Search

Background Many Eastern reports attempted to identify predictive variables for esophago-jejunal anastomosis leakage (EJAL) after total gastrectomy for cancer. There are no definitive answers about reliable risk factors for EJAL. This retrospective study shows the largest Western series focused on this topic. Methods This is a multicenter retrospective study analyzing patients’ datasets collected by 18 Italian referral Centres of the Italian Research Group for Gastric Cancer (GIRCG) from 2000 to 2018. The inclusion criteria were pathological diagnosis of gastric and esophageal (Siewert III) carcinoma requiring total gastrectomy. The primary end point of risk analysis was the occurrence of EJAL; secondary end points were post-operative (30-day) morbidity and mortality, length of stay (LoS), and survival. Results Data of 1 750 patients submitted to total gastrectomy were collected. EJAL developed in 116 (6.6%) patients and represented the 26.3% of all the 441 observed post-operative surgical complications. EJAL diagnosis was followed by a reoperation in 39 (33.6%) patients and by an endoscopic/radiological procedure in 30 cases (25.9%). In 47 patients (40.5%) EJAL was managed with conservative approach. Post-operative LoS and mortality were significantly higher after EJAL occurrence (27 days versus 12 days and 8.6% versus 1.6%, respectively). At risk analysis, comorbidities (particularly, if respiratory), minimally invasive surgery, extended lymphadenectomy, and anastomotic technique resulted significant predictive factors for EJAL. EJAL did not significantly affect survival. Conclusions These results were consistent with Asian experiences: the frequency of EJAL and its higher rate observed in patients with comorbidities or after minimally invasive approach were confirmed.

Background. In 2014, the Italian Consensus for Classification and Reporting of Thyroid Cytology (ICCRTC) reviewed the previous cytological classification proposed in 2007 including the subdivision of TIR 3 category into low risk (TIR 3A) and high risk (TIR 3B). In Italian literature, different rates of malignancy have been correlated to these subcategories. Objectives. The aim of the study is to present our experience on this subclassification for the assessment of the malignancy risk of indeterminate thyroid nodules. We correlated the subdivision into TIR 3A and TIR 3B with the histological report by highlighting the rates of malignancy detected in the two subcategories. On the one hand, we aimed to check if the groups are associated with a real and significant difference risk of malignancy. On the other hand, we evaluated the use of this subdivision in the choice of the appropriate treatment. Study Design. This is a retrospective review of all the patients with an indeterminate nodule who underwent US-FNA and had surgery at ASL Città di Torino between January 2005 and May 2018. Results. 150 patients have been analyzed for the research; 62 (41.3%) had a malignant histological report. Rates of malignancy between TIR 3A (20.8%) and TIR 3B (60.3%) were significantly different (p<0.0001). The subclassification had high sensitivity (75.8%; CI 63.3–85.8%) and NPV (79.3%; CI 68–87.8%) and low specificity (64.8%; CI 53.9–74.7%) and PPV (60.3; CI 48.5–71.2%). The measurement of the accuracy (AUC = 0.7) classified the test as “moderately accurate.” Conclusions. Obtained data show a great rate of false negative (20.8%) and limited AUC (0.7). According to our logistic regression, we argue that the 2014 subclassification into TIR 3A and TIR 3B should be considered for the choice of patient treatment, but at the same time, we believe that the association with other screening tests is necessary to increase the accuracy in the future.

Background Ceftazidime-avibactam (CAZ-AVI) has been approved in Europe for the treatment of complicated intra-abdominal and urinary tract infections, as well as hospital-acquired pneumonia, and for gram-negative infections with limited treatment options. CAZ-AVI displays in vitro activity against Klebsiella pneumoniae carbapenemase (KPC) enzyme producers, but clinical trial data on its efficacy in this setting are lacking. Methods We retrospectively reviewed 138 cases of infections caused by KPC-producing K. pneumoniae (KPC-Kp) in adults who received CAZ-AVI in compassionate-use programs in Italy. Case features and outcomes were analyzed, and survival was then specifically explored in the large subcohort whose infections were bacteremic. Results The 138 patients started CAZ-AVI salvage therapy after a first-line treatment (median, 7 days) with other antimicrobials. CAZ-AVI was administered with at least 1 other active antibiotic in 109 (78.9%) cases. Thirty days after infection onset, 47 (34.1%) of the 138 patients had died. Thirty-day mortality among the 104 patients with bacteremic KPC-Kp infections was significantly lower than that of a matched cohort whose KPC-Kp bacteremia had been treated with drugs other than CAZ-AVI (36.5% vs 55.8%, P = .005). Multivariate analysis of the 208 cases of KPC-Kp bacteremia identified septic shock, neutropenia, Charlson comorbidity index ≥3, and recent mechanical ventilation as independent predictors of mortality, whereas receipt of CAZ-AVI was the sole independent predictor of survival. Conclusions CAZ-AVI appears to be a promising drug for treatment of severe KPC-Kp infections, especially those involving bacteremia.

Over the last two decades, a solid consensus grew in the scientific community that the so-called Citizen Science could contribute to advancing our current knowledge in many disciplines. In particular Hydro-Meteorological (HM) researchers immediately pointed out to the countless advantages of cooperating with Citizen Scientists. In this paper we present the experience made during the Distributed Research Infrastructure for Hydro- Meteorology (DRIHM) project for supporting citizen scientists involvement. The paper describes the different roles participants can assume, based on their capabilities in using and extending the DRIHM virtual collaborative platform and specifically giving a case for identifying and integrating citizen scientists. The major achievement is represented by the possibility for citizen scientists to execute actual simulations using real forecasting models and computational platforms. This can represent a first step for the dissemination of the right culture of the HM risk among the population and to enforce the involvement of citizen scientists in HM data processing and analysis tasks.

Background: Some trial have demonstrated a benefit of adjuvant fluoropirimidine with or without platinum compounds compared with surgery alone. ITACA-S study was designed to evaluate whether a sequential treatment of FOLFIRI [irinotecan plus 5-fluorouracil/folinic acid (5-FU/LV)] followed by docetaxel plus cisplatin improves disease-free survival in comparison with 5-FU/LV in patients with radically resected gastric cancer. Patients and methods: Patients with resectable adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to either FOLFIRI (irinotecan 180 mg/m 2 day 1, LV 100 mg/m 2 as 2 h infusion and 5-FU 400 mg/m 2 as bolus, days 1 and 2 followed by 600 mg/m 2 /day as 22 h continuous infusion, q14 for four cycles) followed by docetaxel 75 mg/m 2 day 1, cisplatin 75 mg/m 2 day 1, q21 for three cycles (sequential arm) or De Gramont regimen (5-FU/LV arm). Results: From February 2005 to August 2009, 1106 patients were enrolled, and 1100 included in the analysis: 562 in the sequential arm and 538 in the 5-FU/LV arm. With a median follow-up of 57.4 months, 581 patients recurred or died (297 sequential arm and 284 5-FU/LV arm), and 483 died (243 and 240, respectively). No statistically significant difference was detected for both disease-free [hazard ratio (HR) 1.00; 95% confidence interval (CI): 0.85–1.17; P= 0.974] and overall survival (OS) (HR 0.98; 95% CI: 0.82–1.18; P= 0.865). Five-year disease-free and OS rates were 44.6% and 44.6%, 51.0% and 50.6% in the sequential and 5-FU/LV arm, respectively. Conclusions: A more intensive regimen failed to show any benefit in disease-free and OS versus monotherapy. Clinical trial registration: ClinicalTrials.gov Identifier: NCT01640782.

The Collective Article 'New Mediterranean Biodiversity Records' of the Mediterranean Marine Science journal offers the means to publish biodiversity records in the Mediterranean Sea. The current article is divided in two parts, for records of alien and native species respectively. The new records of alien species include: the red alga Asparagopsis taxiformis (Crete and Lakonikos Gulf, Greece); the red alga Grateloupia turuturu (along the Israeli Mediterranean shore); the mantis shrimp Clorida albolitura (Gulf of Antalya, Turkey); the mud crab Dyspanopeus sayi (Mar Piccolo of Taranto, Ionian Sea); the blue crab Callinectes sapidus (Chios Island, Greece); the isopod Paracerceis sculpta (northern Aegean Sea, Greece); the sea urchin Diadema setosum (Gökova Bay, Turkey); the molluscs Smaragdia souverbiana, Murex forskoehlii, Fusinus verrucosus, Circenita callipyga, and Aplysia dactylomela (Syria); the cephalaspidean mollusc Haminoea cyanomarginata (Baia di Puolo, Massa Lubrense, Campania, southern Italy); the topmouth gudgeon Pseudorasbora parva (Civitavecchia, Tyrrhenian Sea); the fangtooth moray Enchelycore anatina (Plemmirio marine reserve, Sicily); the silver-cheeked toadfish Lagocephalus sceleratus (Saros Bay, Turkey; and Ibiza channel, Spain); the Indo-Pacific ascidian Herdmania momus in Kastelorizo Island (Greece); and the foraminiferal Clavulina multicamerata (Saronikos Gulf, Greece). The record of L. sceleratus in Spain consists the deepest (350-400m depth) record of the species in the Mediterranean Sea. The new records of native species include: first record of the ctenophore Cestum veneris in Turkish marine waters; the presence of Holothuria tubulosa and Holothuria polii in the Bay of Igoumenitsa (Greece); the first recorded sighting of the bull ray Pteromylaeus bovinus in Maltese waters; and a new record of the fish Lobotes surinamensis from Maliakos Gulf.

Background Homeobox genes are a superclass of transcription factors with diverse developmental regulatory functions, which are found in plants, fungi and animals. In animals, several Antennapedia (ANTP)-class homeobox genes reside in extremely ancient gene clusters (for example, the Hox, ParaHox, and NKL clusters) and the evolution of these clusters has been implicated in the morphological diversification of animal bodyplans. By contrast, similarly ancient gene clusters have not been reported among the other classes of homeobox genes (that is, the LIM, POU, PRD and SIX classes). Results Using a combination of in silico queries and phylogenetic analyses, we found that a cluster of three PRD-class homeobox genes (Homeobrain (hbn), Rax (rx) and Orthopedia (otp)) is present in cnidarians, insects and mollusks (a partial cluster comprising hbn and rx is present in the placozoan Trichoplax adhaerens). We failed to identify this 'HRO' cluster in deuterostomes; in fact, the Homeobrain gene appears to be missing from the chordate genomes we examined, although it is present in hemichordates and echinoderms. To illuminate the ancestral organization and function of this ancient cluster, we mapped the constituent genes against the assembled genome of a model cnidarian, the sea anemone Nematostella vectensis, and characterized their spatiotemporal expression using in situ hybridization. In N. vectensis, these genes reside in a span of 33 kb with the same gene order as previously reported in insects. Comparisons of genomic sequences and expressed sequence tags revealed the presence of alternative transcripts of Nv-otp and two highly unusual protein-coding polymorphisms in the terminal helix of the Nv-rx homeodomain. A population genetic survey revealed the Rx polymorphisms to be widespread in natural populations. During larval development, all three genes are expressed in the ectoderm, in non-overlapping territories along the oral-aboral axis, with distinct temporal expression. Conclusion We report the first evidence for a PRD-class homeobox cluster that appears to have been conserved since the time of the cnidarian-bilaterian ancestor, and possibly even earlier, given the presence of a partial cluster in the placozoan Trichoplax. Very similar clusters comprising these three genes exist in Nematostella and diverse protostomes. Interestingly, in chordates, one member of the ancestral cluster (homeobrain) has apparently been lost, and there is no linkage between rx and orthopedia in any of the vertebrates. In Nematostella, the spatial expression of these three genes along the body column is not colinear with their physical order in the cluster but the temporal expression is, therefore, using the terminology that has been applied to the Hox cluster genes, the HRO cluster would appear to exhibit temporal but not spatial colinearity. It remains to be seen whether the mechanisms responsible for the evolutionary conservation of the HRO cluster are the same mechanisms responsible for cohesion of the Hox cluster and other ANTP-class homeobox clusters that have been widely conserved throughout animal evolution.

Sex and age are the major determinants of serum levels of dehydroepiandrosterone sulfate (DHEA-S): they are about twice in men than in women and show a progressive reduction from the end of the puberty to aging in both sexes. It has been reported that DHEA-S levels are also negatively influenced by insulin. Moreover, DHEA-S levels reduction has been associated to increased risk for cardiovascular disease, which connotes hyperinsulinemic states, such as obesity. We have evaluated serum levels of DHEA-S and insulin as function of age and body mass index (BMI) in 376 adult women (age 18.1–89.6 yrs, median 42.2; BMI 15.7–57.8 kg/m2, median 32.7) by multiple regression and piecewise regression analysis. Insulin levels positively associated to BMI (p=0.000002) and DHEA-S levels negatively associated with age (p=0.000001). Considering the whole population, DHEA-S levels were related positively with BMI (p=0.0013) independently of age. DHEA-S were also directly related to insulin levels independently of age (p=0.042), but this association disappeared after correction for BMI. Piecewise regression analysis did not reveal a threshold level for the increase of BMI (p=0.0004). Interestingly, DHEA-S levels and BMI were positively associated before but not after menopause. Taking into account only obese population, (no.=143, age 18.7w–67.3 yrs, mean 39.0, median 39.4) DHEA-S levels were again related negatively with age and positively with BMI, while were unrelated with waist to hip ratio (p=0.391). Our data show that increasing body mass and insulin secretion is not associated to DHEA-S reduction in women. This evidence suggests that DHEA-S is unlikely implicated in the pathogenesis of cardiovascular disease in obese women.

Rare cases of myelolipomas associated with adrenocortical lesions responsible for Cushing or Conn syndromes have been described. We report two additional cases of extensive lipomatous changes in incidentally discovered adrenocortical adenomas, which were preoperatively interpreted as myelolipomas on the basis of radiologic findings. Microscopically, the adenomas were composed of sheets and nests of adrenocortical cells, and extensive areas of mature adipose tissue admixed with a bland stromal infiltration of small cells. The impression was that myeloid cells were present, featuring a myelolipoma associated with a clear cell adenoma of the adrenal cortex, but specific immunocytochemical markers of myeloid lineage were not reactive in the small cell component, and these cells consisted of small lymphocytes. The lipomatous tissue may represent a degenerative phenomena within an adrenocortical adenoma or may be an additional neoplastic component of the tumor. Irrespective of their origin, extensive (myelo)lipomatous changes in adrenocortical tumors can lead to misinterpretations in the preoperative work-up of patients with adrenal masses.

Mazza E, Goffi S, Barchi P, Arvat E, Bellone J, Limone P, Ghigo E, Camanni F. Enhanced adrenocorticotrophic hormone and cortisol responses to corticotrophin-releasing hormone in central idiopathic diabetes insipidus. Eur J Endocrinol 1994;130:121–4. ISSN 0804–4643 It is well known that arginine vasopressin (AVP) exerts a stimulatory effect on adrenocorticotrophic hormone (ACTH) secretion. Moreover, there is consistent evidence that the hypothalamic AVP-secreting neurons are involved in the neuroregulation of ACTH secretion. With the aim to throw further light on the interaction between AVP and corticotrophin-releasing hormone (CRH) in the neuroregulation of ACTH secretion, in this study we compared the ACTH and cortisol responses to human CRH (100 μg iv as a bolus) in 18 normal subjects (15 females and three males, age 22–35 years) and seven patients with central isolated diabetes insipidus (six females and one male, age 16–40 years). Two patients were newly diagnosed and five had discontinued substitution therapy with desamino-D-AVP 24 h before testing. All had free access to water before and during the test period. The ACTH and cortisol responses to CRH were higher in subjects with diabetes insipidus than in controls, either when evaluated as peak values (ACTH, mean±sem: 17.0±1.2 vs 7.7±0.7 pmol/l, p=0.0003; cortisol: 611.3±59.4 vs 450.7±21.2 nmol/l, p=0.01) or area under curve values (ACTH: 672.5±75.7 vs 364.0±33.6 pmol·1−1·h−1. p=0.002; cortisol: 29158.0±2937.0 vs 23236.7±1052.1 nmol·l−1 · h−1, p=0.03). These results show that patients with diabetes insipidus have an exaggerated pituitary-adrenal response to CRH. This may be due to the fact that in diabetes insipidus AVP secretion from parvocellular neurons of the paraventricular nucleus in the hypophysial portal system is not impaired. Alternatively, AVP secretion may be defective in both magnocellular and parvocellular hypothalamic AVP-secreting neurons. In this case, it could be hypothesized that adjustment is made to the feedback regulatory mechanisms of the hypothalamic–pituitary–adrenal axis, so that the CRH–ACTH axis assumes a main role with respect to the AVP–ACTH axis. Franco Camanni, Divisione di Endocrinologia, Ospedale Molinette, corso Dogliotti 14, 10126 Torino. Italy

Cholinergic pathways in the central nervous system positively influence growth hormone (GH) secretion. In fact pyridostigmine, a cholinesterase inhibitor, enhances both basal and GH-releasing hormone (GHRH)-induced GH secretion while, conversely, pirenzepine, an antagonist of muscarinic M 1 receptors, inhibits the GH response to GHRH and to other physiological and pharmacological stimuli. The effect of the cholinergic system on GH secretion probably takes place via inhibition of the release of endogenous somatostatin. In this study in 36 normal adults (26 males and 10 females, age 22–35 years) we compared the effects of three cholinesterase inhibitors (pyridostigmine, 120 mg p.o., n = 19; neostigmine, 10 μg/kg i.v., n = 6; physostigmine, 12.5 μg/kg i.v., n = 6) and bethanechol, a direct muscarinic receptor agonist that is mainly active on muscarinic M 3 receptors (25 μg/kg i.v., n = 5), on both basal and GHRH (1 μg/kg i.v.)-stimulated GH secretion. Pyridostigmine, neostigmine and physostigmine induced a significant GH increase (peak vs. basal levels, mean ± S.E.: 10.4 ± 1.6 vs. 0.6 ± 0.2 μ g/l, P = 0.0001; 13.3 ± 1.2 vs. 0.5 ± 1.1 μ g/l, P = 0.004; and 14.9 ± 3.1 vs. 2.7 ± 1.1 μ g/l, P = 0.025;, respectively). These drugs also induced a similar potentiation of the GH response to GHRH (peak: 48.3 ± 5.6 vs. 16.2 ± 2.2 μ g/l, P = 0.0001; 49.2 ± 2.2 vs. 19.9 ± 5.1 μ g/l, P = 0.006; and 76.9 ± 12.4 vs. 18.1 ± 5.3 μ g/1, P = 0.001, respectively). By contrast, bethanechol neither enhanced basal GH secretion (peak vs. basal level: 3.3 ± 1.2 vs. 2.6 ± 1.2 μ g/l) nor potentiated the GH response to GHRH (peak: 16.3 ± 1.3 vs. 15.4 ± 1.6 μ g/l). The present findings strongly confirm the stimulatory role of aetylcholine on GH secretion in man, showing that indirect acetylcholine receptor agonists stimulate GH secretion, while the muscarinic M 3 agonist bethanechol does not. The results exclude that cholinergic stimulation of GH secretion is mediated by muscarinic M 3 receptors, in keeping with the hypothesis that muscarinic M 1 receptors play the main role in the neuroregulation of GH secretion.

Galanin (GAL), a 29 amino acid neuropeptide, is known to increase both basal and growth hormone-releasing hormone (GHRH)-induced growth hormone (GH) secretion while not significantly increasing prolactin (PRL) secretion in man. GAL is also endowed with an inhibiting effect on glucose-stimulated insulin release in animals, but not in man. We studied the effect of GAL (80 pmol/kg/min infused over 60 minutes) on the arginine- (ARG, 30 g infused over 30 minutes) stimulated GH, PRL, insulin, and C-peptide secretion in eight healthy volunteers (age, 20 to 30 years). GAL induced an increase of GH (GAL v saline, area under curve [AUC], mean +/- SEM: 316.5 +/- 73.9 v 93.2 +/- 20.9 micrograms/L/h, P less than .05), but failed to modify both PRL and insulin secretion. GAL enhanced the ARG-induced stimulation of both GH (1,634.1 +/- 293.1 v 566.9 +/- 144.0 micrograms/L/h, P less than .02) and PRL secretion (1,541.9 +/- 248.8 v 1,023.8 +/- 158.7 micrograms/L/h, P less than .02). On the contrary, GAL blunted the ARG-stimulated insulin (816.3 +/- 87.7 v 1,322.7 +/- 240.9 mU/L/h, P less than .05), as well as C-peptide secretion (105.1 +/- 9.8 v 132.8 +/- 17.3 micrograms/L/h, P less than .02). ARG administration induced a transient increase of glucose levels (P less than .01 v baseline) followed by a significant decrease (P less than .05 v baseline). This latter effect was prevented by the coadministration of GAL. In conclusion, these results show that in man GAL potentiates the GH response to ARG, suggesting that these drugs act at the hypothalamic level, at least in part, via different mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)

The adrenergic system is involved in the neural control of GH secretion with both stimulatory and inhibitory influences mainly mediated via GHRH and/or somatostatin modulation. To throw further light on adrenergic neuroregulation of somatotrophic function in man, the effect of various catecholamine agonists and antagonists on basal or GHRH-stimulated GH secretion was studied. Twenty-one adult males aged 20-30 years underwent the following studies: 1. clonidine (CLON), alpha 2-agonist, (15 micrograms/min infused i.v. from 0 to +10 min) alone and preceded by yohimbine (YOH), alpha 2-antagonist, (30 mg orally at -50 min); 2. GHRH (GHRH 44, 1 microgram/kg i.v. bolus at 0 min) alone and preceded by YOH; 3. CLON alone and combined with methoxamine (METHOX), alpha 1-agonist, (1 mg/min infused i.v. from -10 to +10 min); 4. GHRH alone and combined with i.v. infusion of phentolamine (PHEN), alpha 1/alpha 2-antagonist, (0.5 mg/min from -60 to +30 min); 5. GHRH alone and combined with i.v. infusion of salbutamol (SAL), beta 2-agonist, (10 micrograms/min from -5 to +15 min). The GH response to CLON was inhibited by YOH (area under the response curve, mean +/- S.E.: 672.6 +/- 143.0 vs. 219.6 +/- 16.7 micrograms/l/h, P less than 0.05) but was not modified by METHOX (278.4 +/- 94.1 vs. 216.7 +/- 115.5 micrograms/l/h). On the other hand, YOH was unable to affect the GH response to GHRH (339.3 +/- 19.1 vs. 518 +/- 172.8 micrograms/l/h).(ABSTRACT TRUNCATED AT 250 WORDS)

Increased cholinergic tone induced by pyridostigmine (PD) increases basal plasma GH levels and potentiates the GH response to GHRH in normal adults. In this study the effects of PD (60 mg, orally) on both basal and GHRH (1 microgram/kg)-induced GH secretion in seven children with familial short stature (FSS), six with GH deficiency (GHD) and 10 with constitutional growth delay (CGD) were studied and compared with results obtained by stimulation with insulin-induced hypoglycemia (IH) and GHRH alone. The mean peak plasma GH levels were variable, but individual values were frequently low in all groups after both IH [FSS, 9.7 +/- 1.3 (+/- SEM) ng/mL; GHD, 1.6 +/- 0.4 ng/mL; CGD, 7.0 +/- 0.8 ng/mL] and GHRH (FSS, 23.8 +/- 6.6 ng/mL; GHD, 11.1 +/- 5.8 ng/mL; CGD, 15.1 +/- 4.5 ng/mL) administration. PD induced GH responses (FSS, 14.5 +/- 1.6 ng/mL; GHD, 3.8 +/- 0.8 ng/mL; CGD, 18.3 +/- 3.2 ng/mL) that in many children in the FSS and CGD groups were higher than those after IH and GHRH treatment. PD clearly increased the GH response to GHRH in all children [FSS, 69.5 +/- 9.4 ng/mL (P less than 0.01 vs. other stimuli); GHD, 18.0 +/- 7.5 ng/mL; CGD, 50.0 +/- 8.5 ng/mL (P less than 0.01 vs. other stimuli)]. We conclude that in children with short stature, as in adults, enhancement of cholinergic tone increases both basal and GHRH-induced GH secretion, and that PD plus GHRH is the best provocative stimulus for evaluating the somatotroph response.

Recently, a new long-acting form of bromocriptine (Parlodel LA, Sandoz) has been developed and it has already been found to be effective in lowering plasma PRL levels in normal volunteers and postpartum women. This work reports the clinical, hormonal and radiological effects of a single 50 mg dose of long-acting bromocriptine in 10 patients with tumorous hyperprolactinemia (2 microprolactinomas, 6 macroprolactinomas, 1 acromegaly and 1 nonsecreting macroadenoma). A rapid and long-lasting (28 days) normalization of PRL levels was observed in patients with microprolactinoma, acromegaly and nonsecreting adenoma. None of the 6 patients with macroprolactinoma underwent normalization of plasma PRL, but the latter was markedly reduced (61–80% of basal levels). A second injection of the drug in 5 macroprolactinoma patients induced a further reduction of plasma PRL levels in 2 of them. No changes in the tumor size were observed either after the first or the second injection of long-acting bromocriptine in any of the patients. This injectable form of bromocriptine induced nausea and/or mild hypotension Jasting a few h in 4 of the 10 patients and was better tolerated than the oral form as regards both the duration and intensity of the side effects. Thus, as this drug has proved to be efficacious and well tolerated by the patients, this long-acting form of bromocriptine may be a valid therapeutical approach for initiating medical treatment of patients with prolactinoma.

To throw light onto the mechanism(s) by which the cholinergic system influences growth hormone (GH) release, the effects of two muscarinic receptor blockers, pirenzepine and atropine, and of an acetylcholinesterase inhibitor, pyridostigmine bromide, on the GH response to GHRH-44 were studied in 19 normal volunteers. Moreover, the effects of pirenzepine administration on plasma GH levels both in basal conditions and after stimulation by GHRH-44 and TRH were studied in 9 acromegalics. Both pirenzepine (0.6 mg/kg i.v., 5 min before GHRH) and atropine (1 mg i.m., 15 min before GHRH) blunted the GH response to GHRH (1 microgram/kg i.v. bolus) (area under the response curve, AUC: 81.3 +/- 17.3 vs. 481.2 +/- 211.3 ng/ml/h for pirenzepine and 100.2 +/- 27.0 vs. 364.7 +/- 81.0 ng/ml/h for atropine; p less than 0.01). Pyridostigmine (120 mg orally, 30 min before GHRH) induced a variable but significant (p less than 0.02) rise in basal plasma GH levels and, furthermore, an unequivocal potentiation of the GH response to GHRH (AUC: 1044.6 +/- 245.3 vs. 481.2 +/- 211.3 ng/ml/h; p less than 0.01). In all but one acromegalics 0.6 mg/kg i.v. pirenzepine was unable to modify the basal GH levels whilst it showed a variable inhibitory effect on the GH response to GHRH. The GH response to TRH (200 micrograms i.v. bolus) was instead unmodified by pirenzepine. In conclusion, muscarinic receptor blockade inhibits while cholinergic potentiation seems to positively modulate the GH response to GHRH. Therefore, the cholinergic system seems to positively modulate the GHRH effect on somatotrophs.(ABSTRACT TRUNCATED AT 250 WORDS)

In the treatment of hyperprolactinemia bromocriptine is generally administered in 3 daily doses during the day. Due to the limited compliance of patients under this long term regimen, in 16 hyperprolactinemic patients we investigated the efficacy and tolerability of the treatment with this dopaminergic drug administered as a single evening dose. This dose was the same which the patients had been assuming previously on a tid basis. Chronic treatment (4-12 months) with an oral single evening dose of bromocriptine is able to control plasma PRL at least as well as the traditional tid regimen (2.8-21.6 ng/ml vs 1.2-31.8 ng/ml). Furthermore, during this single dose regimen the side effects were of lesser intensity and extent. Since the compliance of the patients with the single dose regimen was very good and the efficacy the same in reducing plasma PRL and controlling the clinical manifestations with a lower rate of side effects, we suggest to extend this regimen to all patients with hyperprolactinemia treated with bromocriptine after successful reduction of plasma PRL levels is obtained.

Background Msx originated early in animal evolution and is implicated in human genetic disorders. To reconstruct the functional evolution of Msx and inform the study of human mutations, we analyzed the phylogeny and synteny of 46 metazoan Msx proteins and tracked the duplication, diversification and loss of conserved motifs. Results Vertebrate Msx sequences sort into distinct Msx1, Msx2 and Msx3 clades. The sister-group relationship between MSX1 and MSX2 reflects their derivation from the 4p/5q chromosomal paralogon, a derivative of the original "MetaHox" cluster. We demonstrate physical linkage between Msx and other MetaHox genes (Hmx, NK1, Emx) in a cnidarian. Seven conserved domains, including two Groucho repression domains (N- and C-terminal), were present in the ancestral Msx. In cnidarians, the Groucho domains are highly similar. In vertebrate Msx1, the N-terminal Groucho domain is conserved, while the C-terminal domain diverged substantially, implying a novel function. In vertebrate Msx2 and Msx3, the C-terminal domain was lost. MSX1 mutations associated with ectodermal dysplasia or orofacial clefting disorders map to conserved domains in a non-random fashion. Conclusion Msx originated from a MetaHox ancestor that also gave rise to Tlx, Demox, NK, and possibly EHGbox, Hox and ParaHox genes. Duplication, divergence or loss of domains played a central role in the functional evolution of Msx. Duplicated domains allow pleiotropically expressed proteins to evolve new functions without disrupting existing interaction networks. Human missense sequence variants reside within evolutionarily conserved domains, likely disrupting protein function. This phylogenomic evaluation of candidate disease markers will inform clinical and functional studies.