Three-dimensional simulation of aesthetic outcome from breast-conserving surgery compared with viewing photographs or standard care: randomized clinical trial.

INTRODUCTION: Over half of women with surgically managed breast cancer in the UK undergo breast-conserving treatment (BCT). While photographs are shown prior to reconstructive surgery or complex oncoplastic procedures, standard practice prior to breast conservation is to simply describe the likely aesthetic changes. Patients have expressed the desire for more personalized information about likely appearance after surgery. The hypothesis was that viewing a three-dimensional (3D) simulation improves patients' confidence in knowing their likely aesthetic outcome after surgery. METHODS: A randomized, controlled trial of 117 women planning unilateral BCT was undertaken. The randomization was three-way: standard of care (verbal description alone, control group), viewing two-dimensional (2D) photographs, or viewing a 3D simulation before surgery. The primary endpoint was the comparison between groups' median answer on a visual analogue scale (VAS) for the question administered before surgery: 'How confident are you that you know how your breasts are likely to look after treatment?' RESULTS: The median VAS in the control group was 5.2 (i.q.r. 2.6-7.8); 8.0 (i.q.r. 5.7-8.7) for 2D photography, and 8.9 (i.q.r. 8.2-9.5) for 3D simulation. There was a significant difference between groups (P < 0.010) with post-hoc pairwise comparisons demonstrating a statistically significant difference between 3D simulation and both standard care and viewing 2D photographs (P < 0.010 and P = 0.012, respectively). CONCLUSION: This RCT has demonstrated that women who viewed an individualized 3D simulation of likely aesthetic outcome for BCT were more confident going into surgery than those who received standard care or who were shown 2D photographs of other women. The impact on longer-term satisfaction with outcome remains to be determined.Registration number: NCT03250260 (http://www.clinicaltrials.gov).

Most women with breast cancer are able to have an operation to remove the cancer while preserving the breast ('lumpectomy'). Whilst cancer control is the most important goal, appearance after surgery has been shown to affect long-term quality of life and is considered when planning treatment. Currently, surgeons simply describe the likely changes in appearance and, for more complex procedures, photographs of other women are shown. Patients themselves have indicated they would like more information regarding the likely changes to their breast after treatment. The authors have developed a way to simulate appearance following lumpectomy and radiotherapy using three-dimensional (3D) photographs. The study invited women undergoing lumpectomy to be assigned at random to one of three groups receiving standard care (discussion), a two-dimensional photograph, or the 3D simulation before their operation. The authors have demonstrated that showing a woman her simulation prior to surgery improves confidence going into treatment.

Identification of a novel mutation in the autoimmune regulator (AIRE-1) gene in a French family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is clinically characterized by the presence of two of the three major clinical symptoms: Addison's disease and/or hypoparathyroidism and/or chronic mucocutaneous candidiasis. Because of its autosomal recessive inheritance, this rare disorder constitutes an interesting model for understanding the molecular background of autoimmunity. Recently, mutations in the autoimmune regulator (AIRE-1) gene have been identified in APECED patients. Here we report, in a large French APECED family, the identification of a novel AIRE-1 missense mutation (Pro326Leu) in association with the Arg257Stop mutation which is detected in more than 80% of mutant Finnish AIRE-1 alleles. This Pro326Leu substitution occurs in the first plant homeodomain (PHD)-type zinc-finger domain of the protein which has been identified in a number of nuclear proteins involved in chromatin-mediated transcriptional regulation, such as ATRX, TIF1, KRIP-1 and Mi-2 autoantigen. This mutation highlights the key role of this amino acid in the structure of the PHD domain and confirms that exon 8 constitutes a mutational hotspot.

Effect of the serotonin 5-HT4 receptor agonist cisapride on aldosterone secretion in corticotropic insufficiency and primary hyperaldosteronism.

Serotonin (5-HT) stimulates aldosterone secretion in man through activation of 5-HT4 receptors coupled to adenylyl cyclase via a Gs regulatory protein. In adrenocortical cells, the levels of expression of the Gs protein and ACTH receptor are decreased when the cells are deprived of ACTH and angiotensin II (ANG II). In order to examine the possible influence of ACTH and ANG II on the responsiveness of human glomerulosa cells to 5-HT, we have investigated the effect of cisapride, a 5-HT4 receptor agonist, on plasma aldosterone in patients with suppressed plasma ACTH, i.e. patients with corticotropic insufficiency (CI), and in patients with suppressed renin-ANG II activity, i.e. patients with primary hyperaldosteronism (PH) including both aldosterone-producing adenoma and idiopathic hyperaldosteronism. After 2 h of recumbency, all patients received a single oral dose of 10 mg cisapride. In the CI group, cisapride induced a 5-fold increase in plasma aldosterone levels without any modification of plasma renin, potassium or cortisol levels. Combined administration of cisapride and ACTH caused an increase in plasma aldosterone similar to that produced by ACTH alone. In the PH group, cisapride was still able to cause a 3.6-fold increase in plasma aldosterone levels while renin remained suppressed throughout the study. Taken together, these data show that cisapride stimulates aldosterone secretion in CI and PH patients, indicating that prolonged suppression of plasma ACTH or renin-ANG II activity does not affect the sensitivity of glomerulosa cells to 5-HT. The present study also demonstrates that the stimulatory effects of 5-HT and ACTH on aldosterone secretion are not additive.

Acro-oto-ocular syndrome: further evidence for a new autosomal recessive disorder.

We report on a patient born to consanguineous parents and presenting with pseudopapilledema, mixed hearing loss, and minor facial and limb anomalies. To our knowledge, there is just one similar description of this syndrome in three members of a Brazilian kindred whose parents were also consanguineous, suggesting autosomal recessive inheritance. We compare the findings of our patient with these previous reported cases and discuss the differential diagnoses of this new syndrome, which we suggest be named the acro-oto-ocular syndrome.

Renal tubular damage: an extraintestinal manifestation of chronic inflammatory bowel disease.

OBJECTIVE: To investigate whether treatment of inflammatory bowel disease (IBD) with 5-aminosalicylate or sulphasalazine in IBD may induce renal tubular damage. DESIGN AND METHODS: The urinary enzymes beta-N-acetyl-D-glucosaminidase ( beta-NAG), dipeptidylpeptidase 4 (DPP4) and alanine aminopeptidase (AAP) were measured as markers of renal tubular damage in 104 consecutive patients with Crohn's disease and in 43 consecutive patients with ulcerative colitis (all with normal serum creatinine values). Control values were gained from 65 healthy persons. RESULTS: The normal values (mean +/- SD) for the urinary enzymes investigated (U/g creatinine in the urine) were: DPP4 4.5 +/- 2.2, beta-NAG 1.6 +/- 1.4, AAP 11.4 +/- 6.5. In 28% of the patients with ulcerative colitis elevated beta-NAG levels of more than the mean + 2 x SD were measured. This pathological enzymuria was nearly exclusively found in patients with active disease (CAI > 6): DPP4 15.6 +/- 25.3, beta-NAG 8.3 +/- 10.1, AAP 24.7 +/- 50.1 (all three enzymes were significantly elevated). The highest values were measured in patients with active ulcerative colitis before start of therapy. Nineteen per cent of the patients with Crohn's disease had elevated beta-NAG levels of more than the mean + 2 x SD. There was no significant difference in enzymuria between patients with active (CDAI > 150) and patients with inactive Crohn's disease (CDAI < or = 150). DPP4 and AAP were normal in both groups. A correlation between the enzymuria and the cumulative doses of 5-aminosalicylic acid, sulphasalazine or prednisolone could not be found. The courses of enzymuria in three patients who presented with the first severe manifestation of IBD are described. They were treated with either corticosteroids and 5-aminosalicylic acid or corticosteroids and sulphasalazine. Before onset of therapy, very high urine enzyme values were measured. They almost normalized in the course of successful medical therapy despite increasing cumulative doses of 5-aminosalicylic acid or sulphasalazine. CONCLUSIONS: Renal tubular damage can frequently be observed in IBD. Our results suggest that this is an extraintestinal manifestation of the disease and not a toxic side-effect of anti-inflammatory therapy using 5-aminosalicylic acid or sulphasalazine.

Lack of effect of the serotonin4 receptor agonist zacopride on ACTH secretion in normal men.

OBJECTIVE: In the present study, we investigated the effect of zacopride on corticotropin (ACTH) and cortisol secretion in healthy volunteers. Male subjects received a single oral dose of placebo, 10 micrograms zaco-pride or 400 micrograms zacopride. Plasma ACTH, cortisol and aldosterone concentrations were measured before and during the 3 h following the administration of the drug. RESULTS: For none of the doses did zacopride cause any modification of plasma ACTH or cortisol levels. In contrast, administration of 400 micrograms zacopride induced a significant increase in plasma aldosterone levels. CONCLUSION: Our results indicate that in humans serotonin-evoked stimulation of ACTH secretion is not mediated through serotonin4 (5-HT4) receptors. Together with previous findings, these data indicate that the stimulatory effect of 5-HT4 receptor agonists on aldosterone secretion in man can be ascribed solely to a direct action on glomerulosa cells.

The serotonin-4 receptor agonist cisapride and angiotensin-II exert additive effects on aldosterone secretion in normal man.

In animals and man, serotonin (5-HT) exerts a direct stimulatory action on adrenocortical cells through activation of 5-HT4 receptors. In rats, 5-HT also potentiates the stimulatory effect of angiotensin-II (Ang II) on aldosterone secretion. The aim of the present study was to investigate the effect of concomitant administration of the 5-HT4 receptor agonist, cisapride, and Ang II on aldosterone secretion in normal human subjects. Eight healthy male volunteers pretreated with dexamethasone received, at 1-week intervals in random order and simple blind fashion, the following treatments: 1) a single oral dose of 10 mg cisapride, 2) a single oral dose of placebo, 3) a perfusion of graded doses of Ang II (from 1-4 ng/kg.min), 4) a perfusion of placebo, and 5) a single oral dose of 10 mg cisapride associated with a perfusion of Ang II. The oral doses of cisapride and placebo were also administered after a 3-day period of a low sodium diet (10 mmol/day). Plasma aldosterone levels increased significantly within 90 min after the administration of cisapride without any change in renin levels. The comparison between the net increase in aldosterone production induced by cisapride, Ang II, and cisapride plus Ang II showed that the stimulatory effects of cisapride and Ang II on aldosterone secretion were only additive. Similarly, the increase in plasma aldosterone levels induced by a sodium-restricted diet was just additive with the cisapride-evoked stimulation of aldosterone secretion. These results provide further evidence that the action of 5-HT on glomerulosa cells is mediated through activation of 5-HT4 receptors. The data also indicate that in humans, 5-HT does not potentiate the stimulatory effect of Ang II on aldosterone secretion.

Pseudo-phaeochromocytoma after multiple drug interactions involving the selective monoamine oxidase inhibitor selegiline.

A patient presented with paroxysmal hypertension and typical clinical features of phaeochromocytoma, but with a normal adrenal computed tomographic scan and much higher plasma noradrenaline than adrenaline concentrations. Urinary vanillylmandelic acid concentrations were only moderately elevated. This syndrome probably arose as a consequence of an interaction between the monoamine oxidase inhibitor selegiline, the sympathomimetic agent ephedrine, and a tricyclic antidepressant. The mechanism of the interaction is thought to be related to increased sympathetic release of noradrenaline by ephedrine, inhibition of catabolism by selegiline, and inhibition of reuptake of noradrenaline by the tricyclic. Although newer selective monoamine oxidase inhibitors are considered to be safer than earlier non-selective inhibitors, they can also contribute to drug interactions mimicking phaeochromocytoma.

Effect of the serotonin-4 receptor agonist zacopride on aldosterone secretion from the human adrenal cortex: in vivo and in vitro studies.

We have recently shown that serotonin (5-HT) stimulates cortisol secretion from human adrenocortical tissue in vitro through activation of 5-HT4 receptors. The aim of the present study was to investigate the effect of the 5-HT4 agonist racemic zacopride on aldosterone secretion from the human adrenal gland in vivo and in vitro. In vivo studies were conducted on 28 healthy volunteers pretreated with dexamethasone. The subjects received a single oral dose of placebo, 10 micrograms zacopride, or 400 micrograms zacopride. Plasma aldosterone levels increased significantly within 90 min after the administration of 400 micrograms zacopride, remained elevated for 60 min, and gradually returned to the baseline within 180 min. In contrast, the administration of 10 micrograms zacopride or placebo did not modify the aldosterone concentration. No significant changes were observed in renin, ACTH, or cortisol levels. In vitro studies were conducted on perifused human adrenocortical slices. Administration of 20-min pulses of zacopride (from 10(-11) - 10(-6) mol/L) induced a dose-dependent increase in aldosterone secretion. The minimal effective dose was 10(-10) mol/L, and half-maximal stimulation was obtained with a dose of 7 x 10(-8) mol/L. Zacopride was 100 times more potent in stimulating aldosterone than cortisol release. Taken together, the present data suggest that 5-HT-evoked aldosterone secretion involves the activation of 5-HT4 receptors.

Effects of the new somatostatin analogue (BIM 23014) on blood glucose homeostasis in normal men.

Changes in blood glucose homeostasis induced by the new somatostatin analogue BIM 23014 (BIM) were studied. Eight normal men (study 1) received either vehicle or 1000, 2000 and 3000 micrograms BIM as a 24 h s.c. infusion. Blood glucose, plasma insulin, C-peptide, glucagon and growth hormone (GH) were measured before treatment and then hourly for 24 h. In five normal men (study 2) an oral glucose tolerance test (OGTT) was performed during vehicle infusion and then on days 1 and 7 of a continuous s.c. infusion of 2000 micrograms BIM daily for 7 days. The same biological parameters as in study 1 were measured before OGTT and then twice-hourly for 5 h. Dose-dependent and transient glucose intolerance was observed in the first half of study 1. Except for glucagon, BIM significantly (P < 0.01) reduced plasma insulin, C-peptide and GH levels. In study 2 BIM infusion induced glucose intolerance and a drop in plasma insulin and C-peptide on day 1 which disappeared on day 7 of infusion. Higher on day 7 than on day 1, plasma GH secretion was significantly (P < 0.01) reduced throughout BIM infusion. In contrast plasma glucagon levels were not modified at any time. Side-effects were abdominal cramps and diarrhoea which were observed in most subjects when increasing BIM daily dose. In conclusion, BIM infusion induced transient changes in glucose homeostasis and insulin secretion in normal men. By contrast, plasma GH levels remained reduced throughout the treatment. BIM appears to be a useful tool to selectively inhibit GH secretion.

Serotonin-induced stimulation of cortisol secretion from human adrenocortical tissue is mediated through activation of a serotonin4 receptor subtype.

The occurrence of serotonin in the human adrenal gland was demonstrated both by immuno-histochemical and biochemical approaches. Using specific polyclonal antibodies to serotonin, the presence of numerous immunoreactive cells was revealed by means of the peroxidase-antiperoxidase technique. These cells exhibited the morphological characteristics of mast cells. Combination of high performance liquid chromatography and electrochemical detection showed the presence of substantial amounts of both serotonin and its metabolite 5-hydroxyindolacetic acid in adrenocortical extracts. The role of serotonin in the regulation of steroidogenesis from human adrenocortical slices was studied in vitro using a perifusion system technique coupled to a specific radioimmunoassay for cortisol. Graded doses of serotonin (from 10(-8) M to 3 x 10(-7) M) increased cortisol production in a dose-dependent manner. Prolonged exposure of adrenal fragments to serotonin (10(-7) M) induced a biphasic response, i.e. a rapid and transient increase in cortisol secretion followed by a plateau phase, suggesting the existence of a desensitization phenomenon. The stimulatory effect of serotonin (10(-7) M) was not altered during infusion of the serotonin1 and/or serotonin2 receptor antagonists methysergide (10(-6) M) and ketanserin (10(-6) M), respectively. In contrast, ICS 205 930 (10(-6) M), a non-selective serotonin3/serotonin4 antagonist, totally abolished the response of adrenal slices to serotonin (10(-7) M). The benzamide derivative zacopride, considered as a serotonin4 agonist, induced a robust stimulation of cortisol secretion. In addition, the corticotropic effects of serotonin (10(-7) M) and zacopride (10(-6) M) were not additive. Incubation of adrenocortical fragments with zacopride (10(-6) M) or serotonin (10(-6) M) caused a significant increase in cAMP formation. Taken together, these data suggest that serotonin, locally released by intra-adrenal mast-like cells, may act as a paracrine factor to stimulate cortisol secretion in man. Our results also indicate that serotonin-induced corticosteroid production is mediated through activation of a serotonin4 receptor subtype positively coupled to adenylate cyclase.

[Hypoglycemia induced by cibenzoline in the elderly]. / Hypoglycémie induite par la cibenzoline chez le sujet âgé.

Hypoglycaemia induced by class IA antiarrhythmic agents has been described. A case of cibenzoline-induced hypoglycaemia with favourable outcome is reported. The patient's age (84 years), increased renal impairment and malnutrition acted as facilitating factors. Blood insulin levels were normal in both absolute and relative values. Therapeutic overdosage in relation to age and renal function has been found in 20 out of 24 cases published or recorded by the French pharmacovigilance system. The mechanism of this hypoglycaemia is uncertain; absolute or relative hyperinsulinism has been detected in only 5 out of 14 controlled cases.

[Dynamics of gonadotropin secretion in oligospermia with isolated elevation of follicle stimulating hormone (FSH)]. / Dynamique de la sécrétion gonadotrope dans les oligospermies à FSH isolément élevée.

The mechanism of oligospermia with high level of follicle stimulating hormone (FSH) and normal levels of luteinizing hormone (LH) and testosterone is subject to controversy: pituitary origin with slowing down of LH pulses, or primary gonadal deficiency? We studied 23 men presenting with this hormonal profile. Compared with a control population, these men had decreased mean testosteronaemia, increased mean LH level, both at baseline and under LHRH, and increased area under the LH pulsatility curve. A positive correlation was found between LH and FSH plasma levels. These data are in favour of a primary gonadal deficiency, and we therefore expected to find an increased frequency and amplitude of LH pulses. In fact, the frequency was normal and the amplitude increased in one half of these men, while the frequency was reduced and the amplitude also increased in the other half. There was no difference in plasma FSH levels between these two groups. Pulsed administration of LHRH restored physiological stimulation, but it did not result in normalisation of the FSH/LH ratio and cannot be regarded as a suitable treatment. It would therefore seem that the mechanism of oligospermia with isolated high FSH level is an abnormal feedback of gonadal peptides and steroids.