Infection of BALB/c mice with the filarial nematode Litomosoides sigmodontis: role of CD4+ T cells in controlling larval development.

Litomosoides sigmodontis is the only filaria which develops from infective larvae into adults in immunocompetent laboratory mice. Depletion of CD4+ T cells from infected BALB/c mice resulted in worm and microfilarial burdens significantly higher than those of infected controls. Th2 cytokines, eosinophilia, and immunoglobulin E, which were strongly induced in infected controls, were diminished in CD4-depleted mice.     

Rivaroxaban plasma levels in patients admitted for bleeding events: insights from a prospective study

Background

Serious bleeding events have been frequently described in patients taking direct oral anticoagulants (DOAC). In secondary analyses of phase 3 trials, DOAC plasma concentrations were shown to correlate with bleeding outcomes. This study aimed to describe rivaroxaban plasma levels in patients admitted to the emergency department (ED) for bleeding events. For each patient, risk factors for experiencing bleeding events were also investigated.

Methods

This analysis was part of an observational study conducted in the ED of two teaching hospitals. Plasma samples from 10 rivaroxaban-treated patients admitted for bleeding events were collected. Rivaroxaban plasma concentrations were determined by calibrated chromogenic anti-Xa assay. The measured rivaroxaban levels were then extrapolated at trough using a published population pharmacokinetic (PopPK) model, and compared to on-therapy ranges observed in large clinical trials. For each patient, clinical, medication and ABCB1 genotype data were collected.

Results

Rivaroxaban measurements varied from 5 to 358 ng/ml, with a post-intake delay ranging from 9 to 38 h. At trough, estimated plasma concentrations were between 12 and 251 ng/ml (median value 94 ng/ml). Four patients had higher-than-expected rivaroxaban levels. Inadequate dose regimen, excessive alcohol consumption and lack of treatment reassessment were observed in several patients. Half of patients were taking ≥1 drug with potential pharmacokinetics interactions (e.g. amiodarone, diltiazem), while half of patients were taking ≥1 drug increasing the risk of bleeding. All 3 patients with available genotyping data and higher-than-expected rivaroxaban levels were heterozygous or homozygous mutated for the ABCB1 1236C?>?T, 2677G?>?T, 3435 C?>?T and rs4148738 single nucleotide polymorphisms (SNP).

Conclusions

Rivaroxaban patients admitted to the ED for bleeding events showed highly variable plasma concentrations. This analysis underlines the usefulness of rapid DOAC measurement and the value of PopPK models to estimate concentrations at trough in a context where the post-intake delay is unmanageable. Close patient follow-up, including renal function assessment and drug interactions review, is essential for bleeding risk minimization.

     

Comparative genomic hybridization shows complex genomic changes of plasmacytoid urothelial carcinoma

ObjectivesTo describe genomic imbalances in plasmacytoid urothelial carcinoma (PUC), which is a rare and aggressive variant of urothelial carcinoma (UC).Methods and materialsIn total, 25 formalin-fixed paraffin-embedded PUCs were analyzed by metaphase comparative genomic hybridization. Genomic imbalances were considered to be characteristic if they were detected in≥20% of the cases. Chromosome regions deviating by≥3 standard deviations from the average chromosome profile were scored as chromosomal gains or losses. Copy-number variations (CNVs) of CDH1 (16q 22.1), SNAI1 (20q 13.1), CCND1 (11q13.3), ERBB2 (17q12), and FOXO3 (6q21) were validated using quantitative polymerase chain reaction.ResultsChromosomal aberrations were detected in every PUC analyzed, and the average number of aberrations was 10.24 (ranging from 1–15). Characteristic aberrations were gains on 1q (48%), 3p (20%), 6p (32%), 11q (72%), 15q (36%), 16q (44%), 17p (76%), 17q (88%), and 20q (88%) and losses on 2q (24%) 4p (36%), 4q (84%), 5q (44%), 6q (68%), 13q (20%), and Xq (52%). polymerase chain reaction-based analysis of CNV for CCND1 (11q13) showed a deletion in 73% of the cases. CDH1 (16q22) was deleted in 72% and amplified in 5%. ERBB2 (17q12) displayed remarkably few copy-number alterations, with only 14% showing an amplification. SNAI1 (20q13) showed reduced gene copy numbers in 59.1% of the cases, whereas no copy-number gains were detected. FOXO3 (6q21) exhibited the lowest number of copy-number alterations, with 9% of all cases showing an amplification.ConclusionsIn PUCs, the frequency of aneuploidy and the complexity of genomic changes per tumor are greater than those described in conventional UC. The aberrations described in PUC involve the same regions that are associated with aggressive biological behavior in conventional UC. Gains on 11q, 17q, 17p, and 20q and losses on 4q and 6q affect most PUCs and seem to harbor important chromosomal regions for PUC carcinogenesis. Large-scale deletions on chromosome 9 were not detected. CNV analysis indicates heterozygous deletion of CDH1 as one underlying mechanism of loss of membranous E-cadherin in PUC. Loss of CCND1 and SNAI1 is a common molecular feature and could contribute to the aggressive biological behavior of PUC.     

Comparison of different cardiac markers in monitoring percutaneous coronary interventions with frequent use of stents and gpIIbIIIa-antagonists

Studies from the early 1990s found elevations of creatine kinase (CK) and its isoform CK-MB in 5-30% of patients after PCI, indicating minor myocardial damage. Less is known about the influence of modern improved PCI-techniques on the frequency of elevated cardiac markers and the correlation between different commonly used markers, especially cardiac troponins. From 1997 to 2001, 1486 patients undergoing PCI during the regular working hours were included in the prospective "Ludwigshafen Infarctlet Registry". Myocardial infarction in the past 48 hours was an exclusion criterion. Clinical and procedural data were documented. Follow-up data were obtained from discharge up to one year. PCI-related elevations of troponin T were found in 18%, of total-CK in 11%, of CK-MB in 33% and of myoglobin in 23% of cases. The correlation between the different markers was poor. Compared with troponin T, other markers showed low sensitivity (total-CK 58%, CK-MB 27%, myoglobin 22%) and, especially total-CK, low specificity. Stenting, side branch occlusion or major dissection, complex lesion morphology, gpIIbIIIa-antagonist application, proximal stenosis and unstable angina were independent predictors of an elevated troponin T in multivariate analysis. Due to this weak correlation between more specific and sensitive troponins and the other markers, troponins are preferred in monitoring after PCI. In addition to lesion characteristics, particularly stenting is associated with an increased rate of elevated troponin.     

Clinical profile and management of heart failure: rural community hospital vs. metropolitan heart center

BACKGROUND: Knowledge on clinical characteristics and prognosis of patients with heart failure originates from studies of selected populations in clinical trials or from epidemiological observations. Reports on the large numbers of patients with heart failure treated in community hospitals are sparse. OBJECTIVE: Are there differences in patient characteristics and heart failure management between a metropolitan heart center (HC) and a rural community hospital (RCH)? PATIENTS AND METHODS: Retrospective analysis of medical charts from all patients admitted for heart failure (ICD 428.x, NYHA II-IV, EF<45%) between May 1997 and April 1998 and discharged alive from a rural community hospital. A similar, but prospective registry was available at the HC. Follow-up information was obtained by request at registration authorities. RESULTS: Patient groups comprised 120 in RCH and 146 in HC. Mean age was 75+/-11 and 66+/-11 years, respectively (P<0.001); 48% (RCH) vs. 74% (HC) of patients were male (P<0.001). On admission the proportion of functional class IV was 69% (RCH) vs. 17% (HC) (P<0.001). At discharge, the rate of ACE-inhibitors was 74% (RCH) vs. 98% (HC); 11% (RCH) vs. 43% (HC) of patients received beta-blocker therapy. Ninety-six percent of patients in HC underwent and 22% in RCH had undergone invasive diagnostics. One-year mortality rate of patients discharged alive was 26% in RCH and 19% in HC (P=n.s. after adjustment for age and gender). CONCLUSION: Heart failure management according to current guidelines, using beta-blockers and ACE inhibitors, and invasive cardiac examination was significantly less performed in the rural community hospital than in the metropolitan heart center. Therefore, strategies to improve heart failure management according to guidelines are urgently needed.     

Preventing cancer, cardiovascular disease, and diabetes: a common agenda for the American Cancer Society, the American Diabetes Association, and the American Heart Association

Collectively, cardiovascular disease (including stroke), cancer, and diabetes account for approximately two thirds of all deaths in the United States and about 700 billion dollars in direct and indirect economic costs each year. Current approaches to health promotion and prevention of cardiovascular disease, cancer, and diabetes do not approach the potential of the existing state of knowledge. A concerted effort to increase application of public health and clinical interventions of known efficacy to reduce prevalence of tobacco use, poor diet, and insufficient physical activity-the major risk factors for these diseases-and to increase utilization of screening tests for their early detection could substantially reduce the human and economic cost of these diseases. In this article, the ACS, ADA, and AHA review strategies for the prevention and early detection of cancer, cardiovascular disease, and diabetes, as the beginning of a new collaboration among the three organizations. The goal of this joint venture is to stimulate substantial improvements in primary prevention and early detection through collaboration between key organizations, greater public awareness about healthy lifestyles, legislative action that results in more funding for and access to primary prevention programs and research, and reconsideration of the concept of the periodic medical checkup as an effective platform for prevention, early detection, and treatment.     

From the Cover: Illusory faces are more likely to be perceived as male than female

Despite our fluency in reading human faces, sometimes we mistakenly perceive illusory faces in objects, a phenomenon known as face pareidolia. Although illusory faces share some neural mechanisms with real faces, it is unknown to what degree pareidolia engages higher-level social perception beyond the detection of a face. In a series of large-scale behavioral experiments (n_total = 3,815 adults), we found that illusory faces in inanimate objects are readily perceived to have a specific emotional expression, age, and gender. Most strikingly, we observed a strong bias to perceive illusory faces as male rather than female. This male bias could not be explained by preexisting semantic or visual gender associations with the objects, or by visual features in the images. Rather, this robust bias in the perception of gender for illusory faces reveals a cognitive bias arising from a broadly tuned face evaluation system in which minimally viable face percepts are more likely to be perceived as male.

Human faces convey a rich amount of social information beyond their identity (1–3). We are able to rapidly evaluate the age (4), gender (5, 6), and emotional expression (7) of the faces of individuals, even if they are not known to us, in addition to more abstract traits, such as trustworthiness and aggressiveness (8, 9). Although these judgements are based on visual information, biases have been identified that suggest that both perceptual and cognitive factors are involved in face evaluation (10–13). For example, people tend to judge faces as closer to their own age (10, 13), and damage to the amygdala is associated with perceiving unfamiliar faces as more trustworthy and approachable (12). Biases in face perception have important implications for understanding the neural processing of faces and their role in complex social behaviors (3). However, it is still unknown to what extent these behavioral biases arise from the tuning of the underlying face-processing mechanisms or, alternatively, from the nature of the experimental stimuli and task (10, 11). Here we approach this question from a new angle by examining face evaluation for a different class of faces: illusory faces in inanimate objects.Face pareidolia is the spontaneous perception of illusory facial features in inanimate objects (Fig. 1), and can be thought of as a natural error of our face detection system (14–18). It has recently been shown that nonhuman primates also experience face pareidolia (14, 15), and that illusory faces engage similar neural mechanisms to real faces in the human brain (18). However, it is unclear to what degree higher-level social perception beyond the detection of a face occurs in pareidolia. Investigation of face evaluation in illusory faces has the potential to reveal new insight into the underlying mechanisms of face perception. A key feature of face pareidolia is that it involves the spontaneous perception of a face in an inanimate object, and consequently it is an example of face perception that is divorced from many characteristics that typically accompany the faces of living organisms, such as the motion of facial muscles (e.g., to form emotional expressions), chronological age, and biological sex. The primary question we address here is whether illusory faces are perceived to have these traits even in the absence of their biological specification. As there is no a priori reason why an illusory face should be perceived to have a specific age, gender or expression, any reliable perception of these attributes would be informative about inherent properties of the underlying system.Open in a separate windowFig. 1.Distribution of face ratings for 10 representative illusory face images from the set of 256 images used in Exp. 1a. Each image [n_(images) = 256] received 100 ratings [total n_{(participants)} = 800] in Exp. 1a. Below each image is the median ($\tilde{x}$) face-rating score, and a frequency plot of the distribution of face ratings for each image. Note: the scale of the y axis is different across frequency plots.Studies using human faces have suggested potential biases in the perceived characteristics of human faces along dimensions such as age (10, 13) and gender (10, 11, 19) under conditions of visual uncertainty. However, determining the potential origin and generality of these biases has proven difficult and highlights the fundamental challenges inherent in understanding how the perception of specific traits is linked to face processing. Human faces are visually complex, and our brains are incredibly well-adapted to processing faces as a cohesive whole (20). Consequently, it is challenging to empirically isolate particular aspects of a human face (e.g., biological sex) from other interdependencies (e.g., identity). Additionally, since human faces have a biologically specified age and gender, it is necessary to introduce uncertainty via deliberate experimental manipulation of the stimuli. Studies of human faces have used various forms of image manipulation, including removing hair (21, 22), showing silhouettes of faces in profile (23), adding visual noise (24), and synthetically generating faces by morphing along stimulus dimensions, such as gender (10, 11, 19). A critical advantage of using pareidolia to probe the tuning of the face-processing system is that no decisions about stimulus manipulation need to be made, as attributes such as gender and age are unspecified for illusory faces: there is no ground truth. This circumvents the concern that any observable biases are due to choices made in stimulus manipulation (10, 11), and instead any biases observed in the characteristics perceived for these faces are likely to be reflective of the underlying tuning of the face-processing system.In a series of large-scale behavioral experiments (total n = 3,815) we show that illusory faces in objects are perceived to have a distinct emotional expression, age, and gender.^* Furthermore, we discovered a clear bias to perceive illusory faces as male rather than female, at a ratio of ∼4:1. This male bias for pareidolia is highly robust across images and people (Exps. 1a, 3a, and 3b), and cannot be explained by the corresponding object identity (Exps. 1b and 4), object label (Exp. 1b), color (Exps. 2 and 3), or object image content (Exp. 4) of the illusory face images. In contrast, using the same paradigm, we find that human face morphs created from an equal contribution of male and female faces are more likely to be perceived as female than male, although the female bias is smaller in magnitude than the male bias observed for pareidolia (Exp. 5). Together, these results demonstrate that gender evaluation is inextricably linked to face detection, and reveal that these mechanisms are engaged not only by human faces, but also by examples in which the minimal amount of visual information required for face detection occurs. It is important to emphasize that no assignment of gender is necessary for illusory faces as they do not have a biological sex. The existence of a compelling and biased categorization of gender for illusory faces is suggestive of a broadly tuned face evaluation system in which the features that are sufficient for face detection are not generally sufficient for the perception of female.     

Single-Unit Recordings Reveal the Selectivity of a Human Face Area

The exquisite capacity of primates to detect and recognize faces is crucial for social interactions. Although disentangling the neural basis of human face recognition remains a key goal in neuroscience, direct evidence at the single-neuron level is limited. We recorded from face-selective neurons in human visual cortex in a region characterized by functional magnetic resonance imaging (fMRI) activations for faces compared with objects. The majority of visually responsive neurons in this fMRI activation showed strong selectivity at short latencies for faces compared with objects. Feature-scrambled faces and face-like objects could also drive these neurons, suggesting that this region is not tightly tuned to the visual attributes that typically define whole human faces. These single-cell recordings within the human face processing system provide vital experimental evidence linking previous imaging studies in humans and invasive studies in animal models.SIGNIFICANCE STATEMENT We present the first recordings of face-selective neurons in or near an fMRI-defined patch in human visual cortex. Our unbiased multielectrode array recordings (i.e., no selection of neurons based on a search strategy) confirmed the validity of the BOLD contrast (faces–objects) in humans, a finding with implications for all human imaging studies. By presenting faces, feature-scrambled faces, and face-pareidolia (perceiving faces in inanimate objects) stimuli, we demonstrate that neurons at this level of the visual hierarchy are broadly tuned to the features of a face, independent of spatial configuration and low-level visual attributes.