in those with severe liver dysfunction (p0.02). In contrast, no significant changes were seen in the arterial or portal venous pressures during inhalation of oxygen. Arterial concentrations of catecholamines, renin, endothelin-1, and calcitonin gene-related peptide were all increased in patients with cirrhosis, but only the catecholamine concentrations decreased significantly (noradrenaline -13%, p0.02 and adrenaline -16%, p0.01) in response to oxygen.During oxygen inhalation cardiac output decreases and systemic vascular resistance increases in association with a decrease in arterial concentrations of catecholamine, but oxygen supply in patients with cirrhosis does not normalise the hyperdynamic circulation or the low arterial blood pressure.

The rat medullary thyroid carcinoma cell line, CA-77, is known to express the calcitonin gene and the cell line has been used for characterization of procalcitonin. The present investigations concentrate on a molecular characterization of the calcitonin gene-related peptide (CGRP) expressed by a subclone of this cell line. The investigations demonstrate that this subclone produces significantly more CGRP compared to calcitonin. Gel chromatography of cell extracts demonstrates heterogeneity for both CGRP and calcitonin, but a significant amount of immunoreactivity elutes corresponding to the elution position for synthetic CGRP and calcitonin, respectively. The gel chromatogram for CGRP demonstrates four immunoreactive peaks with Kd of 0.42, 0.53, 0.68, and 0.85. The immunoreactive peak with Kd 0.42 elutes corresponding to synthetic rat CGRP. The four immunoreactive peaks were characterized by high pressure liquid chromatography followed by sequence analysis and mass spectrometry. The immunoreactive peak with Kd 0.42 was identified as rat alpha-CGRP as was the peak with Kd 0.53. The peak with Kd 0.68 was identified as 19-37 rat alpha-CGRP and the peak with Kd 0.85 as 28-37 rat alpha-CGRP. In summary, we find that the CA-77 cell line expresses large quantities of normally processed amidated alpha-CGRP and specific fragments thereof. However, the cell line does not express detectable levels of rat beta-CGRP. The findings indicate that the CA-77 cell line can be useful for studies of calcitonin/CGRP gene expression.

Effects of a single dose of 200 IU of nasal salmon calcitonin (SCT) on calcium metabolism and biochemical markers of bone turnover were investigated in 12 healthy male volunteers in a randomized, placebo-controlled, cross-over design. The nasal spray was given in the morning, and subsequently blood and urine samples were collected for 26 hours. There was a significant decrease in serum ionized calcium with a nadir 4 hours after administration of nasal SCT accompanied by a significant increase in serum parathyroid hormone (P = 0.01) and serum calcitriol (P = 0.04). Nasal SCT did not reduce urinary hydroxyproline/creatinine. Urinary deoxypyridinoline/creatinine was lowered significantly 2 hours after administration of nasal SCT and throughout the first 24 hours, but remained unchanged for the last 2 hours. On a 24-hour basis, urinary deoxypyridinoline/creatinine decreased from 14.1 (3.5) nmol/mmol to 11.7 (3.2) nmol/mmol after nasal SCT (P = 0.04). Nasal SCT did not change the serum levels of alkaline phosphatase, osteocalcin, and the carboxyterminal propeptide of type 1 procollagen. The results indicate that nasal SCT given as a single dose provokes a modest decrease in bone resorption lasting several hours, but leaves bone formation unaffected.

Pharmacokinetics of recombinant human non-glycosylated bacterially-synthesized (E. coli) granulocyte-macrophage colony-stimulating factor (GM-CSF) were studied following single intravenous (i.v.) and subcutaneous (s.c.) bolus injection, and compared to equivalent doses of glycosylated mammalian-derived CHO-GM-CSF. Each route of administration gave a different GM-CSF concentration-time profile. The highest peak serum concentrations (Cmax) were observed following i.v. bolus injection. After i.v. administration, a two-phase decline in concentration was noted for both types of GM-CSF with a significantly shorter t1/2 alpha of 7.8 minutes for the E. coli GM-CSF versus 20.0 min for the CHO-GM-CSF, while no significant difference was observed for the terminal phase. Following s.c. administration of equivalent doses, a higher peak serum concentration was observed in the E. coli-treated patients and, again, a faster elimination where pretreatment serum levels were reached after 16-20 h, versus more than 48 h after administration of CHO-GM-CSF. Although the non-glycosylated E. coli GM-CSF thus seems to undergo a faster elimination that the glycosylated CHO-GM-CSF no significant difference could be demonstrated in the in vivo effect of corresponding doses of the two compounds with respect to stimulation of granulopoiesis--with reservation for small patient numbers and a large individual variations in response.

Calcitonin is expressed in medullary thyroid carcinomas (MTC). It is processed from a large molecular weight precursor and is flanked at its C-terminal end by a 21 aminoacid peptide (PDN-21) formed in equimolar concentrations to calcitonin by enzymatic cleavage of the prohormone. This investigation compared basal measurements of calcitonin and PDN-21 and the response of the two peptides following pentagastrin stimulation in normal controls and in family members with C-cell hyperplasia or early neoplasia. The results showed that calcitonin and PDN-21 may both be used in family screening for the MEN-2 syndrome, but the unstimulated circulating concentrations of calcitonin were higher and more influenced by C-cell hypersecretion than PDN-21 (P less than 0.01), and the increase in stimulated concentrations of calcitonin were significantly higher than for PDN-21 (P less than 0.01). These findings may be explained by differences with respect to secretion and metabolic clearance rate for the two peptides.

A rat medullary thyroid carcinoma cell line, CA77, was used to study the effect of a series of biosynthesized protease inhibitors on the proteolytic cleavage of the endogenously synthesized pro-CGRP. This cell line efficiently converted the pro-CGRP to mature CGRP as assessed by chromatography of cell extracts followed by radioimmunoassay for CGRP. CA77 cells were transfected with expression vectors encoding protease inhibitors: the Arg-serpins, α 1 -antitrypsin Pittsburgh (358 Met → Arg) and plasminogen activator inhibitor 1, the Kazal type serine protease inhibitor, pancreatic secretory trypsin inhibitor, and the general thiol protease inhibitor, cystatin C. Only the chromatography of cell extracts from CA77 cells transfected with a plasmid encoding cystatin C showed an apparent higher content of unprocessed pro-CGRP as compared to non-transfected cells. No effect on pro-CGRP processing could be measured in the CA77 cells transfected with plasmids encoding the three serine protease inhibitors. CA77 cells were also transfected with two constructs encoding chimeric proteins consisting of cystatin C and the precursor for neuropeptide Y. Release experiments using 8-bromo cAMP as the secretagogue showed that the chimer was co-released with CGRP. However, no effect of this chimer upon pro-CGRP processing could be detected. It is concluded that the processing of pro-CGRP in the CA77 cell line was very efficient and that four different protease inhibitors and two cystatin C/NPY chimers synthesized by this neuroendocrine cell line had only minimal effect upon the processing of CGRP.

Calcitonin gene-related peptide (CGRP), a highly potent vasodilator, is expressed from the calcitonin-gene and has been localized to nerve fibers of the cardiovascular system, suggesting involvement in the physiologic regulation of vascular tone. In this investigation serum concentrations of CGRP were measured in patients with untreated mild to moderate essential hypertension (WHO I-II) and compared with concentrations in sex- and age-matched normal controls to assess a possible relationship between changes in concentrations of CGRP and this condition. The study showed no significant difference in concentrations of CGRP between patients and the normotensive controls. However, a weak but significant positive correlation was found between systolic (SBP), diastolic (DBP), mean blood pressures (MBP), and circulating concentrations of CGRP when calculated for all individuals included in the study. No correlation was found between heart rates (HR) and concentrations of CGRP. In the normotensive control group, but not in patients with hypertension, a significant positive correlation was present between body weights and concentrations of CGRP. These findings do not support the hypothesis that low expression of CGRP plays a causal role in essential hypertension, but the results do not exclude a potential receptor defect for CGRP to be involved in the disease.

The etiology of the hyperkinetic circulatory state in cirrhosis is equivocal and reduced peripheral vascular resistance is a major unsolved problem in hepatic pathophysiology. It is therefore sensible to search for vasodilators. A recently discovered neuropeptide, calcitonin gene-related peptide (CGRP), is a highly potent vasodilator. We determined the circulating concentration of immunoreactive CGRP in different vascular beds in 35 patients with cirrhosis and in eight patients with minor disorders. Plasma CGRP was significantly increased in the cirrhotic patients compared with patients with minor disorders (59 vs. 46 pmol/l, p less than 0.01), as well as with 232 healthy persons (37 pmol/l, p less than 0.0001). Moreover, circulating CGRP increased significantly with the severity of cirrhosis (Child-Turcotte group A, 56; group B, 59; group C, 71 pmol/l; p less than 0.025). No significant arterio-venous net extraction or release of CGRP was found across the hepato-intestinal system, kidney, lung or limb. In conclusion, elevated circulating CGRP may play a role in the haemodynamic derangement of cirrhosis. The lack of organ arterio-venous differences suggests a widespread release and degradation of CGRP in many tissues and gives no evidence of decreased degradation as the cause of increased plasma CGRP in patients with cirrhosis.

P. Hasbak, O. Saetrum Opgaard, K. Eskesen, S. Schifter, H. Arendrup, J. Longmore, and L. Edvinsson Department of Clinical Experimental Research, University Hospital of Copenhagen, Glostrup, Denmark; Department of Clinical Physiology and Nuclear Medicine, University Hospital of Copenhagen, Glostrup, Denmark; Department of Pharmacology, College of Medicine, University of California at Irvine, Irvine, CA; Department of Thoracic Surgery, Rigshospitalet, Copenhagen, Denmark; Merck Sharp & Dohme, Neuroscience Research Centre, Harlow, Essex, U.K.

P. Hasbak, C. Lundby, N.V. Olsen, S. Schifter, and I.L. Kanstrup Department of Clinical Physiology and Nuclear Medicine, University Hospital of Herlev, Herlev; Department of Clinical Physiology and Nuclear Medicine, University Hospital of Glostrup, Glostrup; Department of Clinical Experimental Research, University Hospital of Glostrup, Glostrup; Department of Pharmacology, Panum Institute, University of Copenhagen, Denmark

Creatine kinase (CK-BB), neuron specific enolase (NSE), ACTH, calcitonin, serotonin and gastrin releasing peptide (GRP) were measured in serum or plasma before and immediately after initiation of treatment in patients with small cell lung cancer (SCC). Pretherapeutic elevated concentrations of CK-BB were found in 82% of extensive disease patients and in 50% of patients with local disease. NSE was raised in 72% with extensive disease versus 14% of patients with local disease. Calcitonin and ACTH were raised in 27% and 28%, respectively, in all patients without significant difference between extensive and local disease patients. Serotonin was generally overall elevated in 10% and GRP in 7% but elevations were seen only in patients with extensive disease. Out of the four most frequently elevated substances at least one marker was elevated in 80% of all the patients, including 91% in extensive stage patients and 71% in limited stage patients. Frequent initial monitoring of the substances showed an increase in the concentrations of pretherapeutic elevated CK-BB and NSE on day 1 or 2 followed by a sharp decrease within 1 week. These changes were correlated to objective clinical response determined within 4-8 weeks. The results indicate that serum CK-BB and NSE are potential markers for SCC at the time of diagnosis and that changes in the concentrations during the first course of cytostatic therapy are promising as biochemical tests for early detection of response to chemotherapy.

SUMMARY Calcitonin gene-related peptide (CGRP) is a hormone formed by alternative post-transcriptional processing of the calcitonin gene. It is a neuropeptide localized to discrete regions of the central nervous system (CNS) and in nerve fibres associated with blood vessels. It is also expressed in medullary carcinomas of the thyroid and lung carcinoma cell lines. The latter finding suggests a possible value for CGRP as tumour marker in lung carcinomas. In this investigation of 22 patients undergoing operation for lung tumours, pre and post-operative levels of serum CGRP were measured. Preoperative as well as postoperative serum CGRP levels were significantly elevated when compared to age-matched normals. However, no evidence could be found for CGRP gene expression in tumour tissue from the same patients as judged by immunocyto-chemistry or in-situ hybridization using CGRP cRNA probes. CGRP has been localized to nerve fibres in relation to pulmonary blood vessels and has been shown to be a potent vasodilator. These findings, and the absence of evidence for synthesis in tumours, as opposed to cell lines derived from lung carcinomas, suggests that the lack of post-operative normalization of serum CGRP concentrations may be related to physiological changes in cardiovascular haemodynamics following surgery. Elevated pre-operative serum CGRP levels may also reflect a consequence of the lung carcinoma leading to increased release of CGRP from sites in the vasculature yet to be determined, but does not indicate synthesis de novo and secretion of CGRP by the tumours.

This investigation deals with the potential additional value of serum CGRP measurements as compared to calcitonin in screening for medullary carcinoma of the thyroid (MTC) in families with multiple endocrine neoplasia type 2 (MEN 2). Basal as well as pentagastrin-stimulated values for CGRP are evaluated in relation to the corresponding levels for calcitonin. Serum CGRP is within normal range in most family members with pathological calcitonin response to the pentagastrin stimulation test. Furthermore, these potentially affected family members do not respond to the pentagastrin stimulation test with an increase in CGRP. Pentagastrin stimulation tests performed in patients with manifest MTC affect the serum CGRP levels inconstantly and in two patients, with elevated basal level of CGRP, stimulation caused a release of calcitonin while concentrations of CGRP remained unaffected. We conclude that determination of serum CGRP adds no information to that of serum calcitonin in MEN 2 family screening for MTC.

The study comprises 74 patients alive 30 days after the start of treatment of pulmonary embolism with heparin (n = 32), streptokinase (n = 22) or embolectomy (n = 20). The cumulative 5-year survival was 100% in the embolectomy group, compared to 75 +/- 7% (SE) in the medically treated patients (p less than 0.05). Cancer caused 78% of the late deaths. At follow-up 0.5-8.7 years after treatment the treatment groups were indistinguishable as regards right-sided heart catheterization data, pulmonary artery rest-obstruction, right ventricular diameter and wall thickness, ventilatory function and ECG changes. The embolectomized patients were in a more favourable NYHA classification level than the medically treated. Chronic pulmonary artery hypertension was found in 75% of patients with greater than or equal to 3 anamnestic recurrent embolic episodes before diagnosis compared to 8% of patients with less than or equal to 2 recurrent episodes (p less than 0.001). Patients with irreversible cardiocirculatory shock before embolectomy all had abnormal pulmonary vascular resistance (greater than 1.5 mmHg/l/min), depressed ventilatory function and more than 25% reduced pulmonary perfusion at follow-up. The major prognostic factors thus were cancer, the number of recurrent episodes and the degree of cardiocirculatory affection in the acute event. Although the embolectomized patients were the most affected initially, they had a good prognosis. This led us to extend our indications for embolectomy to include all patients with central emboli, irrespective of the degree of cardiocirculatory impairment.

Retinoblastoma is found in a hereditary and nonhereditary form. Long survivors treated for the hereditary form seem to be predisposed for developing a second primary tumor later in life. The retinoblastoma genes are supposed to be responsible for this disposition. This report describes the development of a Ewing's tumor in a nine-year-old girl, who had both eyes removed in early life for retinoblastoma.