Search

We report the first result of a direct search for a cosmic axion background (CaB)-a relativistic background of axions that is not dark matter-performed with the axion haloscope, the Axion Dark Matter eXperiment (ADMX). Conventional haloscope analyses search for a signal with a narrow bandwidth, as predicted for dark matter, whereas the CaB will be broad. We introduce a novel analysis strategy, which searches for a CaB induced daily modulation in the power measured by the haloscope. Using this, we repurpose data collected to search for dark matter to set a limit on the axion photon coupling of a CaB originating from dark matter cascade decay via a mediator in the 800-995 MHz frequency range. We find that the present sensitivity is limited by fluctuations in the cavity readout as the instrument scans across dark matter masses. Nevertheless, we suggest that these challenges can be surmounted using superconducting qubits as single photon counters, and allow ADMX to operate as a telescope searching for axions emerging from the decay of dark matter. The daily modulation analysis technique we introduce can be deployed for various broadband rf signals, such as other forms of a CaB or even high-frequency gravitational waves.

The article presents results from a clinical trial conducted by the American Red Cross that examined the screening of donated blood for Chagas disease, a zoonotic disease caused by the parasite Trypanosoma cruzi. The Red Cross study found that some donations tested positive for Trypanosoma cruzi. The Chagas disease screening test was developed by Ortho-Clinical Diagnostics. It is an enzyme-linked immunosorbent assay that uses epimastigote lysate antigens to detect Trypanosoma cruzi antibodies in serum and plasma.

We describe the first implementation of a Josephson Traveling Wave Parametric Amplifier (JTWPA) in an axion dark matter search. The operation of the JTWPA for a period of about two weeks achieved sensitivity to axion-like particle dark matter with axion-photon couplings above 10-13 Ge V-1 over a narrow range of axion masses centered around 19.84 µeV by tuning the resonant frequency of the cavity over the frequency range of 4796.7-4799.5 MHz. The JTWPA was operated in the insert of the axion dark matter experiment as part of an independent receiver chain that was attached to a 0.56-l cavity. The ability of the JTWPA to deliver high gain over a wide (3 GHz) bandwidth has engendered interest from those aiming to perform broadband axion searches, a longstanding goal in this field., (© 2023 Author(s). Published under an exclusive license by AIP Publishing.)

Axion dark matter experiment ultra-low noise haloscope technology has enabled the successful completion of two science runs (1A and 1B) that looked for dark matter axions in the 2.66-3.1 μeV mass range with Dine-Fischler-Srednicki-Zhitnisky sensitivity [Du et al., Phys. Rev. Lett. 120, 151301 (2018) and Braine et al., Phys. Rev. Lett. 124, 101303 (2020)]. Therefore, it is the most sensitive axion search experiment to date in this mass range. We discuss the technological advances made in the last several years to achieve this sensitivity, which includes the implementation of components, such as the state-of-the-art quantum-noise-limited amplifiers and a dilution refrigerator. Furthermore, we demonstrate the use of a frequency tunable microstrip superconducting quantum interference device amplifier in run 1A, and a Josephson parametric amplifier in run 1B, along with novel analysis tools that characterize the system noise temperature.

This Letter reports on a cavity haloscope search for dark matter axions in the Galactic halo in the mass range 2.81-3.31  μeV. This search utilizes the combination of a low-noise Josephson parametric amplifier and a large-cavity haloscope to achieve unprecedented sensitivity across this mass range. This search excludes the full range of axion-photon coupling values predicted in benchmark models of the invisible axion that solve the strong CP problem of quantum chromodynamics.

Background: Physician-assisted suicide (PAS) is a controversial practice, currently legal in nine states and the District of Columbia. No prior study explores the views of the American Geriatrics Society (AGS) membership on PAS., Design: We surveyed 1488 randomly selected AGS members via email., Participants: A total of 369 AGS members completed the survey (24.8% response rate)., Analysis: We conducted bivariate correlation analyses of beliefs related to support for PAS. We also conducted qualitative analysis of open-ended responses., Results: There was no consensus regarding the acceptability of PAS, with 47% supporting and 52% opposing this practice. PAS being legal in the respondent's state, belief that respect for autonomy alone is sufficient to justify PAS, and intent to prescribe or support requests for PAS if legal in state of practice all correlated with support for PAS. There was no consensus on whether the AGS should oppose, support, or adopt a neutral stance on PAS. Most respondents believed that PAS is more complex among patients with low health literacy, low English proficiency, disability, dependency, or frailty. Most respondents supported mandatory palliative care consultation and independent assessments from two physicians. Themes identified from qualitative analysis include role of the medical profession, uncertainty of the role of professional organizations, potential unintended consequences, autonomy, and ethical and moral considerations., Conclusion: There was no consensus among respondents regarding the acceptability of PAS. Respondents expressed concern about vulnerable older populations and the need for safeguards when responding to requests for PAS. Ethical, legal, and policy discussions regarding PAS should consider vulnerable populations. J Am Geriatr Soc 68:23-30, 2019., (© 2019 The American Geriatrics Society.)

The μeV axion is a well-motivated extension to the standard model. The Axion Dark Matter eXperiment (ADMX) collaboration seeks to discover this particle by looking for the resonant conversion of dark-matter axions to microwave photons in a strong magnetic field. In this Letter, we report results from a pathfinder experiment, the ADMX "Sidecar," which is designed to pave the way for future, higher mass, searches. This testbed experiment lives inside of and operates in tandem with the main ADMX experiment. The Sidecar experiment excludes masses in three widely spaced frequency ranges (4202-4249, 5086-5799, and 7173-7203 MHz). In addition, Sidecar demonstrates the successful use of a piezoelectric actuator for cavity tuning. Finally, this publication is the first to report data measured using both the TM_{010} and TM_{020} modes.

This Letter reports the results from a haloscope search for dark matter axions with masses between 2.66 and 2.81  μeV. The search excludes the range of axion-photon couplings predicted by plausible models of the invisible axion. This unprecedented sensitivity is achieved by operating a large-volume haloscope at subkelvin temperatures, thereby reducing thermal noise as well as the excess noise from the ultralow-noise superconducting quantum interference device amplifier used for the signal power readout. Ongoing searches will provide nearly definitive tests of the invisible axion model over a wide range of axion masses.

In the late 20th century, cosmology became a precision science. Now, at the beginning of the next century, the parameters describing how our universe evolved from the Big Bang are generally known to a few percent. One key parameter is the total mass density of the universe. Normal matter constitutes only a small fraction of the total mass density. Observations suggest this additional mass, the dark matter, is cold (that is, moving nonrelativistically in the early universe) and interacts feebly if at all with normal matter and radiation. There's no known such elementary particle, so the strong presumption is the dark matter consists of particle relics of a new kind left over from the Big Bang. One of the most important questions in science is the nature of this dark matter. One attractive particle dark-matter candidate is the axion. The axion is a hypothetical elementary particle arising in a simple and elegant extension to the standard model of particle physics that nulls otherwise observable CP-violating effects (where CP is the product of charge reversal C and parity inversion P) in quantum chromo dynamics (QCD). A light axion of mass 10(-(6-3)) eV (the invisible axion) would couple extraordinarily weakly to normal matter and radiation and would therefore be extremely difficult to detect in the laboratory. However, such an axion is a compelling dark-matter candidate and is therefore a target of a number of searches. Compared with other particle dark-matter candidates, the plausible range of axion dark-matter couplings and masses is narrowly constrained. This focused search range allows for definitive searches, where a nonobservation would seriously impugn the dark-matter QCD-axion hypothesis. Axion searches use a wide range of technologies, and the experiment sensitivities are now reaching likely dark-matter axion couplings and masses. This article is a selective overview of the current generation of sensitive axion searches. Not all techniques and experiments are discussed, but I hope to give a sense of the current experimental landscape of the search for dark-matter axions.

It has been understood since 1897 that accelerating charges must emit electromagnetic radiation. Although first derived in 1904, cyclotron radiation from a single electron orbiting in a magnetic field has never been observed directly. We demonstrate single-electron detection in a novel radio-frequency spectrometer. The relativistic shift in the cyclotron frequency permits a precise electron energy measurement. Precise beta electron spectroscopy from gaseous radiation sources is a key technique in modern efforts to measure the neutrino mass via the tritium decay end point, and this work demonstrates a fundamentally new approach to precision beta spectroscopy for future neutrino mass experiments.

Hidden U(1) gauge symmetries are common to many extensions of the standard model proposed to explain dark matter. The hidden gauge vector bosons of such extensions may mix kinetically with standard model photons, providing a means for electromagnetic power to pass through conducting barriers. The axion dark matter experiment detector was used to search for hidden vector bosons originating in an emitter cavity driven with microwave power. We exclude hidden vector bosons with kinetic couplings χ>3.48×10⁻⁸ for masses less than 3  μeV. This limit represents an improvement of more than 2 orders of magnitude in sensitivity relative to previous cavity experiments.

Scalar fields with a "chameleon" property, in which the effective particle mass is a function of its local environment, are common to many theories beyond the standard model and could be responsible for dark energy. If these fields couple weakly to the photon, they could be detectable through the afterglow effect of photon-chameleon-photon transitions. The ADMX experiment was used in the first chameleon search with a microwave cavity to set a new limit on scalar chameleon-photon coupling βγ excluding values between 2×10(9) and 5×10(14) for effective chameleon masses between 1.9510 and 1.9525  μeV.

Axions in the microeV mass range are a plausible cold dark-matter candidate and may be detected by their conversion into microwave photons in a resonant cavity immersed in a static magnetic field. We report the first result from such an axion search using a superconducting first-stage amplifier (SQUID) replacing a conventional GaAs field-effect transistor amplifier. This experiment excludes KSVZ dark-matter axions with masses between 3.3 microeV and 3.53 microeV and sets the stage for a definitive axion search utilizing near quantum-limited SQUID amplifiers.

Purpose: In older adults detrusor overactivity (DO) is almost as common in continent individuals as in those with urge incontinence (UUI). Thus, UUI likely reflects the contribution of additional factors. We postulated that of functionally independent individuals in whom transient causes were excluded those in whom DO was accompanied by UUI would be more likely to have smaller functional bladder capacity, less warning and less ability to avert urine loss in the face of DO., Materials and Methods: While blinded to continence status, we reviewed the records of all 52 cognitively intact and nonobstructed volunteers older than 65 years who had DO associated with urgency during urodynamic testing and had been asked to try to prevent leakage for 2 minutes. Of these individuals 31 were continent at home., Results: In patients with UI mean functional bladder capacity +/- SD was smaller (313 +/- 153 vs 390 +/- 178 ml, p = 0.06) and warning was briefer (87 +/- 81 vs 120 +/- 116 ml), although the association with warning was less impressive (p = 0.14). The ability to forestall leakage for at least 2 minutes correlated strongly with being continent at home (p < 0.002). For continence detrusor suppression at the onset of DO was more important than sphincter contraction., Conclusions: Urge incontinence in older adults involves more than simply the presence of DO. Physical function, cognitive function and medications are already known to be important for continence. Our data suggest that functional bladder capacity and the ability to suppress involuntary contraction (and possibly warning) are also potentially important covariates. These factors may represent additional potential targets for behavioral and pharmacological therapy.

Theoretical arguments predict that the distribution of cold dark matter in spiral galaxies has peaks in velocity space associated with nonthermalized flows of dark matter particles. We searched for the corresponding peaks in the spectrum of microwave photons from axion to photon conversion in a cavity detector for dark matter axions. We found none and place limits on the density of any local flow of axions as a function of the flow velocity dispersion over the axion mass range 1.98 to 2.17 microeV.

Spinal cord injury (SCI) involves the loss of neurons and glia due to initial mechanical and secondary biochemical mechanisms. Treatment with the sodium channel blocker tetrodotoxin (TTX) reduces acute white matter pathology and increases both axon density and hindlimb function chronically at 6 weeks after injury. We investigated the cellular composition of residual white matter chronically to determine whether TTX also has a significant effect on the numbers and types of cells present. Rats received an incomplete thoracic contusion injury, in the presence or absence of TTX (0.15 nmole) injected focally, beginning at 15 min prior to injury. Six weeks later, cell density was significantly increased in the residual white matter of the dorsal, lateral, and ventral funiculi, both rostral and caudal to the injury site in both TTX-treated and injury control groups. Oligodendrocyte and astrocyte density was similar to normal but large numbers of cells expressing microglia/macrophage markers were present. Labeling with the progenitor markers nestin and NG2 showed that precursor cell density had also doubled or tripled as compared with uninjured controls. Some of these cells were also labeled for antigens that indicate their possible progression along an oligodendrocyte or astrocyte lineage. Our results support the hypothesis that the beneficial effect of TTX in SCI is related to its preservation of axons per se; no effect on chronic white matter cell composition was detected. They highlight the profound changes in cellular composition in preserved white matter chronically at 6 weeks after injury, including the accumulation of endogenous progenitor cells and the persistence of activated macrophages/microglia. The manipulation of these endogenous cells may be used in the future to enhance recovery after SCI., (copyright (c) 2004 Wiley-Liss, Inc.)

Focal injection of the sodium channel blocker tetrodotoxin (TTX) into the injury site at either 5 or 15 min after a standardized thoracic contusion spinal cord injury (SCI) reduces white matter pathology and loss of axons in the first 24 hr after injury. Focal injection of TTX at 15 min after SCI also reduces chronic white matter loss and hindlimb functional deficits. We have now tested the hypothesis that the reduction in chronic deficits with TTX treatment is associated with long-term preservation of axons after SCI and compared both acute (24 hr) and chronic (6 weeks) effects of TTX administered at 15 min prior to and 5 min or 4 hr after SCI. Our results indicate a significant reduction of acute white matter pathology in rats treated with TTX at 15 min before and 5 min after injury but no effect when treatment was delayed until 4 hr after contusion. Compared with injury controls, groups treated with TTX at 5 min and 4 hr after injury did not show a significant deficit reduction, nor was there a significant sparing of white matter at 6 weeks compared with injury controls. In contrast, the group treated with TTX at 15 min before SCI demonstrated significantly reduced hindlimb functional deficits beginning at 1 week after injury and throughout the 6 weeks of the study. This was associated with a significantly higher axon density in the ventromedial white matter at 6 weeks. The results demonstrate that blockade of sodium channels preserves axons from loss after SCI and points to the importance of time of administration of such drugs for therapeutic effectiveness., (Copyright 2001 Wiley-Liss, Inc.)

Alterations in the expression of ionotropic glutamate receptors (GluR) contribute to neuronal loss after brain ischemia and epilepsy. In order to determine whether altered expression of GluR subunits might contribute to cell loss after spinal cord injury (SCI), we performed a time course study of subunit mRNA expression using quantitative in situ hybridization. Expression was studied in ventral horn motor neurons (VMN) and glia in adjacent ventral white matter at 15 min and 4, 8, and 24 h after SCI in tissue sections 4 mm rostral and caudal to the injury epicenter. We found that the AMPA subunit GluR2 was significantly down-regulated in VMN at 24 h, but not at the earlier times examined, although half the loss of VMN in these locations occurs by 8 h after injury. No changes in the normal expression of GluR2 or GluR4 were found in white matter where glial loss occurs after SCI. NMDA subunits NR1 and NR2A were significantly and rapidly up-regulated in VMN after SCI, but only caudal to the lesion site, while VMN loss is similar rostral and caudal to the epicenter. Thus, the temporal pattern of AMPA and the spatial pattern of NMDA subunit expression changes were distinct from the pattern of VMN loss after SCI. We conclude that altered GluR subunit expression after SCI is unlikely to be involved in secondary cell loss and instead may be involved with plasticity and reorganization of the injured spinal cord.

The secondary loss of neurons and glia over the first 24 h after spinal cord injury (SCI) contributes to the permanent functional deficits that are the unfortunate consequence of SCI. The progression of this acute secondary cell death in specific neuronal and glial populations has not previously been investigated in a quantitative manner. We used a well-characterized model of SCI to analyze the loss of ventral motoneurons (VMN) and ventral funicular astrocytes and oligodendrocytes at 15 min and 4, 8, and 24 h after an incomplete midthoracic contusion injury in the rat. We found that both the length of lesion and the length of spinal cord devoid of VMN increased in a time-dependent manner. The extent of VMN loss at specified distances rostral and caudal to the injury epicenter progressed symmetrically with time. Neuronal loss was accompanied by a loss of glial cells in ventral white matter that was significant at the epicenter by 4 h after injury. Oligodendrocyte loss followed the same temporal pattern as that of VMN while astrocyte loss was delayed. This information on the temporal-spatial pattern of cell loss can be used to investigate mechanisms involved in secondary injury of neurons and glia after SCI.

An in vitro investigation was undertaken to study the roles of Na+ and Cl- in mammalian spinal cord (SC) neuron deterioration and death after injury involving physical disruption of the plasma membrane. Individual SC neurons in monolayer cultures were subjected to UV laser microbeam transection of a primary dendrite. Neurons lesioned in modified ionic environments (MIEs) where 50%-75% of the NaCl was replaced with sucrose had higher survival (65%-75%) than neurons lesioned in medium with normal (125 mM) NaCl (28%; p < 0.001). Subsequent experiments found a comparable increase in lesioned neuron survival in MIEs in which only Na+ was replaced with specific ionic substitutes; however, replacement of Cl- was not protective. Electron microscope examinations of neurons fixed <16 min after lesioning showed a dramatic decrease in vesiculation of the smooth endoplasmic reticulum and Golgi apparatus in the low NaCl or low Na+ MIEs. It is hypothesized that Na+ entry after membrane disruption may stimulate elevation of [Ca+2]i leading to ultrastructural disruption and death of injured neurons. The results of these studies suggest that a low NaCl MIE may be useful as an irrigant to limit damage spread and cell death within CNS tissues during surgery or after trauma.

Focal microinjection of tetrodotoxin (TTX), a potent voltage-gated sodium channel blocker, reduces neurological deficits and tissue loss after spinal cord injury (SCI). Significant sparing of white matter (WM) is seen at 8 weeks after injury and is correlated to a reduction in functional deficits. To determine whether TTX exerts an acute effect on WM pathology, Sprague Dawley rats were subjected to a standardized weight-drop contusion at T8 (10 gm x 2.5 cm). TTX (0. 15 nmol) or vehicle solution was injected into the injury site 5 or 15 min later. At 4 and 24 hr, ventromedial WM from the injury epicenter was compared by light and electron microscopy and immunohistochemistry. By 4 hr after SCI, axonal counts revealed reduced numbers of axons and significant loss of large (>/=5 micrometer)-diameter axons. TTX treatment significantly reduced the loss of large-diameter axons. In addition, TTX significantly attenuated axoplasmic pathology at both 4 and 24 hr after injury. In particular, the development of extensive periaxonal spaces in the large-diameter axons was reduced with TTX treatment. In contrast, there was no significant effect of TTX on the loss of WM glia after SCI. Thus, the long-term effects of TTX in reducing WM loss after spinal cord injury appear to be caused by the reduction of acute axonal pathology. These results support the hypothesis that TTX-sensitive sodium channels at axonal nodes of Ranvier play a significant role in the secondary injury of WM after SCI.

Focal microinjection of 2, 3-dihyro-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX), an antagonist of the AMPA/kainate subclass of glutamate receptors, reduces neurological deficits and tissue loss after spinal cord injury. Dose-dependent sparing of white matter is seen at 1 month after injury that is correlated to the dose-related reduction in chronic functional deficits. To determine whether NBQX exerts an acute effect on white matter pathology, female, adult Spague Dawley rats were subjected to a standardized weight drop contusion at T-8 (10 gm x 2.5 cm) and NBQX (15 nmol) or vehicle (VEH) solution focally injected into the injury site 15 min later. At 4 and 24 hr, tissue from the injury epicenter was processed for light and electron microscopy, and the histopathology of ventromedial white matter was compared. The axonal injury index, a quantitative representation of axoplasmic and myelinic pathologies, was significantly lower in the NBQX group at 4 hr (2.7 +/- 0.24, mean +/- SE) and 24 hr (1.4 +/- 0.19) than in VEH controls (3.8 +/- 0.33 and 2.1 +/- 0.20, respectively). Counts of glial cell nuclei indicated a loss of at least 60% at 4 and 24 hr after injury in the VEH group compared with uninjured controls. NBQX treatment reduced this glial loss by half. Immunohistochemistry revealed that the spared glia were primarily oligodendrocytes. Thus, the chronic effects of NBQX in reducing white matter loss after spinal cord injury appear to be attributable to the reduction of acute pathology and may be mediated through the protection of glia, particularly oligodendrocytes.

Dendrites were transected from murine spinal neurons. Unlesioned neurons showed dark nucleolar and patchy cytoplasmic jun immunostaining. By 0.5 and 2 h, most lesioned neurons stained intensely throughout the soma. However, at 24 h only dead neurons displayed intense somal staining, and 100% of the surviving cells stained like unlesioned controls. Correlation of immunostaining patterns with viability, injury, and death suggests jun gene expression may influence the survival of neurons after physical injury.

There is abundant evidence for large amounts of unseen matter in the universe. This dark matter, by its very nature, couples feebly to ordinary matter and is correspondingly difficult to detect. Nonetheless, several experiments are now underway with the sensitivity required to detect directly galactic halo dark matter through their interactions with matter and radiation. These experiments divide into two broad classes: searches for weakly interacting massive particles (WIMPs) and searches for axions. There exists a very strong theoretical bias for supposing that supersymmetry (SUSY) is a correct description of nature. WIMPs are predicted by this SUSY theory and have the required properties to be dark matter. These WIMPs are detected from the byproducts of their occasional recoil against nucleons. There are efforts around the world to detect these rare recoils. The WIMP part of this overview focuses on the cryogenic dark matter search (CDMS) underway in California. Axions, another favored dark matter candidate, are predicted to arise from a minimal extension of the standard model that explains the absence of the expected large CP violating effects in strong interactions. Axions can, in the presence of a large magnetic field, turn into microwave photons. It is the slight excess of photons above noise that signals the axion. Axion searches are underway in California and Japan. The axion part of this overview focuses on the California effort. Brevity does not allow me to discuss other WIMP and axion searches, likewise for accelerator and satellite based searches; I apologize for their omission.

Ciliary neurotrophic factor (CNTF) has been found to increase neuronal survival during development and after axotomy. The present study tested the effects of CNTF on lesioned and uninjured mouse spinal cord (SC) neurons grown in tissue culture. An initial toxicity study found that a 24-72 h exposure of SC cultures to concentrations of CNTF above 1000 ng/ml caused stress and death of unlesioned neurons and glia. Pre-selected SC neurons were then subjected to transection of a primary dendrite 100 microns from the edge of the perikaryon (approximately 50% average survival at 24 h). Application of CNTF at concentrations ranging from 0.5 to 1000 ng/ml immediately after lesioning had no statistically significant effects on SC neuron survival 24 h after dendrotomy. Separation of control (no CNTF) and CNTF-treated cells into groups of putative alpha-motor (multipolar with somal diameters > or = 25 microns) and non-alpha-motor neurons (< 25 microns somal diameters) also failed to reveal any significant differences in survival. The lack of protection by CNTF of lesioned SC neurons in mature (21-28 DIV) cultures may reflect a loss of sensitivity to CNTF that occurs with development. Alternatively, protection by CNTF may require co-factors or factors that are released from target or other cells after injury but that are not present in SC cultures.

The major sensorimotor deficits that result from traumatic spinal cord injury (SCI) are due to loss of axons in ascending and descending pathways of the white matter (WM). Experimental treatments administered after a standardized SCI can reduce WM loss and long-term functional deficits. Thus, a significant proportion of WM loss occurs secondary to the mechanical injury and may be a target for therapeutic intervention. Presently, we know little of how and when secondary injury mechanisms operate in the WM after SCI. We therefore used a standardized rat model of clinically relevant contusion injury to examine axonal pathology over the first 24 h by light and electron microscopy. Based on qualitative evaluation of tissue at 15 min, 4 h, and 24 h after a "mild" SCI produced with a weight-drop device (10 g x 2.5 cm), we selected areas from the ventromedial WM at the lesion epicenter for quantitative analyses. We compared axon number and the proportion of axons with various axoplasmic and myelin abnormalities over time after SCI, as well as the effect of axon size on degree of pathology and loss. We found by 4 h postinjury (pi) axonal pathology was more severe than at 15 min and that a significant loss of large diameter axons had occurred; no significant additional loss of axons was seen by 24 h pi. When we compared axonal pathology after a more severe contusion (10 g x 17.5 cm), we found a greater loss of axons at 4 h. In addition, a higher proportion of the remaining axons demonstrated pathological alterations. We developed a semi-quantitative Axonal Injury Index (AII) as an overall measure of axonal pathology that was sensitive to the effects of injury severity at 4 h pi. The AII has greater statistical power than our individual measures of axonal pathology. Our results suggest that it may be possible to use the AII at 4 h pi to assess effects of potential therapeutic agents on acute axonal pathology after SCI.

CARN 750 (injectable acemannan) is a polydispersed beta-(1,4)-linked acetylated mannan isolated from the Aloe barbadensis plant. It has multiple therapeutic properties including activity in wound repair and as a biological agent for the treatment of neoplasia in animals as well as the ability to activate macrophages. We report herein that CARN 750 directly or indirectly has significant hematoaugmenting properties. We observed that the subcutaneous administration of CARN 750 significantly increases splenic and peripheral blood cellularity, as well as hematopoietic progenitors in the spleen and bone marrow as determined by the interleukin-3-responsive colony-forming unit culture assay and the high-proliferative-potential colony-forming-cell (HPP-CFC) assay (a measure of primitive hematopoietic precursors) in myelosuppressed (7 Gy) C57BL/6 mice. The greatest hematopoietic effect was observed following sublethal irradiation in mice receiving 1 mg CARN 750/ animal, with less activity observed at higher or lower doses. Further, CARN 750, following daily injection, has activity equal to or greater than the injection of an optimal dose of granulocyte-colony-stimulating factor (G-CSF) in myelosuppressed mice. In this comparison, significantly greater activity was observed in the splenic and peripheral blood cellularity, and in the frequency and absolute number of splenic HPP-CFC as compared to the mice receiving G-CSF at 3 micrograms/animal. CARN 750, when administered to myelosuppressed animals, decreased the frequency of lymphocytes with a concomitant significant increase in the frequency of polymorphonuclear leukocytes (PMN). However, owing to the increased cellularity, a significant increase in the absolute number of PMN, lymphocytes, monocytes and platelets was observed, suggesting activity on multiple cell lineages. The latter is the primary difference in activity as compared to G-CSF which has activity predominantly on PMN.

Neurites were transected from spinal neurons in media with normal (125 microM) or reduced NaCl (sucrose substitution). After 12 h the normal ionic environment (conditioned medium with serum) was restored. A one-factor ANOVA comparison found a significant difference in 48 h survival (P = 0.0001). Survival was highest when NaCl was reduced 50% (74% +/- 19 vs. 22% +/- 19 in normal NaCl). Na(+)- and Cl-mediated deterioration may contribute to both gray and white matter injury in CNS trauma.

An in vitro investigation was undertaken to provide information regarding the effectiveness of methylprednisolone sodium succinate (MPSS) as a treatment for the primary mechanical injury of spinal cord (SC) trauma. Exposure of uninjured mouse SC cells to MPSS for 24 h caused neuronal stress when the concentration exceeded 150 micrograms/mL; neuronal death occurred at concentrations above 600 micrograms/mL. The concentration range for MPSS protection of SC neurons subjected to a defined physical injury (laser microbeam transection of a primary dendrite 100 microns from the perikaryon) was very narrow: survival in the 30 micrograms/mL group differed significantly from the untreated control group (68.5% +/- 14.1 vs. 47.1% +/- 14.1), treatment with 20 or 60 micrograms/mL MPSS did not increase survival, and treatment with 100 micrograms/mL MPSS accelerated ultrastructural deterioration and increased the likelihood of death. Enhanced survival of lesioned neurons was observed when 30 micrograms/mL MPSS was applied within 15 min of dendrotomy but not when MPSS was administered 2 h after lesioning. Multimicroelectrode plate (MMEP) studies of SC network electrical activity indicated that MPSS associated readily with neuronal membranes. This finding was consistent with the hypothesis that MPSS may protect lesioned neurons by stabilizing damaged membranes, enhancing lesion resealing, and limiting the spread of ion-mediated damage. However, comparisons of neurite die-back 24 h after dendrotomy found no significant difference between MPSS-treated and control neurons. Application of 30 or 100 micrograms/mL MPSS increased the spontaneous burst activity of SC networks grown on MMEPs, however, there was no evidence that the increased excitability at these concentrations was the result of specific actions of MPSS on GABA or NMDA synapses.

Several complex carbohydrates have been found to significantly stimulate hematopoiesis. CARN 750, a polydispersed beta-(1,4)-linked acetylated mannan isolated from the Aloe vera plant, has been shown to have activity in wound repair, to function as a antineoplastic, and to activate macrophages. We report, herein, the hematoaugmenting properties of CARN 750 and its optimal dose and timing of administration in an animal model of irradiation-induced myelosuppression. We observed that subcutaneous injections of 1 mg/animal of CARN 750 had equal or greater stimulatory activity for white blood cell (WBC) counts and spleen cellularity as well as on the absolute numbers of neutrophils, lymphocytes, monocytes and platelets than did higher or lower doses of CARN 750 or an optimal dose of granulocyte-colony stimulating factor (G-CSF). Hematopoietic progenitors, measured as interleukin-3-supported colony forming units-culture (CFU-C) and high proliferative potential colony-forming cells (HPP-CFC) assays, were similarly increased by CARN 750 in the spleen but not in the bone marrow. The frequency of splenic HPP-CFCs and absolute number of splenic HPP-CFCs and CFU-Cs were optimally increased by 1 mg/animal of CARN 750. In contrast, bone marrow cellularity, frequency and absolute number of HPP-CFCs and CFU-Cs had as a dosage optimum 2 mg/animal of CARN 750. These parameters were similarly increased by G-CSF. In studies to determine the optimal protocol for the administration of CARN 750 we found that the hematopoietic activity of CARN 750 increased with the frequency of administration. The greatest activity in myelosuppressed mice was observed for all hematopoietic parameters except the platelet number in mice receiving daily administration of 1 mg/animal of CARN 750 with activity equal to or greater than G-CSF.

Acemannan, a complex carbohydrate shown to stimulate interleukin-1, tumor necrosis factor alpha and prostaglandin E2 production by macrophages, has also demonstrated antiviral activity in vitro against human immunodeficiency virus, Newcastle disease virus and influenza virus. A pilot study was undertaken to determine acemannan's effect in 49 feline immunodeficiency virus (FIV) infected cats with clinical signs of disease (Stage 3, 4 or 5), 23 of which had severe lymphopenia. Cats received acemannan either by intravenous (Group 1) or subcutaneous (Group 2) injection once weekly for 12 weeks, or by daily oral (Group 3) administration for 12 weeks. Upon entry into the study, cats were randomly assigned to one of the three groups. Laboratory analyses were performed at the beginning of the study and at Weeks 6 and 12. Cats were allowed to continue with a predetermined maintenance regimen of acemannan after completing the 12-week study. Thirteen cats died during the course of treatment. Upon necropsy, the most frequent histopathologic findings were neoplastic, kidney and pancreatic disease. Friedman's two-way ANOVA test showed no significant differences in efficacy among groups administered acemannan by the different routes. Therefore, groups were combined and a signed-ranks test was used to determine changes over time. A significant increase was seen in lymphocyte counts (P < 0.001). Neutrophil counts decreased significantly (P = 0.007), as did incidence of sepsis (P = 0.008). When cats entering with lymphopenia were analyzed separately, a much greater increase in lymphocyte counts was noted (235%) compared with non-lymphopenic cats (42%). A survival rate of 75% was found for all three groups. Thirty-six of 49 animals are alive 5-19 months post-entry. These results suggest that acemannan therapy may be of significant benefit in FIV-infected cats exhibiting clinical signs of disease.