Delay differential equations in a nonlinear cochlear model.

The human auditory system performs its primary function in the cochlea, the main organ of the inner ear, where the spectral analysis of a sound signal and its transduction into a neural signal occur. It is filled with liquid and divided in two cavities by the basilar membrane (BM). A sound stimulus propagates in air as an acoustic pressure wave through the outer and the middle ear. The pressure of the stapes on the oval window (boundary between the middle and the inner ear) causes the cochlear fluid to flow between the two cavities through a hole at the end of the BM. A spatial partial differential equation of fluid-dynamics describes this physical process. As a consequence of the differential pressure between the two cavities, each micro-element of the BM oscillates as a forced damped harmonic oscillator. The BM displacement is amplified by the overlying outer hair cells (OHCs) through a nonlinear nonlocal active feedback mechanism. The latter can be modeled by means of various representations. Among them, the delayed stiffness model of Talmadge et al. (J. Acoust. Soc. Am. 104, 1998) has been considered in this thesis. Specifically, the cochlear nonlinearity is introduced as a quadratic function of the BM displacement in the passive linear damping function. Moreover, the active mechanism is described by two additional forces, each one proportional to the BM displacement delayed by a slow and a fast feedback constant time, respectively. According to this model, a time delay differential equation (DDE) of the second order describes the oscillating dynamics of the BM. A different formulation of the nonlinear active mechanism, driven by the OHCs, is expressed as a nonlinear function of the BM velocity by the anti-damping model of Moleti et al. (J. Acoust. Soc. Am. 133, 2013). In this case the model equations do not contain time delays. The numerical integration of the above mentioned models has been obtained by finite differencing with respect to the space variable in the state space, as introduced by Elliott et al. (J. Acoust. Soc. Am. 122, 2007), and then integrating in time with the adaptive package introduced by Bertaccini and Sisto as a modification of the popular Matlab ode15s package (J. Comput. Phys. 230, 2011). The semidiscrete formulation of the delayed stiffness model and the anti-damping model has a non trivial mass matrix, and eigenvalues of the system matrix with large negative real part and imaginary part. That is why an implicit solver with an infinite region of absolute stability should be used. Therefore, the customized Matlab ode15s package by Bertaccini and Sisto seems to be the convenient choice to integrate the problem at hand numerically. In particular, for the delayed stiffness model, an integrator for constant DDEs (the method of steps; Bellen and Zennaro, Oxford University Press 2003) has been formulated and based on the customized ode15s. All these topics have been discussed in this doctoral thesis, which is subdivided in the following chapters. Chapter 1 describes the anatomy of the human ear, with special regard to the cochlea. Some experimental evidences about the cochlear mechanisms are discussed, in order to support the cochlear modeling. Two physical models with one degree of freedom are shown: the anti-damping model of Sisto et al. (J. Acoust. Soc. Am. 128, 2010) and Moleti et al. (J. Acoust. Soc. Am. 133, 2013), and the delayed stiffness model of Talmadge et al. (J. Acoust. Soc. Am. 104, 1998). Chapter 2 discusses the general theory of DDEs, with greater reference to constant and time dependent DDEs from Bellen and Zennaro (Oxford University Press 2003). Existence and uniqueness of time dependent DDEs are briefly analyzed, while the method of steps is shown as a basic approach to find a numerical approximation of the DDEs solution. According to this method, IVPs of constant DDEs (as for the semidiscrete delayed stiffness model) are turned into IVPs of ODEs in a subinterval (of length less than or equal to the time delay) of the whole integration interval. Each IVP of ODEs can be integrated by means of any ODEs numerical method, and its convergence is then discussed. Chapter 3 describes the main tools used to find an approximate solution of the considered models. In particular, the discretization for spatial partial derivatives by means of finite differences is shown. Such a representation turns a model, which is continuous in the space-time domain, into a semidiscrete model to be integrated in time. The models considered in this thesis are stiff, so the phenomenon of stiffness is discussed and the ode15s package of Matlab for integrating stiff ODEs is described. Nevertheless, greater benefits can be obtained by using the ode15s package customized by Bertaccini and Sisto as a hybrid direct-iterative solver which exploits Krylov subspace methods. Chapter 4 shows the semidiscrete formulation of the continuous models (anti-damping model and delayed stiffness model) in the state space with respect to the spatial variable, as introduced by Elliott et al. (J. Acoust. Soc. Am. 122, 2007). The algebraic properties of the semidiscrete models are discussed in order to show why the customized ode15s package may perform a faster numerical integration of the semidiscrete models and how this solver can be used in an integration numerical technique for constant DDEs (the method of steps). Chapter 5 shows the results produced by the numerical experiments of the delayed stiffness model by supplying a sinusoidal tone, and compares them with the numerical results produced by the anti-damping model. Some considerations about the numerical approach of the time integration are also discussed, and a part of the simplified code used for integrating the semidiscrete delayed stiffness model, is reported. The results are comparable with those obtained by the anti-damping model, and then the numerical experimental evidences seem to justify the proposed integration technique for constant DDEs. Delayed model properties of tonotopicity, anti-damping and nonlinearity are verified, as well as the dependence of the approximate solution on some free parameters of the model. The cochlear response described by the delayed stiffness model shows a typical tall and broad BM activity pattern. This behavior is also found in the numerical results of a model with two degree of freedom produced by Neely and Kim (J. Acoust. Soc. Am. 79, 1986) and Elliott et al. (J. Acoust. Soc. Am. 122, 2007)

RNA-Sequence analysis of primary alveolar macrophages after in vitro infection with porcine reproductive and respiratory syndrome virus strains of differing virulence

Porcine reproductive and respiratory syndrome virus (PRRSV) mainly infects porcine alveolar macrophages (PAMs), resulting in porcine reproductive and respiratory syndrome (PRRS) in pigs. Most of the transcriptomic studies on PAMs infected with PRRSV conducted thus far have made use of microarray technology. Here, we investigated the transcriptome of PAMs in vitro at 12 h post-infection with two European PRRSV strains characterized by low (Lelystad, LV) and high (Lena) virulence through RNA-Seq. The expression levels of genes, isoforms, alternative transcription start sites (TSS) and differential promoter usage revealed a complex pattern of transcriptional and post-transcriptional gene regulation upon infection with the two strains. Gene ontology analysis confirmed that infection of PAMs with both the Lena and LV strains affected signaling pathways directly linked to the innate immune response, including interferon regulatory factors (IRF), RIG1-like receptors, TLRs and PKR pathways. The results confirmed that interferon signaling is crucial for transcriptional regulation during PAM infection. IFN-beta 1 and IFN-alpha omega, but not IFN-alpha, were up-regulated following infection with either the LV or Lena strain. The down-regulation of canonical pathways, such as the interplay between the innate and adaptive immune responses, cell death and TLR3/TLR7 signaling, was observed for both strains, but Lena triggered a stronger down-regulation than LV. This analysis contributes to a better understanding of the interactions between PRRSV and PAMs and outlines the differences in the responses of PAMs to strains with different levels of virulence, which may lead to the development of new PRRSV control strategies

Factors Affecting Indoor Radon Levels in Buildings Located in a Karst Area: A Statistical Analysis

In this paper, the averages annual radon concentrations in buildings placed in a karst area are analyzed in order to understand which factors may affect the occurrence of high levels of radon indoor. Statistical analysis on the radon dataset is performed using analytical factors described by two or three levels according to the characteristic of the measured buildings. The factors that determine higher radon levels in terms of arithmetic mean (AM) at ground floor (GF) are mainly the presence of sedimentary calcareous rock (SCR) in walls and the direct attack or crawl space as type of foundation. At first floors (FF), the presence of walls of only SCR showed radon levels higher (in terms of AM) than the one found for walls of mixed typology. These outcomes suggest that in karstic area buildings with SCR as the main construction material and direct attack or crawl space as the type of foundation, can be considered as radon-prone buildings. Moreover, this study confirms the need to measure radon levels not only at below ground floor and at GF, but also at FF and above for buildings in karst areas with construction materials including SCR blocks

Oral hygiene orientation and caries experience for cerebral palsy patients using oral medication

A presença de prejuízos associados à paralisia cerebral (PC) requer muitas vezes o uso de medicamentos de uso contínuo e por longos períodos de tempo. Dentre os efeitos colaterais adversos destes medicamentos destacam-se a diminuição do fluxo salivar e aumento do risco para doença cárie. Objetivo: Verificar se os responsáveis pelos pacientes com PC receberam orientações quanto à realização da higiene bucal após a administração dos medicamentos de uso contínuo via oral e a experiência de cárie nos pacientes com PC. Método: Participaram deste estudo transversal, 205 crianças com diagnóstico médico de PC, de ambos os gêneros, com idades entre 0 a 12 anos (6,6 ± 2,9) que frequentavam um programa de prevenção em Odontologia numa instituição de referência em reabilitação em São Paulo-SP. Os dados relativos ao gênero, desordem do movimento e padrão clínico da PC foram coletados dos prontuários. Sob a forma de entrevista, os responsáveis relatavam se a criança fazia uso ou não de algum medicamento de uso contínuo, e, em caso afirmativo, qual a forma de apresentação dos mesmos; se os responsáveis haviam recebido orientação prévia sobre a importância da realização higiene bucal após a utilização dos medicamentos, quem realizava a higiene bucal da criança, e com que frequência esta era realizada. A experiência de cárie foi registrada segundo o índice de dentes cariados (C, c) perdidos (P, e) ou obturados (O, o) por dente (D, d) (CPOD). Foram constituídos dois grupos segundo o uso (grupo 1: G1) ou não (grupo 2: G2) de medicamentos sob a forma contínua. Foram usados os testes do Qui-quadrado e teste t de Student. Fixou-se o nível de significância em 5%. Resultados: Os grupos G1 (n = 110) e o G2 (n = 95) eram homogêneos quanto ao gênero (p = 0,343) e a idade (p = 0,514). Entretanto diferiram significantemente em relação ao padrão clínico, apresentando G1 porcentagens significantemente maiores de pacientes com tetraparesia (p < 0,001). Analisando apenas o G1, observou-se que os subgrupos em uso de medicamentos sob a forma solução oral (solução; n = 65) ou em uso de comprimidos (comprimido; n = 45) diferiram significantemente quanto à orientação prévia para a realização da higiene bucal (p = 0,013), apresentando o grupo solução maior porcentagem dos responsáveis orientados. Com relação à realização da higiene oral, o subgrupo solução apresentou porcentagens significantemente maiores (p = 0,044) de crianças que requeriam supervisão e realização da higiene bucal dos responsáveis quando comparado ao grupo comprimido. A comparação da experiência de cárie entre os grupos G1 e G2 mostrou que o G1 apresentou valores significantemente maiores para o valor do índice CPOD (p = 0,048), e menor número de pacientes livres de cárie (p = 0,016) quando comparado a G2. Conclusão: Embora os responsáveis pelos pacientes que recebiam medicamento sob a forma de solução oral sob a forma contínua fossem os mais orientados quanto à realização da higiene bucal após a administração dos medicamentos, estes pacientes apresentavam maior experiência de cárie.The presence of damage associated with cerebral palsy (CP) often requires the long-term continuous use of prescription drugs. Among the adverse side effects of these drugs are decreased salivary flow and increased risk for caries. Objective: To determine whether those responsible for CP patients received orientation regarding the necessity of oral hygiene after the administration of drugs of continuous oral use and the caries experience in patients with CP. Method: Participating in this study were 205 children with medical diagnosis of CP, of both genders, aged 0-12 years (6.6 ± 2.9) attending a preventive program in dentistry in a reference institution of rehabilitation in São Paulo-SP. The data regarding gender, movement disorder and clinical types of CP were collected from medical records. In an interview format, the caregivers reported whether there was use of any continuous medicine. They were asked what form it took, whether the caregivers had received prior guidance on the importance of oral hygiene after the use of medicines, who performed the oral child’s hygiene, and how often it was done. Their caries experience was recorded based on whether a given tooth was decayed (D, d) missing (M, m) or filled (F, f) (DMFT). The sample was divided into two groups according to whether they used continuous drugs (group 1: G1) or did not (group 2: G2). The Chi-square test and Student’s t test were used, with the level of significance set up at 5%. Results: G1 (n = 110) and G2 (n = 95) were similar in terms of gender (p = 0.343) and age (p = 0.514). However, they differed significantly in relation to the clinical pattern, with G1 presenting significantly higher percentages of patients with tetraparesis (p < 0.001). Considering only the G1, it was observed that the subgroup that used medicine in oral solution form (solution, n = 65) differed significantly from that using tablets (tablets, n = 45) in relation to their previous orientation for hygiene oral (p = 0.013), in that the solution subgroup had been better oriented. With regard to oral hygiene, the solution subgroup had significantly higher percentages (p = 0.044) of children requiring supervision and completion of the oral hygiene when compared to the tablet group. The comparison of caries experience between G1 and G2 showed that the G1 had significantly higher values for their DMF index (p = 0.048), and fewer caries-free patients (p = 0.016) when compared to G2. Conclusion: Although those responsible for the patients receiving medication in the form of oral solution were better oriented, these patients presented higher values of caries experience

Progetto Geosoglie

Il Centro Funzionale Decentrato (CFD) della Regione Sardegna si propone di sviluppare con il Progetto GEOSOGLIE una attività di ricerca e sviluppo sui temi del rischio idrogeologico e in particolare dei processi di innesco dei fenomeni franosi in funzione di specifici valori pluviometrici di soglia e della propensione al dissesto dei versanti. In questo lavoro viene presentata la struttura e lo sviluppo del progetto nelle sue fasi funzionali.The Decentralized Functional Centre (Centro Funzionale Decentrato, CFD) of Regione Autonoma della Sardegna, through the Project GEOSOGLIE, aims to develop research activities on hydrological risk issues and, in particolar, on the trigger processes of landslides according to specific rainfall thresholds. Moreover, the susceptivity to landslide will be mapped. In this paper we present the structure and the operational development of the project describing its functional phases

Fasting glucose and body mass index as predictors of activity in breast cancer patients treated with everolimus-exemestane: the EverExt study

Evidence on everolimus in breast cancer has placed hyperglycemia among the most common high grade adverse events. Anthropometrics and biomarkers of glucose metabolism were investigated in a observational study of 102 postmenopausal, HR + HER2- metastatic breast cancer patients treated with everolimus-exemestane in first and subsequent lines. Best overall response (BR) and clinical benefit rate (CBR) were assessed across subgroups defined upon fasting glucose (FG) and body mass index (BMI). Survival was estimated by Kaplan-Meier method and log-rank test. Survival predictors were tested in Cox models. Median follow up was 12.4 months (1.0-41.0). The overall cohort showed increasing levels of FG and decreasing BMI (p < 0.001). Lower FG fasting glucose at BR was more commonly associated with C/PR or SD compared with PD (p < 0.001). We also observed a somewhat higher BMI associated with better response (p = 0.052). More patients in the lowest FG category achieved clinical benefit compared to the highest (p < 0.001), while no relevant differences emerged for BMI. Fasting glucose at re-assessment was also predictive of PFS (p = 0.037), as confirmed in models including BMI and line of therapy (p = 0.049). Treatment discontinuation was significantly associated with changes in FG (p = 0.014). Further research is warranted to corroborate these findings and clarify the underlying mechanisms

Comparison of salivary cytokines levels among individuals with Down syndrome, cerebral palsy and normoactive

Individuals with Down syndrome (DS) present increased susceptibility to infections and high prevalence of periodontal disease. The objective of this study is to evaluate the salivary concentrations of IL-1?, IL-6, IL-8, IL-10, TNF? and IL-12p70 of DS individuals and compare to cerebral palsy (CP) and normoactive patients (all with gingivitis). Twenty-two individuals with DS, 24 with CP and 22 normoactive participated in this cross-sectional study. Salivary flow rate, osmolality rate, Oral Hygiene Index, Gingival Index (GI) and salivary inflammatory markers IL-1?, IL-6, IL-8, IL-10, TNF? and IL-12p70 were evaluated. Shapiro-Wilks, Chi-square, ANOVA One-Way and Kruskal Wallis tests were applied with significance level at 5%. The groups were homogenous for gender, age, and IL12p70 cytokine (p>0.05). GI was significantly higher in DS compared to CP and healthy (p<0.05). CP presented reduced salivary flow and increased osmolality rate. CP showed significantly higher values for TNF?, IL10, and IL6 compared to DS and normoactive (p<0.05). DS and CP presented significantly higher values of IL-1? and IL8 compared to normoactive (p<0.05). Individuals with CP have higher risk to develop periodontal disease due to reduced salivary flow rate, increased salivary osmolality rate and elevated TNF?, IL-10, IL-6 compared to DS

Tooth avulsion accidents due to urgent and emergency orotracheal intubation

Intubation is necessary during critical situations to reduce the risk of death. In Brazil, a need exists to determine the prevalence of tooth avulsions in emergency and urgent care. The objective of this study was to identify the causes of orotracheal intubation (OTI), the number of tooth avulsions, and the avulsed teeth that result from urgent and emergency intubation. The sample consisted of 116 patients (total group) in intensive care units (ICUs) distributed across Group 1 (G1), which was composed of 71 patients from an urgent-care hospital, and Group 2 (G2), which was composed of 45 patients from an emergency hospital. Clinical examinations showed dental alveolus with signs of recent exodontia in the upper and lower anterior regions. Sociodemographic data and the reason for intubation were evaluated. The Shapiro-Wilk normality test, chi-square test, Fisher?s exact test, Mann-Whitney U test, and univariate logistic regression were performed with a significance level of 5%. The avulsion prevalence was 4.3%, with more cases receiving emergency intubation (n=4). All avulsions occurred in adults, and a significant difference (p=0.011) was observed with regard to the elderly. A 1-year reduction in age increased the chance of tooth avulsion during intubation by 1.09 times; being female increased the chance by 2.88 times. Pulmonary problems were the major causes of intubation, with the highest tooth avulsion prevalence observed during emergency intubation. The avulsed teeth were 11, 12, 13, 22, 32, and 33 across all cases