Sensitivity of the human auditory cortex to acoustic degradation of speech and non-speech sounds

The perception of speech is usually an effortless and reliable process even in highly adverse listening conditions. In addition to external sound sources, the intelligibility of speech can be reduced by degradation of the structure of speech signal itself, for example by digital compression of sound. This kind of distortion may be even more detrimental to speech intelligibility than external distortion, given that the auditory system will not be able to utilize sound source-specific acoustic features, such as spatial location, to separate the distortion from the speech signal. The perceptual consequences of acoustic distortions on speech intelligibility have been extensively studied. However, the cortical mechanisms of speech perception in adverse listening conditions are not well known at present, particularly in situations where the speech signal itself is distorted. The aim of this thesis was to investigate the cortical mechanisms underlying speech perception in conditions where speech is less intelligible due to external distortion or as a result of digital compression. In the studies of this thesis, the intelligibility of speech was varied either by digital compression or addition of stochastic noise. Cortical activity related to the speech stimuli was measured using magnetoencephalography (MEG). The results indicated that degradation of speech sounds by digital compression enhanced the evoked responses originating from the auditory cortex, whereas addition of stochastic noise did not modulate the cortical responses. Furthermore, it was shown that if the distortion was presented continuously in the background, the transient activity of auditory cortex was delayed. On the perceptual level, digital compression reduced the comprehensibility of speech more than additive stochastic noise. In addition, it was also demonstrated that prior knowledge of speech content enhanced the intelligibility of distorted speech substantially, and this perceptual change was associated with an increase in cortical activity within several regions adjacent to auditory cortex. In conclusion, the results of this thesis show that the auditory cortex is very sensitive to the acoustic features of the distortion, while at later processing stages, several cortical areas reflect the intelligibility of speech. These findings suggest that the auditory system rapidly adapts to the variability of the auditory environment, and can efficiently utilize previous knowledge of speech content in deciphering acoustically degraded speech signals.Puheen havaitseminen on useimmiten vaivatonta ja luotettavaa myös erittäin huonoissa kuunteluolosuhteissa. Puheen ymmärrettävyys voi kuitenkin heikentyä ympäristön häiriölähteiden lisäksi myös silloin, kun puhesignaalin rakennetta muutetaan esimerkiksi pakkaamalla digitaalista ääntä. Tällainen häiriö voi heikentää ymmärrettävyyttä jopa ulkoisia häiriöitä voimakkaammin, koska kuulojärjestelmä ei pysty hyödyntämään äänilähteen ominaisuuksia, kuten äänen tulosuuntaa, häiriön erottelemisessa puheesta. Akustisten häiriöiden vaikutuksia puheen havaitsemiseen on tutkttu laajalti, mutta havaitsemiseen liittyvät aivomekanismit tunnetaan edelleen melko puutteelisesti etenkin tilanteissa, joissa itse puhesignaali on laadultaan heikentynyt. Tämän väitöskirjan tavoitteena oli tutkia puheen havaitsemisen aivomekanismeja tilanteissa, joissa puhesignaali on vaikeammin ymmärrettävissä joko ulkoisen äänilähteen tai digitaalisen pakkauksen vuoksi. Väitöskirjan neljässä osatutkimuksessa lyhyiden puheäänien ja jatkuvan puheen ymmärrettävyyttä muokattiin joko digitaalisen pakkauksen kautta tai lisäämällä puhesignaaliin satunnaiskohinaa. Puheärsykkeisiin liittyvää aivotoimintaa tutkittiin magnetoenkefalografia-mittauksilla. Tutkimuksissa havaittiin, että kuuloaivokuorella syntyneet herätevasteet voimistuivat, kun puheääntä pakattiin digitaalisesti. Sen sijaan puheääniin lisätty satunnaiskohina ei vaikuttanut herätevasteisiin. Edelleen, mikäli puheäänien taustalla esitettiin jatkuvaa häiriötä, kuuloaivokuoren aktivoituminen viivästyi häiriön intensiteetin kasvaessa. Kuuntelukokeissa havaittiin, että digitaalinen pakkaus heikentää puheäänien ymmärrettävyyttä voimakkaammin kuin satunnaiskohina. Lisäksi osoitettiin, että aiempi tieto puheen sisällöstä paransi merkittävästi häiriöisen puheen ymmärrettävyyttä, mikä heijastui aivotoimintaan kuuloaivokuoren viereisillä aivoalueilla siten, että ymmärrettävä puhe aiheutti suuremman aktivaation kuin heikosti ymmärrettävä puhe. Väitöskirjan tulokset osoittavat, että kuuloaivokuori on erittäin herkkä puheäänien akustisille häiriöille, ja myöhemmissä prosessoinnin vaiheissa useat kuuloaivokuoren viereiset aivoalueet heijastavat puheen ymmärrettävyyttä. Tulosten mukaan voi olettaa, että kuulojärjestelmä mukautuu nopeasti ääniympäristön vaihteluihin muun muassa hyödyntämällä aiempaa tietoa puheen sisällöstä tulkitessaan häiriöistä puhesignaalia

Two-Dimensional Electrophoresis of Tau Mutants Reveals Specific Phosphorylation Pattern Likely Linked to Early Tau Conformational Changes

The role of Tau phosphorylation in neurofibrillary degeneration linked to Alzheimer's disease remains to be established. While transgenic mice based on FTDP-17 Tau mutations recapitulate hallmarks of neurofibrillary degeneration, cell models could be helpful for exploratory studies on molecular mechanisms underlying Tau pathology. Here, “human neuronal cell lines” overexpressing Wild Type or mutated Tau were established. Two-dimensional electrophoresis highlights that mutated Tau displayed a specific phosphorylation pattern, which occurs in parallel to the formation of Tau clusters as visualized by electron microscopy. In fact, this pattern is also displayed before Tau pathology onset in a well established mouse model relevant to Tau aggregation in Alzheimer's disease. This study suggests first that pathological Tau mutations may change the distribution of phosphate groups. Secondly, it is possible that this molecular event could be one of the first Tau modifications in the neurofibrillary degenerative process, as this phenomenon appears prior to Tau pathology in an in vivo model and is linked to early steps of Tau nucleation in Tau mutants cell lines. Such cell lines consist in suitable and evolving models to investigate additional factors involved in molecular pathways leading to whole Tau aggregation

Methylation screening of the TGFBI promoter in human lung and prostate cancer by methylation-specific PCR

<p>Abstract</p> <p>Background</p> <p>Hypermethylation of the <it>TGFBI </it>promoter has been shown to correlate with decreased expression of this gene in human tumor cell lines. In this study, we optimized a methylation-specific polymerase chain reaction (MSP) method and investigated the methylation status of the <it>TGFBI </it>promoter in human lung and prostate cancer specimens.</p> <p>Methods</p> <p>Methylation-specific primers were designed based on the methylation profiles of the <it>TGFBI </it>promoter in human tumor cell lines, and MSP conditions were optimized for accurate and efficient amplification. Genomic DNA was isolated from lung tumors and prostatectomy tissues of prostate cancer patients, bisulfite-converted, and analyzed by MSP.</p> <p>Results</p> <p>Among 50 lung cancer samples, 44.0% (22/50) harbored methylated CpG sites in the <it>TGFBI </it>promoter. An analysis correlating gene methylation status with clinicopathological cancer features revealed that dense methylation of the <it>TGFBI </it>promoter was associated with a metastatic phenotype, with 42.9% (6/14) of metastatic lung cancer samples demonstrating dense methylation vs. only 5.6% (2/36) of primary lung cancer samples (<it>p </it>< 0.05). Similar to these lung cancer results, 82.0% (41/50) of prostate cancer samples harbored methylated CpG sites in the <it>TGFBI </it>promoter, and dense methylation of the promoter was present in 38.9% (7/18) of prostate cancer samples with the feature of locoregional invasiveness vs. only 19.4% (6/31) of prostate cancer samples without locoregional invasiveness (<it>p </it>< 0.05). Furthermore, promoter hypermethylation correlated with highly reduced expression of the <it>TGFBI </it>gene in human lung and prostate tumor cell lines.</p> <p>Conclusion</p> <p>We successfully optimized a MSP method for the precise and efficient screening of <it>TGFBI </it>promoter methylation status. Dense methylation of the <it>TGFBI </it>promoter correlated with the extent of <it>TGFBI </it>gene silencing in tumor cell lines and was related to invasiveness of prostate tumors and metastatic status of lung cancer tumors. Thus, <it>TGFBI </it>promoter methylation can be used as a potential prognostic marker for invasiveness and metastasis in prostate and lung cancer patients, respectively.</p

Environmental and vegetation controls on the spatial variability of CH4 emission from wet-sedge and tussock tundra ecosystems in the Arctic

Aims Despite multiple studies investigating the environmental controls on CH4 fluxes from arctic tundra ecosystems, the high spatial variability of CH4 emissions is not fully understood. This makes the upscaling of CH4 fluxes from plot to regional scale, particularly challenging. The goal of this study is to refine our knowledge of the spatial variability and controls on CH4 emission from tundra ecosystems. Methods CH4 fluxes were measured in four sites across a variety of wet-sedge and tussock tundra ecosystems in Alaska using chambers and a Los Gatos CO2 and CH4 gas analyser. Results All sites were found to be sources of CH4, with northern sites (in Barrow) showing similar CH4 emission rates to the southernmost site (ca. 300 km south, Ivotuk). Gross primary productivity (GPP), water level and soil temperature were the most important environmental controls on CH4 emission. Greater vascular plant cover was linked with higher CH4 emission, but this increased emission with increased vascular plant cover was much higher (86 %) in the drier sites, than the wettest sites (30 %), suggesting that transport and/or substrate availability were crucial limiting factors for CH4 emission in these tundra ecosystems. Conclusions Overall, this study provides an increased understanding of the fine scale spatial controls on CH4 flux, in particular the key role that plant cover and GPP play in enhancing CH4 emissions from tundra soils

Revealing Real-Time Emotional Responses: a Personalized Assessment based on Heartbeat Dynamics

Emotion recognition through computational modeling and analysis of physiological signals has been widely investigated in the last decade. Most of the proposed emotion recognition systems require relatively long-time series of multivariate records and do not provide accurate real-time characterizations using short-time series. To overcome these limitations, we propose a novel personalized probabilistic framework able to characterize the emotional state of a subject through the analysis of heartbeat dynamics exclusively. The study includes thirty subjects presented with a set of standardized images gathered from the international affective picture system, alternating levels of arousal and valence. Due to the intrinsic nonlinearity and nonstationarity of the RR interval series, a specific point-process model was devised for instantaneous identification considering autoregressive nonlinearities up to the third-order according to the Wiener-Volterra representation, thus tracking very fast stimulus-response changes. Features from the instantaneous spectrum and bispectrum, as well as the dominant Lyapunov exponent, were extracted and considered as input features to a support vector machine for classification. Results, estimating emotions each 10 seconds, achieve an overall accuracy in recognizing four emotional states based on the circumplex model of affect of 79.29%, with 79.15% on the valence axis, and 83.55% on the arousal axis

Sedation in palliative care – a critical analysis of 7 years experience

BACKGROUND: The administration of sedatives in terminally ill patients becomes an increasingly feasible medical option in end-of-life care. However, sedation for intractable distress has raised considerable medical and ethical concerns. In our study we provide a critical analysis of seven years experience with the application of sedation in the final phase of life in our palliative care unit. METHODS: Medical records of 548 patients, who died in the Palliative Care Unit of GK Havelhoehe between 1995–2002, were retrospectively analysed with regard to sedation in the last 48 hrs of life. The parameters of investigation included indication, choice and kind of sedation, prevalence of intolerable symptoms, patients' requests for sedation, state of consciousness and communication abilities during sedation. Critical evaluation included a comparison of the period between 1995–1999 and 2000–2002. RESULTS: 14.6% (n = 80) of the patients in palliative care had sedation given by the intravenous route in the last 48 hrs of their life according to internal guidelines. The annual frequency to apply sedation increased continuously from 7% in 1995 to 19% in 2002. Main indications shifted from refractory control of physical symptoms (dyspnoea, gastrointestinal, pain, bleeding and agitated delirium) to more psychological distress (panic-stricken fear, severe depression, refractory insomnia and other forms of affective decompensation). Patients' and relatives' requests for sedation in the final phase were significantly more frequent during the period 2000–2002. CONCLUSION: Sedation in the terminal or final phase of life plays an increasing role in the management of intractable physical and psychological distress. Ethical concerns are raised by patients' requests and needs on the one hand, and the physicians' self-understanding on the other hand. Hence, ethically acceptable criteria and guidelines for the decision making are needed with special regard to the nature of refractory and intolerable symptoms, patients' informed consent and personal needs, the goals and aims of medical sedation in end-of-life care

HNF1α inhibition triggers epithelial-mesenchymal transition in human liver cancer cell lines

<p>Abstract</p> <p>Background</p> <p>Hepatocyte Nuclear Factor 1α (HNF1α) is an atypical homeodomain-containing transcription factor that transactivates liver-specific genes including albumin, α-1-antitrypsin and α- and β-fibrinogen. Biallelic inactivating mutations of <it>HNF1A </it>have been frequently identified in hepatocellular adenomas (HCA), rare benign liver tumors usually developed in women under oral contraceptives, and in rare cases of hepatocellular carcinomas developed in non-cirrhotic liver. HNF1α-mutated HCA (H-HCA) are characterized by a marked steatosis and show activation of glycolysis, lipogenesis, translational machinery and mTOR pathway. We studied the consequences of HNF1α silencing in hepatic cell lines, HepG2 and Hep3B and we reproduced most of the deregulations identified in H-HCA.</p> <p>Methods</p> <p>We transfected hepatoma cell lines HepG2 and Hep3B with siRNA targeting HNF1α and obtained a strong inhibition of HNF1α expression. We then looked at the phenotypic changes by microscopy and studied changes in gene expression using qRT-PCR and Western Blot.</p> <p>Results</p> <p>Hepatocytes transfected with HNF1α siRNA underwent severe phenotypic changes with loss of cell-cell contacts and development of migration structures. In HNF1α-inhibited cells, hepatocyte and epithelial markers were diminished and mesenchymal markers were over-expressed. This epithelial-mesenchymal transition (EMT) was related to the up regulation of several EMT transcription factors, in particular <it>SNAIL </it>and <it>SLUG</it>. We also found an overexpression of TGFβ1, an EMT initiator, in both cells transfected with HNF1α siRNA and H-HCA. Moreover, TGFβ1 expression is strongly correlated to HNF1α expression in cell models, suggesting regulation of TGFβ1 expression by HNF1α.</p> <p>Conclusion</p> <p>Our results suggest that HNF1α is not only important for hepatocyte differentiation, but has also a role in the maintenance of epithelial phenotype in hepatocytes.</p

Promoting Patient Safety and Preventing Medical Error in Emergency Departments

An estimated 108,000 people die each year from potentially preventable iatrogenic injury. One in 50 hospitalized patients experiences a preventable adverse event. Up to 3% of these injuries and events take place in emergency departments. With long and detailed training, morbidity and mortality conferences, and an emphasis on practitioner responsibility, medicine has traditionally faced the challenges of medical error and patient safety through an approach focused almost exclusively on individual practitioners. Yet no matter how well trained and how careful health care providers are, individuals will make mistakes because they are human. In general medicine, the study of adverse drug events has led the way to new methods of error detection and error prevention. A combination of chart reviews, incident logs, observation, and peer solicitation has provided a quantitative tool to demonstrate the effectiveness of interventions such as computer order entry and pharmacist order review. In emergency medicine (EM), error detection has focused on subjects of high liability: missed myocardial infarctions, missed appendicitis, and misreading of radiographs. Some system-level efforts in error prevention have focused on teamwork, on strengthening communication between pharmacists and emergency physicians, on automating drug dosing and distribution, and on rationalizing shifts. This article reviews the definitions, detection, and presentation of error in medicine and EM. Based on review of the current literature, recommendations are offered to enhance the likelihood of reduction of error in EM practice.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74930/1/j.1553-2712.2000.tb00466.x.pd