Dietary Vitamin E Modulation of Cytokine Production by Splenocytes and Thymocytes from Alcohol-Fed Mice

As vitamin E enhances immune responses, it may reduce dietary ethanol (EtOH)-induced immune suppression, thereby favorably afffecting host disease resistance. The effects of dietary vitamin E at higher level in alcohol-fed female C57BL/6 mice was determined via in vitro cytokine production by splenocytes and thymocytes, and some other immune functions. A 15-fold increase of vitamin E (160IU/liter) in a liquid diet (National Council Research), with or without EtOH (4.5%, v/v), was fed to mice for 10 weeks. Vitamin E supplementation restored production of interleukin-2, -5, -6, -10, and inter-feron-γ by concanavalin A (Con A)-stimulated splenocytes and in terleukin-6 and tumor necrosis factor-a by lipopolysaccharide-stimulated splenocytes, which were suppressed by dietary EtOH. However, it had no effect on interleukin-4 secretion, which was also reduced by splenocytes from EtOH-fed mice. Vitamin E supplementation also restored EtOH-suppressed, mitogen-induced splenocyte proliferation, but not thymocyte proliferation, although it slightly increased production of immunoglobulin A and G by lipopolysaccha-ride-stimulated splenocytes, which were suppressed by dietary EtOH. Dietary vitamin E, furthermore, significantly increased interleu-kin-2 and -6 secretion by Con A-stimulated thymocytes, which were suppressed by dietary EtOH, although it had no effect on interleukin- 4 and interferon-γ production by Con A-stimulated thymocytes from EtOH-fed mice. These data suggest that dietary vitamin E supple-mentation can modulate dysregulation of cytokines initiated by dietary EtOH and restore immune dysfunctions induced by EtOH ingestion.     

The universal algorithm of maturation for secretory and excretory protein precursors.

During maturation, most proteins undergo different posttranslational modifications. In most simple cases, signal peptidases remove the signal or leader peptide from the precursors of the secretory proteins during their translocation across the ER membrane. For biologically active proteins, such as enzymes, regulatory and defense proteins, toxins, etc., additional maturation-regulating mechanisms were shown to proceed with limited proteolysis of inactive precursors by specific enzymes. A number of specific enzymes from different cell types selectively cleave proproteins at specific processing sites. In this work, we analyzed the sequences of protein precursors synthesized in the excretory glands of different animals and identified new, non-traditional processing sites. They differ from the motifs previously identified in secreted proteins' precursors and enabled us to reconstruct the sequence of events leading to the conversion of protein precursors into the final products (mature proteins). We also found that in animals, the maturation mechanism of secretory and excretory proteins and the set of enzymes involved are species specific. The processing sites identified in protein precursors in this study are useful for a more detailed genome analysis and more accurate mature protein sequence prediction.     

Decreasing sensitivity to neuroleptic agents in developing rats; evidence for a pharmacodynamic factor

Developing rats are far more sensitive than adults to the behavioral effects of haloperidol. The present results support the hypothesis that this change may reflect age-related changes in brain responses such as alterations in drug-receptor or drug-effector mechanisms. Dose-response studies of catalepsy and ptosis were conducted in male Sprague-Dawley rats aged 30, 56, or 100 days. Resulting dose-effect curves were approximately parallel and showed rightward shifts with highly significant progressive increases of ED₅₀. Similar developmental decreases in drug sensitivity (3–6 ×) were found following systemic (PO or IP) administration of haloperidol or the phenothiazine neuroleptic perphenazine, which differ markedly in structure, potency, distribution, and metabolism. Age-related decreases in drug sensitivity (3–4 ×) were also found using intracerebroventricular (ICV) administration of both agents in an attempt to bypass potential pharmacokinetic influences. Since the age-dependent decrease in sensitivity to both neuroleptics was found during the rising phase of drug action (1st hour) and ranked: PO>IP>ICV, some change in absorption and distribution of both drugs may occur in addition to the apparently important maturational decrease in target-organ sensitivity indicated by the responses to direct ICV injection and by the similarity of results obtained with dissimilar agents.     

Maturation of Peyer's patch dendritic cells in vitro upon stimulation via cytokines or CD40 triggering

In mouse Peyer's patches (PP), dendritic cells (DC) are localized in T cell areas as NLDC145⁺ CD11c+ cells, and in the dome and corona region of the follicle as NLDC145? CD11c+ cells, respectively, suggesting the presence of two different DC populations with distinct roles in antigen uptake, processing, and presentation. However, it is not clear how this relates to DC maturation. In this report, we demonstrate that freshly-isolated CD11c+ DC have the properties of immature DC since they endocytose soluble antigens, phagocytose particulate material such as latex beads, synthetize major histocompatibility complex (MHC) class II and invariant chain, but, at the same time, display low stimulatory activity for resting T cells, as shown in mixed-lymphocyte reaction and oxidative mitogenesis assays. When cultured for 24 h in the presence of the cytokines granulocyte-macrophage colony-stimulating factor and tumor necrosis factor or anti-CD40, the cells undergo dramatic phenotypic and functional changes characteristic of DC maturation. After 24 h stimulation in vitro, CD11c+ cells lose the ability to take up proteins such as ovalbumin, and in parallel with this decline, the biosynthesis of MHC class II and invariant chain is dramatically down-regulated or eliminated. On the other hand cells treated in vitro exhibit on the cell surface higher levels of MHC class II, of co-stimulatory molecules (CD80, CD86), of adhesion molecules (CD44, intercellular adhesion molecule-1), and acquire expression of the interdigitating DC surface marker NLDC145. Concomitantly, the ability to stimulate naive T cells drastically increased after in vitro treatment with both stimuli. Taken together, our results indicate that the majority of DC in the PP are immature in terms of their antigen-uptake capacity. These sentinel antigen presenting cells are strategically positioned at the dome region of PP, where antigens are transcytosed via the M cells from the gut lumen. A second population of mature interdigitating NLDC145⁺ CD11c+ DC stimulates naive unprimed T cells in interfollicular areas by up-regulation of surface ligands and accessory signals.     

Maturation of Startle Modulation

This study of the maturation of prestimulation-induced modulation of startle in 3 to 8 year old children and adults demonstrated significant effects of age on both startle magnitude and onset latency. Startle was evoked by 104dB(SPL) 50-ms bursts of white noise, and the amplitude and onset latency of the blink reflex were measured after integration of the obicularis oculi EMG. Prestimulation with 75dB 1000 Hz tones resulted in severe inhibition of both amplitude and latency in adults when 20-ms tones preceded the startling stimuli by 120 ms or 250 ms. Following sustained prestimulation for 2000 ms, the adults showed modest nonsignificant response facilitation. Eight-year-old children showed mature inhibitory and facilitatory startle amplitude modulation, but significantly less inhibition and more facilitation of onset latency compared to adults. Preschool children showed significantly less amplitude and latency inhibition and more facilitation than 8-year-olds and adults. In response to prestimulation 120 ms before startling stimuli, the preschool children actually showed latency facilitation. Modulation of startle by prestimulation is mediated by brainstem neuronal networks. These findings suggest that brainstem mechanisms which mediate startle response modulation undergo development during early childhood and do not mature until about 8 years of age.     

IL-21 induces both rapid maturation of human CD34+ cell precursors towards NK cells and acquisition of surface killer Ig-like receptors

The NK cell maturation from CD34(+) Lin(-) hematopoietic cell precursors is a complex process that requires the direct contact with stromal cells and/or the synergistic effect of different cytokines. In this study we show that IL-21 is capable of inducing an accelerated NK cell maturation when added to cultures of CD34(+) Lin(-) cells isolated from human cord blood supplemented with IL-15, Flt3-L and SCF. After 25 days of culture, 50% of CD56(+) cells expressed various NK cell markers including the NKp46 and NKp30 triggering receptors, the CD94/NKG2A inhibitory receptor and CD16. At day 35, substantial fractions of NK cells expressed KIR, CD8 and CD2, i.e. surface markers expressed by mature NK cells, that are virtually undetectable in developing NK cells cultured in the absence of IL-21. Remarkably, similar to mature NK cells all these markers were included in the CD56(dim) cell fraction, while the CD56(bright) population was only composed of CD94/NKG2A(-) and CD94/NKG2A(+) cells. Thus, IL-21 allows the induction of a full NK cell maturation in vitro and offers an important tool for dissecting the molecular mechanisms involved in different steps of NK cell maturation and in the acquisition of a mature KIR repertoire.     

Methods and considerations for longitudinal structural brain imaging analysis across development

Magnetic resonance imaging (MRI) has allowed the unprecedented capability to measure the human brain in vivo. This technique has paved the way for longitudinal studies exploring brain changes across the entire life span. Results from these studies have given us a glimpse into the remarkably extended and multifaceted development of our brain, converging with evidence from anatomical and histological studies. Ever-evolving techniques and analytical methods provide new avenues to explore and questions to consider, requiring researchers to balance excitement with caution. This review addresses what MRI studies of structural brain development in children and adolescents typically measure and how. We focus on measurements of brain morphometry (e.g., volume, cortical thickness, surface area, folding patterns), as well as measurements derived from diffusion tensor imaging (DTI). By integrating finding from multiple longitudinal investigations, we give an update on current knowledge of structural brain development and how it relates to other aspects of biological development and possible underlying physiological mechanisms. Further, we review and discuss current strategies in image processing, analysis techniques and modeling of brain development. We hope this review will aid current and future longitudinal investigations of brain development, as well as evoke a discussion amongst researchers regarding best practices.     

Age-Related Morphological Changes in Auditory Middle-Latency Response

Age-related changes in the waveforms of the middle latency response (MLR) were investigated in 9 adults and 28 children aged between 4 and 14 years. The children were classified into three groups according to their age. For obtaining characteristic configurations in the responses for each group, composite group averaging was performed by sum-mating the individual recordings in each group. With high-pass digital filtering at 20 Hz, composite MLR for adults showed a well-defined Na-Pa-Nb-Pb complex with peak latencies at about 17, 30, 45 and 63 ms, respectively. The composite response for children aged 4-7 years was characterized by a broad positive deflection (Pa) followed by a negative peak (Nb) at about 40 and 60 ms after stimulus onset, respectively. The peak latency of Pa was close to the adult value in the composite MLR for subjects aged 8-11 years, while the complete adult pattern in the later part of the response was not reached even in the composite response for subjects aged 12-14 years.     

Physical development in children and adolescents with bronchial asthma

Bronchial asthma is the most common chronic disease in children of developmental age. Data from the auxological literature indicate that children with disturbances in growth may also suffer from atopic disorders. The aim of the present study was to evaluate somatic growth in children with bronchial asthma using anthropological methods. The study was carried out using anthropometric measurements and information on the severity and course of the disease on 261 children with bronchial asthma. Mean body height was lower than in healthy peers and about 5% of subjects were short. Mean BMI and skinfold thicknesses were significantly higher and lean body mass was lower in the study group. Seventeen percent of the children were overweight or obese, and 8% were underweight. Body build was more robust in the girls examined. Longitudinal studies will help determine to what degree the disease itself directly affects physical development, and to what degree treatment does.