Divergent Age-Dependent Conformational Rearrangement within Aß Amyloid Deposits in APP23, APPPS1, and AppNL-F Mice.

Amyloid plaques composed of fibrils of misfolded Aß peptides are pathological hallmarks of Alzheimer's disease (AD). Aß fibrils are polymorphic in their tertiary and quaternary molecular structures. This structural polymorphism may carry different pathologic potencies and can putatively contribute to clinical phenotypes of AD. Therefore, mapping of structural polymorphism of Aß fibrils and structural evolution over time is valuable to understanding disease mechanisms. Here, we investigated how Aß fibril structures in situ differ in Aß plaque of different mouse models expressing familial mutations in the AßPP gene. We imaged frozen brains with a combination of conformation-sensitive luminescent conjugated oligothiophene (LCO) ligands and Aß-specific antibodies. LCO fluorescence mapping revealed that mouse models APP23, APPPS1, and AppNL-F have different fibril structures within Aß-amyloid plaques depending on the AßPP-processing genotype. Co-staining with Aß-specific antibodies showed that individual plaques from APP23 mice expressing AßPP Swedish mutation have two distinct fibril polymorph regions of core and corona. The plaque core is predominantly composed of compact Aß40 fibrils, and the corona region is dominated by diffusely packed Aß40 fibrils. Conversely, the AßPP knock-in mouse AppNL-F, expressing the AßPP Iberian mutation along with Swedish mutation has tiny, cored plaques consisting mainly of compact Aß42 fibrils, vastly different from APP23 even at elevated age up to 21 months. Age-dependent polymorph rearrangement of plaque cores observed for APP23 and APPPS1 mice >12 months, appears strongly promoted by Aß40 and was hence minuscule in AppNL-F. These structural studies of amyloid plaques in situ can map disease-relevant fibril polymorph distributions to guide the design of diagnostic and therapeutic molecules.

Framework and baseline examination of the German National Cohort (NAKO).

The German National Cohort (NAKO) is a multidisciplinary, population-based prospective cohort study that aims to investigate the causes of widespread diseases, identify risk factors and improve early detection and prevention of disease. Specifically, NAKO is designed to identify novel and better characterize established risk and protection factors for the development of cardiovascular diseases, cancer, diabetes, neurodegenerative and psychiatric diseases, musculoskeletal diseases, respiratory and infectious diseases in a random sample of the general population. Between 2014 and 2019, a total of 205,415 men and women aged 19-74 years were recruited and examined in 18 study centres in Germany. The baseline assessment included a face-to-face interview, self-administered questionnaires and a wide range of biomedical examinations. Biomaterials were collected from all participants including serum, EDTA plasma, buffy coats, RNA and erythrocytes, urine, saliva, nasal swabs and stool. In 56,971 participants, an intensified examination programme was implemented. Whole-body 3T magnetic resonance imaging was performed in 30,861 participants on dedicated scanners. NAKO collects follow-up information on incident diseases through a combination of active follow-up using self-report via written questionnaires at 2-3 year intervals and passive follow-up via record linkages. All study participants are invited for re-examinations at the study centres in 4-5 year intervals. Thereby, longitudinal information on changes in risk factor profiles and in vascular, cardiac, metabolic, neurocognitive, pulmonary and sensory function is collected. NAKO is a major resource for population-based epidemiology to identify new and tailored strategies for early detection, prediction, prevention and treatment of major diseases for the next 30 years.

How experience with tone in the native language affects the L2 acquisition of pitch accents.

This paper tested the ability of Mandarin learners of German, whose native language has lexical tone, to imitate pitch accent contrasts in German, an intonation language. In intonation languages, pitch accents do not convey lexical information; also, pitch accents are sparser than lexical tones as they only associate with prominent words in the utterance. We compared two kinds of German pitch-accent contrasts: (1) a "non-merger" contrast, which Mandarin listeners perceive as different and (2) a "merger" contrast, which sounds more similar to Mandarin listeners. Speakers of a tone language are generally very sensitive to pitch. Hypothesis 1 (H1) therefore stated that Mandarin learners produce the two kinds of contrasts similarly to native German speakers. However, the documented sensitivity to tonal contrasts, at the expense of processing phrase-level intonational contrasts, may generally hinder target-like production of intonational pitch accents in the L2 (Hypothesis 2, H2). Finally, cross-linguistic influence (CLI) predicts a difference in the realization of these two contrasts as well as improvement with higher proficiency (Hypothesis 3, H3). We used a delayed imitation paradigm, which is well-suited for assessing L2-phonetics and -phonology because it does not necessitate access to intonational meaning. We investigated the imitation of three kinds of accents, which were associated with the sentence-final noun in short wh-questions (e.g., Wer malt denn Mandalas, lit: "Who draws PRT mandalas?" "Who likes drawing mandalas?"). In Experiment 1, 28 native speakers of Mandarin participated (14 low- and 14 high-proficient). The learners' productions of the two kinds of contrasts were analyzed using General Additive Mixed Models to evaluate differences in pitch accent contrasts over time, in comparison to the productions of native German participants from an earlier study in our lab. Results showed a more pronounced realization of the non-merger contrast compared to German natives and a less distinct realization of the merger contrast, with beneficial effects of proficiency, lending support to H3. Experiment 2 tested low-proficient Italian learners of German (whose L1 is an intonation language) to contextualize the Mandarin data and further investigate CLI. Italian learners realized the non-merger contrast more target-like than Mandarin learners, lending additional support to CLI (H3).

In vivo targeting and multimodal imaging of cerebral amyloid-ß aggregates using hybrid GdF3 nanoparticles.

Aim: To propose a new multimodal imaging agent targeting amyloid-ß (Aß) plaques in Alzheimer's disease. Materials & methods: A new generation of hybrid contrast agents, based on gadolinium fluoride nanoparticles grafted with a pentameric luminescent-conjugated polythiophene, was designed, extensively characterized and evaluated in animal models of Alzheimer's disease through MRI, two-photon microscopy and synchrotron x-ray phase-contrast imaging. Results & conclusion: Two different grafting densities of luminescent-conjugated polythiophene were achieved while preserving colloidal stability and fluorescent properties, and without affecting biodistribution. In vivo brain uptake was dependent on the blood-brain barrier status. Nevertheless, multimodal imaging showed successful Aß targeting in both transgenic mice and Aß fibril-injected rats.

The design and study of a new contrast agent targeting amyloid-ß (Aß) plaques in Alzheimer's disease (AD) is proposed. Aß plaques are the earliest pathological sign of AD, silently appearing in the brain decades before the symptoms of the disease are manifested. While current detection of Aß plaques is based on nuclear medicine (a technique using a radioactive agent), a different kind of contrast agent is here evaluated in animal models of AD. The contrast agent consists of a nanoparticle made of gadolinium and fluorine ions (core), and decorated with a molecule previously shown to bind to Aß plaques (grafting). The core is detectable with MRI and x-ray imaging, while the grafting molecule is detectable with fluorescence imaging, thus allowing different imaging methods to be combined to study the pathology. In this work, the structure, stability and properties of the contrast agent have been verified in vitro (in tubes and on brain sections). Then the ability of the contrast agent to bind to Aß plaques and provide a detectable signal in MRI, x-ray or fluorescence imaging has been demonstrated in vivo (in rodent models of AD). This interdisciplinary research establishes the proof of concept that this new class of versatile agent contrast can be used to target pathological processes in the brain.

Are there sustained psychological impacts in women diagnosed with in-situ or early invasive breast cancers?

Purpose: The detection of a ductal carcinoma in-situ (DCIS) or an early invasive breast cancer (EIBC), particularly by population-wide mammography-screening-programs, is controversial as an unknown proportion of these cases may be due to overdiagnosis. We investigated whether women with such potentially overdiagnosed breast cancers suffer from sustained adverse psycho-social consequences. Methods: Standardized questionnaires were mailed to 900 survivors, diagnosed with either DCIS or EIBC, requesting self-reports on quality of life using EORTC Quality of Life Questionnaire C-30. Levels of anxiety and depression were assessed using the HADS questionnaires. Item score values in the study group were compared to reference data obtained from normative studies in the German female reference population. Results: The 577 women who returned completed questionnaires had a mean age of 65.1 years, 387 (67%) had been diagnosed by mammography screening. Median time since diagnosis was 5.9 years. There were no substantial differences between the study sample and the reference population for most of the items. While most score values were even slightly more favorable in the study group, the scores for cognitive function were moderately lower, especially among younger patients. Score values for anxiety were generally higher among younger women (50 to 59 years) from the study group, while depression scores were lower irrespective of age. Conclusions: This study indicates that the diagnosis of DCIS or EIBC, which is predominantly a result of screening, does not seem to induce sustained, adverse psychological impacts in affected women when compared with the respective general female population. Only anxiety levels remained elevated among younger women.

Remote Testing of the Familiar Word Effect With Non-dialectal and Dialectal German-Learning 1-2-Year-Olds.

Variability is pervasive in spoken language, in particular if one is exposed to two varieties of the same language (e.g., the standard variety and a dialect). Unlike in bilingual settings, standard and dialectal forms are often phonologically related, increasing the variability in word forms (e.g., German Fuß "foot" is produced as [fus] in Standard German and as [fs] in the Alemannic dialect). We investigate whether dialectal variability in children's input affects their ability to recognize words in Standard German, testing non-dialectal vs. dialectal children. Non-dialectal children, who typically grow up in urban areas, mostly hear Standard German forms, and hence encounter little segmental variability in their input. Dialectal children in turn, who typically grow up in rural areas, hear both Standard German and dialectal forms, and are hence exposed to a large amount of variability in their input. We employ the familiar word paradigm for German children aged 12-18 months. Since dialectal children from rural areas are hard to recruit for laboratory studies, we programmed an App that allows all parents to test their children at home. Looking times to familiar vs. non-familiar words were analyzed using a semi-automatic procedure based on neural networks. Our results replicate the familiarity preference for non-dialectal German 12-18-month-old children (longer looking times to familiar words than vs. non-familiar words). Non-dialectal children in the same age range, on the other hand, showed a novelty preference. One explanation for the novelty preference in dialectal children may be more mature linguistic processing, caused by more variability of word forms in the input. This linguistic maturation hypothesis is addressed in Experiment 2, in which we tested older children (18-24-month-olds). These children, who are not exposed to dialectal forms, also showed a novelty preference. Taken together, our findings show that both dialectal and non-dialectal German children recognized the familiar Standard German word forms, but their looking pattern differed as a function of the variability in the input. Frequent exposure to both dialectal and Standard German word forms may hence have affected the nature of (prelexical and/or) lexical representations, leading to more mature processing capacities.

Aren't Prosody and Syntax Marking Bias in Questions?

As first observed by Ladd in 1981, English polar questions with high negation (e.g., Aren't they adding a menu item?) can be used both to check the speaker's belief that the proposition p is true (e.g., p = they are adding a menu item) and to check the addressee's belief that p is not true (¬p). We hypothesized that this ambiguity can be disambiguated prosodically. We further hypothesized that the prosodic disambiguation is absent in German, because the checked proposition can be marked morpho-syntactically, with questions with high negation checking p and low negation questions (e.g., Are they not adding a menu item?) checking ¬p.A production study tested these hypotheses with 24 speakers of Western Canadian English and German each (764 and 767 total utterances, respectively). The results showed that, when the speaker originally believed p and the addressee implied ¬p, English speakers preferred questions with high negation over low negation questions, confirming Ladd's observation, and used intonation to mark whose proposition they were checking, as hypothesized. By contrast, German speakers marked this distinction morpho-syntactically, realizing mostly questions with high negation to check their own proposition and low negation questions to check the addressee's proposition. Their prosody, in turn, was largely determined by the morpho-syntactic question form. The study further manipulated the speaker's certainty of the checked proposition, but, in contrast to studies on Romance languages, found that certainty itself was not marked.

The Mode of Detection Is Not Associated with Quality of Life in Women with Breast Cancer.

INTRODUCTION: Apart from saving lives, mammography screening programs (MSP) are expected to reduce negative side effects of treatment by detecting cancer earlier, when it is more responsive to less aggressive treatment. This study compared quality of life (QoL) among women with breast cancers that were detected either by screening mammography, as interval cancers, or clinically among women not participating in the MSP. METHODS: Retrospective study of first-ever invasive breast cancers detected among MSP-eligible women aged 50-69 years between 2006 and 2012 in Münster, Germany. EORTC QLQ-C30 and -BR23 questionnaires were mailed to 1,399 cases still alive in 2015 (response rate 64.1%). RESULTS: Women's responses were obtained on average 6.1 years after diagnosis. Mean crude and age-adjusted scores for overall QoL, breast and body image (BBI), and five functional scales (FS) were comparable between groups of detection mode. Clearly lower adjusted means for most scores were observed in women with interval cancers, if time since diagnosis was less than 5 years. Cases younger than 60 years showed lower values for some FS, particularly among interval and screen-detected cases. DISCUSSION/CONCLUSION: In summary, cases with breast cancer showed health-related score values that were similar to the general population of the same age. There was also no indication that mode of detection markedly influenced these scores. However, after adjusting for tumor stage and other influential factors, screening participants appeared more susceptible to score declines after a diagnosis of cancer than non-participants.

Prominent microglial inclusions in transgenic mouse models of α-synucleinopathy that are distinct from neuronal lesions.

Alpha-synucleinopathies are a group of progressive neurodegenerative disorders, characterized by intracellular deposits of aggregated α-synuclein (αS). The clinical heterogeneity of these diseases is thought to be attributed to conformers (or strains) of αS but the contribution of inclusions in various cell types is unclear. The aim of the present work was to study αS conformers among different transgenic (TG) mouse models of α-synucleinopathies. To this end, four different TG mouse models were studied (Prnp-h[A53T]αS; Thy1-h[A53T]αS; Thy1-h[A30P]αS; Thy1-mαS) that overexpress human or murine αS and differed in their age-of-symptom onset and subsequent disease progression. Postmortem analysis of end-stage brains revealed robust neuronal αS pathology as evidenced by accumulation of αS serine 129 (p-αS) phosphorylation in the brainstem of all four TG mouse lines. Overall appearance of the pathology was similar and only modest differences were observed among additionally affected brain regions. To study αS conformers in these mice, we used pentameric formyl thiophene acetic acid (pFTAA), a fluorescent dye with amyloid conformation-dependent spectral properties. Unexpectedly, besides the neuronal αS pathology, we also found abundant pFTAA-positive inclusions in microglia of all four TG mouse lines. These microglial inclusions were also positive for Thioflavin S and showed immunoreactivity with antibodies recognizing the N-terminus of αS, but were largely p-αS-negative. In all four lines, spectral pFTAA analysis revealed conformational differences between microglia and neuronal inclusions but not among the different mouse models. Concomitant with neuronal lesions, microglial inclusions were already present at presymptomatic stages and could also be induced by seeded αS aggregation. Although nature and significance of microglial inclusions for human α-synucleinopathies remain to be clarified, the previously overlooked abundance of microglial inclusions in TG mouse models of α-synucleinopathy bears importance for mechanistic and preclinical-translational studies.

[Assessment of self-reported cardiovascular and metabolic diseases in the German National Cohort (GNC, NAKO Gesundheitsstudie): methods and initial results]. / Erfassung selbst berichteter kardiovaskulärer und metabolischer Erkrankungen in der NAKO Gesundheitsstudie: Methoden und erste Ergebnisse.

BACKGROUND: Data on self-reported cardiovascular and metabolic diseases are available for the first 100,000 participants of the population-based German National Cohort (GNC, NAKO Gesundheitsstudie). OBJECTIVES: To describe assessment methods and the frequency of self-reported cardiovascular and metabolic diseases in the German National Cohort. MATERIALS AND METHODS: Using a computer-based, standardized personal interview, 101,806 participants (20-75 years, 46% men) from 18 nationwide study centres were asked to use a predefined list to report medical conditions ever diagnosed by a physician, including cardiovascular or metabolic diseases. For the latter, we calculated sex-stratified relative frequencies and compared these with reference data. RESULTS: With regard to cardiovascular diseases, 3.5% of men and 0.8% of women reported to have ever been diagnosed with a myocardial infarction, 4.8% and 1.5% with angina pectoris, 3.5% and 2.5% with heart failure, 10.1% and 10.4% with cardiac arrhythmia, 2.7% and 1.8% with claudicatio intermittens, and 34.6% and 27.0% with arterial hypertension. The frequencies of self-reported diagnosed metabolic diseases were 8.1% and 5.8% for diabetes mellitus, 28.6% and 24.5% for hyperlipidaemia, 7.9% and 2.4% for gout, and 10.1% and 34.3% for thyroid diseases. Observed disease frequencies were lower than reference data for Germany. CONCLUSIONS: In the German National Cohort, self-reported cardiovascular and metabolic diseases diagnosed by a physician are assessed from all participants, therefore representing a data source for future cardio-metabolic research in this cohort.

Prenuclear L∗+H Activates Alternatives for the Accented Word.

Previous processing studies have shown that constituents that are prosodically marked as focus lead to an activation of alternatives. We investigate the processing of constituents that are prosodically marked as contrastive topics. In German, contrastive topics are prosodically realized by prenuclear L∗+H accents. Our study tests (a) whether prenuclear accents (as opposed to nuclear accents) are able to activate contrastive alternatives, (b) whether they do this in the same way as constituents prosodically marked as focus with nuclear accents do, which is important for semantic modeling, and (c) whether the activation of alternatives is caused by pitch accent type (prenuclear L∗+H as contrastive accent vs. prenuclear L+H∗ as non-contrastive accent) or by differences in F0-excursion (related to prominence). We conducted two visual-world eye-tracking studies, in which German listeners heard declarative utterances (e.g., The swimmer wanted to put on flappers) and watched displays that depicted four printed words: one that was a contrastive alternative to the subject noun (e.g., diver), one that was non-contrastively related to it (e.g., sports), the object (e.g., flappers), which had to be clicked, and an unrelated distractor. Experiment 1 presented participants with two naturally produced intonation conditions, a broad focus control condition with a prenuclear L+H∗ accent on the subject and a contrastive topic condition with a prenuclear L∗+H accent. The results showed that participants fixated more on the contrastive alternative when the subject was produced with an L∗+H accent, with the same effect size and timing as reported for focus constituents. Experiment 2 resynthesized the stimuli so that peak height and F0-excursion were the same across intonation conditions. The effect was the same, but the time course was slightly later. Our results suggest that prenuclear L∗+H immediately leads to the activation of alternatives during online processing, and that the F0-excursion of the accent lends little. The results are discussed with regard to the processing of contrastive focus accents and theories of contrastive topic.

Synthesis of a Novel Curcumin Derivative as a Potential Imaging Probe in Alzheimer's Disease Imaging.

BACKGROUND: Curcumin has been of interest in the field of Alzheimer's disease. Early studies on transgenic mice showed promising results in the reduction of amyloid plaques.However, curcumin is very poorly soluble in aqueous solutions and not easily accessible to coupling as it contains only phenolic groups as potential coupling sites. For these reasons only few imaging studies using curcumin bound as an ester were performed and curcumin is mainly used as nutritional supplement. METHODS: In the present study we produced an aminoethyl ether derivative of curcumin using a nucleophilic substitution reaction. This is a small modification and should not impact the properties of curcumin while introducing an easily accessible reactive amino group. This novel compound could be used to couple curcumin to other molecules using the standard methods of peptide synthesis. We studied the aminoethyl-curcumin compound and a tripeptide carrying this aminoethyl-curcumin and the fluorescent dye fluorescein (FITC-curcumin) in vitro on cell culture using confocal laser scanning microscopy and flow cytometry. Then these two substances were tested ex vivo on brain sections prepared from transgenic mice depicting Alzheimer-like ß-amyloid plaques. RESULTS: In the in vitro CLSM microscopy and flow cytometry experiments we found dot-like unspecific uptake and only slight cytotoxicity correlating with this uptake. As these measurements were optimized for the use of fluorescein as dye we found that the curcumin at 488nm fluorescence excitation was not strong enough to use it as a fluorescence marker in these applications. In the ex vivo sections CLSM experiments both the aminoethyl-curcumin and the FITC-curcumin peptide bound specifically to ß- amyloid plaques. CONCLUSION: In conclusion we successfully produced a novel curcumin derivative which could easily be coupled to other imaging or therapeutic molecules as a sensor for amyloid plaques.

Early Aß reduction prevents progression of cerebral amyloid angiopathy.

OBJECTIVE: Clinical trials targeting ß-amyloid peptides (Aß) for Alzheimer disease (AD) failed for arguable reasons that include selecting the wrong stages of AD pathophysiology or Aß being the wrong target. Targeting Aß to prevent cerebral amyloid angiopathy (CAA) has not been rigorously followed, although the causal role of Aß for CAA and related hemorrhages is undisputed. CAA occurs with normal aging and to various degrees in AD, where its impact and treatment is confounded by the presence of parenchymal Aß deposition. METHODS: APPDutch mice develop CAA in the absence of parenchymal amyloid, mimicking hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D). Mice were treated with a ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor. We used 3-dimensional ultramicroscopy and immunoassays for visualizing CAA and assessing Aß in cerebrospinal fluid (CSF) and brain. RESULTS: CAA onset in mice was at 22 to 24 months, first in frontal leptomeningeal and superficial cortical vessels followed by vessels penetrating the cortical layers. CSF Aß increased with aging followed by a decrease of both Aß40 and Aß42 upon CAA onset, supporting the idea that combined reduction of CSF Aß40 and Aß42 is a specific biomarker for vascular amyloid. BACE1 inhibitor treatment starting at CAA onset and continuing for 4 months revealed a 90% Aß reduction in CSF and largely prevented CAA progression and associated pathologies. INTERPRETATION: This is the first study showing that Aß reduction at early disease time points largely prevents CAA in the absence of parenchymal amyloid. Our observation provides a preclinical basis for Aß-reducing treatments in patients at risk of CAA and in presymptomatic HCHWA-D. ANN NEUROL 2019;86:561-571.

Phenolic Bis-styrylbenzo[ c]-1,2,5-thiadiazoles as Probes for Fluorescence Microscopy Mapping of Aß Plaque Heterogeneity.

A fluorescent bis-styryl-benzothiadiazole (BTD) with carboxylic acid functional groups (X-34/Congo red analogue) showed lower binding affinity toward Aß1-42 and Aß1-40 fibrils than its neutral analogue. Hence, variable patterns of neutral OH-substituted bis-styryl-BTDs were generated. All bis-styryl-BTDs showed higher binding affinity to Aß1-42 fibrils than to Aß1-40 fibrils. The para-OH on the phenyl rings was beneficial for binding affinity while a meta-OH decreased the affinity. Differential staining of transgenic mouse Aß amyloid plaque cores compared to peripheral coronas using neutral compared to anionic bis-styryl ligands indicate differential recognition of amyloid polymorphs. Hyperspectral imaging of transgenic mouse Aß plaque stained with uncharged para-hydroxyl substituted bis-styryl-BTD implicated differences in binding site polarity of polymorphic amyloid plaque. Most properties of the corresponding bis-styryl-BTD were retained with a rigid alkyne linker rendering a probe insensitive to cis-trans isomerization. These new BTD-based ligands are promising probes for spectral imaging of different Aß fibril polymorphs.

Herpes zoster incidence in Germany - an indirect validation study for self-reported disease data from pretest studies of the population-based German National Cohort.

BACKGROUND: Until now, herpes zoster (HZ)-related disease burden in Germany has been estimated based on health insurance data and clinical findings. However, the validity of self-reported HZ is unclear. This study investigated the validity of self-reported herpes zoster (HZ) and its complication postherpetic neuralgia (PHN) using data from the pretest studies of the German National Cohort (GNC) in comparison with estimates based on health insurance data. METHODS: Data of 4751 participants aged between 20 and 69 years from two pretest studies of the GNC carried out in 2011 and 2012 were used. Based on self-reports of physician-diagnosed HZ and PHN, age- and sex-specific HZ incidence rates and PHN proportions were estimated. For comparison, estimates based on statutory health insurance data from the German population were considered. RESULTS: Eleven percent (95%-CI, 10.4 to 12.3, n = 539) of the participants reported at least one HZ episode in their lifetime. Our estimated age-specific HZ incidence rates were lower than previous estimates based on statutory health insurance data. The PHN proportion in participants older than 50 years was 5.9% (1.9 to 13.9%), which was in line with estimates based on health insurance data. CONCLUSION: As age- and sex-specific patterns were comparable with that in health insurance data, self-reported diagnosis of HZ seems to be a valid instrument for overall disease trends. Possible reasons for observed differences in incidence rates are recall bias in self-reported data or overestimation in health insurance data.

When (not) to Look for Contrastive Alternatives: The Role of Pitch Accent Type and Additive Particles.

This study investigates how pitch accent type and additive particles affect the activation of contrastive alternatives. In Experiment 1, German listeners heard declarative utterances (e.g., The swimmer wanted to put on flippers) and saw four printed words displayed on screen: one that was a contrastive alternative to the subject noun (e.g., diver), one that was non-contrastively related (e.g., pool), the object (e.g., flippers), and an unrelated distractor. Experiment 1 manipulated pitch accent type, comparing a broad focus control condition to two narrow focus conditions: with a contrastive or non-contrastive accent on the subject noun (nuclear L+H* vs. H+L*, respectively, followed by deaccentuation). In Experiment 2, the utterances in the narrow focus conditions were preceded by the unstressed additive particle auch ("also"), which may trigger alternatives itself. It associated with the accented subject. Results showed that, compared to the control condition, participants directed more fixations to the contrastive alternative when the subject was realized with a contrastive accent (nuclear L+H*) than when it was realized with non-contrastive H+L*, while additive particles had no effect. Hence, accent type is the primary trigger for signaling the presence of alternatives (i.e., contrast). Implications for theories of information structure and the processing of additive particles are discussed.

The Prosody of Rhetorical and Information-Seeking Questions in German.

This paper reports on the prosody of rhetorical questions (RQs) and information-seeking questions (ISQs) in German for two question types-polar questions and constituent questions (henceforth "wh-questions"). The results are as follows: Phonologically, polar RQs were mainly realized with H-% (high plateau), while polar ISQs mostly ended in H-^H% (high-rise). Wh-RQs almost exclusively terminated in a low edge tone, whereas wh-ISQs allowed for more tonal variation (L-%, L-H%, H-^H%). Irrespective of question type, RQs were mainly produced with L*+H accents. Phonetically, RQs were more often realized with breathy voice quality than ISQs, in particular in the beginning of the interrogative. Furthermore, they were produced with longer constituent durations than ISQs, in particular at the end of the interrogative. While the difference between RQs and ISQs is reflected in the intonational terminus of the utterance, this does not happen in the way suggested in the semantic literature, and in addition, accent type and phonetic parameters also play a role. Crucially, a simple distinction between rising and falling intonation is insufficient to capture the realization of the different illocution types (RQs, ISQs), against frequent claims in the semantic and pragmatic literature. We suggest alternative ways to interpret the findings.

Evaluation of the methodological quality of articles on autologous breast reconstruction.

BACKGROUND: Breast cancer remains the most common cancer among women worldwide. Autologous breast reconstruction may contribute toward restoring body image and improving quality of life after mastectomy. This systematic literature review describes differences in the quality and type of studies investigating autologous breast reconstruction techniques over time. METHODS: MEDLINE was searched for articles related to the surgical techniques, namely, TRAM, LADO, DIEP, and SGAP/IGAP, for the periods 1970 to 2007 and 2008 to 2010. The quality and type of studies were compared across the two time periods. Full-texts were evaluated according to prespecified quality criteria. RESULTS: The MEDLINE searches yielded 1,057 articles for review; of them, 517 articles were excluded, and 314 had a completed quality criteria checklist and hence were included; of these 314 articles, 206 articles investigated TRAM flaps, 85 investigated LADO flaps, 74 investigated DIEP flaps, and 6 investigated SGAP/IGAP flaps. A total of 218 articles were published between 1970 and 2007 compared to 96 articles published between 2008 and 2010. The comparison of quality scores between the two time periods showed a shift toward higher scores in the period 2008 to 2010. The DIEP technique was investigated more frequently between 2008 and 2010 than between 1970 and 2007, whereas the percentage of articles focusing on the TRAM flap decreased. The percentage of articles investigating the LADO and SGAP/IGAP techniques remained constant across the time periods. CONCLUSIONS: Results relating to the methodological quality of articles on breast reconstruction with autologous tissue show that the quality of publications has improved with time, whereas research interests concerning the type of surgical technique investigated have changed in focus.

Differences in Breast Cancer Characteristics by Mammography Screening Participation or Non-Participation.

BACKGROUND: The goal of the German Mammography Screening Program (MSP) is to enable the early detection and less intensive treatment of breast cancer. We compared tumor characteristics and prognostic markers in breast cancers that were detected by screening in the MSP, in the interval after a negative screening, or among non-participants in screening. METHODS: This retrospective series includes all of the 1531 cases of invasive and in situ breast cancer (DCIS, ductal carcinoma in situ) that were newly diagnosed in two certified breast care centers in Münster in the period 2006-2012 among women in the MSP target population. Complete information on the tumor characteristics, tumor biology, and primary surgical treatment were available for all cases. The mode of cancer detection was determined from the state cancer registry of North Rhine-Westphalia. Due to the retrospective design of this case series, there was no randomized allocation. RESULTS: The 874 cases of breast cancer among MSP participants (714 detected by screening, 160 in the interval after a negative screen) and the 657 cases among non-participants arose in women of similar age (mean, 60.2 versus 59.3 years). MSP participants with breast cancer had DCIS more commonly than non-participants did (23% versus 13%); invasive carcinomas were smaller (74% versus 55% in the T1 stage), less commonly node-positive (25% versus 31%), less commonly high-grade (19% versus 27%), and less commonly triple-negative (7% versus 12%); MSP participants received neoadjuvant treatment less frequently (2% versus 8%) and more frequently underwent breast-conserving surgery (75% versus 62%). They less commonly had a guideline-based indication for adjuvant chemotherapy (46% versus 52%). CONCLUSION: MSP participants with invasive breast cancer can generally be treated with less intensive surgical and systemic therapy than non-participants, even if interval cancers are also taken into account. Future studies should also investigate quality of life after a diagnosis of invasive carcinoma in screening participants.

Microglia turnover with aging and in an Alzheimer's model via long-term in vivo single-cell imaging.

To clarify the role of microglia in brain homeostasis and disease, an understanding of their maintenance, proliferation and turnover is essential. The lifespan of brain microglia, however, remains uncertain, and reflects confounding factors in earlier assessments that were largely indirect. We genetically labeled single resident microglia in living mice and then used multiphoton microscopy to monitor these cells over time. Under homeostatic conditions, we found that neocortical resident microglia were long-lived, with a median lifetime of well over 15 months; thus, approximately half of these cells survive the entire mouse lifespan. While proliferation of resident neocortical microglia under homeostatic conditions was low, microglial proliferation in a mouse model of Alzheimer's ß-amyloidosis was increased threefold. The persistence of individual microglia throughout the mouse lifespan provides an explanation for how microglial priming early in life can induce lasting functional changes and how microglial senescence may contribute to age-related neurodegenerative diseases.