Consensus on a core curriculum in American training programs in pediatric hematology-oncology: a report from the ASPHO Training Committee.

The Training Committee (TC) of the American Society of Pediatric Hematology/Oncology created a foundation of common goals and objectives that could provide a structure for fellowship programs. The TC conducted a survey of program directors for input into the structure of their programs and training methods and the results are presented here. Additionally, a suggested core program is outlined, taking into account the new common requirements as stipulated by the ACGME and ABP, and additional suggestions from the program directors. This paper highlights the suggested training objectives and educational opportunities that should be afforded all fellows in this sub-specialty. The goal of this consensus statement is to provide a model curriculum to improve quality and consistency of training and achieve compliance with new requirements while simultaneously recognizing the importance of alternative approaches that emphasize each program's unique strengths and character.

Chronic ethanol modulates delta and mu-opioid receptor expression in rat CNS: immunohistochemical analysis with quantitiative confocal microscopy.

Ethanol consumption affects levels of endogenous opioids as well as opioid receptors in both animals and humans. We studied the expression of delta (delta) and mu (mu) opioid receptors (ORs) in brain sections of adult male Sprague-Dawley rats after 2 weeks of consuming ethanol in a liquid diet, with comparisons to sections from pair-fed control animals. Immunohistochemical staining for the ORs, using selective antibodies, and quantitation of confocal images, revealed increased expression of delta-ORs in hippocampal CA1 of the chronic ethanol-treated rats. In contrast, mu-ORs decreased in their expression after ethanol treatment in multiple brain areas, including cortex, hippocampus, midbrain colliculi, striatum and nucleus accumbens. The alterations in immunoreactive OR expression may be related to reduced functional coupling of the ORs to G-proteins, as found in prior studies in several brain regions, using the same chronic ethanol diet protocol. Changes in OR expression and functional coupling in the CNS may be factors in ongoing ethanol consumption and tolerance.

Double-elevating osteotomy for late-presenting infantile Blount's disease: the importance of concomitant lateral epiphysiodesis.

We reviewed 34 knees in 24 children after a double-elevating osteotomy for late-presenting infantile Blount's disease. The mean age of patients was 9.1 years (7 to 13.5). All knees were in Langenskiöld stages IV to VI. The operative technique corrected the depression of the medial joint line by an elevating osteotomy, and the remaining tibial varus and internal torsion by an osteotomy just below the apophysis. In the more recent patients (19 knees), a proximal lateral tibial epiphysiodesis was performed at the same time. The mean pre-operative angle of depression of the medial tibial plateau of 49 degrees (40 degrees to 60 degrees ) was corrected to a mean of 26 degrees (20 degrees to 30 degrees ), which was maintained at follow-up. The femoral deformity was too small to warrant femoral osteotomy in any of our patients. The mean pre-operative mechanical varus of 30.6 degrees (14 degrees to 66 degrees ) was corrected to 0 degrees to 5 degrees of mechanical valgus in 29 knees. In five knees, there was an undercorrection of 2 degrees to 5 degrees of mechanical varus. At follow-up a further eight knees, in which lateral epiphysiodesis was delayed beyond five months, developed recurrent tibial varus associated with fusion of the medial proximal tibial physis.

Stachybotrys chartarum alters surfactant-related phospholipid synthesis and CTP:cholinephosphate cytidylyltransferase activity in isolated fetal rat type II cells.

Stachybotry chartarum, a fungal contaminant of water-damaged buildings commonly grows on damp cellulose-containing materials. It produces a complex array of mycotoxins. Their mechanisms of action on the pulmonary system are not entirely clear. Previous studies suggest spore products may depress formation of disaturated phosphatidylcholine (DSPC), the major surface-active component of pulmonary surfactant (PS). If S. chartarum can indeed affect formation of this phospholipid, then mold exposure may be a significant issue for pulmonary function in both mature lung and developing fetal lung. To address this possibility, fetal rat type II cells, the principal source of DSPC, were used to assess effects of S. chartarum extract on formation of DSPC. Isolated fetal rat lung type II cells prelabeled with 3H-choline and incubated with spore extract showed decreased incorporation of 3H-choline into DSPC. The activity of CTP:cholinephosphate cytidylyltransferase (CPCT), the rate-limiting enzyme in phosphatidylcholine synthesis was reduced by approximately 50% by a 1:10 dilution of spore extract. Two different S. chartarum extracts (isolates from S. chartarum (Cleveland) and S. chartarum (Hawaiian)) were used to compare activity of CPCT in the presence of phosphatidylglycerol (PG), a known activator. PG produced an approximate two-fold increase in CPCT activity. The spore isolate from Hawaii did not alter enzyme activity. S. chartarum (Cleveland) eliminated the PG-induced activation of CPCT. These results support previous observations that mold products alter PS metabolism and may pose a risk in developing lung, inhibiting surfactant synthesis. Different isolates of the same species of fungus are not equivalent in terms of potential exposure risks.

Chronic ethanol consumption reduces delta-and mu-opioid receptor-stimulated G-protein coupling in rat brain.

BACKGROUND: Ethanol consumption is thought to enhance the release of endogenous opioids acting at opioid receptors (ORs) in the central nervous system. Prior studies have shown that chronic ethanol consumption in alcohol-preferring rats uncouples mu-ORs from Gi proteins. The purpose of this study was to investigate the potential for uncoupling of the delta- and the mu-OR after chronic ethanol consumption in a nonpreferring rat strain. METHODS: We used radiohistochemical methods to study mu- and delta-OR-stimulated G-protein coupling in brain tissue of rats ingesting liquid diets containing 6.7% ethanol (v/v) for 16 days, as compared with 0% ethanol pair-fed control rats. Sections of brain from pair-fed and ethanol-treated rats were incubated with guanylyl 5'-[gamma-[35S]-thio]-triphosphate ([35S]-GTPgammaS) in the absence and presence of d-Pen2,d-Pen5 enkephalin (DPDPE), a delta-OR agonist, or Tyr-d-Ala-Gly-N(me)Phe-Gly-ol-enkephalin (DAMGO), a mu-OR agonist. RESULTS: DPDPE significantly stimulated [35S]-GTPgammaS binding in the hippocampal dentate gyrus (DG), CA1, cerebellum, and inferior colliculus of untreated pair-fed controls. By contrast, DPDPE-stimulated [35S]-GTPgammaS binding was reduced significantly in those brain regions in the ethanol-consuming group. DAMGO stimulated [35S]-GTPgammaS binding in cortex, caudate, nucleus accumbens, DG, CA1, and superior and inferior colliculi, whereas the DG, CA1, and colliculi showed a significant reduction of binding after chronic ethanol. Basal [35S]-GTPgammaS binding was not different between the two diet groups. CONCLUSIONS These data are the first to demonstrate functional uncoupling of delta-ORs from G proteins after chronic ethanol consumption. Uncoupling may result from modulation of receptors, possibly by internalization or phosphorylation. Alterations in functional coupling of both delta- and mu-ORs and subsequent effects may contribute to continued ethanol consumption.

Data mining of spectroscopic data for biomarker discovery.

The goals of precise diagnosis, prevention and treatment of disease can be realized through the discovery of biological markers. Spectroscopic tools can simultaneously detect and quantify multiple small molecule and macromolecular components of biological samples, and are therefore ideal methods for the discovery of previously uncharacterized markers. However, the identification of meaningful spectral features is complicated by the lack of foreknowledge of the molecular nature of a disease, spectral noise and biological variability that is uncorrelated with the disease state. Pattern recognition techniques, both statistical and machine-learning, have been increasingly used in recent years with spectroscopic data to identify markers and classify patients into disease subsets. This review summarizes recent developments, limitations and future prospects in the use of data mining techniques with magnetic resonance spectroscopy, mass spectrometry and optical spectroscopy for the discovery of biomarkers.

Analysis of pulmonary surfactant by Fourier-transform infrared spectroscopy following exposure to Stachybotrys chartarum (atra) spores.

Lung cells are among the first tissues of the body to be exposed to air-borne environmental contaminants. Consequently the function of these cells may be altered before other cells are affected. As gas exchange takes place in the lungs, changes in cellular function may have serious implications for the processes of oxygen uptake and carbon dioxide elimination. In order for these processes to occur, the lung must maintain a high degree of expandability. This latter function is accomplished in part by the pulmonary surfactant which is synthesized and released by alveolar type II cells. Earlier studies have shown that exposure to gas phase materials such as smoke or organic solvents can alter the composition and function of the surfactant. The present study examines the ability of highly toxigenic mold spores to alter surfactant composition. Stachybotrys chartarum spores suspended in saline were instilled into mouse trachea as described earlier. After 24 h, the lungs were lavaged and the different processing stages of surfactant isolated by repeated centrifugation. Intracellular surfactant was isolated from the homogenized lung tissue by centrifugation on a discontinuous sucrose gradient. Samples were extracted into chloroform-methanol, dried and analyzed by Fourier-Transform infrared spectroscopy (FTIR). Exposure to S. chartarum induced an overall reduction of phospholipid among the three surfactant subfractions. The intermediate and spent surfactant fractions in particular were reduced to about half of the values observed in the saline-treated group. The relative distribution of phospholipid was also altered by spore exposure. Within the intracellular surfactant pool, higher levels of phospholipid were detected after spore exposure. In addition, changes were observed in the nature of the phospholipids. In particular strong intramolecular hydrogen bonding, together with other changes, suggested that spore exposure was associated with absence of an acyl chain esterified on the glycerol backbone, resulting in elevated levels of lysophospholipid in the samples. This study shows that mold spores and their products induce changes in regulation of both secretion and synthesis of surfactant, as well as alterations in the pattern of phospholipid targeting to the pulmonary surfactant pools.

Recombinant urate oxidase for the prophylaxis or treatment of hyperuricemia in patients With leukemia or lymphoma.

PURPOSE: To improve the control of hyperuricemia in patients with leukemia or lymphoma, we tested a newly developed uricolytic agent, recombinant urate oxidase (SR29142; Rasburicase; Sanofi-Synthelabo, Inc, Paris, France), which catalyzes the oxidation of uric acid to allantoin, a highly water-soluble metabolite readily excreted by the kidneys. PATIENTS AND METHODS: We administered Rasburicase intravenously, at 0.15 or 0.20 mg/kg, for 5 to 7 consecutive days to 131 children, adolescents, and young adults with newly diagnosed leukemia or lymphoma, who either presented with abnormally high plasma uric acid concentrations or had large tumor cell burdens. Blood levels of uric acid, creatinine, phosphorus, and potassium were measured daily. The pharmacokinetics of Rasburicase, the urinary excretion rate of allantoin, and antibodies to Rasburicase were also studied. RESULTS: At either dosage, the recombinant enzyme produced a rapid and sharp decrease in plasma uric acid concentrations in all patients. The median level decreased by 4 hours after treatment, from 9.7 to 1 mg/dL (P =.0001), in the 65 patients who presented with hyperuricemia, and from 4.3 to 0.5 mg/dL (P =.0001) in the remaining 66 patients. Despite cytoreductive chemotherapy, plasma uric acid concentrations remained low throughout the treatment (daily median level, 0.5 mg/dL). The urinary excretion rate of allantoin increased during Rasburicase treatment, peaking on day 3. Serum phosphorus concentrations did not change significantly during the first 3 days of treatment, decreased significantly by day 4 in patients presenting with hyperuricemia (P =.0003), and fell within the normal range in all patients by 48 hours after treatment. Serum creatinine levels decreased significantly after 1 day of treatment in patients with or without hyperuricemia at diagnosis (P =.0003 and P =.02, respectively) and returned to normal range in all patients by day 6 of treatment. Toxicity was negligible, and none of the patients required dialysis. The mean plasma half-lives of the agent were 16.0 +/- 6.3 (SD) hours and 21.1 +/- 12.0 hours, respectively, in patients treated at dosages of 0.15 or 0.20 mg/kg. Seventeen of the 121 assessable patients developed antibodies to the enzyme. CONCLUSION: Rasburicase is safe and highly effective for the prophylaxis or treatment of hyperuricemia in patients with leukemia or lymphoma.

Self-concept differentiation across the adult life span.

This study used 2 measures to examine 158 adults' (80 men, 78 women; ages 20 to 88 years) self-concept differentiation (SCD) across 5 role-specific self-representations. Findings revealed that the 2 measures did not assess SCD in similar ways and that they showed different associations with age. Specifically, the 1st measure was not significantly related to age, whereas the 2nd measure showed a curvilinear, U-shaped association with age. The 2nd SCD index also showed significant associations with several measures of emotional adjustment and 6 dimensions of psychological well-being. Additional analyses showed that age moderated the associations between SCD and positive and negative psychological well-being. A high level of SCD was associated with lower positive and higher negative psychological well-being for both young and older adults. However, this effect was significantly more pronounced in older adults.

Posterior iliac osteotomy in ischiopagus tetrapus twins.

Eight hemipelvises in ischiopagus tetrapus conjoined twins were assessed retrospectively to determine whether posterior iliac osteotomy is appropriate to reconstruct pelvic symmetry. Although clinical and radiological similarity exists with classic bladder exstrophy, axial and three-dimensional computed tomography showed the pelvic deformity to be very different. In classic bladder exstrophy, the deformity is one of shortening and external rotation of the anterior segment, and external rotation of the posterior segment. The deformity in the ischiopagus tetrapus pelvis is purely one of external rotation of the posterior segment. Posterior iliac osteotomy alone was therefore able to restore pelvic symmetry in seven of the eight hemipelvises, and prevented rediastasis of the symphysis pubis in all patients.

Nursing leaders predict top trends for 2000.

Nursing Management's Editorial Advisory Board predicts the top 10 trends that will impact nurse leaders in 2000. Use them to lead in the new millennium.

Outcomes management: from concepts to application.

This article provides an introduction to the definition of and rationale for outcomes management and includes a brief review of the outcomes management literature. A model for outcomes management, which links processes that can be changed in care delivery to outcomes that can be measured in a patient population, is reviewed. Guidelines for application of the outcomes management model and practical examples of application to two surgical patient populations are presented. Finally, issues important to outcomes management as a tool for performance improvement are discussed.

Beryllofluoride mimics phosphorylation of NtrC and other bacterial response regulators.

Two-component systems, sensor kinase-response regulator pairs, dominate bacterial signal transduction. Regulation is exerted by phosphorylation of an Asp in receiver domains of response regulators. Lability of the acyl phosphate linkage has limited structure determination for the active, phosphorylated forms of receiver domains. As assessed by both functional and structural criteria, beryllofluoride yields an excellent analogue of aspartyl phosphate in response regulator NtrC, a bacterial enhancer-binding protein. Beryllofluoride also appears to activate the chemotaxis, sporulation, osmosensing, and nitrate/nitrite response regulators CheY, Spo0F, OmpR, and NarL, respectively. NMR spectroscopic studies indicate that beryllofluoride will facilitate both biochemical and structural characterization of the active forms of receiver domains.

Perturbing the DNA sequence selectivity of metallointercalator-peptide conjugates by single amino acid modification.

Metallointercalator-peptide conjugates that provide small molecular mimics to explore peptide-nucleic acid recognition have been prepared. Specifically, a family of peptide conjugates of [Rh(phi)(2)(phen')](3+) [where phi = 9,10-phenanthrenequinone diimine and phen' = 5-(amidoglutaryl)-1,10-phenanthroline] has been synthesized and their DNA-binding characteristics examined. Single amino acid modifications were made from the parent metallointercalator-peptide conjugate [Rh(phi)(2)(phen')](3+)-AANVAIAAWERAA-CONH(2), which targets 5'-CCA-3' site-specifically. Moving the glutamate at position 10 in the sequence of the appended peptide to position 6 {[Rh(phi)(2)(phen')](3+)-AANVAEAAWARAA-CONH(2)} changed the sequence preference of the metallointercalator-peptide conjugate to 5'-ACA-3'. Subsequent mutation of the glutamate at position 6 to arginine {[Rh(phi)(2)(phen')](3+)-AANVARAAWARAA-CONH(2)} caused more complex changes in DNA recognition. Thermodynamic dissociation constants were determined for these metallointercalator-peptide conjugates by photoactivated DNA cleavage assays with the rhodium intercalators. At 55 degrees C in the presence of 5 mM MnCl(2), [Rh(phi)(2)(phen')](3+)-AANVAIAAWERAA-CONH(2) binds to a 5'-CCA-3' site with K(d) = 5.7 x 10(-)(8) M, whereas [Rh(phi)(2)(phen')](3+)-AANVAEAAWARAA-CONH(2) binds to its target 5'-ACA-3' site with K(d) = 9.9 x 10(-8) M. The dissociation constant for [Rh(phi)(2)(phen')](3+) with random-sequence DNA is 7.0 x 10(-7) M. Structural models have been developed and refined to account for the observed sequence specificities. As with much larger DNA-binding proteins, with these metal-peptide conjugate mimics, single amino acid changes can lead to single or multiple base changes in the DNA site targeted.

Diurnal variation in saliva estriol level during pregnancy: a pilot study.

OBJECTIVE: The object of the study was to characterize daily values and patterns of salivary estriol levels during normal pregnancy at mid to late gestation. STUDY DESIGN: We measured salivary estriol levels in a clinical research center setting with an established enzyme-linked immunosorbent assay. Fourteen pregnant women (24-36 weeks' gestation) submitted unstimulated saliva samples hourly from 10:00 am until 10:00 pm and at midnight and 2:00, 4:00, 6:00, and 8:00 am. RESULTS: Each subject demonstrated greater salivary estriol levels at night (10:00 pm-6:00 am) than in the daytime (8:00 am-9:00 pm, P <.001). Salivary estriol levels consistently increased at 10:00 pm, peaked at 4:00 am, and returned to daytime levels between 6:00 and 7:00 am. Salivary estriol concentrations were stable during daylight hours. CONCLUSIONS: (1) There was a dramatic diurnal variation in salivary estriol levels (nadir during daylight with nighttime apogee). (2) Diurnal patterns and salivary estriol levels were consistent in each of 14 subjects evaluated in the latter half of pregnancy. Samples for baseline measurements of salivary estriol level should be obtained during daylight hours (8:00 am-8:00 pm).

A meta-analysis of salivary estriol (sE(3)) as a means to identify women at risk for preterm birth due to fetal-placental endocrine mechanisms.

Objective: 1) Analyze overall performance of salivary estriol testing in two similarly conducted large multicenter prospective trials and 2) gain information regarding the highly integrated and regulated endocrine mechanisms controlling parturition.Methods: Meta-analysis of evaluable mother-perinate dyads from two large prospective trials was conducted. Overall, 993 pregnant women were followed prospectively with weekly saliva samples from 24 weeks to delivery.Results: 1) Occurrence of a single positive test (sE(3) >/= 2.1 ng/mL) predicted delivery prior to 37 weeks gestation (P <.0003; OR 3.4, 95% CI 1.7-6.8). If a rescreen test at one week was also >/=2.1 ng/mL (8.9% of all subjects) then relative risks of preterm birth increased to 6.86 CI (3.2-14.5) P <.0001. Having two consecutive positive tests was associated with a mean time to delivery of 2.3 weeks (negative predictive value of 97%). 2) Survival analysis of women delivering at term and preterm demonstrated that sE(3) >/= 2.1 ng/mL predicted onset of labor and birth in approximately 3 weeks:Conclusion: Meta-analysis of these two large prospective trials confirms that 1) an sE(3) >/= 2.1 ng/mL provides timely warning of a presumed endocrine signal for impending preterm and term parturition, 2) the 2-3 week mean time to delivery after a positive signal allows time for intervention, and 3) lack of a positive sE(3) signal allows a confident prediction (NPV) that delivery will not occur within 2-3 weeks.

Cloning and characterization of the calreticulin gene from Ricinus communis L.

A full-length cDNA encoding a calreticulin-like protein was isolated by immune-screening a germinating castor bean endosperm cDNA library with antisera raised to the total lumenal fraction of purified plant endoplasmic reticulum. The calcium-binding properties of the recombinant protein were characterized and shown to be essentially identical to those reported for the mammalian calreticulin. Calcium overlays and immune blot analysis confirmed the endoplasmic lumenal identity of this reticuloplasmin. Probing protein blots of endoplasmic reticulum subfractions with radio-iodinated calreticulin showed specific associations with various polypeptides including one identified as the abundant reticuloplasmin protein disulfide isomerase. Characterization of the corresponding genomic clones revealed that calreticulin is encoded by a single gene of 3 kb in castor. The full genomic sequence reveals the presence of 12 introns, 12 translated exons, and one exon containing the last three amino acids of the translated sequence and the 3'-untranslated region of the gene. Northern blot analysis of RNA isolated from various organ tissues showed a basal constitutive level of expression throughout the plant, but more abundant mRNA being detected in tissues active in secretion. This was confirmed by analysis of transgenic tobacco plants containing 1.8 kb of 5'-untranslated genomic sequence fused to the beta-glucuronidase reporter gene (GUS) showed a more localized pattern of expression. Activity being localized to the vasculature (phloem, root hairs and root tip) in vegetative tissue, and being strongly expressed in the floral organs including the developing and germinating seed.