Structural identification of SAR-943 metabolites generated by human liver microsomes in vitro using mass spectrometry in combination with analysis of fragmentation patterns

SAR-943 (32-deoxo rapamycin) is a proliferation signal inhibitor via interaction with the mammalian target of rapamycin (mTOR). Most importantly, SAR-943 has improved chemical stability compared to rapamycin (sirolimus) and is currently under investigation as a drug coated on coronary stents. It was the goal of this study to identify the SAR-943 metabolites generated after incubation with human liver microsomes using high-resolution mass spectrometry (MS) and MS/iontrap (MS(n)) and comparison of fragmentation patterns of the metabolites with those of SAR-943 and other known rapamycin derivatives. Our study showed that SAR-943 is mainly hydroxylated and/or demethylated by human liver microsomes. The structures of the following metabolites were identified: O-demethylated metabolites: 39-O-desmethyl, 16-O-desmethyl and 27-O-desmethyl SAR-943; hydroxylated metabolites: hydroxy piperidine SAR-943, 11-hydroxy, 12-hydroxy, 14-hydroxy, 23-hydroxy, 24-hydroxy, 25-hydroxy, 46-hydroxy and 49-hydroxy SAR-943; didemethylated metabolites: 16,39-O-didesmethyl and 27,39-O-didesmethyl SAR-943; demethylated-hydroxylated metabolites: 39-O-desmethyl, 23- or 24-hydroxy and 39-O-desmethyl, hydroxy piperidine SAR-943 and dihydroxylated metabolites: 12-,23- or 24-dihydroxy SAR-943. In addition, several other demethylated-hydroxylated and dihydroxylated metabolites were detected. However, their exact structures could not be identified.     

A nonclassical dihydrogen adduct of S = ½ Fe(I)

We have exploited the capacity of the "(SiP(iPr)(3))Fe(I)" scaffold to accommodate additional axial ligands and characterized the mononuclear S = ? H(2) adduct complex (SiP(iPr)(3))Fe(I)(H(2)). EPR and ENDOR data, in the context of X-ray structural results, revealed that this complex provides a highly unusual example of an open-shell metal complex that binds dihydrogen as a ligand. The H(2) ligand at 2 K dynamically reorients within the ligand-binding pocket, tunneling among the energy minima created by strong interactions with the three Fe-P bonds.     

Lambda-fold 2-perfect 6-cycle systems in equipartite graphs

A 6-cycle system of a graph G is an edge-disjoint decomposition of G into 6-cycles. Graphs G, for which necessary and sufficient conditions for existence of a 6-cycle system have been found, include complete graphs and complete equipartite graphs. A 6-cycle system of G is said to be 2-perfect if the graph formed by joining all vertices distance 2 apart in the 6-cycles is again an edge-disjoint decomposition of G, this time into 3-cycles, since the distance 2 graph in any 6-cycle is a pair of disjoint 3-cycles.Necessary and sufficient conditions for existence of 2-perfect 6-cycle systems of both complete graphs and complete equipartite graphs are known, and also of λ-fold complete graphs. In this paper, we complete the problem, giving necessary and sufficient conditions for existence of λ-fold 2-perfect 6-cycle systems of complete equipartite graphs.     

Spasmodic dysphonia and vocal fold paralysis:Outcomes of voice problems on work-related functioning

Patients at a university voice disorder clinic diagnosed with spasmodicdysphonia (SD, n = 68) or vocal fold paralysis (VFP, n = 57) reported vocal symptoms and adverse work outcomes in contrast to a nondisordered group (ND, n = 68). Patients with SD most frequently cited symptoms of effortfulness (57%) and weakness (54%), VFP cited hoarseness (70%) and weakness (60%), while the nondisordered reported hoarseness (28%). SD and VFP produced greater (p<.05) adverse work outcomes than the nondisordered in the past (SD: 65%, VFP: 41%, ND: 3%), potential future (SD: 78%, VFP: 65%, ND: 19%), and current job performance (SD: 64%, VFP: 46%, ND: 2%). These disorders significantly disrupt socioeconomic outcomes and research is needed to improve functional ability and quality of life.     

Episodic paroxysmal laryngospasm: Voice and pulmonary function assessment and management

Episodic paroxysmal laryngospasm (EPL) is a sign of laryngeal dysfunction, often without a specific organic etiology, which can masquerade as asthma, vocal fold paralysis, or a functional voice disorder. The intermittent respiratory distress of EPL may precipitate an apparent upper airway obstructive emergency, resulting in unnecessary endotracheal intubation, cardiopulmonary resuscitation, or tracheostomy. During 27 months, seven women and three men, ages 30–76 years, were assessed by a high diagnostic index of suspicion, an intensive history including psychosocial factors, physical examination of the airways, provocative asthma testing, and swallowing studies. Videolaryngoscopy, stroboscopy, and pulmonary flow-volume loop testing were definitive. The classic appearance was paradoxic inspiratory adduction of the anterior vocal folds with a posterior diamond-shaped glottic gap. During an attack of stridor or wheezing, attenuation of the inspiratory flow rate as depicted by the flow-volume loop suggested partial extrathoracic upper airway obstruction. Swallowing evaluation by videolaryngoscopy and videoesophagography may uncover gastroesophageal reflux disease. Hallmarks of management include patient and family education by observation of laryngoscopic videos, a specific speech therapy program, psychotherapy, and medical treatment of associated disorders. Electromyography may become a valuable future adjunct. Unlike laryngeal dystonia, patients with EPL do not benefit from botulinum toxin type A.     

Limit surfaces of Riemann examples

The family of embedded, singly periodic minimal surfaces of Riemann have as limit-surfaces the helicoid, the catenoid, a single plane, or an infinite set of equally-spaced parallel planes.     

Functional impact of nodules: A case-comparison study

Patients diagnosed with nodules (NO = 40) in a large university hospital clinic and an age-stratum matched nondiseased group (ND = 200) described adverse outcomes of vocal impairment on work and work-related communications. NOs were significantly more likely than NDs to report symptoms of hoarseness (73% vs. 26%), high-note difficulty (70% vs. 20%), difficulty speaking with a lower voice (53% vs. 13%) and a tired voice (50% vs. 10%), and their greatest source of physical discomfort was associated with scratchiness (61% vs. 3%). The average number of symptoms was four in NOs and less than one in NDs. Nodule patients were most concerned about the effects their voice problem would have on their future career (78% vs. 24%) and 49% of NOS reported their voice problem had an adverse work effect in the past compared with 4% of NDs. Having a voice condition limited current job performance in 39% of the NO group but only in 2% of the ND group. The results suggest that a diagnosis of nodules plays a major role in disrupting careers and work activities and that available educational programs and additional research are needed for improving their functional ability and preventing adverse outcomes in the lives of individuals with voice disorders.