Neural phoneme discrimination in variable speech in newborns - Associations with dyslexia risk and later language skills.

A crucial skill in infant language acquisition is learning of the native language phonemes. This requires the ability to group complex sounds into distinct auditory categories based on their shared features. Problems in phonetic learning have been suggested to underlie language learning difficulties in dyslexia, a developmental reading-skill deficit. We investigated auditory abilities important for language acquisition in newborns with or without a familial risk for dyslexia with electrophysiological mismatch responses (MMRs). We presented vowel changes in a sequence of acoustically varying vowels, requiring grouping of the stimuli to two phoneme categories. The vowel changes elicited an MMR which was significantly diminished in infants whose parents had the most severe dyslexia in our sample. Phoneme-MMR amplitude and its hemispheric lateralization were associated with language test outcomes assessed at 28 months, an age at which it becomes possible to behaviourally test children and several standardized tests are available. In addition, statistically significant MMRs to violations of a complex sound-order rule were only found in infants without dyslexia risk, but these results are very preliminary due to small sample size. The results demonstrate the relevance of the newborn infants' readiness for phonetic learning for their emerging language skills. Phoneme extraction difficulties in infants at familial risk may contribute to the phonological deficits observed in dyslexia.

Stress urinary incontinent women, the influence of age and hormonal status on estrogen receptor alpha and beta gene expression and protein immunoexpression in paraurethral tissues.

The underlying cause of stress urinary incontinence (SUI) is an anatomical abnormality associated with paraurethral connective tissue dysfunction. The question as to whether estrogens affect the quality of that tissue remains unexplained. Samples of paraurethral connective tissue from 81 women were examined (the SUI's n = 49; the control's n = 32). In both groups, the patients were subdivided into pre- and postmenopausals. Primary study outcome was comparison of the estrogen receptor alpha (ERα) and the estrogen receptor beta (ERß) gene and protein in paraurethral tissue between SUI and control group. Secondary study outcome was comparison of these receptors according to hormonal status of the patients and their age. In both examined groups, we found both ER proteins. The ERα gene expression was detected in-19/32 (SUI) samples and in 24/31 (control), and ERß gene expression 31/32 and 30/31 samples, respectively. The SUI's had significantly lower ERa gene expression premenopausally than the control's. The analysis found considerably lower ERß and reduced ERα gene expression in postmenopausals, approaches the significance level. There was also significant decrease in both receptors' genes expression in post-53 women, compared to younger patients. Spearman's correlation test revealed a statistically significant decrease in ERß gene with age. Both estrogen receptors are found in women's paraurethral tissue, so this tissue is an estrogen target. No correlation between ERß gene expression and immunoexpression and SUI was found. The ERα gene seems to play a key role in SUI in the premenopausal period, but ERß gene expression in the paraurethral connective tissue decreases with age.

Phylogenetics of Australasian gall flies (Diptera: Fergusoninidae): Evolutionary patterns of host-shifting and gall morphology.

This study investigated host-specificity and phylogenetic relationships in Australian galling flies, Fergusonina Malloch (Diptera: Fergusoninidae), in order to assess diversity and explore the evolutionary history of host plant affiliation and gall morphology. A DNA barcoding approach using COI data from 203 Fergusonina specimens from 5gall types on 56 host plant species indicated 85 presumptive fly species. These exhibited a high degree of host specificity; of the 40 species with multiple representatives, each fed only on a single host genus, 29 (72.5%) were strictly monophagous, and 11 (27.5%) were reared from multiple closely related hosts. COI variation within species was not correlated with either sample size or geographic distance. However variation was greater within oligophagous species, consistent with expectations of the initial stages of host-associated divergence during speciation. Phylogenetic analysis using both nuclear and mitochondrial genes revealed host genus-restricted clades but also clear evidence of multiple colonizations of both host plant genus and host species. With the exception of unilocular peagalls, evolution of gall type was somewhat constrained, but to a lesser degree than host plant association. Unilocular peagalls arose more often than any other gall type, were primarily located at the tips of the phylogeny, and did not form clades comprising more than a few species. For ecological reasons, species of this gall type are predicted to harbor substantially less genetic variation than others, possibly reducing evolutionary flexibility resulting in reduced diversification in unilocular gallers.

Genetic differentiation associated with host plants and geography among six widespread species of South American Blepharoneura fruit flies (Tephritidae).

Tropical herbivorous insects are astonishingly diverse, and many are highly host-specific. Much evidence suggests that herbivorous insect diversity is a function of host plant diversity; yet, the diversity of some lineages exceeds the diversity of plants. Although most species of herbivorous fruit flies in the Neotropical genus Blepharoneura are strongly host-specific (they deposit their eggs in a single host plant species and flower sex), some species are collected from multiple hosts or flowers and these may represent examples of lineages that are diversifying via changes in host use. Here, we investigate patterns of diversification within six geographically widespread Blepharoneura species that have been collected and reared from at least two host plant species or host plant parts. We use microsatellites to (1) test for evidence of local genetic differentiation associated with different sympatric hosts (different plant species or flower sexes) and (2) examine geographic patterns of genetic differentiation across multiple South American collection sites. In four of the six fly species, we find evidence of local genetic differences between flies collected from different hosts. All six species show evidence of geographic structure, with consistent differences between flies collected in the Guiana Shield and flies collected in Amazonia. Continent-wide analyses reveal - in all but one instance - that genetically differentiated flies collected in sympatry from different host species or different sex flowers are not one another's closest relatives, indicating that genetic differences often arise in allopatry before, or at least coincident with, the evolution of novel host use.

Biased relevance filtering in the auditory system: A test of confidence-weighted first-impressions.

Although first-impressions are known to impact decision-making and to have prolonged effects on reasoning, it is less well known that the same type of rapidly formed assumptions can explain biases in automatic relevance filtering outside of deliberate behavior. This paper features two studies in which participants have been asked to ignore sequences of sound while focusing attention on a silent movie. The sequences consisted of blocks, each with a high-probability repetition interrupted by rare acoustic deviations (i.e., a sound of different pitch or duration). The probabilities of the two different sounds alternated across the concatenated blocks within the sequence (i.e., short-to-long and long-to-short). The sound probabilities are rapidly and automatically learned for each block and a perceptual inference is formed predicting the most likely characteristics of the upcoming sound. Deviations elicit a prediction-error signal known as mismatch negativity (MMN). Computational models of MMN generally assume that its elicitation is governed by transition statistics that define what sound attributes are most likely to follow the current sound. MMN amplitude reflects prediction confidence, which is derived from the stability of the current transition statistics. However, our prior research showed that MMN amplitude is modulated by a strong first-impression bias that outweighs transition statistics. Here we test the hypothesis that this bias can be attributed to assumptions about predictable vs. unpredictable nature of each tone within the first encountered context, which is weighted by the stability of that context. The results of Study 1 show that this bias is initially prevented if there is no 1:1 mapping between sound attributes and probability, but it returns once the auditory system determines which properties provide the highest predictive value. The results of Study 2 show that confidence in the first-impression bias drops if assumptions about the temporal stability of the transition-statistics are violated. Both studies provide compelling evidence that the auditory system extrapolates patterns on multiple timescales to adjust its response to prediction-errors, while profoundly distorting the effects of transition-statistics by the assumptions formed on the basis of first-impressions.

Hypoxia inducible factor (HIF)-2α accelerates disease progression in mouse models of leukemia and lymphoma but is not a poor prognosis factor in human AML.

Hypoxia-inducible factor (HIF)-1α accumulation promotes hematopoietic stem cells' quiescence and is necessary to maintain their self-renewal. However, the role of HIF-2α in hematopoietic cells is less clear. We investigated the role of HIF-2α in leukemia and lymphoma cells. HIF-2α expression was high in subsets of human and mouse leukemia and lymphoma cells, whereas it was low in normal bone marrow leukocytes. To investigate the role of HIF-2α, we transduced human HIF-2α cDNA in mouse syngeneic models of myeloid preleukemia and a transgenic model of B lymphoma. Ectopic expression of HIF-2α accelerated leukemia cell proliferation in vitro. Mice transplanted with cells transduced with HIF-2α died significantly faster of leukemia or B lymphoma than control mice transplanted with empty vector-transduced cells. Conversely, HIF-2α knockdown in human myeloid leukemia HL60 cells decreased proliferation in vitro and significantly prolonged animal survival following transplantation. In human acute myeloid leukemia (AML), HIF-2α mRNA was significantly elevated in several subsets such as the t(15;17), inv(16), complex karyotype and favorable cytogenetic groups. However, patients with high HIF-2α expression had a trend to higher disease-free survival in univariate analysis. The different effects of HIF-2α overexpression in mouse models of leukemia and human AML illustrates the complexity of this mutliclonal disease.

Efficacy and safety of non-hormonal remedies for vaginal dryness: open, prospective, randomized trial.

OBJECTIVES: To prove non-inferiority of the first non-hormonal vaginal cream in Germany, Vagisan(®) Moisturising Cream (CREAM), compared to a non-hormonal vaginal gel (GEL) for vulvovaginal atrophy (VVA) symptom relief. METHOD: This was a 12-week multicenter, open-label, prospective, randomized, two-period, cross-over phase-III trial. The primary endpoint was the cumulative VVA subjective symptom score of the respective treatment period. Secondary endpoints were assessment of single VVA subjective and objective symptoms, VVA objective symptom score, vaginal pH, safety parameters, overall assessment of efficacy, tolerability and evaluation of product properties. In total, 117 women were randomly allocated to either one of the two treatments, each administered for 4 weeks; 92 women were included in the per-protocol analysis (primary analysis). The main outcome measure was cumulative VVA subjective symptom score. RESULTS: Regarding VVA symptom relief, results confirmed non-inferiority of CREAM compared to GEL and even indicated superiority of CREAM. Frequency and intensity of subjective symptoms and objective findings were clearly reduced, with CREAM showing better results compared to GEL. Mean VVA objective symptom score significantly decreased; improvement was significantly greater with CREAM. Vaginal pH decreased only following CREAM treatment. Tolerability was superior for CREAM: burning and itching, mostly rated as mild, occurred markedly less often with CREAM than with GEL. Overall satisfaction with treatment efficacy, tolerability and most product properties were rated significantly superior for CREAM. CONCLUSIONS: Subjective and objective VVA symptoms were reliably and safely reduced by both non-hormonal topical products. However, efficacy and tolerability of CREAM were shown to be superior to GEL.

HIF-1α is required for hematopoietic stem cell mobilization and 4-prolyl hydroxylase inhibitors enhance mobilization by stabilizing HIF-1α.

Many patients with hematological neoplasms fail to mobilize sufficient numbers of hematopoietic stem cells (HSCs) in response to granulocyte colony-stimulating factor (G-CSF) precluding subsequent autologous HSC transplantation. Plerixafor, a specific antagonist of the chemokine receptor CXCR4, can rescue some but not all patients who failed to mobilize with G-CSF alone. These refractory poor mobilizers cannot currently benefit from autologous transplantation. To discover alternative targetable pathways to enhance HSC mobilization, we studied the role of hypoxia-inducible factor-1α (HIF-1α) and the effect of HIF-1α pharmacological stabilization on HSC mobilization in mice. We demonstrate in mice with HSC-specific conditional deletion of the Hif1a gene that the oxygen-labile transcription factor HIF-1α is essential for HSC mobilization in response to G-CSF and Plerixafor. Conversely, pharmacological stabilization of HIF-1α with the 4-prolyl hydroxylase inhibitor FG-4497 synergizes with G-CSF and Plerixafor increasing mobilization of reconstituting HSCs 20-fold compared with G-CSF plus Plerixafor, currently the most potent mobilizing combination used in the clinic.

Event-related potential correlates of sound organization: early sensory and late cognitive effects.

We tested whether incoming sounds are processed differently depending on how the preceding sound sequence has been interpreted by the brain. Sequences of a regularly repeating three-tone pattern, the perceived organization of which spontaneously switched back and forth between two alternative interpretations, were delivered to listeners. Occasionally, a regular tone was exchanged for a slightly or moderately lower one (deviants). The electroencephalogram (EEG) was recorded while listeners continuously marked their perception of the sound sequence. We found that for both the regular and the deviant tones, the early exogenous P1 and N1 amplitudes varied together with the perceived sound organization. Percept-dependent effects on the late endogenous N2 and P3a amplitudes were only found for deviant tones. These results suggest that the perceived sound organization affects sound processing both by modulating what information is extracted from incoming sounds as well as by influencing how deviant sound events are evaluated for further processing.

Detecting violations of temporal regularities in waking and sleeping two-month-old infants.

Correctly processing rapid sequences of sounds is essential for developmental milestones, such as language acquisition. We investigated the sensitivity of two-month-old infants to violations of a temporal regularity, by recording event-related brain potentials (ERPs) in an auditory oddball paradigm from 36 waking and 40 sleeping infants. Standard tones were presented at a regular 300 ms inter-stimulus interval (ISI). One deviant, otherwise identical to the standard, was preceded by a 100 ms ISI. Two other deviants, presented with the standard ISI, differed from the standard in their spectral makeup. We found significant differences between ERP responses elicited by the standard and each of the deviant sounds. The results suggest that the ability to extract both temporal and spectral regularities from a sound sequence is already functional within the first few months of life. The scalp distribution of all three deviant-stimulus responses was influenced by the infants' state of alertness.

Hematopoietic stem cell mobilizing agents G-CSF, cyclophosphamide or AMD3100 have distinct mechanisms of action on bone marrow HSC niches and bone formation.

The CXCR4 antagonist AMD3100 is progressively replacing cyclophosphamide (CYP) as adjuvant to granulocyte colony-stimulating factor (G-CSF) to mobilize hematopoietic stem cells (HSC) for autologous transplants in patients who failed prior mobilization with G-CSF alone. It has recently emerged that G-CSF mediates HSC mobilization and inhibits bone formation via specific bone marrow (BM) macrophages. We compared the effect of these three mobilizing agents on BM macrophages, bone formation, osteoblasts, HSC niches and HSC reconstitution potential. Both G-CSF and CYP suppressed niche-supportive macrophages and osteoblasts, and inhibited expression of endosteal cytokines resulting in major impairment of HSC reconstitution potential remaining in the mobilized BM. In sharp contrast, although AMD3100 was effective at mobilizing HSC, it did not suppress osteoblasts, endosteal cytokine expression or reconstitution potential of HSC remaining in the mobilized BM. In conclusion, although G-CSF, CYP and AMD3100 efficiently mobilize HSC into the blood, their effects on HSC niches and bone formation are distinct with both G-CSF and CYP targeting HSC niche function and bone formation, whereas AMD3100 directly targets HSC without altering niche function or bone formation.

The endosteal 'osteoblastic' niche and its role in hematopoietic stem cell homing and mobilization.

The concept of hematopoietic stem cell (HSC) niche was formulated in 1978, but HSC niches remained unidentified for the following two decades largely owing to technical limitations. Sophisticated live microscopy techniques and genetic manipulations have identified the endosteal region of the bone marrow (BM) as a preferential site of residence for the most potent HSC - able to reconstitute in serial transplants - with osteoblasts and their progenitors as critical cellular elements of these endosteal niches. This article reviews the path to the discovery of these endosteal niches (often called 'osteoblastic' niches) for HSC, what cell types contribute to these niches with their known physical and biochemical features. In the past decade, a first wave of research uncovered many mechanisms responsible for HSC homing to, and mobilization from, the whole BM tissue. However, the recent discovery of endosteal HSC niches has initiated a second wave of research focusing on the mechanisms by which most primitive HSC lodge into and migrate out of their endosteal niches. The second part of this article reviews the current knowledge of the mechanisms of HSC lodgment into, retention in and mobilization from osteoblastic niches.

Cancer of the accessory breast--a case report.

Breast neoplasm may develop in ectopically located glandular tissue. This paper presents an interesting and rare case of a 50-year-old female who despite regular mammography screening examination developed an invasive accessory breast cancer. Clinical examination revealed a 2 cm - tumour localized 4 cm below the left inframammary fold. The lesion was immobile, the skin and the atrophic nipple were retracted, the tumour infiltrated the thoracic wall. Oligobiopsy and additional examinations showed an invasive stage IIIB ductal breast cancer (Bloom II, G-2). The receptor status was: ER(+), PGR(+), HER2(-). The increased level of cancer antigen 15.3 was found. The patient was submitted to pre-operative chemotherapy. She also underwent surgery and subsequently post-operative chemotherapy and radiotherapy. On the basis of the presented case, it could be concluded that the accessory mammary glands are out of the image of screening breast examinations. Accessory breast cancer is usually diagnosed by clinical examination and ultrasonography. Preventive resection of accessory breast in women at high risk of developing breast cancer can be considered as the treatment of choice in most patients.

Intravaginally applied metronidazole is as effective as orally applied in the treatment of bacterial vaginosis, but exhibits significantly less side effects.

OBJECTIVE: Metronidazole is the drug of choice for the treatment of bacterial vaginosis (BV). However, so far the oral administration has not been clinically compared to the intravaginal application regarding efficacy, side effects and patient satisfaction in a scientific sound fashion. STUDY DESIGN: Therefore, this randomized, double-blind, placebo-controlled clinical trial was designed to demonstrate non-inferiority of short-term intravaginal (i.vag.) application of metronidazole (2x 1000 mg pessaries 24h apart) vs. a single oral dose (p.o.) of metronidazole (1 x 2000 mg tablets) in 263 patients with BV (double-dummy design). The follow-up period was 12 weeks. In addition, the number and the type of adverse events induced by the two regimens were compared, assuming better tolerability of the intravaginal application. RESULTS: Following the diagnosis of BV a total of 129 women (mean age 36.2 years) was orally treated with a single dose of 2g metronidazole whereas a total of 134 patients (mean age 35.5 years) was treated intravaginally with 1g metronidazole each day on two consecutive days and included in the per-protocol analysis. Non-inferiority of i.vag. application compared to p.o. administration was statistically significant regarding efficacy: Following intravaginal application the cure rate, assessed on day 8 after starting of the treatment, was 92.5% as compared to 89.9% after oral administration. Nausea was the most common adverse event reported in 10.2% i.vag. vs. 30.4% p.o. of all cases (p<0.001), abdominal pain in 16.8% i.vag. vs. 31.9% p.o. (p<0.01), a "metallic taste" in 8.8% i.vag. vs. 17.9% p.o. (p<0.05). Women treated i.vag. were highly satisfied with the treatment and more content as compared to the women treated p.o. with metronidazole (p<0.05, intent-to-treat analysis). CONCLUSION: In this clinical trial the intravaginal application was as effective as the oral administration of metronidazole in treating BV. However, significantly less adverse events were reported after short-term intravaginal as compared to oral application (p=0.023) and probably led to a better patient compliance.

Mobilization of bone marrow-derived progenitors.

Bone marrow (BM) is a source of various stem and progenitor cells in the adult, and it is able to regenerate a variety of tissues following transplantation. In the 1970s the first BM stem cells identified were hematopoietic stem cells (HSCs). HSCs have the potential to differentiate into all myeloid (including erythroid) and lymphoid cell lineages in vitro and reconstitute the entire hematopoietic and immune systems following transplantation in vivo. More recently, nonhematopoietic stem and progenitor cells have been identified that can differentiate into other cell types such as endothelial progenitor cells (EPCs), contributing to the neovascularization of tumors as well as ischemic tissues, and mesenchymal stem cells (MSCs), which are able to differentiate into many cells of ectodermal, endodermal, and mesodermal origins in vitro as well as in vivo. Following adequate stimulation, stem and progenitor cells can be forced out of the BM to circulate into the peripheral blood, a phenomenon called "mobilization." This chapter reviews the molecular mechanisms behind mobilization and how these have led to the various strategies employed to mobilize BM-derived stem and progenitor cells in experimental and clinical settings. Mobilization of HSCs will be reviewed first, as it has been best-explored--being used extensively in clinics to transplant large numbers of HSCs to rescue cancer patients requiring hematopoietic reconstitution--and provides a paradigm that can be generalized to the mobilization of other types of BM-derived stem and progenitor cells in order to repair other tissues.

The development of the perceptual organization of sound by frequency separation in 5-11-year-old children.

The analysis of the auditory scene begins from the moment we hear sounds, making it possible for the infant to distinguish the mother's voice from other sounds in the environment. The purpose of the study was to determine, in two experiments, whether the frequency separation threshold, at which the perception of a mixture of sounds turns from being perceived as one stream to two streams, differs between two groups of school-aged children (ages 5-8 and 9-11 years) and adults. The results show a developmental course for the perception of auditory streams that is not simply dependent upon frequency discrimination. This suggests that maturation of the stream segregation process follows a longer developmental course than maturation of simple feature discrimination. The data indicate that the ability to hear distinct sound streams in the environment takes time to develop and becomes sharpened with experience and maturity.

The role of predictive models in the formation of auditory streams.

Sounds provide us with useful information about our environment which complements that provided by other senses, but also poses specific processing problems. How does the auditory system distentangle sounds from different sound sources? And what is it that allows intermittent sound events from the same source to be associated with each other? Here we review findings from a wide range of studies using the auditory streaming paradigm in order to formulate a unified account of the processes underlying auditory perceptual organization. We present new computational modelling results which replicate responses in primary auditory cortex [Fishman, Y.I., Arezzo, J.C., Steinschneider, M., 2004. Auditory stream segregation in monkey auditory cortex: effects of frequency separation, presentation rate, and tone duration. J. Acoust. Soc. Am. 116, 1656-1670; Fishman, Y. I., Reser, D. H., Arezzo, J.C., Steinschneider, M., 2001. Neural correlates of auditory stream segregation in primary auditory cortex of the awake monkey. Hear. Res. 151, 167-187] to tone sequences. We also present the results of a perceptual experiment which confirm the bi-stable nature of auditory streaming, and the proposal that the gradual build-up of streaming may be an artefact of averaging across many subjects [Pressnitzer, D., Hupé, J. M., 2006. Temporal dynamics of auditory and visual bi-stability reveal common principles of perceptual organization. Curr. Biol. 16(13), 1351-1357.]. Finally we argue that in order to account for all of the experimental findings, computational models of auditory stream segregation require four basic processing elements; segregation, predictive modelling, competition and adaptation, and that it is the formation of effective predictive models which allows the system to keep track of different sound sources in a complex auditory environment.

[Strategies against the stigmatisation of mentally ill subjects and their practical realisation in the example of Irrsinnig Menschlich e. V]. / Strategien gegen die Stigmatisierung psychisch kranker Menschen und ihre praktische Umsetzung am Beispiel des Irrsinnig Menschlich e. V.

In our society people with mental illness are still stigmatised and exposed to various forms of discrimination. Individual and structural discrimination and discrimination due to self-stigmatisation can be distinguished. The association "Irrsinnig Menschlich" ("Madly human") in Leipzig will serve as a model to present approaches to reduce these different kinds of discrimination of mentally ill people. The school project "Crazy? So what!" and the film festival "Ausnahmezustand" ("state of emergency"), carried out all over Germany in 2006, will be described in more detail. The first evaluation of both projects showed a reduction of stigmatisation to be possible. Students participating in the project tended to decrease their social distance to the mentally ill. These developments were not present with the control groups. Although the majority of the audience at the film festival either knew somebody who is mentally ill or were themselves suffering from a mental illness, the results showed that watching these documentaries can result in a reduction of social distance towards mentally ill people. Only long-term efforts can make anti-stigma campaigns successful and effective. Irrsinnig Menschlich has established the framework for this.

Top-down control over involuntary attention switching in the auditory modality.

We tested the effects of predictability on involuntary attention switching to task-irrelevant sound changes (distraction). Behavioral and neurophysiological evidence are provided, showing that the predictability of task-irrelevant sound changes eliminates effects of distraction even though the automatic auditory change detection system remains responsive. Two indices of distraction, slower task performance and cortical brain responses associated with attention switching, were seen only in the unpredictable condition, in which the irrelevant acoustic changes were unexpected. Attention was not involuntarily drawn away from the primary task when the subjects had foreknowledge of when the irrelevant changes would occur. These results demonstrate attentional control over orienting to sound changes and suggest that involuntary attention switching occurs mainly when an irrelevant stimulus change is unexpected. The present data allowed observation of the temporal dynamics of attention switching in the human brain.

Event-related potential correlates of sound duration: similar pattern from birth to adulthood.

The effects of sound duration on event-related potentials (ERP) were studied in newborns and adults. Increasing tone duration from 200 to 300 ms led to the enhancement of the N2 peak amplitude, whereas two peaks became distinguishable in the N2 response elicited by 400 ms long tones. The sound-duration related ERP changes most likely reflect contribution from the sustained potential, although the observed results can also be explained by assuming the elicitation of a sound-duration sensitive frontocentrally negative ERP component (duration-sensitive N2; DN2). The pattern of duration-related changes observed in newborn infants was very similar to that in adults, regardless of the structural differences between adult and infant ERPs. The results suggest that sound duration is processed already at birth in a similar way as in adulthood.