Neutrophilic myeloid-derived suppressor cells in cord blood modulate innate and adaptive immune responses.

Neonates show an impaired anti-microbial host defence, but the underlying immune mechanisms are not understood fully. Myeloid-derived suppressor cells (MDSCs) represent an innate immune cell subset characterized by their capacity to suppress T cell immunity. In this study we demonstrate that a distinct MDSC subset with a neutrophilic/granulocytic phenotype (Gr-MDSCs) is highly increased in cord blood compared to peripheral blood of children and adults. Functionally, cord blood isolated Gr-MDSCs suppressed T cell proliferation efficiently as well as T helper type 1 (Th1), Th2 and Th17 cytokine secretion. Beyond T cells, cord blood Gr-MDSCs controlled natural killer (NK) cell cytotoxicity in a cell contact-dependent manner. These studies establish neutrophilic Gr-MDSCs as a novel immunosuppressive cell subset that controls innate (NK) and adaptive (T cell) immune responses in neonates. Increased MDSC activity in cord blood might serve as key fetomaternal immunosuppressive mechanism impairing neonatal host defence. Gr-MDSCs in cord blood might therefore represent a therapeutic target in neonatal infections.

Saccades are spatially, not retinocentrically, coded.

Most models of the saccadic eye movement system imply that saccades are programmed for a certain distance and direction. Electrical stimulation of the brain was used to move the eyes of monkeys just before saccades to visual targets. Despite the stimulation-induced perturbation, saccades brought gaze to the target locations. This compensation indicates that saccades are coded to direct the eyes to a certain position in the orbit (or in space).

Neuronal circuitry controlling the near response.

Experiments in primates have contributed greatly to our understanding of the neural mechanisms involved in the eye movements required to view objects at different distances. Early work focused on the circuitry for generating horizontal vergence eye movements alone. However, vergence eye movements are associated with lens accommodation and are usually accompanied by saccadic eye movements, so more recent work has been directed at understanding the interactions between vergence and accommodation, and between vergence and saccades. A new model explains the neural basis for interactions between vergence and accommodation by a neural network in which pre-motor elements are shared by these two systems. The effects of saccades on vergence eye movements appear to be the result of shared pre-motor circuits as well. Current evidence suggests that pontine omnipause neurons, known to be crucial for the generation of saccades, play an important role in the vergence pre-motor circuitry.

Radiofrequency dosimetry for the Ferris-wheel mouse exposure system.

Numerical and experimental methods were employed to assess the individual and collective dosimetry of mice used in a bioassay on the exposure to pulsed radiofrequency energy at 900 MHz in the Ferris-wheel exposure system (Utteridge et al., Radiat. Res. 158, 357-364, 2002). Twin-well calorimetry was employed to measure the whole-body specific absorption rate (SAR) of mice for three body masses (23 g, 32 g and 36 g) to determine the lifetime exposure history of the mice used in the bioassay. Calorimetric measurements showed about 95% exposure efficiency and lifetime average whole-body SARs of 0.21, 0.86, 1.7 and 3.4 W kg(-1) for the four exposure groups. A larger statistical variation in SAR was observed in the smallest mice because they had the largest variation in posture inside the plastic restrainers. Infrared thermography provided SAR distributions over the sagittal plane of mouse cadavers. Thermograms typically showed SAR peaks in the abdomen, neck and head. The peak local SAR at these locations, determined by thermometric measurements, showed peak-to-average SAR ratios below 6:1, with typical values around 3:1. Results indicate that the Ferris wheel fulfills the requirement of providing a robust exposure setup, allowing uniform collective lifetime exposure of mice.

Purkinje cell activity in rats following chronic treatment with harmaline.

Harmaline and related alkaloids produce a fine, generalized motor tremor with a frequency of 8-14 Hz in many mammalian species. The tremor is though to be initiated by the synchronous activation of cells in the inferior olive. Repeated administration of the drug at tremorogenic doses results in the rapid development of tolerance in the rat. Since the generation of cerebellar cyclic 3',5'-guanosine monophosphate by harmaline or apomorphine is reduced in harmaline-tolerant rats, it is possible that the site of tolerance is the olivocerebellar system. The present study used extracellular single unit recording techniques to determine whether harmaline tolerance was associated with changes in the firing patterns of Purkinje cells in the cerebellar vermis of the rat. In non-tolerant animals, the majority (8/13) of Purkinje cells recorded in the vermis responded to harmaline with a rhythmic increase in complex spike rate and a prolonged suppression of simple spikes. In harmaline-tolerant animals, only one cell in 14 could be identified that showed this response. In these animals, a variety of responses not encountered in experimentally naive animals were observed. Since the complex spike activity of Purkinje cells is presumed to reflect the activity of climbing fibers originating in the cells of the inferior olive, the results of the studies reported here support the conclusion that a reduction in the synchronous activation of cells at the olivocerebellar level blocks the appearance of tremor in harmaline-tolerant animals.

Multisite, double-blind, placebo-controlled trial of porcine secretin in autism.

OBJECTIVE: To examine the efficacy of intravenous porcine secretin for the treatment of autistic disorder. METHOD: Randomized, double-blind, placebo-controlled, crossover design. Fifty-six subjects with autistic disorder received either a secretin or placebo infusion at baseline and the other substance at week 4. Subjects were given the Autism Diagnostic Observation Schedule (ADOS) and other pertinent developmental measures at baseline and at weeks 4 and 8 to assess drug effects. RESULTS: For the primary efficacy analysis, change of ADOS social-communication total score from week 0 to week 4, no statistically significant difference was obtained between placebo (-0.8 +/- 2.9) and secretin groups (-0.6 +/- 1.4; t54 = 0.346, p < .73). The other measures showed no treatment effect for secretin compared with placebo. CONCLUSION: There was no evidence for efficacy of secretin in this randomized, placebo-controlled, double-blind trial.

Movement fields of saccade-related burst neurons in the monkey superior colliculus.

The presaccadic burst of superior colliculus (SC) neurons was examined in detail to determine whether or not information concerning the vector components (amplitude and direction) of a saccade is contained within the burst. Results indicate that the pattern of spike activity originating from a single saccade-related burst neuron in the SC does not encode saccade direction or amplitude. Identical discharges may precede a wide range of saccades. Neither the magnitude, configuration nor timing of the discharge are related in any unique way to the duration of the saccade alone or the amplitude of the saccade alone. Furthermore, it is unlikely that information concerning saccade amplitude or direction is encoded by different types of signals originating from different SC neurons. For different neurons, there is no consistent relationship between the parameters of the burst and the optimal saccade amplitude or direction. It is suggested that the discharge of saccade-related burst neurons of the SC serves as a trigger input to pontine circuitry generating the required saccadic burst signals. Information concerning saccade direction and amplitude is not contained within the trigger signal, but must be extracted from the spatial distribution of SC activity.

Serotonergic modulation of eye blinks in cat and monkey.

Serotonergic modulation of spontaneous and reflexive blinking was studied in four cats and one monkey. In cats, facial nucleus injections of the type-2 serotonin receptor (5-HT2) antagonist ketanserin tended to increase the latency of the first (R1) and second (R2) components of the blink reflex to supraorbital nerve stimulation. Injections of serotonin tended to increase and of ketanserin, to decrease the duration and amplitude of R2. Serotonin also produced unilateral blepharospasm and hemifacial spasm. In the monkey, the 5-HT2 agonist 2,5-dimethoxy-4-iodoamphetamine increased spontaneous blink frequency while ketanserin decreased both peak blink velocity and spontaneous blink frequency. These findings in cat and monkey indicate that serotonergic innervation of the facial nucleus has a behaviorally important role in modulation of spontaneous and reflexive blinks and suggest that dysfunction of serotonergic systems could be important to the pathophysiology of some cases of blepharospasm.

Neuropharmacological correlates of the motor syndrome of the genetically dystonic (dt) rat.

The research program described here has focused primarily on identifying sites of dysfunction in the central nervous system of rat mutants described as dystonic. The evidence strongly favors the position that there is a defect in the cerebellum of the dt rat. At present it seems reasonable to propose as a working hypothesis that there is a defect in the Purkinje cells that renders these neurons less sensitive to the excitatory neurotransmitters released by the climbing and parallel fibers. The finding that an abnormality in GAD activity in the deep cerebellar nuclei is relatively localized when first detected but spreads over time as the motor syndrome intensifies may indicate that there is a progressive decline in the function of the Purkinje cells. The fact that electrophysiological techniques detect a mixture of relatively normal and abnormal Purkinje cell activity in animals with advanced symptoms is consistent with such a proposal. Finding significant abnormalities in the cerebellum of the dt rat does not necessarily mean that this is the site of the primary defect responsible for the motor syndrome seen in these animals. We have failed to detect any signs of dysfunction in the basal ganglia, the presumed locus of a defect in human torsion dystonia. However, our investigations have been limited almost exclusively to the striatum. Thus, the possibility of defects at other sites, such as the globus pallidus or thalamus must be considered. Although we have not yet demonstrated that the abnormalities detected in the cerebellum are causally related to the behavior of the dt rat, the behavioral syndrome is consistent with a cerebellar defect. It has been suggested that the cerebellum is important for the continuing calibration of coordinated motor behavior. Important observations on the effects of cerebellar lesions have come from the study of the oculomotor system. Lesions in the cerebellum have been shown to eliminate the ability to recalibrate the saccadic eye movement system and to destroy the adaptive plasticity of the vestibulo-ocular reflex A cerebellar defect could result in a failure in motor learning or in the calibration of motor systems that must take place as the rat pup masters adult patterns of locomotion. We note that lesions of the climbing fiber system with 3-AP lead to some of the same biochemical effects seen in dt rats but do not produce an identical behavioral syndrome.(ABSTRACT TRUNCATED AT 400 WORDS)

Synchronous independent lung ventilation.

Ventilated patients with unilateral lung disease present a unique challenge because each lung requires independent FiO2, PEEP, and mode settings. With early implementation of Synchronous Independent Lung Ventilation, each lung is treated individually and chances for survival may increase. Critical care nurses face new challenges in assessing and preventing complications for these patients.

Waiting list statistics as performance indicators: observations on their use in hospital management.

Improvements in data collection and the types of statistics collected have enhanced the usefulness of waiting list statistics as a measure of hospital performance. But these changes are not sufficient for waiting list statistics to be used effectively for management purposes. The statistics need to be viewed alongside activity data if clinicians and managers are to identify specific areas that need improvement. This means that how the data are analysed and presented is also important. During a study into the management of waiting lists, we observed that waiting list data were typically presented in a way that made interpretation difficult. A simple but effective solution was found by using available PC-based software, but obstacles remain. These stem from limitations of current information systems and the awareness among staff of the potential of common software packages.

Quantitative evaluations of mechanisms of radiofrequency interactions with biological molecules and processes.

The complexity of interactions of electromagnetic fields up to 10(12) Hz with the ions, atoms, and molecules of biological systems has given rise to a large number of established and proposed biophysical mechanisms applicable over a wide range of time and distance scales, field amplitudes, frequencies, and waveforms. This review focuses on the physical principles that guide quantitative assessment of mechanisms applicable for exposures at or below the level of endogenous electric fields associated with development, wound healing, and excitation of muscles and the nervous system (generally, 1 to 10(2) V m(-1)), with emphasis on conditions where temperature increases are insignificant (<<1 K). Experiment and theory demonstrate possible demodulation at membrane barriers for frequencies < or =10 MHz, but not at higher frequencies. Although signal levels somewhat below system noise can be detected, signal-to-noise ratios substantially less than 0.1 cannot be overcome by cooperativity, signal averaging, coherent detection, or by nonlinear dynamical systems. Sensory systems and possible effects on biological magnetite suggest paradigms for extreme sensitivity at lower frequencies, but there are no known radiofrequency (RF) analogues. At the molecular level, vibrational modes are so overdamped by water molecules that excitation of molecular modes below the far infrared cannot occur. Two RF mechanisms plausibly may affect biological matter under common exposure conditions. For frequencies below approximately 150 MHz, shifts in the rate of chemical reactions can be mediated by radical pairs and, at all frequencies, dielectric and resistive heating can raise temperature and increase the entropy of the affected biological system.

Saccade-vergence interactions in macaques. II. Vergence enhancement as the product of a local feedback vergence motor error and a weighted saccadic burst.

In the accompanying paper we reported that intrasaccadic vergence enhancement during combined saccade-vergence eye movements reflects saccadic dynamics, which implies the involvement of saccadic burst signals. This involvement was not predicted by the Multiply Model of Zee et al. We propose a model wherein vergence enhancement is the result of a multiplicative interaction between a weighted saccadic burst signal and a nonvisual short-latency estimate of the vergence motor error at the time of the saccade. The enhancement of vergence velocity by saccades causes the vergence goal to be approached more rapidly than if no saccade had occurred. The adjustment of the postsaccadic vergence velocity to this faster reduction in vergence motor error occurred with a time course too fast for visual feedback. This implies the presence of an internal estimate of the progress of the movement and indicates that vergence responses are under the control of a local feedback mechanism. It also implies that the vergence enhancement signal is included in the vergence feedback loop and is an integral part of the vergence velocity command. Our multiplicative model is able to predict the peak velocity of the vergence enhancement as a function of cyclopean saccadic dynamics, smooth vergence dynamics, and saccade-vergence timing with remarkable precision. It performed equally well for both horizontal and vertical saccades with very similar parameters, suggesting a common mechanism for all saccadic directions. A saccade-vergence additive model is also presented, although it would require external switching elements. Possible neural implementations are discussed.