Citations

The present study used real-time confocal microscopy to examine the effects of the β2-adrenoceptor agonist salbutamol on regulation of intracellular Ca2+concentration ([Ca2+]i) in myotubes derived from neonatal mouse limb muscles. Immunocytochemical staining for ryanodine receptors and skeletal muscle myosin confirmed the presence of sarcomeres. The myotubes displayed both spontaneous and ACh-induced rapid (<2-ms rise time) [Ca2+]itransients. The [Ca2+]itransients were frequency modulated by both low and high concentrations of salbutamol. Exposure to α-bungarotoxin and tetrodotoxin inhibited ACh-induced [Ca2+]itransients and the response to low concentrations of salbutamol but not the response to higher concentrations. Preexposure to caffeine inhibited the subsequent [Ca2+]iresponse to lower concentrations of salbutamol and significantly blunted the response to higher concentrations. Preexposure to salbutamol diminished the [Ca2+]iresponse to caffeine. Inhibition of dihydropyridine-sensitive Ca2+channels with nifedipine or PN-200-110 did not prevent [Ca2+]ielevations induced by higher concentrations of salbutamol. The effects of salbutamol were mimicked by the membrane-permeant analog dibutyryl adenosine 3′,5′-cyclic monophosphate. These data indicate that salbutamol effects in skeletal muscle predominantly involve enhanced sarcoplasmic reticulum Ca2+release.

Abstract FACIAL NERVE MONITORING Question 1 Does intraoperative facial nerve monitoring during vestibular schwannoma surgery lead to better long-term facial nerve function? Target Population This recommendation applies to adult patients undergoing vestibular schwannoma surgery regardless of tumor characteristics. Recommendation Level 3: It is recommended that intraoperative facial nerve monitoring be routinely utilized during vestibular schwannoma surgery to improve long-term facial nerve function. Question 2 Can intraoperative facial nerve monitoring be used to accurately predict favorable long-term facial nerve function after vestibular schwannoma surgery? Target Population This recommendation applies to adult patients undergoing vestibular schwannoma surgery. Recommendation Level 3: Intraoperative facial nerve can be used to accurately predict favorable long-term facial nerve function after vestibular schwannoma surgery. Specifically, the presence of favorable testing reliably portends a good long-term facial nerve outcome. However, the absence of favorable testing in the setting of an anatomically intact facial nerve does not reliably predict poor long-term function and therefore cannot be used to direct decision-making regarding the need for early reinnervation procedures. Question 3 Does an anatomically intact facial nerve with poor electromyogram (EMG) electrical responses during intraoperative testing reliably predict poor long-term facial nerve function? Target Population This recommendation applies to adult patients undergoing vestibular schwannoma surgery. Recommendation Level 3: Poor intraoperative EMG electrical response of the facial nerve should not be used as a reliable predictor of poor long-term facial nerve function. COCHLEAR NERVE MONITORING Question 4 Should intraoperative eighth cranial nerve monitoring be used during vestibular schwannoma surgery? Target Population This recommendation applies to adult patients undergoing vestibular schwannoma surgery with measurable preoperative hearing levels and tumors smaller than 1.5 cm. Recommendation Level 3: Intraoperative eighth cranial nerve monitoring should be used during vestibular schwannoma surgery when hearing preservation is attempted. Question 5 Is direct monitoring of the eighth cranial nerve superior to the use of far-field auditory brain stem responses? Target Population This recommendation applies to adult patients undergoing vestibular schwannoma surgery with measurable preoperative hearing levels and tumors smaller than 1.5 cm. Recommendation Level 3: There is insufficient evidence to make a definitive recommendation. The full guideline can be found at: https://www.cns.org/guidelines/guidelines-manage-ment-patients-vestibular-schwannoma/chapter_4.

Abstract Please see the full-text version of this guideline (https://www.cns.org/guidelines/guidelines-management-patients-vestibular-schwannoma/chapter_3) for the target population of each recommendation listed below. STEREOTACTIC RADIOSURGERY Question 1 What is the overall probability of maintaining serviceable hearing following stereotactic radiosurgery utilizing modern dose planning, at 2, 5, and 10 yr following treatment? Recommendation Level 3 : Individuals who meet these criteria and are considering stereotactic radiosurgery should be counseled that there is moderately high probability (>50%-75%) of hearing preservation at 2 yr, moderately high probability (>50%-75%) of hearing preservation at 5 yr, and moderately low probability (>25%-50%) of hearing preservation at 10 yr. Question 2 Among patients with AAO-HNS (American Academy of Otolaryngology-Head and Neck Surgery hearing classification) class A or GR (Gardner-Robertson hearing classification) grade I hearing at baseline, what is the overall probability of maintaining serviceable hearing following stereotactic radiosurgery, utilizing modern dose planning, at 2, 5, and 10 yr following treatment? Recommendation Level 3 : Individuals who meet these criteria and are considering stereotactic radiosurgery should be counseled that there is a high probability (>75%-100%) of hearing preservation at 2 yr, moderately high probability (>50%-75%) of hearing preservation at 5 yr, and moderately low probability (>25%-50%) of hearing preservation at 10 yr. Question 3 What patient- and tumor-related factors influence progression to nonserviceable hearing following stereotactic radiosurgery using ≤13 Gy to the tumor margin? Recommendation Level 3: Individuals who meet these criteria and are considering stereotactic radiosurgery should be counseled regarding the probability of successful hearing preservation based on the following prognostic data: the most consistent prognostic features associated with maintenance of serviceable hearing are good preoperative word recognition and/or pure tone thresholds with variable cut-points reported, smaller tumor size, marginal tumor dose ≤12 Gy, and cochlear dose ≤4 Gy. Age and sex are not strong predictors of hearing preservation outcome. MICROSURGERY Question 4 What is the overall probability of maintaining serviceable hearing following microsurgical resection of small to medium-sized sporadic vestibular schwannomas early after surgery, at 2, 5, and 10 yr following treatment? Recommendation Level 3 : Individuals who meet these criteria and are considering microsurgical resection should be counseled that there is a moderately low probability (>25%-50%) of hearing preservation immediately following surgery, moderately low probability (>25%-50%) of hearing preservation at 2 yr, moderately low probability (>25%-50%) of hearing preservation at 5 yr, and moderately low probability (>25%-50%) of hearing preservation at 10 yr. Question 5 Among patients with AAO-HNS class A or GR grade I hearing at baseline, what is the overall probability of maintaining serviceable hearing following microsurgical resection of small to medium-sized sporadic vestibular schwannomas early after surgery, at 2, 5, and 10 yr following treatment? Recommendation Level 3: Individuals who meet these criteria and are considering microsurgical resection should be counseled that there is a moderately high probability (>50%-75%) of hearing preservation immediately following surgery, moderately high probability (>50%-75%) of hearing preservation at 2 yr, moderately high probability (>50%-75%) of hearing preservation at 5 yr, and moderately low probability (>25%-50%) of hearing preservation at 10 yr. Question 6 What patient- and tumor-related factors influence progression to nonserviceable hearing following microsurgical resection of small to medium-sized sporadic vestibular schwannomas? Recommendation Level 3: Individuals who meet these criteria and are considering microsurgical resection should be counseled regarding the probability of successful hearing preservation based on the following prognostic data: the most consistent prognostic features associated with maintenance of serviceable hearing are good preoperative word recognition and/or pure tone thresholds with variable cut-points reported, smaller tumor size commonly less than 1 cm, and presence of a distal internal auditory canal cerebrospinal fluid fundal cap. Age and sex are not strong predictors of hearing preservation outcome. CONSERVATIVE OBSERVATION Question 7 What is the overall probability of maintaining serviceable hearing with conservative observation of vestibular schwannomas at 2, 5, and 10 yr following diagnosis? Recommendation Level 3: Individuals who meet these criteria and are considering observation should be counseled that there is a high probability (>75%-100%) of hearing preservation at 2 yr, moderately high probability (>50%-75%) of hearing preservation at 5 yr, and moderately low probability (>25%-50%) of hearing preservation at 10 yr. Question 8 Among patients with AAO-HNS class A or GR grade I hearing at baseline, what is the overall probability of maintaining serviceable hearing with conservative observation at 2 and 5 yr following diagnosis? Recommendation Level 3: Individuals who meet these criteria and are considering stereotactic radiosurgery should be counseled that there is a high probability (>75%-100%) of hearing preservation at 2 yr, and moderately high probability (>50%-75%) of hearing preservation at 5 yr. Insufficient data were available to determine the probability of hearing preservation at 10 yr for this population subset. Question 9 What patient and tumor-related factors influence progression to nonserviceable hearing during conservative observation? Recommendation Level 3: Individuals who meet these criteria and are considering observation should be counseled regarding probability of successful hearing preservation based on the following prognostic data: the most consistent prognostic features associated with maintenance of serviceable hearing are good preoperative word recognition and/or pure tone thresholds with variable cut-points reported, as well as nongrowth of the tumor. Tumor size at the time of diagnosis, age, and sex do not predict future development of nonserviceable hearing during observation. The full guideline can be found at: https://www.cns.org/guidelines/guidelines-manage-ment-patients-vestibular-schwannoma/chapter_3.

Abstract QUESTION 1 What is the expected diagnostic yield for vestibular schwannomas when using a magnetic resonance imaging (MRI) to evaluate patients with previously published definitions of asymmetric sensorineural hearing loss? TARGET POPULATION These recommendations apply to adults with an asymmetric sensorineural hearing loss on audiometric testing. RECOMMENDATION Level 3: On the basis of an audiogram, it is recommended that MRI screening on patients with ≥10 decibels (dB) of interaural difference at 2 or more contiguous frequencies or ≥15 dB at 1 frequency be pursued to minimize the incidence of undiagnosed vestibular schwannomas. However, selectively screening patients with ≥15 dB of interaural difference at 3000 Hz alone may minimize the incidence of MRIs performed that do not diagnose a vestibular schwannoma. QUESTION 2 What is the expected diagnostic yield for vestibular schwannomas when using an MRI to evaluate patients with asymmetric tinnitus, as defined as either purely unilateral tinnitus or bilateral tinnitus with subjective asymmetry? TARGET POPULATION These recommendations apply to adults with subjective complaints of asymmetric tinnitus. RECOMMENDATION Level 3: It is recommended that MRI be used to evaluate patients with asymmetric tinnitus. However, this practice is low yielding in terms of vestibular schwannoma diagnosis (<1%). QUESTION 3 What is the expected diagnostic yield for vestibular schwannomas when using an MRI to evaluate patients with a sudden sensorineural hearing loss? TARGET POPULATION These recommendations apply to adults with a verified sudden sensorineural hearing loss on an audiogram. RECOMMENDATION Level 3: It is recommended that MRI be used to evaluate patients with a sudden sensorineural hearing loss. However, this practice is low yielding in terms of vestibular schwannoma diagnosis (<3%). The full guideline can be found at: https://www.cns.org/guidelines/guidelines-management-patients-vestibular-schwannoma/chapter_2.

AbstractBackgroundThromboembolic events following splenectomy are not uncommon. However, the role of thromboprophylaxis and risk factors for thrombosis, as well as the clinical course and outcomes, are not well characterized.MethodsA retrospective review of individuals who underwent splenectomy between January 2006 and December 2015 in two university hospitals.ResultsOverall, 297 patients underwent splenectomy [open splenectomy (n = 199), laparoscopic splenectomy (n = 98)]. Mechanical (thigh‐length pneumatic compression stockings) and pharmacologic thromboprophylaxis (40 mg enoxaparin daily, starting 12 h after surgery until discharge) was provided for all patients. One hundred and sixteen patients (39%) also received an extended thromboprophylaxis course of enoxaparin for 2–4 weeks after discharge. Twenty‐three patients (7.7%) experienced thrombotic complications following splenectomy, including 16 cases (5.4%) of portal‐splenic mesenteric venous thrombosis (PSMVT), 5 (1.7%) pulmonary embolism and 2 (0.7%) deep vein thrombosis. Longer operative time (mean operative time of 405 vs. 273 min, P = 0.03) was independently associated with PSMVT. Post‐splenectomy thrombocytosis was not associated with thrombosis (P = 0.41). The overall thrombosis rate was significantly lower in patients who received an extended thromboprophylaxis course following splenectomy (3.4 vs. 10.5%, P = 0.02). Complete resolution of thrombosis was observed in most cases (n = 20, 87.0%), with no recurrent thrombosis during a mean follow‐up of 38 ± 25 months.ConclusionsThromboembolic complications, mainly PSMVT, are common following splenectomy. Longer operative time was associated with thrombosis. Significantly lower rates of thrombosis were found in patients who received an extended thromboprophylaxis course.

Chromophobe renal cell carcinoma (chRCC) typically shows ~7 chromosome losses (1, 2, 6, 10, 13, 17, and 21) and ~31 exonic somatic mutations, yet carries ~5%–10% metastatic incidence. Since extensive chromosomal losses can generate proteotoxic stress and compromise cellular proliferation, it is intriguing how chRCC, a tumor with extensive chromosome losses and a low number of somatic mutations, can develop lethal metastases. Genomic features distinguishing metastatic from nonmetastatic chRCC are unknown. An integrated approach, including whole-genome sequencing (WGS), targeted ultradeep cancer gene sequencing, and chromosome analyses (FACETS, OncoScan, and FISH), was performed on 79 chRCC patients including 38 metastatic (M-chRCC) cases. We demonstrate that TP53 mutations (58%), PTEN mutations (24%), and imbalanced chromosome duplication (ICD, duplication of ≥ 3 chromosomes) (25%) were enriched in M-chRCC. Reconstruction of the subclonal composition of paired primary-metastatic chRCC tumors supports the role of TP53 , PTEN , and ICD in metastatic evolution. Finally, the presence of these 3 genomic features in primary tumors of both The Cancer Genome Atlas kidney chromophobe (KICH) ( n = 64) and M-chRCC ( n = 35) cohorts was associated with worse survival. In summary, our study provides genomic insights into the metastatic progression of chRCC and identifies TP53 mutations, PTEN mutations, and ICD as high-risk features.

ABSTRACTBioinformatics tools are imperative for the in depth analysis of heterogeneous high‐throughput data. Most of the software tools are developed by specific laboratories or groups or companies wherein they are designed to perform the required analysis for the group. However, such software tools may fail to capture “what the community needs in a tool”. Here, we describe a novel community‐driven approach to build a comprehensive functional enrichment analysis tool. Using the existing FunRich tool as a template, we invited researchers to request additional features and/or changes. Remarkably, with the enthusiastic participation of the community, we were able to implement 90% of the requested features. FunRich enables plugin for extracellular vesicles wherein users can download and analyse data from Vesiclepedia database. By involving researchers early through community needs software development, we believe that comprehensive analysis tools can be developed in various scientific disciplines.