Uptake and use of recommendations for the diagnosis, severity scoring and management of chronic GVHD: an international survey of the EBMT-NCI Chronic GVHD Task Force.

In 2005, the National Institutes of Health (NIH) consensus conference published a series of papers recommending methods to improve the conduct of clinical trials in chronic GVHD. Although the NIH recommendations were primarily aimed at strengthening research, several papers addressed issues relevant for clinical practice, particularly diagnosis, severity scoring, and ancillary and supportive care practices. We conducted an international survey to assess the uptake of these recommendations, identify barriers to greater use and document the use and perceived effectiveness of available treatments. The response rate for the American survey of 1387 practitioners was 21.8%, and it was 24.6% for 407 centers surveyed in Europe, Asia, Australia and Africa. Most respondents were familiar with the NIH consensus recommendations (94-96%) and used them in practice. Multiple barriers to greater use were reported. Besides lack of time (55-62%), unfamiliarity with the recommendations, scarcity of evidence supporting the impact of recommendations on outcomes, insufficient training/experience in chronic GVHD management and inaccessibility of subspecialists were also endorsed. Systemic corticosteroids were reported to be the most effective treatment for chronic GVHD, but many others were perceived to have moderate or great success. Therapeutic management of steroid-refractory chronic GVHD was identified as the highest priority for research.

Cognitive deficits induced by 56Fe radiation exposure.

Exposing rats to particles of high energy and charge (e.g., 56Fe) disrupts neuronal systems and the behaviors mediated by them; these adverse behavioral and neuronal effects are similar to those seen in aged animals. Because cognition declines with age, and our previous study showed that radiation disrupted Morris water maze spatial learning and memory performance, the present study used an 8-arm radial maze (RAM) to further test the cognitive behavioral consequences of radiation exposure. Control rats or rats exposed to whole-body irradiation with 1.0 Gy of 1 GeV/n high-energy 56Fe particles (delivered at the alternating gradient synchrotron at Brookhaven National Laboratory) were tested nine months following exposure. Radiation adversely affected RAM performance, and the changes seen parallel those of aging. Irradiated animals entered baited arms during the first 4 choices significantly less than did controls, produced their first error sooner, and also tended to make more errors as measured by re-entries into non-baited arms. These results show that irradiation with high-energy particles produces age-like decrements in cognitive behavior that may impair the ability of astronauts to perform critical tasks during long-term space travel beyond the magnetosphere.

Brain signaling and behavioral responses induced by exposure to (56)Fe-particle radiation.

Previous experiments have demonstrated that exposure to 56Fe-particle irradiation (1.5 Gy, 1 GeV) produced aging-like accelerations in neuronal and behavioral deficits. Astronauts on long-term space flights will be exposed to similar heavy-particle radiations that might have similar deleterious effects on neuronal signaling and cognitive behavior. Therefore, the present study evaluated whether radiation-induced spatial learning and memory behavioral deficits are associated with region-specific brain signaling deficits by measuring signaling molecules previously found to be essential for behavior [pre-synaptic vesicle proteins, synaptobrevin and synaptophysin, and protein kinases, calcium-dependent PRKCs (also known as PKCs) and PRKA (PRKA RIIbeta)]. The results demonstrated a significant radiation-induced increase in reference memory errors. The increases in reference memory errors were significantly negatively correlated with striatal synaptobrevin and frontal cortical synaptophysin expression. Both synaptophysin and synaptobrevin are synaptic vesicle proteins that are important in cognition. Striatal PRKA, a memory signaling molecule, was also significantly negatively correlated with reference memory errors. Overall, our findings suggest that radiation-induced pre-synaptic facilitation may contribute to some previously reported radiation-induced decrease in striatal dopamine release and for the disruption of the central dopaminergic system integrity and dopamine-mediated behavior.

Identification of delta- and mu-type opioid receptors on human and murine dendritic cells.

The purpose of this study was to evaluate mu- and delta-opioid receptors (OR) on human and murine dendritic cells (DC). Expression of mu- and delta-OR mRNA on DC was demonstrated by RT-PCR. The immunocytochemical and Western blot analyses revealed the expression of OR protein in DC. Radioreceptor assay demonstrated the specific saturated temperature-dependent binding of [3H]-labeled opioid ligand on DC and B(max)=2.8+/-0.3 fmol/10(6) cells and K(D)=4.8+/-1.0 nM were calculated by a Scatchard analysis. Finally, OR ligands DADLE and DAGO dose-dependently modulated the capacity of DC to induce T cell proliferation in an MLR assay. Importantly, expression of functional OR on DC was significantly increased upon TNF-alpha-induced DC maturation. Thus, these data suggest a new mechanism of opioid-dependent neuroendocrine immunomodulation.

Role of locus coeruleus in foot shock-evoked Fos expression in rat brain.

The robust activation of locus coeruleus neurons in response to a variety of stressors, in conjunction with the widespread outputs of the locus coeruleus, suggest that the locus coeruleus may be important in mediating responses to stress. Previous studies in rats have demonstrated that exposure to foot shock elicits Fos expression, a marker of neuronal activation, in the locus coeruleus and other brain sites. In order to evaluate the involvement of the locus coeruleus in foot shock-induced activation of other brain sites, shock-induced Fos expression was examined in the locus coeruleus and other brain areas known to be activated by foot shock, following direct inhibition of the locus coeruleus by local infusion of muscimol, a GABA agonist, prior to foot shock. Control rats received infusions of artificial cerebrospinal fluid into the locus coeruleus or muscimol into areas outside of locus coeruleus. Rats infused with artificial cerebrospinal fluid and then exposed to foot shock had significant increases in Fos expression in several brain areas, including locus coeruleus, nucleus O, several subdivisions of the hypothalamus, subnuclei of amygdala, bed nucleus of the stria terminalis and cingulate cortex. Inhibition of the locus coeruleus prior to foot shock significantly inhibited Fos expression in the locus coeruleus, nucleus O, some subdivisions of the hypothalamus including the magnocellular and medial parvicellular paraventricular hypothalamic nucleus, subnuclei of amygdala, and cingulate cortex. In contrast, inhibition of the locus coeruleus did not affect shock-induced Fos expression in other areas, including certain subdivisions of the hypothalamus and bed nucleus of the stria terminalis. We suggest that foot shock may activate multiple pathways, with activation of certain discrete nuclei requiring input from the locus coeruleus and activation of others occurring independently of locus coeruleus input.

Spatial learning and memory deficits induced by exposure to iron-56-particle radiation.

It has previously been shown that exposing rats to particles of high energy and charge (HZE) disrupts the functioning of the dopaminergic system and behaviors mediated by this system, such as motor performance and an amphetamine-induced conditioned taste aversion; these adverse behavioral and neuronal effects are similar to those seen in aged animals. Because cognition declines with age, spatial learning and memory were assessed in the Morris water maze 1 month after whole-body irradiation with 1.5 Gy of 1 GeV/nucleon high-energy (56)Fe particles, to test the cognitive behavioral consequences of radiation exposure. Irradiated rats demonstrated cognitive impairment compared to the control group as seen in their increased latencies to find the hidden platform, particularly on the reversal day when the platform was moved to the opposite quadrant. Also, the irradiated group used nonspatial strategies during the probe trials (swim with no platform), i.e. less time spent in the platform quadrant, fewer crossings of and less time spent in the previous platform location, and longer latencies to the previous platform location. These findings are similar to those seen in aged rats, suggesting that an increased release of reactive oxygen species may be responsible for the induction of radiation- and age-related cognitive deficits. If these decrements in behavior also occur in humans, they may impair the ability of astronauts to perform critical tasks during long-term space travel beyond the magnetosphere.

The stability of and intercorrelations among cardiovascular, immune, endocrine, and psychological reactivity.

One hundred fifteen college students were exposed to an evaluative speech task twice, separated by 2 weeks. At both sessions, we assessed cardiovascular, endocrine, immune, and psychological response at baseline and during the task. We found stability across sessions for stress-induced increases in anxiety and task engagement, heart rate, blood pressure, norepinephrine (but not epinephrine), cortisol, natural killer cell cytotoxicity, and numbers of circulating CD3+, CD8+, and CD56+ (but not CD4+ or CD19+) lymphocytes. The stable cardiovascular, immune, and endocrine reactivities were intercorrelated, providing evidence of a unified physiological stress response across these outcomes. Although stable stress-induced increases in task engagement were associated with the physiological stress responses, stress-induced anxiety was not.

Magnesium activation of GTP hydrolysis or incubation in S-adenosyl-l-methionine reverses iron-56-particle-induced decrements in oxotremorine enhancement of K+-evoked striatal release of dopamine.

Previous research has determined that the deficits in motor behavior seen in aged animals irradiated with (56)Fe particles involved alterations in muscarinic receptor sensitivity. In the present experiments, we determined whether increasing either membrane fluidity by exposure of striatal slices from irradiated ((56)Fe particles) animals to S-adenosyl-l-methionine (SAM) or GTP hydrolysis with Mg(2+) would reverse this (56)Fe-particle-induced loss of muscarinic receptor sensitivity, as has been observed in aged animals. Results indicated that, while increasing Mg(2+) concentrations in the incubation medium was effective in reducing the radiation effects, SAM was able to effect some reversal of the radiation effects only at the lower concentration (200 microM). These results suggest that similar mechanisms may be involved in the deficits in signal transduction seen after (56)Fe-particle irradiation to those seen in aging, and that these may include changes in the membrane structure or composition that could alter subsequent responsiveness of transduction pathways. The results further suggest that, as has been reported previously, (56)Fe-particle irradiation may accelerate brain aging, and that since these HZE particles contribute at least 1% of the dose that astronauts would receive from cosmic rays, long-term exposure on extended space flights (e.g. to Mars) may produce similar deficits that could have immediate or delayed effects on behavior.

5-HT3 receptor antagonists ameliorate emesis in the ferret evoked by neutron or proton radiation.

BACKGROUND: Nausea and vomiting produced by sub-lethal doses of X- or gamma-rays can be ameliorated by serotonin subtype-three (5-hydroxytryptamine; 5-HT3) receptor antagonists. The effectiveness of these anti-emetics on blocking the emetic responses induced by fission neutron or proton radiation exposure was evaluated in the ferret animal model. HYPOTHESIS: 5-HT3 receptor antagonists or bilateral vagotomy will ameliorate that emesis evoked by fission neutrons or protons. METHODS: Groups of ferrets were exposed to whole-body or head-shielded radiations of varying qualities: fission spectrum neutons, high-energy protons, or gamma-rays. Prior to that exposure, some groups were either vagotomized or received subcutaneous (s.c.) or oral (p.o.) treatment with various doses of the 5-HT3 receptor antagonist antiemetics eusatron and ondansetron. RESULTS: We demonstrated that both eusatron and ondansetron effectively abolished the emesis normally induced by 2-Gy doses of either 60Co gamma or neutron:gamma, mixed-field irradiation, the latter with a neutron-to-total dose ratio (Dn/Dt) of 0.9+/-2% (%SD). Different routes of delivery of the anti-emetics yielded different degrees of inhibition of the emetic responses; p.o. treatment was less efficacious than s.c. treatment for the emesis to fission neutrons. Eusatron was significantly more effective than ondansetron on a mg x kg(-1) basis. Bilateral vagotomy also attenuated or abolished the emetic responses to the mixed-field neutron exposures. Furthermore, emesis induced by exposure to 2.5 Gy of 200-MeV protons was effectively abolished by ondansetron. CONCLUSION: These results are consistent with the concept that similar physiological and pharmacological mechanisms underlie the emetic responses to different qualities of radiation.

Persistence of the notochordal canal: MR and plain film appearance.

We report a case of an unusually prominent persistent notochordal canal involving the T12-L5 vertebrae. This rare anatomic variation was discovered as an incidental finding in a patient with lymphoma undergoing MR imaging for evaluation of back pain. MR images showed a vertically oriented canal contiguous with the intervertebral disks traversing the anterior aspect of each affected vertebral body. Plain films showed a sclerotic rimmed central channel that flared at each vertebral endplate to merge with the disk spaces.

Stressor-induced alteration of cytokine production in multiple sclerosis patients and controls.

OBJECTIVE: We administered an acute psychological stressor to multiple sclerosis (MS) patients and normal controls to determine whether differences in subjective and physiological responses to stress may underlie the susceptibility of MS patients to stress-related exacerbations. METHOD: Twenty-five MS patients (18 female, 7 male) and 25 age- and gender-matched controls participated in the study. They were asked to give a 5-minute videotaped speech defending themselves in a hypothetical scenario in which they were wrongly accused of stealing. Subjective and autonomic responses were monitored, and blood was sampled at baseline, 5, 20, and 60 minutes after the stressor to assess mitogen-stimulated production of interleukin-1beta(IL-1beta), interleukin-4 (IL-4), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma). RESULTS: MS patients and controls demonstrated similar subjective and physiological responses to the stressor that were independent of gender, mood, and disability status. The macrophage-derived cytokines IL-1beta and TNF-alpha were increased during the stressor, and remained elevated through 60 minutes. Th1 lymphocyte-derived IFN-gamma production also was increased at 5 and 60 minutes relative to baseline; however, there was no change in the Th2 lymphocyte-derived cytokine IL-4. CONCLUSIONS: These results favor the hypothesis that MS patients do not differ in stress response from normal controls; however, psychological stress may enhance cellular immune responses that would be potentially harmful to MS patients.

Injection of corticotropin-releasing hormone into the locus coeruleus or foot shock increases neuronal Fos expression.

Previous research suggests that corticotropin-releasing hormone can act in the locus coeruleus to increase the firing of locus coeruleus neurons and elicit physiological responses resembling those associated with stress. The present study used immunocytochemical detection of Fos as a measure of neuronal activation to identify brain areas that were activated by bilateral injections of corticotropin-releasing hormone into the locus coeruleus of rats. Injection of corticotropin-releasing hormone into the locus coeruleus increased the expression of Fos in the locus coeruleus as compared with injection of vehicle into the locus coeruleus or injection of corticotropin-releasing hormone into neighbouring pontine sites. The pattern of Fos expression throughout the brain after injections of corticotropin-releasing hormone into the locus coeruleus was generally consistent with the anatomical organization of efferent projections arising from the locus coeruleus; increased Fos expression was observed in many brain areas including the ventral lateral septum, septohypothalamic nucleus, bed nucleus of the stria terminalis, the central amygdaloid nucleus, the dorsomedial nuclei of the hypothalamus, and the thalamic paraventricular and rhomboid nuclei. Foot shock also increased Fos expression in the locus coeruleus and the other brain regions that expressed Fos after corticotropin-releasing hormone injections into the locus coeruleus. A few brain regions, most notably the hypothalamic paraventricular nucleus, expressed Fos in response to foot shock but not corticotropin-releasing hormone. These results indicate that local injection of corticotropin-releasing hormone into the locus coeruleus stimulates the activity of the locus coeruleus neurons. However, the pattern of Fos expression throughout the brain evoked by injection of corticotropin-releasing hormone into the locus coeruleus does not fully replicate the effects of foot shock.

Effects of exposure to different types of radiation on behaviors mediated by peripheral or central systems.

The effects of exposure to ionizing radiation on behavior may result from effects on peripheral or on central systems. For behavioral endpoints that are mediated by peripheral systems (e.g., radiation-induced conditioned taste aversion or vomiting), the behavioral effects of exposure to heavy particles (56Fe, 600 MeV/n) are qualitatively similar to the effects of exposure to gamma radiation (60Co) and to fission spectrum neutrons. For these endpoints, the only differences between the different types of radiation are in terms of relative behavioral effectiveness. For behavioral endpoints that are mediated by central systems (e.g., amphetamine-induced taste aversion learning), the effects of exposure to 56Fe particles are not seen following exposure to lower LET gamma rays or fission spectrum neutrons. These results indicate that the effects of exposure to heavy particles on behavioral endpoints cannot necessarily be extrapolated from studies using gamma rays, but require the use of heavy particles.

Contrast-enhanced magnetization transfer MR of the brain: importance of precontrast images.

PURPOSE: To determine the importance of obtaining precontrast T1-weighted magnetization transfer (MT) MR images for better interpretation contrast-enhanced T1-weighted MT images. METHODS: One hundred fifty-five patients referred for MR imaging of the brain were examined prospectively with noncontrast T1-weighted imaging, noncontrast T1-weighted imaging with MT, contrast-enhanced T1-weighted imaging, and contrast-enhanced T1-weighted imaging with MT. In the patients who had abnormally increased signal intensity on postcontrast images (with or without MT), the four imaging sequences were evaluated with regard to number of lesions and lesional signal intensity. For each of the sequences, two experienced neuroradiologists subjectively graded the lesions on a scale of 1 to 4 (4 being the most conspicuous) with regard to abnormally increased signal intensity. RESULTS: Twenty-two of the 155 patients had increased signal intensity on one or more of the postcontrast sequences. Eight of these 22 patients had increased signal intensity of one or more lesions on images without MT. All these lesions were seen better on images obtained with MT. An additional six of the 22 patients had increased signal intensity of one or more lesions on images obtained with MT that was not detected on images obtained without MT. Eight of the 22 patients had no high signal intensity on noncontrast images with or without MT. One of the eight had increased number and conspicuity of lesions on postcontrast MT images. CONCLUSIONS: A significant number of patients had increased signal intensity on noncontrast T1-weighted images with MT that was not seen on noncontrast T1-weighted images without MT. This high signal intensity was also visible on postcontrast MT images, and would have been mistaken for pathologic enhancement if noncontrast MT images had not been available for comparison.

Immune system differences in men with hypo- or hypercholesterolemia.

Substantial epidemiologic evidence indicates that relative hypocholesterolemia in apparently healthy individuals is associated with increased subsequent mortality from cancer and other nonatherosclerotic causes of death. To test a hypothesis potentially underlying these unexplained associations, we evaluated whether individuals with hypo- and hypercholesterolemia differ in various enumerative and functional indices of the immune system. Nineteen healthy adult men with a mean age of 46 years and a mean total cholesterol concentration of 151 mg/dl constituted a low cholesterol group and were compared with 39 men of a similar age whose total cholesterol averaged 261 mg/dl. Relative to the high cholesterol group, hypocholesterolemic men had significantly fewer circulating lymphocytes, fewer total T cells, and fewer CD8+ cells (P's < 0.05). Trends toward fewer CD4+ cells and less IL-2 release in response to PHA were also noted in the low, compared to the high, cholesterol group. The low and high cholesterol groups did not differ in number of B lymphocytes, level of PHA-induced proliferation, number of natural killer (NK) cells, or degree of NK cytotoxicity. These data provide preliminary evidence of immune system differences in healthy individuals with hypo- and hypercholesterolemia.

Social ties and susceptibility to the common cold.

OBJECTIVE: To examine the hypothesis that diverse ties to friends, family, work, and community are associated with increased host resistance to infection. DESIGN: After reporting the extent of participation in 12 types of social ties (eg, spouse, parent, friend, workmate, member of social group), subjects were given nasal drops containing 1 of 2 rhinoviruses and monitored for the development of a common cold. SETTING: Quarantine. PARTICIPANTS: A total of 276 healthy volunteers, aged 18 to 55 years, neither seropositive for human immunodeficiency virus nor pregnant. OUTCOME MEASURES: Colds (illness in the presence of a verified infection), mucus production, mucociliary clearance function, and amount of viral replication. RESULTS: In response to both viruses, those with more types of social ties were less susceptible to common colds, produced less mucus, were more effective in ciliary clearance of their nasal passages, and shed less virus. These relationships were unaltered by statistical controls for prechallenge virus-specific antibody, virus type, age, sex, season, body mass index, education, and race. Susceptibility to colds decreased in a dose-response manner with increased diversity of the social network. There was an adjusted relative risk of 4.2 comparing persons with fewest (1 to 3) to those with most (6 or more) types of social ties. Although smoking, poor sleep quality, alcohol abstinence, low dietary intake of vitamin C, elevated catecholamine levels, and being introverted were all associated with greater susceptibility to colds, they could only partially account for the relation between social network diversity and incidence of colds. CONCLUSIONS: More diverse social networks were associated with greater resistance to upper respiratory illness.

Dissociation of hypnotic-anesthetic actions of alpha 2 agonists from cyclic AMP in the rat.

alpha 2 adrenergic agonists are used clinically for their anesthetic, analgesic, and sympatholytic actions in surgical patients. All alpha 2 adrenergic receptors, when activated by alpha 2-adrenergic agonists, are able to inhibit adenylate cyclase. We have examined the alpha 2-adrenoceptor-mediated anesthetic actions of dexmedetomidine, a highly selective alpha 2-adrenergic agonist, after pretreatment of the animals with rolipram, a cyclic AMP (cAMP)-specific phosphodiesterase inhibitor, cAMP accumulation and monoamine turnover were measured in the locus coeruleus (LC) and hippocampus (HC) following administration of rolipram [275 mg/kg, intraperitoneally (IP)] and dexmedetomidine (100-500 mg/kg, IP). The hypnotic response to dexmedetomidine was also measured in these animals. In other experiments, rats were stereotactically cannulated in the LC with an indwelling catheter, and after the second day, the tail-flick analgesic response to dexmedetomidine (3.5 mg/0.2 ml LC), following rolipram (275 mg/kg, IP) pretreatment, was assessed. In the presence of elevated cAMP levels, the hypnotic, analgesic, and sympatholytic effects of dexmedetomidine persisted. These data suggest that adenylate cyclase activity does not mediate the cellular responses to alpha 2-adrenergic agonists but instead may act in concert with other alpha 2-adrenoceptor-coupled effector mechanisms to transduce the anesthetic actions of these agents.