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Byline: A.J. Baime, Giannella M. Garrett STYLE 'I don't think age has much to do with friendship.' --Fashion icon and textile maven Iris Apfel, 95, and high-fashion jewelry designer Alexis [...]

With her sweeping mobility, earthy passion and soaring lines, Ballet Hispanico's Shelby Colona illuminates the stage. Performing the featured role in Annabelle Lopez Ochoa's Linea Recta last season, Colona was [...]

'Do not bother to walk on stage unless you have the power to dominate it, and make it yours entirely,' wrote Jose Limon in An Unfinished Memoir. That's exactly what [...]

Michaela DePrince was only 3 when her parents died in Sierra Leone's brutal civil war, landing her in an orphanage. But in a moment worthy of the big screen, her [...]

To develop a score to predict mortality in patients with bloodstream infections (BSIs) due to carbapenemase-producing Enterobacteriaceae (CPE).

In a single‐center prospective cohort study to assess the risk factors for infection with carbapenem‐resistant Klebsiella pneumoniaeafter liver transplantation, the authors analyze the significance of carbapenem‐resistant K. pneumoniaerectal carriage before and after liver transplantation, and develop a risk score that effectively discriminates patients at low versus higher risk for infection.

Background:Pituitary tumors account for approximately 10–15% of intracranial neoplasms. Aim:Using the cDNA microarray method, we have previously compared expression under two distinct conditions: a pool of 4 clinically non-functioning pituitary adenomas (NFPA) and a spinal cord metastasis of a non-functioning pituitary carcinoma, in order to gain biological insights into genomic changes of pituitary neoplasias. In the present study, we further investigated the mRNA expression of 3 selected genes previously described as being involved in other neoplasias based on a series of 60 pituitary adenomas: CRABP1(cellular retinoic acid binding protein 1), GRP (gastrin-releasing peptide), and RERG (Ras-related, estrogen-regulated, growth inhibitor). Material and methods:The expression of CRABP1, GRP, and RERG was determined by quantitative RT-PCR. Results:A significantly higher content of CRABP1mRNA was observed in NFPA compared to functioning adenomas, and PRL-secreting adenomas showed a lower expression of this gene compared to normal pituitary. A lower expression of GRP mRNA was detected in NFPA compared to normal pituitary and also to functioning adenomas. RERG mRNA was overexpressed in NFPA in comparison to functioning adenomas and to normal pituitary. Among the functioning adenomas, only the ACTH-secreting adenomas presented a higher expression of RERG mRNA compared to normal pituitary. Conclusions:The findings of differential expression of CRABP1in prolactinomas and of RERG in NFPA compared to normal pituitary suggests that retinoic acid and estrogen receptor, respectively, could be involved in the tumorigenesis of these adenomas subtypes. Additional studies are required to further confirm this hypothesis.

GH secretagogues (GHS) have been used for the differential diagnosis of ACTH-dependent Cushing’s syndrome (CS) since 1997 due to their ability to increase ACTH and cortisol levels in Cushing’s disease. The aim of this study was to correlate ACTH response to GH-releasing peptide-6 (GHRP-6) in vivowith GH secretagogue receptor type 1a (GHSR-1a) mRNA expression in a patient with lung carcinoid tumor. The patient was a 26-yr-old male with diagnosis of ACTH-dependent CS. He presented negative responses to human CRH and desmopressin tests; yet, a significant increase in ACTH after the GHRP-6 test was observed. Sellar magnetic resonance imaging (MRI) showed slight posterior hypointensity, but bilateral petrosal sinus sampling did not show central gradient. Computed tomography (CT) and MRI of thorax/abdomen/cervical were negative and 111In-pentetreotide scintigraphy depicted abnormal uptake on the right lung. The patient was submitted to right thoracotomy for exeresis of lung nodule and hilar lymph node which were characterized as atypical lung carcinoid tumor and he presented clinical and laboratorial remission after surgery. GHSR-1 a mRNA expression was studied with real-time quantitative PCR and tumor data were compared with fragments of normal lung and pituitary. There was a higher GHSR-1 a expression in the lung carcinoid tumor as compared with normal tissues. The ACTH response to GHRP-6 in a patient with ectopic ACTH production by a lung carcinoid tumor was associated with GHSR-1a expression in the tumor tissue, suggesting an association between GHSR-1a mRNA overexpression and the in vivoresponse to GHS.

Diagnostic strategies, malignancy predictors and long-term survival were retrospectively evaluated in patients with hyperinsulinemic hypoglycemia (64 insulinomas). Lower median glycemia was 30 (range 20–53) mg/dl [1.6 (1.1–2.9) mmol/l] with concurrent insulin of 48 (13.2–217) μU/ml and 15 (2–46) μU/ml measured by radioimmunoassay (RIA) and immunofluorimetric assay (IFMA), respectively. All patients with insulinomas had a positive prolonged fast within 48 h. Sensitivity of localization methods was: ultrasonography (US) 23%, computed tomography (CT) 28%, magnetic resonance imaging (MRI) 65%, endoscopic US 75%, arteriography 38%, portal venous sampling 67%, selective arterial calcium stimulation 67%, intraoperative US 94% and palpation 92%. Nine patients (14%) had malignant insulinomas. Age at diagnosis (mean±SD, 53.8±19 vs 39.4±16.3 yr; p=0.03), insulin (1372±730 vs 785±659% (percentage of the method’s diagnostic cut-off; 6 and 3 μU/ml for RIA and IFMA, respectively; p=0.007) and C-peptide levels (9.8±2.9 vs 3.9±2.8 ng/ml (3.2±0.9 vs 1.3±0.9 nmol/l; p=0.006), and tumor size (6.2±4.1 vs 1.5±0.6 cm; p=0.0002) were increased in malignant insulinomas. C-peptide level above 6.1 ng/ml (2.0 nmol/l) had a 100% sensitivity and 96% specificity, and tumor size above 2.6 cm yielded a sensitivity of 88% and specificity of 100% in predicting malignancy. Survival of patients with malignant insulinomas was significantly impaired (16 vs 100% at 5 yr; p=0.0000001). The diagnosis of insulinoma can be made within 48 h of fasting. The association between intraoperative US and palpation evidenced the tumor in 95% of the patients. C-peptide and tumor size were reliable malignancy predictors.

The new antihypertensive I1-receptor agonist (4) was rationally synthetized by the insertion of a phenyl group in the ortho position of the aromatic ring of the I1-selective antagonist (3). This "antagonismagonism" modulation, highlights the existence of expected analogies between I1- and α2-adrenoreceptor systems. Chirality proves to be crucial for the activation of I1-receptors, since the cardiovascular effects are produced exclusively by the (S)-(+)-4 enantiomer.

A series of new α1-adrenoreceptor antagonists (5−18) was prepared by introducing various substituents (Topliss approach) into the ortho, meta, and para positions of the benzyloxy function of the phendioxan open analogue 4 (“openphendioxan”). All the compounds synthesized were potent antagonists and generally displayed, similarly to 4, the highest affinity values at α1D- with respect to α1A- and α1B-AR subtypes and 5-HT1A subtype. By sulforhodamine B (SRB) assay on human PC-3 prostate cancer cells, the new compounds showed antitumor activity (estimated on the basis of three parameters GI50, TGI, LC50), at low micromolar concentration, with 7 (“clopenphendioxan”) exhibiting the highest efficacy. Moreover, this study highlighted for the first time α1D- and α1B-AR expression in PC3 cells and also demonstrated the involvement of these subtypes in the modulation of apoptosis and cell proliferation. A significant reduction of α1D- and α1B-AR expression in PC3 cells was associated with the apoptosis induced by 7. This depletion was completely reversed by norepinephrine.

A series of derivatives structurally related to biphenyline (3) was designed with the aim to modulate selectivity toward the α2-AR subtypes. The results obtained demonstrated that the presence of a correctly oriented function with positive electronic effect (+σ) in portion X of the ligands is an important factor for significant α2C-subtype selectivity (imidazolines 5, 13, 16, and 19). Homology modeling and docking studies support experimental data and highlight the crucial role for the hydrogen bond between the pyridine nitrogen in position 3 of 5 and the NH-indole ring of Trp6.48, which is favorably oriented in the α2C-subtype, only.

The α- and β-methyl derivatives of 2-phenylethylimidazoline (compounds 7 and 8) and the corresponding enantiomers were prepared and tested with the purpose of studying the role played by the ethylene bridge in modulating I1- and I2-IBS selectivity. The α-methylation appeared to be extremely critical regarding the affinity and selectivity for the I1-IBS subtypes (I1/I2 = 186 for imidazoline 7) and the stereospecificity of interaction (eudismic ratio (S)-(−)-7/(R)-(+)-7 = 5888). Instead, even if in a more limited fashion, the β-methylation tended toward I2-IBS selectivity (I2/I1 = 50 for imidazoline 8). The unsubstituted compound 4 (I2/I1 = 1479) proved to be considerably more potent and selective with respect to I2-IBS subtypes.

We have recently identified 3-[(1-methyl)-4,5-dihydro-1H-imidazol-2-yl)methyl]pyridine (homoazanicotine, 8) as a novel nicotinic acetylcholinergic (nACh) receptor ligand. In the present investigation, after we determined that 8 binds selectively at nicotinic (Ki = 7.8 nM) vs muscarinic (Ki > 10 000 nM) acetylcholinergic receptors, we examined its structure−affinity relationships for nACh receptor binding. The features investigated included the influence of (i) the composition of connector that separates the two rings, (ii) the N-methyl group, (iii) the ring opening of the imidazoline ring, (iv) the pyridine nitrogen atom, and (v) the aromatization of the imidazoline ring on nACh receptor affinity. As with nicotine, the parent structure seems optimal and most structural changes reduce nACh receptor affinity. Also, as with nicotine analogues, alteration of the spacer group influences affinity in a manner that is somewhat different than that seen with the parent structure.

WB4101 (1)-related compounds 5−10 were synthesized, and their biological profile at α1-adrenoreceptor (AR) subtypes and 5-HT1A serotoninergic receptors was assessed by binding assays in Chinese hamster ovary and HeLa cell membranes expressing the human cloned receptors. Moreover, their receptor selectivity was further determined in functional experiments in isolated rat prostate (α1A), vas deferens (α1A), aorta (α1D), and spleen (α1B). In functional assays, compound 5 was the most potent at α1D-ARs with a reversed selectivity profile (α1D > α1A > α1B) relative to both prototype 1 and phendioxan (2) (α1A > α1D > α1B), whereas compound 8, bearing a carbonyl moiety at position 1, was the most potent at α1A-ARs with a selectivity profile similar to that of prototypes. The least potent of the series was the trans isomer 6, suggesting that optimum α1-AR blocking activity in this series is associated with a cis relationship between the 2-side chain and the 4-phenyl ring rather than a trans relationship as previously observed for the 2-side chain and the 3-phenyl ring in 2 and related compounds. Binding affinity results were not in complete agreement with the selectivity profiles deriving from functional experiments. Although a firm explanation was not available, neutral and negative antagonism and receptor dimerization were considered as two possibilities to account for the difference between binding and functional affinities. Finally, compound 5 was selected for a modeling study in comparison with 1, mephendioxan (3), and open phendioxan (4) to achieve information on the physicochemical interactions that account for its high affinity toward α1d/D-ARs.

A number of derivatives structurally related to cirazoline (1) were synthesized and studied with the purpose of modulating α2-adrenoreceptors selectivity versus both α1-adrenoreceptors and I2 imidazoline binding sites. The most potent α2-agonist was 2-[1-(biphenyl-2-yloxy)ethyl]-4,5-dihydro-1H-imidazole (7), whose key pharmacophoric features closely matched those found in the α2-agonist 2-(3-exo-(3-phenylprop-1-yl)-2-exo-norbornyl)amino-2-oxazoline (15).³⁰ (S)-(−)-7 was the most potent of the two enantiomers, confirming the stereospecificity of the interaction with α2-adrenoreceptors. This eutomer was tested on two algesiometric paradigms and, because of the interaction with α2-adrenoreceptors, showed a potent and long-lasting antinociceptive activity, since it was abolished by the selective α2-antagonist RX821002.

A series of 2- trans -styryl-imidazoline ( tracizoline ) congeners were designed and tested to develop 2-D and 3-D QSAR models for their binding to imidazoline (I 2 ) receptor. The important role of lipophilicity was assessed by classical 2-D QSAR study (Hansch approach) and by comparative molecular field analysis (CoMFA) with the inclusion of the molecular lipophilicity potential (MLP), as an additional descriptor, besides standard steric and electrostatic fields. Results from these studies were compared to those obtained in a previous modeling study of I 2 receptor ligands and integrated into a new, comprehensive model, based on about sixty I 2 receptor ligands. This model revealed, at the three-dimensional level, the most significant steric, electrostatic, and lipophilic interactions accounting for high I 2 receptor affinity.

WB 4101-related benzodioxans 3−9 were synthesized, and their biological profiles at α1-adrenoreceptor subtypes and 5-HT1A serotoninergic receptors were assessed by binding assays in CHO and HeLa cells membranes expressing the human cloned receptors. Furthermore, receptor selectivity of selected benzodioxan derivatives was further determined in functional experiments in isolated rat vas deferens (α1A) and aorta (α1D) and guinea pig spleen (α1B), in additional receptor binding assays in rat cortex membranes containing α2-adrenoreceptors and 5-HT2 serotoninergic receptors, and in rat striatum membranes containing D2 dopaminergic receptors. An analysis of the results of receptor binding experiments for benzodioxan-modified derivatives 3−9 showed high affinity and selectivity toward the α1a-adrenoreceptor subtype for compounds 3−5 and 7 and a reversed selectivity profile for 9, which was a selective α1d antagonist. Furthermore, the majority of structural modifications performed on the prototype 1 (WB 4101) led to a marked decrease in the affinity for 5-HT1A serotoninergic receptors, which may have relevance in the design of selective α1A-adrenoreceptor antagonists. The exception to these findings was the chromene derivative 8, which exhibited a 5-HT1A partial agonist profile.

The enantiomers of trans-[2-(2,6-dimethoxyphenoxy)ethyl][(3-p-tolyl-2,3-dihydro-1,4-benzodioxin-2-yl)methyl]amine (mephendioxan, 2) were synthesized from the chiral trans-3-p-tolyl-2,3-dihydro-1,4-benzodioxin-2-carboxylic acids [(+)-3 and (−)-3] which in turn were obtained through the resolution of the racemic acid with (R)- and (S)-α-methylbenzylamine. Comparison of CD spectra of the enantiomers of 2 with that of (2S,3S)-3-methyl-2-phenyl-1,4-benzodioxane allowed the assignment of the 2S,3S configuration to the (−)-enantiomer of 2 and of the 2R,3R configuration to the other enantiomer. The binding profile of the enantiomers of 2 was assessed at α1, α2, D2, and 5-HT1A receptors, in comparison to WB 4101 (1), 5-methylurapidil, and (+)-niguldipine. In addition, the two enantiomers were investigated at native and cloned α1-adrenoreceptor subtypes. (−)-2 was 10−30 times as potent as the (+)-enantiomer at α1-adrenoreceptor subtypes in both functional and binding assays. It was 36-fold selective for the α1A- versus α1B-adrenoreceptor and 60- and 20-fold selective in binding to the α1a-adrenoreceptor relative to α1b and α1d subtypes, respectively. Furthermore, the enantiomer (−)-2 displayed selectivities of 12000-, 2500-, and 250-fold in binding to α1a-adrenoreceptors relative to α2-adrenoreceptors and 5-HT1A and D2 receptors. These results indicate that (−)-2 may be a valuable tool in the characterization of α1-adrenoreceptor subtypes.

Racemate and corresponding enantiomers of muscarinic agonists carrying a 1,3-oxathiolane nucleus were studied on isolated preparations of guinea-pig ileum and atria and of rat urinary bladder. The efficacy of these agonists were determined according to the method of Furchgott and Bursztyn (1967) and enantio-selectivity and tissue-selectivity were investigated.

Recently, the synthesis of desethermuscarine 1-3 and of two of its three possible isomers, allo- and epi- desethermuscarine, 4,5 was reported. These substances, having muscarinic activity, have shown to be extremely interesting in the study of the cholinergic receptor. As a result, the role of the ether oxygen in muscarinic activity appears to be revised. Yet, due to lack of data on the fourth isomer, a complete picture of the activity of these compounds is impossible to date.

We have recently reported the synthesis of allo- and epi-dese-thermuscarine from 4t-methyl- and 4c-methyl-3c-hydroxy-1r-(N, N, -di-methylcarboxamido) cyclopentane, (II) and (III) respectively. Although this stereospecific synthetic route is simple in concept, it actually requires several steps to obtain II and III, and results in low yields.2

In order to get information about the role of the oxygen atom in position 1 of dioxolane I and thus about the corresponding binding site of the muscarinic receptor, Elferink and Salemink2 have synthesized the sulfur analog II as a cis/trans mixture in a 4:1 or 8:1 ratio, depending upon the synthetic method. This compound proved to be very active as muscarinic agent and might provide useful tool in Structure-Activity Relationship (SAR) studies on muscarinic receptor, if it were available as a pure cis form3.

The article present the author's personal narrative of his photograph safari in Linyati Wildlife Reserve in Botswana and the witness of the feeding feast of painted wolves over a carcass of an impala.

The article presents a profile of actor, singer and ballet dancer Giuseppe Bausilio. Details related to him include his current Broadway show being Hello and Dolly!, the secret behind his success being loads of hard work and little good luck, and comments from American choreographer Andy Blankenbuehler.

The article presents how some ballet instructors teach ballet students with different goals. Pamela Pibrisco, ballet instructor at Steps on Broadway in New York City, states that focusing on the mechanics of movements is the language that the whole class understands. The author states that Chip Morris, director of Acton School of Ballet in West Acton, Massachusetts, likes to reference student's activities outside of ballet to engage and motivate them.

An interview with Dresden Semperoper Ballet mistress and former ballet dancer Laura Graham is presented. When asked how choreographer William Forsythe influences her coaching style, she claims that Forsythe is her inspiration and that she learned a lot about movement and space from him. She also reveals that she is considering teaching ballet to teenagers in schools.

An interview with dance teacher Finis Jhung regarding his coaching with the boys of "Billy Elliot: The Musical" theater in the U.S. is presented. When asked on his priorities of the training, he says that he is concentrating on their feet to help them gain a better balance as they will dance in a raked stage. He states that the hardest part in training male dancers is to make them understand on preparation. He notes that he always see himself in the boys' performance, which makes him feel great.

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