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Jonas Nygren

Publications and source records attributed to Jonas Nygren.

36 records · Page 2Linked to original sources
PubMed2004

Effect of short-term prednisone use on blood flow, muscle protein metabolism, and function.

Glucocorticoids can cause muscle atrophy, but the effect on muscle protein metabolism in humans has not been adequately studied to know whether protein synthesis, breakdown, or both are altered. We tested the effect of 6 d of oral prednisone (Pred, 0.5 mg/kg.d) on muscle protein metabolism and function. Six healthy subjects (three men/three women, 22-41 yr) completed two trials (randomized, double-blind, cross-over) with Pred and placebo. Fasting glucose, insulin, IGF-I, and glucagon were higher on Pred vs. placebo, whereas IGF-II and IGF binding protein-1 and -2 were lower. Whole-body amino acid fluxes, blood urea nitrogen, and urinary nitrogen loss were not statistically different between trials. Leg blood flow was 25% lower on Pred leading to 15-30% lower amino acid flux among the artery, vein, and muscle. However, amino acid net balance and rates of protein synthesis and breakdown were unchanged, as were synthesis rates of total mixed, mitochondrial, sarcoplasmic, and myosin heavy chain muscle proteins. Muscle mitochondrial function, muscle strength, and resting energy expenditure were also unchanged. These results demonstrate that a short-term moderate dose of prednisone affects glucose metabolism but has no effect on whole-body or leg muscle protein metabolism or muscle function.

Administration, Oral↗
PubMed2004

Intensive insulin treatment in critically ill trauma patients normalizes glucose by reducing endogenous glucose production.

Critical illness is associated with insulin resistance and hyperglycemia. Intensive insulin treatment to normalize blood glucose during feeding has been shown to improve morbidity and mortality in patients in intensive care. The mechanisms behind the glucose-controlling effects of insulin in stress are not well understood. Six previously healthy, severely traumatized patients (injury severity score > 15) were studied early (24-48 h) after trauma. Endogenous glucose production (EGP) and whole-body glucose disposal (WGD) were measured (6,6-(2)H(2)-glucose) at basal, during total parenteral nutrition (TPN), and during TPN plus insulin to normalize blood glucose (TPN+I). Six matched volunteers served as controls. At basal and TPN, concentrations of glucose and insulin were higher in patients (P < 0.05). During TPN+I, insulin concentrations were 30-fold higher in patients. At basal, WGD and EGP were 30% higher in patients (P < 0.05). During TPN, EGP decreased in both groups but less in patients, resulting in 110% higher EGP than controls (P < 0.05). Normoglycemia coincided with reduced EGP, resulting in similar rates in both groups. WGD did not change during TPN or TPN+I and was not different between the groups. In conclusion, in healthy subjects, euglycemia is maintained during TPN at physiological insulin concentrations by a reduction of EGP, whereas WGD is maintained at basal levels. In traumatized patients, hyperglycemia is due to increased EGP. In contrast to controls, normalization of glucose concentration during TPN needs high insulin infusion rates and is accounted for by a reduction in EGP, whereas WGD is not increased.

Adult↗
PubMed2003

Cleavage of cellular DNA by calicheamicin gamma1.

It is assumed that the efficient antitumor activity of calicheamicin gamma1 is mediated by its ability to introduce DNA double-strand breaks in cellular DNA. To test this assumption we have compared calicheamicin gamma1-mediated cleavage of cellular DNA and purified plasmid DNA. Cleavage of purified plasmid DNA was not inhibited by excess tRNA or protein indicating that calicheamicin gamma1 specifically targets DNA. Cleavage of plasmid DNA was not affected by incubation temperature. In contrast, cleavage of cellular DNA was 45-fold less efficient at 0 degrees C as compared to 37 degrees due to poor cell permeability at low temperatures. The ratio of DNA double-strand breaks (DSB) to single-stranded breaks (SSB) in cellular DNA was 1:3, close to the 1:2 ratio observed when calicheamicin gamma1 cleaved purified plasmid DNA. DNA strand breaks introduced by calicheamicin gamma1 were evenly distributed in the cell population as measured by the comet assay. Calicheamicin gamma1-induced DSBs were repaired slowly but completely and resulted in high levels of H2AX phosphorylation and efficient cell cycle arrest. In addition, the DSB-repair deficient cell line Mo59J was hyper sensitive to calicheamicin gamma. The data indicate that DSBs is the crucial damage after calicheamicin gamma1 and that calicheamicin gamma1-induced DSBs are recognized normally. The high DSB:SSB ratio, specificity for DNA and the even damage distribution makes calicheamicin gamma1 a superior drug for studies of the DSB-response and emphasizes its usefulness in treatment of malignant disease.

Aminoglycosides↗
PubMed2003

New developments facilitating nutritional intake after gastrointestinal surgery.

PURPOSE OF REVIEW: Conventional perioperative care includes a period of semistarvation before bowel function returns and adequate oral intake is allowed. It has been clearly shown that there is no need for restriction in oral intake after, at least lower, gastrointestinal surgery, and that early oral feeding does not increase the risk for dehiscense of the anastomosis. In contrast, early feeding reduces postoperative complications. Even if early oral intake is allowed, however, it is common that side effects such as nausea and vomiting prevent patients from reaching the target energy intakes. Thus, developing routines and treatments that promote sufficient early oral intake after surgery and maintain adequate energy intake in the postoperative period are probably of great importance for the outcome from surgery. RECENT FINDINGS: There are a number of factors which may facilitate early oral intake after gastrointestinal surgery including effective pain relief using epidural anaesthesia while avoiding opioids, minimizing sodium and fluid administration perioperatively and substantially reducing preoperative fasting. In addition, sufficient preoperative information, intensive mobilization, energy-dense hospital food and oral supplements may all contribute to improved energy intake after surgery. SUMMARY: In general, there is a great need for randomized controlled trials examining factors important for the regulation of oral intake after surgery and also the effects of early oral intake after upper gastrointestinal surgery. Future areas of research may also include regulation of appetite and use of peripherally acting opioid antagonists.

Abdomen↗
PubMed2003

Similar outcome after colonic pouch and side-to-end anastomosis in low anterior resection for rectal cancer: a prospective randomized trial.

OBJECTIVES: To compare a colonic J-pouch or a side-to-end anastomosis after low-anterior resection for rectal cancer with regard to functional and surgical outcome. SUMMARY BACKGROUND DATA: A complication after restorative rectal surgery with a straight anastomosis is low-anterior resection syndrome with a postoperatively deteriorated anorectal function. The colonic J-reservoir is sometimes used with the purpose of reducing these symptoms. An alternative method is to use a simple side-to-end anastomosis. METHODS: One-hundred patients with rectal cancer undergoing total mesorectal excision and colo-anal anastomosis were randomized to receive either a colonic pouch or a side-to-end anastomosis using the descending colon. Surgical results and complications were recorded. Patients were followed with a functional evaluation at 6 and 12 months postoperatively. RESULTS: Fifty patients were randomized to each group. Patient characteristics in both groups were very similar regarding age, gender, tumor level, and Dukes' stages. A large proportion of the patients received short-term preoperative radiotherapy (78%). There was no significant difference in surgical outcome between the 2 techniques with respect to anastomotic height (4 cm), perioperative blood loss (500 ml), hospital stay (11 days), postoperative complications, reoperations or pelvic sepsis rates. Comparing functional results in the 2 study groups, only the ability to evacuate the bowel in <15 minutes at 6 months reached a significant difference in favor of the pouch procedure. CONCLUSIONS: The data from this study show that either a colonic J-pouch or a side-to-end anastomosis performed on the descending colon in low-anterior resection with total mesorectal excision are methods that can be used with similar expected functional and surgical results.

Adult↗
PubMed2003

Effect of hyperthyroidism on spontaneous physical activity and energy expenditure in rats.

Thyroid hormone excess is associated with increased energy expenditure. The contributions of increases in spontaneous physical activity and nonexercise activity thermogenesis (NEAT) to this effect have not been defined. To address the hypothesis that hyperthyroidism is associated with increased spontaneous physical activity and NEAT, we rendered rats hyperthyroid by using continuous infusion of high-dose triiodothyronine for 14 days and measured the effects on physical activity and NEAT. On day 14, in the hyperthyroid group the mean +/- SD triiodothyronine concentration was 755 +/- 137 (range 574-919) ng/dl and in the control group 59 +/- 0.5 (58-59) ng/dl. Over the 14-day treatment period, mean spontaneous physical activity increased in the hyperthyroid rats from 24 +/- 7 to 36 +/- 6 activity units (AU)/min; P < 0.001 but did not increase in the controls (23 +/- 7 vs. 22 +/- 4 AU/min). Also, over the 14-day period, daily NEAT increased in the hyperthyroid rats from 8.1 +/- 2.8 to 19.7 +/- 5.0 kcal/day (P < 0.001) but did not increase in the controls (8.7 +/- 3.5 cf 9.4 +/- 1.7 kcal/day; not significant). In conclusion, hyperthyroidism is associated with increased spontaneous physical activity and NEAT.

Animals↗
PubMed2003

Splanchnic release of ghrelin in humans.

Ghrelin is a novel polypeptide identified in rat stomach, and it increases GH release, gastric motility, and appetite and modulates many other organ functions. It has been reported that ghrelin may be released from a variety of other tissues, but the absolute contribution of the splanchnic bed remains to be defined. We quantified the splanchnic output of ghrelin in 22 healthy people after an overnight fast, with indwelling catheters in the femoral artery and hepatic vein. Splanchnic ghrelin output was calculated by multiplying veno-arterial difference in ghrelin concentration with splanchnic plasma flow (measured by indicator dye dilution technique). Plasma ghrelin was measured using (125)I-labeled ghrelin and rabbit polyclonal antibody raised against octanoylated human ghrelin. Ghrelin concentrations in the artery and in the hepatic veins were 960 +/- 82 pg/ml and 1102 +/- 90 pg/ml (P < 0.001), respectively. The veno-arterial concentration difference was 143 +/- 38 pg/ml, amounting to 15% of the arterial concentration. The splanchnic output of ghrelin was 141 +/- 43 ng/min (P < 0.003). Assuming that the half-life of ghrelin is less than 60 min, the splanchnic output would explain the entire amount of circulating ghrelin in the postabsorptive state. We conclude that a substantial amount of ghrelin is being released from the splanchnic bed in the postabsorptive state in healthy human subjects and that splanchnic bed is the major source of circulating ghrelin in humans.

Adult↗
PubMed2003

Activation of the DNA-dependent protein kinase by drug-induced and radiation-induced DNA strand breaks.

The DNA-dependent protein kinase (DNA-PK) is a DNA-end activated protein kinase that is required for efficient repair of DNA double-strand breaks (DSBs) and for normal resistance to ionizing radiation. DNA-PK is composed of a DNA-binding subunit, Ku, and a catalytic subunit, DNA-PKcs (PRKDC). We have previously shown that PRKDC is activated when the enzyme interacts with the terminal nucleotides of a DSB. These nucleotides are often damaged when DSBs are introduced by anticancer agents and could therefore prevent recognition by DNA-PK. To determine whether DNA-PK could recognize DNA strand breaks generated by agents used in the treatment of cancer, we damaged plasmid DNA with anticancer drugs and ionizing radiation. The DNA breaks were tested for the ability to activate purified DNA-PK. The data indicate that DSBs produced by bleomycin, calicheamicin and two types of ionizing radiation ((137)Cs gamma rays and N(7+) ions: high and low linear energy transfer, respectively) activate DNA-PK to levels matching the kinase activation obtained with simple restriction endonuclease-induced DSBs. In contrast, the protein-linked DSBs produced by etoposide and topoisomerase II failed to bind and activate DNA-PK. Our findings indicate that DNA-PK recognizes DSBs regardless of chemical complexity but cannot recognize the protein-linked DSBs produced by etoposide and topoisomerase II.

Aminoglycosides↗
PubMed2003

Differential regulation of protein dynamics in splanchnic and skeletal muscle beds by insulin and amino acids in healthy human subjects.

To determine the in vivo effect of amino acids (AAs) alone or in combination with insulin on splanchnic and muscle protein dynamics, we infused stable isotope tracers of AAs in 36 healthy subjects and sampled from femoral artery and vein and hepatic vein. The subjects were randomized into six groups and were studied at baseline and during infusions of saline (group 1), insulin (0.5 mU. kg(-1). min(-1)) (group 2), insulin plus replacement of AAs (group 3) insulin plus high-dose AAs (group 4), or somatostatin and baseline replacement doses of insulin, glucagon and GH plus high dose of AAs (group 5) or saline (group 6). Insulin reduced muscle release of AAs mainly by inhibition of protein breakdown. Insulin also enhanced AA-induced muscle protein synthesis (PS) and reduced leucine transamination. The main effect of AAs on muscle was the enhancement of PS. Insulin had no effect on protein dynamics or leucine transamination in splanchnic bed. However, AAs reduced protein breakdown and increased synthesis in splanchnic bed in a dose-dependent manner. AAs also enhanced leucine transamination in both splanchnic and muscle beds. Thus insulin's anabolic effect was mostly on muscle, whereas AAs acted on muscle as well as on splanchnic bed. Insulin achieved anabolic effect in muscle by inhibition of protein breakdown, enhancing AA-induced PS, and reducing leucine transamination. AAs largely determined protein anabolism in splanchnic bed by stimulating PS and decreasing protein breakdown.

Adult↗
PubMed2002

DNA fragmentation and morphological changes in apoptotic human lymphocytes.

Cell suspensions enriched in cells at various stages of apoptosis were obtained by separation of irradiated human peripheral blood lymphocytes on density gradients at different post-irradiation times. The state of DNA fragmentation in the cells was determined by comet assay and pulsed field gel electrophoresis. The morphologically distinguishable features of apoptosis such as chromatin condensation and cell shrinkage correlated with discrete stages of DNA fragmentation. It was found that >/=50 kbp fragmentation of DNA occurs already in cells of normal density whereas the subsequent DNA fragmentation onto fragments <50 kbp occurs in parallel with cell shrinkage and simultaneous increase in cell density. The observed stages of DNA fragmentation seem to be separated in time that could allow in case of abortive apoptosis formation of chromosomal aberrations.

Apoptosis↗
PubMed2002

Matrix association of early- and late-replicating chromatin studied by single-cell electrophoresis.

CHO-K1 cells were synchronized at the G(1)/S border by mitotic shake-off and aphidicolin incubation. Pulse-labeling with tritium was done at 30 min, 2 or 5 h into the S-phase, with chase incubations for different times in non-radioactive medium. The cells were subjected to neutral microelectrophoresis to extend the DNA into "comets," after which the label was visualized through autoradiography. At zero chase time, all label was positioned in the head. The displacement of label into the tails increased with time, reaching a maximum at about 5 h after the pulse. A lag phase of 2-3 h was observed for the early-labeled cells before the displacement started. Also, more label was released after overnight serum starvation, but this was reversed through a 3-h incubation at normal growth conditions. It was found that late-replicating chromatin is organized in larger domains than early-replicating chromatin, and DNA polymerase seems to be an important organizer. Early-replicating chromatin has other important attachments to the nuclear matrix, dependent on metabolic activity.

Animals↗
PubMed2002

Dietary antioxidants preserve endothelium dependent vasorelaxation in overfed rats.

OBJECTIVE: A high fat diet contributes to obesity and acutely impairs endothelium dependent vasorelaxation. While a high cholesterol diet chronically impairs endothelium dependent vasorelaxation in rabbits, this model is associated with severe hypercholesterolemia. The effect of chronic high fat feeding on endothelial function in the setting of more normal lipid levels has not been studied. Our aim was to study vascular function in rats overfed for 6 months and to determine the role of oxidative stress in the alteration of vascular function associated with this diet. METHODS: Forty-five male Sprague-Dawley rats were placed on the following diets for 6 months, control diet, high fat diet or high fat diet supplemented with vitamins A, E and selenium. Six months later blood samples were collected and vascular function was assessed in the aorta. RESULTS: The rats fed a high fat diet were heavier than controls (608.4 +/- 41.8 vs. 700.3 +/- 50.1 vs. 699.5 +/- 52.6 g, P<0.05 for control vs. high fat and high fat plus antioxidant groups) but lipid levels were similar in each group (cholesterol, 145.9 +/- 53.4 vs. 140.5 +/- 44.0 vs. 152.7 +/- 36.1 mg/dl and triglycerides, 173.2 +/- 106.7 vs. 197.4 +/- 131.3 vs. 166.1 +/- 65.3 mg/dl, P, NS). Relaxations to acetylcholine and calcium were significantly impaired in the high fat diet group compared with controls (EC(50), 6.90 +/- 0.22, 7.12 +/- 0.32; AUC, 96.9 +/- 51.6, 155.5 +/ - 73.7) but were not different between the antioxidant supplemented group and controls (EC(50), 7.06 +/- 0.37; AUC, 151.9 +/- 67.4). Relaxations to DEA NONOate were similar in each group. CONCLUSIONS: Dietary antioxidants preserved endothelium dependent vasorelaxation in rats fed a high fat diet for 6 months.

Analysis of Variance↗
PubMed2002

Toxicological characterization of a novel in vivo benzo[a]pyrene metabolite, 7-oxo-benz[d]anthracene-3,4-dicarboxylic acid anhydride.

Recently, we described a new in vivo pathway in the metabolism of benzo[a]pyrene (BP) that involves an opening of the aromatic ring system. One of the products of this pathway, isolated from rat urine, was the anhydride of 7-oxo-benz[d]anthracene-3,4-dicarboxylic acid (ABADA). We have now investigated the effect of ABADA on several cellular targets, known to be important in tumor formation. ABADA was as efficient as BP-7,8-diol-9,10-epoxide in inducing direct strand breaks but not alkali labile sites in DNA in HT-29 cells and exhibited weak mutagenic activity in Salmonella typhimurium strain TA 102. The cytotoxicity of ABADA to HCT 116 cells appeared to be due to apoptosis, as caspase-3 activity and poly-ADP-ribose polymerase (PARP) cleavage was observed. COX-2 promoter activity was induced by ABADA in HCT 116 cells. In conclusion, this novel metabolic pathway may also be contributing to the carcinogenicity of BP.

Anhydrides↗
PubMed2002

Glucose flux is normalized by compensatory hyperinsulinaemia in growth hormone-induced insulin resistance in healthy subjects, while skeletal muscle protein synthesis remains unchanged.

The aim of this present investigation was to study the relationship between the reduction in insulin sensitivity accompanying 5 days of treatment with growth hormone (GH; 0.05 mg.24 h(-1).kg(-1)) and intracellular substrate oxidation rates in six healthy subjects, while maintaining glucose flux by a constant glucose infusion and adjusting insulin infusion rates to achieve normoglycaemia (feedback clamp). Protein synthesis rates in skeletal muscle (flooding dose of L-[(2)H(5)]phenylalanine) were determined under these conditions. We also compared changes in insulin sensitivity after GH treatment with simultaneous changes in energy requirements, protein synthesis rates, nitrogen balance, 3-methylhistidine excretion in urine, body composition and the hormonal milieu. After GH treatment, 70% more insulin was required to maintain normoglycaemia (P<0.01). The ratio between glucose infusion rate and serum insulin levels decreased by 34% at the two levels of glucose infusion tested (P<0.05). Basal levels of C-peptide, insulin-like growth factor (IGF)-I and IGF-binding protein-3 increased almost 2-fold, while levels of glucose, insulin, glucagon, GH and IGF-binding protein-1 remained unchanged. Non-esterified fatty acid levels decreased (P<0.05). In addition, 24 h urinary nitrogen excretion decreased by 26% (P<0.01) after GH treatment, while skeletal muscle protein synthesis and 3-methylhistidine excretion in urine remained unchanged. Energy expenditure increased by 5% (P<0.05) after treatment, whereas fat and carbohydrate oxidation were unaltered. In conclusion, when glucose flux was normalized by compensatory hyperinsulinaemia under conditions of GH-induced insulin resistance, intracellular rates of oxidation of glucose and fat remained unchanged. The nitrogen retention accompanying GH treatment seems to be due largely to improved nitrogen balance in non-muscle tissue.

Adult↗
PubMed2002

Modulation of post-operative insulin resistance by pre-operative carbohydrate loading.

Insulin resistance develops as a response to virtually all types of surgical stress. There is an increasing body of evidence that suggests that insulin resistance in surgical stress is not beneficial for outcome. A recent large study in intensive-care patients showed that aggressive treatment of insulin resistance using intravenous insulin reduced mortality and morbidity substantially. Similarly, in burn patients, intensive insulin and glucose treatment has been shown to improve N economy and enhance skin-graft healing. In surgical patients insulin resistance has been characterized in some detail, and has been shown to have many similarities with metabolic changes seen in patients with type 2 diabetes. This finding may be important since insulin resistance has been shown to be one independent factor that influences length of stay. When patients about to undergo elective surgery have been treated with glucose intravenously or a carbohydrate-rich drink instead of overnight fasting, insulin resistance was reduced by about half. A small meta-analysis showed that when post-operative insulin resistance was reduced by pre-operative carbohydrates, length of hospital stay was shortened. Overnight intravenous glucose at high doses improved post-operative N economy. This type of treatment has also been shown repeatedly to reduce cardiac complications after open-heart surgery. Furthermore, if the carbohydrates are given as a drink pre-operatively, pre-operative thirst, hunger and anxiety are markedly reduced. In summary, preventing or treating insulin resistance in surgical stress influences outcome. Fasting overnight is not an optimal way to prepare patients for elective surgery. Instead, pre-operative carbohydrates have clinical benefits.

Anxiety↗
PubMed2002

Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes.

Metformin is an effective hypoglycemic drug that lowers blood glucose concentrations by decreasing hepatic glucose production and increasing glucose disposal in skeletal muscle; however, the molecular site of metformin action is not well understood. AMP-activated protein kinase (AMPK) activity increases in response to depletion of cellular energy stores, and this enzyme has been implicated in the stimulation of glucose uptake into skeletal muscle and the inhibition of liver gluconeogenesis. We recently reported that AMPK is activated by metformin in cultured rat hepatocytes, mediating the inhibitory effects of the drug on hepatic glucose production. In the present study, we evaluated whether therapeutic doses of metformin increase AMPK activity in vivo in subjects with type 2 diabetes. Metformin treatment for 10 weeks significantly increased AMPK alpha2 activity in the skeletal muscle, and this was associated with increased phosphorylation of AMPK on Thr172 and decreased acetyl-CoA carboxylase-2 activity. The increase in AMPK alpha2 activity was likely due to a change in muscle energy status because ATP and phosphocreatine concentrations were lower after metformin treatment. Metformin-induced increases in AMPK activity were associated with higher rates of glucose disposal and muscle glycogen concentrations. These findings suggest that the metabolic effects of metformin in subjects with type 2 diabetes may be mediated by the activation of AMPK alpha2.

AMP-Activated Protein Kinases↗