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Behavioral evidence for a cholinoceptive pontine inhibitory area: descending control of spinal motor output and sensory input.

Earlier studies have shown that microinjection of the cholinergic agonist carbamylcholine (carbachol) into the rostral pontine tegmentum of the cat elicits postural atonia. However, conflicting reports exist regarding other concomitant behavioral changes. The present study has demonstrated that a variety of functions supporting animals' responsiveness to external stimuli including postural somatomotor, sympathetic visceromotor and nociceptive somatosensory functions are differentially affected depending upon the injection sites. Sites associated with maximal effects on each of these functions are clustered in the dorsal pontine tegmentum, i.e. cholinoceptive pontine inhibitory area (CPIA). In a medial area of CPIA, which corresponds to an area caudal to the ventral tegmental nucleus of Gudden and ventromedial to the principal nucleus of locus coeruleus, postural somatomotor and sympathetic visceromotor functions were maximally suppressed. In a laterally adjacent area ventral to the principal nucleus of locus coeruleus, somatomotor function was predominantly suppressed. Nociceptive somatosensory function was primarily suppressed following microinjections into a more lateral area surrounding the lateral half of the brachium conjunctivum. Several lines of evidence suggest that each of these phenomena ultimately involves descending influences on the spinal motor output and/or sensory input. There was no correlation between maximal suppression of these spinal cord functions and signs of desynchronized sleep such as rapid eye movement. Carbachol microinjection into wide areas of CPIA also suppressed orienting behaviors. Taken together, these data suggest that CPIA is a system which primarily regulates animals' responsiveness to external stimuli, in part by influencing segmentally organized behaviors.

Animals↗

Mass casualty management of a large-scale bioterrorist event: an epidemiological approach that shapes triage decisions.

The threat of a BT event has catalyzed serious reflection on the troublesome issues that come with event management and triage. Such reflection has had the effect of multiplying the efforts to find solutions to what could become a catastrophic public health disaster. Management options are becoming more robust, as are reliable detection devices and rapid access to stockpiled antibiotics and vaccines. There is much to be done, however, especially in the organizing, warehousing, and granting/exercising authority for resource allocations. The introduction of these new options should encourage one to believe that, in time, evolving standards of care will make it possible to rethink the currently unthinkable consequences. Unfortunately the cost of such preparedness is high and out of reach of most governments. Most of the developing world has neither the will nor the means to plan for BT events and remains overwhelmed with basic public health concerns (i.e., water, food, sanitation, shelter) that must take priority. Therefore, developed countries will be expected to respond using international exogenous resources to mitigate the effects of such a disaster. As a result, the state capacity of the effected government will be severely compromised. If triage and management of casualties is further compromised, terrorists will have met their goals. One could argue that health sciences will continue for decades to play catch up with the advanced technology driving potential bioagent weaponry. If one lesson was learned from the review of the former Soviet Union's biological weapons program, it is that the unthinkable remains an option to terrorists who have comparable expertise. It is crucial to develop realistic strategies for a BT event. Triage planning (the process of establishing criteria for health care prioritization) permits society to see cases in the context of diverse moral perspectives, limited resources, and compelling health care demands. This includes a competent and compassionate management and triage system and an in-depth and accurate health information system that appropriately addresses every level of threat or consequence. In a PICE stage I to III BT event resources will be compromised. Triage and management will be one process requiring multiple levels of cooperation, coordination, and decision-making. An immediate challenge to existing emergency medical services systems (EMSS) is the recognition that locally there will be a shift of emphasis and decision-making from prehospital first responders to community public health authorities. The author suggests that a working relationship, in most areas, between EMSS and the public health system is lacking. As priorities shift in a BT event to hospitals and public health care systems, they need to: 1. Improve their capabilities and capacities in surveillance, discovery, and in the consequences of different triage and management decisions and interventions in a BT environment, starting at the local level. 2. Develop triage and management systems (with clear lines of authority) based on public health and epidemiologic requirements, capability, and capacity (triage teams, categories, tags, rapid response, established operational priorities, resource-driven responsible management process), and link local level surveillance systems with those at the national or regional level. 3. Use a triage and management system that reflects the population (cohort) at risk, such as the epidemiologic based SEIRV triage framework. 4. Develop an organizational capacity that uses lateral decision-making skills, pre-hospital outpatient centers for triage-specific treatments, health information systems, and resource-driven hospital level pre-designated protocols appropriate for a surge of unprecedented proportions. Such standards of care, it is recommended, should be set at the local to federal levels and spelled out in existing incident-management system protocols.

Bioterrorism↗

Interactions of surfactant protein A with pathogens.

The lung is an organ with a large inner surface that is continuously in contact with the environment. Infection of this organ is prevented by several mechanisms. A recently described defence system is collectin-mediated innate immunity of the lung. Collectins are multimeric proteins characterized by carbohydrate recognition domains bound to collagen stalks. Surfactant protein (SP)-A and SP-D are collectins that are present in the epithelial lining fluid of the lung. SP-A interacts with viruses, bacteria and fungi. Furthermore, SP-A binds to various other inhaled glycoconjugates. SP-A receptors on phagocytic cells have been described that are important to ensure rapid pathogen clearance. This innate defence system of the lung may be particularly important during infections in young children when the acquired immune system has not yet become fully established. Also in later life SP-A could be very important to prevent the lungs from infections by pathogens not previously encountered. In addition, SP-A may limit the inflammatory response in the lungs, thus preventing damage to the delicate lung epithelia. Recently, evidence was presented that SP-A may modulate the allergic response to various glycosylated inhaled antigens. The presence of SP-A (and SP-D) in other organs indicates that these collectins may have a general role in mucosal immunity. In this review the interactions of SP-A with a variety of pathogens and its implications are discussed.

Bacteria↗

Induction of fascin spikes in breast cancer cells by activation of the insulin-like growth factor-I receptor.

Insulin-like growth factor-I receptor (IGF-IR) signaling contributes to the formation of mammary carcinomas and has chiefly been studied with regard to the proliferative and anti-apoptotic effects of IGF-IR signaling. However, IGF-IR activation also affects the actin cytoskeleton and alterations in cell migratory behavior are of known importance for the malignant conversion and metastasis of epithelial cells. The actin-binding protein fascin is found in cell projections and spikes that are involved in the locomotion of mesenchymal cells. Fascin expression is typically low in normal epithelial cells, but is markedly upregulated in several types of carcinomas. Here, we also demonstrate increased fascin expression in breast carcinoma cell lines and adopt MCF-7 human mammary carcinoma cells that over-express wild-type or kinase-inactivated forms of the IGF-IR as a model system to test the hypothesis that IGF-IR activation induces fascin projections. We show that the time-dependent dissociation of cell colonies that occurs upon receptor activation by IGF-I involves the formation of dynamic, fascin-containing lateral cell projections that co-localize with ruffling membranes in association with protrusive activity and cell migratory phenotype. The molecular mechanism of these effects is completely dependent on IGF-IR tyrosine kinase activity and is mediated by a phosphatidylinositol (PI) 3-kinase-dependent process. In demonstrating transduction of fascin spike assembly by activation of a peptide growth factor receptor, these novel data reveal a wide role for fascin spikes in cell motility and provide new insight into the complex effects of IGF-IR signaling on actin cytoskeletal organization.

Actins↗

Engineering autoactivating forms of matrix metalloproteinase-9 and expression of the active enzyme in cultured cells and transgenic mouse brain.

Matrix metalloproteinases (MMPs) are hypothesized to play an important role in the pathogenesis of several central nervous system disorders. Increased levels of expression of MMP-9 (gelatinase B) and MMP-2 (gelatinase A) have been observed in Alzheimer's disease, stroke, multiple sclerosis, and amyotrophic lateral sclerosis. This suggests an aberrant regulation of MMPs that could lead to inappropriate expression of MMP activity. To allow us to evaluate the effect of increased levels of active MMP-9 in the central nervous system, mutant forms of the enzyme were designed to autocatalytically remove the pro domain, yielding active enzyme. This was accomplished by modifying residues in the cysteine switch autoinhibitor region of the propeptide. Stable cell lines and transgenic mice that express G100L and D103N autoactive forms of human MMP-9 were developed to study the role of dysregulation of MMP-9 in disease.

Amino Acid Sequence↗

A dominant-negative mutant of the platelet-derived growth factor A-chain increases survival of hamsters implanted intracerebrally with the highly invasive CxT24-neo3 glioblastoma cell.

Evidence is accumulating to suggest a role for PDGF in stimulating malignant growth in astrocytoma, although it has been obtained using model systems (growth in 2-dimensional cell culture, athymic nude mice) that do not assess the complex interactions of these tumors with normal brain tissue. In the current study, the highly invasive hamster glioblastoma cell line CxT24-neo3 was used as a model to study the role of platelet-derived growth factor (PDGF) in mediating malignant growth both in vitro and in vivo when implanted directly into the right lateral ventricle of the brain. Co-expression of PDGF B-chain mRNA and PDGF alpha-receptors was detected in these cells, indicating potential for autocrine activation of their growth. CxT24-neo3 cells transfected with wild-type and receptor binding-deficient forms of the PDGF A- and B-chains displayed alterations in their abilities to grow as three-dimensional spheroids, with overexpression of wild-type B-chain resulting in increased spheroid formation, but a decreased rate of spheroid growth. Influence of these PDGF polypeptides on tumor invasion and survival time in vivo was evaluated following implantation of these spheroids in the brain. While all hamsters implanted with control spheroids died within 21 d (average 17 d), those implanted with cells expressing the receptor binding-deficient A-chain survived for much greater periods of time (average 80 d). Modest increases in survival were also seen in cells stably expressing wild-type A-chain (25 d) and mutant B-chain (26 d) proteins. The present study suggests an important role of PDGF in mediating the malignant growth of the CxT24-neo3 cell line in cerebral cortex, possibly via paracrine interactions with normal cortical cell types (i.e., glia, neurons).

Animals↗

Difference between visual feedback and visual suppression upon the stabilization of body sway in normal subjects.

We developed a system to feedback the center of foot pressure by vision using a microcomputer. The subjects were instructed to adjust the center of foot pressure (displayed on the computer display at real time) to the point of intersection of the two stable (horizontal and vertical) lines on the computer display. The peak of the power spectra of body sway shifted significantly to the higher frequency range in the Y component (the lateral direction) in the visual feedback condition. Thus, we conclude that the visual feedback of body sway depends mainly on the error signals between the fovea and the image in the lateral direction to stabilize body sway.

Adult↗

The origin of cortical neurons.

Neurons of the mammalian cerebral cortex comprise two broad classes: pyramidal neurons, which project to distant targets, and the inhibitory nonpyramidal cells, the cortical interneurons. Pyramidal neurons are generated in the germinal ventricular zone, which lines the lateral ventricles, and migrate along the processes of radial glial cells to their positions in the developing cortex in an 'inside-out' sequence. The GABA-containing nonpyramidal cells originate for the most part in the ganglionic eminence, the primordium of the basal ganglia in the ventral telencephalon. These cells follow tangential migratory routes to enter the cortex and are in close association with the corticofugal axonal system. Once they enter the cortex, they move towards the ventricular zone, possibly to obtain positional information, before they migrate radially in the direction of the pial surface to take up their positions in the developing cortex. The mechanisms that guide interneurons throughout these long and complex migratory routes are currently under investigation.

Animals↗

Levocetirizine: a review of its use in the management of allergic rhinitis and skin allergies.

Levocetirizine (Xyzal) is a selective, potent, oral histamine H(1) receptor antagonist of the latest generation that is licensed for the symptomatic treatment of allergic rhinitis (including persistent allergic rhinitis [PER]) and chronic idiopathic urticaria (CIU). Large, well designed trials indicate that levocetirizine is effective and generally well tolerated in the treatment of allergic rhinitis and CIU. Its pharmacological profile offers many positive aspects: a rapid onset and long duration of antihistaminic effect; rapid absorption and high bioavailability; a low potential for drug interactions; a low volume of distribution; and a lack of effect on cognition, psychomotor function and the cardiovascular system. Allergen challenge chamber studies suggest that levocetirizine has better efficacy than desloratadine, loratadine or fexofenadine. Well controlled, long-term studies with other later-generation H(1) receptor antagonists are required to fully define its clinical profile relative to other agents in this class. Overall, levocetirizine is a valuable addition to the oral H(1) receptor antagonists available for the treatment of allergic rhinitis and as first-line therapy in patients with CIU.

Cetirizine↗

A turn-key transportable eye-tracking instrument for clinical assessment.

This paper describes a combined instrument (eye tracker and target generator, both head mounted, with integrated data analysis) that tests parameters of saccadic eye movement and fixation control to give insight into the status of functional brain systems. Using three minilasers, the target generato rprojects three visual stimuli, a fixation point and two lateral stimuli, with programmable timing. The controller allows the selection of overlap, 200-msec gap, or remembered saccade trials. Size, maximal velocity, and reaction time are determined for each primary saccade. The number of prosaccades and antisaccades are counted. More saccades--for example, the occurrence and latency of corrective saccades--may be evaluated off line by an interactive PC analysis program. The eye position data can be transferred to a PC. Off-line analysis compares each observed variable relative to an age-matched control group (300 healthy control subjects 7-70 years of age, tested in the overlap condition with prosaccade instructions and in the gap condition with antisaccades). The diagnostic results can be used to elaborate an individual optomotor training program.

Fixation, Ocular↗

Strategies toward maximum detergent efficiency.

Detergent Z demonstrated the most reliable cleaning and detergent delivery system. After the initial detergent evaluation, the data were compared against all detergents. It was found that acceptably cleaned items ranged from 37% to 85% per evaluation. Labor and material costs could be reduced greatly with the use of detergent Z, which had the best cleaning results. We also observed the advantage of a sensor in the detergent delivery system which can override some less obvious equipment malfunctions. Since detergent Z also exhibited the least amount of residue build-up, a savings in maintenance costs could be expected later on. The vendor of detergent Z showed great interest and concern for our department's needs and quality assurance by offering us numerous technical resources during the evaluation. One year following our detergent studies, detergent Z and its related line of cleaning products are being utilized in our hospital. We found that the four months spent analyzing detergents used in our utensil washers provided an interesting resource project that has been a positive investment in improved operations for the decontamination area. In Central Service alone, 61.7 hours a week were saved by the change in products. Quality of cleaning continues to be high. The practice of a weekly acid bath for the utensil washers has been discontinued; the acid bath will now be given when necessary, and has not been done since detergent Z was put into use six months ago. During the next fiscal year, savings of detergent, utilities and labor are conservatively projected at $30,000.

Central Supply, Hospital↗

Intraventricular 5,7-dihydroxytryptamine lesions disrupt acquisition of working memory task rules but not performance once learned.

The serotonergic system is implicated in learning and memory and its disorder, e.g. after 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") abuse. This study examined the effects of widespread depletion of serotonin (5-HT) using intraventricular injection of 5,7-dihydroxytryptamine (5,7-DHT) on the learning of a working memory task in the dark agouti (DA) rat. The lesion impaired acquisition but not later performance of a nonspatial working memory rule, as measured using nonmatch to sample object recognition in the Y-maze. The lesion had a marginal effect on choice completion times over the course of testing. However, nonspecific effects did not provide a good account of the reduction in choice accuracy as this persisted when completion times were taken into account statistically. Similarly, in a second experiment, the same lesioned rats were slowed in the acquisition of spatial alternation in the T-maze. However, in the open field, there were no comparably long-lasting effects of the serotonergic depletion on line crossings and defecation, only a transient reduction in activity on the first day.Together, these data suggest that the serotonergic system is important in the acquisition of working memory tasks in the rat and that this outcome was unlikely to be the result of nonspecific effects of the lesion.

5,7-Dihydroxytryptamine↗

NOVOcan: a molecular link among selected glial cells.

The nervous system is generated from cells lining the ventricular system. Our understanding of the fate potentials and lineage relationships of these cells is being re-evaluated, both because of recent demonstrations that radial glia can generate neurons and because of the identification of fate-determining genes. A variety of intrinsic and extrinsic molecules, including proteoglycans, regulate embryonic and postnatal brain development. Using probes modeled after species conserved domains of heparan sulfate proteoglycans, we cloned a novel gene called novocan, raised monoclonal antibodies against a segment of the predicted amino acid sequence of the expressed protein (NOVOcan) and used the antibodies to establish the cell and tissue localization of NOVOcan in postnatal rat brains by immunohistochemistry. NOVOcan was expressed in cells lining the ventricles, including a variety of radial glia during early postnatal development. Later, as radial glia disappeared and ependymal cells appeared, NOVOcan was detected in ependymal cells and in tanycytes, a specialized form of ependymal cell resembling radial glia. NOVOcan was absent in two known progeny of radial glia, mature astrocytes and neurons. Whereas NOVOcan was also absent in mature oligodendrocytes (OLGs), it was present in OLG precursors in developing white matter. These studies set the stage for determining the roles of NOVOcan in brain cell lineage patterns as well as in other aspects of development.

Adult↗

The Drosophila zygotic lethal gene shuttle craft is required maternally for proper embryonic development.

The Drosophila gene shuttle craft (stc) is expressed zygotically in the embryonic central nervous system (CNS) where it is required to maintain the proper morphology of motoneuronal axon nerve routes following their migration from the ventral cord. Here, we report that a prominent maternal source of STC protein is also present throughout both oogenesis and embryogenesis. To determine whether this maternal component is required in the ovary and/or embryo, we used the Drosophila autosomal dominant female sterile technique to generate germ-line clones that lacked the stc maternal function. Our results demonstrate that a maternally derived source of STC protein is required during embryogenesis but not oogenesis. In contrast to the zygotic phenotype, the primary defect in embryos derived from stc germ-line clones affects segmentation by causing disruptions and deletions in distinct thoracic (T1-T3) and abdominal (A4-A8) segments. These localized defects are responsible for additional phenotypes observed later in development which include gaps in the ventral nerve cord and deletions of denticle belts in the cuticle. An additional phenotype occurring in all other neuromeric segments consists of the misguided migration of motoneuronal axons as they project out of the ventral nerve cord. Thus, the stc zygotic function is required later in development and cannot correct the segmentation and subsequent CNS abnormalities associated with loss of its earlier acting maternally derived activity.

Animals↗

Loop-diuretic inhibition of adrenaline-stimulated Cl- secretion in a cultured epithelium of renal origin (MDCK).

Loop diuretics (furosemide, bumetanide, piretanide) inhibit the adrenaline-stimulated short-circuit current due to transepithelial Cl- secretion in cultured renal epithelial layers (MDCK). The inhibition of Cl- secretion by loop diuretics is consistent with the presence of basal-lateral 'cotransport' since inhibition is observed only with the basal applications of loop diuretics, is of high potency (half-maximal bumetanide inhibition being observed at 0.8 microM, bumetanide being more potent than furosemide) and is without effect upon the adrenaline-stimulated increase in tissue conductance. Loop diuretics are also shown to inhibit a component of K+ efflux across the basal-lateral surfaces. Cellular uptake of [3H]bumetanide across both apical and basal surfaces of intact epithelial layers was measured in order to localize the cotransport system. A component of cellular [3H]bumetanide uptake sensitive to competition by 0.1 mM unlabelled loop diuretic is only observed from the basal-lateral cell surfaces. There is no evidence for transepithelial bumetanide secretion as is seen in renal cortex.

Animals↗

Lymphatic and blood vasculature of the forming corpus luteum.

The process of lymphatic vascularization of the corpus luteum was examined during luteinization following the first and second ovulations in young rats. In the corpus luteum formed after the first ovulation, blood vessels permeate the luteal parenchyma which at this stage shows laminar organization. Thereafter, a nest of connective tissue appears in the central portion of the corpus luteum. At this time lymphatics are not found. Luteinization following the second ovulation is similar to that of the first generation until the later stages when lymphatic vessels start to appear initially in the peripheral zone of the corpus luteum and subsequently in the central connective tissue nest. These lymphatic vessels are lined with endothelial cells that stain darkly with toluidine dye.

Animals↗

Visuospatial neglect in near and far space: dissociation between line bisection and letter cancellation.

The differential performance on a line bisection and a cancellation task in near and far space was studied. A group of 10 patients with severe left-sided visuospatial neglect and a group of 10 right-brain damaged patients without neglect were examined. The stimuli were presented at a distance of 60 cm (near space) and 160 cm (far space), respectively, and corrected for visual angle. In the line bisection task, patients were asked to point to the estimated line centre with a pencil (near space) or a stick (far space). In the cancellation task, patients pointed to all target stimuli they could detect using either a pencil (near space) or a stick (far space). Most patients with left hemineglect showed a more prominent neglect in far space as compared to near space for the line bisection task, whereas no difference of performance between near and far space was found in the control patients. In contrast, no group showed a distance effect in the cancellation task. The observation that only line bisection is influenced by the distance of the stimulus suggests that line bisection and cancellation are processed differentially. It is proposed that line bisection requires an allocentric reference system focusing attention on objects, whereas cancellation tasks are based on an egocentric reference system responsible for visuospatial attention. Our results indicate that distance changes perception within the allocentric but not within the egocentric system.

Adult↗

Descending noradrenergic influences on pain.

Multiple separate and distinct supraspinally organized descending inhibitory systems have been identified which are capable of powerfully modulating spinal nociceptive transmission. Until recently, brainstem sites known to be involved in the centrifugal modulation of spinal nociceptive transmission were few in number, being limited to midline structures in the midbrain and medulla (e.g., periaqueductal gray and nucleus raphe magnus). However, with continued investigation, that number has increased and brainstem sites previously thought to be primarily involved in cardiovascular function and autonomic regulation (e.g., nucleus tractus solitarius; locus coeruleus/subcoeruleus (LC/SC); A5 cell group; lateral reticular nucleus) also have been demonstrated to play a role in the modulation of spinal nociceptive transmission. Spinal monoamines (norepinephrine (NE) and serotonin) have been shown to mediate stimulation-produced descending inhibition of nociceptive transmission from these brainstem sites. The majority of NE-containing fibers and terminations in the spinal cord arise from supraspinal sources; thus, the LC/SC, the parabrachial nuclei, the Kölliker-Fuse nucleus and the A5 cell group have all been suggested as possible sources of the spinal noradrenergic (NA) innervation involved in the centrifugal modulation of spinal nociceptive transmission. Several lines of evidence suggest that the LC/SC plays a significant role in a functionally important descending inhibitory NA system. Focal electrical stimulation in the LC produces an antinociception and increases significantly the spinal content of NA metabolites. The inhibition of the nociceptive tail-flick withdrawal reflex produced by electrical stimulation in the LC/SC has been demonstrated to be mediated by postsynaptic alpha 2-adrenoceptors in the lumbar spinal cord. Similarly, electrical or chemical stimulation given in the LC/SC inhibits noxious-evoked dorsal horn neuronal activity. Thus, results reported in electrophysiological experiments confirm those reported in functional studies and the NA coeruleospinal system appears to play a significant role in spinal nociceptive processing.

Adrenergic Fibers↗