Supplementing an energy adequate, higher protein diet with protein does not enhance fat-free mass restoration after short-term severe negative energy balance.

Negative energy balance during military operations can be severe and result in significant reductions in fat-free mass (FFM). Consuming supplemental high-quality protein following such military operations may accelerate restoration of FFM. Body composition (dual-energy X-ray absorptiometry) and whole body protein turnover (single-pool [15N]alanine method) were determined before (PRE) and after 7 days (POST) of severe negative energy balance during military training in 63 male US Marines (means ± SD, 25 ± 3 yr, 84 ± 9 kg). After POST measures were collected, volunteers were randomized to receive higher protein (HIGH: 1,103 kcal/day, 133 g protein/day), moderate protein (MOD: 974 kcal/day, 84 g protein/day), or carbohydrate-based low protein control (CON: 1,042 kcal/day, 7 g protein/day) supplements, in addition to a self-selected, ad libitum diet, for the 27-day intervention (REFED). Measurements were repeated POST-REFED. POST total body mass (TBM; -5.8 ± 1.0 kg, -7.0%), FFM (-3.1 ± 1.6 kg, -4.7%), and net protein balance (-1.7 ± 1.1 g protein·kg-1·day-1) were lower and proteolysis (1.1 ± 1.9 g protein·kg-1·day-1) was higher compared with PRE (P < 0.05). Self-selected, ad libitum dietary intake during REFED was similar between groups (3,507 ± 730 kcal/day, 2.0 ± 0.5 g protein·kg-1·day-1). However, diets differed by protein intake due to supplementation (CON: 2.0 ± 0.4, MOD: 3.2 ± 0.7, and HIGH: 3.5 ± 0.7 g·kg-1·day-1; P < 0.05) but not total energy (4,498 ± 725 kcal/day). All volunteers, independent of group assignment, achieved positive net protein balance (0.4 ± 1.0 g protein·kg-1·day-1) and gained TBM (5.9 ± 1.7 kg, 7.8%) and FFM (3.6 ± 1.8 kg, 5.7%) POST-REFED compared with POST (P < 0.05). Supplementing ad libitum, energy-adequate, higher protein diets with additional protein may not be necessary to restore FFM after short-term severe negative energy balance.NEW & NOTEWORTHY This article demonstrates 1) the majority of physiological decrements incurred during military training (e.g., total and fat-free mass loss), with the exception of net protein balance, resolve and return to pretraining values after 27 days and 2) protein supplementation, in addition to an ad libitum, higher protein (~2.0 g·kg-1·day-1), energy adequate diet, is not necessary to restore fat-free mass following short-term severe negative energy balance.

Effects of an amylopectin and chromium complex on the anabolic response to a suboptimal dose of whey protein.

BACKGROUND: Previous research has demonstrated the permissive effect of insulin on muscle protein kinetics, and the enhanced insulin sensitizing effect of chromium. In the presence of adequate whole protein and/or essential amino acids (EAA), insulin has a stimulatory effect on muscle protein synthesis, whereas in conditions of lower blood EAA concentrations, insulin has an inhibitory effect on protein breakdown. In this study, we determined the effect of an amylopectin/chromium (ACr) complex on changes in plasma concentrations of EAA, insulin, glucose, and the fractional rate of muscle protein synthesis (FSR). METHODS: Using a double-blind, cross-over design, ten subjects (six men, four women) consumed 6 g whey protein + 2 g of the amylopectin-chromium complex (WPACr) or 6 g whey protein (WP) after an overnight fast. FSR was measured using a primed, continuous infusion of ring-d5-phenylalanine with serial muscle biopsies performed at 2, 4, and 8 h. Plasma EAA and insulin were assayed by ion-exchange chromatography and ELISA, respectively. After the biopsy at 4 h, subjects ingested their respective supplement, completed eight sets of bilateral isotonic leg extensions at 80% of their estimated 1-RM, and a final biopsy was obtained 4 h later. RESULTS: Both trials increased EAA similarly, with peak levels noted 30 min after ingestion. Insulin tended (p = 0.09) to be higher in the WPACr trial. Paired samples t-tests using baseline and 4-h post-ingestion FSR data separately for each group revealed significant increases in the WPACr group (+0.0197%/h, p = 0.0004) and no difference in the WP group (+0.01215%/hr, p = 0.23). Independent t-tests confirmed significant (p = 0.045) differences in post-treatment FSR between trials. CONCLUSIONS: These data indicate that the addition of ACr to a 6 g dose of whey protein (WPACr) increases the FSR response beyond what is seen with a suboptimal dose of whey protein alone.

Pediatric T- and NK-cell lymphomas: new biologic insights and treatment strategies.

T- and natural killer (NK)-cell lymphomas are challenging childhood neoplasms. These cancers have varying presentations, vast molecular heterogeneity, and several are quite unusual in the West, creating diagnostic challenges. Over 20 distinct T- and NK-cell neoplasms are recognized by the 2008 World Health Organization classification, demonstrating the diversity and potential complexity of these cases. In pediatric populations, selection of optimal therapy poses an additional quandary, as most of these malignancies have not been studied in large randomized clinical trials. Despite their rarity, exciting molecular discoveries are yielding insights into these clinicopathologic entities, improving the accuracy of our diagnoses of these cancers, and expanding our ability to effectively treat them, including the use of new targeted therapies. Here, we summarize this fascinating group of lymphomas, with particular attention to the three most common subtypes: T-lymphoblastic lymphoma, anaplastic large cell lymphoma, and peripheral T-cell lymphoma-not otherwise specified. We highlight recent findings regarding their molecular etiologies, new biologic markers, and cutting-edge therapeutic strategies applied to this intriguing class of neoplasms.

Redundancy and specificity of the metalloprotease system mediating oncogenic NOTCH1 activation in T-ALL.

Oncogenic mutations in NOTCH1 are present in over 50% of T-cell lymphoblastic leukemias (T-ALLs). Activation of NOTCH1 requires a double proteolytic processing in the extracellular region of the receptor (S2) and in the transmembrane domain (S3). Currently, anti-NOTCH1 therapies based on the inhibition of S3 processing via small molecule γ-secretase inhibitors are in development. Here we report on the characterization of the protease system responsible for S2 processing of NOTCH1 in T-ALL. Analysis of NOTCH1 heterodimerization (HD) class I, NOTCH1 HD class II and NOTCH1 JME alleles characterized by increased and aberrant S2 processing shows that both ADAM10 (a disintegrin and metalloprotease 10), a metalloprotease previously implicated in activation of wild-type NOTCH1 in mammalian cells, and ADAM17, a closely related protease capable of processing NOTCH1 in vitro, contribute to the activation of oncogenic forms of NOTCH1. However, and despite this apparent functional redundancy, inhibition of ADAM10 is sufficient to blunt NOTCH1 signaling in T-ALL lymphoblasts. These results provide further insight on the mechanisms that control the activation of oncogenic NOTCH1 mutants and identify ADAM10 as potential therapeutic target for the inhibition of oncogenic NOTCH1 in T-ALL.

Artificial gravity maintains skeletal muscle protein synthesis during 21 days of simulated microgravity.

We sought to determine the effects of longitudinal loading (artificial gravity) on skeletal muscle protein kinetics in 15 healthy young males after 21 days of 6 degrees head-down tilt bed rest [experimental treatment (Exp) group: n = 8, 31 +/- 1 yr; control (Con) group; n = 7, 28 +/- 1 yr, means +/- SE]. On days 1 and 21 of bed rest, postabsorptive venous blood samples and muscle biopsies (vastus lateralis and soleus) were obtained during a 1-h pulse bolus infusion protocol (0 min, l-[ring-(13)C(6)]phenylalanine, 35 mumol/kg; 30 min, l-[ring-(15)N]phenylalanine, 35 mumol/kg). Outcome measures included mixed muscle fractional synthesis (FSR) and breakdown rates (FBR). The Exp group experienced 1 h of longitudinal loading (2.5G at the feet) via a short-radius centrifuge during each day of bed rest. Mixed muscle FSR in the Con group was reduced by 48.5% (day 1, 0.081 +/- 0.000%/h vs. day 21, 0.042 +/- 0.000%/h; P = 0.001) in vastus lateralis after 21 days of bed rest, whereas the Exp group maintained their rate of protein synthesis. A similar but nonsignificant change in FSR was noted for the soleus muscle (Exp, -7%; Con, -22%). No changes in muscle protein breakdown were observed. In conclusion, 1 h of daily exposure to artificial gravity maintained the rate of protein synthesis of the vastus lateralis and may represent an effective adjunct countermeasure to combat the loss of muscle mass and functional during extended spaceflight.

NOTCH inhibition and glucocorticoid therapy in T-cell acute lymphoblastic leukemia.

Inhibition of NOTCH1 signaling with gamma-secretase inhibitors (GSIs) has been proposed as a molecularly targeted therapy in T-cell acute lymphoblastic leukemia (T-ALL). However, GSIs seem to have limited antileukemic activity in human T-ALL and are associated with severe gastrointestinal toxicity resulting from inhibition of NOTCH signaling in the gut. Inhibition of NOTCH1 signaling in glucocorticoid-resistant T-ALL restored glucocorticoid sensitivity and co-treatment with glucocorticoids inhibited GSI-induced gut toxicity. Thus, combination therapies with GSIs plus glucocorticoids may offer a new opportunity for the use of anti-NOTCH1 therapies in human T-ALL.

Genomic tools for dissecting oncogenic transcriptional networks in human leukemia.

Chromatin immunoprecipitation (ChIP)-chip and ChIP-seq technologies are rapidly expanding our capacity to interrogate the location of transcription factor-binding sites in the human genome and to map the pattern of chromatin modifications associated with the regulation of gene expression. The application of these techniques to the study of hematologic malignancies will complement gene expression profiling studies to elucidate the structure and function of oncogenic transcriptional networks involved in the pathogenesis of leukemias and lymphomas.

The deleterious effects of bed rest on human skeletal muscle fibers are exacerbated by hypercortisolemia and ameliorated by dietary supplementation.

Prolonged inactivity associated with bed rest in a clinical setting or spaceflight is frequently associated with hypercortisolemia and inadequate caloric intake. Here, we determined the effect of 28 days of bed rest (BR); bed rest plus hypercortisolemia (BRHC); and bed rest plus essential amino acid (AA) and carbohydrate (CHO) supplement (BRAA) on the size and function of single slow- and fast-twitch muscle fibers. Supplementing meals, the BRAA group consumed 16.5 g essential amino acids and 30 g sucrose at 1100, 1600, and 2100 h, and the BRHC subjects received 5 daily doses of 10-15 mg of oral hydrocortisone sodium succinate throughout bed rest. Bed rest induced atrophy and loss of force (mN) and power (muN.FL.s(-1)) in single fibers was exacerbated by hypercortisolemia where soleus peak force declined by 23% in the type I fiber from a prevalue of 0.78 +/- 0.02 to 0.60 +/- 0.02 mN post bed rest (compared to a 7% decline with bed rest alone) and 27% in the type II fiber (1.10 +/- 0.08 vs. 0.81 +/- 0.05 mN). In the BRHC group, peak power dropped by 19, 15, and 11% in the soleus type I, and vastus lateralis (VL) type I and II fibers, respectively. The AA/CHO supplement protected against the bed rest-induced loss of peak force in the type I soleus and peak power in the VL type II fibers. These results provide evidence that an AA/CHO supplement might serve as a successful countermeasure to help preserve muscle function during periods of relative inactivity.

Activating mutations in NOTCH1 in acute myeloid leukemia and lineage switch leukemias.

Activating mutations in NOTCH1 are found in over 50% of human T-cell lymphoblastic leukemias (T-ALLs). Here, we report the analysis for activating NOTCH1 mutations in a large number of acute myeloid leukemia (AML) primary samples and cell lines. We found activating mutations in NOTCH1 in a single M0 primary AML sample, in three (ML1, ML2 and CTV-1) out of 23 AML cell lines and in the diagnostic (myeloid) and relapsed (T-lymphoid) clones in a patient with lineage switch leukemia. Importantly, the ML1 and ML2 AML cell lines are derived from an AML relapse in a patient initially diagnosed with T-ALL. Overall, these results demonstrate that activating mutations in NOTCH1 are mostly restricted to T-ALL and are rare in AMLs. The presence of NOTCH1 mutations in myeloid and T-lymphoid clones in lineage switch leukemias establishes the common clonal origin of the diagnostic and relapse blast populations and suggests a stem cell origin of NOTCH1 mutations during the molecular pathogenesis of these tumors.

CUTLL1, a novel human T-cell lymphoma cell line with t(7;9) rearrangement, aberrant NOTCH1 activation and high sensitivity to gamma-secretase inhibitors.

Activating mutations in NOTCH1 are present in over 50% of human T-cell lymphoblastic leukemia (T-ALL) samples and inhibition of NOTCH1 signaling with gamma-secretase inhibitors (GSI) has emerged as a potential therapeutic strategy for the treatment of this disease. Here, we report a new human T-cell lymphoma line CUTLL1, which expresses high levels of activated NOTCH1 and is extremely sensitive to gamma-secretase inhibitors treatment. CUTLL1 cells harbor a t(7;9)(q34;q34) translocation which induces the expression of a TCRB-NOTCH1 fusion transcript encoding a membrane-bound truncated form of the NOTCH1 receptor. GSI treatment of CUTLL1 cells blocked NOTCH1 processing and caused rapid clearance of activated intracellular NOTCH1. Loss of NOTCH1 activity induced a gene expression signature characterized by the downregulation of NOTCH1 target genes such as HES1 and NOTCH3. In contrast with most human T-ALL cell lines with activating mutations in NOTCH1, CUTLL1 cells showed a robust cellular phenotype upon GSI treatment characterized by G1 cell cycle arrest and increased apoptosis. These results show that the CUTLL1 cell line has a strong dependence on NOTCH1 signaling for proliferation and survival and supports that T-ALL patients whose tumors harbor t(7;9) should be included in clinical trials testing the therapeutic efficacy NOTCH1 inhibition with GSIs.

A new recurrent 9q34 duplication in pediatric T-cell acute lymphoblastic leukemia.

Over the last decade, genetic characterization of T-cell acute lymphoblastic leukemia (T-ALL) has led to the identification of a variety of chromosomal abnormalities. In this study, we used array-comparative genome hybridization (array-CGH) and identified a novel recurrent 9q34 amplification in 33% (12/36) of pediatric T-ALL samples, which is therefore one of the most frequent cytogenetic abnormalities observed in T-ALL thus far. The exact size of the amplified region differed among patients, but the critical region encloses approximately 4 Mb and includes NOTCH1. The 9q34 amplification may lead to elevated expression of various genes, and MRLP41, SSNA1 and PHPT1 were found significantly expressed at higher levels. Fluorescence in situ hybridization (FISH) analysis revealed that this 9q34 amplification was in fact a 9q34 duplication on one chromosome and could be identified in 17-39 percent of leukemic cells at diagnosis. Although this leukemic subclone did not predict for poor outcome, leukemic cells carrying this duplication were still present at relapse, indicating that these cells survived chemotherapeutic treatment. Episomal NUP214-ABL1 amplification and activating mutations in NOTCH1, two other recently identified 9q34 abnormalities in T-ALL, were also detected in our patient cohort. We showed that both of these genetic abnormalities occur independently from this newly identified 9q34 duplication.

Amino acid supplementation alters bone metabolism during simulated weightlessness.

High-protein and acidogenic diets induce hypercalciuria. Foods or supplements with excess sulfur-containing amino acids increase endogenous sulfuric acid production and therefore have the potential to increase calcium excretion and alter bone metabolism. In this study, effects of an amino acid/carbohydrate supplement on bone resorption were examined during bed rest. Thirteen subjects were divided at random into two groups: a control group (Con, n = 6) and an amino acid-supplemented group (AA, n = 7) who consumed an extra 49.5 g essential amino acids and 90 g carbohydrate per day for 28 days. Urine was collected for n-telopeptide (NTX), deoxypyridinoline (DPD), calcium, and pH determinations. Bone mineral content was determined and potential renal acid load was calculated. Bone-specific alkaline phosphatase was measured in serum samples collected on day 1 (immediately before bed rest) and on day 28. Potential renal acid load was higher in the AA group than in the Con group during bed rest (P < 0.05). For all subjects, during bed rest urinary NTX and DPD concentrations were greater than pre-bed rest levels (P < 0.05). Urinary NTX and DPD tended to be higher in the AA group (P = 0.073 and P = 0.056, respectively). During bed rest, urinary calcium was greater than baseline levels (P < 0.05) in the AA group but not the Con group. Total bone mineral content was lower after bed rest than before bed rest in the AA group but not the Con group (P < 0.05). During bed rest, urinary pH decreased (P < 0.05), and it was lower in the AA group than the Con group. These data suggest that bone resorption increased, without changes in bone formation, in the AA group.

The effect of prolonged euglycemic hyperinsulinemia on lean body mass after severe burn.

BACKGROUND: The hypermetabolic response to burn increases protein catabolism. Euglycemic hyperinsu-linemia with exogenous insulin maintains muscle protein by continued stimulation of net protein synthesis. Our aim was to determine the effect of euglycemic hyperinsulinemia over the entire hospitalization on muscle anabolism by investigating lean body mass (LBM) as the primary endpoint. METHODS: Eighteen subjects between the ages of 2 and 18 with burns of more than 40% were prospectively randomized into 2 groups, a control (n = 9) and a treatment group (n = 9). The treatment group was given continuous intravenous insulin at a rate of at least 1.5 microU/kg/min to maintain serum glucose levels between 100 to 140 mg/dL. Treatment was instituted 24 to 48 hours after arrival and continued until the patient's injury was 95% healed. All patients received continuous enteral feeding. Patients underwent body composition studies by dual-energy x-ray absorptiometry (DEXA) scan on postoperative day 6 after initial burn excision and when 95% healed. RESULTS: Nutritional intakes were not different between groups. In the control, subjects continued catabolism resulted in peripheral muscle wasting and centripetal obesity with diminished truncal LBM. The treatment group had improvement in lean body mass (P =.004) and bone mass (P =.025). The treatment group also had less peripheral muscle wasting with overall increases in upper/lower extremity LBM (P =.005). Hospital length of stay in days per percent of total body surface area burned was decreased in the insulin group (control = 1.03 +/- 0.1 vs 0.7 +/- 0.9 for insulin patients; P <.05). CONCLUSIONS: Euglycemic hyperinsulinemia throughout the hospital course mitigates muscle catabolism and preserves lean body mass.

Molecular cloning and developmental expression of Tlx (Hox11) genes in zebrafish (Danio rerio).

Tlx (Hox11) genes are orphan homeobox genes that play critical roles in the regulation of early developmental processes in vertebrates. Here, we report the identification and expression patterns of three members of the zebrafish Tlx family. These genes share similar, but not identical, expression patterns with other vertebrate Tlx-1 and Tlx-3 genes. Tlx-1 is expressed early in the developing hindbrain and pharyngeal arches, and later in the putative splenic primordium. However, unlike its orthologues, zebrafish Tlx-1 is not expressed in the cranial sensory ganglia or spinal cord. Two homologues of Tlx-3 were identified: Tlx-3a and Tlx-3b, which are both expressed in discrete regions of the developing nervous system, including the cranial sensory ganglia and Rohon-Beard neurons. However, only Tlx-3a is expressed in the statoacoustic cranial ganglia, enteric neurons and non-neural tissues such as the fin bud and pharyngeal arches and Tlx-3b is only expressed in the dorsal root ganglia.

Immune responses and latent herpesvirus reactivation in spaceflight.

BACKGROUND: Increased frequency and severity of herpesvirus infections are common in individuals with impaired cellular immunity, a phenomenon observed in both the elderly and astronauts alike. This study investigated immune responses and latent herpesvirus reactivation during a 9-d spaceflight. In addition, adrenocortical and immune responses of an elderly astronaut (payload specialist-2, PS2; age 77) who flew on this mission were compared with that of younger crewmembers. HYPOTHESIS: Spaceflight and associated stresses will decrease cellular immunity and reactivate latent herpesviruses. METHODS: Blood and urine samples, collected from the seven crewmembers who flew on the Space Shuttle Discovery (STS-95), were analyzed for levels of neuroendocrine hormones, leukocyte and lymphocyte subsets, and evidence of herpes-virus reactivation. RESULTS: Prior to flight, increased antibody titers to latent Epstein-Barr virus were found. During flight, acute changes in dehydroepiandrosterone sulfate (DHEAS) and cortisol resulted in a pronounced decrease in the DHEAS/cortisol ratio by the end of the mission for PS2 and a younger crewmember. Shedding of cytomegalovirus (CMV) in urine and increased CMV antibody titers also occurred inflight. At landing, the percent increases in adrenocorticotropic hormone and cortisol were greatest for PS2 as compared with the other six crewmembers. A significant neutrophilia also was observed in all crewmembers. Notably, PS2 had large increases in monocytes and natural killer cells at landing while other crewmembers showed little change or a decrease. CONCLUSIONS: These findings indicate that spaceflight and associated stresses reactivate latent herpesviruses and suggest that acute changes in neuroendocrine hormones mediate these changes in part by downregulating cellular immunity. Moreover, the similarities between aging and spaceflight suggest that the study of the immune system in elderly subjects may be useful as a predictive model for astronauts enduring long-term spaceflights.

Testosterone administration in severe burns ameliorates muscle catabolism.

OBJECTIVE: To assess the effects of testosterone administration on muscle protein metabolism after severe burn injury. We hypothesized that restoration of blood testosterone concentrations would restore an important anabolic stimulus to skeletal muscle, and would further increase the anabolic response of muscle to amino acid supplementation. DESIGN: Pre- and postintervention trial conducted between September 1997 and July 1999. SETTING: Burn intensive care unit. PATIENTS: Six severely burned male patients (>70% total body surface area). INTERVENTION: Testosterone enanthate, 200 mg/wk (intramuscularly), for 2 wks. MEASUREMENTS AND MAIN RESULTS: Muscle protein synthesis, breakdown, and amino acid kinetics were determined. After a basal period in each study, we subsequently investigated the response to acute amino acid supplementation during enteral feeding. Total testosterone increased significantly from baseline to the low normal range after 1 wk, and to upper normal range after two injections (p <.001). Protein synthesis was unchanged, however, protein synthetic efficiency increased 2-fold (p <.01). Protein breakdown decreased almost 2-fold after testosterone enanthate (p <.05), resulting in an improvement in net amino acid balance to a value that was approximately zero (p <.0001). Amino acid supplementation at either time point provided no additional effects. CONCLUSIONS: Restoration of blood testosterone can ameliorate the muscle catabolism of severe burn injury with normal feedings.

Altered GLUT1 and GLUT3 gene expression and subcellular redistribution of GLUT4: protein in muscle from patients with acanthosis nigricans and severe insulin resistance.

Multiple isoforms of glucose transporters are found in muscle, the tissue that normally accounts for 85% of insulin-stimulated glucose uptake. Glucose uptake into muscle cells in the fasting state is mediated primarily by GLUT1 and GLUT3 glucose transporters, whereas postprandial (insulin-stimulated) and exercise-related increments in muscle glucose uptake are mediated primarily by GLUT4. To determine if glucose transporters are abnormally expressed in muscle from insulin-resistant subjects, muscle samples were obtained from 10 normal subjects and 6 obese, nondiabetic subjects with severe insulin resistance and acanthosis nigricans. Both GLUT4 total protein and mRNA were normal in the insulin-resistant subjects. Muscle GLUT3 protein and mRNA were lower than controls by 62% and 71%, respectively. GLUT1 mRNA was twice normal, whereas GLUT1 protein content was not significantly increased. GLUT4 protein was markedly redistributed to the muscle plasma membrane in subjects with severe insulin resistance compared with normals (92% v 40% GLUT4 in plasma membrane-enriched fractions, P <.001), whereas the percentage of GLUT1 and GLUT3 protein found in the plasma membrane-enriched fractions was not different from controls. These data document differences in the expression of genes for GLUT1 and GLUT3 in muscle from normal and insulin-resistant subjects. Further, insulin resistance with fasting hyperinsulinemia was associated with a redistribution of GLUT4 to the muscle cell surface with no change in total GLUT4 protein. These data suggest that glucose transporter gene expression and their basal distribution in human muscle are related to insulin resistance and could be determinants of whole body insulin responsiveness.

Anabolic effects of oxandrolone after severe burn.

OBJECTIVE: To explore the hypothesis that oxandrolone may reverse muscle catabolism in cachectic, critically ill pediatric burn patients. SUMMARY BACKGROUND DATA: Severe burn causes exaggerated muscle protein catabolism, contributing to weakness and delayed healing. Oxandrolone is an anabolic steroid that has been used in cachectic hepatitis and AIDS patients. METHODS: Fourteen severely burned children were enrolled during a 5-month period in a prospective cohort analytic study. There was a prolonged delay in the arrival of these patients to the burn unit for definitive care. This neglect of skin grafting and nutritional support resulted in critically ill children with significant malnutrition. On arrival, all patients underwent excision and skin grafting and received similar clinical care. Subjects were studied 5 to 7 days after admission, and again after 1 week of oxandrolone treatment at 0.1 mg/kg by mouth twice daily or no pharmacologic treatment. Muscle protein kinetics were derived from femoral arterial and venous blood samples and vastus lateralis muscle biopsies during a stable isotope infusion. RESULTS: Control and oxandrolone subjects were similar in age, weight, and percentage of body surface area burned. Muscle protein net balance decreased in controls and improved in the oxandrolone group. The improvement in the oxandrolone group was associated with increased protein synthesis efficiency. Muscle protein breakdown was unchanged. CONCLUSIONS: In burn victims, oxandrolone improves muscle protein metabolism through enhanced protein synthesis efficiency. These findings suggest the efficacy of oxandrolone in impeding muscle protein catabolism in cachectic, critically injured children.

Clinical implications of recurring chromosomal and associated molecular abnormalities in acute lymphoblastic leukemia.

Comprehensive study of the major chromosomal/molecular abnormalities in children and adults with acute lymphoblastic leukemia (ALL) has demonstrated prognostic utility for many of these anomalies, to the extent that cytogenetic and molecular genetic evaluations are now required for optimal clinical management of newly diagnosed cases. For example, the t(12;21)/TEL-AML1 (ETV6-CBFA2) or hyperdiploid karyotypes each identifies subgroups of children who can be cured with well-tolerated chemotherapy based primarily on drugs with few long-term toxicities, such as L-asparaginase and antimetabolites. By contrast, the t(1;19)/E2A-PBX1 identifies a subtype of ALL that responds much better to more intensive regimens that rely on genotoxic drugs. At the extreme end of the risk spectrum, the t(4;11)/MLL-AF4 and t(9;22)/BCR-ABL almost always confer a dire prognosis in both children and adults with ALL, who warrant high-dose chemotherapy and hematopoietic stem cell rescue to sustain or even induce first remission. Such chromosomal/molecular markers are being incorporated into risk classification schemes, as they convey prognostic information that cannot be gleaned from conventional risk factors such as immunophenotype, presenting age, and the initial circulating leukemic blast cell count. The most exciting prospect is the discovery of drugs that inhibit specific oncogenes, as illustrated by the BCR-ABL tyrosine kinase inhibitor STI-571.