| 1381. |
- Unemo, Magnus, 1970-
(författare)
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Genotypic and phenotypic characterisation of Neisseria gonorrhoeae
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The bacterium Neisseria gonorrhoeae (the gonococcus) is the aetiological agent of gonorrhoea, which remains a major sexually transmitted infection/disease (STI/STD) worldwide. The incidence of gonorrhoea was previously high in many countries, Sweden included. The incidence in Sweden culminated in 1970 with 487 cases per 100,000 inhabitants. After that, the incidence declined almost every year until an all-time low of 2.4 was observed in 1996. ln 1997 the incidence of gonorrhoea began to significantly increase in Sweden, due mainly to a larger number of domestic cases of young heterosexuals of both sexes and homosexual men. This observation, in combination with the widespread use of suboptimal methods for characterisation and, in some countries, for diagnosis of the bacterium, as well as the rapid increase of resistance to several antibiotics, has intensified the research in the field of N. gonorrhoeae.In the present thesis (paper 1), a high prevalence of decreased susceptibility or resistance to several of the traditionally used gonorrhoea antibiotics was identified and correlated to the geographic area of exposure, especially Asia. Nevertheless, effective antibiotics for treating gonorrhoea are at hand. A substantial genetic heterogeneity within identical serological variants (serovars), i.e. intraserovar, as well as interserovar of N. gonorrhoeae strains circulating within the community was revealed, emphasising the importance of using highly discriminative (DNA-based) epidemiological characterisation methods for the bacteria (papers II-V). Effective DNA-based characterisation methods, i.e. pulsed-field gel electrophmesis (PFGE) of genomic DNA digested with rarely cutting restriction endonucleases and porB gene sequencing, were adapted, optimised and evaluated against conventional phenotypic methods, as epidemiological tools on Swedish N. gonorrhoeae isolates. These molecular techniques showed a significantly higher discriminatory ability, reproducibility, and objectivity than the serovar determinations using the Genetic Systems (OS) or the Pharmacia panel (Ph) ofmonoclonal antibodies (MAbs) (papers II & III). According to a comparison of serologic and genetic parB-based typing of N. gonorrhoeae, the precise amino acid residues of porB, critical for the reactivity of several of the GS MAbs, were difficult to identity (paper IV). In papers IV & V, a determination of genetic group (genogroup) and genetic variant (genovar) was developed based on real-time PCR of the entire porB gene with subsequent sequence analysis in real-time by synthesis, i.e. pyrosequencing technology, of short, highly polymorphic porB gene segments. This method provides a rapid, high-throughput, objective, highly discriminative, typeable, portable for interlaboratory comparisons, and reproducible molecular characterisation for N. gonorrhoeae. Genogroup and genovar determination can complement or even replace the internationally established serovar determination in routine use for following the transmission of individual strains in the community and confirming presumed epidemiological connections or discriminating isolates of suspected clusters of gonorrhoea cases.
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| 1382. |
- Unge, Peter
(författare)
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Pharmacological therapy of Helicobacter pylori infection
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The discovery of Helicobacter pylori (H. pylori) opened the doors to new insight and therapy for peptic ulcer disease. Earlier eradication treatment modalities based on bismuth compounds, with or without additional antimicrobials, were not well accepted mainly because of the, at least hypothetical, risks for neurological and/or renal side effects. The first proton pump inhibitor, omeprazole, had been proven as a very effective short-term anti-ulcer therapy, but after withdrawal of the drug, the recurrence rate was high. theoretically, acid suppression was believed to increase the H. pylori infestation as the environment became more neutral. On the other hand, acid suppression could increase the effect of acid labile antimicrobials. This was not investigated before the studies presented in this thesis were performed.A small pilot study (Paper I) in 24 patients showed that 7 out of 8 patients treated for fourteen days with omeprazole 40 mg o.m. + amoxicillin 750 mg b.i.d. were cleared of H. pylori, while it remained in 7/8 patients on omeprazole as monotherapy and in 2/7 patients on amoxicillin as monotherapy. However, the eradication rates 4 weeks after treatment were 5/8, 0/8 and 1/7 in the three groups, respectively. These results were confirmed in a large study (Paper II) comprising 248 consecutive patients with active duodenal ulcer disease. All had an initial treatment period for two weeks with omeprazole 40 mg o.m., followed by continued omeprazole in combination with amoxicillin 750 mg b.i.d. or amoxicillin placebo for a further two weeks. In the dual therapy group, 54% of patients were H. pylori eradicated compared to 4% in the omeprazole mono therapy group. Furthermore, the duodenal ulcer relapse rate was significantly lower in the combination group compared to the monotherapy group (p<0,001). Paper III represents a study that was preformed to assess whether improved results could be obtained by adding two antimicrobials to omeprazole. In total 787 patients were randomized to six treatment arms, where omeprazole was combined with two of the three antimicrobials amoxicillin, metronidazole and c!arithromycin in various doses and combinations. The results showed that one week's treatment was sufficient for a very high eradication rate. A combination of omeprazole 20 mg b.i.d. + amoxicillin 1000 mg b.i.d. + clarithromycin 500 mg b.i.d. was superior to a combination with a lower clarithromycin dose of 250 mg b.i.d. or amoxicillin in combination with metronidazole, but not significantly better than the other two arms containing metronidazole+ clarithromycin in a dose of 250 mg b.i.d. 500 mg b.i.d. Paper IV was designed to establish whether or not acid suppression is necessary during antimicrobial treatment. In total 539 patients were randomized. Eradication rates with omeprazole added to antimicrobials were much higher than in treatment groups not receiving omeprazole. In metronidazole resistant strains, only 76% were eradicated in comparison to 95% in susceptible strains. Amoxicillin resistance did not occur and clarithromycin resistance was found in only 3% of patients. Thus, papers I-IV proved the efficacy ofthe new treatment modality, which, however, represented high costs in the short-term perspective.The cost-effectiveness of various treatment strategies in regular use at that time was evaluated in paper V. The economic model showed that in comparison to continuous therapy with gastric acid suppressive drugs, the extra initial cost for eradication therapy was paid within one year and, in comparison to intermittent therapy, within three years.Conclusion: These studied have shown convincingly that eradication of H. pylori with a combination of gastric acid suppression and two antimicrobials (amoxicillin and clarithromycin) is the most effective treatment in PUD, giving a high eradication rate and consequently lower peptic ulcer recurrence. Thus, this treatment strategy is also very cost-effective for society.
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| 1383. |
- Ungerbäck, Jonas
(författare)
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Inflammation and Intestinal Homeostasis-Associated Genes in Colorectal Cancer
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Colorectal cancer (CRC) is a global ‘killer’ and every year more than 1.2 million new individuals are affected and approximately 600 000 succumb to the disorder. Several mechanisms such as inactivation of tumor suppressor genes, activation of oncogenes and dysregulation of cell fate determinating pathways e.g. Wnt and Notch can initiate a cancerous cell growth and promote colorectal tumorigenesis. In addition, most tumors are exposed to an inflammatory environment, which together with the presence of mitogenic and angiogenic signals may sustain several hallmarks of cancer. Genetic alterations in inflammatory genes are associated with chronic inflammatory bowel disease, which is a strong risk factor of developing CRC. Scientists have for a long time looked for ‘the Key’ that would unlock the ‘cancer door’ but more likely cancer should be considered as not one but many diseases where almost every single patient is genetically and clinically unique. Hence recent research has turned to identify such inter-individual discrepancies and to find disease markers and strategies for guiding clinicians when tailoring individual management and optimized therapy. A deeper understanding of the regulation and genetic variation of inflammation and intestinal-homeostasis associated genes is pivotal to find potential targets for future therapies.The present thesis focuses on genetic variation and alterations in inflammatory genes as well as genes specifically involved in maintaining intestinal homeostasis. The most common anti-inflammatory drugs, NSAIDs, inhibit the prostanoid-generating COX-enzymes and are associated with decreased CRC risk when administered for a long time. Unfortunately, continuous NSAID treatment may lead to severe side-effects such as gastrointestinal bleeding, possibly through the ablation of non-PGE2 prostanoids. Therefore, a more specific inhibition of PGE2 has been suggested to be superior to classical NSAIDs. In papers I and II, the terminal PGE2 generating enzyme mPGES1 was studied in the context of intestinal cancer. Unexpectedly, ApcMin/+ mice with a targeted deletion of the mPGES1 encoding gene displayed significantly more and larger intestinal adenomas as compared to their wilde-type (wt) littermates. Probably this was due to the redirected generation of PGE2 towards non-PGE2 prostanoids seen in the murine tumors, resulting in enhanced pro-tumorigenic activity of these transmitter substances. Next, with a battery of functional and descriptive assays we investigated whether the outcome of mPGES1 expression and activity could depend on the genetic profile of the tumor e.g. the Apc mutational status. Indeed, high expression of mPGES1 was associated with the presence of wt-Apc, both in vitro and in vivo, most likely depending on mPGES1 mRNA stabilization rather than upregulation through β–catenin/Lef/Tcf4 signaling.NFκB is a major regulator of inflammation e.g. through the production of inflammatory cytokines. Variations in genes controlling inflammation and angiogenesis could potentially be used as biomarkers to identify patients with increased risk of CRC development, and/or to identify those with high risk of a rapidly progressing disease. Further, such analyzes have been suggested to select patients, which may benefit from specific anti-inflammatory or anti-angiogenic therapies. In paper III, genetic alterations in NFκB associated genes were studied among CRC patients and healthy controls. The NFκB negative regulator TNFAIP3 was found to exert tumor suppressive functions in CRC and moreover, homozygous mutant TNFAIP3 (rs6920220), homozygous mutant NFκB -94 ATTG ins/del and heterozygous NLRP3 (Q705K) were identified as prognostic markers for identifying CRC patients with a high risk of rapid progression. Further studies, which focus on the potential to treat such patients with anti-inflammatory IL-1β targeting therapies, are warranted.In the intestinal epithelium, Notch and Wnt signaling function in synergy to maintain homeostasis and together these pathways promote stem cell renewal and drive proliferation. Thus, dysregulation and/or overactivation of one of the two pathways could potentially lead to simultaneous activation of the other. While the genetic mechanisms explaining aberrant Wnt signaling in CRC are well-known, the reasons for the Notch pathway activation are less so. Further, relatively little is known about the mechanisms linking the two pathways in CRC. In paper IV, we addressed this question with a set of experimental in vitro assays, hereby identifying Notch2 together with several additional genes classically belonging to the Notch pathway, as putative targets for canonical and non-canonical Wnt signaling. We therefore suggest that aberrant Notch signaling in colon cancer cells may be the result of dysregulated Wnt signaling.In summary, the results here presented add a couple of pieces to the immensely complex jigsaw puzzle connecting intestinal homeostasis, inflammation and CRC. These results may aid in identifying future biomarkers or potential drug targets that could take us to the next level in the war against cancer.
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| 1384. |
- Unosson, Mitra, 1945-
(författare)
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Malnutrition in hospitalised elderly patients
- 1993
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of the present study was to assess nutritional status in elderly patients admitted to geriatric clinic and emergency care hospital, to describe the differences between malnourished and well-nourished patients, to study changes of nutritional status during the recovery period and to evaluate the effects of dietary supplementation.In a geriatric clinic, 501 newly admitted patients were randomly allocated either to a group that received an extra nutritional supplementation or to one that did not. These groups were followed during the hospital stay for up to 26 weeks. In addition, fifty patients with hip fracture and fifty with acute stroke were followed for two months during recovery.The main measurements were: nutritional status assessed by using anthropometric measurements, serum protein analyses and delayed hypersensitivity skin tests; demographical, social and medical characteristics; a modified Norton scale, including mental condition, activity, mobility, food intake, fluid intake and general physical condition; the development and healing of pressure sores.The prevalence of protein-energy malnutrition was 28.5% among elderly admitted to the geriatric clinic, 38% among patients with hip fracture, and 8% among those with acute stroke. Nutritional status on admission to the emergency care hospital did not predict the patients' discharge or need of prolonged hospital care. During the recovery period, the nutritional status of all patients deteriorated, but significantly more in those who remainedhospitalised. There were no significant differences in functional status between malnourished and well-nourished patients on admission to emergency care hospital, while on admission to the geriatric clinic the malnourished patients had significantly impaired functional status. Significantly more patients with protein-energy malnutrition had, or developed, pressure sores. Nutritional supplement, taken as part of the standard hospital diet, generally preserved the patients' nutritional status and functional condition and reduced the mortality especially among initially well-nourished patients.The findings highlight the importance of sufficient and nourishing food so as to maintain good nutritional status and prevent the development of malnutrition.
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| 1385. |
- Uustal Fornell, Eva, 1960-
(författare)
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Pelvic floor dysfunction : a clinical and epidemiological study
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In a prospective study established in 1990, anal sphincter rupture at delivery was found in 2.4% of women and 47% of these women had problems with fecal incontinence. Although less severe, fecal incontinence was also found among 45% in a comparison group without anal sphincter rupture. In a follow-up study after ten years, no improvement was noted in either group. Women with anal sphincter rupture were more subjectively incontinent and had lower anal pressures than the comparison group. Women with subsequent vaginal deliveries had lower anal pressures and more incontinence than those delivered by caesarean section or no subsequent delivery.In an epidemiological study of 1368 women, urinary incontinence was found in 9% of 40-year-olds and 19% of 60-year-olds. Flatus incontinence was found in 9% and 19%, incontinence for liquid stool in 5% and 8% and for solid stool 0.3% and 1. 7% in 40-year-olds and 60-year-olds, respectively. Genital prolapse symptoms were found in 4% (genital bulge), 15% (pelvic heaviness) and use of finger in vagina or perineum by defecation (12%) in all women.Factors associated with urinary and fecal incontinence were anal sphincter rupture, chronic bronchitis, overweight, multiparity, age, hiatus and groin hernias and hysterectomy. Prolapse symptoms were associated with vaginal delivery and large tears at delivery but not with overweight. All types of incontinence and genital prolapse were strongly associated with each other.For epidemiological studies, the definition of urinary incontinence as leakage weekly or more often is suggested. The concept of flatus incontinence needs careful operationalization to be of value in differentiating symptoms of anal sphincter dysfunction from disorders of bowel motility and normal passing of wind. A model for operationalization is proposed. Possible measures for the prevention of PFD could be prevention of chronic bronchitis, overweight and large injuries at delivery, especially after large tears and anal sphincter rupture.
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| 1386. |
- Vahdat Shariatpanahi, Aida, 1982-
(författare)
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The Importance of Macrophages, Lipid Membranes and Seeding in Experimental AA Amyloidosis
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Amyloidosis is a group of protein misfolding diseases caused by tissue deposition of fibrillary protein aggregates termed amyloid. Amyloid A (AA) amyloidosis is a systemic form of amyloidosis that occurs as a complication of chronic inflammatory diseases, such as rheumatoid arthritis, familial Mediterranean fever and chronic infections, such as tuberculosis. AA amyloid is derived from the precursor protein serum amyloid A and is deposited in several organs preferably kidneys, liver and spleen. AA amyloidosis can be induced in mice by long standing inflammatory stimulation and concurrent administration of tissue extracts of AA amyloid, referred to as amyloid enhancing factor (AEF), reduces the time for amyloid deposition in the marginal zone of the spleen from 5 weeks to 2 days. The general aim of this thesis was to investigate the mechanisms involved in the development of AA amyloid in the mouse model of AA amyloidosis.Amyloid was induced in inflamed mice by injection of AEF and amyloid toxicity to splenic macrophages was investigated. We found that the marginal zone macrophages were very sensitive to amyloid formation and increasing amyloid load caused progressive depletion of these cells, whereas red pulp macrophages and metallophilic marginal zone macrophages appeared unaffected. To clarify the role of splenic macrophages in amyloidogenesis, macrophages were depleted by clodronate containing liposomes. We displayed that in the absence of splenic macrophages, especially marginal zone macrophages, amyloid formation was delayed implying a crucial role of macrophages in amyloid formation.The effect of lipid membranes on amyloid formation was studied and we showed that liposomes exhibited an amyloidogenic effect in inflamed mice although not as powerful as AEF. Following the fate of the liposomes, we showed that liposomes were rapidly cleared by uptake in the spleen and liver and colocalized with lysosomes. A tentative mechanism might be that accumulation of liposomes in lysosomes interfere with the SAA degradation process facilitating amyloid formation.Finally the conformational properties of two AEF (AEF1 and AEF2) preparations were studied using conformation sensitive luminescent-conjugated oligothiophenes (LCOs). We found that AEF1 and AEF2 displayed significantly different ultrastructure as well as conformation and consequently induced different cytotoxicity in vitro. Inducing amyloid formation in inflamed mice by AEF1 and AEF2 revealed that the polymorph of the amyloid aggregates was replicated in vivo.In summary, the results obtained in this thesis indicate an important role for macrophages for the formation of amyloid. The existence of amyloid strains has long been an in vitro finding, but the finding that AEF ultrastructure drives the morphology of newly formed amyloid in vivo opens up for new studies that can help us to understand the formation of homologous and heterologous fibrils. Thus, the fundamental mechanisms of various amyloid diseases are similar and the results presented in the thesis can increase the understanding of other amyloid diseases.
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| 1387. |
- Valdimarsson, Trausti
(författare)
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Bone in coeliac disease
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Patients with untreated and treated coeliac disease were examined regarding bone mineral density (BMD) and biochemical factors of importance for bone metabolism. The occurrence of disturbances and their correction during treatment with a gluten-free diet were studied. BMD was measured in the forearm using single photon absorptiometry and in the hip and spine using dual-energy X-ray absorptiometry.Among the 288 adult patients with known coeliac disease in our catchment area, 13 patients with persistent villous atrophy of the proximal small bowel mucosa despite dietary recommendation were identified and compared with matched control-patients whose intestinal mucosa had normalised at least 4 years earlier. BMD was reduced in patients with persistent villous atrophy but within normal limits in patients responsive to the diet.In 105 adult patients with untreated coeliac disease, HN.ID was reduced compared to a local healthy control group. During the first year on a gluten-free diet the BMD increased rapidly (by a median of 3 %in the spine) even in patients with minor symptoms and in older patients. Secondary hyperparathyroidism was found in 27% of untreated patients and these patients had more severely reduced BMD compared to those with normal initial parathyroid hormone. Twenty-three % of the untreated patients also had low serum calcidiol (25-hydroxyvitarnin D) levels. BMD continued to increase in the second and third follow-up years, but only became normal within three years in the group of patients without initial secondary hyperparathyroidism.In 29 consecutive adult patients with untreated coeliac disease, serum insulin-like growth factor I and BMD were lower than in matched controls. In 14 untreated patients with normal parathyroid hormone values the increase in insulin-like growth factor I correlated positively to the increase in BMD during the first year after starting a gluten-free diet.In 46 adult patients with coeliac disease trt;atedfor 8-12 years in routine care, median BMD was normal but five patients who did not follow strict gluten-free diet had a lower BMD in the femoral neck than the group of 41 patients who claimed strict adherence.TI1ese studies show that untreated coeliac disease is associated with a low B:MD. BMD inereases rapidly when a gluten-free diet is followed, even in older patients. Circulating insulin-like growth factor I may reflect some changes in hone metabolism but its pathogenetic role behind the low BMD seen in adults with coeliac disease is unclear. Secondary hyperparathyroidism is common and vitamin D deficiency also seems to be an important underlying mechanism. These findings underline the importance of a gluten-free diet for all patients with coeliac disease.
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| 1388. |
- van Ettinger-Veenstra, Helene, 1982-
(författare)
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Mind your Language, All Right? Performance-dependent neural patterns of language
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The main aim of this dissertation was to investigate the difference in neural language patternsrelated to language ability in healthy adults. The focus lies on unraveling the contributions of theright‐hemispheric homologues to Broca’s area in the inferior frontal gyrus (IFG) and Wernicke’s areain the posterior temporal and inferior parietal lobes. The functions of these regions are far from fullyunderstood at present. Two study populations consisting of healthy adults and a small group ofpeople with generalized epilepsy were investigated. Individual performance scores in tests oflanguage ability were correlated with brain activation obtained with functional magnetic resonanceimaging during semantic and word fluency tasks. Performance‐dependent differences were expectedin the left‐hemispheric Broca’s and Wernicke’s area and in their right‐hemispheric counterparts.PAPER I revealed a shift in laterality towards right‐hemispheric IFG and posterior temporal lobeactivation, related to high semantic performance. The whole‐brain analysis results of PAPER IIrevealed numerous candidate regions for language ability modulation. PAPER II also confirmed thefinding of PAPER I, by showing several performance‐dependent regions in the right‐hemispheric IFGand the posterior temporal lobe.In PAPER III, a new study population of healthy adults was tested.Again, the right posterior temporal lobe was related to high semantic performance. A decrease in lefthemisphericIFG activation could be linked to high word fluency ability. In addition, task difficultywas modulated. Increased task complexity showed to correlate positively with bilateral IFGactivation.Lastly, PAPER IV investigated anti‐correlated regions. These regions are commonly knownas the default mode network (DMN) and are normally suppressed during cognitive tasks. It wasfound that people with generalized epilepsy had an inadequate suppression of regions in the DMN,and showed poorer performance in a complex language test. The results point to neural adaptabilityin the IFG and temporal lobe. Decreased left‐lateralization of the IFG and increased rightlateralizationof the posterior temporal lobe are proposed as characteristics of individuals with highlanguage ability.
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| 1389. |
- van Vliet, Jolanda S., 1970-
(författare)
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Balancing body perception during growth and development
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Among children and adolescents, the drive to be slender and the fear of being fat is a growing public health concern. This trend stands in contrast to the increasing prevalence of overweight reported worldwide. Both feeling too fat and being overweight are associated with physical, psychological and social health-related issues from a shortand long-term perspective. The aim of this thesis is to study body perception in relation to actual body size and the bodily changes that occur naturally during puberty. Another objective is to identify risk factors for overweight, overweight perception and unhealthy eating habits in childhood and adolescence.This thesis describes the prevalence of 1) perception of overweight, 2) overweight/obesity and 3) unhealthy eating habits in Finland and Sweden. We compare our results with the World Health Organization (WHO) Health Behaviour in Schoolchildren (HBSC) survey in 2001/2002 and 2009/2010. Our cross-sectional studies were performed on a female cohort of 11-18 year old girls in Finland and a cohort of boys and girls 7-17 years in Sweden.In both Finland and Sweden, the prevalence of overweight increased over time, especially among boys. Also perception of overweight increased over time – not just among girls, but also among boys. We found social inequality in overweight, particularly in boys in relation to maternal socioeconomic status. No social inequality, but age and gender differences were found in relation to perception of overweight, where girls older than 13 years showed the highest prevalence. Body perception among girls agreed better with international reference values for waist circumference (WC) than for body mass index (BMI). Breast development and acne increased the risk for overweight perception, particularly among non-overweight girls. Perception of overweight was the strongest risk factor for dieting and skipping breakfast in both boys and girls. These behaviours were more common among adolescents than among younger boys and girls. Skipping breakfast was related to unbalanced food consumption patterns in both sexes, but in a gender-specific way.We have shown that body perception during growth and development relates to a complex age- and gender-specific balance between body size, stage and timing of pubertal maturation, eating habits as well as parental and peer influences. From a broader perspective, improving adequate body perception entails optimising this balance by influencing one or more of the individual, societal and environmental factors that determine health outcomes among children and adolescents, tracking into adulthood.
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| 1390. |
- Vanhanen, Ingemar
(författare)
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Metabolic intervention with amino acids in coronary surgery : A clinical study with special reference to effects of glutamate and aspartate on myocardial metabolism
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Amino acids, particularly glutamate and aspartate, have been suggested to be important for the tolerance to myocardial ischemia and for the recovery of the oxidative metabolism of the heart after ischemia. The objective of the present work was to investigate myocardial metabolism and how it is influenced by intravenous supply of glutamate and aspartate in association with coronary artery bypass grafting (CABG). Three groups, comprising a total of 49 patients, were studied with classical organ balance technique. 30 patients with stable angina were studied 1-2 hour after CABG and 19 patients with unstable angina were studied before cardiopulmonary bypass (CPB) and during early reperfusion.Glutamate infusion early after elective CABG caused a dose-dependent linear increase in arterial levels and increased myocardial uptake of glutamate. The greatest impact on myocardial glutamate uptake was achieved by increasing arterial whole blood level by less than 100 μmol/L, while a further increase of arterial level was associated with marginal effects on myocardial uptake. The fractional uptake of lactate increased during glutamate infusion, whereas myocardial exchange of other substrates remained essentially unaffected. These metabolic changes were associated with improved myocardial performance.Aspartate infusion in the same setting resulted in a dose-dependent linear increase of both arterial aspartate level and myocardial uptake of aspartate. No positive effects on myocardial metabolism or function were demonstrated. However, considerable interactions with glutamate metabolism, compatible with competitive inhibition of myocardial glutamate uptake were observed.In patients with unstable angina the only substrate extracted by the heart immediately before CPB was free fatty acids (FFAs). In contrast, during glutamate infusion a significant myocardial uptake of glutamate and lactate was also found. The uptake of lactate correlated with arterial levels of lactate (r0.83; p<0.01). Myocardial metabolism during early reperfusion was characterized by dynamic changes including low oxygen extraction, lactate release, a shift towards increased glucose utilization. At the end of the study period oxygen extraction had normalized but in the control group there was still no uptake of lactate. Glutamate infusion resulted in myocardial uptake of glutamate and a significant myocardial uptake of lactate was found at the end of the study period (15 minutes after weaning from CPB). A substantial uptake ofFFAs was observed in both groups.In conclusion, this study demonstrates beneficial metabolic effects of myocardial glutamate augmentation in association with CABG. The normal lactate metabolism in patients with unstable angina before revascularization suggests enhanced myocardial tolerance to ischemia and the improved lactate metabolism during early reperfusion and after completion of surgery is compatible with improved recovery of the oxidative metabolism.
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