Smoking, polyuria and impaired vision.

The pituitary gland can be involved in a variety of medical conditions, including metastatic tumors. Metastases to the pituitary gland, although absolutely rare, more commonly affect the posterior pituitary lobe and so frequently present with diabetes insipidus. We report on a 48-year-old male heavy smoker patient suffering from sudden onset of polyuria and persistent thirst. Laboratory results revealed central diabetes insipidus. Computed tomography (CT) scan of the brain showed a mass located in the sella turcica and in the suprasellar region. CT scan of the chest showed a mass in the right superior lobe with mediastinal lymphadenopathy, with bronchoscopy and biopsy features of pulmonary adenocarcinoma. The patient received radiotherapy on the pituitary gland and adjuvant chemotherapy, and as intrasellar and suprasellar mass decreased in size, urinary output was accordingly reduced. Therefore, is that in patients with risk factors for cancer and sudden onset of diabetes insipidus pituitary metastasis should be taken into account in differential diagnosis.

A cross-sectional nationwide survey on esophageal atresia and tracheoesophageal fistula.

BACKGROUND: Our study aims at disclosing epidemiology and most relevant clinical features of esophageal atresia (EA) pointing to a model of multicentre collaboration. METHODS: A detailed questionnaire was sent to all Italian Units of pediatric surgery in order to collect data of patients born with EA between January and December 2012. The results were crosschecked by matching date and place of birth of the patients with those of diagnosis-related group provided by the Italian Ministry of Health (MOH). RESULTS: A total of 146 questionnaires were returned plus a further 32 patients reported in the MOH database. Basing on a total of 178 patients with EA born in Italy in 2012, the incidence of EA was calculated in 3.33 per 10,000 live births. Antenatal diagnosis was suspected in 29.5% patients. 55.5% showed associated anomalies. The most common type of EA was Gross type C (89%). Postoperative complications occurred in 37% of type C EA and 100% of type A EA. A 9.5% mortality rate was reported. CONCLUSIONS: This is the first Italian cross-sectional nationwide survey on EA. We can now develop shared guidelines and provide more reliable prognostic expectations for our patients.

Universal template approach to drug design: polyamines as selective muscarinic receptor antagonists.

The concept that polyamines may represent a universal template in the receptor recognition process is embodied in the design of new selective muscarinic ligands. Tetraamines 4-7 and 16-20 and diamine diamides 8-15 were synthesized, and their pharmacological profiles at muscarinic receptor subtypes were assessed by functional experiments in isolated guinea pig left atrium (M2) and ileum (M3) and by binding assays in rat cortex (M1), heart (M2), submaxillary gland (M3), and NG 108-15 cells (M4). It has been confirmed that appropriate substituents on the terminal nitrogens of a tetraamine template can tune both affinity and selectivity for muscarinic receptors. The novel tetraamine C-tripitramine (17) was able to discriminate significantly M1 and M2 receptors versus the other subtypes, and in addition it was 100-fold more lipophilic than the lead compound tripitramine. Compound 14 (tripinamide), in which the tetraamine backbone was transformed into a diamine diamide one, retained high affinity for muscarinic subtypes, displaying a binding affinity profile (M2 > M1 > M4 > M3) qualitatively similar to that of tripitramine. Both these ligands, owing to their improved lipophilicity relative to tripitramine and methoctramine, could serve as tools in investigating cholinergic functions in the central nervous system. Furthermore, notwithstanding the fact that the highest affinity was always associated with muscarinic M2 receptors, for the first time polyamines were shown to display high pA2 values also toward muscarinic M3 receptors.

Synthesis and anticonvulsant activity of 2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives.

A series of 2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives were synthesized and evaluated for anticonvulsant activity. The compounds were assayed, intraperitoneally in mice and per os in rats, against seizures induced by maximal electroshock (MES) and pentylenetetrazole (scMet). Neurologic deficit was evaluated by the rotarod test. The compounds were prepared to determine the relationship between the 2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives' structures and anticonvulsant activity. Several of these compounds showed significant anticonvulsant activity. Compounds 43 and 45 were the most active of the series against MES-induced seizures with ED50 values of 8.7 and 7.6 mg/kg, respectively. Compound 45 displayed good protection against MES-induced seizures and low toxicity in rats with an oral ED50 of 18.6 mg/kg and a protective index (PI = TD50/ED50) of < 26.9. In vitro receptor binding studies revealed that compounds 43 and 45 bind to sigma 1 receptors with nanomolar affinities.

(+)-cis-N-ethyleneamino-N-normetazocine derivatives. Novel and selective sigma ligands with antagonist properties.

A series of (+)-cis-N-normetazocine derivatives has been described, and their affinities for sigma1, sigma2, and phencyclidine (PCP) sites and opioid, muscarinic (M2), dopamine (D2), and serotonin (5-HT2) receptors were evaluated. The effect of the N-substitution with a substituted ethylamino spacer was investigated. Compounds 8c-11c displayed high affinities for sigma1 sites and for opioid receptors. Substitution of the second basic nitrogen either with alkyl or cycloalkyl substituents give compounds (1a-6a) with high affinity and selectivity for sigma1 binding sites. Compounds 1a-5a were further characterized in vivo, and their agonist/antagonist activity was evaluated. In mouse, compound 1a and 2a as well as haloperidol suppressed in a dose-related manner the stereotyped behavior induced by (+)-SKF 10,047. Compounds 3a-5a and (+)-pentazocine do not affect the stereotyped behavior induced by ip injection of (+)-SKF 10,047. Therefore, from this series of compounds we identified potent and selective sigma1 ligands which might prove useful to unveil the functional role of sigma1 sites.

Analysis of the muscarinic receptor subtype mediating inhibition of the neurogenic contractions in rabbit isolated vas deferens by a series of polymethylene tetra-amines.

The pharmacological characteristics of the presynaptic muscarinic receptor subtype, which mediates inhibition of the neurogenic contractions in the prostatic portion of rabbit vas deferens, have been investigated by using a series of polymethylene tetra-amines, which were selected for their ability to differentiate among muscarinic receptor subtypes. It was found that all tetra-amines antagonized McN-A-343-induced inhibition in electrically stimulated rabbit vas deferens in a competitive manner and with affinity values (pA:(2)) ranging between 6.27+/-0.09 (spirotramine) and 8.51+/-0.02 (AM170). Competition radioligand binding studies, using native muscarinic receptors from rat tissues (M(1), cortex; M(2), heart; M(3), submaxillary gland) or from NG 108-15 cells (M(4)) and human cloned muscarinic M(1)-M(4) receptors expressed in CHO-K1 cells, were undertaken with the same tetra-amines employed in functional assays. All antagonists indicated a one-site fit. The affinity estimates (pK:(i)) of tetra-amines calculated in binding assays using native receptors were similar to those obtained using cloned receptors. Among these compounds some displayed selectivity between muscarinic receptor subtypes, indicating that they may be valuable tools in receptor characterization. Spirotramine was selective for M(1) receptors versus all other subtypes (pK:(i) native: M(1), 7.32+/-0.10; M(2), 6.50+/-0.11; M(3), 6.02+/-0.13; M(4), 6.28+/-0.16; pK:(i) cloned: M(1), 7.69+/-0.08; M(2), 6.22+/-0.14; M(3), 6.11+/-0.16; 6.35+/-0.11) whereas CC8 is highly selective for M(2) receptors versus the other subtypes (pK:(i) native: M(1), 7.50+/-0.04; M(2), 9.01+/-0.12; M(3), 6.70+/-0.08; M(4), 7.56+/-0.04; pK:(i) cloned: M(1), 7.90+/-0.20; M(2), 9.04+/-0.08; M(3), 6.40+/-0.07; M(4), 7.40+/-0.04). Furthermore, particularly relevant for this investigation were tetra-amines dipitramine and AM172 for their ability to significantly differentiate M(1) and M(4) receptors. The apparent affinity values (pA:(2)) obtained for tetra-amines in functional studies using the prostatic portion of rabbit vas deferens correlated most closely with the values (pK:(i)) obtained at either native or human recombinant muscarinic M(4) receptors. This supports the view that the muscarinic receptor mediating inhibition of neurogenic contractions of rabbit vas deferens may not belong to the M(1) type but rather appears to be of the M(4) subtype.

Striated muscle cells in non-neoplastic lung tissue: a clinicopathologic study.

This study was performed to study the prevalence, origin, and clinical implication of striated muscle cells in congenital non-neoplastic lung abnormalities. Five cases of striated muscle cell proliferation within congenital non-neoplastic pulmonary abnormalities were identified from a series of 31 (16%) resected specimens obtained at King's College Hospital, London, during the period 1992 to 1998. Lung tissue was also obtained from 48 normal human fetuses and serial sections stained for the presence of striated muscle. A histologic and immunohistochemical study of the clinical cases and the fetal material was performed by using phosphotungstic acid hematoxylin staining and immunostaining for myoglobin and desmin. Striated muscle cells were identified either as a diffuse or a focal proliferation within the lung interstitia of five infants. The congenital lung anomalies were intra-abdominal pulmonary sequestration associated with congenital cystic adenomatoid malformation (CCAM), intrathoracic sequestration again with features of CCAM, an intrathoracic sequestration associated with a congenital diaphragmatic hernia, and 2 Stocker type II intrathoracic CCAMs. Striated muscle cells were not identified in any section of lung tissue derived from the fetal series. Striated muscle cells proliferation in non-neoplastic lung tissue is more common than usually reported. Although the exact origin of such cells is speculative, because it is always detected within pulmonary anomalies, a wide morphogenetic error is likely. The clinical implication of its presence has to be further defined. HUM PATHOL 31:1477-1481.

2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives: novel, potent and selective sigma1 receptor ligands.

A series of original 2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives were evaluated for their affinity at sigma1 and sigma2 receptor subtypes in competition binding experiments, using [3H](+)-pentazocine or [3H]1,3-di-o-tolyl-guanidine (DTG) in the presence of 100 nM (+)-N-allylnormetazocine (NANM) in guinea-pig brain membranes. Several of these derivatives showed preferential selectivity for sigma1 binding sites. Compound 1 [3-(1-piperidinoethyl)-6-propylbenzothiazolin-2-one] emerged as a potent sigma1 receptor ligand (Ki = 0.6 nM) and displayed a moderate selectivity over the sigma2 receptor subtype (Ki for sigma2/Ki for sigma1 = 29). Compounds 2 [3-(1-piperidinopropyl)-6-propanoylbenzothiazolin-2-one] and 3 [3-(1-piperidinopropyl)-6-propanoylbenzoxazolin-2-one] still showed rather high affinities for sigma1 binding sites with Ki values of 2.3 and 8.5 nM, respectively. On the contrary, they had 87- and 58-fold less affinity at sigma2 receptors, respectively. Unlike their potent affinity for sigma binding sites, these compounds had negligible affinity for mu-, delta- and kappa-opioid receptors, 5-HT2, dopamine D2, and muscarinic M2 receptors. Sigma receptor ligands may affect neuronal transmission and display, in animal models, antipsychotic, cognitive, motor, neuroprotective and anticonvulsant activity. Therefore, on the basis of these findings, these novel sigma receptor ligands were assayed, in mice, in three tests: maximal electroshock, subcutaneous pentylenetetrazol and rotarod neurotoxicity. Compound 1, administered intraperitoneally, was the most effective against maximal electroshock-induced seizures and was devoid of significant neurotoxic effects.

Characterization of a putative calcitonin receptor in IMR 32 human neuroblastoma cells.

In this study we characterized calcitonin (CT) receptors in human neuroblastoma IMR 32 cells. Saturation binding assays indicated that [125I]-human CT bound with high affinity to IMR 32 cell membranes (K(d) = 253.6 pM; Bmax = 3.84 fmol/ mg protein). In competition binding studies, human adrenomedullin displayed high affinity for these sites (IC50 = 30 nM) whereas human alpha calcitonin-gene related peptide (alphaCGRP; IC50 = 145 nM) and human amylin (IC50 = 415 nM) showed lower affinity. These peptides increased cAMP levels in viable cells; the relative potencies were: human CT > human adrenomedullin > human cCGRP > or = human amylin. The expression of mRNA coding for the published sequences of the human calcitonin receptor and of the human calcitonin receptor-like receptorwas evaluated by reverse transcriptase-polymerase chain reaction. Electrophoretic analysis did not confirm the occurrence of mRNA coding for the above mentioned receptors in these cells. This study suggests the presence of a novel, putative CT receptor in IMR 32 cells.

Intra-abdominal pulmonary sequestration associated with congenital cystic adenomatoid malformation of the lung: just an unusual combination of rare pathologies?

A case of intra-abdominal pulmonary sequestration associated with histological features of congenital cystic adenomatoid malformation (CCAM) of the lung is reported. The lesion consisted of a Stocker type II CCAM in which numerous striated muscle cells were present. A review of the literature of this rare combination of congenital pulmonary anomalies is presented.

A hydrogel based on a polyaspartamide: characterization and evaluation of in-vivo biocompatibility and drug release in the rat.

This paper deals with the characterization of a new microparticulate hydrogel obtained by gamma irradiation of alpha, beta-poly[N-(2-hydroxyethyl)-DL-aspartamide] (PHEA). When enzymatic digestion of PHEA hydrogel was evaluated using various concentrations of pepsin and alpha-chymotrypsin no degradation occurred within 24 h. In-vivo studies showed that this new material is biocompatible after oral administration to rats. PHEA hydrogel was also studied as a system for delivery of diflunisal, an anti-inflammatory drug. In-vitro release studies in simulated gastrointestinal juice (pH 1 or 6.8) showed that most of the drug was released at pH 6.8. In-vivo studies indicated that diflunisal-loaded PHEA microparticles significantly improved the gastric tolerance and oral bioavailability of the drug in comparison with free diflunisal. These results suggest the potential application of PHEA hydrogel as a new delivery system for the oral administration of anti-inflammatory drugs.

Neonatal diaphragmatic hemangioma.

The first neonatal case of a hemangioma of the diaphragm in a neonate is reported. After 25 months the patient is well with no signs of recurrence. Diaphragmatic tumors should be considered in the differential diagnosis of neonatal thoracic masses.

Concepts and considerations for repair of a severe cloacal anomaly.

A 1.8 kg chromosomally normal child was suspected antenatally to have a cloacal anomaly and oligohydramnios. Both parents had a chromosome 9 inversion (inv [9] [p11 q13]). Postnatal study showed a high confluence of the urinary, genital and intestinal tracts. Because of prematurity, a right colostomy was performed on a short colon, but the genitourinary tract was not drained. Poor weight gain, urinary tract infection and septicaemia led to a one-stage reconstruction at 5 months of age and a weight of 3.2 kg. Follow-up although short at 15 months, is encouragingly suggestive of urinary and faecal continence. The vagina is patent. This paper considers concepts in cloacal management and submits for evaluation an alternative surgical plan to the presently almost exclusively accepted posterior sagittal approach of Peña and De Vries.

Megacalycosis on duplex system upper moiety.

The authors report a rare case of megacalycosis located on a duplex system upper moiety, and analyse the problems related to its pathology, etiopathogenesis, clinical manifestations and diagnosis.

[Morpho-functional evaluation of subjects who had undergone surgery for ano-rectal malformations using the Peña technique]. / Valutazione morfo-funzionale dei soggetti operati per malformazione ano-rettale secondo la tecnica di Peña.

The approach to patients with Ano-Rectal Malformations (ARM) has undergone a substantial change in these last years due to the evolution of the studies of the anatomy and physiology carried out by Peña and de Vries. The authors report their experience on 15 patients and analyse the clinical and instrumental results according to the quality of life of the patients. There are different clinical criteria for the postoperative evaluation of these patients. The authors considered the Kelly, Kiesewetter, Peña and Holdschneider methods and compared the different values obtained. Moreover, they analysed the results of anorectal manometry performed in 10 patients and their correlations with clinical scores. The authors assert that the TC or NMR tests are unnecessary for these patients, since these methods demonstrate a correct position of the rectum within the muscular structure, but do not allow a correct evaluation of the quality of life of these patients. The clinical results obtained by the authors are satisfying; however, the number of patients is limited and the follow-up is relatively short.