Renal and vascular effects of atrial natriuretic factor during cardiopulmonary bypass.

STUDY OBJECTIVE: To evaluate renal and vasodilator effects of synthetic atrial natriuretic factor (ANF) in patients undergoing cardiopulmonary bypass (CPB) with special reference to the applicability of ANF as a diuretic and natriuretic. DESIGN: The study consisted of two parts. The first 15 consecutive patients in a university hospital received a pharmacologically effective bolus dose of 100 micrograms ANF, as demonstrated previously in other studies, or placebo. After analysis of the bolus data (see "Results" section below), the 12 subsequent patients were administered ANF 50 micrograms as a constant 30-min infusion at a rate of 1.67 micrograms/min or placebo. PATIENTS: The patients were scheduled for elective coronary artery bypass grafting operation. There was no evidence of congestive heart failure in any patient, and no one had an endocrine or renal disorder. INTERVENTIONS: After achievement of hypothermia (29 to 30 degrees C of rectal temperature) during CPB, a bolus dose of ANF 100 micrograms was given or an infusion of ANF 1.67 micrograms/min for 30 min, ie, a total dose of 50 micrograms was started. The control patients received placebo correspondingly. Intravenous fluids were administered according to a predetermined scheme. MEASUREMENTS AND MAIN RESULTS: For the pharmacologic effects of ANF urine volume, urinary sodium excretion and mean arterial pressure (MAP) were measured. Only three of the eight patients receiving the bolus dose of ANF had a diuretic and natriuretic response to the drug, and the responses were significantly related (r = 0.91, p less than 0.05 and r = 0.98, p less than 0.001, respectively) to the prevailing MAP at the time of the bolus administration. The bolus dose of ANF decreased MAP significantly (p less than 0.001 vs placebo) from 65 +/- 6 (mean +/- SEM) to 55 +/- 6 mm Hg within 5 min. The infusion of ANF did not affect MAP, but it increased urine output (16.1 +/- 5.0 ml/min, when the data obtained during the 30-min infusion and a 30-min period after the infusion were combined) and urinary sodium excretion (1,651 +/- 514 microEq/min) significantly (p less than 0.05 and p less than 0.01, respectively) as compared with the corresponding values of 3.3 +/- 1.1 ml/min and 386 +/- 141 microEq/min after placebo. CONCLUSIONS: Prevailing arterial pressure is an important determinant of the diuretic and natriuretic activity of synthetic ANF in patients undergoing CPB. A low-dose infusion of ANF (50 micrograms within 30 min) provides diuresis and natriuresis without significant changes in MAP in these patients.     

Cyclin D3 drives inertial cell cycling in dark zone germinal center B cells

During affinity maturation, germinal center (GC) B cells alternate between proliferation and somatic hypermutation in the dark zone (DZ) and affinity-dependent selection in the light zone (LZ). This anatomical segregation imposes that the vigorous proliferation that allows clonal expansion of positively selected GC B cells takes place ostensibly in the absence of the signals that triggered selection in the LZ, as if by “inertia.” We find that such inertial cycles specifically require the cell cycle regulator cyclin D3. Cyclin D3 dose-dependently controls the extent to which B cells proliferate in the DZ and is essential for effective clonal expansion of GC B cells in response to strong T follicular helper (Tfh) cell help. Introduction into the Ccnd3 gene of a Burkitt lymphoma–associated gain-of-function mutation (T283A) leads to larger GCs with increased DZ proliferation and, in older mice, clonal B cell lymphoproliferation, suggesting that the DZ inertial cell cycle program can be coopted by B cells undergoing malignant transformation.     

Nucleoprotein‐specific nonneutralizing antibodies speed up LCMV elimination independently of complement and FcγR

CD8⁺ T cells have an essential role in controlling lymphocytic choriomeningitis virus (LCMV) infection in mice. Here, we examined the contribution of humoral immunity, including nonneutralizing antibodies (Abs), in this infection induced by low virus inoculation doses. Mice with impaired humoral immunity readily terminated infection with the slowly replicating LCMV strain Armstrong but showed delayed virus elimination after inoculation with the faster replicating LCMV strain WE and failed to clear the rapidly replicating LCMV strain Docile, which is in contrast to the results obtained with wild‐type mice. Thus, the requirement for adaptive humoral immunity to control the infection was dependent on the replication speed of the LCMV strains used. Ab transfers further showed that LCMV‐specific IgG Abs isolated from LCMV immune serum accelerated virus elimination. These Abs were mainly directed against the viral nucleoprotein (NP) and completely lacked virus neutralizing activity. Moreover, mAbs specific for the LCMV NP were also able to decrease viral titers after transfer into infected hosts. Intriguingly, neither C3 nor Fcγ receptors were required for the antiviral activity of the transferred Abs. In conclusion, our study suggests that rapidly generated nonneutralizing Abs specific for the viral NP speed up virus elimination and thereby may counteract T‐cell exhaustion.     

Body-image dissatisfaction is strongly associated with chronic dysphoria

Background

Individual depressive symptoms may contribute to the risk of chronic depression. This study aimed to explore which symptoms predict chronic dysphoria, a hallmark of depression.

Methods

1057 participants from the population-based Young Finns study were examined for four times during a 16-year period. Those with a modified Beck’s Depression Inventory score in the upper third at all four screenings were considered to have chronic dysphoria (n=135). Participants with only one high depression score formed the reference group of transient dysphoria (n=179). Individual items of the Inventory were analyzed in terms of their association with dysphoria status and chronicity, controlling for potential confounding factors, such as personality assessed using the Temperament and Character Inventory.

Results

Body-image dissatisfaction was strongly associated with chronically elevated dysphoria (Bonferroni-corrected p=0.006). The degree of body-image dissatisfaction was associated with the probability for chronic dysphoria in a dose–response manner, with the estimated probability ranging from 0.01 to 0.60 as a function of item response. The association remained after adjustments for a wide range of personality characteristics.

Limitations

The study relied on self-reports of mood and personality, and lacked information on external opinion on participants appearances. The requirement of full time-series data may have resulted in attrition-related bias.

Conclusions

Body-image dissatisfaction was a strong predictor of chronic depression characterized by dysphoria. This finding suggests that dysfunctional attitude towards oneself might represent a potentially important target for cognitive therapies and preventive interventions.     

Correlation of Pneumococcal Antibody Concentration and Avidity with Patient Clinical and Immunologic Characteristics

Purpose

The quality of an antibody response is determined by both the concentration and the strength of antigen-binding, or avidity, of the antibodies produced. Currently, only antibody concentration is routinely evaluated in the clinical assessment of humoral immunity. Here we studied correlations of avidities and concentrations of antibodies to pneumococcal polysaccharides with immunologic and clinical characteristics of patients with recurrent infections.

Methods

We measured concentration and avidity of antibodies to 12 pneumococcal serotypes in 78 children aged 0.6–18 years with recurrent bacterial respiratory infections, and in 80 individuals who were being tested for peanut allergy, ages 0.4–15 years, serving as a comparison group. Avidity was assessed by measuring antibody binding in the presence of thiocyanate.

Results

Antibody concentrations and avidities correlated positively for very few types contained in the conjugated pneumococcal vaccine (PCV7) in both patients and controls with some dependence on age; there were even fewer correlations for non-PCV7 types. Antibody concentrations and avidities negatively correlated with age for most of the PCV7 types. There was no consistent correlation of total IgG or IgG subclasses with either concentrations or avidities. Overall, antibody concentrations were higher and avidities were lower in patients compared to controls. Patients requiring chronic antibiotic use tended to have higher antibody concentrations and lower avidities for most serotypes than patients who did not. We identified several patients having many infections with apparent good antibody concentrations with low avidity for many types.

Conclusion

Antibody concentration and avidity correlate with patient clinical characteristics and distinguish patients from controls. Measurement of antibody avidity may provide another dimension for the clinical assessment of pneumococcal polysaccharide antibody response.     

A robust heart sound segmentation algorithm for commonly occurring heart valve diseases

The first step towards detection of valvular heart diseases from heart sound signal (phonocardiogram) is segmentation. A segmentation algorithm provides the location of the first and second heart sounds which in turn helps to locate and analyse the murmur. Established phonocardiogram based segmentation methods use an electrocardiographic (ECG) signal as a continuous auxiliary input in a complex instrumentation setup. This paper proposes an automatic segmentation method that does not require any such auxiliary signal. Compared to other approaches without auxiliary signal, this work extensively utilizes biomedical domain features for reduction of time and computational complexities and is more accurate. The performance of the algorithm is evaluated for nine commonly occurring pathological cases and normal heart sound for various sampling frequencies, recording environments and age group of subjects. The proposed algorithm yields an overall accuracy of 97.47% and is compared with two competing techniques. In addition, the robustness of the algorithm is shown against additive white Gaussian noise contamination at various SNR levels.     

Moderate early life stress improves adult zebrafish (Danio rerio) working memory but does not affect social and anxiety‐like responses

Early life stress (ELS) is defined as a short or chronic period of trauma, environmental or social deprivation, which can affect different neurochemical and behavioral patterns during adulthood. Zebrafish (Danio rerio) have been widely used as a model system to understand human neurodevelopmental disorders and display translationally relevant behavioral and stress‐regulating systems. In this study, we aimed to investigate the effects of moderate ELS by exposing young animals (6‐weeks postfertilization), for 3 consecutive days, to three stressors, and analyzing the impact of this on adult zebrafish behavior (16‐week postfertilization). The ELS impact in adults was assessed through analysis of performance on tests of unconditioned memory (free movement pattern Y‐maze test), exploratory and anxiety‐related task (novel tank diving test), and social cohesion (shoaling test). Here, we show for the first time that moderate ELS increases the number of alternations in turn‐direction compared to repetitions in the unconditioned Y‐maze task, suggesting increased working memory, but has no effect on shoal cohesion, locomotor profile, or anxiety‐like behavior. Overall, our data suggest that moderate ELS may be linked to adaptive flexibility which contributes to build “resilience” in adult zebrafish by improving working memory performance.     

Recirculating IL-1R2+ Tregs fine-tune intrathymic Treg development under inflammatory conditions

The vast majority of Foxp3⁺ regulatory T cells (Tregs) are generated in the thymus, and several factors, such as cytokines and unique thymic antigen-presenting cells, are known to contribute to the development of these thymus-derived Tregs (tTregs). Here, we report the existence of a specific subset of Foxp3⁺ Tregs within the thymus that is characterized by the expression of IL-1R2, which is a decoy receptor for the inflammatory cytokine IL-1. Detailed flow cytometric analysis of the thymocytes from Foxp3^hCD2xRAG1^GFP reporter mice revealed that the IL-1R2⁺ Tregs are mainly RAG1^GFP– and CCR6⁺CCR7^–, demonstrating that these Tregs are recirculating cells entering the thymus from the periphery and that they have an activated phenotype. In the spleen, the majority of IL-1R2⁺ Tregs express neuropilin-1 (Nrp-1) and Helios, suggesting a thymic origin for these Tregs. Interestingly, among all tissues studied, the highest frequency of IL-1R2⁺ Tregs was observed in the thymus, indicating preferential recruitment of this Treg subset by the thymus. Using fetal thymic organ cultures (FTOCs), we demonstrated that increased concentrations of exogenous IL-1β blocked intrathymic Treg development, resulting in a decreased frequency of CD25⁺Foxp3⁺ tTregs and an accumulation of CD25⁺Foxp3⁻ Treg precursors. Interestingly, the addition of IL-1R2⁺ Tregs, but not IL-1R2⁻ Tregs, to reaggregated thymic organ cultures (RTOCs) abrogated the IL-1β-mediated blockade, demonstrating that these recirculating IL-1R2⁺ Tregs can quench IL-1 signaling in the thymus and thereby maintain thymic Treg development even under inflammatory conditions.