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1دورية أكاديمية
المؤلفون: Deckers, E A, Kruijff, S, Brouwers, A H, van der Steen, K, Hoekstra, H J, Thompson, J F, Vállez García, David, Wevers, K P
المصدر: Deckers , E A , Kruijff , S , Brouwers , A H , van der Steen , K , Hoekstra , H J , Thompson , J F , Vállez García , D & Wevers , K P 2020 , ' The association between active tumor volume, total lesion glycolysis and levels of S-100B and LDH in stage IV melanoma patients ' , European Journal of Surgical Oncology , vol. 46 , no. 11 , pp. 2147-2153 . https://doi.org/10.1016/j.ejso.2020.07.011Test
مصطلحات موضوعية: Melanoma, PET, Biomarkers, S-100B, LDH, Staging, FDG-PET/CT, LACTATE-DEHYDROGENASE, MALIGNANT-MELANOMA, SERUM S-100B, SURVIVAL, GUIDELINES, IPILIMUMAB, DIAGNOSIS, PROTEIN, ASSAYS
الوصف: Introduction: The Standardized Uptake Value (SUV) in single lesions on F-18-FDG PET/CT scans and serum S-100B concentrations are inversely associated with disease-free survival in stage IV melanoma. The aim of this study was to assess the association between biomarkers (S-100B, LDH) and the PET-derived metrics SUVmean/max, metabolic active tumor volume (MATV), and total lesion glycolysis (TLG) in stage IV melanoma in order to understand what these biomarkers reflect and their possible utility for follow-up. Methods: In 52 stage IV patients the association between PET-derived metrics and the biomarkers S-100B and LDH was assessed and the impact on survival analyzed. Results: S-100B was elevated (>0.15 mu g/l) in 37 patients (71%), LDH in 11 (21%). There was a correlation between S-100B and LDH (R-2 = 0.19). S-100B was correlated to both MATV (R-2 = 0.375) and TLG (R-2 = 0.352), but LDH was not. Higher MATV and TLG levels were found in patients with elevated S-100B (p <0.001) and also in patients with elevated LDH (>250 U/l) (p <0.001). There was no association between the biomarkers and SUVmean/max. Survival analysis indicated that LDH was the only predictor of melanoma-specific survival. Conclusion: In newly diagnosed stage IV melanoma patients S-100B correlates with F-18-FDG PET/CT derived MATV and TLG in contrast to LDH, is more often elevated than LDH (71% vs. 21%) and seems to be a better predictor of disease load and disease progression. However, elevated LDH is the only predictor for survival. The biomarkers, S-100B and LDH appear to describe different aspects of the extent of metastatic disease and of tumornecrosis. (C) 2020 The Authors. Published by Elsevier Ltd.
وصف الملف: application/pdf
الإتاحة: https://doi.org/10.1016/j.ejso.2020.07.011Test
https://hdl.handle.net/11370/2b02e666-5947-499c-b576-a401e4a08c07Test
https://research.rug.nl/en/publications/2b02e666-5947-499c-b576-a401e4a08c07Test
https://pure.rug.nl/ws/files/156760140/The_association_between_active_tumor_volume_total_lesion_glycolysis_and_levels_of_S_100B_and_LDH_in_stage_IV_melanoma_patients.pdfTest -
2دورية أكاديمية
المصدر: Nguyen , K T T , Frijlink , H W & Hinrichs , W L J 2020 , ' Inhomogeneous Distribution of Components in Solid Protein Pharmaceuticals : Origins, Consequences, Analysis, and Resolutions ' , Journal of Pharmaceutical Sciences , vol. 109 , no. 1 , pp. 134-153 . https://doi.org/10.1016/j.xphs.2019.10.010Test
مصطلحات موضوعية: phase separation(s), freeze-drying, spray drying, protein formulation(s), stability, solid-state, analysis, imaging method(s), spectroscopy, AMORPHOUS PHASE-SEPARATION, HUMAN GROWTH-HORMONE, NEAR-INFRARED SPECTROSCOPY, GLASS-TRANSITION TEMPERATURES, DRYING-INDUCED VARIATIONS, ATOMIC-FORCE MICROSCOPY, RAY-POWDER DIFFRACTION, STORAGE STABILITY, LACTATE-DEHYDROGENASE, FREEZE-CONCENTRATION
الوصف: Successful development of stable solid protein formulations usually requires the addition of one or several excipients to achieve optimal stability. In these products, there is a potential risk of an inhomogeneous distribution of the various ingredients, specifically the ratio of protein and stabilizer may vary. Such inhomogeneity can be detrimental for stability but is mostly neglected in literature. In the past, it was challenging to analyze inhomogeneous component distribution, but recent advances in analytical techniques have revealed new options to investigate this phenomenon. This paper aims to review fundamental aspects of the inhomogeneous distribution of components of freeze-dried and spray-dried protein formulations. Four key topics will be presented and discussed, including the sources of component inhomogeneity, its consequences on protein stability, the analytical methods to reveal component inhomogeneity, and possible solutions to prevent or mitigate inhomogeneity.
وصف الملف: application/pdf
الإتاحة: https://doi.org/10.1016/j.xphs.2019.10.010Test
https://hdl.handle.net/11370/9ab1993a-9d57-480f-94ff-4a7f02f99df6Test
https://research.rug.nl/en/publications/9ab1993a-9d57-480f-94ff-4a7f02f99df6Test
https://pure.rug.nl/ws/files/117125702/1_s2.0_S0022354919306458_main.pdfTest -
3دورية أكاديمية
المؤلفون: Grasmeijer, Niels, Tiraboschi, Valeria, Woerdenbag, Herman J, Frijlink, Henderik W, Hinrichs, Wouter L J
المصدر: Grasmeijer , N , Tiraboschi , V , Woerdenbag , H J , Frijlink , H W & Hinrichs , W L J 2019 , ' Identifying critical process steps to protein stability during spray drying using a vibrating mesh or a two-fluid nozzle ' , European Journal of Pharmaceutical Sciences , vol. 128 , pp. 152-157 . https://doi.org/10.1016/j.ejps.2018.11.027Test
مصطلحات موضوعية: Spray drying, L-Lactic dehydrogenase, Enzymatic activity, Twofluid nozzle, Vibrating mesh nozzle, LACTATE-DEHYDROGENASE, NATIVE STRUCTURE, STABILIZATION, JET, PRESERVATION, NEBULIZATION, MECHANISMS, TREHALOSE, STORAGE, SUGARS
الوصف: The aim of this study was to identify critical steps to protein stability during spray drying using two different nozzle types: a vibrating mesh nozzle and a standard two-fluid nozzle in a Buchi B-90 spray dryer. L-Lactic dehydrogenase was used as a model protein as it is a heat and shear stress sensitive protein. Trehalose was used as excipient because of its excellent stabilizing capacities. The entire spray drying process was split up into smaller steps and after each step the enzymatic activity of the protein was measured. With the vibrating mesh nozzle in total 78% of activity was lost About 68% was due to atomizing and healing and 10% was caused by dehydration and circulation of the liquid. With the two-fluid nozzle the total activity loss was only 23%, to which atomization, dehydration, and circulation contributed almost equally. Healing was not an issue, as the two-fluid nozzle could be cooled with water. In conclusion, the type and the configuration of the nozzle used for spray drying are important determinants for maintaining protein stability, as atomizing, healing, ultra-sonication, and recirculation of the feed solution negatively influence it The possibility to cool the two-fluid nozzle offers an important advantage to the vibrating mesh nozzle in the spray drying process of proteins. In this study, we show that, next to the optimization of the formulation, optimization of the spray drying process should be taken into account to maintain protein stability.
وصف الملف: application/pdf
الإتاحة: https://doi.org/10.1016/j.ejps.2018.11.027Test
https://hdl.handle.net/11370/e7ff696c-7361-48d9-925f-2fbbfdcb0877Test
https://research.rug.nl/en/publications/e7ff696c-7361-48d9-925f-2fbbfdcb0877Test
https://pure.rug.nl/ws/files/71887805/1_s2.0_S0928098718305189_main.pdfTest -
4دورية أكاديمية
المؤلفون: Mensink, Maarten A, Frijlink, Henderik W, van der Voort Maarschalk, Kees, Hinrichs, Wouter L J
المصدر: Mensink , M A , Frijlink , H W , van der Voort Maarschalk , K & Hinrichs , W L J 2017 , ' How sugars protect proteins in the solid state and during drying (review) : Mechanisms of stabilization in relation to stress conditions ' , European Journal of Pharmaceutics and Biopharmaceutics , vol. 114 , pp. 288-295 . https://doi.org/10.1016/j.ejpb.2017.01.024Test
مصطلحات موضوعية: Biologicals, Storage stability, Temperature, Water activity, Vitrification, Mobility, Degradation, MINI FREEZE-DRYER, CHEMICAL-STABILITY, LACTATE-DEHYDROGENASE, LYOPHILIZED FORMULATIONS, INFRARED-SPECTROSCOPY, THERAPEUTIC PROTEINS, DRIED PROTEINS, AGGREGATION, GLASSES
الوصف: This review aims to provide an overview of current knowledge on stabilization of proteins by sugars in the solid state in relation to stress conditions commonly encountered during drying and storage. First protein degradation mechanisms in the solid state (i.e. physical and chemical degradation routes) and traditional theories regarding protein stabilization (vitrification and water replacement hypotheses) will be briefly discussed. Secondly, refinements to these theories, such as theories focusing on local mobility and protein-sugar packing density, are reviewed in relationship to the traditional theories and their analogies are discussed. The last section relates these mechanistic insights to the stress conditions against which these sugars are used to provide protection (i.e. drying, temperature, and moisture). In summary sugars should be able to adequately form interactions with the protein during drying, thereby maintaining it in its native conformation and reducing both local and global mobility during storage. Generally smaller sugars (disaccharides) are better at forming these interactions and reducing local mobility as they are less inhibited by steric hindrance, whilst larger sugars can reduce global mobility more efficiently. The principles outlined here can aid in choosing a suitable sugar as stabilizer depending on the protein, formulation and storage condition-specific dominant route of degradation. (C) 2017 The Authors. Published by Elsevier B.V.
وصف الملف: application/pdf
الإتاحة: https://doi.org/10.1016/j.ejpb.2017.01.024Test
https://hdl.handle.net/11370/2acaf0d9-8867-45ab-941a-77257a8fde1eTest
https://research.rug.nl/en/publications/2acaf0d9-8867-45ab-941a-77257a8fde1eTest
https://pure.rug.nl/ws/files/42077476/How_sugars_protect_proteins_in_the_solid_state_and_during_drying.pdfTest -
5دورية أكاديمية
المؤلفون: Neves, A.R., Pool, W., Solopova, A., Kok, J., Santos, H, Kuipers, O.P.
المصدر: Neves , A R , Pool , W , Solopova , A , Kok , J , Santos , H & Kuipers , O P 2010 , ' Towards Enhanced Galactose Utilization by Lactococcus lactis ' , Applied and environmental microbiology , vol. 76 , no. 21 , pp. 7048 - 7060 . https://doi.org/10.1128/AEM.01195-10Test
مصطلحات موضوعية: DEPENDENT PHOSPHOTRANSFERASE SYSTEM, TAGATOSE 6-PHOSPHATE PATHWAY, CONTROLLED GENE-EXPRESSION, GRAM-POSITIVE BACTERIA, SUBSP CREMORIS MG1363, STREPTOCOCCUS-LACTIS, ACID BACTERIA, IN-VIVO, CARBOHYDRATE-METABOLISM, LACTATE-DEHYDROGENASE
الوصف: Accumulation of galactose in dairy products due to partial lactose fermentation by lactic acid bacteria yields poor-quality products and precludes their consumption by individuals suffering from galactosemia. This study aimed at extending our knowledge of galactose metabolism in Lactococcus lactis, with the final goal of tailoring strains for enhanced galactose consumption. We used directed genetically engineered strains to examine galactose utilization in strain NZ9000 via the chromosomal Leloir pathway (gal genes) or the plasmid-encoded tagatose 6-phosphate (Tag6P) pathway (lac genes). Galactokinase (GalK), but not galactose permease (GalP), is essential for growth on galactose. This finding led to the discovery of an alternative route, comprising a galactose phosphotransferase system (PTS) and a phosphatase, for galactose dissimilation in NZ9000. Introduction of the Tag6P pathway in a galPMK mutant restored the ability to metabolize galactose but did not sustain growth on this sugar. The latter strain was used to prove that lacFE, encoding the lactose PTS, is necessary for galactose metabolism, thus implicating this transporter in galactose uptake. Both PTS transporters have a low affinity for galactose, while GalP displays a high affinity for the sugar. Furthermore, the GalP/Leloir route supported the highest galactose consumption rate. To further increase this rate, we over-expressed galPMKT, but this led to a substantial accumulation of alpha-galactose 1-phosphate and alpha-glucose 1-phosphate, pointing to a bottleneck at the level of alpha-phosphoglucomutase. Overexpression of a gene encoding alpha-phosphoglucomutase alone or in combination with gal genes yielded strains with galactose consumption rates enhanced up to 50% relative to that of NZ9000. Approaches to further improve galactose metabolism are discussed.
وصف الملف: application/pdf
الإتاحة: https://doi.org/10.1128/AEM.01195-10Test
https://hdl.handle.net/11370/d038d652-44cf-44e4-a6d7-b03bc6eb916fTest
https://research.rug.nl/en/publications/d038d652-44cf-44e4-a6d7-b03bc6eb916fTest
https://pure.rug.nl/ws/files/10437507/2010ApplEnvirMicrobiolNeves.pdfTest -
6دورية أكاديمية
المؤلفون: Neves, Ana R., Pool, Wietske A., Castro, Rute, Mingote, Ana, Santos, Filipe, Kok, Jan, Kuipers, Oscar P., Santos, Helena
المصدر: Neves , A R , Pool , W A , Castro , R , Mingote , A , Santos , F , Kok , J , Kuipers , O P & Santos , H 2006 , ' The alpha-phosphoglucomutase of Lactococcus lactis is unrelated to the alpha-D-phosphohexomutase superfamily and is encoded by the essential gene pgmH ' , The Journal of Biological Chemistry , vol. 281 , no. 48 , pp. 36864-36873 . https://doi.org/10.1074/jbc.M607044200Test
مصطلحات موضوعية: NUCLEAR-MAGNETIC-RESONANCE, IN-VIVO, ACID BACTERIA, EXOPOLYSACCHARIDE BIOSYNTHESIS, BETA-PHOSPHOGLUCOMUTASE, LIPOPOLYSACCHARIDE BIOSYNTHESIS, CELLULAR PHOSPHOGLUCOMUTASE, STREPTOCOCCUS-PNEUMONIAE, LACTATE-DEHYDROGENASE, GALACTOSE UTILIZATION
الوصف: alpha-Phosphoglucomutase (alpha-PGM) plays an important role in carbohydrate metabolism by catalyzing the reversible conversion of alpha-glucose 1-phosphate to glucose 6-phosphate. Isolation of alpha-PGM activity from cell extracts of Lactococcus lactis strain MG1363 led to the conclusion that this activity is encoded by yfgH, herein renamed pgmH. Its gene product has no sequence homology to proteins in the alpha-D-phosphohexomutase superfamily and is instead related to the eukaryotic phosphomannomutases within the haloacid dehalogenase superfamily. In contrast to known bacterial alpha-PGMs, this 28-kDa enzyme is highly specific for alpha-glucose 1-phosphate and glucose 6-phosphate and showed no activity for mannose phosphate. To elucidate the function of pgmH, the metabolism of glucose and galactose was characterized in mutants overproducing or with a deficiency of alpha-PGM activity. Overproduction of alpha-PGM led to increased glycolytic flux and growth rate on galactose. Despite several attempts, we failed to obtain a deletion mutant of pgmH. The essentiality of this gene was proven by using a conditional knock- out strain in which a native copy of the gene was provided in trans under the control of the nisin promoter. Growth of this strain was severely impaired when alpha-PGM activity was below the control level. We show that the novel L. lactis alpha-PGM is the only enzyme that mediates the interconversion of alpha-glucose 1-phosphate to glucose 6-phosphate and is essential for growth.
وصف الملف: application/pdf
الإتاحة: https://doi.org/10.1074/jbc.M607044200Test
https://hdl.handle.net/11370/111d66bc-ccce-4ec2-ba9e-1ac6e3effb84Test
https://research.rug.nl/en/publications/111d66bc-ccce-4ec2-ba9e-1ac6e3effb84Test
https://pure.rug.nl/ws/files/6701131/2006JBiolChemNevesSupp.pdfTest
https://pure.rug.nl/ws/files/6701132/2006JBiolChemNeves.pdfTest -
7دورية أكاديمية
المؤلفون: Weide, Benjamin, Martens, Alexander, Hassel, Jessica C., Berking, Carola, Postow, Michael A., Bisschop, Kees, Simeone, Ester, Mangana, Johanna, Schilling, Bastian, Di Giacomo, Anna Maria, Brenner, Nicole, Kaehler, Katharina, Heinzerling, Lucie, Gutzmer, Ralf, Bender, Armin, Gebhardt, Christoffer, Romano, Emanuela, Meier, Friedegund, Martus, Peter, Maio, Michele, Blank, Christian, Schadendorf, Dirk, Dummer, Reinhard, Ascierto, Paolo A., Hospers, Geke, Garbe, Claus, Wolchok, Jedd D.
المصدر: Weide , B , Martens , A , Hassel , J C , Berking , C , Postow , M A , Bisschop , K , Simeone , E , Mangana , J , Schilling , B , Di Giacomo , A M , Brenner , N , Kaehler , K , Heinzerling , L , Gutzmer , R , Bender , A , Gebhardt , C , Romano , E , Meier , F , Martus , P , Maio , M , Blank , C , Schadendorf , D , Dummer , R , Ascierto , P ....
مصطلحات موضوعية: CELL LUNG-CANCER, METASTATIC MELANOMA, LACTATE-DEHYDROGENASE, UNTREATED MELANOMA, PD-1 BLOCKADE, T-CELLS, IPILIMUMAB, NIVOLUMAB, SAFETY, RESPONSES
الوصف: Purpose: Biomarkers for outcome after immune-checkpoint blockade are strongly needed as these may influence individual treatment selection or sequence. We aimed to identify baseline factors associated with overall survival (OS) after pembrolizumab treatment in melanoma patients. Experimental Design: Serum lactate dehydrogenase (LDH), routine blood count parameters, and clinical characteristics were investigated in 616 patients. Endpoints were OS and best overall response following pembrolizumab treatment. Kaplan-Meier analysis and Cox regression were applied for survival analysis. Results: Relative eosinophil count (REC) >= 1.5%, relative lymphocyte count (RLC) >= 17.5%, Conclusions: High REC and RLC, low LDH, and absence of metastasis other than soft-tissue/lung are independent baseline characteristics associated with favorable OS of patients with melanoma treated with pembrolizumab. Presence of four favorable factors in combination identifies a subgroup with excellent prognosis. In contrast, patients with no favorable factors present have a poor prognosis, despite pembrolizumab, and additional treatment advances are still needed. A potential predictive impact needs to be further investigated. (C)2016 AACR.
الإتاحة: https://doi.org/10.1158/1078-0432.CCR-16-0127Test
https://hdl.handle.net/11370/2d96fa4d-f5e9-4fe9-9f75-e3a8c534f76dTest
https://research.rug.nl/en/publications/2d96fa4d-f5e9-4fe9-9f75-e3a8c534f76dTest -
8دورية أكاديمية
المؤلفون: Wevers, K. P., Kruijff, S., Speijers, M. J., Bastiaannet, E., Kobold, A. C. Muller, Hoekstra, H. J.
المصدر: Wevers , K P , Kruijff , S , Speijers , M J , Bastiaannet , E , Kobold , A C M & Hoekstra , H J 2013 , ' S-100B : A Stronger Prognostic Biomarker than LDH in Stage IIIB-C Melanoma ' , Annals of Surgical Oncology , vol. 20 , no. 8 , pp. 2772-2779 . https://doi.org/10.1245/s10434-013-2949-yTest
مصطلحات موضوعية: LACTATE-DEHYDROGENASE, MALIGNANT-MELANOMA, S100B PROTEIN, SERUM S100B, IV MELANOMA, METASTATIC MELANOMA, CUTANEOUS MELANOMA, SURVIVAL, RISK, RELAPSE
الوصف: In melanoma patients with nodal macrometastases, the distinction between good and poor prognosis is based on the presence of primary melanoma ulceration or metastatic involvement of 4 or more lymph nodes in the 7th edition of the American Joint Committee on Cancer (AJCC) classification. We hypothesized that biomarkers would increase the accurateness of staging in these patients. The aim was to assess and compare the prognostic impact of biomarkers S-100B and LDH and to determine the best timing of their measurement in stage IIIB-C melanoma. A total of 119 patients underwent therapeutic lymph node dissection (TLND) for nodal macrometastases with serum S-100B and LDH level measurements preoperatively. In 75 of them, S-100B and LDH were also measured on postoperative days 1 and 2. S-100B and LDH levels on days 0, 1, and 2 were compared for their association with disease-free survival (DFS) and disease-specific survival (DSS). At a median follow-up of 17 (range 1-89) months, S-100B levels at all time points were associated with DFS. In multivariable analysis, preoperative S-100B and S-100B measured on day 2 showed the strongest association with DFS (hazard ratio [HR] 2.55, P = 0.007 and HR 3.80, P = 0.01). For DSS, the preoperative S-100B level was the strongest independent predictor (HR 2.81, P = 0.01). LDH measurements showed a significant association with DSS in univariate analysis only when measured preoperatively (HR 2.46, P = 0.01). In multivariable analysis, LDH measurement was not associated with melanoma prognosis. The S-100B level measured preoperatively is, in contrast to LDH, one of the most important independent predictors of melanoma prognosis in patients undergoing TLND for nodal macrometastases.
الإتاحة: https://doi.org/10.1245/s10434-013-2949-yTest
https://hdl.handle.net/11370/49a62ea4-e140-4f46-8780-8ca6e1ac2a16Test
https://research.rug.nl/en/publications/49a62ea4-e140-4f46-8780-8ca6e1ac2a16Test -
9دورية أكاديمية
المؤلفون: de Graaf, Trude, de Jong, Steven, deVries, EGE, Mulder, NH
المصدر: de Graaf , T , de Jong , S , deVries , EGE & Mulder , NH 1997 , ' Expression of proteins correlated with the unique cisplatin-sensitivity of testicular cancer ' , Anticancer Research , vol. 17 , no. 1A , pp. 369-375 .
مصطلحات موضوعية: cisplatin, drug resistance, protein, human, testicular cancer, two-dimensional gel electrophoresis, CARCINOMA CELL-LINES, DAMAGE-RECOGNITION PROTEINS, TUMOR-SUPPRESSOR PROTEIN, DNA-BINDING PROTEINS, LACTATE-DEHYDROGENASE, ACQUIRED-RESISTANCE, LUNG-CANCER, IN-VITRO, GLUTATHIONE, P53
الوصف: Cisplatin (CDDP) has a curative effect in approximately 80% of patients with testicular cancer, in contrast to the frequent development of resistance in patients with small cell lung cancer and ovarian cancer, and to the natural resistance of colon cancer. At present it is unknown which factors explain the unique curability of testicular cancer. Since it is very likely that the absence or presence of specific proteins plays an important role in cellular sensitivity towards CDDP, we have screened the protein patterns of various human CDDP-sensitive cell lines and cell lines with acquired or intrinsic resistance to CDDP of testicular, lung and colon origin. The expression of several proteins appeared to correlate with in vitro CDDP sensitivity. The most striking difference found was a relative increase in expression lactate dehydrogenase (LDH) H-subunit expression in the germ cell lines. In testis and colon tumour samples some of these proteins, LDH-H included, also appeared to correlate with in vivo CDDP sensitivity. In the analysis of the mechanisms of drug-resistance, screening of the protein patterns of intrinsic sensitive and resistant cell lines could be a valuable approach.
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10دورية أكاديميةMYOCARDIAL CARBOHYDRATE, KETONE, AND FATTY-ACID UPTAKE IN CONSCIOUS LAMBS WITH AORTOPULMONARY SHUNTS
المؤلفون: GRATAMA, JWC, DALINGHAUS, M, MEUZELAAR, JJ, GERDING, AM, KOERS, JH, MUSKIET, FAJ, KUIPERS, JRG
المصدر: GRATAMA , JWC , DALINGHAUS , M , MEUZELAAR , JJ , GERDING , AM , KOERS , JH , MUSKIET , FAJ & KUIPERS , JRG 1992 , ' MYOCARDIAL CARBOHYDRATE, KETONE, AND FATTY-ACID UPTAKE IN CONSCIOUS LAMBS WITH AORTOPULMONARY SHUNTS ' , Pediatric Research , vol. 32 , no. 1 , pp. 27-32 .
مصطلحات موضوعية: OXYGEN-CONSUMPTION, LACTATE-DEHYDROGENASE, SUBSTRATE UTILIZATION, HEART-FAILURE, BLOOD-FLOW, METABOLISM, EXERCISE, GLUCOSE, OXIDATION, MUSCLE
الوصف: A left to right shunt increases myocardial work and is often accompanied by increased catecholamine levels. Because both increased myocardial work and increased catecholamine levels may induce increased fatty acid utilization, which could increase resting myocardial oxygen consumption and therefore unfavorably affect coronary reserve, we studied myocardial uptake of glucose, pyruvate, lactate, beta-OH-butyrate, acetoacetate, FFA, and triglycerides in 12 7-wk-old lambs with aortopulmonary left to right shunts (58 +/- 2% of left ventricular output. mean +/- SEM) and in 10 control lambs 2 wk after surgery. Despite the shunt, systemic blood flow in the shunt lambs was maintained at the same level as in the control lambs. This was accomplished by an increased heart rate and stroke volume. Furthermore, the shunt was accompanied by an increased myocardial oxygen consumption in the shunt lambs (834 +/- 70 versus 528 +/- 43-mu-mol O2.min-1.100 g-1; p <0.05). There were no significant differences in arterial substrate concentrations between the two groups. The same was true for arteriovenous differences across the myocardium, with the exception of lactate, which was substantially higher in shunt than in control lambs (72 +/- 25 versus 18 +/- 23-mu-mol/L; p <0.05). As a consequence, myocardial lactate uptake in the shunt lambs was increased 15-fold (18 +/- 6 versus 1 +/- 2-mu-mol.min-1.100 g-1; p <0.02), whereas uptake of the other substrates merely paralleled the increased myocardial blood flow. Our data demonstrate that myocardial substrate uptake is not substantially different between shunt and control lambs, with the exception of lactate, of which the extraction is 10-fold higher than in control lambs. We speculate that the increased myocardial lactate utilization may reflect an increase of lactate and pyruvate dehydrogenase activities.
