Comparison of adriamycin uptake in chick embryo heart and liver cells an murine L5178Y lymphoblasts in vitro: role of drug uptake in cardiotoxicity.

The mechanism of uptake of Adriamycin was investigated in chick embryo heart and liver cells and in murine L5178Y lymphoblasts in vitro. Drug uptake at 4 degrees C for 15 s due to rapid association accounted for a cell:medium distribution ratio of 104 +/- 14 (SE) in heart cells, 10.2 +/- 1.3 in liver cells, and 10.3 +/- 1.5 in L5178Y lymphoblasts. On thin-layer chromatographic analysis, 98% of the radioactivity migrated with the mobility of intact drug, suggesting that drug metabolism was negligible for at least 30 min in both heart and tumor cells. A time course of drug uptake was somewhat different in heart cells compared to that noted for liver or L5178Y cells. The steady state for drug uptake was reached more promptly in heart cells; apparent equilibrium was observed at 6 min in heart cells, at approximately 20 min in L5178Y lymphoblasts, but was not attained by 25 min in liver cells. Temperature dependence of drug uptake also differed in the three cell types; drug uptake was most temperature sensitive in L5178Y cells, intermediate in liver cells, and least temperature dependent in heart cells. Separation of heart, liver, and leukemic cells into membrane and cytosol fractions demonstrated that, at 1 and 30 min, more than 75% of the drug was associated with the membrane fraction. Trichloroacetic acid extraction of cell constituents revealed that, at 1 min, the acid-soluble fraction amounted to 32 +/- 2% of radioactivity in heart cells and 37 +/- 2% in L5178Y cells. Ethanol extraction of these cells demonstrated that, at 1 min, ethanol-soluble components accounted for 49 +/- 2% of radioactivity in heart cells and 27 +/- 2% in leukemic cells. The finding of a large component of rapid association together with evidence of prompt drug binding to cellular constituents made evaluation of unidirectional drug influx impractical. Accordingly, an investigation was undertaken of Adriamycin efflux from chick embryo heart and liver cells and L5178Y lymphoblasts, after the cells had been loaded with drug for various time intervals. In all three cell types, efflux was rapid down to a plateau level, representing nonexchangeable drug. As the period of time for loading cells was increased, there was a progressive rise in the level of nonexchangeable drug. Equilibration of the nonexchangeable pool occurred more rapidly in heart cells than in either liver or leukemic cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Cytotoxic therapy-induced D-xylose malabsorption and invasive infection during remission-induction therapy for acute myeloid leukemia in adults.

PURPOSE: To study the sequential changes in the intestinal absorption of an oral pentose probe, D-xylose, in patients receiving therapy for untreated acute myeloid leukemia (AML), and to correlate these changes to infectious morbidity. PATIENTS AND METHODS: Serial D-xylose absorption studies were conducted in 110 consecutive adult patients admitted to a university-affiliated tertiary care hospital for remission-induction therapy for untreated newly diagnosed AML. Serial serum D-xylose levels were obtained 1 hour after a 5-g oral dose of D-xylose at baseline and weekly for 4 weeks until marrow recovery. These results were correlated with invasive infection using multivariate techniques. RESULTS: The mean (+/- SEM) serum D-xylose levels were 0.88 +/- 0.03, 0.69 +/- 0.03, 0.58 +/- 0.02, 0.53 +/- 0.02, and 0.73 +/- 0.02 mmol/L at baseline and weeks 1 to 4, respectively (P < .0001, analysis of variance [AN-OVA]). Time to malabsorption varied with induction regimen (P = .007, log-rank test). Bloodstream infections during week 2 correlated with malabsorption (P = .007). Neutropenic enterocolitis correlated independently with induction regimen (P = .009), malabsorption at week 2 (P = .02), and the development of candidemia (P = .005). Hepatosplenic fungal infection correlated with induction regimen (P = .03), malabsorption at week 2 (P = .02), and fever at diagnosis (P = .003). Malabsorption was unrelated to the duration of severe neutropenia and the administration of parenteral nutrition. CONCLUSION: Serial D-xylose absorption studies in subjects with AML produced a characteristic profile of cytotoxic therapy-related damage to the functional integrity of the intestinal epithelium that was regimen dependent, myelosuppression independent, and predictive for invasive infectious complications. Further study to validate these observations appears warranted.

Granulocyte-macrophage colony-stimulating factor treatment before doxorubicin and cyclophosphamide chemotherapy priming in women with early-stage breast cancer.

PURPOSE: To determine if inhibition of stem-cell activity induced by granulocyte-macrophage colony-stimulating factor ([GM-CSF]; Sargramostim; Immunex Corporation, Seattle, WA) withdrawal or priming protects hematopoietic stem cells from the cytotoxic effects of adjuvant chemotherapy for early-stage breast cancer. PATIENTS AND METHODS: Serial blood counts were performed in 20 women with early-stage breast cancer receiving four courses of cyclophosphamide and doxorubicin chemotherapy. By a double-blind, placebo-controlled, balanced randomization, subjects received GM-CSF priming on days 5 to 1 for courses 1 and 3 or courses 2 and 4. RESULTS: Compared with before priming, after priming the times to neutrophil nadir (12.8 +/- 2.5 days v 14.8 +/- 1.5 days, respectively; P =.0001) and platelet nadir (mean +/- SD, 10.1 +/- 1.9 days v 11.1 +/- 2.2 days, P <.05) were shorter, indicating a shift of cytotoxicity to later progenitors. The neutrophil nadir was similar with and without priming (mean +/- SD, 490 +/- 310/microL v 550 +/- 350/microL, respectively; P =.2); however, on day 16 the mean neutrophil count was higher (mean +/- SD, 1030 +/- 580/microL v 690 +/- 370/microL, P =.004), and the proportion of patients with a neutrophil count less than 500/microL was lower after priming than before (six of 35 or 17. 1% v 12 of 34 or 35.3%, respectively; P =.04). The platelet nadir was higher (mean +/- SD, 166,000 +/- 51,000/microL after priming v 151,000 +/- 45,000/microL before priming, P =.007), and the duration of thrombocytopenia, ie, a platelet count less than 150,000/microL, was shorter (1.5 +/- 2.1 days v 2.8 +/- 2.9 days, P =.0025) after priming. Episodes of fever and neutropenia were not observed. CONCLUSIONS: GM-CSF priming from days 5 to 1 before doxorubicin and cyclophosphamide chemotherapy was associated with an earlier neutrophil and platelet nadir. On day 16, a higher mean neutrophil count and a lower proportion of patients with severe (< 500/microL) neutropenia were observed. Beneficial effects on the severity and duration of thrombocytopenia were also noted. These observations support the hypothesis that GM-CSF priming protects hematopoietic progenitors from the cytotoxic effects of chemotherapy.

Cerebral pressure-flow relationship during cardiopulmonary bypass in the dog at normothermia and moderate hypothermia.

We studied cerebral autoregulation by analyzing cerebral pressure-flow curves during cardiopulmonary bypass (CPB) with alpha-stat (alpha-stat) acid-base management at 28 (n = 9) and 37 degrees C (n = 9) in two groups of dogs. Cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2) were determined multiple times in each animal over an extensive range of cerebral perfusion pressure (CPP). The CPP was altered by changing perfusion flow rate. The dependence of CBF on CPP during normothermic and moderate hypothermic CPB was assessed using a block design analysis of covariance with CPP as the covariate. We anticipated maximal statistical power with this analysis to define if cerebral autoregulation was intact. This method of statistical analysis was compared with the conventional interpretation by linear regression analysis. Animals were administered sodium thiopental until an isoelectric electroencephalogram was obtained to assure stable depth of anesthesia independently of temperature effects. The animals were randomly assigned to either temperature group. The CBF was determined by injection of radioactive microspheres at each of five target CPPs randomly allocated (50, 60, 70, 80, and 90 mm Hg). The brain oxygen content difference was defined as arterial minus superior sagittal sinus (SSS) oxygen content. No difference in CPP, hemoglobin, arterial carbon dioxide tension, or pH was seen between groups at any time period. In both groups, total CBF (tCBF) increased significantly with increasing CPP (p = 0.012 and 0.017 for normothermic and hypothermic CPB, respectively; CPP as covariate). The between-group difference in slopes (CPP x temperature effect) approached statistical significance (p = 0.059).(ABSTRACT TRUNCATED AT 250 WORDS)

Earlier discharge with community-based intervention for low birth weight infants: a randomized trial.

BACKGROUND: Prolonged hospitalization of low birth weight infants increases the risk of medical and psychosocial complications. The feasibility of earlier discharge with community-based follow-up of infants of < or = 2000 g birth weight, without the use of home apnea monitors, was investigated. METHODS: One hundred infants of < or = 2000 g birth weight were randomized to either an intervention or control group. Intervention infants were discharged when readiness criteria were met. Based on assessed need, intervention group families received public health nursing and homemaker services for up to 8 weeks. Control infants were discharged to their homes at the discretion of the attending physician. All infants were assessed blindly at age 1 year with the Bayley and Home Observation for Measurement of the Environment (HOME) scales. RESULTS: There were no group differences in baseline infants' characteristics or in neonatal complications. Infants in the intervention group were discharged from the hospital at an earlier postconceptional age (mean +/- SD 36.6 +/- 1.5 weeks vs 37.3 +/- 1.6 weeks; P < .04). Median length of hospital stay (23 days vs 31.5 days) and mean weight at the time of discharge (2200 +/- 288 g vs 2275 +/- 301 g) were lower, but not significantly, for infants in the intervention group. A secondary analysis by birth weight strata (< or = 1500 g and 1501 through 2000 g) revealed that the most significant reductions in hospital stay and weight at discharge were realized in infants of 1501 through 2000 g birth weight. The persistence of apneic episodes and need for electronic monitoring prevented earlier discharge of infants of < or = 1500 g birth weight. Postdischarge services to the intervention group included 185 public health nurse home visits (3.8 +/- 0.91), 410 phone contacts (8.4 +/- 5), and 2298 homemaker hours (46 +/- 78) of service. At 1 year, there were no deaths and no group differences in rehospitalization rates, use of ambulatory services, or Bayley scores. Intervention families had significantly higher 1-year HOME scores. Minimum cost of hospital care was $873 per day, while the total cost of community-based services averaged $626 per infant. CONCLUSIONS: A significant reduction in average length of hospital stay was achieved for infants of 1501 through 2000 g birth weight. Earlier discharge of infants weighing < or = 1500 g at birth was hampered by persistent apneic episodes and feeding difficulties. A community-based program designed to provide individualized support and education for families of low birth weight infants was cost-effective and had a positive influence on the home environment.

Bleeding/bruising symptomatology in children with and without bleeding disorders.

A questionnaire, designed to assess bleeding/bruising tendencies, was administered to 251 otherwise healthy children undergoing a tonsillectomy and/or adenoidectomy. 23 children with excessive bleeding during or after the operation, with a long bleeding time or who reported taking aspirin recently were excluded, to give a population of 228 non-bleeders. For comparative purposes, 31 patients with bleeding disorders (von Willebrand's disease and/or platelet function defects) were studied. A considerable proportion of "non-bleeding" children reported easy bruising (24%), had bruises at least once a week (36%) and suffered from nosebleeds (39%). The respective frequencies (67%, 68% and 69%) for children with bleeding disorders were significantly higher. Occurrence of bruises usually on more than one part of the body, frequent large bruises or hematomas were rare in "non-bleeders" (4.9%, 3.5% and 2.7% respectively), but more common in "bleeders" (38.5%, 29.6% and 21.7% respectively).

The impact of very low-birth-weight infants on the family is long lasting. A matched control study.

OBJECTIVE: To test the hypothesis that parental stress associated with long-term morbidity of very low-birth-weight infants (VLBWIs) is long lasting. DESIGN: Matched case-control study. SETTING: High-risk newborn follow-up program, Winnipeg, Manitoba. PARTICIPANTS: Parents of 96 Manitoban VLBWIs born from July 1986 through June 1990, compared with parents of full-term controls matched for age, sex, race, domicile, singleton or multiple pregnancy, and birth order. MAIN OUTCOME MEASURES: Mailed questionnaire, including Stein's Impact on Family Scale, positive impact of parenthood, and attitudes toward treating VLBWIs. RESULTS: Families were demographically similar. The parents of VLBWIs had higher scores for financial burden, familial/social impact, personal strain, and mastery (P < .0001). The parents of VLBWIs experienced more impact when children had a functional handicap or low adaptive developmental quotient. Scores were highest when the adaptive developmental quotient was 70 to 85. High scores were associated with low family income and less parental education. Impact did not change over time. Only half of the parents in each group felt that "doctors should try to save every baby." The parents of VLBWIs felt more strongly that cost should never enter into the decision to treat a tiny baby (P < .005). The families of VLBWIs expressed a stronger desire for more children (P < .01), but control families were more likely to have given birth again (46.3% vs 28.2%). CONCLUSIONS: The birth and upbringing of a VLBWI is associated with more long-term stress, even for well-educated nuclear families whose health care is financed by government. Caregivers need increased awareness of the needs of these families so that their medical and social needs are met effectively. Support services should be targeted toward low income, poorly educated parents whose children have functional handicaps.

Biologically variable pulsation improves jugular venous oxygen saturation during rewarming.

BACKGROUND: Conventional pulsatile (CP) roller pump cardiopulmonary bypass (CPB) was compared to computer controlled biologically variable pulsatile (BVP) bypass designed to return beat-to-beat variability in rate and pressure with superimposed respiratory rhythms. Jugular venous O2 saturation (SjvO2) below 50% during rewarming from hypothermia was compared for the two bypass techniques. A SjvO2 less than 50% during rewarming is correlated with cognitive dysfunction in humans. METHODS: Pigs were placed on CPB for 3 hours using a membrane oxygenator with alpha-stat acid base management and arterial filtration. After apulsatile normothermic CPB was initiated, animals were randomized to CP (n = 8) or BVP (roller pump speed adjusted by an average of 2.9 voltage output modulations/second; n = 8), then cooled to a nasopharyngeal temperature of 28 degrees C. During rewarming to stable normothermia, SjvO2 was measured at 5 minute intervals. The mean and cumulative area for SjvO2 less than 50% was determined. RESULTS: No between group difference in temperature existed during hypothermic CPB or during rewarming. Mean arterial pressure, arterial partial pressure O2, and arterial partial pressure CO2 did not differ between groups. The hemoglobin concentration was within 0.4 g/dL between groups at all time periods. The range of systolic pressure was greater with BVP (41 +/- 18 mm Hg) than with CP (12 +/- 4 mm Hg). A greater mean and cumulative area under the curve for SjvO2 less than 50% was seen with CP (82 +/- 96 versus 3.6% +/- 7.3% x min, p = 0.004; and 983 +/- 1158 versus 42% +/- 87% x min; p = 0.004, Wilcoxon 2-sample test). CONCLUSIONS: Computer-controlled BVP resulted in significantly greater SjvO2 during rewarming from hypothermic CPB. Both mean and cumulative area under the curve for SjvO2 less than 50% exceeded a ratio of 20 to 1 for CP versus BVP. Cerebral oxygenation is better preserved during rewarming from moderate hypothermia with bypass that returns biological variability to the flow pattern.

Does iron deficiency raise the seizure threshold?

To determine the effect of iron status on the seizure threshold, measures of iron sufficiency were prospectively evaluated in 51 children presenting to a pediatric emergency department with a febrile illness with (26) or without (25) an associated febrile seizure. A higher proportion of children from the febrile seizure group had a family history of mental retardation (5/26 versus 0/25, P = .02) or of previous febrile seizures (10/26 versus 2/23, P = .01). The two groups were otherwise comparable for age, sex, race, family history of afebrile seizures, temperature at presentation, white blood cell count, differential, and vitamin and antibiotic use. Patients with febrile seizures were less frequently iron deficient as defined by a free erythrocyte protoporphyrin level above 0.80 ng/L (2/23 versus 10/25, P < .01), hemoglobin concentration less than 110 g/L (1/26 versus 6/25, P < .03), hematocrit less than 0.30 L/L (0/22 versus 4/25, P < .02), mean corpuscular hemoglobin less than 20 pg (0/25 versus 3/24, P < .04), mean corpuscular volume less than 65 fL (0/26 versus 4/24, P < .02), and platelet count higher than 550 x 10(9)/L (0/26 versus 3/25, P < .04). This association was even stronger when adjusted for differences in family history. None of the patients in the febrile seizure group was being treated for iron deficiency at presentation, whereas three of 25 controls used an iron supplement (P < .04). Iron deficiency may protect against the development of febrile seizures.

The natural history and predictive value of early language delays in very low birth weight infants.

A cohort of 28 VLBW (less than or equal to 1500 g) infants was assessed at 1 and 3 years of age for hearing, language development and neurological status. Language delays were detected in 11 (39%) infants at 1 year, and in four (15%) at follow up at 3 years of age (P less than 0.05). Language quotients were significantly associated with perinatal variables at 1 but not at 3 years of age. Infants with neurological abnormalities had significantly lower language quotients at the 3-year follow up. No child with a normal language profile at 1 year exhibited a delay at 3 years of age.

Language development of very low birth weight infants and fullterm controls at 12 months of age.

Twenty-eight very low birth weight (VLBW) and 32 full term infants were prospectively assessed at one year of age for hearing, language development and neurological status. The prevalence of conductive hearing deficits was the same in both groups. Language scores in VLBW infants were significantly lower than in fullterm controls and 39% had significant language delays. VLBW infants exhibited a shorter attention span and were less likely to understand simple questions, to recognize objects or body parts when named, to initiate speech-gesture games, to follow simple commands and to imitate or use words consistently. Language quotients were directly associated with gestational age and five minute Apgar scores and inversely associated with severity of intraventricular hemorrhage, bronchopulmonary dysplasia and length of hospital stay. VLBW small for gestational age infants exhibited more advanced language skills than VLBW appropriate for gestational age infants. Language delays were more prevalent among, but not limited to, infants with mild to moderate neurological abnormalities. The influence of prematurity and VLBW on language development is complex and multifactorial and research is continuing to determine the predictive validity and long term significance of the early language delays described in this study.

How Baby-Friendly are Manitoba hospitals? The Provincial Infant Feeding Study. Breastfeeding Promotion Steering Committee of Manitoba.

The Breastfeeding Promotion Steering Committee of Manitoba conducted the cross-sectional Provincial Infant Feeding Study in 1996 to examine: correlation between breastfeeding policies and actual practices in Manitoba hospitals; compliance with Baby-Friendly Hospital Initiative (BFHI) criteria; and associations between hospital practices and two-week breastfeeding duration. Three separate surveys obtained information from: administrators concerning hospital policy; nursing staff concerning hospital practices; and all women giving birth in a five-week period, concerning breastfeeding rates and maternal perceptions of hospital practices. The results highlighted the need for policy and practice changes to comply with BFHI criteria. 92% initiated breastfeeding, and 84% were breastfeeding at two weeks postpartum. Independent predictors of weaning included: in-hospital supplementation (adjusted RR = 2.1, 95% CI 1.02-4.36, p = 0.04); temporarily interrupting breastfeeding while in hospital (adjusted RR = 4.9, 95% CI 2.7-8.9, p = 0.0001); no previous breastfeeding experience (adjusted RR = 2.5, 95% CI 1.4-4.4, p = 0.002); and Grade 12 or less maternal education.

MSAFP levels in aboriginal Canadian women.

Maternal serum alpha-fetoprotein (MSAFP) levels in 529 non-diabetic aboriginal Canadian women were compared with levels in 13,285 non-diabetic non-aboriginal women. A woman was considered to be aboriginal if she was listed on the Indian Register of Canada. After controlling for the gestational age on the date at which the sample was drawn and maternal weight, MSAFP levels appeared to be approximately 4 to 5% higher in aboriginal women. The possible implications of this finding on an MSAFP screening program are discussed.

Tolerance to the bronchoprotective effect of salmeterol in adolescents with exercise-induced asthma using concurrent inhaled glucocorticoid treatment.

OBJECTIVES: The long-acting beta2-adrenergic agonist salmeterol prevents exercise-induced asthma, but tolerance may develop to its bronchoprotective effect. We wanted to ascertain if the development of tolerance could be prevented by using a low-dose treatment regimen of 50 microg once daily, instead of the usual dose of 50 microg twice daily, in adolescents receiving regular glucocorticoid inhalations. Methods. In a randomized, double-blind, 2x28-day crossover study, we administered salmeterol (50 microg) or placebo once daily via a metered-dose inhaler and Nebulizer Chronolog device to monitor compliance. Exercise challenge tests were performed 1 and 9 hours after salmeterol or placebo inhalation on the 1st and 28th day of each treatment period. The primary outcome variable was the maximum decrease in percent predicted FEV1 postexercise. RESULTS: Fourteen subjects with a mean age of 13.1 years completed the study. The first dose of salmeterol had an excellent bronchoprotective effect against exercise-induced asthma at 1 and 9 hours. After the 28th consecutive daily dose of salmeterol, the bronchoprotective effect was significantly greater than that of placebo at 1 hour, but not at 9 hours. CONCLUSIONS: We conclude that a single 50-microg dose of salmeterol has an excellent protective effect against exercise-induced asthma for at least 9 hours, but that this effect may wane during regular once-daily salmeterol treatment, despite the reduced frequency of dosing and despite concomitant use of inhaled glucocorticoids.

The relationship of brachiocephalic vessel atheroma to transient ischemia of the brain and retina.

The relationships between transient cerebral and retinal ischemic symptoms and brachiocephalic angiographic findings were studied in 464 patients. The arterial abnormalities were more often bilateral than the symptoms suggested. Normal angiographic appearances were common, although abnormal arteries in patients without related symptoms were also common. When stenosis of the carotid system was 75 per cent or more, there was a strong correlation with symptoms.

Improved hemophilia A carrier detection by DDAVP stimulation of factor VIII.

We studied the differential increase in FVIIIc and FVIII R:Ag after the intravenous infusion of 0.30 micrograms/kg DDAVP in 20 obligate hemophilia A carriers and in 20 female controls. FVIIIc increased in carriers (59.5 +/- 23.1 to 137.5 +/- 45.9) and in controls (98.0 +/- 20.7 to 259.9 +/- 57.4) (P less than 0.001), but the magnitude of the FVIIIc increase in carriers was less than that in controls by 51.9% (P less than 0.001). FVIII R:Ag increased comparably in carriers (105.2 +/- 30.4 to 171.9 +/- 25.4) and controls (92.1 +/- 33.0 to 165.2 +/- 20.6). Using the post-DDAVP instead of the standard FVIIIc/FVIII R:Ag ratio, hemophilia carrier detection was increased from 85% (with 10% false positive and 20% false negative assignments) to 95% (with 5% false positive and 5% false negative assignments). Toxicity associated with DDAVP infusion correlated linearly with doses greater than 10.5 +/- 1.3 micrograms/m2 (P less than 0.02) and with total doses greater than 17.0 +/- 4.5 micrograms (P less than 0.02). The use of DDAVP improves carrier detection in factor VIII-deficient hemophilia.

Income-based drug benefit policy: impact on receipt of inhaled corticosteroid prescriptions by Manitoba children with asthma.

BACKGROUND: Drug benefit policies are an important determinant of a population's use of prescription drugs. This study was undertaken to determine whether a change in a provincial drug benefit policy, from a fixed deductible and copayment system to an income-based deductible system, resulted in changes in receipt of prescriptions for inhaled corticosteroids by Manitoba children with asthma. METHODS: Using Manitoba's health care administrative databases, we identified a population-based cohort of 10,703 school-aged children who met our case definition for asthma treatment before and after the province's drug benefit policy was changed in April 1996. The effects of the program change on the probability of receiving a prescription for an inhaled corticosteroid and on the mean number of inhaled corticosteroid doses dispensed were compared between a group of children insured under other drug programs (the comparison group) and 2 groups of children insured under the deductible program: those living in low-income neighbourhoods and those living in higher-income neighbourhoods. All analyses were adjusted for a measure of asthma severity. RESULTS: For higher-income children with severe asthma who were covered by the deductible program, the probability of receiving an inhaled corticosteroid prescription and the mean annual number of inhaled corticosteroid doses declined after the change to the drug policy. A trend toward a decrease in receipt of prescriptions was also observed for low-income children, but receipt of prescriptions was unaltered in the comparison group. Before the policy change, among children with severe asthma, the mean annual number of inhaled corticosteroid doses was lowest for low-income children, and this pattern persisted after the change. Among children with mild to moderate asthma, those covered by the deductible program (both low income and higher income) were less likely to receive prescriptions for inhaled corticosteroids than those in the comparison group, and this difference was statistically significant for the higher-income children. INTERPRETATION: The change to an income-based drug benefit policy was associated with a decrease in the use of inhaled corticosteroids by higher-income children with severe asthma and did not improve use of these drugs by low-income children.

Invasive fungal disease in adults undergoing remission-induction therapy for acute myeloid leukemia: the pathogenetic role of the antileukemic regimen.

Using multivariate techniques, we studied the relationships of cytotoxic regimen, intestinal mucosal damage, and fungal colonization in the pathogenesis of invasive fungal disease in 138 patients undergoing induction therapy for untreated acute myeloid leukemia (AML) according to three institutional protocols: AML-84 (cytarabine/daunorubicin), AML-87 (high-dose cytarabine/etoposide/daunorubicin), and AML-88 (mitoxantrone/etoposide). Invasive fungal disease occurred in 36%, 6%, and 2.6% of patients participating in protocols AML-87, AML-84, and AML-88, respectively (chi 2 = 23.465; P < .0001). Protocol AML-87 was the strongest independent predictor in the multivariate model (RR = 26.7; P < .0001). Cytotoxic therapy-related epithelial damage in the gut, as measured by D-xylose malabsorption, correlated with invasive fungal disease and protocol AML-87. Fungal colonization, a predictor of invasive fungal disease, correlated with frequent modifications of antibiotic regimens. These results demonstrate the role of cytotoxic regimen-related gut epithelial damage, antibiotic-prescribing behavior, and fungal colonization in the pathogenesis of invasive fungal disease in patients with leukemia.

Hyperphosphatemia in infantile hypophosphatasia: implications for carrier diagnosis and screening.

Twenty obligate carriers of infantile hypophosphatasia (HOPS), a severe autosomal recessive metabolic bone disorder, were studied and compared with 36 controls. Decreased serum alkaline phosphatase activity and increased urinary phosphoethanolamine excretion were confirmed in the HOPS carriers. Relative hyperphosphatemia was documented for the first time in the carriers. Logistic regression analysis was used to develop models for the diagnosis of and screening for HOPS carriers in the high-risk population of Manitoba Mennonites. Models based on serum alkaline phosphatase activity and on serum phosphate levels with or without urinary phosphoethanolamine excretion were used for diagnostic purposes. A model based on serum alkaline phosphatase activity and on the serum phosphate level was the most suitable for screening.

Acute myeloid leukemia in Manitoba. The consequences of standard "7 + 3" remission-induction therapy followed by high dose cytarabine postremission consolidation for myelosuppression, infectious morbidity, and outcome.

BACKGROUND: To the authors' knowledge, the natural history of myelosuppression and infectious complications associated with the use of standard cytarabine (ARA-C) plus daunorubicin ("7 + 3") remission-induction therapy for adult acute myeloid leukemia (AML) and high dose ARA-C (HDARA-C) consolidation has not been described completely. METHODS: A retrospective study of untreated adult AML patients receiving standard 7 + 3 induction followed by "5 + 2" and HDARA-C consolidation was undertaken to describe the relationship of the myelosuppression profiles, blood product use, and infectious morbidity, and to correlate this finding with the outcome of antileukemic therapy. Multivariate techniques were used to evaluate variables of prognostic importance. RESULTS: Fifty-nine percent of the patients achieved remission after a median of 35 days; almost half (48%) of these patients required more than one 7 + 3 induction course. For one, two, and three induction courses, the mean number of days the patients experienced severe neutropenia (< 0.5 x 10(9)/l) were 22.5 +/- 10.9, 39.3 +/- 14.3, and 47.4 +/- 9.7 days (P < 0.001), respectively, and the infection rates were 1.45, 2.45, and 3 infections per course (P < 0.0001), respectively. The pattern of blood product use was similar. HDARA-C consolidation was the most significant factor related to prolonged disease free survival, however the myelosuppression profiles and infection rates were surprisingly similar to those for the single 7 + 3 induction courses. CONCLUSIONS: The 7 + 3 induction regimen used in this center provided only limited antileukemic activity, while requiring multiple induction courses in a high proportion of patients. The use of multiple induction courses had consequences of prolonged myelosuppression, increased blood product use, and incremental risks of infectious complications. HDARA-C consolidation for those who experienced complete remission appeared to improve disease free survival with myelosuppression comparable with that of patients who received primary induction therapy. The infection risk was acceptable, with only a marginal increase in bacteremic and fungal infections.