Randomized phase II clinical trial of avotermin versus placebo for scar improvement.

BACKGROUND: Scarring is a major problem following skin injury. In early clinical trials, transforming growth factor ß3 (avotermin) improved scar appearance. The aim of this study was to determine whether an injection of avotermin at the time of wound closure is effective in improving scar appearance. METHODS: Study RN1001-0042, a double-blind, randomized, within-patient, placebo-controlled trial, investigated the efficacy and safety of four doses of avotermin given once. Patients undergoing bilateral surgery to remove varicose leg veins by saphenofemoral ligation and long saphenous vein stripping were enrolled at 20 European centres. A total of 156 patients were randomized to receive one of four doses of avotermin (5, 50, 200 or 500 ng per 100 µl, at 100 µl per linear cm of wound margin), administered by intradermal injection to the groin and distal wound margins of one leg; placebo was administered to the other leg. Scar appearance was evaluated by an independent panel of lay people (lay panel), investigators and patients. The primary efficacy variable was lay panel Total Scar Score (ToScar), derived from visual analogue scale scores for groin scars between 6 weeks and 7 months. RESULTS: Avotermin 500 ng significantly improved groin scar appearance compared with placebo (mean lay panel ToScar difference 16·49 mm; P = 0·036). CONCLUSION: Avotermin 500 ng per 100 µl per linear cm of wound margin given once is well tolerated and significantly improves scar appearance.

Somatotropin regulation of protein metabolism in pigs.

A primary goal of exogenous somatotropin treatment is to increase lean body mass. This is accomplished, in part, by increasing the efficiency with which dietary amino acids are used for protein deposition. Somatotropin administration also improves protein balance by minimizing the loss of protein during fasting and maximizing the protein gained during meal absorption. Amino acid catabolism is decreased by somatotropin treatment, as indicated by decreases in blood urea nitrogen, urea synthesis, hepatic urea cycle enzyme activity, and amino acid oxidation. Stable isotope tracer/mass transorgan balance studies have recently demonstrated that somatotropin treatment increases protein anabolism in young, growing swine by increasing protein synthesis in the hind limb and portal-drained viscera in the fed state, with little effect on protein degradation. Detailed study of the tissue-specific responses indicates that somatotropin treatment increases protein synthesis in skeletal muscle by increasing the efficiency of the translational process, but only in the fed state. The somatotropin-induced stimulation of skeletal muscle protein synthesis involves mechanisms that enhance the binding of both mRNA and initiator methionyl-tRNA to the 40S ribosomal subunit. Somatotropin increases protein synthesis in the liver in both the fasted and fed states by increasing ribosome number, with no change in translation initiation. Thus, the protein synthetic response to somatotropin treatment is tissue-specific and dependent on nutritional state.

Reduced Apaf-1 expression in human cutaneous melanomas.

Malignant melanoma is a life-threatening skin cancer due to its highly metastatic character and resistance to radio- and chemotherapy. It is believed that the ability to evade apoptosis is the key mechanism for the rapid growth of cancer cells. However, the exact mechanism for failure in the apoptotic pathway in melanoma cells is unclear. p53, the most frequently mutated tumour suppressor gene in human cancers, is a key apoptosis inducer. However, p53 mutation is only found in 15-20% of melanoma biopsies. Recently, it was found that Apaf-1, a downstream target of p53, is inactivated in metastatic melanoma. Specifically, loss of heterozygosity (LOH) of the Apaf-1 gene was found in 40% of metastatic melanoma. To determine if loss of Apaf-1 expression is indeed involved in melanoma progression, we employed the tissue microarray technology and examined Apaf-1 expression in 70 human primary malignant melanoma biopsies by immunohistochemistry. Our data showed that Apaf-1 expression is significantly reduced in melanoma cells compared with normal nevi (chi(2)=6.02, P=0.014). Our results also revealed that loss of Apaf-1 was not associated with the tumour thickness, ulceration or subtype, patient's gender, age and 5-year survival. In addition, our in vitro apoptosis assay revealed that overexpression of Apaf-1 can sensitise melanoma cells to anticancer drug treatment. Taken together, our data indicate that Apaf-1 expression is significantly reduced in human melanoma and that Apaf-1 may serve as a therapeutic target in melanoma.

Peripheral leptin administration alters hormone and metabolite levels in the young pig.

The present study was conducted to determine if peripheral leptin administration can alter GH secretion or feed intake in young pigs. Six, 6 kg female pigs were fasted overnight and randomly chosen to receive porcine recombinant leptin or saline injections in a crossover design. Three leptin dosages were tested over a 10 day period, 100, 200 or 500 microg/kg body mass (L100, L200 or L500). Leptin was administered in 0.2% bovine serum albumin as a bolus injection into the carotid artery. Blood samples were obtained from the jugular vein over a 24 h period. Leptin delayed feeding in pigs treated with L200 and L500 (P<0.05), while reducing overall intake in pigs treated with L100 (P<0.05). L200 or L500 depressed blood glucose (P<0.05). Plasma insulin levels were elevated by feeding in control animals, while insulin levels were depressed in pigs treated with L200 or L500 (P<0.05). L200 elevated plasma growth hormone (P<0.05) with three peaks apparent at 5, 8, and 13 h post injection. The ability for a single injection of leptin to produce significant changes in hormone and metabolite levels suggests that this peptide has a role in regulation of peripheral metabolism.

The relationship of natural killer cell counts, perforin mRNA and CD2 expression to post-exercise natural killer cell activity in humans.

The aim of this study was to further investigate the mechanism of suppression of natural killer (NK) cell cytotoxic activity in peripheral blood following strenuous exercise. Blood was collected for analysis of NK cell concentration, cytotoxic activity, CD2 surface expression and perforin gene expression from runners (RUN, n=6) and resting controls (CONTROL, n=4) pre-exercise, 0, 1.5, 5, and 24 h following a 60-min treadmill run at 80% of VO2 peak. Natural killer cytotoxic activity, measured using a whole blood chromium release assay, fluctuated minimally in the CONTROL group and increased by 63% and decreased by 43% 0 and 1.5 h post-exercise, respectively, in the RUN group (group x time, P < 0.001). Lytic index (cytotoxic activity per cell) did not change. Perforin mRNA, measured using quantitative real-time polymerase chain reaction (QRT-PCR) decreased from pre- to post-exercise and remained decreased through 24 h. The decrease from pre- to 0 h post-exercise was seen predominately in the RUN group and was inversely correlated (r=- 0.95) to pre-exercise perforin mRNA. The NK cell surface expression of CD2 (lymphocyte function-associated antigen-2) was determined using fluorescent antibodies and flow cytometry. There was no change in the proportion of NK cells expressing CD2 or CD2 density. We conclude that (1) numerical redistribution accounted for most of the change in NK cytotoxic activity following a strenuous run, (2) decrease in perforin gene expression during the run was inversely related to pre-exercise levels but did not parallel changes in cytotoxic activity, and (3) CD2 surface expression was not affected by exercise.

Curcumin induces apoptosis in human melanoma cells through a Fas receptor/caspase-8 pathway independent of p53.

In this study, we investigated the molecular pathways targeted by curcumin during apoptosis of human melanoma cell lines. We found that curcumin caused cell death in eight melanoma cell lines, four with wild-type and four with mutant p53. We demonstrate that curcumin-induced apoptosis is both dose- and time-dependent. We found that curcumin did not induce p53, suggesting that curcumin activates other apoptosis pathways. Our data show that curcumin activates caspases-3 and -8 but not caspase-9, supporting the rationale that apoptosis occurs via a membrane-mediated mechanism. Both a caspase-8 and broad-based caspase inhibitor, but not a caspase-9 specific inhibitor, suppressed curcumin-induced cell death. To further support our hypothesis that curcumin induces activation of a death receptor pathway, we show that curcumin induces Fas receptor aggregation in a FasL-independent manner and that low-temperature incubation, previously shown to inhibit receptor aggregation, prevented curcumin-induced cell death. Moreover, we demonstrate that expression of dominant negative FADD significantly inhibited curcumin-induced cell death. In addition, our results indicate that curcumin also blocks the NF-kappaB cell survival pathway and suppresses the apoptotic inhibitor, XIAP. Since melanoma cells with mutant p53 are strongly resistant to conventional chemotherapy, curcumin may overcome the chemoresistance of these cells and provide potential new avenues for treatment.

Developmental changes in the feeding-induced activation of the insulin-signaling pathway in neonatal pigs.

In neonatal animals, feeding stimulates skeletal muscle protein synthesis, a response that declines with development. Both the magnitude of the feeding response and its developmental decline can be reproduced by insulin infusion, suggesting that an altered responsiveness to insulin is a primary determinant of the developmental decline in the stimulation of protein synthesis by feeding. In this study, 7- and 26-day-old pigs were either fasted overnight or fed porcine milk after an overnight fast. We examined the abundance and degree of tyrosine phosphorylation of the insulin receptor (IR), insulin receptor substrate-1 (IRS-1), and IRS-2 in skeletal muscle and, for comparison, liver. We also evaluated the association of IRS-1 and IRS-2 with phosphatidylinositol 3-kinase (PI 3-kinase). The abundance of IR protein in muscle was twofold higher at 7 than at 26 days, but IRS-1 and IRS-2 abundances were similar in muscle of 7- and 26-day-old pigs. The feeding-induced phosphorylations were greater at 7 than at 26 days of age for IR (28- vs. 13-fold), IRS-1 (14- vs. 8-fold), and IRS-2 (21- vs. 12-fold) in muscle. The associations of IRS-1 and IRS-2 with PI 3-kinase were also increased by refeeding to a greater extent at 7 than at 26 days (9- vs. 5-fold and 6- vs. 4-fold, respectively). In liver, the abundance of IR, IRS-1, and IRS-2 was similar at 7 and 26 days of age. Feeding increased the activation of IR, IRS-1, IRS-2, and PI 3-kinase in liver only twofold, and these responses were unaffected by age. Thus our findings demonstrate that the feeding-induced activation of IR, IRS-1, IRS-2, and PI 3-kinase in skeletal muscle decreases with development. Further study is needed to ascertain whether the developmental decline in the feeding-induced activation of early insulin-signaling components contributes to the developmental decline in translation initiation in skeletal muscle.

Lymphocyte proliferation in response to acute heavy resistance exercise in women: influence of muscle strength and total work.

Little is understood about the immune responses to heavy resistance exercise. The purpose of this investigation was to determine the influence of physical strength and the ability to do more total work on lymphocyte proliferation after an acute bout of heavy resistance exercise. A group of 50 healthy but nonstrength trained women were recruited for the study and tested for their one repetition maximum (i.e. 1 RM or maximal mass lifted once). From the normal distribution of strength the top and bottom 8 women [mean age 22.5 (SD 3.1) years] were asked to volunteer to define our two groups (i.e. high strength and low strength). The two groups were significantly different (P < 0.05) in 1 RM squat strength [low strength 39.9 (SD 4.6) kg, 0.65 (SD 0.08) kg.kg body mass-1 and high strength 72.2 (SD 10.7) kg, 1.1 (SD 0.12) kg.kg body mass-1] but were not significantly different in body mass, age, activity levels, and menstrual status (all in same phase). Each performed a resistance exercise protocol consisting of six sets of 10 RM squats with 2 min rest between the sets. The 10 RM loads and total work were significantly greater in the high strength group than in the low strength group. Blood samples were obtained pre-exercise and immediately post-exercise for test for lactate (significant increase with exercise) and cortisol (no changes) concentrations with no differences noted between groups. Immunological assays on the blood samples determined the incorporation of tritiated thymidine by lymphocytes in responses to concanavalin A (ConA), phytohemagglutinin (PHA), and pokeweed mitogen (PWM). Following the squat exercise, there was a significant decrease in lymphocyte responsiveness to PWM in the high strength but not in the low strength group for both total proliferation and proliferation adjusted per B or T cell. On the other hand, lymphocytes from the low strength group proliferated to a significantly greater extent (adjusted per T cell) in response to ConA and PHA. These data indicate that the heavy resistance exercise protocol reduced the lymphocyte proliferative responses only in the stronger group of subjects. This effect may have been due to the high absolute total work and the greater exercise stress created by the resistance exercise protocol in the high strength group. Therefore, individuals performing at the same relative exercise intensity (i.e. 10 RM) in a resistance exercise protocol may have different immune responses stemming from differences in absolute total work performance.

Effect of resistance training on women's strength/power and occupational performances.

PURPOSE: The effects of resistance training programs on strength, power, and military occupational task performances in women were examined. METHODS: Untrained women aged (mean +/- SD) 23 +/- 4 yr were matched and randomly placed in total- (TP, N = 17 and TH, N = 18) or upper-body resistance training (UP, N = 18 and UH, N = 15), field (FLD, N = 14), or aerobic training groups (AER, N = 11). Two periodized resistance training programs (with supplemental aerobic training) emphasized explosive exercise movements using 3- to 8-RM training loads (TP, UP), whereas the other two emphasized slower exercise movements using 8- to 12-RM loads (TH, UH). The FLD group performed plyometric and partner exercises. Subjects were tested for body composition, strength, power, endurance, maximal and repetitive box lift, 2-mile loaded run, and U.S. Army Physical Fitness Tests before (T0) and after 3 (T3) and 6 months of training (T6). For comparison, untrained men (N = 100) (MEN) were tested once. RESULTS: Specific training programs resulted in significant increases in body mass (TP), 1-RM squat (TP, TH, FLD), bench press (all except AER), high pull (TP), squat jump (TP, TH, FLD), bench throw (all except AER), squat endurance (all except AER), 1-RM box lift (all except aerobic), repetitive box lift (all), push-ups (all except AER), sit-ups (all except AER), and 2-mile run (all). CONCLUSIONS: Strength training improved physical performances of women over 6 months and adaptations in strength, power, and endurance were specific to the subtle differences (e.g., exercise choice and speeds of exercise movement) in the resistance training programs (strength/power vs strength/hypertrophy). Upper- and total-body resistance training resulted in similar improvements in occupational task performances, especially in tasks that involved upper-body musculature. Finally, gender differences in physical performance measures were reduced after resistance training in women, which underscores the importance of such training for physically demanding occupations.

Influence of compression therapy on symptoms following soft tissue injury from maximal eccentric exercise.

STUDY DESIGN: A between groups design was used to compare recovery following eccentric muscle damage under 2 experimental conditions. OBJECTIVE: To determine if a compression sleeve donned immediately after maximal eccentric exercise would enhance recovery of physical function and decrease symptoms of soreness. BACKGROUND: Prior investigations using ice, intermittent compression, or exercise have not shown efficacy in relieving symptoms of delayed onset muscle soreness (DOMS). To date, no study has shown the effect of continuous compression on DOMS, yet this would offer a low cost intervention for patients suffering with the symptoms of DOMS. METHODS AND MEASURES: Twenty nonimpaired non-strength-trained women participated in the study. Subjects were matched for age, anthropometric data, and one repetition maximum concentric arm curl strength and then randomly placed into a control group (n = 10) or an experimental compression sleeve group (n = 10). Subjects were instructed to avoid pain-relieving modalities (eg, analgesic medications, ice) throughout the study. The experimental group wore a compressive sleeve garment for 5 days following eccentric exercise. Subjects performed 2 sets of 50 passive arm curls with the dominant arm on an isokinetic dynamometer with a maximal eccentric muscle action superimposed every fourth passive repetition. One repetition maximum elbow flexion, upper arm circumference, relaxed elbow angle, blood serum cortisol, creatine kinase, lactate dehydrogenase, and perception of soreness questionnaires were collected prior to the exercise bout and daily thereafter for 5 days. RESULTS: Creatine kinase was significantly elevated from the baseline value in both groups, although the experimental compression test group showed decreased magnitude of creatine kinase elevation following the eccentric exercise. Compression sleeve use prevented loss of elbow motion, decreased perceived soreness, reduced swelling, and promoted recovery of force production. CONCLUSIONS: Results from this study underline the importance of compression in soft tissue injury management.

UNC-52/perlecan isoform diversity and function in Caenorhabditis elegans.

The unc-52 gene encodes the nematode homologue of mammalian perlecan, the major heparan sulphate proteoglycan of the extracellular matrix. This is a large complex protein with regions similar to low-density lipoprotein receptors, laminin and neural cell-adhesion molecules. Three major classes of UNC-52/perlecan isoforms are produced through alternative splicing, and these distinct proteins exhibit complex spatial and temporal expression patterns throughout development. The unc-52 gene plays an essential role in myofilament assembly in body-wall muscle during embryonic development.

Anchorage-independent growth of p53-knockout dermal fibroblasts is reversed by wild-type p53.

BACKGROUND: p53 is a 393-residue nuclear phosphoprotein. Mutation of p53 occurs in over half of all human cancers and thus is a crucial step in the process of cell transformation and tumorigenesis. Since tumorigenesis is a multistep process, it generally requires the mutation of certain key oncogenes and/or tumor-suppressor genes. Using p53-deficient mice, we can investigate the p53-dependent mechanisms leading to tumorigenesis. OBJECTIVE: To examine the unique anchorage-independent growth characteristics of dermal fibroblasts isolated from p53-deficient mice. METHODS: The growth characteristics of highly confluent cultured dermal fibroblasts from wild-type (p53+/+) and p53-deficient (p53-/-) mice were compared by DNA fragmentation assay, colony formation in soft agar, and overexpression of a wild-type p53 transgene in p53-deficient cells. RESULTS: p53-/- fibroblasts have a growth rate dramatically higher than p53+/+ cells and detach from plastic cultureware at high density. The detachment of p53-/- cells is not due to apoptosis. Furthermore, these cells have the capacity to grow in soft agar-a hallmark of cell transformation-and this anchorage-independent growth can be reversed by the introduction of a wild-type p53 transgene. CONCLUSION: Dermal fibroblasts isolated from p53-deficient mice show anchorage-independent growth. Therefore, the absence of p53 is sufficient for the initiation of cell transformation in this cell type and establishes this model system as an excellent tool to dissect the molecular steps involved in oncogenesis.

Low-volume circuit versus high-volume periodized resistance training in women.

PURPOSE: The purpose of this investigation was to determine the long-term training adaptations associated with low-volume circuit-type versus periodized high-volume resistance training programs in women. METHODS: 34 healthy, untrained women were randomly placed into one of the following groups: low-volume, single-set circuit (SSC; N = 12); periodized high-volume multiple-set (MS; N = 12); or nonexercising control (CON) group (N = 10). The SSC group performed one set of 8-12 repetitions to muscular failure 3 d x wk(-1). The MS group performed two to four sets of 3-15 repetitions with periodized volume and intensity 4 d x wk(-1). Muscular strength, power, speed, endurance, anthropometry, and resting hormonal concentrations were determined pretraining (T1), after 12 wk (T2), and after 24 wk of training (T3). RESULTS: 1-RM bench press and leg press, and upper and lower body local muscular endurance increased significantly (P < or = 0.05) at T2 for both groups, but only MS showed a significant increase at T3. Muscular power and speed increased significantly at T2 and T3 only for MS. Increases in testosterone were observed for both groups at T2 but only MS showed a significant increase at T3. Cortisol decreased from T1 to T2 and from T2 to T3 in MS. Insulin-like growth factor-1 increased significantly at T3 for SSC and at T2 and T3 for MS. No changes were observed for growth hormone in any of the training groups. CONCLUSION: Significant improvements in muscular performance may be attained with either a low-volume single-set program or a high-volume, periodized multiple-set program during the first 12 wk of training in untrained women. However, dramatically different training adaptations are associated with specific domains of training program design which contrast in speed of movement, exercise choices and use of variation (periodization) in the intensity and volume of exercise.

Resistance training combined with bench-step aerobics enhances women's health profile.

PURPOSE: The purpose of this study was to investigate the comprehensive physiological alterations that take place during the combination of bench-step aerobics (BSA) and resistance exercise training. METHODS: Thirty-five healthy, active women were randomly assigned to one of four groups that either a) performed 25 min of BSA only (SA25); b) performed a combination of 25 min of BSA and a multiple-set upper and lower body resistance exercise program (SAR); c) performed 40 min of BSA only (SA40); or d) served as a control group (C), only performing activities of daily living. Direct assessments for body composition, aerobic fitness, muscular strength, endurance, power, and cross-sectional area were performed 1 wk before and after 12 wk of training. RESULTS: All training groups significantly improved peak VO(2) (3.7 to 5.3 mL O(2).kg(-1).min(-1)), with the greatest improvement observed in the SAR group (P = 0.05). Significant reductions in preexercise heart rates (8-9 bpm) and body fat percent (5--6%) were observed in all training groups after training. Significant reductions in resting diastolic blood pressure were observed for the SAR and SA40 groups (6.7 and 5.8 mm Hg, respectively). Muscular strength and endurance only improved significantly in the SAR group (21 and 11% respectively). All groups demonstrated increased lower body power (11--14%), but only the SAR group significantly improved upper body power (32%). Thigh muscle cross-sectional areas measured via magnetic resonance imaging (MRI) increased primarily for the SAR group. CONCLUSION: BSA is an exercise modality effective for improving physical fitness and body composition in healthy women. The addition of resistance exercise appears to enhance the total fitness profile by improving muscular performances, muscle morphology, and cardiovascular fitness greater than from performing BSA alone. Therefore, the inclusion of both modalities to an exercise program is most effective for improving total body fitness and a woman's health profile.

Dietary fat supplementation effects on in vitro nutrient disappearance and in vivo nutrient intake and total tract digestibility by horses.

Addition of fat to the diet of the equine is a popular method of increasing energy density of the diet while reducing feed intake. Reducing feed intake is of interest to race horse trainers because additional feed is seen as additional weight and, therefore, a hindrance to performance. Limited information is available regarding the interactions of fat with other dietary components, particularly fiber, in the equine digestive system. The effect of dietary fat on in vitro nutrient disappearance in equine cecal fluid was studied in Exp. 1 using a split-plot design within a 2 x 2 Latin square. Two ponies were fed alfalfa (ALF) alone or alfalfa plus 100 g/d corn oil. Five substrates were used to determine in vitro DM disappearance, OM disappearance, NDF disappearance, and total dietary fiber (TDF) disappearance. The substrates included: ALF, tall fescue (TF), red clover (RC), soybean hulls (SBH), and rolled oats (RO). Fat supplementation did not affect in vitro DM, OM, or NDF disappearance. Addition of fat to the diet increased (P < 0.05) the disappearance of NDF in RO. Among substrates, in vitro DM and OM disappearance were highest (P < 0.05) for RO, followed by SBH, ALF, RC, and TF. In vitro NDF and TDF disappearance were highest (P < 0.05) for SBH, followed by RO, ALF, RC, and TF. In Exp. 2, the effects of varying levels of fat on nutrient intake and total tract digestibility were examined using a 4 x 4 Latin square design. Four mature mares were fed a 60% forage-40% concentrate diet containing different concentrations of fat: 0% supplemental fat control (C); 5% supplemental corn oil (5% CO); 10% supplemental corn oil (10% CO); or 15% supplemental corn oil (15% CO). Treatment did not affect intake of the concentrate portion of the diet or CP, gross energy, or NDF intake. Mares consuming the C diet had the highest (P < 0.05) intake of alfalfa cubes, DM, and OM, followed by those on the 10, 5, and 15% CO treatments, respectively. Treatment did not affect nutrient digestibility. Mares consuming the 15% CO diet had the highest (P < 0.05) fat digestibility, whereas those consuming C had the lowest fat digestibility. Fat in the form of CO generally had little effect on in vitro and in vivo nutrient digestibilities in horses.

Developmental changes in the feeding-induced stimulation of translation initiation in muscle of neonatal pigs.

The rapid gain in skeletal muscle mass in the neonate is associated with a marked elevation in skeletal muscle protein synthesis in response to feeding. The feeding-induced response decreases with development. To determine whether the response to feeding is regulated at the level of translation initiation, the expression, phosphorylation, and function of a number of eukaryotic initiation factors (eIF) were examined. Pigs at 7 and 26 days of age were either fasted overnight or fed porcine milk after an overnight fast. In muscle of 7-day-old pigs, the hyperphosphorylated form of the eIF4E repressor protein, 4E-binding protein 1 (4E-BP1), was undetectable in the fasting state but rose to 60% of total 4E-BP1 after feeding; eIF4E phosphorylation was unaffected by feeding status. The amount of eIF4E in the inactive 4E-BP1. eIF4E complex was reduced by 80%, and the amount of eIF4E in the active eIF4E. eIF4G complex was increased 14-fold in muscle of 7-day-old pigs after feeding. The amount of 70-kDa ribosomal protein S6 (p70(S6)) kinase in the hyperphosphorylated form rose 2.5-fold in muscle of 7-day-old pigs after feeding. Each of these feeding-induced responses was blunted in muscle of 26-day-old pigs. eIF2B activity in muscle was unaffected by feeding status but decreased with development. Feeding produced similar changes in eIF characteristics in liver and muscle; however, the developmental changes in liver were not as apparent as in skeletal muscle. Thus the results demonstrate that the developmental change in the acute stimulation of skeletal muscle protein synthesis by feeding is regulated by the availability of eIF4E for 48S ribosomal complex formation. The results further suggest that the overall developmental decline in skeletal muscle protein synthesis involves regulation by eIF2B.

Influence of compression hosiery on physiological responses to standing fatigue in women.

PURPOSE: The purpose of this investigation was to examine the influence of various designs of commercial hosiery, which use graduated compression, on the physiological and performance responses to standing fatigue. METHODS: Twelve healthy women (age = 23.0+/-2.1 yr, height = 165.7+/-5.0 cm, percent body fat = 22.6+/-4.2%, body mass = 60.0+/-8.9 kg) volunteered to participate in this investigation. All subjects completed four identical standing fatigue protocols with different garment conditions each separated by 7 d. The standing fatigue protocol involved a total of 8 h of standing on hard floors during which subjects participated in various tasks and experimental testing procedures. In addition, all activity and dietary profiles of the subjects were carefully controlled 48 h before each experimental session. Before the standing fatigue protocol, subjects completed a battery of tests to establish morning baseline values. Experimental tests included determination of lower leg venous cross-sectional area, blood pressure, heart rate, perceived discomfort ratings, circumferences measurements, total body water, variation in center of pressure during "quiet" standing, vertical jump performance, and specific regional patterns of foot pressures. RESULTS: This investigation demonstrated that commercial hosiery with various forms of graduated compression and construction were effective in mediating a reduction in edema in the ankles and legs while reducing the amount of venous pooling and discomfort in the lower body. Different constructions of garments may mediate these overall effects via different physiological mechanisms related to fluid shifts and muscle tissue damage. CONCLUSION: Wearing various types of graduated compression hose during the day as it relates to women in standing professions may minimize edema and muscle tissue disruption, thereby increasing comfort in the legs.

Expression of the novel tumour suppressor p33(ING1)is independent of p53.

A recently cloned tumour suppressor candidate, p33ING1, has been shown in vitro to collaborate with p53 to execute growth arrest and apoptosis. However, it is unclear as to how the expression of ING1 is regulated in normal and stress conditions. Using a p53-knockout mouse model, we investigated if the expression of ING1 was dependent on p53. We found that there was no difference in ING1 mRNA and protein levels between p53+/+ and p53-/- murine organs. In addition, when normal human epithelial keratinocytes (NHEK) and a keratinocyte cell line, HaCaT, which lacks wild-type p53 function, were exposed to UVB irradiation, the expression levels of ING1 were elevated in both NHEK and HaCaT cells. It is interesting, however, that UVB irradiation did not induce ING1 expression in dermal fibroblasts isolated from p53+/+ and p53-/- mice. Based on our findings, we therefore conclude that the expression of ING1 is independent of p53 status. UV induction of ING1 in keratinocytes suggests that ING1 may play a role in cellular stress response and skin carcinogenesis.

Feeding stimulates protein synthesis in muscle and liver of neonatal pigs through an mTOR-dependent process.

Protein synthesis is repressed in both skeletal muscle and liver after a short-term fast and is rapidly stimulated in response to feeding. Previous studies in rats and pigs have shown that the feeding-induced stimulation of protein synthesis is associated with activation of the 70-kDa ribosomal protein S6 kinase (S6K1) as well as enhanced binding of eukaryotic initiation factor eIF4E to eIF4G to form the active eIF4F complex. In cells in culture, hormones and nutrients regulate both of these events through a protein kinase termed the mammalian target of rapamycin (mTOR). In the present study, the involvement of mTOR in the feeding-induced stimulation of protein synthesis in skeletal muscle and liver was examined. Pigs at 7 days of age were fasted for 18 h, and then one-half of the animals were fed. In addition, one-half of the animals in each group were administered rapamycin (0.75 mg/kg) 2 h before feeding. The results reveal that treating 18-h fasted pigs with rapamycin, a specific inhibitor of mTOR, before feeding prevented the activation of S6K1 and the changes in eIF4F complex formation observed in skeletal muscle and liver after feeding. Rapamycin also ablated the feeding-induced stimulation of protein synthesis in liver. In contrast, in skeletal muscle, rapamycin attenuated, but did not prevent, the stimulation of protein synthesis in response to feeding. The results suggest that feeding stimulates hepatic protein synthesis through an mTOR-dependent process involving enhanced eIF4F complex formation and activation of S6K1. However, in skeletal muscle, these two processes may account for only part of the stimulation of protein synthesis, and thus additional steps may be involved in the response.

Effects of exercise and alkalosis on serum insulin-like growth factor I and IGF-binding protein-3.

This investigation examines the effects of orally induced alkalosis on serum IGF-I and IGFBP3 concentrations in response to an acute 90-s bout of high intensity cycle exercise. Ten healthy, active men, ages 24.60 +/- 4.90 years, participated in a randomized, double-blind, counterbalanced trial order with a cross-over design. Subjects ingested an experimental bicarbonate solution or a placebo solution. Blood was sampled at baseline; pre-exercise; and 0, 5, 10, and 30 min postexercise. The pH between groups for pre-exercise and postexercise time points differed significantly (p < or = .05) in the experimental condition (from 7.42 +/- 0.01 to 7.35 +/- 0.02) versus the placebo condition (from 7.36 +/- 0.01 to 7.25 +/- 0.03). Increases in IGF-I over resting conditions occurred with placebo conditions at 5 and 10 min postexercise and in the experimental condition at 5 min postexercise. Concentrations of IGFBP3 were elevated above baseline at IP in both experimental and placebo conditions.