A possible link between KCNQ2- and STXBP1-related encephalopathies: STXBP1 reduces the inhibitory impact of syntaxin-1A on M current

Summary

Objective

Kv7 channels mediate the voltage-gated M-type potassium current. Reduction of M current due to KCNQ2 mutations causes early onset epileptic encephalopathies (EOEEs). Mutations in STXBP1 encoding the syntaxin binding protein 1 can produce a phenotype similar to that of KCNQ2 mutations, suggesting a possible link between STXBP1 and Kv7 channels. These channels are known to be modulated by syntaxin-1A (Syn-1A) that binds to the C-terminal domain of the Kv7.2 subunit and strongly inhibits M current. Here, we investigated whether STXBP1could prevent this inhibitory effect of Syn-1A and analyzed the consequences of two mutations in STXBP1 associated with EOEEs.

Methods

Electrophysiologic analysis of M currents mediated by homomeric Kv7.2 or heteromeric Kv7.2/Kv7.3 channels in Chinese hamster ovary (CHO) cells coexpressing Syn-1A and/or STXBP1 or mutants STXBP1 p.W28* and p.P480L. Expression and interaction of these different proteins have been investigated using biochemical and co-immunoprecipitation experiments.

Results

Syn-1A decreased M currents mediated by Kv7.2 or Kv7.2/Kv7.3 channels. STXBP1 had no direct effects on M current but dampened the inhibition produced by Syn-1A by abrogating Syn-1A binding to Kv7 channels. The mutation p.W28*, but not p.P480L, failed to rescue M current from Syn-1A inhibition. Biochemical analysis showed that unlike the mutation p.W28*, the mutation p.P480L did not affect STXBP1 expression and reduced the interaction of Syn-1A with Kv7 channels.

Significance

These data indicate that there is a functional link between STXBP1 and Kv7 channels via Syn-1A, which may be important for regulating M-channel activity and neuronal excitability. They suggest also that a defect in Kv7 channel activity or regulation could be one of the consequences of some STXBP1 mutations associated with EOEEs. Furthermore, our data reveal that STXBP1 mutations associated with the Ohtahara syndrome do not necessarily result in protein haploinsufficiency.

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Correlation of Circulating CD64 + /CD163 + Monocyte Ratio and stroma/peri-tumoral CD163 + Monocyte Density with Human Papillomavirus Infected Cervical Lesion Severity

Abstract

HPV infected cervical cells secrete mediators that are gradually changed and have influence on infiltrating M2 phenotypic monocytes in cervical lesions. However, profiles of circulating immune cells in women with cervical lesions and M2 phenotypic monocyte activity in HPV infected cervical lesions are limited. This study aimed to investigate circulating monocyte populations correlated with M2 phenotype density and its activity in HPV infected cervical lesions. HPV DNA was investigated in cervical tissues using PCR. High risk HPV E6/E7 mRNA was detected using in situ hybridization. CD163 immunohistochemical staining was performed for M2 macrophage. CD163 and Arg1 mRNA expression were detected using real-time PCR. Circulating monocyte subpopulations were analyzed using flow cytometry. CD163 and Arg1 mRNA expression were increased according to cervical lesion severity and corresponding with density of M2 macrophage in HSIL and SCC in stroma and peri-tumoral areas. Additionally, the relationship between M2 macrophage infiltration and high risk HPV E6/E7 mRNA expression was found and corresponded with cervical lesion severity. Circulating CD14⁺CD16⁺ and CD14⁺CD163⁺ monocytes were elevated in No-SIL and cervical lesions. Interestingly, CD14⁺CD64⁺ monocyte was greatly elevated in HSIL and SCC, whereas intracellular IL-10⁺ monocytes were not significantly different between cervical lesions. The correlation between increasing ratio of circulating CD64⁺/CD163⁺ monocyte and density of infiltrating CD163⁺ monocytes was associated with severity of HPV infected cervical lesions. The elevated circulating CD64⁺/CD163⁺ monocyte ratio correlates to severity of HPV infected cervical lesions and might be a prognostic marker in cervical cancer progression.

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Improving margin revision: Characterization of tumor bed margins in early oral tongue cancer

Margin evaluation is performed to assess the adequacy of tumor removal [1]. One of the quality initiatives introduced by the American Head and Neck Society deals with the management of patients with oral squamous cell carcinoma (SCC) extending to margins [2]. There are two major approaches to the sampling of margins [3–7]. In the specimen-driven approach, margin clearance is assessed from en bloc resection specimens. Studies have shown that the most relevant margins are those derived from the resection specimen [8–16].

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RELA fusion-positive anaplastic ependymoma: molecular characterization and advanced MR imaging

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Maxillofacial surgery: the impact of the Great War on both sides of the trenches

Abstract

"War is the father and King of all", Heraclitus the obscure philosopher, declares. It certainly appears that the specialty of maxillofacial surgery was greatly advanced during WWI. This article focuses on the circumstances under which the specialty was developed, the significant events and the important figures that played a leading role in the advancement of a new fascinating surgical specialty. The literature leaves no doubt that trench warfare despite its devastating outcome for humanity has forged the shape of modern maxillofacial surgery.

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Rare case report of an aggressive follicular lymphoid hyperplasia in maxilla

Abstract

Follicular lymphoid hyperplasia is a very rare though benign reactive process of an unknown pathogenesis that may resemble a follicular lymphoma, clinically and histologically. Oral reactive follicular hyperplasia (RFH) has been described on the hard or soft palate and at the base of the tongue. We describe here the first case of RFH presenting as an aggressive tumor on the right posterior side of the maxilla in a 24-year-old male patient. The lesion had a clinical evolution of 18 months and was noticed after the surgical extraction of the right third molar, although we cannot assume a cause-effect relation with that surgical event whatsoever. His medical history was unremarkable. Following an incisional biopsy, histological examination revealed lymphoid follicles comprised by germinal centers surrounded by well-defined mantle zones. The germinal centers were positive for Bcl-6, CD10, CD20, CD21, CD23, CD79a, and Ki-67, while negative for Bcl-2, CD2, CD3, CD5, and CD138. The mantle and interfollicular zones were positive for Bcl-2, CD2, CD3, CD5, CD20, and CD138. Both areas were diffusively positive for kappa and lambda, showing polyclonality. The patient underwent a vigorous curettage of the lesion with no reoccurrences at 36 months of follow-up. This case report demonstrates that morphologic and immunohistochemical analyses are crucial to differentiate RFH from follicular lymphoma, leading to proper management.

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Recurrent Metastatic Medullary Thyroid Carcinoma: A Case of Sustained Response to Prolonged Treatment with Somatostatin Analogues

Thyroid , Vol. 0, No. 0.


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Simple, mild, one-step labelling of proteins with gallium-68 using a tris(hydroxypyridinone) bifunctional chelator: a 68 Ga-THP-scFv targeting the prostate-specific membrane antigen

Abstract

Background

Labelling proteins with gallium-68 using bifunctional chelators is often problematic because of unsuitably harsh labelling conditions such as low pH or high temperature and may entail post-labelling purification. To determine whether tris(hydroxypyridinone) (THP) bifunctional chelators offer a potential solution to this problem, we have evaluated the labelling and biodistribution of a THP conjugate with a new single-chain antibody against the prostate-specific membrane antigen (PSMA), an attractive target for staging prostate cancer (PCa). A single-chain variable fragment (scFv) of J591, a monoclonal antibody that recognises an external epitope of PSMA, was prepared in order to achieve biokinetics matched to the half-life of gallium-68. The scFv, J591c-scFv, was engineered with a C-terminal cysteine.

Results

J591c-scFv was produced in HEK293T cells and purified by size-exclusion chromatography. A maleimide THP derivative (THP-mal) was coupled site-specifically to the C-terminal cysteine residue. The THP-mal-J591c-scFv conjugate was labelled with ammonium acetate-buffered gallium-68 from a ⁶⁸Ge/⁶⁸Ga generator at room temperature and neutral pH. The labelled conjugate was evaluated in the PCa cell line DU145 and its PSMA-overexpressing variant in vitro and xenografted in SCID mice.

J591c-scFv was produced in yields of 4–6 mg/l culture supernatant and efficiently coupled with the THP-mal bifunctional chelator. Labelling yields > 95% were achieved at room temperature following incubation of 5 μg conjugate with gallium-68 for 5 min without post-labelling purification. ⁶⁸Ga-THP-mal-J591c-scFv was stable in serum and showed selective binding to the DU145-PSMA cell line, allowing an IC50 value of 31.5 nM to be determined for unmodified J591c-scFv. Serial PET/CT imaging showed rapid, specific tumour uptake and clearance via renal elimination. Accumulation in DU145-PSMA xenografts at 90 min post-injection was 5.4 ± 0.5%ID/g compared with 0.5 ± 0.2%ID/g in DU145 tumours (n = 4).

Conclusions

The bifunctional chelator THP-mal enabled simple, rapid, quantitative, one-step room temperature radiolabelling of a protein with gallium-68 at neutral pH without a need for post-labelling purification. The resultant gallium-68 complex shows high affinity for PSMA and favourable in vivo targeting properties in a xenograft model of PCa.

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Maxillofacial surgery: the impact of the Great War on both sides of the trenches

Abstract

"War is the father and King of all", Heraclitus the obscure philosopher, declares. It certainly appears that the specialty of maxillofacial surgery was greatly advanced during WWI. This article focuses on the circumstances under which the specialty was developed, the significant events and the important figures that played a leading role in the advancement of a new fascinating surgical specialty. The literature leaves no doubt that trench warfare despite its devastating outcome for humanity has forged the shape of modern maxillofacial surgery.

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Rare case report of an aggressive follicular lymphoid hyperplasia in maxilla

Abstract

Follicular lymphoid hyperplasia is a very rare though benign reactive process of an unknown pathogenesis that may resemble a follicular lymphoma, clinically and histologically. Oral reactive follicular hyperplasia (RFH) has been described on the hard or soft palate and at the base of the tongue. We describe here the first case of RFH presenting as an aggressive tumor on the right posterior side of the maxilla in a 24-year-old male patient. The lesion had a clinical evolution of 18 months and was noticed after the surgical extraction of the right third molar, although we cannot assume a cause-effect relation with that surgical event whatsoever. His medical history was unremarkable. Following an incisional biopsy, histological examination revealed lymphoid follicles comprised by germinal centers surrounded by well-defined mantle zones. The germinal centers were positive for Bcl-6, CD10, CD20, CD21, CD23, CD79a, and Ki-67, while negative for Bcl-2, CD2, CD3, CD5, and CD138. The mantle and interfollicular zones were positive for Bcl-2, CD2, CD3, CD5, CD20, and CD138. Both areas were diffusively positive for kappa and lambda, showing polyclonality. The patient underwent a vigorous curettage of the lesion with no reoccurrences at 36 months of follow-up. This case report demonstrates that morphologic and immunohistochemical analyses are crucial to differentiate RFH from follicular lymphoma, leading to proper management.

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Posterior reversible encephalopathy syndrome (PRES) induced by pazopanib, a multi-targeting tyrosine kinase inhibitor, in a patient with soft-tissue sarcoma: case report and review of the literature

Summary

Posterior reversible encephalopathy syndrome (PRES) is a clinical entity characterized by acute neurological symptoms such as severe headache, seizures, and visual disturbance, and by typical reversible lesion on brain magnetic resonance (MR) images. Since PRES is thought to be caused by vascular endothelial injury due to cytotoxic agents or acute systemic hypertension, the number of reports on PRES associated with angiogenesis inhibitors has been increasing. Although five cases that developed PRES due to pazopanib for renal cell carcinoma have already been reported, none of PRES due to pazopanib for soft-tissue sarcoma has been reported thus far. We describe a case of a 49-year-old woman with retroperitoneal soft-tissue sarcoma who developed PRES during pazopanib administration. Pazopanib at 800 mg/day was administered as her third-line treatment at relapse. After 38 days of pazopanib, she was admitted to our hospital with severe headache, vomiting, and systemic hypertension. The next day, she developed consciousness deterioration and visual disturbance together with exacerbated systemic hypertension. Brain MR images revealed hyper-intense signals on FLAIR sequences in the bilateral occipital lobes and the left thalamus. Intravenous nicardipine injection was immediately started to control her blood pressure and pazopanib was discontinued. Her symptoms gradually improved and disappeared on the fifth hospital day. After 2 weeks, hyper-intense signals on a FLAIR sequence disappeared completely. She restarted a low dose of pazopanib under good blood pressure control and experienced no subsequent recurrence of PRES.

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Maxillofacial surgery: the impact of the Great War on both sides of the trenches

Abstract

"War is the father and King of all", Heraclitus the obscure philosopher, declares. It certainly appears that the specialty of maxillofacial surgery was greatly advanced during WWI. This article focuses on the circumstances under which the specialty was developed, the significant events and the important figures that played a leading role in the advancement of a new fascinating surgical specialty. The literature leaves no doubt that trench warfare despite its devastating outcome for humanity has forged the shape of modern maxillofacial surgery.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2y4UAZx

Rare case report of an aggressive follicular lymphoid hyperplasia in maxilla

Abstract

Follicular lymphoid hyperplasia is a very rare though benign reactive process of an unknown pathogenesis that may resemble a follicular lymphoma, clinically and histologically. Oral reactive follicular hyperplasia (RFH) has been described on the hard or soft palate and at the base of the tongue. We describe here the first case of RFH presenting as an aggressive tumor on the right posterior side of the maxilla in a 24-year-old male patient. The lesion had a clinical evolution of 18 months and was noticed after the surgical extraction of the right third molar, although we cannot assume a cause-effect relation with that surgical event whatsoever. His medical history was unremarkable. Following an incisional biopsy, histological examination revealed lymphoid follicles comprised by germinal centers surrounded by well-defined mantle zones. The germinal centers were positive for Bcl-6, CD10, CD20, CD21, CD23, CD79a, and Ki-67, while negative for Bcl-2, CD2, CD3, CD5, and CD138. The mantle and interfollicular zones were positive for Bcl-2, CD2, CD3, CD5, CD20, and CD138. Both areas were diffusively positive for kappa and lambda, showing polyclonality. The patient underwent a vigorous curettage of the lesion with no reoccurrences at 36 months of follow-up. This case report demonstrates that morphologic and immunohistochemical analyses are crucial to differentiate RFH from follicular lymphoma, leading to proper management.

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Improving margin revision: Characterization of tumor bed margins in early oral tongue cancer

Margin evaluation is performed to assess the adequacy of tumor removal [1]. One of the quality initiatives introduced by the American Head and Neck Society deals with the management of patients with oral squamous cell carcinoma (SCC) extending to margins [2]. There are two major approaches to the sampling of margins [3–7]. In the specimen-driven approach, margin clearance is assessed from en bloc resection specimens. Studies have shown that the most relevant margins are those derived from the resection specimen [8–16].

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Book Review.

No abstract available

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Stress and Unusual Events Exacerbate Symptoms in Meniere's Disease: A Longitudinal Study.

Hypothesis: Stress and unusual events are associated with a higher likelihood of attacks and increased symptom severity in Meniere's disease (MD). Background: MD is an unpredictable condition which severely impacts the quality of life of those affected. It is thought that unusual activity and stress may act as an attack trigger in MD, but research in this area has been limited to date. Methods: This was a longitudinal study conducted over two phases. A mobile phone application was used to collect daily data on Meniere's attacks and individual symptoms (aural fullness, dizziness, hearing loss, and tinnitus), as well as prevalence of unusual events (phase I), and stress levels (phase II). There were 1,031 participants (730 women, mean age 46.0 yr) in phase I and 695 participants (484 women, mean age 47.7 yr) in phase II. Panel data regression analyses were employed to examine for associations between unusual events/stress and attacks/symptoms, including the study of 24 hours lead and lag effects. Results: Unusual events and higher stress levels were associated with higher odds of Meniere's attacks and more severe symptoms. The odds of experiencing an attack were 2.94 (95% confidence interval [CI] 2.37, 3.65) with reporting of unusual events and increased by 1.24 (95% CI 1.20, 1.28) per unit increase in stress level. Twenty-four hour lead (OR 1.10 [95% CI 1.07, 1.14]) and lag (OR 1.10 [95% CI 1.06, 1.13]) effects on attacks were also found with increases in stress. Conclusion: This study provides the strongest evidence to date that stress and unusual events are associated with attacks and symptom exacerbation in MD. Improving our understanding of stress and unusual events as triggers in Meniere's may reduce the uncertainty associated with this condition and lead to improved quality of life for affected individuals. Copyright (C) 2017 by Otology & Neurotology, Inc. Image copyright (C) 2010 Wolters Kluwer Health/Anatomical Chart Company

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Response to Letter to the Editor: "Comparison of Acyclovir and Famciclovir for Ramsay Hunt Syndrome".

No abstract available

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Cochlear Implantation in Cochlear Ossification: Retrospective Review of Etiologies, Surgical Considerations, and Auditory Outcomes.

Objectives: 1) To review the surgical and auditory outcomes and complications of cochlear implantation in cases with cochlear ossification. 2) To evaluate association between the extent and etiology of ossification to outcomes. Study Design: Retrospective study. Setting: Otology and skull base surgery center. Subjects and Methods: Charts of 40 patients (42 ears) with cochlear ossification undergoing cochlear implantation were reviewed. Demographic features, operative findings, auditory outcomes, and complications were analyzed. Operative findings included extent of cochlear ossification, extent of drilling required to obtain patent cochlear lumen, approach (posterior tympanotomy/subtotal petrosectomy), electrode insertion (partial/complete, scala tympani/vestibuli), and complications. Auditory outcomes were assessed over a 4-year follow-up period using vowel, word, sentence, and comprehension scores. Patients were divided into groups (otosclerotic/non-otosclerotic and round window/basal turn ossification) for comparison of auditory outcomes. Outcomes were compared with 60 randomly identified controls (adults with postlingual deafness) who underwent implantation with no cochlear ossification. Results: The median age and duration of deafness of patients was 54.39 and 27.15 years, respectively. Etiology of cochlear ossification was otosclerosis in 23 of 42 ears and mixed in 19 of 42 ears (chronic otitis media, temporal bone fractures, idiopathic, meningitis, Cogan's syndrome) with exclusive round window involvement in 54.7% of cases and the rest having partial or complete basal turn ossification. 59.5% ears underwent subtotal petrosectomy for implantation. Three patients underwent scala vestibuli insertion and five had incomplete electrode insertion. Auditory outcomes were comparable in otosclerotic and non-otosclerotic cases and in round window and basal turn ossification cases. No significant differences were observed in auditory scores when compared with controls with no ossification. Conclusions: Cochlear implantation in cochlear ossification is feasible despite surgical challenges and modifications. Auditory outcomes in basal turn ossification appear to be comparable to cases with no ossification with extent of ossification having no significant association with outcomes. Copyright (C) 2017 by Otology & Neurotology, Inc. Image copyright (C) 2010 Wolters Kluwer Health/Anatomical Chart Company

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Cochlear Implant Associated Labyrinthitis: A Previously Unrecognized Phenomenon With a Distinct Clinical and Electrophysiological Impedance Pattern.

Objectives: To report a unique clinical entity "cochlear implant associated labyrinthitis," characterized by a distinct constellation of clinical symptoms and pattern of electrode impedance fluctuations. Study Design: Retrospective chart review. Methods: All patients that underwent cochlear implantation between January 2014 and December 2016 were retrospectively reviewed. All subjects with acute onset dizziness, device performance decline, and characteristic erratic pattern of electrode impedances occurring after an asymptotic postoperative interval were identified and reported. Results: Five patients with the above criteria were identified, representing 1.4% of all implant surgeries performed during this time. The median age at time of implantation was 71 years, and the median time interval between implantation and onset of symptoms was 126 days. All patients exhibited acute onset dizziness, subjective performance deterioration, erratic impedance pattern, and two experienced worsening tinnitus. Two of five patients underwent subsequent CT imaging, where good electrode placement was confirmed without cochlear ossification. Two of five patients received oral prednisone therapy. All patients reported a subjective improvement in symptoms and stabilization of electrode impedances. Three patients subsequently received vestibular testing, where significantly reduced peripheral vestibular function was identified. Conclusions: We describe a unique clinical entity, "cochlear implant associated labyrinthitis," characterized by a distinct constellation of clinical symptoms and corresponding electrode impedance anomalies. The exact cause for this event remains unknown, but may be related to viral illness, delayed foreign body reaction to the electrode, or a reaction to electrical stimulation. Future studies characterizing this unique clinical entity are needed to further elucidate cause and optimal management. Copyright (C) 2017 by Otology & Neurotology, Inc. Image copyright (C) 2010 Wolters Kluwer Health/Anatomical Chart Company

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Changes in Serum Prestin Concentration After Exposure to Cisplatin.

Hypothesis: There are temporal changes in the outer-hair-cell-specific protein, prestin, in the blood after administration of low-dose cisplatin. Methods: Two rodent models of ototoxicity were used. After control and baseline data collection, mice (n = 30) and guinea pigs (n = 10), respectively, were treated with cisplatin at 8 mg/kg. Auditory brainstem responses were recorded on Days 1, 3, 7, and 14 after treatment. Five mice were sacrificed at each time point and serum samples were obtained. A group of 10 guinea pigs were tested and serum samples were collected at each time point. Serum prestin concentrations were measured using separate enzyme-linked immunosorbent assays for each species. Results: Auditory brainstem responses thresholds changed relatively little in mice, but gradually increased in guinea pigs, as a function of time after cisplatin exposure. In contrast, serum prestin concentrations rose, reaching a peak on Days 3 and 7 after cisplatin treatment in mouse and guinea pig, respectively, before declining back to or below baseline/control levels 14 days after treatment. Conclusion: There was a time-dependent pattern of change in serum prestin after exposure to low-dose cisplatin in a resistant (mouse) and sensitive (guinea pig) rodent models. These comparative results suggest prestin may serve as a biomarker for cisplatin ototoxicity. Copyright (C) 2017 by Otology & Neurotology, Inc. Image copyright (C) 2010 Wolters Kluwer Health/Anatomical Chart Company

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Morphological Characteristics of Osseous External Auditory Canal and Its Relationship With External Auditory Canal Cholesteatoma in Patients With Congenital Aural Stenosis.

Objective: To investigate the characteristics of stenotic external auditory canal (EAC) (e.g., shape, length, orientation, and curvature) and to compare them with those of the cholesteatoma and no cholesteatoma groups, which may help to explain cholesteatoma formation to a certain degree. Methods: Computed tomography scans of two groups of patients (with and without EAC cholesteatoma) were analyzed. We determined the degree of microtia, the stenosis of EAC, radius and curvature of osseous EAC bending (abbreviated as OEB-r and OEB-c, respectively), and other anatomic parameters of EAC by using Mimics and Matlab. Results: There was no significant difference in the degree of microtia between the cholesteatoma and no cholesteatoma groups using the Marx grading system. Additionally, no significant difference was found in the stenosis of EAC between the two groups. The OEB-r was smaller in the cholesteatoma group (4.62 +/- 0.62 mm) than in the no cholesteatoma group (7.41 +/- 0.50 mm), and the OEB-c was found to be larger in the cholesteatoma group (1.55 +/- 0.05 x 10 mm-1) than in the no cholesteatoma group (1.10 +/- 0.10 x 10 mm-1). Moreover, the OEB-c (OR, 8.60; 95% CI, 2.67-27.75) was associated with EAC cholesteatoma formation. Conclusion: The curvature of osseous EAC in the cholesteatoma group was significantly larger than that in the no cholesteatoma group. It is suggested that the curvature of osseous EAC was a risk factor for EAC cholesteatoma formation. Copyright (C) 2017 by Otology & Neurotology, Inc. Image copyright (C) 2010 Wolters Kluwer Health/Anatomical Chart Company

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Dexamethasone: The wonder drug in perioperative medicine

Anesthesiologist have a greater understanding of the role of the stress response and the development of inflammation following surgery on clinical outcomes [1,2]. Exacerbation of inflammation after surgery has been shown to be associated with multiple negative postsurgical outcomes (e.g., pain, cardiovascular events) [3]. The reduction of inflammation is, therefore, a common target used by anesthesiologists to minimize postoperative complications [4–7].

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Unilateral Vocal Fold Paralysis in Parkinson Disease: Case Report and Review of the Literature

The objective of this study was to report the first case of unilateral vocal fold paralysis in a patient with Parkinson disease (PD) and to review the literature.

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Laryngocardiac Reflex: A Case Report and Review of the Literature

The vagus nerve has sensory and motor function in the larynx, as well as parasympathetic function in the thorax and abdomen. Stimulation of the superior laryngeal nerve can cause reflexive bradycardia.

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Is the Voice of Professional Voice Users With no Vocal Cord Lesions Similar to That of Non Professional Voice Users?

The objective of this study was to analyze if the voice of professional voice users (PVU) is comparable with that of a nonprofessional voice users (NPVUs), both of whom have no obvious vocal cord lesions.

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Chemical profiling of primary mesothelioma cultures defines subtypes with different expression profiles and clinical responses

Finding new treatment options for patients with malignant pleural mesothelioma is challenging due to the rarity and heterogeneity of this cancer type. The absence of druggable targets further complicates the development of new therapies. Current treatment options are therefore limited and prognosis remains poor. Experimental Design: We performed drug screening on primary mesothelioma cultures to guide treatment decisions of corresponding patients that were progressive after first or second line treatment. Results: We observed a high concordance between in vitro results and clinical outcomes. We defined three subgroups responding differently to the anti-cancer drugs tested. In addition, gene expression profiling yielded distinct signatures that segregated the differently responding subgroups. These genes signatures involved various pathways, most prominently the fibroblast growth factor pathway. Conclusions: Our primary mesothelioma culture system has proved to be suitable to test novel drugs. Chemical profiling of primary mesothelioma cultures allows personalizing treatment for a group of patients with a rare tumor type, where clinical trials are notoriously difficult. This personalized treatment strategy is expected to improve the poor prospects of mesothelioma patients.

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Tumor microvessel density as a prognostic marker in high-risk renal cell carcinoma patients treated on ECOG-ACRIN E2805

Purpose: Increased vascularity is a hallmark of renal cell carcinoma (RCC). Microvessel density (MVD) is one measurement of tumor angiogenesis, however its utility as a biomarker of outcome is unknown. ECOG-ACRIN 2805 (E2805) enrolled 1,943 resected high-risk RCC patients randomized to adjuvant sunitinib, sorafenib, or placebo. We aimed to determine the prognostic and predictive role of MVD in RCC. Methods: We obtained pre-treatment primary RCC nephrectomy tissues from 822 patients on E2805 and constructed tissue microarrays. Using quantitative immunofluorescence we measured tumor MVD as the area of CD34-expressing cells. We determined the association with disease-free survival (DFS), overall survival (OS), treatment arm and clinicopathologic variables. Results: High MVD (above the median) was associated with prolonged OS for the entire cohort (p=0.021) and for patients treated with placebo (p=0.028). The association between high MVD and OS was weaker in patients treated with sunitinib or sorafenib (p=0.060). MVD was not associated with DFS (p=1.00). On multivariable analysis, MVD remained independently associated with improved OS (p=0.013). High MVD correlated with Fuhrman grade 1-2 (p<0.001), clear cell histology (p<0.001), and absence of necrosis (p<0.001) but not with gender, age, sarcomatoid features, lymphovascular invasion, or tumor size. Conclusions:High MVD in resected high-risk RCC patients is an independent prognostic, rather than predictive, biomarker of improved OS. Further studies should assess whether incorporating MVD into clinical models will enhance our ability to predict outcome and if low MVD can be used for selection of high risk patients for adjuvant therapy trials.

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PQR309 is a novel dual PI3K/mTOR inhibitor with pre-clinical antitumor activity in lymphomas as a single agent and in combination therapy

Purpose: Activation of the PI3K/mTOR signaling pathway is recurrent in different lymphoma types and pharmacological inhibition of the PI3K/mTOR pathway has shown activity in lymphoma patients. Here, we extensively characterized the in vitro and in vivo activity and the mechanism of action of PQR309 (bimiralisib), a novel oral selective dual PI3K/mTOR inhibitor under clinical evaluation, in preclinical lymphoma models. Experimental Design: This study included preclinical in vitro activity screening on a large panel of cell lines, both as single agent and in combination, validation experiments on in vivo models and primary cells, proteomics and gene expression profiling and comparison with other signaling inhibitors. Results: PQR309 had in vitro anti-lymphoma activity as single agent and in combination with venetoclax, panobinostat, ibrutinib, lenalidomide, ARV-825, marizomib and rituximab. Sensitivity to PQR309 was associated with specific baseline gene expression features, such as high expression of transcripts coding for BCR pathway. Combining proteomics and RNA profiling, we identified the different contribution of PQR309-induced protein phosphorylation and gene expression changes to the drug mechanism of action. Gene expression signatures induced by PQR309 and of other signaling inhibitors largely overlapped. PQR309 showed activity in cells with primary or secondary resistance to idelalisib. Conclusions: Based on these results, PQR309 appeared as a novel and promising compound being worthwhile developing in the lymphoma setting.

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Molecular subtypes of pulmonary large cell neuroendocrine carcinoma predict chemotherapy treatment outcome

Purpose: Previous genomic studies have identified two mutually exclusive molecular subtypes of large-cell neuroendocrine carcinoma (LCNEC): the RB1 mutated (mostly co-mutated with TP53) and the RB1 wild-type groups. We assessed if these subtypes have a predictive value on chemotherapy outcome. Experimental Design: Clinical data and tumor specimens were retrospectively obtained from the Netherlands Cancer Registry and Pathology Registry. Panel-consensus pathology revision confirmed the diagnosis of LCNEC in 148 of 232 cases. Next-generation sequencing (NGS) for TP53, RB1, STK11, and KEAP1 genes, as well as immunohistochemistry (IHC) for RB1 and P16 was performed on 79 and 109 cases, respectively, and correlated with overall survival (OS) and progression free survival (PFS), stratifying for non-small cell lung cancertype chemotherapy including platinum + gemcitabine or taxanes (NSCLC-GEM/TAX) and platinum-etoposide (SCLC-PE). Results: RB1 mutation and protein loss were detected in 47% (n=37) and 72% (n=78) of the cases, respectively. RB1 wild-type LCNEC patients treated with NSCLC-GEM/TAX had a significantly longer OS (9.6 [95% CI 7.7-11.6] months) than those treated with SCLC-PE (5.8 [5.5-6.1]; P=0.026). Similar results were obtained for patients expressing RB1 in their tumors P=0.001). RB1 staining or P16 loss showed similar results. The same outcome for chemotherapy treatment was observed in LCNEC tumors harboring an RB1 mutation or lost RB1 protein. Conclusions: Patients with LCNEC tumors that carry a wild-type RB1 gene or express the RB1 protein do better with NSCLC-GEM/TAX treatment than with SCLC-PE chemotherapy. However, no difference was observed for RB1 mutated or with lost protein expression.

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Cross-Cancer Analysis Reveals Novel Pleiotropic Associations—Letter

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Cross-Cancer Analysis Reveals Novel Pleiotropic Associations—Response

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CD39 expression defines cell exhaustion in tumor-infiltrating CD8+ T cells

The ability of CD8+ T lymphocytes to eliminate tumors is limited by their ability to engender an immunosuppressive microenvironment. Here we describe a subset of tumor-infiltrating CD8+ T cells marked by high expression of the immunosuppressive ATP ecto-nucleotidase CD39. The frequency of CD39highCD8+ T cells increased with tumor growth but was absent in lymphoid organs. Tumor-infiltrating CD8+ T cells with high CD39 expression exhibited features of exhaustion, such as reduced production of TNF and IL-2 and expression of co-inhibitory receptors. Exhausted CD39+CD8+ T cells from mice hydrolyzed extracellular ATP, confirming that CD39 is enzymatically active. Furthermore, exhausted CD39+CD8+ T cells inhibited IFNγ production by responder CD8+ T cells. In specimens from breast cancer and melanoma patients, CD39+CD8+ T cells were present within tumors and invaded or metastatic lymph nodes, but were barely detectable within non-invaded lymph nodes and absent in peripheral blood. These cells exhibited an exhausted phenotype with impaired production of IFNγ, TNF, IL-2 and high expression of co-inhibitory receptors. Although T cell receptor engagement was sufficient to induce CD39 on human CD8+ T cells, exposure to IL-6 and IL-27 promoted CD39 expression on stimulated CD8+ T cells from human or murine sources. Our findings show how the tumor microenvironment drives the acquisition of CD39 as an immune regulatory molecule on CD8+ T cells, with implications for defining a biomarker of T cell dysfunction and a target for immunotherapeutic intervention.

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CBX8 exhibits oncogenic activity via AKT/{beta}-Catenin activation in hepatocellular carcinoma

Deregulation of Polycomb proteins influences the development and progression of hepatocellular carcinoma (HCC). Here we show that chromobox 8 (CBX8) expression is increased in HCC and correlates with poor outcome in two independent cohorts containing a total of 879 cases. Ectopic expression of CBX8 facilitated tumor growth and metastasis, whereas CBX8 silencing suppressed these effects. CBX8 efficiently activated AKT/β-catenin signaling via upregulation of the transcription factor EGR1 and miR-365-3p in a non-canonical manner: CBX8 directly bound the EGR1 promoter to enhance its activity. In the nucleus, CBX8 also interacted with EGR1 to prevent its degradation. Furthermore, CBX8 increased the transcription of miR-365a-3p, which promoted the nuclear localization of β-catenin by targeting the 3'-UTR ZNRF1. Inhibiting either EGR1 or miR-365a-3p partially rescued CBX8-mediated malignant phenotypes. In clinical samples, CBX8 expression closely correlated with EGR1, miR-365a-3p and nuclear β-catenin. Collectively, our results show that CBX8 functions as an oncogene to upregulate EGR1 and miR-365-3p to stimulate the AKT/β-catenin pathway. This newly identified signaling axis may suggest new therapeutic strategies against HCC.

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Comparative transcriptome analysis quantifies immune cell transcript levels, metastatic progression and survival in osteosarcoma

Overall survival of patients with osteosarcoma (OS) has improved little in the past three decades and better models for study are needed. OS is common in large dog breeds and is genetically inducible in mice, making the disease ideal for comparative genomic analyses across species. Understanding the level of conservation of inter-tumor transcriptional variation across species and how it is associated with progression to metastasis will enable us to more efficiently develop effective strategies to manage OS and improve therapy. In this study, transcriptional profiles of OS tumors and cell lines derived from humans (n=49), mice (n=103) and dogs (n=34) were generated using RNA-sequencing. Conserved inter-tumor transcriptional variation was present in tumor sets from all three species and comprised gene clusters associated with cell cycle and mitosis and with the presence or absence of immune cells. Further, we developed a novel Gene Cluster Expression Summary Score (GCESS) to quantify inter-tumor transcriptional variation and demonstrated that these GCESS values associated with patient outcome. Human OS tumors with GCESS values suggesting decreased immune cell presence were associated with metastasis and poor survival. We validated these results in an independent human OS tumor cohort and in 15 different tumor data sets obtained from The Cancer Genome Atlas (TCGA). Our results suggest that quantification of immune cell absence and tumor cell proliferation may better inform therapeutic decisions and improve overall survival for OS patients.

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A subpopulation of stromal cells controls cancer cell homing to the bone marrow

Breast and prostate cancer cells home to the bone marrow where they presumably hijack the hematopoietic stem cell niche. We characterize here the elusive premetastatic niche by examining the role of mesenchymal stromal cells (MSC) in cancer cell homing. Decreasing the number of MSC pharmacologically enhanced cancer cell homing to the bone marrow in mice. In contrast, increasing the number of these MSC by various interventions including G-CSF administration diminished cancer cell homing. The MSC subpopulation that correlated best with cancer cells expressed stem, endothelial, and pericytic cell markers suggesting these cells represent an undifferentiated component of the niche with vascular commitment. In humans, a MSC subpopulation carrying markers for endothelial and pericytic cells was lower in the presence of cytokeratin+ cells in bone marrow. Taken together, our data show that a subpopulation of MSC with both endothelial and pericytic cell surface markers suppresses the homing of cancer cells to the bone marrow. Similar to the presence of cytokeratin+ cells in the bone marrow, this mesenchymal stromal cell subpopulation could prove useful in determining the risk of metastatic disease, and its manipulation might offer a new possibility for diminishing bone metastasis formation.

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Evidence for Kaposi's Sarcoma originating from Mesenchymal Stem Cell through KSHV-induced Mesenchymal-to-Endothelial Transition

The major transmission route for Kaposi's sarcoma-associated herpesvirus (KSHV) infection is the oral cavity through saliva. Kaposi's sarcoma (KS) frequently occurs in the oral cavity in HIV-positive individuals and is often the first presenting sign of AIDS. However, the oral target cells for KSHV infection and the cellular origin of KS remain unknown. Here we present clinical and experimental evidences that KS spindle cells may originate from virally modified oral mesenchymal stem cells (MSC). AIDS-KS spindle cells expressed neuroectodermal stem cell marker (Nestin) and oral MSC marker CD29, suggesting an oral/craniofacial MSC lineage of AIDS-associated KS. Furthermore, oral MSC were highly susceptible to KSHV infection, and infection promoted multi-lineage differentiation and mesenchymal-to-endothelial transition (MEndT). KSHV infection of oral MSCs resulted in expression of a large number of cytokines, a characteristic of KS, and upregulation of KS signature and MEndT-associated genes. These results suggest that KS may originate from pluripotent MSC and KSHV infection transforms MSC to KS-like cells through MEndT.

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Defining and Correcting Asymmetry in Isolated Unilateral Frontosphenoidal Synostosis: Differences in Orbital Shape, Facial Scoliosis, and Skullbase Twist Compared to Unilateral Coronal Synostosis.

Introduction: Isolated frontosphenoidal synostosis (FS) is a rare cause of fronto-orbital plagiocephaly that can be challenging to distinguish from isolated unicoronal synostosis (UC). The purpose of this paper is to analyze differences in fronto-orbital dysmorphology between the 2 conditions, to describe approaches for surgical correction, and to report surgical outcomes between FS and UC patients in a casecontrol fashion. Methods: Patients treated for craniosynostosis over a 12-year period at our institution were retrospectively evaluated under institutional review board approval. Frontosphenoidal synostosis patients who underwent bilateral fronto-orbital correction of anterior plagiocephaly with minimum 2-year follow-up, adequate pre-, and minimum 2-year postoperative computed tomography scans were included in the case-control portion of the study. These patients were randomly age-matched to UC patients meeting the same inclusion criteria. Preoperative and postoperative orbital shape and volumetric analysis was performed using Mimics software. Results: Twelve FS patients were treated during the study period. Seven of these patients met casecontrol inclusion criteria with average follow-up of 47.5 months. The characteristic FS orbit was a relatively wide, short, and shallow trapezoid, while the characteristic UC orbit was a relatively narrow, tall, and deep parallelogram. Frontosphenoidal synostosis orbits were significantly wider, shorter, shallower, and smaller than UC orbits. Surgical correction tailored to the differential dysmorphologies resulted in statistical equalization of these differences between affected and contralateral control orbits at follow-up, with the exception of UC orbital width, which remained significantly narrower than unaffected contralateral control. One patient in each group required cranioplasty for skull defects at follow-up, while no patient underwent surgical readvancement. Conclusions: Frontosphenoidal synostosis and UC orbital shape differ significantly, and can be normalized using fronto-orbital advancement tailored to the distinct orbital dysmorphologies of these 2 groups. (C) 2017 by Mutaz B. Habal, MD.

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Osteogenesis of Crouzon-Mutated Cells in a Murine Model.

Crouzon syndrome is an autosomal-dominant congenital disease due to a mutation in the fibroblast growth factor receptor 2 protein. The purpose of this study is to evaluate wound-healing potential of Crouzon osteoblasts and adipose-derived stem cells (ADSCs) in a murine model. Parietal skull defects were created in Crouzon and mature wild-type (WT) CD-1 mice. One group of WT and Crouzon mice were left untreated. Another group was transplanted with both WT and Crouzon adipose-derived stem cells. Additional groups compared the use of a fibrin glue scaffold and periosteum removal. Skulls were harvested from each group and evaluated histologically at 8-week and/or 16-week periods. Mean areas of defect were quantified and compared via ANOVA F-test. The average area of defect after 8 and 16 weeks in untreated Crouzon mice was 15.37 +/- 1.08 cm2 and 16.69 +/- 1.51 cm2, respectively. The average area of the defect in untreated WT mice after 8 and 16 weeks averaged 14.17 +/- 1.88 cm2 and 14.96 +/- 2.26 cm2, respectively. WT mice with autologous ADSCs yielded an average area of 15.35 +/- 1.34 cm2 after 16 weeks while Crouzon mice with WT ADSCs healed to an average size of 12.98 +/- 1.89 cm2. Crouzon ADSCs transplanted into WT mice yielded an average area of 15.47 +/- 1.29 cm2 while autologous Crouzon ADSCs yielded an area of 14.22 +/- 3.32 cm2. ANOVA F-test yielded P = .415. The fibroblast growth factor receptor 2 mutation in Crouzon syndrome does not promote reossification of critical-sized defects in mature WT and Crouzon mice. Furthermore, Crouzon ADSCs do not possess osteogenic advantage over WT ADSCs. (C) 2017 by Mutaz B. Habal, MD.

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Transorbital Penetrating Intracranial Injury by a Battery.

The authors report a patient of transorbital penetrating intracranial injury by a battery. A 59-year-old man presented with a foreign body in the left orbital region after an explosion during waste combustion. Physical examination revealed his left eyelid had been punctured and the eyeball ruptured by what appeared to be a battery, which was lodged in the left orbit. The patient was neurologically intact. Facial computed tomography showed a ca. 6.2 x 1.7 cm sized metallic foreign body, probably an electric battery, penetrating through the left orbit and orbital roof and terminating in the left anterior cranial fossa. Clinical presentation, treatment course, and follow-up are discussed. (C) 2017 by Mutaz B. Habal, MD.

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Corticotomy With a Palatal Bone-Borne Retractor for Correcting Severe Bimaxillary Protrusion.

Background: This article presents an alternate surgical treatment method to correct a severe anterior protrusion in the adult patient with an extremely thin alveolus. Methods: In the maxilla, a wide linear corticotomy was performed under local anesthesia. Cortical alveolar bone of the upper first bicuspids area was widely removed. Orthopedic force for bony block movement was applied by a palatal bone-borne type retractor supported by skeletal anchorage. Residual extraction space closure was performed by biocreative orthodontics strategy (BOS). In the mandible, an anterior segmental osteotomy (ASO) and extraction of 1st premolars were performed under local anesthesia. Results: In the maxilla, bony block movement followed by the wide linear corticotomy with a palatal bone-borne type retractor was implemented without complications. Remaining extraction space after the bony block movement was closed effectively by BOS. In the mandible, anterior segmental retraction was achieved effectively by ASO. Conclusions: Wide linear corticotomy with a palatal bone-borne type retractor and ASO under local anesthesia can be an effective alternative to orthognathic surgery in adults with protrusion and an extremely thin alveolus. The biocreative strategy also provides a simple and effective method to retract the 6 anterior teeth. (C) 2017 by Mutaz B. Habal, MD.

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Primary Central Nervous System Lymphoma of Optic Chiasma: Endoscopic Endonasal Treatment.

Background: Isolated primary central nervous system lymphoma arising from anterior visual pathway is very rare. Patient Presentation: A 76-year-old immunocompetent previously healthy man presented bilateral decreased visual acuity in 1 month. Pituitary magnetic resonans imaging (MRI) showed a lobulated mass with homogeneous enhancement after gadolinium administration that arising from optic chiasm suggested that inflammatory disease or an optic glioma. The patient underwent an extended endoscopic endonasal transsphenoidal surgery. Postoperative course and outcomes were wonderful. Histopathological diagnosis was diffuse large B-cell lymphoma. The patient underwent investigations for systemic lymphomatous involvement, did not detect any evidence of systemic disease. Conclusion: In this case, we claimed that differential diagnoses of anterior visual pathway lesions are difficult because of similarity of lesions on clinical and radiological examinations. Biopsy is essential for these lesions. As a biopsy technique, endoscopic endonasal transsphenoidal approach is safer and more effective than open procedures. (C) 2017 by Mutaz B. Habal, MD.

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Bioinformatics Associated With Conjoined Twin Separation.

The separation of conjoined twins is a rare event in the medical field and presents many unique challenges to overcome. With the complexities of today's interconnected healthcare technology and electronic medical record, there are many intricate details that need significant attention to guarantee proper care and accurate record keeping for conjoined twins. Items that require attention are how to digitally represent the twins-as 1 patient or 2, how to incorporate the physiological monitors into the medical record, and how to ensure the proper amount of infrastructure, equipment, and space. With careful planning and consideration, technology can be used as an aid in separating conjoined twins at any institution. (C) 2017 by Mutaz B. Habal, MD.

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Method for Securing Methlymethacrylate Bone Cement Using Histoacryl Glue During Cranioplasty for Contour Deformities.

Methylmethacrylate bone cement (MM-BC) is one of the reconstructive methods: during cranioplasty to correct cranial defects following trauma or cranial surgery. Perfect intraoperative immobilization of the MM-BC is crucial to ensure correct subsequent shaping to best improve contour defects. Current immobilization techniques reported are time-consuming and involve complex metalwork. The authors hereby present a technique that may simplify the immobilization process by using histoacryl glue to secure the MM-BC. This provides a quick, inexpensive, and readily available option providing fixation strong enough to withstand final shaping of the MM-BC. (C) 2017 by Mutaz B. Habal, MD.

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Relationship of a Metopic Ridge and Anterior Cranial Volume Measured by a Noninvasive Laser Shape Digitizer.

Cranial dysmorphology observed in patients with metopic craniosynostosis varies along a spectrum of severity including varying degrees of metopic ridging, bitemporal narrowing, and trigonocephaly. Management has been based upon the subjective clinical impression of presence and severity of trigonocephaly. Severity of cranial dysmorphology does not predict the occurrence or severity of associated abnormal neurodevelopment, as children with mild-to-moderate trigonocephaly may also experience developmental delays. The authors sought to determine the relationship between mild-to-moderate trigonocephaly and anterior cranial volume using a noninvasive laser shape digitizer (STARscanner) in patients with abnormal head shape. An IRB-approved retrospective review of a prospectively maintained database and medical records was performed. Two hundred three patients less than 1 year of age with abnormal head shape were categorized as having a metopic ridge with mild-to-moderate trigonocephaly, metopic ridge without trigonocephaly, or no ridge. Measurements of cranial volume, circumference, and symmetry were calculated by the STARscanner, which quantifies three-dimensional shape of the cranial surface. Measures were analyzed using a series of analyses of variance and post-hoc Tukey honest significant difference. The authors results showed ACV was significantly reduced in patients with mild-to-moderate trigonocephaly compared with those without metopic ridge (P = 0.009), and trended toward significance compared with those with a ridge but without trigonocephaly (P = 0.072). The ratio of anterior-to-posterior cranial volume was significantly reduced in those with mild-to-moderate trigonocephaly compared with those without metopic ridge (P = 0.036). In conclusion, patients with milder anterior cranial deformities demonstrated an association between a metopic ridge with mild-to-moderate trigonocephaly and reduced anterior cranial volume. (C) 2017 by Mutaz B. Habal, MD.

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A New Operative One-Wing Technique to Correct Fronto-Orbital Region in Unilateral Nonsyndromic Plagiocephaly.

Anterior plagiocephaly is a premature closing of unilateral coronal suture. This premature suture fusion causes a series of cranial asymmetry and alteration of the fronto-orbital region. The authors described a new surgical technique to correct the facial asymmetry that reduces the operative time and the possible complications. In a period between 2013and 2016, 12 children affected by nonsyndromic anterior plagiocephaly were treated with this new procedure. Clinical, cranial development, and absence of postoperative complication demonstrated that one-wing surgical bone correction is a useful and innovative technique. (C) 2017 by Mutaz B. Habal, MD.

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Featural generalization in second language identification Performance: Comparing learners with different L1s

Publication date: January 2018
Source:Journal of Phonetics, Volume 66
Author(s): Kenneth de Jong, Yen-chen Hao
The current study examined identification responses by Taiwan Mandarin L1 speakers learning English. Stimuli were monosyllabic and disyllabic native English productions of voiced and voiceless, labial and coronal, plosives and non-sibilant fricatives. Analyses correlated individual identification performance for laryngeal (hereafter, "voicing") contrasts and manner contrasts, obtained from different halves of the overall corpus. Manner accuracy correlations were strong, particularly between voiced and voiceless segments. Manner accuracy also correlated across consonants appearing in different prosodic locations, word-initial, word-final, and intervocalic post-stress and pre-stress positions. Voicing accuracy also correlated across prosodic positions, though not between word-final position and the other positions. These results were interpreted with respect to a previously published corpus of Korean learners. The two corpora showed different patterns of correlation across prosodic positions for voicing, apparently due to the effects of different, prosodically-conditioned voicing allophony in the L1s. Finally, overall segmental and d-prime estimates were compared across the two language groups, revealing very strong similarities in the segmental accuracies for the two L1 groups. Analyses, however, also showed a persistent advantage for Mandarin listeners for manner contrasts. It was proposed that the difficulty of individual segments in specific prosodic locations, combined with the overall characteristics of the L1 phonological system, better account for learners' identification accuracies than does the correspondence of specific L1 and L2 segments.



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Not all geminates are created equal: Evidence from Maltese glottal consonants

Publication date: January 2018
Source:Journal of Phonetics, Volume 66
Author(s): Holger Mitterer
Many languages distinguish short and long consonants or singletons and geminates. At a phonetic level, research has established that duration is the main cue to such distinctions but that other, sometimes language-specific, cues contribute to the distinction as well. Different proposals for representing geminates share one assumption: The difference between a singleton and a geminate is relatively uniform for all consonants in a given language. In this paper, Maltese glottal consonants are shown to challenge this view. In production, secondary cues, such as the amount of voicing during closure and the spectral properties of frication noises, are stronger for glottal consonants than for oral ones, and, in perception, the role of secondary cues and duration also varies across consonants. Contrary to the assumption that gemination is a uniform process in a given language, the results show that the relative role of secondary cues and duration may differ across consonants and that gemination may involve language-specific phonetic knowledge that is specific to each consonant. These results question the idea that lexical access in speech processing can be achieved through features.



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What infant-directed speech tells us about the development of compensation for assimilation

Publication date: January 2018
Source:Journal of Phonetics, Volume 66
Author(s): Helen Buckler, Huiwen Goy, Elizabeth K. Johnson
In speech addressed to adults, words are seldom realized in their canonical, or citation, form. For example, the word 'green' in the phrase 'green beans' can often be realized as 'greem' due to English place assimilation, where word-final coronals take on the place of articulation of neighboring velars. In such a situation, adult listeners readily 'undo' the assimilatory process and perceive the underlying intended lexical form of 'greem' (i.e. they access the lexical representation 'green'). An interesting developmental question is how children, with their limited lexical knowledge, come to cope with phonologically conditioned connected speech processes such as place assimilation. Here, we begin to address this issue by examining the occurrence of place assimilation in the input to English-learning 18-month-olds. Perceptual and acoustic analyses of elicited speech, as well asanalysis of a corpus of spontaneous speech, all converge on the finding that caregivers do not spoon-feed their children canonical tokens of words. Rather, infant-directed speech contains just as many non-canonical realizations of words in place assimilation contexts asadult-directed speech. Implications for models of developmental speech perception are discussed.



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The influence of varying vowel phonation and duration on rhythmic grouping biases among Spanish and English speakers

Publication date: January 2018
Source:Journal of Phonetics, Volume 66
Author(s): Megan J. Crowhurst
Native Mexican Spanish and American English speakers were presented with streams of alternating syllables in which vowel duration and/or creaky phonation were rhythmically varied. Participants' grouping biases were measured as a function of their behaviour in segmenting sequences into recurrent bisyllabic units. Results indicated a creak-last grouping bias in both language groups. Duration varied singly was associated with a weak long-first grouping bias for Spanish and no consistent trend for English. When long creaky and short modal syllables were alternated, there was a significant creak-last bias and again no effect of duration in the English group. However, in the Spanish group, the long-first trend observed for duration varied singly was reversed and the effects of duration and creak were additive. Finally, when short creaky and long modal syllables were alternated, duration effects were highly significant in both language groups (fewer creak-last, more long-last groupings). Creak has been associated with final positions in higher-order prosodic domains in English, and less prevalently in Spanish. The current results show that both English and Spanish speakers can use this cue to segment rhythmic sequences into smaller, foot or word-sized units. This study is the first to establish that creak is perceptually salient for Spanish speakers and to demonstrate that the percept associated with duration can differ depending on whether it is varied singly or together with creak. More generally, the current findings show that grouping effects extend beyond intensity, pitch and duration, the features most often manipulated in rhythmic grouping studies inspired by the Iambic-Trochaic Law.



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The lingual articulation of devoiced /u/ in Tokyo Japanese

Publication date: January 2018
Source:Journal of Phonetics, Volume 66
Author(s): Jason A. Shaw, Shigeto Kawahara
In Tokyo Japanese, /u/ is typically devoiced between two voiceless consonants. Whether the lingual vowel gesture is influenced by devoicing or present at all in devoiced vowels remains an open debate, largely because relevant articulatory data has not been available. We report ElectroMagnetic Articulography (EMA) data that addresses this question. We analyzed both the trajectory of the tongue dorsum across VC1uC2V sequences as well as the timing of C1 and C2. These analyses provide converging evidence that /u/ in devoicing contexts is optionally targetless—the lingual gesture is either categorically present or absent but seldom reduced. When present, the magnitude of the lingual gesture in devoiced /u/ is comparable to voiced vowel counterparts. Although all speakers produced words with and without a vowel height target for /u/, the frequency of targetlessness varied across speakers and items. The timing between C1 and C2, the consonants flanking /u/ was also effected by devoicing but to varying degrees across items. The items with the greatest effect of devoicing on this inter-consonantal interval were also the items with the highest frequency of vowel height targetlessness for devoiced /u/.



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Surgical excision of osteochondroma on mandibular condyle via preauricular approach with zygomatic arch osteotomy

Abstract

Background

Osteochondroma is a benign tumor that tends to develop in mandibular condyle and coronoid process in the craniofacial region. If tumor mass has grown from condyle into the infratemporal space with zygomatic arch obstructing the access, there are risks associated with surgical exposure and local resection of these masses.

Case presentation

This study reports on a case of osteochondroma on mandibular condylar head where we treated with surgical excision via preauricular approach with 3D analysis. After the local resection, there were no surgical and post-operative complications until 8-month follow-up period.

Conclusions

In local excision of osteochondroma, our method is a minimally invasive method. It is a good example of osteochondroma treatment.

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Evaluation of mandibular lingula and foramen location using 3-dimensional mandible models reconstructed by cone-beam computed tomography

Abstract

Background

The positions of the mandibular lingula and foramen have been set as indexes for inferior alveolar nerve (IAN) block and ramus osteotomies in orthognathic surgery. This study aimed to evaluate the anatomical structures of mandibular ramus, especially the mandibular lingula and foramen, by analyzing the cone-beam computed tomography (CBCT) data of young adults.

Methods

We evaluated 121 sides of hemi-mandibular CBCT model of 106 patients (51 male and 55 female patients; 18 to 36 years old). All the measurements were performed using the 2- and 3-dimensional rulers of OnDemand3D® software.

Results

Statistical analysis of the data revealed that there was no significant difference in the mandibular angle between the genders. The mandibular lingula was found to be located at the center of ramus in males, but a little posterior in relation to the center in females. The mandibular lingula was rarely located below the occlusal plane; however, the position of the mandibular foramen was more variable (84.3% below, 12.4% above, and 3.3% at the level of the occlusal plane).

Conclusions

The results of this study provide a valuable guideline for IAN block anesthesia and orthognathic surgery. CBCT can be considered effective and accurate in evaluating the fine structures of the mandible.

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The Influence of Collaboration: Ralph Waters' Friendship With John Lundy and the Spread of Regional Anesthesia.

Ralph Waters, the founder of the anesthesiology department and residency program at the University of Wisconsin-Madison, and John Lundy, the chair at the Mayo Clinic beginning in 1924, collaborated to expand regional anesthetic techniques and knowledge not only at their institutions, but also at institutions around the country through correspondence, meetings, and hosting of other anesthesiologists. The Ralph Waters Collection at the University of Wisconsin Archives was searched for information on Waters' and Lundy's involvement in regional anesthesia. This included publications by Waters and other anesthesiology department faculty, as well as personal correspondence with other leaders in anesthesia at that time. Correspondence between Waters and Lundy from this collection was reviewed in detail. This article underscores the importance of exchange of ideas by physicians through didactics, organizations, and research through the story of Ralph Waters and John Lundy's mutual exchange of ideas and even friendship beginning in the 1920s. Copyright (C) 2017 by American Society of Regional Anesthesia and Pain Medicine.

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ESPGHAN Distinguished Service Award 2017 to Professor Olivier Goulet

No abstract available

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Intestinal Rehabilitation Programs in the Management of Pediatric Intestinal Failure and Short Bowel Syndrome

ABSTRACT: Intestinal failure is a rare, debilitating condition that presents both acute and chronic medical management challenges. The condition is incompatible with life in the absence of the safe application of specialized and individualized medical therapy that includes surgery, medical equipment, nutritional products, and standard nursing care. Intestinal rehabilitation programs are best suited to provide such complex care with the goal of achieving enteral autonomy and oral feeding with or without intestinal transplantation. These programs almost all include pediatric surgeons, pediatric gastroenterologists, specialized nurses, and dietitians; many also include a variety of other medical and allied medical specialists. Intestinal rehabilitation programs provide integrated interdisciplinary care, more discussion of patient management by involved specialists, continuity of care through various treatment interventions, close follow-up of outpatients, improved patient and family education, earlier treatment of complications, and learning from the accumulated patient databases. Quality assurance and research collaboration among centers are also goals of many of these programs. The combined and coordinated talents and skills of multiple types of health care practitioners have the potential to ameliorate the impact of intestinal failure and improve health outcomes and quality of life.

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Starved Guts: Morphologic and Functional Intestinal Changes in Malnutrition

ABSTRACT: Malnutrition contributes significantly to death and illness worldwide and especially to the deaths of children younger than 5 years. The relation between intestinal changes in malnutrition and morbidity and mortality has not been well characterized; however, recent research indicates that the functional and morphologic changes of the intestine secondary to malnutrition itself contribute significantly to these negative clinical outcomes and may be potent targets of intervention. The aim of this review was to summarize current knowledge of experimental and clinically observed changes in the intestine from malnutrition preclinical models and human studies. Limited clinical studies have shown villous blunting, intestinal inflammation, and changes in the intestinal microbiome of malnourished children. In addition to these findings, experimental data using various animal models of malnutrition have found evidence of increased intestinal permeability, upregulated intestinal inflammation, and loss of goblet cells. More mechanistic studies are urgently needed to improve our understanding of malnutrition-related intestinal dysfunction and to identify potential novel targets for intervention.

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Associations Between Dietary Intake Before 6 Months of Age and Rapid Weight Gain Among HIV-exposed Uninfected Infants

Introduction: HIV-exposed, uninfected (HEU) infants are potentially at risk for cardiovascular disease due to in utero exposures. Feeding practices of the infant could compound this risk. Few studies have, however, evaluated dietary intake of HEU infants. We determined dietary factors associated with rapid weight gain (RWG) among HEU infants from birth to 6 months followed at the University of Miami HIV Screening Program. Methods: In this cross-sectional analysis, logistic regression was used to determine dietary factors associated with RWG defined as a >0.67 SD change in weight-for-age z score from birth to assessment (0.3–6 months). Other covariates included demographics, birth, maternal and gestational characteristics, and antiretroviral exposures. Results: A total of 86 full-term HEU infants with a mean age of 3.4 months (SD 1.8 months) were included in this analysis. Fifty-five percent of mothers were obese. Overall, 39.5% of infants exhibited RWG. A significant association between consumption of infant cereal and RWG (odds ratio, 3.52; 95% confidence interval, 1.02–12.10) was found after adjusting for birth weight, current age, and energy intake. Those infants who consumed the highest tertile of protein were less likely to gain weight rapidly after adjusting for the same covariates (odds ratio, 0.15; 95% confidence interval, 0.02–0.94). Conclusions: Overall differences in weight gain during early infancy are at least partly explained by means of infant feeding in young HEU infants in the United States. Dietary counseling for families of HEU should reinforce current feeding practice recommendations of the American Academy of Pediatrics.

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Safe Energy Source in Battery-operated Toys for Children

Objectives: Serious and even fatal consequences of disk batteries ingestion in children are well known. Among other applications, disk batteries are used to power small toys, from which they can be unexpectedly extracted and swallowed. Methods: We tested a new cell intended for little toys (green cell [GC]), after 6 and 12 hours of in vitro close contact with esophageal swine mucosa. The GC was compared with lithium and silver button batteries under the same experimental conditions. Results: Tissues in contact with the GC did not show pH variations nor histological alterations after 6 and 12 hours. In such conditions, statistically significant differences were found between the GC and the lithium and silver batteries. Conclusions: So far, multidisciplinary medical effort has been driven to both emergency approach and subsequent operative strategies in children with ingested batteries. Our trial demonstrates the possibility to primarily prevent battery-induced damages by designing new-generation safe cells with no tissue toxicity to power little toys intended for children.

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Please Do Not Forget Muscle Disease When Evaluating Elevated Transaminases

No abstract available

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Severe Neonatal Cholestasis in Cerebrotendinous Xanthomatosis: Genetics, Immunostaining, Mass Spectrometry

Objectives: Cerebrotendinous xanthomatosis (CTX) is caused by defects in sterol 27-hydroxylase (CYP27A1, encoded by CYP27A1), a key enzyme in the bile acid synthesis pathway. CTX usually presents as neurologic disease in adults or older children. The rare reports of CTX manifest as neonatal cholestasis assess the cholestasis as transient, with patient survival. Our experience differs. Methods: Homozygous or compound heterozygous CYP27A1 mutations were detected in 8 neonatal cholestasis patients by whole exome sequencing, panel sequencing, or Sanger sequencing. Their clinical and biochemical data were retrospectively reviewed. Immunostaining for CYP27A1 was conducted in liver of 4 patients. Mass spectrometry was used to analyze patients' urine samples. Results: All 8 infants had severe cholestasis. Five died from, or were transplanted for, liver failure; 3 cleared their jaundice eventually. Marking for CYP27A1 was weak or absent in 3 of the 4 patient specimens. Mass spectrometry of urine revealed a predominance of sulfated and doubly conjugated (sulfated-glucuronidated) bile alcohols. No patient harbored a putatively pathogenic mutation in genes other than CYP27A1 that have been implicated in cholestatic liver disease. Conclusions: CTX manifest as neonatal cholestasis has a bile acid profile different from CTX manifest in later life, and thus may be overlooked. Immunostaining, mass spectrometry of urine, and genetic studies can support one another in making the diagnosis. A substantial proportion of CTX patients with severe neonatal cholestasis may die or need liver transplantation. CTX manifest in infancy as severe cholestasis warrants further investigation of biochemical diagnostic criteria and best management.

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How to Predict Oral Rehydration Failure in Children With Gastroenteritis

Objectives: Oral rehydration is the standard in most current guidelines for young children with acute gastroenteritis (AGE). Failure of oral rehydration can complicate the disease course, leading to morbidity due to severe dehydration. We aimed to identify prognostic factors of oral rehydration failure in children with AGE. Methods: A prospective, observational study was performed at the Emergency department, Erasmus Medical Centre, Rotterdam, The Netherlands, 2010–2012, including 802 previously healthy children, ages 1 month to 5 years with AGE. Failure of oral rehydration was defined by secondary rehydration by a nasogastric tube, or hospitalization or revisit for dehydration within 72 hours after initial emergency department visit. Results: We observed 167 (21%) failures of oral rehydration in a population of 802 children with AGE (median 1.03 years old, interquartile range 0.4–2.1; 60% boys). In multivariate logistic regression analysis, independent predictors for failure of oral rehydration were a higher Manchester Triage System urgency level, abnormal capillary refill time, and a higher clinical dehydration scale score. Conclusions: Early recognition of young children with AGE at risk of failure of oral rehydration therapy is important, as emphasized by the 21% therapy failure in our population. Associated with oral rehydration failure are higher Manchester Triage System urgency level, abnormal capillary refill time, and a higher clinical dehydration scale score.

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Severe Sarcopenia and Increased Fat Stores in Pediatric Patients With Liver, Kidney, or Intestine Failure

Objectives: Malnutrition and wasting predict clinical outcomes in children with severe chronic illness. Objectively calculated malnutrition in children with end-stage organ failure has not been well studied. This analysis compares children with kidney, liver or intestine failure to healthy controls to quantitate the disparity in muscle and fat stores. Methods: Children younger than 19 years with end-stage liver, kidney, or intestine failure and with pretransplant computed tomography (CT) imaging were selected from the transplant database. Age- and sex-matched healthy controls were selected from the trauma database. Measures of nutrition status included a scaled scoring of core muscle mass, and visceral and subcutaneous fat stores. Analysis was conducted using the pooled and individually matched subject-control differences. Results: There were 81 subjects included in the final analysis (liver [n = 35], kidney [n = 20], and intestine [n = 26]). Children with end-stage liver disease had a 23% reduction in muscle mass, a 69% increase in visceral fat, and a 29% increase in subcutaneous fat. End-stage renal disease patients had a 19% reduction in muscle mass and a 258% increase in subcutaneous fat. Intestine failure patients had a 24% reduction in muscle mass, a 30% increase in visceral fat, and a 46% increase in subcutaneous fat. Conclusions: These results demonstrate significant sarcopenia and increased fat stores in end-stage organ failure patients, which supports the idea of an active physiologic mechanism to store fat while losing muscle mass. Sarcopenia may be related to total protein loss from a catabolic state, or from decreased synthesis (liver), wasting (kidney), or malabsorption (intestine).

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Association of Maternal Gestational Weight Gain With the Infant Fecal Microbiota

Objectives: Pregnancy characteristics may influence the infant fecal microbiota during early life. We aimed to examine associations of maternal gestational weight gain with infant fecal microbiota composition, bacterial community richness, and Shannon diversity index. Methods: We analyzed data from a prospective cohort study of healthy infants. We collected prenatal data, including report of mother's gestational weight gain, and infant fecal samples from 84 infant-mother dyads. By applying 16S rRNA gene sequencing and an unbiased clustering by partitioning around medoids using Bray-Curtis distances, we identified 4 fecal microbiota profiles, and examined the associations of maternal gestational weight gain with the 4 fecal microbiota profiles, bacterial community richness, and Shannon diversity index. Results: Overall, the median age of infants was 4.0 months and 43% were girls. The mothers of the 84 infants gained a mean of 14.2 kg (standard deviation, 5.4 kg) during pregnancy. We identified 4 distinct microbiota profiles: Bifidobacterium-dominant (42%), Enterobacter/Veillonella-dominant (23%), Bacteroides-dominant (19%), and Escherichia-dominant (17%). Infants whose mothers had higher gestational weight gain were less likely to have a Bacteroides-dominant profile, corresponding to a relative risk ratio of 0.83 (95% confidence interval, 0.71–0.96; P = 0.01) per 1 kg increase in weight. In addition, higher gestational weight gain was also associated with lower bacterial community richness and Shannon diversity index (P 

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Cholangioscopic Management of Mirizzi Syndrome in a Pediatric Patient

No abstract available

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Anxiety Associated With High-resolution Anorectal Manometry in Pediatric Patients and Parents

ABSTRACT: High-resolution anorectal manometry is an increasingly common procedure performed in pediatric patients to rule out Hirschsprung and assess anorectal function and sensation. The purpose of the present study was to evaluate anxiety of patients and their parents associated with high-resolution anorectal manometry. Preprocedural anxiety was assessed by standardized questionnaire in all parents and children older than 8 years and observed behavioral distress was recorded by the attending pediatric gastroenterologist. Thirty-five children (mean age = 7.2 years, ±2.8) and their parents completed the study. Patient anxiety was found to be markedly elevated. Observed behavioral distress was elevated compared to more invasive procedures. Self-reported parental anxiety was comparable to adults undergoing endoscopic procedures themselves. Despite the low risk of this procedure, healthcare providers should be aware of the high levels of anxiety and distress that occur in patients and their parents associated with anorectal manometry.

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Screening for NAFLD in Children: Do We Know the Optimal ALT Cut-off?

No abstract available

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Reduced Functional Connectivity Between the Hypothalamus and High-order Cortical Regions in Adolescent Patients With Irritable Bowel Syndrome

ABSTRACT: The hypothalamus plays a critical role in maintaining visceral homeostasis. Altered hypothalamus activation has been implicated in functional gastrointestinal disorders, including irritable bowel syndrome (IBS). One important aspect of homeostatic regulation is the cortical modulation of limbic and paralimbic subsystems, including the hypothalamus, which in turn affects the descending regulatory processes mediating visceral homeostasis. Using neuroimaging, we evaluated hypothalamus functional connectivity in adolescent patients with IBS and age-matched healthy controls who received rectal distension stimulations. More extensive hypothalamus connectivity was observed in liminal than subliminal condition in controls, but not in patients with IBS. Compared with controls, patients with IBS showed significantly reduced hypothalamus connectivity in the bilateral prefrontal cortices, supplementary motor and premotor areas, bilateral sensorimotor cortex, and limbic subareas, which are specifically involved in homeostatic regulation. The findings support the generalized homeostatic regulation model that reduced cortical and limbic modulations of hypothalamus functioning underlies disrupted visceral homeostasis in patients with IBS.

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Early Onset of Wilson Disease: Diagnostic Challenges

Objectives: The aim of the study was to analyze the clinical presentations, diagnosis, and treatment of patients ages ≤5 years with early onset Wilson disease (WD). Methods: Data from 143 pediatric patients with WD treated at our center between January 1996 and November 2015 were retrospectively analyzed. Results: A review of the 143 pediatric patients with WD identified 21 (10 girls, 11 boys) with first symptoms or abnormal liver function test results at age ≤5 years. The diagnosis of WD was confirmed in 8 patients younger than 5 years. At baseline the mean serum alanine aminotransferase level was 222 U/L and the mean serum aspartate aminotransferase level was 130 U/L. The mean serum ceruloplasmin concentration in 16 tested patients was 100 μg/day. Liver copper quantification was >250 μg/g dry weight in 16 patients. The most common mutation was p.H1069Q, with compound heterozygosity in 5 patients and homozygosity in 9. Sixteen patients were treated with zinc salts and 5 with D-penicillamine. Both treatments were effective, with no serious side effects observed after 3 to 24 months. Conclusions: WD can present as early as 2 years of age. Because biochemical tests may be less sensitive in very young children, diagnoses may require a combination of tests. If molecular tests are inconclusive, liver copper content should be measured.

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Using Serum IgE Antibodies to Predict Esophageal Eosinophilia in Children

Objectives: Symptoms of eosinophilic esophagitis are variable and can be nonspecific. Food-specific serum immunoglobulin E (IgE) antibodies are frequently found in patients with eosinophilic esophagitis and are obtained using a widely available blood test. Our objective was to evaluate the ability of food-specific IgE antibodies to predict the presence of esophageal eosinophilia. Methods: We reviewed 144 medical records for pediatric patients having esophageal biopsy and serum analysis for IgE antibodies to food (exploratory group). We performed logistic regression using sex and number of positive food-specific IgE tests to develop a model that predicts ≥15 eosinophils/high-power field (hpf) in the esophagus. We tested the model using 142 additional patients (validation group). Results: The probability of having ≥15 eosinophils/hpf in the esophagus was higher in boys and increased with the number of positive food-specific IgE tests from 12% (95% confidence interval 4.8–26) in girls with 0 foods positive to 86% (95% confidence interval 71–94) for boys with 4 or 5 foods positive. The statistical model using sex and number of positive IgE tests to predict patients having ≥15 eosinophils/hpf showed acceptable discriminative ability (area under the receiver operating characteristic curve 0.80). The performance metrics for the model to predict ≥15 eosinophils/hpf in the validation group were similar (area under the receiver operating characteristic curve 0.75). Conclusions: Requiring only a blood test and a simple algorithm, analysis for IgE antibodies to food may expedite an esophagogastroduodenoscopy and decrease delays in the diagnosis and treatment of patients with nonspecific gastrointestinal symptoms who have increased eosinophils in the esophagus.

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Health Status and Anthropometric Changes in Resettled Refugee Children

Background: Recently the United States has experienced an increase in refugees. Pediatric refugees are at risk for health and nutrition problems. Literature on longitudinal change in nutritional status of resettled pediatric refugees is scant. Objective: The present study reports the health and nutritional status of pediatric refugees and tracks changes in nutritional status. Methods: Data were extracted retrospectively from the records of a community health center in Buffalo, NY. Two cohorts of refugees (0–18 years) were selected. Cohort A was followed during 5 years and consisted of 225 subjects whose initial visit occurred between January 1, 2007 and December 31, 2009. The 199 subjects in cohort B had an initial visit between January 1, 2013 and December 31, 2013 and were followed for 1 year. Cohort B was chosen because vitamin levels were available only for this group. Descriptive and anthropometric data, infectious disease status, and initial vitamin and hemoglobin levels were recorded. Height-for-age (HFA) z scores and body mass index (BMI) z scores were computed. Longitudinal changes were analyzed. Results: The cohorts A and B differed in country of origin and infectious disease burden. On arrival, both cohorts exhibited HFA z scores reflecting short stature. BMI z scores were normal. HFA and BMI z scores increased during 5 years and 1 year for cohorts A and B, respectively. Anemia, vitamin D deficiency, and lead toxicity were identified. Conclusions: Resettled pediatric refugees were short. Some were stunted. Catch-up growth, however, occurred. There were increases in HFA and BMI z scores. Vitamin D deficiency, anemia, and lead toxicity were documented.

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Reduced Bone Mineral Density in Children With Screening-detected Celiac Disease

Objectives: The aim of the study was to assess whether bone mass and metabolism are impaired in genetically at-risk children with screening-detected celiac disease. Methods: Included were 71 children with screening-detected celiac disease diagnosed at 10.0 ± 0.7 (mean ± standard deviation) years and 142 matched controls and 30 children with screening-detected celiac disease diagnosed at 3.3 ± 0.4 years of age presently on a gluten-free diet for 6.9 ± 1.1 years and 60 matched controls. All participants were assessed for bone mineral density (BMD) of total body and spine by dual x-ray absorptiometry, serum 25(OH) vitamin D3, parathyroid hormone (PTH), interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-15, interferon gamma, and tumor necrosis factor alpha. Results: At diagnosis, screening-detected celiac disease children as compared to controls had a mean −0.03 g/cm2 reduced BMD of both total body and spine (P = 0.009 and P = 0.005, respectively), a mean −11.4 nmol/L lower level of 25(OH) vitamin D3 (P 

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A Novel and More Aesthetic Injection Pattern for Malar Cheek Volume Restoration

Abstract

The loss of superior midface contour and projection can be corrected with the use of injectable hyaluronic acid (HA) dermal fillers, however, the most frequently used injection pattern employs a technique which was originally designed for malar implant surgery. Here we describe a novel injection pattern for restoring facial contours with a HA dermal filler inspired by traditional make-up artistry, which includes greater superolateral positioning of injection sites. Importantly, this technique helps injectors avoid creating an excess of volume in the anterior portion of the malar complex. Contributing authors/injectors, who now use this technique exclusively, have found that it has so far provided optimal aesthetic results for hundreds of patients with no observables complications. The malar cheek contributes much to the aesthetic curvature of the face and deserves a thoughtful update for injectable HA, as the traditional technique has never actually been aligned with its medium. In the experience of the contributing authors, this technique helps achieve a greater aesthetic outcome in the correction of midface contour deficiencies and has consistently resulted in high patient satisfaction.

Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://ift.tt/18t7xNj.

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The Incidence of Psychiatric Medication Use and Its Effect on Intraoperative Bleeding in Facial Cosmetic Patients

Abstract

Purpose

Psychiatric medications, particularly the selective serotonin reuptake inhibitors, have been associated with increased surgical bleeding. This study aims to compare intraoperative surgical bleeding between cosmetic surgery patients who are and are not taking psychiatric medications.

Methods

The charts of 392 consecutive patients who underwent cosmetic facial surgery at the senior author's practice were reviewed. Independent variables included self-reported psychiatric history, psychiatric diagnoses, and psychiatric medications as documented in the preoperative history and physical examination. The primary endpoint was administration of desmopressin (DDAVP), our proxy for increased surgical bleeding. Significant predictors of these endpoints were determined via Chi-squared testing.

Results

One hundred and seventeen patients had a psychiatric diagnosis (30%), and 129 patients were taking some class of psychiatric medication (33%). Seventy-two patients received DDAVP (18%). A psychiatric diagnosis did not predict DDAVP administration (14.3% for patients with a psychiatric diagnosis vs. 20.88% for those without, p = 0.14). The use of a psychiatric medication was not associated with DDAVP administration (14.7 vs. 21%, p = 0.14). Male gender significantly predicted DDAVP administration (27.8 vs. 16.9% for females, p = 0.04).

Conclusion

The use of psychiatric medications does not predict increased intraoperative surgical bleeding. This is useful given the prevalence of psychiatric medication use among this patient population and obviates the need for discontinuation of these medications, which otherwise could be consequential.

Level of Evidence IV

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://ift.tt/18t7xNj.

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Book Review.

No abstract available

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Aminoglycoside or Quinolone Ear Drops in the Postoperative Management of Tympanoplasty: What Choice Do We Have?.

No abstract available

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Preventing Facial Nerve Stimulation by Triphasic Pulse Stimulation in Cochlear Implant Users: Intraoperative Recordings.

Hypothesis: Triphasic pulse stimulation of the auditory nerve can prevent unintended facial nerve stimulation (FNS) due to a different electromyographic (EMG) input-output function compared with biphasic pulses. Background: FNS is sometimes observed in cochlear implant (CI) users as an unpleasant side effect of electrical stimulation using biphasic pulse patterns (BPP). Clinical remedies to alleviate FNS are 1) to extend stimulus phase duration or 2) to completely deactivate the electrode. In some cases, these options do not provide sufficient FNS reduction or are detrimental to subject performance. Stimulation using triphasic pulse patterns (TPP) has been shown to prevent FNS more effectively, yet the underlying mechanism remains unclear. Methods: EMG potentials of muscles innervated by the facial nerve (orbicularis oculi and oris muscles) were recorded to quantitatively compare the effect of BPP and TPP stimulation on FNS. Recordings were conducted in five subjects during CI surgery. In two exemplary cases, different leading phase polarities in alternating and non-alternating order were tested. Results: Compared with our previous study in awake patients using surface electrodes (Bahmer and Baumann, 2016), intraoperative recordings using subdermal electrodes showed lower noise content and allowed higher sampling resolution. While inter-subject variation remained high, intra-subject results for different electrode positions were comparable: FNS was strongly reduced for cathodic-first TPP stimulation. In contrast, exemplary cases showed little reduction for anodic-first TPP as well as for alternating stimulation. Conclusion: FNS in CI users can be reduced using TPP stimulation, but the ameliorative effect appears to be dependent on the leading stimulus polarity. Copyright (C) 2017 by Otology & Neurotology, Inc. Image copyright (C) 2010 Wolters Kluwer Health/Anatomical Chart Company

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High Incidence of Bell's Palsy After Mastoidectomy: a Longitudinal Follow-up Study.

Objective: The objective of this study was to compare the prevalence of Bell's palsy in participants who underwent mastoidectomy (to treat chronic otitis media) and nonmastoidectomy participants (control). Methods: Using the national cohort study from the Korean Health Insurance Review and Assessment Service, mastoidectomy patients (2,045) and control participants (8,180) were matched 1:4 for age, sex, income, and region of residence. The prevalence of Bell's palsy in both the groups was measured from 0 to 10 years postoperation. Results: In a sample of 1,025,340 Korean individuals, 7,070 were diagnosed or treated with Bell's palsy between 2002 and 2013; the annual incidence of Bell's palsy was 0.057%. The overall prevalence of Bell's palsy was three times higher in the mastoidectomy group (1.27%) than control group (0.49%) (p

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Cochlear Implantation in Cochlear Ossification: Retrospective Review of Etiologies, Surgical Considerations, and Auditory Outcomes.

Objectives: 1) To review the surgical and auditory outcomes and complications of cochlear implantation in cases with cochlear ossification. 2) To evaluate association between the extent and etiology of ossification to outcomes. Study Design: Retrospective study. Setting: Otology and skull base surgery center. Subjects and Methods: Charts of 40 patients (42 ears) with cochlear ossification undergoing cochlear implantation were reviewed. Demographic features, operative findings, auditory outcomes, and complications were analyzed. Operative findings included extent of cochlear ossification, extent of drilling required to obtain patent cochlear lumen, approach (posterior tympanotomy/subtotal petrosectomy), electrode insertion (partial/complete, scala tympani/vestibuli), and complications. Auditory outcomes were assessed over a 4-year follow-up period using vowel, word, sentence, and comprehension scores. Patients were divided into groups (otosclerotic/non-otosclerotic and round window/basal turn ossification) for comparison of auditory outcomes. Outcomes were compared with 60 randomly identified controls (adults with postlingual deafness) who underwent implantation with no cochlear ossification. Results: The median age and duration of deafness of patients was 54.39 and 27.15 years, respectively. Etiology of cochlear ossification was otosclerosis in 23 of 42 ears and mixed in 19 of 42 ears (chronic otitis media, temporal bone fractures, idiopathic, meningitis, Cogan's syndrome) with exclusive round window involvement in 54.7% of cases and the rest having partial or complete basal turn ossification. 59.5% ears underwent subtotal petrosectomy for implantation. Three patients underwent scala vestibuli insertion and five had incomplete electrode insertion. Auditory outcomes were comparable in otosclerotic and non-otosclerotic cases and in round window and basal turn ossification cases. No significant differences were observed in auditory scores when compared with controls with no ossification. Conclusions: Cochlear implantation in cochlear ossification is feasible despite surgical challenges and modifications. Auditory outcomes in basal turn ossification appear to be comparable to cases with no ossification with extent of ossification having no significant association with outcomes. Copyright (C) 2017 by Otology & Neurotology, Inc. Image copyright (C) 2010 Wolters Kluwer Health/Anatomical Chart Company

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