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ABSTRACT: Septic shock is a major health care problem that affects a heterogeneous population of patients. To improve sepsis management, a key point is to decrease this heterogeneity by stratifying patients according to specific criteria, such as appropriate biomarkers. As the early phase of septic shock is characterized by cardiovascular dysfunction, precursors of vasoactive hormones represent interesting candidates. The objective of the present study was to concomitantly assess the predictive value of C-terminal proendothelin-1 and midregional proatrial natriuretic peptide (CT-proET-1 and MR-proANP, respectively vasoconstrictor and vasodilator) on 28-day mortality following septic shock.
In this observational study which included 99 patients, concentrations of MR-proANP and CT-proET-1 were measured using an immunoluminometric assay three times within the first week after the onset of septic shock.
While MR-proANP concentrations were significantly increased in non-survivors in comparison with survivors, no differences were noted for CT-proET-1. Increased MR-proANP concentrations were significantly associated with mortality after both univariate and multivariate analyses, adjusted for usual clinical confounders [SAPS II (simplified acute physiology score II), SOFA (sepsis-related organ failure assessment) scores and number of co-morbidities].
In septic shock patients, MR-proANP appears to be a good predictor of 28-day mortality, whereas CT-proET-1 does not present any predictive value during monitoring.
Clinical Chemistry and Laboratory Medicine 12/2010; 48(12):1813-20. · 2.15 Impact Factor
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ABSTRACT: Sepsis-induced immunosuppression is postulated to contribute to a heightened risk of nosocomial infection (NI). This prospective, single-center, observational study was conducted to assess whether low monocyte human leukocyte antigen-DR expression (mHLA-DR), proposed as a global biomarker of sepsis immunosuppression, was associated with an increased incidence of NI after septic shock.
The study included 209 septic shock patients. mHLA-DR was measured by flow cytometry at days (D) 3-4 and 6-9 after the onset of shock. After septic shock, patients were screened daily for NI at four sites (microbiologically documented pulmonary, urinary tract, bloodstream, and catheter-related infections). A competing risk approach was used to evaluate the impact of low mHLA-DR on the incidence of NI.
At D3-4, we obtained measurements in 153 patients. Non-survivors (n = 51) exhibited lower mHLA-DR values expressed as means of fluorescence intensities than survivors (n = 102) (33 vs. 67; p < 0.001). The patients who developed NI (n = 37) exhibited lower mHLA-DR values than those without NI (n = 116) (39 vs. 65; p = 0.008). mHLA-DR ≤ 54 remained independently associated with NI occurrence after adjustment for clinical parameters (gender, simplified acute physiology score II, sepsis-related organ failure assessment, intubation, and central venous catheterization) with an adjusted hazards ratio (aHR) of 2.52 (95% CI 1.20-5.30); p = 0.02. Similarly, at D6-9, low mHLA-DR (≤ 57) remained independently associated with NI with an aHR of 2.18 (95% CI 1.04-4.59); p = 0.04.
In septic shock patients, after adjustment with usual clinical confounders (including ventilation and central venous catheterization), persistent low mHLA-DR expression remained independently associated with the development of secondary NI.
European Journal of Intensive Care Medicine 11/2010; 36(11):1859-66. · 5.17 Impact Factor
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ABSTRACT: Improvements in survival after septic shock will most likely rely on our capacity to manage individualized therapies based on the measurement of rapidly accessible biomarkers. As the early phase of septic shock is dominated by severe alterations of the cardiovascular system, the predictive value for mortality of pro-vasopressin (pro-AVP) and pro-adrenomedullin (pro-ADM), two vasoactive pro-hormones, was assessed.
In 99 consecutive patients, pro-hormone concentrations were measured (immunoluminometric assay) three times within the first week after the onset of septic shock.
Pro-AVP and pro-ADM concentrations were significantly increased in non-survivors in comparison with survivors and were significantly associated with mortality after both univariate and multivariate analysis. Importantly, when assessed as a pair, pro-ADM and pro-AVP were even more informative.
Both Pro-ADM and pro-AVP appear to be good biomarkers for the prediction of 28-day mortality after septic shock. However, their association in a single variable tends to improve their predictive capacity.
European Journal of Intensive Care Medicine 09/2009; 35(11):1859-67. · 5.17 Impact Factor
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ABSTRACT: Sepsis syndrome represents the leading cause of death in intensive care unit. Patients present features consistent with a decline in immune responsiveness potentially contributing to mortality. We investigated whether CD4(+)CD25(+) regulatory T cells (Treg) participate in the induction of lymphocyte anergy after sepsis.
Observational study in septic shock patients and experimental study in mice.
We took advantage of the recently described flow cytometric gating strategy using the measurement of CD25 and CD127 expressions for monitoring Treg (CD4(+)CD25(+)CD127(-)Foxp3(+)). In patients the increased circulating Treg percentage significantly correlated with a decreased lympho-proliferative response. In a murine model of sepsis mimicking these observations, the ex vivo downregulation of Foxp3 expression using siRNA was associated with a restoration of this response.
The relative increase in circulating Treg might play a role in lymphocyte anergy described after septic shock and represent a standardizable surrogate marker of declining proliferative capacity after sepsis.
European Journal of Intensive Care Medicine 11/2008; 35(4):678-86. · 5.17 Impact Factor
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La Revue du praticien 12/2007; 57(17):1953-62.
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ABSTRACT: Although it is established that septic shock induces immunosuppression, the mechanisms for this phenomenon remain poorly understood. Human leukocyte antigen-G exerts strong inhibitory effects that are directed at different arms of the immune system. The main objective of the current study was to measure human leukocyte antigen-G (soluble and membrane proteins) in septic shock.
Observational study.
Adult intensive care units in a university hospital.
Sixty-four consecutive patients with septic shock (7 days of follow-up).
None.
We measured plasma human leukocyte antigen-G5 (with enzyme linked immunosorbent assay) and human leukocyte antigen-G1 (with flow cytometry) expression on circulating leukocytes. As early as days 1-2 after the onset of shock, we observed a marked elevation of soluble human leukocyte antigen-G5 in patients: 60 ng/mL (34-146) as median (Q1-Q3) (reference values <5 ng/mL). This increase was stable over time. Most important, we also found at days 1-2 a significant difference between survivors and nonsurvivors: 109 ng/mL (43-183) vs. 37 ng/mL (19-61), respectively (p = .003). This difference remained significant until day 7. Receiver operating characteristic curve analysis showed that human leukocyte antigen-G5 was a good predictor of outcome (areas under curves: 0.76 and 0.84 at days 1-2 and days 3-4, respectively, p < .001). Adjusted logistic regression analysis suggested that human leukocyte antigen-G5 at days 3-5 was a better prognostic marker than decreased monocyte human leukocyte antigen-DR and/or severity score.
The present results show a marked elevation of soluble human leukocyte antigen-G5 protein during septic shock. We may hypothesize that given its potent inhibitory properties and its association with survival, human leukocyte antigen-G5 has an important role in the numerous negative feedback signals that limit the process of inflammation during septic shock.
Critical Care Medicine 09/2007; 35(8):1942-7. · 6.33 Impact Factor
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ABSTRACT: The immediate overwhelming release of inflammatory mediators in septic shock is rapidly followed by strong anti-inflammatory responses inducing a state of immunosuppression. The patients who survive the initial hyper-inflammatory step of septic shock but subsequently die may be those who do not recover from immunosuppression. We assessed whether a low monocyte human leukocyte antigen-DR (mHLA-DR) expression, proposed as a marker of immunosuppression, is an independent predictor of mortality in patients who survived the initial 48 h of septic shock.
Prospective observational study performed in two adult intensive care units at a university hospital.
93 consecutive patients with septic shock.
At days 1-2, mHLA-DR values (determined by flow cytometry) were not significantly different between survivors and non-survivors. A sharp difference became highly significant at days 3-4 when survivors had increased their values, while non-survivors had not (43% vs. 18%, percentage of HLA-DR positive monocyte, p < 0.001). Multivariate logistic regression analysis revealed that low mHLA-DR (< 30%) at days 3-4 remained independently associated with mortality after adjustment for usual clinical confounders, adjusted odds ratio (CI): 6.48 (95% CI: 1.62-25.93).
The present preliminary results show that mHLA-DR is an independent predictor of mortality in septic shock patients. Being a marker of immune failure, low mHLA-DR may provide a rationale for initiating therapy to reverse immunosuppression. After validation of the current results in multicenter studies, mHLA-DR may help to stratify patients when designing a mediator-directed therapy in a time-dependent manner.
Intensive Care Medicine 08/2006; 32(8):1175-83. · 5.40 Impact Factor
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ABSTRACT: Despite improvement in many aspects of the care of maintenance hemodialysis (HD) patients, protein-calorie malnutrition, which is characterized by an insidious loss of somatic protein, is common and is a major risk factor for increased morbidity and mortality. We present here an overview of the current knowledge on protein metabolism in uremic patients with the expectation of providing insights into the mechanisms involved in HD-associated catabolism and outlining the rationale underlying intradialytic nutrition. We concentrate on the discussion of muscle protein metabolism because muscle is the predominant site of protein storage, and its integrity is mandatory for the maintenance of a good quality of life.
Journal of Renal Nutrition 02/2006; 16(1):3-16. · 1.57 Impact Factor
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ABSTRACT: During exercise, there is an increase in amino acid (AA) oxidation accompanied by a depression in whole-body protein synthesis and an increase in protein breakdown. Leucine oxidation increases in proportion to energy expenditure, but the total contribution of BCAA to fuel provision during exercise is minor and insufficient to increase dietary protein requirements. When investigating the effects of AA on the control of muscle protein synthesis (MPS), we showed that increased availability of mixed AAs caused a rise in human MPS to about the same extent as complete meals. Leucine alone (and to some extent other essential, but not nonessential, AAs) can stimulate MPS for a short period, suggesting that leucine acts as a signal as well as a substrate. MPS stimulation by infused AAs shows tachyphylaxis, returning to basal rates after 2 h, possibly explaining why chronically elevated leucine delivery does not elevate MPS clinically. Increased availability of essential amino acids (EAAs) results in dose-related responses of MPS, but, in elderly subjects, there is blunted sensitivity and responsiveness associated with decreased total RNA and mRNA for signaling proteins and signaling activity. Increases of MPS due to EAAs are associated with elevation of signaling activity in the mammalian target of rapamycin (mTOR)/p70 ribosomal subunit S6 kinase eukaryotic initiation factor 4 binding protein 1 pathway, without requiring rises of plasma insulin availability above 10 microU/mL. However, at insulin of <5 microU/mL, AAs appear to stimulate MPS without increasing mTOR signaling. Further increasing availability of insulin to postprandial values increases signaling activity, but has no further effect on MPS.
Journal of Nutrition 02/2006; 136(1 Suppl):264S-8S. · 3.92 Impact Factor
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ABSTRACT: The mechanisms involved during sepsis-induced immunosuppression are far from being extensively established. The objective of the present study was to investigate whether two characteristics of T cells were altered in this situation: the percentage of circulating gammadelta T lymphocytes and the level of CD3 expression on T lymphocytes.
Observational study.
Adult intensive care units in a university hospital.
Patients with septic shock (n = 21) and healthy individuals (n = 21).
None.
In patients, we first observed the decreased percentage of gammadelta T lymphocytes in peripheral blood (1% [0.7-3.1], median [interquartile range]) in comparison with healthy individuals (3.5% [2.1-4.8]). Regarding CD3, we measured a highly significant decrease of its expression on both alphabeta and gammadelta T lymphocytes from patients (p < .005), whereas the CD3 mean fluorescence intensities ratio (gammadelta/alphabeta) was not affected: 2.2 [2.1-2.4] and 2.1 [1.9-2.3] in healthy individuals and septic patients, respectively. The magnitude in the decrease of CD3 expression was thus similar in alphabeta and gammadelta cells, suggesting a common down-regulation mechanism for both T-cell lineages.
Combined with a reduced percentage of monocytes expressing human leukocyte antigen-DR, a reduced CD3 expression may be involved in the failure of antigen presentation depicted after septic shock, whereas the diminished percentage of circulating gammadelta T cells could be partly responsible for the elevated incidence of secondary infections. These two observations constitute additional pieces of the complex puzzle of sepsis-induced immunosuppression.
Critical Care Medicine 12/2005; 33(12):2836-40. · 6.33 Impact Factor
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ABSTRACT: Respiratory variation in arterial pulse pressure is a reliable predictor of fluid responsiveness in mechanically ventilated patients with circulatory failure. The main limitation of this method is that it requires an invasive arterial catheter. Both arterial and pulse oximetry plethysmographic waveforms depend on stroke volume. We conducted a prospective study to evaluate the relationship between respiratory variation in arterial pulse pressure and respiratory variation in pulse oximetry plethysmographic (POP) waveform amplitude.
This prospective clinical investigation was conducted in 22 mechanically ventilated patients. Respiratory variation in arterial pulse pressure and respiratory variation in POP waveform amplitude were recorded simultaneously in a beat-to-beat evaluation, and were compared using a Spearman correlation test and a Bland-Altman analysis.
There was a strong correlation (r2 = 0.83; P < 0.001) and a good agreement (bias = 0.8 +/- 3.5%) between respiratory variation in arterial pulse pressure and respiratory variation in POP waveform amplitude. A respiratory variation in POP waveform amplitude value above 15% allowed discrimination between patients with respiratory variation in arterial pulse pressure above 13% and those with variation of 13% or less (positive predictive value 100%).
Respiratory variation in arterial pulse pressure above 13% can be accurately predicted by a respiratory variation in POP waveform amplitude above 15%. This index has potential applications in patients who are not instrumented with an intra-arterial catheter.
Critical care (London, England) 11/2005; 9(5):R562-8. · 4.61 Impact Factor
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Anne-Lise Debard,
Brigitte Lamy,
Guillaume Monneret,
Jean-Paul Mira,
Alexandre Pachot,
Marion Kleijer,
Marie-Françoise Aillaud,
André Boibieux,
Jacques Bienvenu,
Gérard Carret,
Gérard Fournier, Julien Bohé
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ABSTRACT: Individuals with deficiencies of the late components of complement exhibit a susceptibility to the recurrence of meningococcal disease with a usually mild clinical presentation. We report the recurrence of fulminant meningococcal disease in a complement component C7-deficient patient. We found a total deficiency of FcgammaRIIIb on neutrophils, which could partially explain the unusually severe clinical presentation.
Clinical Infectious Diseases 07/2005; 40(11):1679-83. · 9.15 Impact Factor
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ABSTRACT: Success in treating severe sepsis will require relevant tools to monitor the patient immunoinflammatory status. This study aimed to investigate the feasibility of measuring a panel of immunological mediator mRNAs in whole blood and to study their prognostic values in septic shock patients. At the onset of shock, compared to healthy volunteers, mRNA levels in septic shock patients were increased for IL-10, IL-1beta, and high mobility group B1 (HMGB1) and decreased for transforming growth factor beta 1, the Th1, and Th2 transcription factors, T-bet and GATA-3, respectively. Single parameter analysis highlighted an increased expression of IL-10 and HMGB1 mRNA in nonsurvivors and a significant rise over time of GATA3 in survivors. Combining the expression levels of four genes, hierarchical cluster analysis showed that up to 95% of the patients with a similar outcome displayed transcriptional similarities. These results illustrate both the potential of whole blood mRNA quantification assays and the interest of a multiparametric strategy to better stratify septic patients.
Clinical Immunology 02/2005; 114(1):61-9. · 4.05 Impact Factor
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ABSTRACT: The decreased expression of human leukocyte antigen (HLA)-DR on monocytes is proposed as a major feature of sepsis-induced immunodepression. The objective of the present study was to investigate, in whole blood from septic shock patients, the messenger RNA (mRNA) expression of a gene panel, which is essential to ensure major histocompatibility complex class II protein structure, transport, and peptide loading.
The authors conducted a cohort study.
This study was conducted in intensive care units at a university hospital.
The study included septic shock patients (n = 41) and healthy volunteers (n = 15).
Using quantitative reverse transcriptase-polymerase chain reaction, we found that the highly polymorphic HLA-DRB1 and nonpolymorphic-DRA mRNA levels were significantly decreased in whole blood from patients with septic shock compared with healthy volunteer both on days 1-3 and 4-10 after the onset of shock. This profile was also observed for genes encoding the invariant chain, the transcription factor class II transactivator (CIITA), and the enzymes involved in the peptide loading cathepsin S, HLA-DMA, and -DMB. The monocyte surface expression of HLA-DR measured by flow cytometry was significantly correlated with the whole-blood mRNA levels of HLA-DRB1 and -DRA and to a lesser extent with the other CIITA-regulated genes HLA-DMA and invariant chain. The correlation between HLA-DRB mRNA and cell-surface expression levels was also observed in a small subset of purified monocyte samples. Regarding the temporal relationship, a significant increase of whole-blood HLA-DRA, -DMA, -DMB, invariant chain, and CIITA mRNA level was observed in survivors (p = .001), whereas expressions remained low in nonsurvivors.
A global transcriptional down regulation of a gene panel required for MHC II-restricted antigen presentation may occur in the course of septic shock. Our results suggest that the transcriptional resumption of CIITA-regulated genes might contribute to the recovery of membrane HLA-DR expression observed in survivors. These results obtained at the mRNA level support previous reports describing the loss of monocyte HLA-DR at the protein level and thus confirm the potential of measuring monocyte HLA-DR in septic patient followup.
Critical Care Medicine 02/2005; 33(1):31-8; discussion 236-7. · 6.33 Impact Factor
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ABSTRACT: The shift of T lymphocytes toward a Th2 profile during septic shock has been established on the basis of in vitro cytokine production. In the present study, the Th2 response was investigated at the level of cell surface marker expression (whole blood flow cytometry). In 58 patients with septic shock, we observed a reduced CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) expression on Th2 lymphocytes and regulatory T cells in comparison with 39 healthy volunteers. Eosinophils, which constitutively express CRTH2 in healthy individuals, also exhibited low levels of CRTH2 in patients. In addition, eosinophil CCR3 expression (eotaxin receptor, type 2 chemokine) was strongly correlated with CRTH2, suggesting thus an extended modulation of Th2 related molecules. Importantly, the persistence over time of low levels of CRTH2 or CCR3 expression was found in nonsurvivors. We hypothesize that the restoration of CRTH2/CCR3 expression may be an indicator for optimal recovery after septic shock.
Clinical Immunology 01/2005; 113(3):278-84. · 4.05 Impact Factor
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ABSTRACT: The elevation of the percentage of regulatory CD4+CD25+ T lymphocytes (Treg) has been recently described during septic shock. The objective of the present study was to investigate whether this increased percentage was due to Treg proliferation.
Observational study.
Adult intensive care units in a university hospital.
Patients with septic shock (n = 54) and healthy individuals (n = 30).
None.
In patients, we first confirmed the increased percentage of Treg among CD4+ lymphocytes in comparison with healthy individuals. Surprisingly, regarding absolute counting, we demonstrated that both T CD4+ lineages (CD25+ and CD25-) were diminished immediately after the onset of shock. Then, whereas Treg returned rapidly to healthy donors values, CD4+CD25- T lymphocytes remained dramatically reduced. Finally, Foxp3 (Treg-related gene) messenger RNA quantification enabled us to definitively rule out a lack of proliferation since it was not increased during shock.
The increased percentage of Treg after shock is due not to their proliferation but to a decrease in CD4+CD25- T lymphocyte number. We hypothesize that it might be due to a resistance of Treg to apoptosis processes occurring during septic shock.
Critical Care Medicine 12/2004; 32(11):2329-31. · 6.33 Impact Factor
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ABSTRACT: The diminished expression of HLA-DR on monocytes has been proposed as a reliable marker of immunosuppression occuring during septic shock. The objective of the present observational study was to establish the time-dependent relation between plasma cytokines interleukin (IL)-10, transforming growth factor (TGF)-beta1, tumor necrosis factor (TNF)-alpha and monocyte HLA-DR expression in 38 adult patients with septic shock. All patients (mortality at 28 days: 42%, mean admission SAPS II score: 54) had decreased HLA-DR expression. This expression was significantly lower in non-survivors at all time points. All patients had elevated IL-10 concentrations, the highest values were found in non-survivors. IL-10 was the sole cytokine to significantly correlate with HLA-DR expression (r: -0.6, p<0.001). TNF and TGF values did not provide any prognostic information. TGF levels from septic patients were even found to be decreased in comparison with normal values which suggested that IL-10 is likely more important than TGF regarding the immunosuppressive properties of septic patients' plasma. This preliminary work showed that, at the systemic level, the anti-inflammatory response dominated after septic shock. Monocyte HLA-DR expression and IL-10 measurement deserve to be determined in parallel in a larger longitudinal study. They might constitute helpful indicators for staging patients and making a decision about whether to institute a therapy with molecules able of reversing sepsis-induced immunosuppression.
Immunology Letters 09/2004; 95(2):193-8. · 2.53 Impact Factor
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Cécile Pereira, Julien Bohé,
Sylvaine Rosselli,
Emmanuel Combourieu,
Christian Pommier,
Jean-Pierre Perdrix,
Jean-Christophe Richard,
Michel Badet,
Sandrine Gaillard,
François Philit,
Claude Guérin
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ABSTRACT: To assess incidence and magnitude of the "lower inflection point" of the chest wall, the sigmoidal equation was used in 36 consecutive patients intubated and mechanically ventilated with acute lung injury (ALI). They were 21 primary and 5 secondary ALI, 6 unilateral pneumonia, and 4 cardiogenic pulmonary edema. The lower inflection point was estimated as the point of maximal compliance increase. The low constant flow inflation method and esophageal pressure were used to partition the volume-pressure curves into their chest wall and lung components on zero end-expiratory pressure. The sigmoidal equation had an excellent fit with coefficients of determination >0.90 in all instances. The point of maximal compliance increase of the chest wall ranged from 0 to 8.3 cmH2O (median 1 cmH2O) with no difference between ALI groups. The chest wall significantly contributed to the lower inflection point of the respiratory system in eight patients only. The occurrence of a significant contribution of the chest wall to the lower inflection point of the respiratory system is lower than anticipated. The sigmoidal equation is able to determine precisely the point of the maximal compliance increase of lung and chest wall.
Journal of Applied Physiology 11/2003; 95(5):2064-71. · 3.75 Impact Factor
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ABSTRACT: To test the hypothesis that muscle protein synthesis (MPS) is regulated by the concentration of extracellular amino acids, we investigated the dose-response relationship between the rate of human MPS and the concentrations of blood and intramuscular amino acids. We increased blood mixed amino acid concentrations by up to 240 % above basal levels by infusion of mixed amino acids (Aminosyn 15, 44-261 mg kg-1 h-1) in 21 healthy subjects, (11 men 10 women, aged 29 +/- 2 years) and measured the rate of incorporation of D5-phenylalanine or D3-leucine into muscle protein and blood and intramuscular amino acid concentrations. The relationship between the fold increase in MPS and blood essential amino acid concentration ([EAA], mM) was hyperbolic and fitted the equation MPS = (2.68 x [EAA])/(1.51 + [EAA]) (P < 0.01). The pattern of stimulation of myofibrillar, sarcoplasmic and mitochondrial protein was similar. There was no clear relationship between the rate of MPS and the concentration of intramuscular EAAs; indeed, when MPS was increasing most rapidly, the concentration of intramuscular EAAs was below basal levels. We conclude that the rates of synthesis of all classes of muscle proteins are acutely regulated by the blood [EAA] over their normal diurnal range, but become saturated at high concentrations. We propose that the stimulation of protein synthesis depends on the sensing of the concentration of extracellular, rather than intramuscular EAAs.
The Journal of Physiology 10/2003; 552(Pt 1):315-24. · 4.72 Impact Factor
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ABSTRACT: The components of the stimulatory effect of food on net deposition of protein are beginning to be identified and separated. One of the most important of these appears to be the effect of amino acids per se in stimulating muscle anabolism. Amino acids appear to have a linear stimulatory effect within the range of normal diurnal plasma concentrations from postabsorptive to postprandial. Within this range, muscle protein synthesis (measured by incorporation of stable isotope tracers of amino acids into biopsied muscle protein) appears to be stimulated approximately twofold; however, little further increase occurs when very high concentrations of amino acids (>2.5 times the normal postabsorptive plasma concentration) are made available. Amino acids provided in surfeit of the ability of the system to synthesize protein are disposed of by oxidation, ureagenesis and gluconeogenesis. The stimulatory effect of amino acids appears to be time dependent; a square wave increase in the availability of amino acids causes muscle protein synthesis to be stimulated and to fall back to basal values, despite continued amino acid availability. The relationship between muscle protein synthesis and insulin availability suggests that most of the stimulatory effects occur at low insulin concentrations, with large increases having no effect. These findings may have implications for our understanding of the body's requirements for protein. The maximal capacity for storage of amino acids as muscle protein probably sets an upper value on the extent to which amino acids can be stored after a single meal.
Journal of Nutrition 10/2002; 132(10):3225S-7S. · 3.92 Impact Factor
