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Patients with Goldenhar syndrome exhibit a number of characteristic symptoms, including middle and internal ear malformations that may cause profound hearing loss. Bone-anchored hearing aids have been used to treat these patients in the past, although complications may arise due to the nature of the disease. Herein we present the case of a pediatric patient with Goldenhar syndrome whose hearing aid abutment extruded spontaneously because of poor bone quality, despite adequate thickness. We provide a brief review of the literature and suggest a flexible surgical plan for any syndromic pediatric patient.

Objective: To determine the incidence of high jugular bulb in a group of patients with definite Ménière's disease, and to investigate whether the position or size of the jugular bulb is significantly different in the affected ear than in the unaffected ear., Methods: Retrospective review of patient charts, audiograms, and computed tomography scans to determine the position and size of the jugular bulb in the affected and contralateral ears, as well as other abnormalities., Results: High jugular bulb was found in 57.1 per cent of affected ears. Encroachment of the cochlear and vestibular aqueducts was apparent in 39.3 per cent and 35.7 per cent, respectively, of affected ears. Diverticulum and dehiscence were observed in 28.6 per cent of affected ears. High jugular bulb was significantly associated with encroachment of the cochlear aqueduct (p = 0.003)., Conclusion: The mediolateral and anteroposterior position of the jugular bulb determines encroachment of the surrounding structures. An abnormal position is postulated to contribute to the development of Ménière's disease.

Cholesterol granulomas are the most common lesions involving the petrous apex. However, they are still an uncommon finding overall, and they often remain undiagnosed until they have become extremely large and symptomatic. Many surgical approaches to the petrous apex exist. Factors that often influence the surgical approach include the surgeon's experience, the patient's anatomy, and the patient's hearing status. The purpose of this case report-which involved a 66-year-old woman who was referred to our clinic for evaluation of severe headaches, dizziness, and left-sided pulsatile tinnitus-is to demonstrate the definitive need for an extended middle fossa approach when a bilobed petrous apex mass is encountered.

A series of N-aryl pyridinone inhibitors of p38 mitogen activated protein (MAP) kinase were designed and prepared based on the screening hit SC-25028 (1) and structural comparisons to VX-745 (5). The focus of the investigation targeted the dependence of potency and metabolic stability on the benzyloxy connectivity, the role of the C-6 position and the substitution pattern on the N-phenyl ring. Further optimization produced the highly selective and potent pyridinones 2 and 3. These inhibitors exhibited activity in both acute and chronic models of inflammation., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The synthesis and SAR studies of a novel N-aryl pyridinone class of p38 kinase inhibitors are described. Systematic structural modifications to the HTS lead, 5, led to the identification of (-)-4a as a clinical candidate for the treatment of inflammatory diseases. Additionally, the chiral synthesis and properties of (-)-4a are described., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The synthesis, structure-activity relationship and modeling of a series of 5-substituted-N-aryl pyridazinone based p38alpha inhibitors are described. In comparing the series to the similar N-aryl pyridinone series, it was found that the pyridazinones maintained a weaker interaction to the p38 enzyme, and therefore showed generally weaker binding than the pyridinones., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Starting from an initial HTS screening lead, a novel series of C(5)-substituted diaryl pyrazoles were developed that showed potent inhibition of p38alpha kinase. Key to this outcome was the switch from a pyridyl to pyrimidine at the C(4)-position leading to analogs that were potent in human whole blood based cell assay as well as in a number of animal efficacy models for rheumatoid arthritis. Ultimately, we identified a clinical candidate from this substrate; SD-0006., (Copyright 2010 Elsevier Ltd. All rights reserved.)

We recently described a novel series of aminopyridopyrazinones as PDE5 inhibitors. Efforts toward optimization of this series culminated in the identification of 3-[4-(2-hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, which possessed an excellent potency and selectivity profile and demonstrated robust in vivo blood pressure lowering in a spontaneously hypertensive rat (SHR) model. Furthermore, this compound is brain penetrant and will be a useful agent for evaluating the therapeutic potential of central inhibition of PDE5. This compound has recently entered clinical trials.

Hydroxyapatite bone cement is a versatile material used to reconstruct many types of bony surgical defects, and its applications have been widely reported in the literature. Still, complications of its use do occur. We describe 2 cases of hydroxyapatite resorption and subsequent seroma formation in patients who had undergone retrosigmoid craniotomy. The presentation in both cases mimicked a CSF leak. In both cases, the fragmented cement was removed, and the patient experienced no further complications. While hydroxyapatite cement is a highly useful product for the reconstruction of some craniofacial or skull base defects, we believe that it should not be used for the reconstruction of retrosigmoid/suboccipital craniotomies because it is associated with unacceptably high complication rates. Surgeons must exercise caution in selecting candidates for hydroxyapatite reconstruction of cranial defects.

The identification and evolution of a series of potent and selective p38 inhibitors is described. p38 inhibitors based on a N-benzyl pyridinone high-throughput screening hit were prepared and their SAR explored. Their design was guided by ligand bound co-crystals of p38alpha. These efforts resulted in the identification of 12r and 19 as orally active inhibitors of p38 with significant efficacy in both acute and chronic models of inflammation.

We describe efforts to improve the pharmacokinetic profile of the aminopyridopyrazinone class of PDE5 inhibitors. These efforts led to the discovery of 3-[(trans-4-hydroxycyclohexyl)amino]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, a potent and selective inhibitor of PDE5 with an excellent PK profile.

Efforts to improve the potency and physical properties of the aminopyridiopyrazinone class of PDE5 inhibitors through modification of the core ring system are described. Five new ring systems are evaluated and features that impart improved potency and improved solubility are delineated.

A new class of potent and selective PDE5 inhibitors is disclosed. Guided by X-ray crystallographic data, optimization of an HTS lead led to the discovery of a series of 2-aryl, (N8)-alkyl substituted-6-aminosubstituted pyrido[3,2b]pyrazinones which show potent inhibition of the PDE5 enzyme. Synthetic details and some structure-activity relationships are also presented.

PH-797804 is a diarylpyridinone inhibitor of p38alpha mitogen-activated protein (MAP) kinase derived from a racemic mixture as the more potent atropisomer (aS), first proposed by molecular modeling and subsequently confirmed by experiments. On the basis of structural comparison with a different biaryl pyrazole template and supported by dozens of high-resolution crystal structures of p38alpha inhibitor complexes, PH-797804 is predicted to possess a high level of specificity across the broad human kinase genome. We used a structural bioinformatics approach to identify two selectivity elements encoded by the TXXXG sequence motif on the p38alpha kinase hinge: (i) Thr106 that serves as the gatekeeper to the buried hydrophobic pocket occupied by 2,4-difluorophenyl of PH-797804 and (ii) the bidentate hydrogen bonds formed by the pyridinone moiety with the kinase hinge requiring an induced 180 degrees rotation of the Met109-Gly110 peptide bond. The peptide flip occurs in p38alpha kinase due to the critical glycine residue marked by its conformational flexibility. Kinome-wide sequence mining revealed rare presentation of the selectivity motif. Corroboratively, PH-797804 exhibited exceptionally high specificity against MAP kinases and the related kinases. No cross-reactivity was observed in large panels of kinase screens (selectivity ratio of >500-fold). In cellular assays, PH-797804 demonstrated superior potency and selectivity consistent with the biochemical measurements. PH-797804 has met safety criteria in human phase I studies and is under clinical development for several inflammatory conditions. Understanding the rationale for selectivity at the molecular level helps elucidate the biological function and design of specific p38alpha kinase inhibitors.

We conducted a study to establish standardized measurements of the common anatomic landmarks used during surgery via the middle cranial fossa approach. Results were based on high-resolution computed tomography (CT) images of 98 temporal bones in 54 consecutively presenting patients. Measurements were obtained with the assistance of the standard PACS (picture archiving and communication system) software. We found that the superior semicircular canal (SSC) dome was not the highest point on the temporal bone (i.e., the arcuate eminence) in 78 of the temporal bone images (79.6%). Pneumatization above the SSC and above the internal auditory canal (IAC) was found in 27 (27.6%) and 39 (39.8%) temporal bone images, respectively. The anterior wall of the external auditory canal was always anterior to the anterior wall of the IAC. The mean angles between the SSC and the posterior and anterior walls of the IAC were 42.3 degrees and 60.8 degrees, respectively. We also measured other distances, and we compared our findings with those published by others. We hope that the results of our study will help surgeons safely and rapidly locate anatomic landmarks when performing surgery via the middle cranial fossa approach.

The cytotoxic, cyclic heptadepsipeptide, natural product callipeltin B was synthesized on a solid-phase support in 15% overall yield. Comparison of the 1H NMR spectra of three synthetic isomers with those of callipeltin B confirmed the configurational reassignment of its threonine residues as d-allothreonine and the assignment of the configuration of its beta-methoxytyrosine residue as (2R,3R).

Cerebrospinal fluid (CSF) leaks may occur after acoustic neuroma resection. These leaks are usually the result of an iatrogenic injury during removal. The retrosigmoid approach is commonly associated with leaks that occur through the lateral end of the internal auditory canal, through the perilabyrinthine cells extending to the region of the internal auditory canal, or through the retrosigmoid air cells. We describe a case of an infracochlear CSF leak that developed following the retrosigmoid resection of an acoustic neuroma. To the best of our knowledge, this leak was unique for both its location and etiology.

Van der Woude syndrome is an autosomal dominant disease characterized by lower lip pits with or without cleft lip and/or cleft palate. The lip pits commonly have salivary glands that drain into them, which leads to salivary flow from the lip pits. Lip pits may be associated with submucosal palatal cleft, velopharyngeal insufficiency, or genitourinary or cardiovascular anomalies. The pits are treated by surgical resection. The authors report a case of van der Woude syndrome with isolated lip pits and speech difficulties that had been unrecognized until the patient was 6 years old. The surgical technique is described to ensure that the often-bifurcating tracts are removed entirely.

The absolute stereochemistry of the three unresolved structural components in neamphamide A (1) was determined to be (R)-beta-methoxy-L-tyrosine, (2R,3R,4S)-4-amino-7-guanidino-2,3-dihydroxyheptanoic acid, and (2R,3R,4R)-3-hydroxy-2,4,6-trimethylheptanoic acid. Stereochemical assignments were made by chemical degradation of 1, derivatization of the resulting products, and then spectroscopic and chromatographic comparison of the derivatives with synthetically prepared standards. Using the same analytical protocol developed for 1, the beta-methoxytyrosine residue in papuamide B (2) was found to be (R)-beta-methoxy-D-tyrosine. This represents a rare example of divergent stereochemistry in an unusual amino acid residue that is present in two closely related classes of peptides.

Objective: Given the associated risk of general anesthesia in elderly patients with cardiovascular disease, the authors set out to determine the feasibility of transcanal cochlear implantation under local anesthesia with monitored anesthesia care., Methods: A 70-year-old man with a history of coronary artery bypass grafting, diabetes mellitus, and an American Society of Anesthesiologists Class III cardiac status underwent cochlear implantation under local with monitored anesthesia care., Result: With the described technique and regimen of intravenous remifentanil and dexmedetomidine, the patient tolerated the 60-minute procedure without tachycardia, hyper- or hypotension, or cardiac ischemia., Conclusion: Cochlear implantation using the pericanal electrode technique performed under local anesthesia with monitored anesthesia care is possible in patients at risk for undergoing general anesthesia for cochlear implantation.

The chin is the keystone linking the aesthetics of the face and neck but is often neglected in the analysis. Procedures related to the chin play an important role in defining neck anatomy. Alloplastic implants can provide the illusion of a longer jaw line in a patient with retrogenia. Even greater anatomic changes to the neck result when a sliding genioplasty is performed. This effect is primarily due to the digastric attachments from the mentum and mastoid. Advancing the mentum may have a more direct effect of elevating the position of the hyoid, which sharpens the angle between the jaw and neck. Finally, the diagnosis of a witch's chin is also discussed for the patients who present for aging neck surgery.