Neurocan is upregulated in injured brain and in cytokine-treated astrocytes.

Injury to the CNS results in the formation of the glial scar, a primarily astrocytic structure that represents an obstacle to regrowing axons. Chondroitin sulfate proteoglycans (CSPG) are greatly upregulated in the glial scar, and a large body of evidence suggests that these molecules are inhibitory to axon regeneration. We show that the CSPG neurocan, which is expressed in the CNS, exerts a repulsive effect on growing cerebellar axons. Expression of neurocan was examined in the normal and damaged CNS. Frozen sections labeled with anti-neurocan monoclonal antibodies 7 d after a unilateral knife lesion to the cerebral cortex revealed an upregulation of neurocan around the lesion. Western blot analysis of extracts prepared from injured and uninjured tissue also revealed substantially more neurocan in the injured CNS. Western blot analysis revealed neurocan and the processed forms neurocan-C and neurocan-130 to be present in the conditioned medium of highly purified rat astrocytes. The amount detected was increased by transforming growth factor beta and to a greater extent by epidermal growth factor and was decreased by platelet-derived growth factor and, to a lesser extent, by interferon gamma. O-2A lineage cells were also capable of synthesizing and processing neurocan. Immunocytochemistry revealed neurocan to be deposited on the substrate around and under astrocytes but not on the cells. Astrocytes therefore lack the means to retain neurocan at the cell surface. These findings raise the possibility that neurocan interferes with axonal regeneration after CNS injury.

Comparing astrocytic cell lines that are inhibitory or permissive for axon growth: the major axon-inhibitory proteoglycan is NG2.

Astrocytes, oligodendrocytes, and oligodendrocyte/type 2 astrocyte progenitors (O2A cells) can all produce molecules that inhibit axon regeneration. We have shown previously that inhibition of axon growth by astrocytes involves proteoglycans. To identify inhibitory mechanisms, we created astrocyte cell lines that are permissive or nonpermissive and showed that nonpermissive cells produce inhibitory chondroitin sulfate proteoglycans (CS-PGs). We have now tested these cell lines for the production and inhibitory function of known large CS-PGs. The most inhibitory line, Neu7, produces three CS-PGs in much greater amounts than the other cell lines: NG2, versican, and the CS-56 antigen. The contribution of NG2 to inhibition by the cells was tested using a function-blocking antibody. This allowed increased growth of dorsal root ganglion (DRG) axons over Neu7 cells and matrix and greatly increased the proportion of cortical axons able to cross from permissive A7 cells onto inhibitory Neu7 cells; CS-56 antibody had a similar effect. Inhibitory fractions of conditioned medium contained NG2 coupled to CS glycosaminoglycan chains, whereas noninhibitory fractions contained NG2 without CS chains. Enzyme preparations that facilitated axon growth in Neu7 cultures were shown to either degrade the NG2 core protein or remove CS chains. Versican is present as patches on Neu7 monolayers, but DRG axons do not avoid these patches. Therefore, NG2 appears to be the major axon-inhibitory factor made by Neu7 astrocytes. In the CNS, NG2 is expressed by O2A cells, which react rapidly after injury to produce a dense NG2-rich network, and by some reactive astrocytes. Our results suggest that NG2 may be a major obstacle to axon regeneration.

Prospective evaluation of vitamin E for hot flashes in breast cancer survivors.

PURPOSE: Hot flashes represent a substantial clinical problem for some breast cancer survivors. Although estrogen or progesterone preparations can alleviate these symptoms in many patients, concern remains regarding the use of hormonal preparations in such women. Thus, there is a perceived need for nonhormonal treatments for hot flashes for breast cancer survivors. Based on anecdotal evidence that vitamin E was helpful, we designed a trial to investigate this matter. METHODS: We developed and conducted a placebo-controlled, randomized, crossover trial where, after a 1 week baseline period, patients received 4 weeks of vitamin E 800 IU daily, then 4 weeks of an identical-appearing placebo, or vice versa. Diaries were used to measure potential toxicities and hot flashes during the baseline week and the two subsequent 4-week treatment periods. RESULTS: The 120 patients evaluated for toxicity failed to show any. The 105 patients who finished the first treatment period showed a similar reduction in hot flash frequencies (25% v 22%; P = .90) for the two study arms. A crossover analysis, however, showed that vitamin E was associated with a minimal decrease in hot flashes (one less hot flash per day than was seen with a placebo) (P < or = .05). At the study end, patients did not prefer vitamin E over the placebo (32% v 29%, respectively). CONCLUSION: Although this trial was able to show a statistically significant hot flash reduction with vitamin E compared to a placebo, the clinical magnitude of this reduction was marginal.

Bone marrow transplant today--home tomorrow: ambulatory care issues in pediatric marrow transplantation.

Pediatric marrow transplantation is now an accepted and increasingly successful intensive therapy for a wide range of disorders in children. Supportive therapies that were once thought to be possible only in the acute care setting can now be safely managed in the outpatient arena. This shift is influenced by scientific and patient care advances and by managed care and cost containment trends. The purpose of this article is to examine the interrelated aspects of change in health care delivery and their impact on pediatric bone marrow transplant recipients and families. Nurses working in all aspects of pediatric marrow transplantation have an opportunity and responsibility to impact quality patient care in the outpatient setting.

Bridge grafts of fibroblast growth factor-4-secreting schwannoma cells promote functional axonal regeneration in the nigrostriatal pathway of the adult rat.

Axons damaged in the adult mammalian central nervous system are able to regenerate when their inhibitory glial environment is replaced with a more permissive substrate. Here, we have used long oblique "bridge" grafts of fibroblast growth factor-4-transfected RN-22 schwannoma cells to allow mechanically lesioned nigrostriatal axons to regenerate back to their original target in the adult rat brain. Regenerated axons were able to leave the bridge graft to form terminal arborizations and increase the density of tyrosine hydroxylase-immunoreactive fibres within the striatum. Bridge grafting also resulted in an increase in the number of neurons within the substantia nigra pars compacta taking up the fluorescent retrograde tracer Fluoro-Gold from the striatum. Animals which had received RN-22 bridge grafts showed lower rates of amphetamine-induced rotation 10 weeks after a mechanical lesion of the nigrostriatal tract compared to lesioned controls, the magnitude of the behavioural effect being related to the number of regenerated axons, and this comparative reduction was reversed by mechanical section of the bridge graft. It is concluded that our bridge grafting strategy allowed the partial anatomical and functional regeneration of the mechanically lesioned nigrostriatal tract, an unmyelinated central axon bundle, and that bridge grafting therefore represents a realistic approach to the repair of central nervous system lesions involving axon tract damage.

Transdermal fentanyl in the management of cancer pain in ambulatory patients: an open-label pilot study.

We performed an open-label pilot study to define analgesic efficacy, acceptability, and toxicity of transdermal fentanyl in an ambulatory population of patients with cancer pain. Our 7-day study included 35 patients, all of whom had failed a trial of an opioid analgesic conventionally used for moderate pain. Patients received either a 25 micrograms/hr or 50 micrograms/hr fentanyl transdermal patch depending on prior opioid dose. Pain was measured daily utilizing visual analogue (VAS) and categorical (CAT) scales. Hours of nighttime sleep, quality of life, toxicities, and use of rescue medication were also assessed. There was a 24%-29% reduction in mean VAS and CAT pain scores as compared with the baseline and a 25% increase in mean hours of nighttime sleep. Fifty-nine percent of those patients responding (46% of all study patients) were satisfied to very satisfied with the analgesia provided by transdermal fentanyl. Six percent of all study patients were not at all satisfied with the pain relief obtained. Toxicities were similar to those seen with other opioids. No patient developed severe sedation or respiratory depression. The 25-50 micrograms/hr patch appears to be a safe starting dosage in ambulatory patients previously receiving opioids conventionally used for moderate pain.

Functional and anatomical reconstruction of the 6-hydroxydopamine lesioned nigrostriatal system of the adult rat.

In an attempt to reconstruct the 6-hydroxydopamine lesioned nigrostriatal system of the adult rat we have combined homotopic grafting of embryonic ventral mesencephalon suspensions with the implantation of long oblique "bridge" grafts of fibroblast growth factor-4-transfected RN-22 schwannoma cells stretching from the site of the neuronal grafts to the striatum. At seven weeks after receiving both grafts, animals were killed and processed for immunohistochemistry against tyrosine hydroxylase. Tyrosine hydroxylase-immunoreactive axons were seen to extend from the nigral grafts, along the bridge graft to the striatum where terminal arborizations could be seen. The retrograde tracer Fluoro-gold was injected intrastriatally in some of the experimental animals and was taken up by grafted neurons confirming their projection to the striatum. In parallel to the anatomical reconstruction of the system, a decrease in amphetamine-induced rotation was demonstrated in those animals receiving both grafts which had received > 98% complete lesions. This decrease was greatest in those animals with the most tyrosine hydroxylase-immunoreactive axons in their bridge grafts. The presence of the bridge graft also led to an increase in neuronal graft survival with twice as many tyrosine hydroxylase-immunoreactive neurons being found in the grafts of those animals that had received both grafts compared to those that had received a neuronal graft but no bridge graft.

Prospective evaluation of a chamomile mouthwash for prevention of 5-FU-induced oral mucositis.

BACKGROUND: Stomatitis has been found to be a major dose-limiting toxicity from bolus 5-fluorouracil-based (5-FU) chemotherapy regimens, despite the use of oral cryotherapy. Pursuant to preliminary data which suggested that a chamomile mouthwash might ameliorate this toxicity, a prospective trial was developed to test chamomile in this situation. METHODS: A Phase III, double-blind, placebo-controlled clinical trial was designed. Patients were entered into the study at the time of their first cycle of 5-FU-based chemotherapy. All patients received oral cryotherapy for 30 minutes with each dose of 5-FU. In addition, each patient was randomized to receive a chamomile or placebo mouthwash thrice daily for 14 days. Stomatitis scores were determined by health care providers and by patients themselves. RESULTS: There were 164 evaluable and well-stratified patients equally randomized to both treatment groups. There was no suggestion of any stomatitis difference between patients randomized to either protocol arm. There was also no suggestion of toxicity. Subset analysis did reveal unsuspected differential effects between males and females that could not be explained by reasons other than chance. CONCLUSION: The resultant data from this clinical trial did not support the prestudy hypothesis that chamomile could decrease 5-FU-induced stomatitis.

Redundant leading and following zeros in comparative numerical judgment.

The objective was to provide a more comprehensive understanding of how people make numerical comparative judgments when digits are contained in numbers with redundant leading or following zeros, e.g., 00080 and 800.000. These sequences of numbers often appear on computer display terminals (VDT) as line numbers, but surprisingly little research has been done on this. The experiment manipulated three aspects of numerical stimuli: (1) redundant leading zeros, (2) redundant following zeros, and (3) length of string of digits. The subjects were to push one of the two button-switches to respond whether two stimulus numbers shown on the computer screen were equal or unequal. The target stimuli contained several forms of redundant zeros, and each performance was assessed by response RT of the subjects. Analysis indicated five significant findings: (1) Redundant leading zeros hindered performance, (2) The effect of redundant following zeros depended on the stimulus type, (3) Over-all, longer digits took more processing time, (4) The RTs for the second-block trials were significantly faster than the first, and (5) Task performance was facilitated when the redundant zero representations were identical in both stimuli of a pair. Nonlexicographic processing seems to occur when feature identification can be used for numerical identification, that is, when the format is consistent. The research has implications for those in computer science to provide numerical formats which make comparative judgments as easy as possible.

Latent transition analysis and how it can address prevention research questions.

The objective of this chapter is to introduce latent transition analysis (LTA) to the substance use prevention research community. LTA is a new methodological technique for testing stage-sequential models, such as models of substance use onset. LTA estimates several different sets of parameters. One of these sets is the transition probability matrix, which contains information about the probability of movement between stages in the model. LTA can be used to evaluate the effectiveness of prevention intervention programs by comparing the transition probability matrices of the program and control groups. If the prevention program is successful, the transition probability matrices will indicate that the probability of moving to a more advanced stage of drug use is lower for the program participants than for the control group. An advantage of taking a stage-sequential approach is that examining the transition probability matrix reveals how effective a program is for individuals entering the program with different levels and types of substance use experience. In this chapter, LTA is used to evaluate a variety of models of the early onset process separately for Anglo, Latino, and Asian-American adolescents, measured in seventh grade and again in eighth grade. Although somewhat different models are found to fit the three ethnic groups best, the differences likely are due to differences in the overall amount of substance use experience. Based on these results, it is suggested that, to be most effective, prevention programs should take place earlier for Anglos and Latinos, and later, followed by boosters, for Asian Americans.

Early onset of reduced morphine analgesia by ingestion of sweet solutions.

Morphine analgesia can be reduced by prior exposure to food and flavored fluids. The early onset of reduced morphine-induced analgesia (RMA) was studied in 82 male Wistar rats after allowing them access to either a dextrose-saccharin solution or unflavored tap water for 6 or 3 h (Experiment 1, n = 40) or for 3 h, 90, or 45 min (Experiment 2, n = 42). Morphine (4 mg/kg) was injected subcutaneously at the end of the drinking period, and after 25 min a series of tail flick tests was conducted. Morphine produced strong analgesia in all rats that drank unflavored tap water; however, in rats that drank the flavored solution, the analgesic effect of morphine was significantly attenuated following exposures of 6 or 3 h, but not following exposures of 90 or 45 min. Similar quantities of flavored fluid were consumed by groups at all exposure durations; thus, RMA was determined by duration of exposure and not amount consumed. No analgesia attributable to flavor consumption per se was observed. The results suggest that RMA is mediated by endogenous opioid activity in the gustatory and analgesic systems by a mechanism akin to tolerance that requires about 3 h to operate.

Goodness-of-Fit Testing for Latent Class Models.

Latent class models with sparse contingency tables can present problems for model comparison and selection, because under these conditions the distributions of goodness-of-fit indices are often unknown. This causes inaccuracies both in hypothesis testing and in model comparisons based on normed indices. In order to assess the extent of this problem, we carried out a simulation investigating the distributions of the likelihood ratio statistic G(2), the Pearson statistic ⊃(2), and a new goodness-of-fit index suggested by Read and Cressie (1988). There were substantial deviations between the expectation of the chi-squared distribution and the means of the G(2) and Read and Cressie distributions. In general, the mean of the distribution of a statistic was closer to the expectation of the chi-squared distribution when the average cell expectation was large, there were fewer indicator items, and the latent class measurement parameters were less extreme. It was found that the mean of the χ(2) distribution is generally closer to the expectation of the chi-squared distribution than are the means of the other two indices we examined, but the standard deviation of the χ(2) distribution is considerably larger than that of the other two indices and larger than the standard deviation of the chi-squared distribution. We argue that a possible solution is to forgo reliance on theoretical distributions for expectations and quantiles of goodness-of-fit statistics. Instead, Monte Carlo sampling (Noreen, 1989) can be used to arrive at an empirical central or noncentral distribution.

Developmental hierarchy during early human B-cell ontogeny after autologous bone marrow transplantation using autografts depleted of CD19+ B-cell precursors by an anti-CD19 pan-B-cell immunotoxin containing pokeweed antiviral protein.

Sequential immunophenotypes of bone marrow (BM) and peripheral blood (PBL) lymphoid cells from 15 B-lineage acute lymphoblastic leukemia (ALL) patients who underwent autologous bone marrow transplantation (BMT) during complete remission were determined by dual-color immunofluorescence and multiparameter flow cytometry. Autografts were depleted of CD19+ B-cell precursors by an immunochemopurging protocol that combines B43-PAP, a potent anti-CD19 immunotoxin, and the cyclophosphamide congener 4-hydroperoxycyclophosphamide (4-HC). A marked interpatient variation was observed in the appearance and expansion of B-cell precursors repopulating the posttransplant marrow. The expression of CD10 and CD19 antigens during early B-cell ontogeny post-BMT preceded the expression of CD20, CD21, CD22, CD40, and sIgM. The surface antigen profiles of the emerging B-cell precursors were similar to those of fetal liver or fetal bone marrow B-cell precursors. Our comparisons of BM and PBL samples from patients in the early post-BMT period demonstrated that (1) PBL initially contains fewer B-lineage cells than does BM, and (2) circulating B-lineage lymphoid cells have a more mature immunophenotype than do BM B-lineage lymphoid cells. Comparison of the surface antigen profiles of day 30 versus day 100 or year 1 BM or PBL lymphoid cells showed an increase in the percentages of CD10+CD22- undifferentiated lymphocyte precursors, as well as CD19+sIgM- B-cell precursors (pre-pre-B), consistent with a time-dependent expansion of these B-cell precursor populations post-BMT. Importantly, the percentages of CD10+CD22+ and CD19+sIgM+ B-cell precursor (pre-B) populations also increased between 30 days and 1 year post-BMT, confirming the ability of emerging immature B-cell precursors to differentiate along the B-precursor pathway. The acquisition and expression of B-lineage differentiation antigens at different stages of the post-BMT B-cell ontogeny support the notion that the expression of these antigens is developmentally programmed. Similar to patients in previous autologous BMT studies, recipients of B-cell precursor-depleted autografts had normal or nearly normal serum immunoglobulin levels, suggesting that the maturing B-cell/plasma cell populations can produce and secrete immunoglobulins. The development of a functional CD19+ B-lineage lymphoid compartment in recipients of autografts which were depleted of CD19+ B-cell precursors corroborates the previously postulated existence of CD19- B-lineage lymphoid progenitor cells.

The effects of stereotyped behaviour on orienting and tonic cardiac activity.

The relationship of cardiac activity to stereotyped behaviour was studied in profoundly mentally retarded persons, using both inter-group comparisons. The first intra-group comparison involved examining the relative magnitude of an orienting response to an auditory stimulus during the occurrence or nonoccurrence of stereotyped body rocking. While no differences were found between periods of rocking and non-rocking when behavioural measures of orienting were used, smaller changes in post-tone heart rate were observed during periods of stereotyped rocking. A second intra-group comparison found that stereotyped behaviour was associated with a significant increase in heart rate but no change in heart rate variability when compared to periods of no stereotyped activity. Finally, using an inter-group comparison, individuals who displayed stereotyped body rocking exhibited higher tonic heart rates and lower heart rate variability during periods of no stereotyped behaviour than was observed in matched control subjects. This result suggests that stereotyped behaviour may be correlated with reduced vagal tone.

Time-series analysis of stereotyped movements: relationship of body-rocking to cardiac activity.

The pathological stereotypies frequently observed among severely mentally retarded and autistic persons are highly rhythmical in nature. Most attempts to quantify such behavior, however, have not analyzed stereotypy in terms of its cyclical properties. In the present paper we have detailed a method for electronically transducing stereotyped body-rocking and analyzing its frequency and amplitude characteristics with a standard polygraph and microprocessor. The relationship between stereotyped body-rocking and cardiac activity was also described using time-series analysis. The method described should provide a sensitive index of various experimental manipulations and treatment effects.