Motor and Visual-spatial Cognitive Abilities in Children Treated for Infantile Esotropia.

While many studies have investigated links between motor and visual spatial cognitive abilities in typically developing children, only a few studies have tested this link among children with innate handicaps. Therefore, we assessed motor abilities (using the M-ABC-2) and visual spatial cognitive skills (using the Block Design subtest of the WPPSI-III and a picture mental rotation task, PRT) of 5-7 year old typically developing children (n= 17) and same-aged children with severe deficits in stereopsis due to infantile esotropia (n= 17). Compared to the typically developing children, children with esotropia showed significantly poorer motor performances, especially in manual dexterity and ball skills, and significantly poorer and slower performance on the visual spatial cognitive tasks. Especially the girls treated for infantile esotropia needed more time to mentally rotate the pictures of the PRT correctly. Overall, this study showed that perceptual, motor and cognitive processes are interconnected and that children treated for infantile esotropia had an increased risk of motor and visual spatial cognitive deficits.

Secondary mitral regurgitation-Insights from microRNA assessment.

BACKGROUND: While secondary mitral regurgitation (sMR) is associated with adverse outcome in heart failure with reduced ejection fraction (HFrEF), key pathophysiologic mechanisms remain poorly understood and might be elucidated by microRNAs (miRNA/miR), that were recently related to cardiac remodelling. This study sought to assess (i) the differences of miRNA profiles in patients with severe sMR compared to matched disease controls, (ii) the correlation between circulating miRNAs and surrogates of sMR severity as well as (iii) the prognostic implications of miRNA levels in severe sMR. MATERIALS AND METHODS: Sixty-six HFrEF patients were included, of these 44 patients with severe sMR 2:1 matched to HFrEF controls with no/mild sMR. A comprehensive set of miRNAs (miR-21, miR-29a, miR-122, miR-132, miR-133a, miR-let7i) were measured and correlated to echocardiographic sMR severity. RESULTS: miRNA patterns differed distinctly between patients with severe sMR and HFrEF controls (P < .05). Among the panel of assessed miRNAs, miR-133a correlated most strongly with surrogates of sMR severity (r = -0.41, P = .001 with sMR vena contracta width). Interestingly, elevated levels of miR-133 were associated with an increased risk for cardiovascular death and/or HF hospitalizations with and adjusted HR of 1.85 (95% CI 1.24-2.76, P = .003). CONCLUSIONS: This study unveils distinct pathophysiologic maladaptions at a cellular level in patients with severe sMR compared to no/mild sMR by showing significant differences in miRNA profiles and correlations with sMR severity, supporting the concept that sMR drives cardiac remodelling in heart failure. Moreover, the increased risk for adverse outcome in HFrEF patients with severe sMR conveyed by miR-133a might indicate irreversible myocardial damage.

Plasma Neprilysin Displays No Relevant Association With Neurohumoral Activation in Chronic HFrEF.

Background Neprilysin is a transmembrane endopeptidase involved in the breakdown of a variety of vasoactive peptides and serves as a therapeutic target in heart failure with reduced ejection fraction (HFrEF). This study aimed to investigate the relationship of circulating neprilysin with neurohumoral activation and the impact of plasma neprilysin activity on prognosis in HFrEF. Methods and Results A total of 369 chronic HFrEF patients were enrolled prospectively. Plasma neprilysin concentration and activity were determined by a specific ELISA and a fluorometric method. The association between plasma neprilysin and heart failure (HF) severity, neurohumoral activation, ie norepinephrine and absolute renin concentration, as well as all-cause mortality was assessed. Median plasma neprilysin concentrations and activity levels were 413 pg/mL (interquartile range 0-4111) and 2.36 nmol/mL per minute (interquartile range 1.16-4.59). No correlation could be shown between plasma neprilysin concentrations and activity (rs=0.09, P=0.088). Plasma neprilysin activity correlated with HF severity reflected by New York Heart Association stage (P=0.003) and tertiles of N-terminal pro-B-type natriuretic peptide (P<0.001), whereas neprilysin concentrations did not (P=0.220; P=0.849). There was no relevant relationship between plasma neprilysin concentrations and activity, with neurohumoral activation reflected by absolute renin concentration (rs=-0.02, P=0.648; rs=0.03, P=0.574) or norepinephrine levels (rs=-0.06, P=0.248; rs=0.20, P<0.001). Neither circulating neprilysin concentrations nor activity were associated with outcome. Conclusions Plasma neprilysin concentrations and activity are not directly related to neurohumoral activation, indicating that neprilysin regulation is either more complex or not correctly mirrored by circulating neprilysin as a biomarker. Circulating neprilysin concentrations and activity were not associated with overall survival, implicating limited prognostic value of plasma neprilysin measurements in HFrEF patients.

GDF-15 in solid vs non-solid treatment-naïve malignancies.

AIM: GDF-15 is an established cardiovascular risk marker but is equally implicated in tumour biology. Elevated levels of GDF-15 have indeed been observed in distinct tumour entities. This study aimed to explore the relation of GDF-15 to other cardiac biomarkers and the general association of GDF-15 on prognosis in an unselected cohort of treatment-naïve cancer patients. METHODS: We prospectively enrolled 555 consecutive patients at time of diagnosis of malignant disease prior receiving anticancer therapy. Plasma GDF-15 concentrations were determined alongside other cardiac and routine laboratory markers. All-cause mortality was defined as primary endpoint. RESULTS: GDF-15 levels were 338 ng/L (IQR:205-534) for the total cohort, and values were comparable for different tumour entities except breast cancer. Metastatic disease was characterized by higher plasma GDF-15 [435 ng/L (IQR:279-614) vs 266 ng/L (IQR:175-427), P < .001]. GDF-15 correlated positively with inflammatory status reflected by CRP, SAA and IL-6 [r = .31, P < .001, r = .23, P < .001 and r = .14, P = .002] and cardiac biomarkers as NT-proBNP, hsTnT, MR-proADM and CT-proET-1 [r = .46; r = .46; r = .59 and r = .50; P < .001 for all]. GDF-15 was significantly associated with all-cause mortality after multivariate adjustment [adj.HR for ln(GDF-15) 1.78, 95%CI:1.47-2.16, P < .001]. There was a significant interaction between solid and haematological malignancies with loss of association of GDF-15 with outcome in myelodysplastic and myeloproliferative disease. CONCLUSIONS: Elevated plasma GDF-15 is associated with progressing disease severity and poor prognosis in solid tumours of treatment-naïve cancer patients. GDF-15 increase is accompanied by worsening systemic inflammation and a subclinical functional impairment of different organs including the heart. GDF-15 represents a promising target for our pathophysiologic understanding in cardio-oncology linking conditions of both cardiac and neoplastic disease.

The circulating form of neprilysin is not a general biomarker for overall survival in treatment-naïve cancer patients.

The transmembrane zink-metalloendopeptidase neprilysin (NEP) is implicated in cardiovascular disease but also tumor biology. The aim of the study was to investigate the relationship of circulating NEP (cNEP) levels with established cardiovascular biomarkers and its effect on overall survival in an unselected cohort of treatment-naïve cancer patients. 555 consecutive cancer patients prior anticancer therapy were enrolled prospectively. NEP levels were determined alongside routine laboratory parameters, established cardiac biomarkers, i.e. NT-proBNP, hsTnT, MR-proANP, MR-proADM, CT-proET-1 and Copeptin, and inflammatory parameters, i.e. CRP, IL-6 and SAA, in venous plasma samples. All-cause mortality was the primary endpoint. cNEP levels of 276 pg/ml (IQR: 0-5981) displayed a weak inverse correlation with age [r = -0.12, p = 0.023] and inflammatory status [r = -0.14, p = 0.007 CRP; r = -0.20, p < 0.001 IL-6 and r = -0.18, p < 0.001 SAA]. cNEP was comparable between different tumor entities and stages and not related to functional parameters of other organ systems as kidney, liver or especially the heart. Moreover, cNEP was not associated with overall survival in the total cohort [adj.HR for ln (cNEP) 1.00, 95% CI: 0.94-1.06, p = 0.887] but in myelodysplatic malignancies [adj.HR for ln (cNEP) 1.27, 95% CI: 1.01-1.61, p = 0.044]. In conclusion, cNEP lacks association with outcome but for myelodysplastic disease. cNEP shows no correlation with established cardiovascular biomarkers related to prognosis, thereby holding a limited potential as a biomarker in cardio-oncology.

The Development of Implicit Memory From Infancy to Childhood: On Average Performance Levels and Interindividual Differences.

The present multimethod longitudinal study aimed at investigating development and stability of implicit memory during infancy and early childhood. A total of 134 children were followed longitudinally from 3 months to 3 years of life assessing different age-appropriate measures of implicit memory. Results from structural equation modeling give further evidence that implicit memory is stable from 9 months of life on, with earlier performance predicting later performance. Second, it was found that implicit memory is present from early on, and no age-related improvements are found from 3 months on. Results are discussed with respect to the basic brain structures implicit memory builds on, as well as methodological issues.

Waiting for the Second Treat: Developing Culture-Specific Modes of Self-Regulation.

The development of self-regulation has been studied primarily in Western middle-class contexts and has, therefore, neglected what is known about culturally varying self-concepts and socialization strategies. The research reported here compared the self-regulatory competencies of German middle-class (N = 125) and rural Cameroonian Nso preschoolers (N = 76) using the Marshmallow test (Mischel, 2014). Study 1 revealed that 4-year-old Nso children showed better delay-of-gratification performance than their German peers. Study 2 revealed that culture-specific maternal socialization goals and interaction behaviors were related to delay-of-gratification performance. Nso mothers' focus on hierarchical relational socialization goals and responsive control seems to support children's delay-of-gratification performance more than German middle-class mothers' emphasis on psychological autonomous socialization goals and sensitive, child-centered parenting.

[The Motor Development of Children with Infantile Esotropia]. / Die motorische Entwicklung von Kindern mit frühkindlichem Innenschielen.

Background Until now, many studies have investigated the link between motor development and visual-spatial abilities in infancy and childhood. Most of these studies found evidence that there is such a link in typically developing children or children with locomotor delay. Only a few studies have tested the consequences of this link in children with abnormal visual development because of infantile esotropia. Moreover, little is known about the effects of late surgery on motor development. Patients and Methods We assessed the motor abilities of 3- to 7-year old children with severe deficits in stereopsis due to infantile esotropia (angle ≥ 12°) and typically developing children prior to and 12 to 16 months after surgery. We used the Movement Assessment Battery for Children (Movement ABC-2). Results Prior to and one year after surgery, the strabismic children showed significantly lower global motor scores than normal children. Moreover, in the strabismic children, we found significant differences relative to the healthy children in the subscales assessing manual dexterity and balance prior to and significant differences in the subscales assessing manual dexterity and ball skills after surgery. Overall, the strabismic group did not demonstrate improvements in motor development after surgery. However, the children with a positive Bagolini striated glass test following surgery performed better in the subscale assessing balance than children with a negative Bagolini striated glass test. Conclusions Motor skills were poorer in children with infantile esotropia, both prior to and following surgery. Moreover, the children with improved binocular vision after surgery demonstrated better balance skills. Possible explanations and practical implications are discussed.

Host cell binding of the flagellar tip protein of Campylobacter jejuni.

Flagella are nanofibers that drive bacterial movement. The filaments are generally composed of thousands of tightly packed flagellin subunits with a terminal cap protein, named FliD. Here, we report that the FliD protein of the bacterial pathogen Campylobacter jejuni binds to host cells. Live-cell imaging and confocal microscopy showed initial contact of the bacteria with epithelial cells via the flagella tip. Recombinant FliD protein bound to the surface of intestinal epithelial cells in a dose-dependent fashion. Search for the FliD binding site on the host cell using cells with defined glycosylation defects indicated glycosaminoglycans as a putative target. Heparinase treatment of wild type cells and an excess of soluble heparin abolished FliD binding. Binding assays showed direct and specific binding of FliD to heparin. Addition of an excess of purified FliD or heparin reduced the attachment of viable C. jejuni to the host cells. The host cell binding domain of FliD was mapped to the central region of the protein. Overall, our results indicate that the C. jejuni flagellar tip protein FliD acts as an attachment factor that interacts with cell surface heparan sulfate glycosaminoglycan receptors.

Is Perceptual Priming Affected by Culture? A Study With German Middle-Class and Cameroonian Nso Farmer Children.

The authors explored priming in children from different cultural environments with the aim to provide further evidence for the robustness of the priming effect. Perceptual priming was assessed by a picture fragment completion task in 3-year-old German middle-class and Cameroonian Nso farmer children. As expected, 3-year-olds from both highly diverging cultural contexts under study showed a priming effect, and, moreover, the effect was of comparable size in both cultural contexts. Hence, the children profited similarly from priming, which was supported by the nonsignificant interaction between cultural background and identification performance as well as the analysis of absolute difference scores. However, a culture-specific difference regarding the level of picture identification was found in that German middle-class children identified target as well as control pictures with less perceptual information than children in the Nso sample. Explanations for the cross-cultural demonstration of the priming effect as well as for the culturally diverging levels on which priming occurs are discussed.

Rural N(SO) and German middle-class mothers' interaction with their 3- and 6-month-old infants: A longitudinal cross-cultural analysis.

This study aims to analyze culture-specific development of maternal interactional behavior longitudinally. Rural Cameroonian Nso mothers (n = 72) and German middle-class mothers (n = 106) were observed in free-play interactions with their 3- and 6-month-old infants. Results reveal the expected shift from a social to a nonsocial focus only in the German middle-class mothers' play interactions but not the rural Nso mothers' play. Nso mothers continue their proximal interactional style with a focus on body contact and body stimulation, whereas German middle-class mothers prefer a distal style of interaction with increasing object-centeredness. These cultural differences are in line with broader cultural models and become more accentuated as the infants grow older.

Experience with headwear influences the other-race effect in 4-year-old children.

The other-race effect (ORE) implies the better recognition of faces of one's own race compared with faces of a different race. It demonstrates that face recognition is shaped by daily experience with human faces. Such experience mainly includes structural information of own-race faces and also information on the way faces are usually seen, as a whole or partly covered by scarves or other headwear. In two experiments, we investigated how this mode of presentation is related to the occurrence of the ORE during childhood. In Experiment 1, 4-year-old German children (N = 104), accustomed to seeing faces without headwear in daily life, were asked to recognize female Caucasian or African faces, presented either as a whole or wearing a woolen hat, in a forced choice paradigm. In Experiment 2, 4-year-olds from rural Cameroon (N = 70), accustomed to seeing faces with and without headwear in daily life, participated in the same task. In both groups, the ORE was present in the familiar mode of presentation, that is, in whole faces in German children and in whole and partly covered faces in Cameroonian children. The results are discussed in relation to the role of experience for face recognition processes.

High turnover of tissue factor enables efficient intracellular delivery of antibody-drug conjugates.

Antibody-drug conjugates (ADC) are emerging as powerful cancer treatments that combine antibody-mediated tumor targeting with the potent cytotoxic activity of toxins. We recently reported the development of a novel ADC that delivers the cytotoxic payload monomethyl auristatin E (MMAE) to tumor cells expressing tissue factor (TF). By carefully selecting a TF-specific antibody that interferes with TF:FVIIa-dependent intracellular signaling, but not with the procoagulant activity of TF, an ADC was developed (TF-011-MMAE/HuMax-TF-ADC) that efficiently kills tumor cells, with an acceptable toxicology profile. To gain more insight in the efficacy of TF-directed ADC treatment, we compared the internalization characteristics and intracellular routing of TF with the EGFR and HER2. Both in absence and presence of antibody, TF demonstrated more efficient internalization, lysosomal targeting, and degradation than EGFR and HER2. By conjugating TF, EGFR, and HER2-specific antibodies with duostatin-3, a toxin that induces potent cytotoxicity upon antibody-mediated internalization but lacks the ability to induce bystander killing, we were able to compare cytotoxicity of ADCs with different tumor specificities. TF-ADC demonstrated effective killing against tumor cell lines with variable levels of target expression. In xenograft models, TF-ADC was relatively potent in reducing tumor growth compared with EGFR- and HER2-ADCs. We hypothesize that the constant turnover of TF on tumor cells makes this protein specifically suitable for an ADC approach.

The other-race effect in 3-year-old German and Cameroonian children.

Recognizing individual faces is an important human ability that highly depends on experience. This is reflected in the so called other-race effect; adults are better at recognizing faces from their own ethnic group, while very young infants do not show this specialization yet. Two experiments examined whether 3-year-old children from two different cultural backgrounds show the other-race effect. In Experiment 1, German children (N = 41) were presented with a forced choice paradigm where they were asked to recognize female Caucasian or African faces. In Experiment 2, 3-year-olds from Cameroon (N = 66) participated in a similar task using the same stimulus material. In both cultures the other-race effect was present; children were better at recognizing individual faces from their own ethnic group. In addition, German children performed at a higher overall level of accuracy than Cameroonians. The results are discussed in relation to cultural aspects in particular.

Phagocytosis escape by a Staphylococcus aureus protein that connects complement and coagulation proteins at the bacterial surface.

Upon contact with human plasma, bacteria are rapidly recognized by the complement system that labels their surface for uptake and clearance by phagocytic cells. Staphylococcus aureus secretes the 16 kD Extracellular fibrinogen binding protein (Efb) that binds two different plasma proteins using separate domains: the Efb N-terminus binds to fibrinogen, while the C-terminus binds complement C3. In this study, we show that Efb blocks phagocytosis of S. aureus by human neutrophils. In vitro, we demonstrate that Efb blocks phagocytosis in plasma and in human whole blood. Using a mouse peritonitis model we show that Efb effectively blocks phagocytosis in vivo, either as a purified protein or when produced endogenously by S. aureus. Mutational analysis revealed that Efb requires both its fibrinogen and complement binding residues for phagocytic escape. Using confocal and transmission electron microscopy we show that Efb attracts fibrinogen to the surface of complement-labeled S. aureus generating a 'capsule'-like shield. This thick layer of fibrinogen shields both surface-bound C3b and antibodies from recognition by phagocytic receptors. This information is critical for future vaccination attempts, since opsonizing antibodies may not function in the presence of Efb. Altogether we discover that Efb from S. aureus uniquely escapes phagocytosis by forming a bridge between a complement and coagulation protein.

How Crawling and Manual Object Exploration are Related to the Mental Rotation Abilities of 9-Month-Old Infants.

The present experiment examined whether the mental rotation ability of 9-month-old infants was related to their abilities to crawl and manually explore objects. Forty-eight 9-month-old infants were tested; half of them had been crawling for an average of 9.3 weeks. The infants were habituated to a video of a simplified Shepard-Metzler object rotating back and forth through a 240° angle around the longitudinal axis of the object. They were tested with videos of the same object rotating through a previously unseen 120° angle and with a mirror image of the display. All of the infants also participated in a manual object exploration task, in which they freely explored five toy blocks. The results showed that the crawlers looked significantly longer at the novel (mirror) object than at the familiar object, independent of their manual exploration scores. The non-crawlers looking times, in contrast, were influenced by the manual exploration scores. The infants who did not spontaneously explore the toy blocks tended to show a familiarity preference, whereas those who explored the toy blocks preferred to look at the novel object. Thus, all of the infants were able to master the mental rotation task but it seemed to be the most complex process for infants who had no crawling experience and who did not spontaneously explore objects.

Aberrant promotor methylation in MDS hematopoietic cells during in vitro lineage specific differentiation is differently associated with DNMT isoforms.

Aberrant promoter methylation may contribute to the hematopoietic disturbances in myelodysplastic syndromes (MDS). To explore a possible mechanism, we therefore analyzed expression of DNA methyltransferase (DNMT) subtypes kinetics and aberrant promoter methylation of key regulatory genes during MDS hematopoiesis. An in vitro model of MDS lineage-specific hematopoiesis was generated by culturing CD34+ cells from healthy donors (n=7) and MDS patients (low-risk: RA/n=6, RARS/n=3; high-risk: RAEB/n=4, RAEB-T/n=2) with EPO, TPO and GCSF. Promoter methylation analysis of key genes involved in the control of apoptosis (p73, survivin, DAPK), DNA-repair (hMLH1), differentiation (RARb, WT1) and cell cycle control (p14, p15, p16, CHK2) was performed by methylation specific PCR of bisulfite-treated genomic DNA. Expression of DNMT1, DNMT3a and DNMT3b was analyzed and correlated with gene promoter methylation for each lineage at different time points. DNMT expression (all isoforms) was increased during thrombopoiesis whereas elevated DNMT1 level were seen during erythropoiesis. Associations between aberrant promoter methylation and DNMT expression were found in high-risk MDS for all lineages and during erythropoiesis. Hypermethylation of p15, p16, p73, survivin, CHK2, RARb and DAPK were associated with elevated DNMT isoform expression. No general overexpression of DNMT subtype was detected during MDS hematopoiesis. However a negative association of DNMT3a and 3b expression with MDS disease risk (IPSS) could be observed. Our data indicate that all mammalian DNMT isoforms may be involved in the aberrantly methylated phenotype in MDS but seem also to be essential for the differentiation of normal hematopoietic stem cells. In particular elevated DNMT1 expression may in particular contribute to ineffective erythropoiesis in MDS.