Self-regulation of response patterning: implications for psychophysiological research and therapy

This paper develops the basic premise that learning to self-regulate a pattern of responses can have different consequences from those observed when controlling individual functions alone. It is suggested that the self-regulation of patterns of responses can be a particularly sensitive and effective procedure for (a) uncovering biological linkages and constraints between responses in the intact human, (b) investigating how multiphysiological systems combine to produce unique subjective experiences and effects on performance, and (c) enhancing the clinical effectiveness of biofeedback procedures by training patients to integrate and coordinate voluntarily specific patterns of cognitive, autonomic, and motor responses. These hypotheses are illustrated by basic research involving biofeedback training for patterns of blood pressure, heart rate and EEG activity, related experiments on the cognitive self-regulation of patterns of physiological responses using affective imagery and meditation procedures, and case studies of patients treated with biofeedback. The concept of electronic biofeedback as an "unnatural act" is presented with the goal of placing self-regulation within a more biobehavioral perspective emphasizing the natural patterning of physiological processes.     

Vertebrate gastrulation and axial patterning: editorial overview, Part 2

Three rats were trained with an oddball paradigm, in which 5 kHz frequent and 10 kHz target rare tones were presented with a probability of 0.8 and 0.2. Pressing the lever within 2 s following the onset of the target tones was rewarded with a drop of food paste. Long latency event-related potentials (ERPs) corresponding to those in humans could be recorded in rats. After the administration of metamfetamine (0.2 mg/kg), the amplitude of surface and intracortical N1 increased, indicating an augmentation of the primary cortical response. Surface P3 showed a decrease of amplitude, accompanied by an increase of intracortical negativity. These alterations of ERPs may be caused by the dysregulation of central noradrenergic system.     

Glycogen synthase kinase-3 and dorsoventral patterning in Xenopus embryos

Glycogen synthase kinase 3 (GSK-3) is homologous to the product of the Drosophila gene shaggy (zeste-white 3), which is required for signalling by wingless during Drosophila development. To test whether GSK-3 is also involved in vertebrate pattern formation, its role was investigated during early Xenopus development. It was found that dominant-negative GSK-3 mutants induced dorsal differentiation, whereas wild-type GSK-3 induced ventralization. These results indicate that GSK-3 is required for ventral differentiation, and suggest that dorsal differentiation may involve the suppression of GSK-3 activity by a wingless/wnt-related signal.     

Lithium homeostasis in Xenopus oocytes: implications for the study of signal transduction

The Xenopus oocyte has been shown to be a useful model for the study of signal transduction pathways. The present study investigated whether or not the oocyte could be used to study the effects of lithium on signal transduction mechanisms by comparing the dynamics of lithium homeostasis in the oocyte and a human immortalized hippocampal cell line using Flame Atomic Emission Spectroscopy (FAES). A biphasic pattern of lithium uptake was observed in the oocyte in the presence of 5 mM extracellular lithium. The late phase of lithium uptake, which started after 30 minutes of incubation time, was sensitive to phloretin, an inhibitor of Na+/Li+ counter-transport. Differences in lithium efflux kinetics further characterized the two observed phases of accumulation and also suggested that lithium might be distributed in different pools within the oocyte, including one sequestered in organelles or associated with cytosolic proteins. An analogous sequestered pool was not, however, observed in the hippocampal cell line indicating that lithium is distributed differently in these cell types. This suggests that the Xenopus oocyte might not be a suitable model for evaluating the effects of lithium on signal transduction pathways because of the unknown contribution of the sequestered pool on predicting relevant physiological effects.     

Binuclear Drosophila oocytes: consequences and implications for dorsal-ventral patterning in oogenesis and embryogenesis

The position of the nucleus along the anterior rim of stage 8 Drosophila oocytes presages the dorsal side of the egg and the developing embryo. In this paper, we address the question of whether the oocyte has a previously determined dorsal side to which the nucleus is drawn, or whether nuclear position randomly determines the dorsal side. To do so, we have taken advantage of a genetic system in which Drosophila oocytes occasionally become binuclear. We find that (i) the two nuclei migrate independently to their respective positions on the anterior rim, sometimes selecting the same site, sometimes not, (ii) the two nuclei are equivalent in their ability to induce a dorsal-ventral pattern in the overlying follicular epithelium, and (iii) at any position around the anterior circumference of the egg chamber the follicle cell sheet is equally responsive to the Gurken signal associated with the oocyte nuclei. These results argue that the dorsal-ventral axis is determined arbitrarily by the randomly selected position of the nucleus on the anterior rim of the oocyte. Some of the binuclear eggs support embryonic development. However, despite the duplication of dorsal chorion structures, the majority of such embryos show normal dorsal-ventral patterning. Thus, processes exist in the ventral follicular epithelium or in the perivitelline space that compensate for the expansion of dorsal follicle cell fates and consequently allow the formation of a normal embryonic axis.     

Axial patterning in the leech: developmental mechanisms and evolutionary implications

The subcutaneous distribution and number of Pacinian corpuscles were studied in ten fresh cadaver hands. They were found to cluster close to nerves and vessels at the metacarpophalangeal joints and the proximal phalanx. The total mean number in the hand was 300 (192-424). The percentage of the total was 44 to 60% in the fingers, 23 to 48% in the metacarpophalangeal area and 8 to 18% in the thenar and hypothenar regions. Corpuscles in palmar skin overlying the distal phalanx were smaller than receptors in the metacarpophalangeal area. The lowest density of corpuscles was along the nerves and vessels of the middle phalanx.     

Bmp-4 acts as a morphogen in dorsoventral mesoderm patterning in Xenopus

The marginal zone is a ring of tissue that gives rise to a characteristic dorsoventral pattern of mesoderm in amphibian embryos. Bmp-4 is thought to play an important role in specifying ventral mesodermal fate. Here we show (1) that different doses of Bmp-4 are sufficient to pattern four distinct mesodermal cell types and to pattern gene expression in the early gastrula marginal zone into three domains, (2) that there is a graded requirement for a Bmp signal in mesodermal patterning, and (3) that Bmp-4 has long-range activity which can become graded in the marginal zone by the antagonizing action of noggin. The results argue that Bmp-4 acts as a morphogen in dorsoventral patterning of mesoderm.     

Conserved Sp?tzle/Toll signaling in dorsoventral patterning of Xenopus embryos

Three Cynomolgus monkeys (Macaca fascicularis) learned a flavour-visual conditional discrimination problem, in which one of two possible food items was presented at the beginning of each trial, and acted as an instruction cue to signal which of two visually distinct stimulus objects the animal must displace on that trial in order to obtain a further food reward. The task was learned first in light then in dark conditions. Following rhinal cortex ablation the animals were unable to use the flavour properties of the food items to guide visual choices, performing at close to chance levels. Postoperative performance on a food preference test showed that their problem in associating a flavour cue with a visual object in the conditional learning task also extended to aberrant choice of foods based on their visual appearance.     

Remodeling of chromatin loops does not account for specification of replication origins during Xenopus development

The right mammary gland of 12 lactating goats was inoculated intracisternally with 1 ml of Mycoplasma capricolum subsp. capripneumoniae (Mcc) containing 10(6) colony-forming units (CFU), while their left mammary halves received 1 ml of sterile PPLO broth only. Two goats served as uninfected controls. The clinical mastitis that developed in the infected mammary halves within 24 h was initially acute but became increasingly chronic by the end of the experiment at 24 days post inoculation (DPI). The disease was characterized by atrophy of the infected mammary halves, leading to marked agalactia and an increase in somatic cell counts, with a preponderance of neutrophils initially and lymphocytes later. The Mycoplasma was re-isolated from infected mammary secretions up to 16 DPI but not from blood. Histopathology revealed that the mastitis was acute and purulent initially, followed by infiltration of lymphonuclear cells and fibroplasia in the lymphomononuclear cells and fibroplasia in the interacinar tissue, and later by massive fibrosis. Immunohistology demonstrated the presence of Mycoplasma-like bodies localized mainly on the surface of acinar/duct epithelial cells. The studies showed that Mcc was highly pathogenic in the caprine mammary gland.     

Induction of blood cells in Xenopus embryo explants

A Xenopus-specific anti-leukocyte monoclonal antibody designated XL-2 was isolated and used to identify leukocytes in tailbud embryos and activin A-treated explants of blastula animal cap. XL-2 bound to a 135-kDa polypeptide in western blots of protein extracts from adult thymocytes, tailbud embryos, tadpoles, and explants. In cell suspensions, it immunostained the cell surface of all types of adult leukocytes including lymphocytes, monocyte/macrophages, thrombocytes, and granulocytes. At embryonic stage 24, immunocytochemistry revealed XL-2-positive leukocytes, the earliest time at which such cells have been recognized. Whole-mount staining of tailbud embryos and tadpoles showed a widely dispersed population of XL-2-reactive leukocytes, many of which had elongated shapes and ameboid pseudopodia. In activin A-treated animal caps, XL-2 recognized a subpopulation of cells within the lumen of the central fluid-filled cavity as well as cells in the interstitium of mesenchymal and mesothelial components of the explant. Together, activin A and human interleukin-11 induced 100% of explants to form lumenal blood cells. Compared to activin A alone, murine stem cell factor plus activin A significantly increased the numbers of XL-2-reactive leukocytes and erythrocytes. These results support the view that activin A induces leukocyte and erythrocyte progenitors during Xenopus embryogenesis.     

Emergence of new viral infections: implications for the blood supply

Sepsis and peritonitis remain a serious challenge for surgical patients, despite improvement in surgical therapy and intensive care and the introduction of new powerful antibiotics. Recent in vitro studies revealed the potential of certain antibiotics, e.g. penicillin-binding protein (PBP) 3-specific antibiotics, to cause antibiotic-induced endotoxin release. Other types of antibiotics, e.g., PBP 2-specific antibiotics, were associated with no or less endotoxin release. Further in vitro experiments and investigations in animals support the hypothesis of antibiotic-induced endotoxin release, but there is little clinical evidence. The clinical significance of endotoxin is subject of open dispute with many pro's and contra's. Endotoxin, although an important trigger, may not be the only factor to induce cytokine release, e.g., peptidoglycans were able to stimulate cells to release cytokines. Gram-positive pathogens have gained more importance in clinical sepsis and may not be sufficiently reflected in current clinical studies. The hypothesis that neutralization of endotoxin and pro-inflammatory cytokines is beneficial in sepsis was seriously challenged by the results of recent clinical and experimental studies. The better understanding of mechanisms in endotoxin-induced cell activation and cell, cell-receptor and soluble receptor interactions led to new treatment options. Recent reports on the complex pathogenesis of peritonitis and the detection of pathogen-related factors with intraperitoneal immune response may have implications on clinical studies investigating the potential of new compounds and the effect of antibiotics on endotoxin release. However, only few reports are available on the clinical significance of antibiotic-induced endotoxin release, and association of endotoxin release with pathogens, mortality or alteration of physiological parameters were not observed. With regard to the particulars of these studies, e.g., a small study population or low mortality rate, mortality may not be an ideal outcome parameter for these studies. There is clinical evidence for antibiotic-induced endotoxin release. However, the need for well-designed and performed studies using newly developed monitoring devices in intensive care therapy is obvious.     

The origins, benefits, harms, and implications of emergency medicine clinical policies

Emergency physicians desire to provide their patients with care that is of the highest quality and is cost effective. Any tool that promotes these aims is good and should be used. Clinical policies have been proposed as a new method of prompting physicians to provide better care. While there is no direct evidence that emergency medicine clinical policies improve care, there is indirect evidence that they may be useful. ACEP has initiated a process for the development and evaluation of selected clinical policies. We anxiously await information that sheds light on the value of policies in enhancing the clinical practice of emergency medicine.     

The relationship of lead in soil to lead in blood and implications for standard setting

As part of a soil lead regulation process, this review was conducted to determine the association between lead in soil and established human health effects of lead or validated biomarkers of lead exposure. We reviewed only studies where soil exposure could be distinguished from other sources of lead and whose design could reasonably be used to infer a causal relationship between soil lead and either biomarkers or health effects. No such studies of health effects were found. Studies describing a quantitative relationship between soil lead and blood lead did meet our criteria: 22 cross-sectional studies in areas with polluted soil; and three prospective studies of soil lead pollution abatement trials. The cross-sectional studies indicated that, compared to children exposed to soil lead levels of 100 ppm, those exposed to levels of 1000 ppm had mean blood lead concentrations 1.10-1.86 times higher and those exposed to soil lead levels of 2000 ppm had blood lead concentrations 1.13-2.25 times higher. The prospective studies showed effects within the ranges predicted by the cross-sectional studies. Differences in results between studies were surprisingly modest and likely explainable by random sampling error, different explanatory variables included in data analyses and differences in methods of measuring lead in environmental specimens.     

Estimation of axial blood velocity using the Doppler equation corrected for broadening

To estimate axial velocity for vessels that are so narrow that their width is comparable to the minimum length of the range cell, it has been customary to substitute the maximum Doppler frequency fmax into the classical Doppler equation [eqn (1)]. It was shown here that this ignores transit time broadening, which can lead to significant errors at large beam-to-flow angles. We use a relation [eqn (2)], which does take this broadening into account, and give in vivo experimental proof of this allows accurate estimation of the axial velocity even when the range cell extends across the whole vessel lumen. It may be concluded, therefore, that, by using the above procedure for taking transit time spectral broadening into account, more accurate velocity estimates can be obtained for laminar flow than is possible with the current method using the classical Doppler equation uncorrected for broadening.     

Mapping of the ligand-selective domain of the Xenopus laevis corticotropin-releasing factor receptor 1: implications for the ligand-binding site

The nonselective human corticotropin-releasing factor receptor 1 (hCRF-R1) and the ligand-selective Xenopus CRF-R1 (xCRF-R1) were compared. To understand the interactions of sauvagine and ovine CRF, both high-affinity ligands for hCRF-R1 but surprisingly weak ligands for xCRF-R1, chimeric receptors of hCRF-R1 and xCRF-R1 followed by double or multiple point mutations were constructed. Binding studies and cAMP assays demonstrated that the N-terminal domain exhibited the complete ligand selectivity of xCRF-R1. The important region was mapped between amino acids 70 and 89; replacement of amino acids Arg76, Asn81, Gly83, Leu88, and Ala89 in hCRF-R1 with the corresponding amino acids of xCRF-R1 (Gln76, Gly81, Val83, His88, and Leu89) resulted in a receptor that had approximately 30-fold higher affinity for human/rat CRF than for sauvagine. Mutagenesis of these amino acids in xCRF-R1 to the human sequence completely abolished the ligand selectivity of xCRF-R1. Mutagenesis of amino acids 88 and 89 in hCRF-R1 or xCRF-R1 had only a minor (approximately 2.5-fold) effect on the ligand selectivity of the mutant receptor. Substitution of Arg76, Asn81, and Gly83 in hCRF-R1 with the corresponding sequence of xCRF-R1 (Gln76, Gly81, and Val83) resulted in a receptor with approximately 11-fold higher affinity for human/rat CRF compared with ovine CRF or sauvagine. When only two of these three amino acids were mutated, no effect on the ligand selectivity was observed. On the basis of these data, it is suggested that amino acids 70-89 of CRF-R1 are important for the ligand binding site.