Shriners Hospitals for Children

This study was designed to evaluate the effects of enriching an essential amino acid (EAA) mixture with leucine on muscle protein metabolism in elderly and young individuals. Four (2 elderly and 2 young) groups were studied before and after ingestion of 6.7 g of EAAs. EAAs were based on the composition of whey protein [26% leucine (26% Leu)] or were enriched in leucine [41% leucine (41% Leu)]. A primed, continuous infusion of L-[ring-2H5]phenylalanine was used together with vastus lateralis muscle biopsies and leg arteriovenous blood samples for the determinations of fractional synthetic rate (FSR) and balance of muscle protein. FSR increased following amino acid ingestion in both the 26% (basal: 0.048 +/- 0.005%/h; post-EAA: 0.063 +/- 0.007%/h) and the 41% (basal: 0.036 +/- 0.004%/h; post-EAA: 0.051 +/- 0.007%/h) Leu young groups (P < 0.05). In contrast, in the elderly, FSR did not increase following ingestion of 26% Leu EAA (basal: 0.044 +/- 0.003%/h; post-EAA: 0.049 +/- 0.006%/h; P > 0.05) but did increase following ingestion of 41% Leu EAA (basal: 0.038 +/- 0.007%/h; post-EAA: 0.056 +/- 0.008%/h; P < 0.05). Similar to the FSR responses, the mean response of muscle phenylalanine net balance, a reflection of muscle protein balance, was improved (P < 0.05) in all groups, with the exception of the 26% Leu elderly group. We conclude that increasing the proportion of leucine in a mixture of EAA can reverse an attenuated response of muscle protein synthesis in elderly but does not result in further stimulation of muscle protein synthesis in young subjects.

The transfer of gram-positive bacteria, particularly multiresistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), among patients is a growing concern. One critical aspect of bacterial transfer is the ability of the microorganism to survive on various common hospital surfaces. The purpose of this study was to determine the survival of 22 gram-positive bacteria (vancomycin-sensitive and -resistant enterococci and methicillin-sensitive and -resistant staphylococci) on five common hospital materials: smooth 100% cotton (clothing), 100% cotton terry (towels), 60% cotton-40% polyester blend (scrub suits and lab coats), 100% polyester (privacy drapes), and 100% polypropylene plastic (splash aprons). Swatches were inoculated with 10(4) to 10(5) CFU of a microorganism, assayed daily by placing the swatches in nutritive media, and examining for growth after 48 h. All isolates survived for at least 1 day, and some survived for more than 90 days on the various materials. Smaller inocula (10(2)) survived for shorter times but still generally for days. Antibiotic sensitivity had no consistent effect on survival. The long survival of these bacteria, including MRSA and VRE, on commonly used hospital fabrics, such as scrub suits, lab coats, and hospital privacy drapes, underscores the need for meticulous contact control procedures and careful disinfection to limit the spread of these bacteria.

We recently demonstrated that muscle protein synthesis was stimulated to a similar extent in young and elderly subjects during a 3-h amino acid infusion. We sought to determine if a more practical bolus oral ingestion would also produce a similar response in young (34 +/- 4 yr) and elderly (67 +/- 2 yr) individuals. Arteriovenous blood samples and muscle biopsies were obtained during a primed (2.0 micromol/kg) constant infusion (0.05 micromol.kg(-1).min(-1)) of L-[ring-2H5]phenylalanine. Muscle protein kinetics and mixed muscle fractional synthetic rate (FSR) were calculated before and after the bolus ingestion of 15 g of essential amino acids (EAA) in young (n = 6) and elderly (n = 7) subjects. After EAA ingestion, the rate of increase in femoral artery phenylalanine concentration was slower in elderly subjects but remained elevated for a longer period. EAA ingestion increased FSR in both age groups by approximately 0.04%/h (P < 0.05). However, muscle intracellular (IC) phenylalanine concentration remained significantly higher in elderly subjects at the completion of the study (young: 115.6 +/- 5.4 nmol/ml; elderly: 150.2 +/- 19.4 nmol/ml). Correction for the free phenylalanine retained in the muscle IC pool resulted in similar net phenylalanine uptake values in the young and elderly. EAA ingestion increased plasma insulin levels in young (6.1 +/- 1.2 to 21.3 +/- 3.1 microIU/ml) but not in elderly subjects (3.0 +/- 0.6 to 4.3 +/- 0.4 microIU/ml). Despite differences in the time course of plasma phenylalanine kinetics and a greater residual IC phenylalanine concentration, amino acid supplementation acutely stimulated muscle protein synthesis in both young and elderly individuals.

We have investigated the mechanisms of the anabolic effect of insulin on muscle protein metabolism in healthy volunteers, using stable isotopic tracers of amino acids. Calculations of muscle protein synthesis, breakdown, and amino acid transport were based on data obtained with the leg arteriovenous catheterization and muscle biopsy. Insulin was infused (0.15 mU/min per 100 ml leg) into the femoral artery to increase femoral venous insulin concentration (from 10 +/- 2 to 77 +/- 9 microU/ml) with minimal systemic perturbations. Tissue concentrations of free essential amino acids decreased (P < 0.05) after insulin. The fractional synthesis rate of muscle protein (precursor-product approach) increased (P < 0.01) after insulin from 0.0401 +/- 0.0072 to 0.0677 +/- 0.0101%/h. Consistent with this observation, rates of utilization for protein synthesis of intracellular phenylalanine and lysine (arteriovenous balance approach) also increased from 40 +/- 8 to 59 +/- 8 (P < 0.05) and from 219 +/- 21 to 298 +/- 37 (P < 0.08) nmol/min per 100 ml leg, respectively. Release from protein breakdown of phenylalanine, leucine, and lysine was not significantly modified by insulin. Local hyperinsulinemia increased (P < 0.05) the rates of inward transport of leucine, lysine, and alanine, from 164 +/- 22 to 200 +/- 25, from 126 +/- 11 to 221 +/- 30, and from 403 +/- 64 to 595 +/- 106 nmol/min per 100 ml leg, respectively. Transport of phenylalanine did not change significantly. We conclude that insulin promoted muscle anabolism, primarily by stimulating protein synthesis independently of any effect on transmembrane transport.

Although the MYC oncogene has been implicated in cancer, a systematic assessment of alterations of MYC, related transcription factors, and co-regulatory proteins, forming the proximal MYC network (PMN), across human cancers is lacking. Using computational approaches, we define genomic and proteomic features associated with MYC and the PMN across the 33 cancers of The Cancer Genome Atlas. Pan-cancer, 28% of all samples had at least one of the MYC paralogs amplified. In contrast, the MYC antagonists MGA and MNT were the most frequently mutated or deleted members, proposing a role as tumor suppressors. MYC alterations were mutually exclusive with PIK3CA, PTEN, APC, or BRAF alterations, suggesting that MYC is a distinct oncogenic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such as immune response and growth factor signaling; chromatin, translation, and DNA replication/repair were conserved pan-cancer. This analysis reveals insights into MYC biology and is a reference for biomarkers and therapeutics for cancers with alterations of MYC or the PMN.

BACKGROUND: Both the Tanner-Whitehouse-III RUS score, which is based on the radiographic appearance of the epiphyses of the distal part of the radius, the distal part of the ulna, and small bones of the hand, and the digital skeletal age skeletal maturity scoring system, which is based on just the metacarpals and phalanges, correlate highly with the curve acceleration phase in girls with idiopathic scoliosis. However, these systems require an atlas and access to the scoring system, making their use impractical in a busy clinical setting. We sought to develop a simplified system that would correlate highly with scoliosis behavior but that would also be rapid and reliable for clinical practice. METHODS: A simplified staging system involving the use of the Tanner-Whitehouse-III descriptors was developed. It was tested for intraobserver and interobserver reliability by six individuals on thirty skeletal age radiographs. The system was compared with the timing of the curve acceleration phase in a cohort of twenty-two girls with idiopathic scoliosis. RESULTS: The average intraobserver unweighted kappa value was 0.88, and the average weighted kappa value was 0.96. The percentage of exact matches between readings for each rater was 89%, and 100% of the differences were within one unit. The average interobserver unweighted kappa value was 0.71, and the average weighted kappa value was 0.89. The percentage of exact matches between two reviewers was 71%, and 97% of the interobserver differences were within one stage or matched. The agreement was highest between the most experienced raters. Interobserver reliability was not improved by the use of a classification-specific atlas. The correlation of the staging system with the curve acceleration phase was 0.91. CONCLUSIONS: The simplified skeletal maturity scoring system is reliable and correlates more strongly with the behavior of idiopathic scoliosis than the Risser sign or Greulich and Pyle skeletal ages do. The system has a modest learning curve but is easily used in a clinical setting and, in conjunction with curve type and magnitude, appears to be strongly prognostic of future scoliosis curve behavior.

STUDY DESIGN: This was a prospective study of two cohort groups of patients (one group receiving anterior instrumentation and the other posterior instrumentation) receiving treatment for thoracic idiopathic scoliosis. OBJECTIVE: To present the 2-year postoperative results of a prospective multicenter study comparing the use of anterior instrumentation with that of posterior multisegmented hook instrumentation for the correction of adolescent thoracic idiopathic scoliosis. SUMMARY OF BACKGROUND DATA: Despite reports of satisfactory results, problems have been reported with posterior systems, including worsening of the lumbar curve after surgery and failure to correct hypokyphosis. Theoretically, the advantages of anterior instrumentation include prevention of lumbar curve decompensation by shortening the convexity of the thoracic curve. In addition, by removing the disc, better correction of thoracic hypokyphosis could be obtained. METHODS: Seventy-eight patients who underwent an anterior spinal fusion using flexible threaded rods and nuts (Harms-MOSS instrumentation, De Puy-Motech-Acromed, Cleveland, OH) were analyzed and compared with 100 patients who underwent posterior spinal fusion with multisegmented hook systems. Parameters of comparison included coronal and sagittal correction, balance, distal lumbar fusion levels, and complication. All patients had idiopathic thoracic curves of King Types II to V. The average age at surgery was 14 years in each group, the average preoperative curve 57 degrees, and the minimum duration of follow-up for all patients 24 months. All data were collected prospectively and analyzed via Epl into statistical analysis (Centers of Disease Control, Atlanta, GA). RESULTS: Average coronal correction of the main thoracic curve was 58% in the anterior group and 59% in the posterior group (P = 0.92). Analysis of sagittal contour showed that the posterior systems failed to correct a preoperative hypokyphosis (sagittal T5 to T12 less than 20 degrees) in 60% of cases, whereas 81% were normal postoperatively in the anterior group. However, hyperkyphosis (sagittal T5 to T12 greater than 40 degrees) occurred after surgery in 40% of the anterior group when the preoperative kyphosis was greater than 20 degrees. Postoperative coronal balance was equal in both groups. An average of 2.5 (range, 0-6) distal fusion levels were saved using the anterior spinal instrumentation according to the criteria used for determining posterior fusion levels in this study. Selective fusion of the thoracic curve (distal fusion level T11, T12, L1) was performed in 76 of 78 patients (97%) in the anterior group as compared with only 18 of 100 (18%) in the posterior group. Surgically confirmed pseudarthrosis occurred in 4 of 78 patients (5%) in the anterior group and in 1 of 100 patients (1%) in the posterior group (P = 0.10). Loss of correction greater than 10 degrees occurred in 18 of 78 patients (23%) in the anterior group and in 12 of 100 patients (12%) in the posterior group (P = 0.01). Implant breakage occurred in 24 patients (31%) of the anterior group and in only 1 patient (1%) of the posterior group. CONCLUSIONS: 1) Coronal correction and balance were equal in both the anterior and posterior groups, even though the anterior group had the majority of curves (97%) fused short or to L1, whereas only 18% were fused short or to L1 in the posterior group. 2) In the anterior group there was a better correction of sagittal profile in those with a preoperative hypokyphosis less than 20 degrees. However, hyperkyphosis (with a mean of 54 degrees) occurred in 40% of those in the anterior group with a preoperative kyphosis of more than 20 degrees. 3) An average of 2.5 lumbar levels can be saved with anterior fusion and instrumentation according to the criteria used for choosing posterior fusion levels in this study. 4) Using the 3.2-mm flexible rod in this study, loss of correction, pseudarthrosis, and rod breakage were unacceptably highe

A severe burn leads to hypermetabolism and catabolism resulting in compromised function and structure of essential organs. The massive release of cytokines is implicated in this hypermetabolic response. The aim of the present study was to compare cytokine expression profiles from severely burned children without signs of infections or inhalation injury (n = 19) to the cytokine profiles from normal, noninfected, nonburned children (n = 14). The Bio-Plex suspension array system was used to measure the concentration of 17 cytokines. The expression of proinflammatory and anti-inflammatory cytokines was maximal during the first week after thermal injury. Significant increases were measured for 15 mediators during the first week after thermal injury: interleukin (IL) 1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 p70, IL-13, IL-17, interferon gamma, monocyte chemoattractant protein 1, macrophage inflammatory protein 1beta, and granulocyte colony-stimulating factor (P < 0.05). Granulocyte-macrophage colony-stimulating factor was significantly increased during the second week after burn (P < 0.05). Within 5 weeks, the serum concentrations of most cytokines decreased, approaching normal levels. When compared with the cytokine levels measured in normal children, a total of 16 cytokines were significantly altered (P < 0.05). After severe burn, a specific cytokine expression profile is observed in patients without complications such as inhalation injury or sepsis. The cytokine concentrations decrease during 5 weeks after burn but remain elevated over nonburned values. Furthermore, the elevation in most serum cytokine levels during the first week after burn may indicate a potential window of opportunity for therapeutic intervention.

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.

In 2003, the first reports describing osteonecrosis of the jaw (ONJ) in patients receiving bisphosphonates (BP) were published. These cases occurred in patients with cancer receiving high-dose intravenous BP; however, 5% of the cases were in patients with osteoporosis receiving low-dose bisphosphonate therapy. We present the results of a systematic review of the incidence, risk factors, diagnosis, prevention, and treatment of BP associated ONJ. We conducted a comprehensive literature search for relevant studies on BP associated ONJ in oncology and osteoporosis patients published before February 2008.All selected relevant articles were sorted by area of focus. Data for each area were abstracted by 2 independent reviewers. The results showed that the diagnosis is made clinically. Prospective data evaluating the incidence and etiologic factors are very limited. In oncology patients receiving high-dose intravenous BP, ONJ appears to be dependent on the dose and duration of therapy, with an estimated incidence of 1%-12% at 36 months of exposure. In osteoporosis patients, it is rare, with an estimated incidence < 1 case per 100,000 person-years of exposure. The incidence of ONJ in the general population is not known. Currently, there is insufficient evidence to confirm a causal link between low-dose BP use in the osteoporosis patient population and ONJ. We concluded BP associated ONJ is associated with high-dose BP therapy primarily in the oncology patient population. Prevention and treatment strategies are currently based on expert opinion and focus on maintaining good oral hygiene and conservative surgical intervention.

BACKGROUND: Scoliosis progression during adolescence is closely related to patient maturity. Maturity has various indicators, including chronological age, height and weight changes, and skeletal and sexual maturation. It is not certain which of these indicators correlates most strongly with scoliosis progression. The purpose of the present study was to evaluate various maturity measurements and how they relate to scoliosis progression. METHODS: Physically immature girls with idiopathic scoliosis were evaluated every six months through their growth spurt with serial spinal radiographs; hand skeletal ages; Oxford pelvic scores; Risser sign determinations; height; weight; sexual staging; and serologic studies of the levels of selected growth factors, estradiol, bone-specific alkaline phosphatase, and osteocalcin. These measurements were then correlated with the curve-acceleration phase. RESULTS: The period and pattern of curve acceleration began during Risser stage 0 for all patients. Skeletal maturation scores derived with the use of the Tanner-Whitehouse-III RUS method, particularly those for the metacarpals and phalanges, were superior to all other indicators of maturity. Regression of the scores provided good estimates of maturity relative to the period of curve progression (Pearson r = 0.93). The initiation of this period occurred simultaneously with digital changes from Tanner-Whitehouse-III stage F to G. At this stage, curves also separated into rapid, moderate, and low-acceleration patterns, with specific curve types in the rapid and moderate-acceleration groups. The low-acceleration group was not confined to a specific curve type. CONCLUSIONS: The curve-acceleration phase separates curves into various types of curve progression. The Tanner-Whitehouse-III RUS scores are highly correlated with timing relative to the curve-acceleration phase and provide better maturity determination and prognosis determination during adolescence than the other parameters tested. Accurate skeletal maturity determination should be used as the primary maturity measurement in girls with idiopathic scoliosis.

Magnetic resonance spectroscopy studies have shown that intramyocellular lipids (IMCL) and liver fat (LFAT) levels vary with insulin sensitivity and obesity, which are common in the elderly. Thus, magnetic resonance spectroscopy was used to investigate the hypothesis that IMCL and LFAT are increased in the elderly. IMCL and LFAT in young (aged 20-32 yr) and elderly (aged 65-74 yr) were measured fasted, and glucose, insulin, total free fatty acids levels, and free fatty acids profiles were measured during a 2-h oral glucose tolerance test. Body fat percentage was determined with dual x-ray absorptiometry. The elderly had significantly greater IMCL (0.12 +/- 0.01 vs. 0.08 +/- 0.01, mean +/- sem; P = 0.01) and LFAT (0.28 +/- 0.06 vs. 0.08 +/- 0.01; P = 0.004; expressed as ratios to Intralipid standard) than the young. The elderly had increased insulin resistance as calculated by the Matsuda model compared with the young (5.1 +/- 0.9 vs. 9.9 +/- 1.4; P = 0.02). Regression analysis of all subjects indicated that the increases in IMCL and LFAT were correlated with insulin sensitivity, glycosylated hemoglobin, plasma lipids, and body fat. Furthermore, the correlation between insulin sensitivity and IMCL and LFAT remained significant, after accounting for the effect of body fat. Increases of IMCL and LFAT occur in elderly individuals and may be related to insulin resistance.

BACKGROUND: The recent number and rate of infant hospitalizations with a respiratory syncytial virus (RSV)-coded diagnosis have not been published. METHODS: Retrospective data analysis. National Hospital Discharge Survey data for 1997 to 1999 were analyzed for discharges of infants < 1 year old with an RSV-coded diagnosis (ICD-9-CM 466.11, 480.1, 079.6). Hospitalization rates were estimated with annual midyear Census data. RESULTS: RSV bronchiolitis was the leading primary diagnosis annually for all infants hospitalized for any reason. Between 1997 and 1999, 297 684 RSV-coded discharges of infants with an RSV-coded diagnosis occurred. The associated hospitalization rate was 25.2 per 1000 infants. RSV-coded discharges peaked in February. CONCLUSION: RSV bronchiolitis was the leading cause of hospital admissions of infants younger than age 1 year for any reason between 1997 and 1999.

We have studied eight endurance-trained women at rest and during exercise at 25, 65, and 85% of maximal oxygen uptake. The rate of appearance (R(a)) of free fatty acids (FFA) was determined by infusion of [(2)H(2)]palmitate, and fat oxidation rates were determined by indirect calorimetry. Glucose kinetics were assessed with [6,6-(2)H(2)]glucose. Glucose R(a) increased in relation to exercise intensity. In contrast, whereas FFA R(a) was significantly increased to the same extent in low- and moderate-intensity exercise, during high-intensity exercise, FFA R(a) was reduced compared with the other exercise values. Carbohydrate oxidation increased progressively with exercise intensity, whereas the highest rate of fat oxidation was during exercise at 65% of maximal oxygen uptake. After correction for differences in lean body mass, there were no differences between these results and previously reported data in endurance-trained men studied under the same conditions, except for slight differences in glucose metabolism during low-intensity exercise (Romijn JA, Coyle EF, Sidossis LS, Gastaldelli A, Horowitz JF, Endert E, and Wolfe RR. Am J Physiol Endocrinol Metab 265: E380-E391, 1993). We conclude that the patterns of changes in substrate kinetics during moderate- and high-intensity exercise are similar in trained men and women.

We have determined the individual and combined effects of insulin and prior exercise on leg muscle protein synthesis and degradation, amino acid transport, glucose uptake, and alanine metabolism. Normal volunteers were studied in the postabsorptive state at rest and about 3 h after a heavy leg resistance exercise routine. The leg arteriovenous balance technique was used in combination with stable isotopic tracers of amino acids and biopsies of the vastus lateralis muscle. Insulin was infused into a femoral artery to increase the leg insulin concentrations to high physiologic levels without substantively affecting the whole-body level. Protein synthesis and degradation were determined as rates of intramuscular phenylalanine utilization and appearance, and muscle fractional synthetic rate (FSR) was also determined. Leg blood flow was greater after exercise than at rest (P&amp;lt;0.05). Insulin accelerated blood flow at rest but not after exercise (P&amp;lt;0.05). The rates of protein synthesis and degradation were greater during the postexercise recovery (65+/-10 and 74+/-10 nmol x min(-1) x 100 ml(-1) leg volume, respectively) than at rest (30+/-7 and 46+/-8 nmol x min(-1) x 100 ml(-1) leg volume, respectively; P&amp;lt;0.05). Insulin infusion increased protein synthesis at rest (51+/-4 nmol x min(-1) x 100 ml(-1) leg volume) but not during the postexercise recovery (64+/-9 nmol x min(-1) x 100 ml(-1) leg volume; P&amp;lt;0.05). Insulin infusion at rest did not change the rate of protein degradation (48+/-3 nmol x min(-1) 100 ml(-1) leg volume). In contrast, insulin infusion after exercise significantly decreased the rate of protein degradation (52+/-9 nmol x min(-1) x 100 ml(-1) leg volume). The insulin stimulatory effects on inward alanine transport and glucose uptake were three times greater during the postexercise recovery than at rest (P&amp;lt;0.05). In contrast, the insulin effects on phenylalanine, leucine, and lysine transport were similar at rest and after exercise. In conclusion, the ability of insulin to stimulate glucose uptake and alanine transport and to suppress protein degradation in skeletal muscle is increased after resistance exercise. Decreased amino acid availability may limit the stimulatory effect of insulin on muscle protein synthesis after exercise.

We tested the role of different intracellular proteolytic pathways in sepsis-induced muscle proteolysis. Sepsis was induced in rats by cecal ligation and puncture; controls were sham operated. Total and myofibrillar proteolysis was determined in incubated extensor digitorum longus muscles as release of tyrosine and 3-methylhistidine, respectively. Lysosomal proteolysis was assessed by using the lysosomotropic agents NH4Cl, chloroquine, leupeptin, and methylamine. Ca(2+)-dependent proteolysis was determined in the absence or presence of Ca2+ or by blocking the Ca(2+)-dependent proteases calpain I and II. Energy-dependent proteolysis was determined in muscles depleted of ATP by 2-deoxyglucose and 2.4-dinitrophenol. Muscle ubiquitin mRNA and the concentrations of free and conjugated ubiquitin were determined by Northern and Western blots, respectively, to assess the role of the ATP-ubiquitin-dependent proteolytic pathway. Total and myofibrillar protein breakdown was increased during sepsis by 50 and 440%, respectively. Lysosomal and Ca(2+)-dependent proteolysis was similar in control and septic rats. In contrast, energy-dependent total and myofibrillar protein breakdown was increased by 172% and more than fourfold, respectively, in septic muscle. Ubiquitin mRNA was increased severalfold in septic muscle. The results suggest that the increase in muscle proteolysis during sepsis is due to an increase in nonlysosomal energy-dependent protein breakdown, which may involve the ubiquitin system.

Rat serum has been shown to stimulate DNA synthesis in primary cultures of adult rat hepatocytes 2-3 times more potently than serum from several other mammalian sources, including humans. Parallel to its stimulation of thymidine incorporation into DNA, rat serum increased the total DNA content of the hepatocyte cultures over time, and also increased the frequency of nuclear labeling and mitosis. Moreover, normal rat serum, derived from whole blood (NRS), stimulated DNA synthesis in hepatocytes twice as effectively as platelet-poor rat serum, derived from plasma (ppNRS). Addition of a rat platelet lysate (RPL) to ppNRS restored the activity to equal that of NRS. The avid binding of the active principle to CM Sephadex and its sensitivity to trypsin digestion suggest that it is a cationic polypeptide with an apparent molecular weight of about 65,000, as determined by gel filtration. It was inactivated by reduction of disulfide bonds, or by exposure to pH below 5.5, to NaCl concentration below 0.05 M, to 65 degrees C for 30 min, or to 100 degrees C for 10 min. Although it resembles the human platelet-derived mitogen platelet-derived growth factor (PDGF) in several of its properties, it differs in others. Hence the hepatocyte growth factor from rat platelets, which accounts for 50% of the DNA synthesis-stimulatory activity of rat serum, appears to be a distinct entity.

Background: There are many anatomical changes during pregnancy that could potentially lead to substantial alterations in gait. Gait deviations may contribute to a variety of musculoskeletal overuse conditions associated with pregnancy, such as low-back, hip, and calf pain. Because we are aware of little research on this topic, the purpose of this study was to objectively analyze gait during pregnancy. Methods: Three-dimensional gait analysis was performed on fifteen women during the second half of the last trimester of pregnancy and again one year post partum. Selected kinematic and kinetic parameters for the pregnancy and one-year postpartum conditions were compared with use of paired t tests (95 percent significance level). Results: Overall, gait kinematics were remarkably unchanged during pregnancy. No evidence of a so-called waddling gait during pregnancy was found. Maximum anterior pelvic tilt during gait increased a mean of 4 degrees during pregnancy, although individual subject-to-subject variation (range, an increase of 13 degrees to a decrease of 10 degrees) was observed. Significant increases in hip and ankle kinetic gait parameters, however, were observed during pregnancy (p < 0.05). Conclusions: Significant increases in kinetic gait parameters during pregnancy (p < 0.05) explain how gait motion remained relatively unchanged despite increases in body mass and width as well as changes in mass distribution about the trunk. This finding indicates that during pregnancy there may be an increased demand placed on hip abductor, hip extensor, and ankle plantar flexor muscles during walking. Clinical Relevance: Many of the common musculoskeletal problems associated with pregnancy may be due, in part, to musculoskeletal overuse injuries incurred as a consequence of secondary gait deviations that compensate for changes in body mass and distribution. Physicians caring for pregnant women with musculoskeletal problems should emphasize the value of exercise and conditioning during pregnancy for both preventative and rehabilitative management.

PURPOSE: To examine the prognostic significance of lumican and decorin, two abundant small leucine-rich proteoglycans in breast tissue stroma. EXPERIMENTAL DESIGN: Lumican and decorin expression was examined in a cohort of 140 invasive breast carcinomas by Western blot analysis. All cases were axillary lymph node-negative and treated by adjuvant endocrine therapy. RESULTS: Lumican and decorin expression was highly correlated (r = 0.45, P < 0.0001), but although low levels of lumican were associated with large tumor size (P = 0.0496), negative estrogen receptor (P = 0.0024) and progesterone receptor status (P = 0.0116), and increased host inflammatory response (P = 0.0077), low decorin levels were associated only with large tumor size (P = 0.0496). However, using univariate analysis, low levels of lumican and decorin were both associated with a shorter time to progression (P = 0.0013 and 0.0262) and poorer survival (P = 0.001 and 0.0076). In multivariate analysis using the Cox regression model, low decorin was also shown to be an independent predictive factor for recurrence (hazard ratio 2.25: 95% confidence interval 1-5, P = 0.047) and survival (hazard ratio 3.39: 95% confidence interval 1.2-9.6, P = 0.021). CONCLUSIONS: These results suggest that low levels of small leucine-rich proteoglycans in breast tumors may be associated with a worse prognosis in lymph node-negative invasive breast carcinomas and warrant further study with larger patient cohorts.

Down’s syndrome (DS), caused by trisomy of human chromosome 21, is the most common genetic cause of intellectual disability. Here we use induced pluripotent stem cells (iPSCs) derived from DS patients to identify a role for astrocytes in DS pathogenesis. DS astroglia exhibit higher levels of reactive oxygen species and lower levels of synaptogenic molecules. Astrocyte-conditioned medium collected from DS astroglia causes toxicity to neurons, and fails to promote neuronal ion channel maturation and synapse formation. Transplantation studies show that DS astroglia do not promote neurogenesis of endogenous neural stem cells in vivo. We also observed abnormal gene expression profiles from DS astroglia. Finally, we show that the FDA-approved antibiotic drug, minocycline, partially corrects the pathological phenotypes of DS astroglia by specifically modulating the expression of S100B, GFAP, inducible nitric oxide synthase, and thrombospondins 1 and 2 in DS astroglia. Our studies shed light on the pathogenesis and possible treatment of DS by targeting astrocytes with a clinically available drug. Down’s syndrome is characterized by intellectual disability and other neuropathological symptoms. Here, the authors show that astroglia derived from induced pluripotent stem cells from Down’s syndrome patients impair the development of neurons, and that this can be attenuated with the drug minocycline.