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The main objective of this study is to assess the effect of soft skills and emotional intelligence on burnout among health-care professionals in Lebanon.

Abstract Background The mechanism by which HIV-1 induces AIDS is still unknown. Previously, synthetic peptides corresponding to the conserved immunosuppressive (isu) domain in gp41 of HIV-1 had been shown to inhibit proliferation and to modulate cytokine expression of immune cells. The question is, whether the viral gp41 can do the same. Results We show for the first time that two trimeric forms of glycosylated gp41 released from transfected human cells modulated expression of cytokines and other genes in human PBMCs in the same manner, but at least seven hundred-fold stronger compared to that induced by the isu peptide. Single amino acid substitutions in the isu domain of gp41 introduced by site-directed mutagenesis abrogated this property. Furthermore, replication-competent HIV-1 with a mutation in the isu domain of gp41 did not modulate the cytokine expression, while wild-type virus did. Interestingly, most of the abrogating mutations were not reported in viral sequences derived from infected individuals, suggesting that mutated non-immunosuppressive viruses were eliminated by immune responses. Finally, immunisation of rats with gp41 mutated in the isu domain resulted in increased antibody responses compared with the non-mutated gp41. These results show that non-mutated gp41 is immunosuppressive in immunisation experiments, i.e. in vivo, and this has implications for the vaccine development. Conclusions These findings indicate that the isu domain of gp41 modulates cytokine expression in vitro and suppresses antibody response in vivo and therefore may contribute to the virus induced immunodeficiency.

Assessment of differences in the response of three different populations of the tropical cladoceran Moinodaphnia macleayi to uranium exposure was evaluated. The populations tested included a laboratory stock (maintained for 10 years), a wild population collected from Bowerbird Billabong (an uncontaminated environment), and a population collected from Djalkmara Billabong (a relatively contaminated environment with elevated levels of uranium), located on the Ranger uranium mine site, Jabiru East, NT, Australia. Chronic and acute toxicity of uranium was determined for all three populations. The no-observed-effect-concentration (NOEC; reproduction) and lowest observed-effect-concentration (LOEC; reproduction) for uranium ranged between 8-31 mug L-1 and 20-49 mug L-1, respectively, for all three populations. The 48 h EC50 (immobilization-lethality) for uranium rangedbetween 160-390 mug L-1 for all three populations. There was little difference in the response of the three populations of M. macleayi to acute and chronic uranium exposure, although the responseof the laboratory population to chronic uranium exposure appeared more variable than the 'wild' populations. There was no apparent tolerance in the population of M. macleayi obtained from Djalkmara Billabong when exposed to elevated levels of uranium. M. macleayi was significantly more sensitive to uranium exposure than other species previously tested. It was concluded that the sensitivity of the laboratory population (to uranium) is still representative of natural M. macleayi populations. [ABSTRACT FROM AUTHOR]

Objective: Evaluate the sensitivity and financial costs of Trans-Impedance Matrix recordings, Spread of Excitation functions, and x-rays in detecting cochlear implant tip foldovers., Setting: Tertiary academic medical center., Patients: 113 ears of 108 patients., Interventions: Following cochlear implantation and before concluding surgery, intraoperative Trans-Impedance Matrix recordings, Spread of Excitation functions, and x-rays were conducted to evaluate presence of tip foldover., Main Outcome Measures: Presence of tip foldover; recording time necessary for and costs of Trans-Impedance Matrix, spread of excitation, and x-rays., Results: There were six tip foldovers. Trans-Impedance Matrix showed 100% sensitivity, 100% specificity, 100% positive predictive value, and 100% negative predicative value in detecting tip foldovers. Spread of excitation showed 29% sensitivity, 99% specificity, 67% positive predictive value, and 95% negative predicative value. Trans-Impedance Matrix recordings were completed significantly faster than spread of excitation and x-rays. Elimination of x-rays from our intraoperative workflow results in a twofold cost reduction., Conclusion: Trans-Impedance Matrix recordings have potential great clinical utility in evaluating proper CI placement intraoperatively and reducing costs of surgery while not compromising patient care. Given the low tip foldover rate, a multicenter study is in progress to evaluate the sensitivity, specificity, positive predictive value, and negative predicative value of Trans-Impedance Matrix in a larger dataset. This can provide better guidance to cochlear implant clinics interested in evaluating the impact of using Trans-Impedance Matrix on patient care as well as the economics of reducing use of intraoperative imaging., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of Otology & Neurotology, Inc.)

Protein misfolding and mislocalization are common to both familial and sporadic forms of amyotrophic lateral sclerosis (ALS). Maintaining proteostasis through induction of heat shock proteins (HSP) to increase chaperoning capacity is a rational therapeutic strategy in the treatment of ALS. However, the threshold for upregulating stress-inducible HSPs remains high in neurons, presenting a therapeutic obstacle. This study used mouse models expressing the ALS variants FUS R521G or SOD1 G93A to follow up on previous work in cultured motor neurons showing varied effects of the HSP co-inducer, arimoclomol, and class I histone deacetylase (HDAC) inhibitors on HSP expression depending on the ALS variant being expressed. As in cultured neurons, neither expression of the transgene nor drug treatments induced expression of HSPs in cortex, spinal cord or muscle of FUS R521G mice, indicating suppression of the heat shock response. Nonetheless, arimoclomol, and RGFP963, restored performance on cognitive tests and improved cortical dendritic spine densities. In SOD1 G93A mice, multiple HSPs were upregulated in hindlimb skeletal muscle, but not in lumbar spinal cord with the exception of HSPB1 associated with astrocytosis. Drug treatments improved contractile force but reduced the increase in HSPs in muscle rather than facilitating their expression. The data point to mechanisms other than amplification of the heat shock response underlying recovery of cognitive function in ALS-FUS mice by arimoclomol and class I HDAC inhibition and suggest potential benefits in counteracting cognitive impairment in ALS, frontotemporal dementia and related disorders., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Heather Durham reports financial support was provided by Merck, Sharpe & Dohme Corporation, McGill Faculty of Medicine. Heather Durham reports financial support was provided by Brain Canada Foundation and ALS Society of Canada. Heather Durham reports equipment, drugs, or supplies was provided by BioMarin Pharmaceutical Inc. Chantelle Septhton reports financial support was provided by Brain Canada Foundation and ALS Society of Canada and FRSQ. Mario Fernandez Comaduran reports financial support was provided by Fonds de Recherche du Québec Nature et Technologies and Mitacs Globalink Graduate Fellowship, Consejo Nacional de Ciencia y Tecnología. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

A simple and robust cell culture system is essential for generating authentic SARS-CoV-2 stocks for evaluation of viral pathogenicity, screening of antiviral compounds, and preparation of inactivated vaccines. Evidence suggests that Vero E6, a cell line commonly used in the field to grow SARS-CoV-2, does not support efficient propagation of new viral variants and triggers rapid cell culture adaptation of the virus. We generated a panel of 17 human cell lines overexpressing SARS-CoV-2 entry factors and tested their ability to support viral infection. Two cell lines, Caco-2/AT and HuH-6/AT, demonstrated exceptional susceptibility, yielding highly concentrated virus stocks. Notably, these cell lines were more sensitive than Vero E6 cells in recovering SARS-CoV-2 from clinical specimens. Further, Caco-2/AT cells provided a robust platform for producing genetically reliable recombinant SARS-CoV-2 through a reverse genetics system. These cellular models are a valuable tool for the study of SARS-CoV-2 and its continuously emerging variants., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Objectives: Weight loss has been proposed as risk factor for patulous Eustachian tube (PET), however, it has not been well-characterized how this subpopulation responds to standard treatments. This study aimed to evaluate PET symptom improvement in the setting of and absence of rapid weight loss., Methods: This retrospective case series included patients diagnosed with PET at an academic institution. Demographic characteristics, medical comorbidities, presenting symptoms, treatment, and outcomes of symptom improvement were reviewed. Univariate analysis modeled the likelihood of symptom improvement between rapid weight loss and non-rapid weight loss patients., Results: A total of 124 patients (median age 55 years, 61 % female) were included. At diagnosis, 7 (5.6 %) patients were underweight, 40 (32.3 %) were normal weight, 32 (25.8 %) were overweight, and 45 (36/3 %) were obese. There were 39 (31.5 %) patients who had history of weight loss prior to presentation; of these, 22 (17.7 %) noted rapid weight loss and 17 (13.7 %) had non-rapid weight loss. There were 62 (50.0 %) patients who were recommended conservative treatment, and 62 (50.0 %) who underwent medical and/or surgical treatment. Symptom resolution was achieved in 49 (39.5 %) patients. On univariate analysis, patients with rapid weight loss were significantly more likely to experience improvement (p = 0.006) than non-rapid weight loss. Rapid weight loss patients had a four-fold increased likelihood of symptom improvement compared to non-rapid weight loss patients (OR = 4.8, p = 0.053)., Conclusions: While rapid weight loss and bariatric surgery are reported risk factors for the development of PET, our findings suggest that patients with rapid weight loss are significantly more likely to achieve symptom improvement than non-rapid weight loss., Competing Interests: Declaration of competing interest None of the authors have significant conflicts of interest with any companies or organizations whose products or services may be discussed in this article., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives/hypothesis: To investigate patient-specific characteristics that independently predict for progressive hearing loss in patients with enlarged vestibular aqueduct (EVA). Utilize multivariable predictive models to identify subgroups of patients with significantly different progression risks., Study Design: Retrospective analysis of patients evaluated at an academic tertiary care center. Cohort included 74 ears of patients with a diagnosis of EVA as defined by the Cincinnati criteria., Methods: Hearing trajectories were characterized, and a Kaplan-Meier estimator was utilized to determine progressive phenotype probabilities across the first 10 years after diagnosis. Cox proportional hazard regression was used to identify patient characteristics that independently altered this probability. Stratified risk groups were delineated from generated nomogram scores., Results: Male gender was associated with a 4.53 hazard ratio for progressive hearing loss (95% confidence interval [CI], 2.53 to 12.59). Each millimeter increase in operculum size was independently associated with an 80.40% increase in expected hazard (95% CI, 40.18 to 120.62). Each dB increase in air pure tone average at time of diagnosis decreased expected hazard by 1.59% (95% CI, -3.02 to -0.17). The presence of incomplete partition type II was associated with a 2.44 hazard ratio (95% CI, 1.04 to 5.72). Risk groups stratified by median nomogram score evidenced the discriminative ability of our model with the progression probability in the high-risk group being six times higher at 1 year, nearly five times greater at 3 years, and three times greater at 9 years., Conclusions: EVA patient characteristics can be used to predict hearing loss probability with a high degree of accuracy (C-index of 0.79). This can help clinicians make more proactive management decisions by identifying patients at high risk for hearing loss., Level of Evidence: 4 Laryngoscope, 132:1439-1445, 2022., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)

Semaan et al. (J Forensic Res, 2020, 11, 453) discuss a mock case "where eight different individuals [P 1 through P 8 ] could not be excluded in a mixed DNA analysis. Even though … expert DNA mixture analysis software was used." Two of these are the true donors. The LRs reported are incorrect due to the incorrect entry of propositions into LRmix Studio. This forced the software to account for most of the alleles as drop-in, resulting in LRs 60-70 orders of magnitude larger than expected. P 1 , P 2 , P 4 , P 5 , and P 8 can be manually excluded using peak heights. This has relevance when using LRmix which does not use peak heights. We extend the work using the same two reference genotypes who were the true contributors as Semaan et al. (J Forensic Res, 2020, 11, 453). We simulate three two-donor mixtures with peak heights using these two genotypes and analyze using STRmix™. For the simulated 1:1 mixture, one of the non-donors' LRs supported him being a contributor when no conditioning was used. When considered in combination with any other potential donors (i.e., with conditioning), this non-donor was correctly eliminated. For the 3:1 mixture, all results correctly supported that the non-donors were not contributors. The low-template 4:1 mixture LRs with no conditioning showed support for all eight profiles as donors. However, the results from pair-wise conditioning showed that only the two ground truth donors had LRs supporting that they were contributors to the mixture. We recommend the use of peak heights and conditioning profiles, as this allows better sensitivity and specificity even when the persons share many alleles., (© 2021 American Academy of Forensic Sciences.)

Introduction: Ankylosing spondylitis (AS) patients seems to be at risk of osteoporosis but bone screening is not often performed. The objective was to evaluate the effect of vertebral ankylosis on scanographic bone attenuation coefficient (SBAC) on lumbar vertebrae in AS patients., Methods: This study included AS patients fulfilling New York criteria who underwent both thoraco-abdomino-pelvic computed tomography and X-rays during routine follow-up. The modified stoke ankylosing spondylitis spinal score (mSASSS) was scored on X-rays, and the presence of at least one syndesmophyte (mSASSS≥2) defined mSASSS+ patients. Ankylosis of a lumbar vertebra was defined by the presence of bone bridges to its two adjacent vertebrae. The SBAC was measured from L1 to L5, and the fracture threshold was set at SBAC≤145 HU., Results: A total of 73 AS patients were included (mean age: 60.3 [±10.7] years, 65 men [89%]). Sixty patients (82.2%) were mSASSS+; 13 patients (17.8%) presented ankylosis of at least one lumbar vertebra. The SBAC of each lumbar vertebra was not significantly different between mSASSS- and mSASSS+ patients. The SBAC was lower for patients with at least one bone bridge than for patients without (P<0.05). Patients with lumbar vertebral ankylosis had a higher risk of presenting an SBAC≤145 HU (OR: 4.95 (95% CI: 1.1-17.4))., Conclusion: The presence of a bone bridge and complete ankylosis of lumbar vertebra were associated with a higher risk of SBAC under the fracture threshold, suggesting structural deterioration of trabecular bone in ankylosed vertebrae in AS patients., (Copyright © 2020 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.)

Purpose : Non-pathological child cortical bone (NPCCB) studies can provide clinicians with vital information and insights. However, assessing the anisotropic elastic properties of NPCCB remains a challenge for the biomechanical engineering community. For the first time, this paper provides elastic moduli values for NPCCB specimens in two perpendicular directions (longitudinal and transverse) and for two different structural components of bone tissue (osteon and interstitial lamellae). Materials and Methods : Microindentation is one of the reference methods used to measure bone stiffness. Here, 8 adult femurs (mean age 82 ± 8.9 years), 3 child femurs (mean age 13.3 ± 2.1 years), and 16 child fibulae (mean age 10.2 ± 3.9 years) were used to assess the elastic moduli of adult and child bones by microindentation. Results : For adult specimens, the mean moduli measured in this study are 18.1 (2.6) GPa for osteons, 21.3 (2.3) GPa for interstitial lamellae, and 13.8 (1.7) GPa in the transverse direction. For child femur specimens, the mean modulus is 14.1 (0.8) GPa for osteons, lower than that for interstitial lamellae: 15.5 (1.5) GPa. The mean modulus is 11.8 (0.7) GPa in the transverse direction. Child fibula specimens show a higher elastic modulus for interstitial lamellae 15.8 (1.5) than for osteons 13.5 (1.6), with 10.2 (1) GPa in the transverse direction. Conclusion : For the first time, NPCCB elastic modulus values are provided in longitudinal and transverse directions at the microscale level.

The assessment of the anisotropic elastic properties of non-pathological child cortical bone remains a challenge for the biomechanical engineering community and an important clinical issue. Resonant ultrasound spectroscopy (RUS) can be used to determine bone stiffness coefficients from the mechanical resonances of bone specimens. Here, a RUS protocol was used on 7 fibula specimens from children (mean age 14 ± 3 years) to estimate the whole elastic stiffness tensor of non-pathological child cortical bone considered as orthotropic. Despite a small number of sample, results are consistent with this hypothesis, even if a trend towards transverse isotropy is discussed. Indeed, the average values of the 9 independent stiffness coefficients obtained in this study for child bone are: C 11 = 16.73 ± 0.19 GPa, C 22 = 16.19 ± 0.12 GPa, C 33 = 24.47 ± 0.30 GPa, C 44 = 4.14 ± 0.08 GPa, C 55 = 4.16 ± 0.07 GPa, C 66 = 3.13 ± 0.05 GPa, C 12 = 10.14 ± 0.20 GPa, C 13 = 10.67 ± 0.27 GPa, C 23 = 10.25 ± 0.14 GPa., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: The purpose of this work is to explore audiometry following cochlear implantation (CI) in patients with enlarged vestibular aqueduct (EVA) and to investigate the effects of inner ear morphological variation on post CI audiometry., Methods: This was a retrospective review of both natural and cochlear-implant-aided audiometry results, using all available measurements in a mixed-effects model accounting for longitudinal change and the grouping structure of ears. Patients who visited our tertiary academic medical center between 2000 and 2016 were identified as having EVA according to Cincinnati criteria on radiological examination; patients eligible for CI were then selected for analysis., Results: Multivariable modeling showed a statistically significant hearing improvement in ears with EVA undergoing CI with regards to pure tone average (-64.0 dB, p < 0.0001), speech reception threshold (-57.90 dB, p < 0.0001), and word score (34.8%, p > 0.0001). Vestibular aqueduct midpoint size and the presence of incomplete partition type II (IP II) did not have significant independent associations with audiometric findings. However, multivariable modeling revealed a statistically significant interaction between IP II and CI such that IP II ears demonstrated a decrease in WS improvement of 30.2% (p = 0.0059) compared to non-IP II ears receiving CI., Conclusion: There is a statistically significant audiometric benefit to ears with EVA receiving CI. Morphology, specifically the presence of IP II, may hinder CI benefit in terms of word score however this finding needs clinical validation. This data improves personalization of surgical counseling and planning for patients with EVA considering CI., (Copyright © 2018 Elsevier Inc. All rights reserved.)

OBJECTIVE There is no definitive or consensus classification system for the jugular bulb position that can be uniformly communicated between a radiologist, neurootologist, and neurosurgeon. A high-riding jugular bulb (HRJB) has been variably defined as a jugular bulb that rises to or above the level of the basal turn of the cochlea, within 2 mm of the internal auditory canal (IAC), or to the level of the superior tympanic annulus. Overall, there is a seeming lack of consensus, especially when MRI and/or CT are used for jugular bulb evaluation without a dedicated imaging study of the venous anatomy such as digital subtraction angiography or CT or MR venography. METHODS A PubMed analysis of "jugular bulb" comprised of 1264 relevant articles were selected and analyzed specifically for an HRJB. A novel classification system based on preliminary skull base imaging using CT is proposed by the authors for conveying the anatomical location of the jugular bulb. This new classification includes the following types: type 1, no bulb; type 2, below the inferior margin of the posterior semicircular canal (SCC), subclassified as type 2a (without dehiscence into the middle ear) or type 2b (with dehiscence into the middle ear); type 3, between the inferior margin of the posterior SCC and the inferior margin of the IAC, subclassified as type 3a (without dehiscence into the middle ear) and type 3b (with dehiscence into the middle ear); type 4, above the inferior margin of the IAC, subclassified as type 4a (without dehiscence into the IAC) and type 4b (with dehiscence into the IAC); and type 5, combination of dehiscences. Appropriate CT and MR images of the skull base were selected to validate the criteria and further demonstrated using 3D reconstruction of DICOM files. The microsurgical significance of the proposed classification is evaluated with reference to specific skull base/posterior fossa pathologies. RESULTS The authors validated the role of a novel classification of jugular bulb location that can help effective communication between providers treating skull base lesions. Effective utilization of the above grading system can help plan surgical procedures and anticipate complications. CONCLUSIONS The authors have proposed a novel anatomical/radiological classification system for jugular bulb location with respect to surgical implications. This classification can help surgeons in complication avoidance and management when addressing HRJBs.

Purpose: The purpose of this work is to identify the role of incomplete partition type II on hearing loss among patients with enlarged vestibular aqueduct (EVA)., Background: EVA is a common congenital inner ear malformation among children with hearing loss, where vestibular aqueduct morphology in this population has been shown to correlate to hearing loss. However, the impact of incomplete partition between cochlear turns on hearing loss has not been, despite meaningful implications for EVA pathophysiology., Methods: A retrospective review of radiology reports for patients who had computed tomography (CT) scans with diagnoses of hearing loss at a tertiary medical center between January 2000 and June 2016 were screened for EVA. CT scans of the internal auditory canal (IAC) for those patients with EVA were examined for evidence of incomplete partition type II (IP-II), measurements of midpoint width and operculum width a second time, and patients meeting Cincinnati criteria for EVA selected for analysis. Statistical analysis including chi-square, Wilcoxon rank-sum, and t-tests were used to identify differences in outcomes and clinical predictors, as appropriate for the distribution of the data. Linear mixed models of hearing test results for all available tests were constructed, both univariable and adjusting for vestibular aqueduct morphometric features, with ear-specific intercepts and slopes over time., Results: There were no statistically significant differences in any hearing test results or vestibular aqueduct midpoint and operculum widths. Linear mixed models, both univariable and those adjusting for midpoint and operculum widths, did not indicate a statistically significant effect of incomplete partition type II on hearing test results., Conclusions: Hearing loss due to enlarged vestibular aqueduct does not appear to be affected by the presence of incomplete partition type II. Our results suggest that the pathophysiological processes underlying hearing loss in enlarged vestibular aqueduct may not be a result of cochlear malformation, and instead are more likely to involve vestibular aqueduct or cellular and molecular-level mechanisms of hearing loss., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Importance: Elucidating the relationship between vestibular aqueduct size and hearing loss progression may inform the prognosis and counseling of patients who have an enlarged vestibular aqueduct (EVA)., Objectives: To examine the association between vestibular aqueduct size and repeated measures of hearing loss., Design, Setting, and Participants: For this retrospective medical record review, 52 patients with a diagnosis of hearing loss and radiologic diagnosis of EVA according to the Valvassori criterion were included. All available speech reception threshold and word recognition score data was retrieved; mixed-effects models were constructed where vestibular aqueduct size, age at diagnosis of hearing loss, and time since diagnosis of hearing loss were used to predict repeated measures of hearing ability. This study was performed at an academic tertiary care center., Exposures: Variable vestibular aqueduct size, age at first audiogram, length of time after first audiogram., Main Outcomes and Measures: Speech reception threshold (dB) and word recognition score (%) during routine audiogram., Results: Overall, 52 patients were identified (29 females [56%] and 23 males [44%]; median age at all recorded audiograms, 7.8 years) with a total of 74 ears affected by EVA. Median (range) vestibular aqueduct size was 2.15 (1.5-5.9) mm, and a median (range) of 5 (1-18) tests were available for each patient. Each millimeter increase in vestibular aqueduct size above 1.5 mm was associated with an increase of 17.5 dB in speech reception threshold (95% CI, 7.2 to 27.9 dB) and a decrease of 21% in word recognition score (95% CI, -33.3 to -8.0 dB). For each extra year after a patient's first audiogram, there was an increase of 1.5 dB in speech recognition threshold (95% CI, 0.22 to 3.0 dB) and a decrease of 1.7% in word recognition score (95% CI, -3.08 to -0.22 dB)., Conclusions and Relevance: Hearing loss in patients with an EVA is likely influenced by vestibular aqueduct midpoint width. When considering hearing loss prognosis, vestibular aqueduct midpoint width may be useful for the clinician who counsels patients affected by EVA.

While most studies of submonolayer island nucleation and growth have been based on the assumption of ordinary monomer diffusion corresponding to diffusion exponent μ=1, in some cases either subdiffusive (μ<1) or superdiffusive (μ>1) behavior may occur. Here we present general expressions for the exponents describing the flux dependence of the island and monomer densities as a function of the critical island size i, substrate dimension d, island fractal dimension d&#95;{f}, and diffusion exponent μ, where 0≤μ≤2. Our results are compared with kinetic Monte Carlo simulations for the case of irreversible island growth (i=1) with 0≤μ≤2 and d=2 as well as simulation results for d=1, 3, and 4, and excellent agreement is found.

Background: Tinnitus is a source of considerable morbidity, and neuromodulation has been shown to be a potential treatment option. However, the location of the primary auditory cortex within Heschl gyrus in the temporal operculum presents challenges for targeting and electrode implantation., Objective: To determine whether anatomic targeting with intraoperative verification using evoked potentials can be used to implant electrodes directly into the Heschl gyrus (HG)., Methods: Nine patients undergoing stereo-electroencephalogram evaluation for epilepsy were enrolled. HG was directly targeted on volumetric magnetic resonance imaging, and framed stereotaxy was used to implant an electrode parallel to the axis of the gyrus by using an oblique anterolateral-posteromedial trajectory. Intraoperative evoked potentials from auditory stimuli were recorded from multiple electrode contacts. Postoperatively, stimulation of each electrode was performed and participants were asked to describe the percept. Audiometric analysis was performed for 2 participants during subthreshold stimulation., Results: Sounds presented to the contralateral and ipsilateral ears produced evoked potentials in HG electrodes in all participants intraoperatively. Stimulation produced a reproducible sensation of sound in all participants with perceived volume proportional to amplitude. Four participants reported distinct sounds when different electrodes were stimulated, with more medial contacts producing tones perceived as higher in pitch. Stimulation was not associated with adverse audiometric effects. There were no complications of electrode implantation., Conclusion: Direct anatomic targeting with physiological verification can be used to implant electrodes directly into primary auditory cortex. If deep brain stimulation proves effective for intractable tinnitus, this technique may be useful to assist with electrode implantation., Abbreviations: DBS, deep brain stimulatorEEG, electroencephalographyHG, Heschl gyrus.

Xenotransplantation has been proposed as a solution to the shortage of suitable human donors for transplantation and pigs are currently favoured as donor animals. However, xenotransplantation may be associated with the transmission of zoonotic microorganisms. Whereas most porcine microorganisms representing a risk for the human recipient may be eliminated by designated pathogen free breeding, multiple copies of porcine endogenous retroviruses (PERVs) are integrated in the genome of all pigs and cannot be eliminated this way. PERVs are released as infectious particles and infect human cells. The zinc finger nuclease (ZFN) technology allows knocking out specifically cellular genes, however it was not yet used to eliminate multiple integrated proviral sequences with a strong conservation in the target sequence. To reduce the risk of horizontal PERV transmission and to knock out as many as possible proviruses, for the first time the powerful tool of the ZFN technology was used. ZFN were designed to bind specifically to sequences conserved in all known replication-competent proviruses. Expression and transport of the ZFN into the nucleus was shown by Western blot analysis, co-localisation analysis, PLA and FRET. Survival of transfected cells was analysed using fluorescent ZFN and cell counting. After transfection a strong expression of the ZFN proteins and a co-localisation of the expressed ZFN proteins were shown. However, expression of the ZFN was found to be extremely toxic for the transfected cells. The induced cytotoxicity was likely due to the specific cutting of the high copy number of the PERV proviruses, which is also commonly observed when ZFN with low specificity cleave numerous off-target sites in a genome. This is the first attempt to knock out multiple, nearly identical, genes in a cellular genome using ZFN. The attempt failed, and other strategies should be used to prevent PERV transmission.

Background: Squamous cell carcinoma of the oral cavity (OSCC) is a common cancer form with relatively low 5-year survival rates, due partially to late detection and lack of complementary molecular markers as targets for treatment. Molecular profiling of head and neck cancer has revealed biological similarities with basal-like breast and lung carcinoma. Recently, we showed that 16 genes were consistently altered in invasive breast tumors displaying varying degrees of aggressiveness., Methods: To extend our findings from breast cancer to another cancer type with similar characteristics, we performed an integrative analysis of transcriptomic and proteomic data to evaluate the prognostic significance of the 16 putative breast cancer-related biomarkers in OSCC using independent microarray datasets and immunohistochemistry. Predictive models for disease-specific (DSS) and/or overall survival (OS) were calculated for each marker using Cox proportional hazards models., Results: We found that CBX2, SCUBE2, and STK32B protein expression were associated with important clinicopathological features for OSCC (peritumoral inflammatory infiltration, metastatic spread to the cervical lymph nodes, and tumor size). Consequently, SCUBE2 and STK32B are involved in the hedgehog signaling pathway which plays a pivotal role in metastasis and angiogenesis in cancer. In addition, CNTNAP2 and S100A8 protein expression were correlated with DSS and OS, respectively., Conclusions: Taken together, these candidates and the hedgehog signaling pathway may be putative targets for drug development and clinical management of OSCC patients.

The deregulation of key cellular pathways is fundamental for the survival and expansion of neoplastic cells, which in turn can have a detrimental effect on patient outcome. To develop effective individualized cancer therapies, we need to have a better understanding of which cellular pathways are perturbed in a genetically defined subgroup of patients. Here, we validate the prognostic value of a 13-marker signature in independent gene expression microarray datasets (n = 1,141) and immunohistochemistry with full-faced FFPE samples (n = 71). The predictive performance of individual markers and panels containing multiple markers was assessed using Cox regression analysis. In the external gene expression dataset, six of the 13 genes (AZGP1, NME5, S100A8, SCUBE2, STC2 and UBE2C) retained their prognostic potential and were significantly associated with disease-free survival (p < 0.001). Protein analyses refined the signature to a four-marker panel [AZGP1, Prolactin-inducible protein (PIP), S100A8 and UBE2C] significantly correlated with cycling, high grade tumors and lower disease-specific survival rates. AZGP1 and PIP were found in significantly lower levels in invasive breast tissue as compared with adjacent normal tissue, whereas elevated levels of S100A8 and UBE2C were observed. A predictive model containing the four-marker panel in conjunction with established clinical variables outperformed a model containing the clinical variables alone. Our findings suggest that deregulated AZGP1, PIP, S100A8 and UBE2C are critical for the aggressive breast cancer phenotype, which may be useful as novel therapeutic targets for drug development to complement established clinical variables., (© 2013 UICC.)

This case is an example of a translabyrinthine resection of a small intracanalicular acoustic tumor. The patient is a 69-year-old right-handed woman with complaints of progressive incapacitating vertigo and right-sided hearing loss worsening over the past 3 years. She had normal facial nerve function with imaging demonstrating progressive increase in size of a small right-sided acoustic tumor. A translabyrinthine approach was performed, and the mass was resected completely. Facial nerve function remained normal immediately after surgery. The video can be found here: http://youtu.be/27ARlLLSbKE .

Background: To establish the safety of xenotransplantation when cells, tissues, or organs of pigs are used, an effective screening for potential zoonotic microorganisms has to be performed. In doing so, special attendance has to be paid to porcine endogenous retroviruses (PERVs) that are widely distributed as proviruses in the genome of pigs. PERV-A and PERV-B are present in all pigs, they infect human cells in vitro and therefore represent a direct risk. PERV-C infects only pig cells; however, recombinant PERV-A/C infecting human cells and replicating at a higher rate were found in pigs indicating an indirect risk. To prevent the transmission of PERV, it was suggested to use animals characterized by a low expression of PERV-A and PERV-B that are free of PERV-C and cannot generate recombinants. Göttingen minipigs are used for numerous biomedical investigations and they are well characterized; however, the prevalence and the expression of PERV in these animals were not yet investigated., Methods: The presence and expression of all PERVs including a new variant (nv) of PERV-C and PERV-A/C were analyzed using PCR and real-time PCR methods. Altogether, 15 animals belonging to different families were analyzed. To make a low expression better measurable, peripheral blood mononuclear cells (PBMCs) of the animals were stimulated with phytohaemagglutinin generally increasing the expression of PERV and allowing a better classification into animals with high and low expression. As a major end point, the release of virus particles able to infect susceptible human 293 cells was investigated., Results: PERV-A, PERV-B, PERV-C, and PERV-Cnv were found in the genome of all investigated Göttingen minipigs, but recombinant PERV-A/Cs were not found. When the expression of PERV was compared with that in previously analyzed pig strains, it was higher than in German landrace and some other pigs, but lower than in Yucatan miniature pigs. Virus particles able to infected human 293 cells were not detected even after mitogen treatment of the PBMCs., Conclusion: The Göttingen minipigs are well defined concerning their physiologic parameters, their health status, and their genetics, and therefore, they may be considered as donor animals for at least cell xenotransplantation. When the prevalence and the expression of PERVs were analyzed in these animals, it was demonstrated that although PERV-A, -B, and -C proviruses were found in all animals, their expression was low. Additional investigations are required to assess the suitability of Göttingen minipigs and other animals for xenotransplantation in terms of microbiological safety., (© 2013 John Wiley & Sons A/S.)

Porcine endogenous retroviruses (PERV) are widely distributed in the genomes of pigs. PERV-A and PERV-B are present in all pigs. They infect human cells in vitro and therefore represent a risk for xenotransplantation when pig cells, tissues or organs are used. PERV-C infects only pig cells and is not present in the genomes of all pigs. However, PERV-A/C recombinants infecting human cells and characterized by high replication titers were found in pigs. To select PERV-C-free animals that cannot generate such recombinants, PCR-based assays were developed (Kaulitz et al., J Virol Methods, 175:60, 2011). When screening for PERV-C in German wild boars (Sus scrofa scrofa), applying these methods, a new variant of PERV-C was identified. Whereas in all 125 wild boar only the new variant of PERV-C was found, different variants were present in some landrace pigs, and most importantly, some pigs were totally free of PERV-C.

The transmembrane envelope protein gp41 of the human immunodeficiency virus HIV-1 plays an important role during infection allowing fusion of the viral and cellular membrane. In addition, there is increasing evidence that gp41 may contribute to the immunodeficiency induced by HIV-1. Recombinant gp41 and a synthetic peptide corresponding to a highly conserved domain in gp41, the immunosuppressive (isu) domain, have been shown to inhibit mitogen-induced activation of human peripheral blood mononuclear cells (PBMCs) and to increase release of IL-6 and IL-10 from these cells. We recently reported that a single mutation in the isu domain of gp41 abrogated the immunosuppressive properties and that HIV-1 sequences containing such abrogating mutations had never been isolated from infected individuals. Here, we studied the influence of the isu peptide on the release of 66 cytokines and the expression of 27,000 genes in PBMCs. Incubation of PBMCs with isu peptide homopolymers increased the expression of 16 cytokines among them IL-6 and IL-10, and decreased that of IL-2 and CXCL9. Interestingly, the extend of cytokine modulation was donor-dependent. Among the genes up-regulated were IL-6, IL-8, IL-10 but also MMP-1, TREM-1 and IL-1beta. Most importantly, genes involved in innate immunity such as FCN1 and SEPP1 were found down-regulated. Many changes in cytokine expression demonstrated in our experiments were also found in HIV-1 infected individuals. These data indicate that the isu domain of gp41 has a broad impact on gene expression and cytokine release and therefore may be involved in HIV-1 induced immunopathogenesis.

The design, implementation, and characterization of a microelectromechanical systems (MEMS) capacitive accelerometer-based middle ear microphone are presented in this paper. The microphone is intended for middle ear hearing aids as well as future fully implantable cochlear prosthesis. Human temporal bones acoustic response characterization results are used to derive the accelerometer design requirements. The prototype accelerometer is fabricated in a commercial silicon-on-insulator (SOI) MEMS process. The sensor occupies a sensing area of 1 mm × 1 mm with a chip area of 2 mm × 2.4 mm and is interfaced with a custom-designed low-noise electronic IC chip over a flexible substrate. The packaged sensor unit occupies an area of 2.5 mm × 6.2 mm with a weight of 25 mg. The sensor unit attached to umbo can detect a sound pressure level (SPL) of 60 dB at 500 Hz, 35 dB at 2 kHz, and 57 dB at 8 kHz. An improved sound detection limit of 34-dB SPL at 150 Hz and 24-dB SPL at 500 Hz can be expected by employing start-of-the-art MEMS fabrication technology, which results in an articulation index of approximately 0.76. Further micro/nanofabrication technology advancement is needed to enhance the microphone sensitivity for improved understanding of normal conversational speech.

Background: Porcine endogenous retroviruses (PERVs) represent a risk of xenotransplantation using porcine cells, tissues, or organs, as they are integrated in the porcine genome and have been shown to be able to infect human cells in vitro. To increase viral safety by RNA interference, transgenic pigs expressing a PERV-specific small hairpin (sh)RNA targeted to a highly conserved sequence in the pol gene (pol2) were generated in which expression of PERVs was reduced (Xenotransplantation, 15, 2008, 38). However, it remains to be shown how long expression of the shRNA and the RNA interference is effective in reducing PERV expression., Methods: To analyze the long-term duration of RNA interference, expression of the PERV-specific pol2 shRNA and inhibition of PERV expression was studied repeatedly in fibroblasts and peripheral blood mononuclear cells (PBMCs) of transgenic pigs over a period of 3 yr, when animals were sacrificed and expression was studied in different organs. Expression of the PERV-specific shRNA was measured using a newly developed real-time PCR, and expression of PERV was measured using a PERV-specific real-time PCR., Results: Over a period of 3 yr, PERV-specific shRNA and green fluorescent protein (GFP) as reporter of the vector system were consistently expressed in transgenic animals. PERV expression was significantly reduced during the entire period. Levels of PERV and shRNA expression were different in the various organs. PERV expression was highest in the spleen and the lungs and lowest in liver and heart. However, in all organs of the transgenic pigs, PERV expression was inhibited compared with the vector control animals., Conclusions: Transgenic pigs expressing PERV-specific shRNA maintained their specific RNA interference long term, suggesting that PERV expression in the xenotransplants will be suppressed over extended periods of time., (© 2012 John Wiley & Sons A/S.)

Object: Although benign and slow growing, glomus jugulare tumors can be locally aggressive because of their proximity to lower cranial nerves and major vascular structures. Surgical resection frequently leads to complications, and radiosurgery alone often does not relieve symptoms. We report a novel treatment paradigm of tailored surgical resection followed by staged radiosurgery that allows for tissue diagnosis and immediate improvement of symptoms and tumor control without the morbidity of radical surgical resection., Methods: Five patients with glomus jugulare tumors and contraindications to extensive surgery each underwent an outpatient otologic procedure to resect the portion of the tumor in the middle ear and mastoid with no attempt to remove tumor in the jugular bulb. Each patient returned 2-5 months later for Gamma Knife radiosurgery to the remainder of the tumor, which consisted of one 15-Gy dose prescribed to the 50% isodose curve. Patients were followed through outpatient visits and surveillance MR imaging for up to 3 years., Results: All patients were successfully treated as outpatients. Each had improvement or resolution of pulsatile tinnitus and otalgia and preserved or improved hearing. One patient developed a delayed facial palsy prior to radiosurgery that resolved completely; there were no other changes in cranial nerve function after either procedure. Tumor volume was stable or reduced in all patients at most recent follow-up, and there were no immediate or delayed complications., Conclusions: Staged outpatient microsurgical and radiosurgical therapy for glomus jugulare tumors in the symptomatic patient is safe and yields favorable results regarding tumor size, tinnitus, hearing and cranial nerve status.

Background: Drug errors constitute a public health problem. The objective of our study was to describe drug circuit essential steps in the Lebanese hospitals, starting at prescription to administration, in comparison with Lebanese accreditation standards. We also evaluated technical drug errors., Methods: A cross sectional study of all hospitals in Beirut and Mount Lebanon was carried out, where a pharmacist and a nurse per hospital answered anonymous standardized questionnaires., Results: We found the drug circuit suffered from gaps in all 59 hospitals that were visited: doctors should increase efforts to clarify prescriptions and furnish necessary information for nurses, pharmacists better apply accreditation standards, and nurses verify and re-verify treatments before administration., Conclusion: Regulatory laws are necessary for all involved actors for best responding to the responsibility in question, that is patient security.

Objective: The relationships between adipocytokines, sex steroids and the GH/IGF-I axis is poorly studied and subject to controversy in healthy elderly male subjects. We investigated the association between both adiponectin and leptin, and the metabolic syndrome (MetS), lipid parameters, insulin sensitivity, sex steroids and IGF-I in healthy non-diabetic Lebanese men., Design and Methods: In this cross-sectional study, a total of 153 healthy non-diabetic men aged 50 and above (mean age 59.3 +/- 7 years) had a detailed clinical and biological evaluation. Subjects were classified according to the National Cholesterol Education Program criteria of the MetS. Insulin sensitivity was determined by the Quantitative Insulin Sensitivity Check Index (QUICKI)., Results: Subjects with the MetS had lower adiponectin and higher leptin levels (P < 0.0001 for both variables) compared with individuals without the MetS. Adiponectin was significantly correlated with waist size, triglycerides, high-density lipoprotein (HDL) cholesterol and QUICKI (r = -0.33, -0.26, 0.45 and 0.36 respectively, P < 0.0001 for all variables). The relation between adiponectin and HDL cholesterol, triglycerides and QUICKI remained significant after adjustment for age and body mass index (BMI). Also, leptin was strongly correlated with waist size and QUICKI (r = 0.63 and -0.63 respectively, P < 0.001 for both variables). However, its relation to the lipid profile was weak (for cholesterol r = 0.16, P < 0.05; for triglycerides r = 0.17, P < 0.05) and disappeared after adjustment for BMI. Adiponectin was positively correlated with sex hormone-binding globulin (SHBG) (r = 0.39, P < 0.001) and inversely correlated with free-androgen index (r = -0.24, P < 0.01), estradiol and dehydroepiandrosterone sulfate (r = -0.165, P < 0.05; r = -0.21, P < 0.01 respectively). This difference remained significant for SHBG after adjustment for age and BMI (r = 0.20, P < 0.005). Finally, leptin was inversely correlated with total testosterone and SHBG (r = -0.44, P < 0.001; r = -0.30, P < 0.001 respectively); the relation with testosterone remained significant after adjustment for BMI. No significant relationship of either adiponectin or leptin with GH or IGF-I values was observed. In a stepwise multiple regression analysis, the independent predictors of adiponectin were HDL cholesterol, QUICKI, age and BMI (P < 0.0001, P = 0.005, P = 0.002 and P = 0.047 respectively) while for leptin, it was QUICKI, waist size and testosterone (P < 0.0001, P < 0.0001 and P = 0.004 respectively). The adjusted R2 values were 0.34 and 0.55., Conclusion: Our results show that in a healthy elderly male population, both adiponectin and leptin are related to insulin sensitivity, independent of age and BMI. While adiponectin is independently related to triglycerides and HDL cholesterol, the weak relationship of leptin to the lipid profile is completely mediated by BMI. In addition, and more interestingly, both adipocytokines are strongly associated with sex steroids. We speculate that SHBG is regulated by adiponectin and that there is an inhibitory effect of testosterone on the adiponectin gene. Further studies are needed to fully elucidate these relationships.

Objective: The relationship between osteoprotegerin (OPG) and lipid profile, insulin sensitivity, adipocytokines and sex steroids has been poorly studied and subject to controversy. The purpose of this study was to look at the correlates of OPG in an elderly male population., Design: One hundred and fifty-one nondiabetic, elderly Lebanese men (age range 50-83) were recruited in this cross-sectional study based on voluntary enrolment., Measurements: In all the subjects, serum OPG levels were measured and related to clinical parameters (age, waist, body mass index (BMI), systolic and diastolic blood pressure), as well as to metabolic and hormonal parameters. The following fasting laboratory measurements were performed: plasma glucose and insulin levels, total cholesterol, triglycerides and HDL cholesterol, adiponectin, leptin, as well as sex steroids (testosterone, SHBG, free androgen index, ooestradiol, DHEAS), GH and IGF-1. QUICKI index was calculated as a measure of insulin sensitivity., Results: OPG levels were significantly correlated with age (r = 0.28, P < 0.0001) but not with BMI, waist, systolic or diastolic blood pressure. There was a trend towards higher OPG levels in subjects without, compared to subjects with the metabolic syndrome (3.58 +/- 1.28 vs. 3.26 +/- 1.04 pmol/l, P = 0.09). OPG was negatively correlated with fasting glucose and triglyceride levels (r = -0.18, P = 0.031 and r = -0.19, P = 0.02, respectively) and positively correlated with the QUICKI index (r = 0.17, P = 0.033), HDL cholesterol (r = 0.21, P = 0.009) and adiponectin levels (r = 0.27, P = 0.001). No significant correlations were reported with total or LDL cholesterol levels and with leptin levels. After adjustment for age, OPG is still correlated with triglycerides (r = -0.19, P = 0.02), glucose (r = -0.21, P = 0.011) and adiponectin (r = 0.19, P = 0.02). Finally, OPG was positively associated with SHBG (r = 0.31, P < 0.001) and negatively associated with free androgen index (r =-0.346, P < 0.001); both correlations persisted after adjustment for age (r = 0.21, P = 0.009 and r = -0.23, P = 0.005, respectively). No significant correlation was found between OPG and oestradiol levels while a weak negative correlation was demonstrated with DHEAS (r = -0.18, P = 0.025). Also, no significant correlation was found between OPG and GH or IGF-1 values. In a multiple regression analysis with a stepwise model, the main determinants of OPG were free androgen index and adiponectin (P < 0.0001 and P = 0.015, respectively)., Conclusion: Our results show that circulating OPG levels are favourably associated with some components of the metabolic syndrome. Also, for the first time, an association between OPG and adiponectin is described. Finally, the negative correlation we found between OPG and free androgen index may suggest a potential role of OPG in the increase in cardiovascular disease related to ageing and sex steroid deficiency.

System miniaturization and steady progress towards a totally implantable prosthetic system is the current trend in cochlear implant technology. To achieve this objective, the external microphone of present implants needs to be implantable. This goal can be accomplished by placing a miniature accelerometer on the ossicular chain in the middle ear to detect and convert bone vibrations into an electrical signal for further processing and stimulating cochlear electrodes. This paper describes the characterization of the umbo of a human temporal bone before and after the removal of the incus to determine the impact of the resulting change in umbo mechanics and attached accelerometer performance. With the removal of the incus, the umbo vibration acceleration frequency response in the direction perpendicular to the tympanic membrane increases by 5 dB below 2 kHz. Above 2 kHz the response diverges due to the change of ossicular chain resonant frequency caused by the removal of the incus. However, at each frequency the umbo vibration acceleration exhibits a linear function of the input sound pressure level (SPL) with a slope of 20 dB per decade before and after removal of the incus. A commercial accelerometer attached to the umbo shows similar characteristics. From the measurement results of umbo characterization, a miniaturized implantable accelerometer with a packaged mass below 20 milligrams, a sensing resolution of 35 microg rms/square root Hz, and a bandwidth of 10 kHz would be required to detect normal conversation.

Introduction: Metalloproteinases (MMPs) promote cell migration and tumour invasion by degradation of the extracellular matrix. Activators and inhibitors (such as membrane type 1-matrix metalloproteinase or MT1-MMP and tissue inhibitor metalloproteinase 2 or TIMP-2) regulate metalloproteinase activity. The objective of this study was to determine the prognostic value of stromal immunolabelling with MMP-2, MT1-MMP and TIMP-2 in clinically localized prostate cancer., Material and Methods: The immunohistochemical study was performed on 30 radical prostatectomy specimens. The results were compared to preoperative PSA, Gleason score, pT stage and biochemical recurrence with a minimum follow-up of 5 years., Results: Stromal immunolabelling with MMP-2 is correlated with stage pT3 (p=0.0022, OR=17.5). No correlation was observed with the other histoprognostic parameters. No statistical link was established with MT1-MMP and TIMP-2., Conclusion: Stromal immunolabelling with MMP-2 is a histoprognostic marker of capsular effraction in prostatic adenocarcinoma. When performed on prostatic biopsies, it can predict the pT3 stage, allowing adaptation of the initial treatment in some patients.

The potential of two hydra species, Hydra vulgaris (pink) and Hydra viridissima (green), for use as invertebrate models for toxicity testing of waterborne metals was investigated. The acute and subchronic toxicities of cadmium (a nonessential metal) and zinc (an essential metal) were determined. Results showed that both the hydra species were more sensitive to cadmium than to zinc, and that green hydra were more sensitive than pink hydra. The mean (SE) 96 h LC50 values of cadmium and zinc for pink hydra were 83 (8.5) and 2300 (150) micrograms/L, respectively. For green hydra, the respective 96 h LC50 values for cadmium and zinc were 3.0 (0.0) and 935 (46.5) micrograms/L. The respective 7-day no-observed-effect-concentrations (NOEC) and lowest-observed-effect-concentrations (LOEC) for pink hydra were < 13 and 13 micrograms/L for cadmium, and < 250 and 250 micrograms/L for zinc. The respective 7-day NOEC and LOEC values for green hydra were 0.4 and 0.8, microgram/L for cadmium, and 38 and 75 micrograms/L for zinc. Neither 1, 2, or 3 x 90-min pulse-exposures to 0.4, 0.8, or 1.5 micrograms/L of cadmium had any significant deleterious effect on total green hydra numbers after seven days in clean water. Green hydra appeared to be excellent freshwater invertebrate models for testing dissolved metals based on their sensitivity and the ability to rapidly assess population reproduction in the laboratory.