Exploring the role of extracellular matrix proteins to develop biomarkers of plaque vulnerability and outcome.

Cardiovascular disease (CVD) is the most common cause of death in industrialized countries. One underlying cause is atherosclerosis, which is a systemic disease characterized by plaques of retained lipids, inflammatory cells, apoptotic cells, calcium and extracellular matrix (ECM) proteins in the arterial wall. The biologic composition of an atherosclerotic plaque determines whether the plaque is more or less vulnerable, that is prone to rupture or erosion. Here, the ECM and tissue repair play an important role in plaque stability, vulnerability and progression. This review will focus on ECM remodelling in atherosclerotic plaques, with focus on how ECM biomarkers might predict plaque vulnerability and outcome.

Supplemental oxygen therapy does not affect the systemic inflammatory response to acute myocardial infarction.

BACKGROUND: Oxygen therapy has been used routinely in normoxemic patients with suspected acute myocardial infarction (AMI) despite limited evidence supporting a beneficial effect. AMI is associated with a systemic inflammation. Here, we hypothesized that the inflammatory response to AMI is potentiated by oxygen therapy. METHODS: The DETermination of the role of Oxygen in suspected Acute Myocardial Infarction (DETO2X-AMI) multicentre trial randomized patients with suspected AMI to receive oxygen at 6 L min-1 for 6-12 h or ambient air. For this prespecified subgroup analysis, we recruited patients with confirmed AMI from two sites for evaluation of inflammatory biomarkers at randomization and 5-7 h later. Ninety-two inflammatory biomarkers were analysed using proximity extension assay technology, to evaluate the effect of oxygen on the systemic inflammatory response to AMI. RESULTS: Plasma from 144 AMI patients was analysed whereof 76 (53%) were randomized to oxygen and 68 (47%) to air. Eight biomarkers showed a significant increase, whereas 13 were decreased 5-7 h after randomization. The inflammatory response did not differ between the two treatment groups neither did plasma troponin T levels. After adjustment for increase in troponin T over time, age and sex, the release of inflammation-related biomarkers was still similar in the groups. CONCLUSIONS: In a randomized controlled setting of normoxemic patients with AMI, the use of supplemental oxygen did not have any significant impact on the early release of systemic inflammatory markers.

Stress-induced release of the S100A8/A9 alarmin is elevated in coronary artery disease patients with impaired cortisol response.

Psychological stress is thought to be an important trigger of cardiovascular events, yet the involved pathways and mediators are largely unknown. Elevated systemic levels of the pro-inflammatory alarmin S100A8/A9 correlate with poor prognosis in coronary artery disease (CAD) patients. Here, we investigated the links between S100A8/A9 release and parameters of anti-inflammatory glucocorticoid secretion in two different cohorts subjected to a psychological stress test. In the first cohort of 60 CAD patients, psychological stress induced a rapid increase of circulating S100A8/A9. This rapid S100A8/A9 response strongly correlated with elevated evening saliva cortisol levels, suggesting an association with a dysregulated hypothalamic-pituitary-adrenal (HPA) axis. In the second cohort of 27 CAD patients and 28 controls, elevated S100A8/A9 levels were still detectable 24 h after stress in 40% of patients and 36% of controls, with a tendency for higher levels in patients. The sustained S100A8/A9 response was associated with a poor rapid cortisol release after stress in patients, but not in the control group. Our findings reveal for the first time that acute psychological stress induces elevated levels of S100A8/A9. We also provide hypothesis-generating evidence that dysregulated cortisol secretion in CAD patients might be associated with an exaggerated pro-inflammatory S100A8/A9 response.

Simulating effects of brain atrophy in longitudinal PET imaging with an anthropomorphic brain phantom.

In longitudinal positron emission tomography (PET), the presence of volumetric changes over time can lead to an overestimation or underestimation of the true changes in the quantified PET signal due to the partial volume effect (PVE) introduced by the limited spatial resolution of existing PET cameras and reconstruction algorithms. Here, a 3D-printed anthropomorphic brain phantom with attachable striata in three sizes was designed to enable controlled volumetric changes. Using a method to eliminate the non-radioactive plastic wall, and manipulating BP levels by adding different number of events from list-mode acquisitions, we investigated the artificial volume dependence of BP due to PVE, and potential bias arising from varying BP. Comparing multiple reconstruction algorithms we found that a high-resolution ordered-subsets maximization algorithm with spatially variant point-spread function resolution modeling provided the most accurate data. For striatum, the BP changed by 0.08% for every 1% volume change, but for smaller volumes such as the posterior caudate the artificial change in BP was as high as 0.7% per 1% volume change. A simple gross correction for striatal volume is unsatisfactory, as the amplitude of the PVE on the BP differs depending on where in the striatum the change occurred. Therefore, to correctly interpret age-related longitudinal changes in the BP, we must account for volumetric changes also within a structure, rather than across the whole volume. The present 3D-printing technology, combined with the wall removal method, can be implemented to gain knowledge about the predictable bias introduced by the PVE differences in uptake regions of varying shape.

Functional and homeostatic defects of regulatory T cells in patients with coronary artery disease.

OBJECTIVE: Regulatory T cells (Tregs) are considered atheroprotective, and low levels have been associated with the acute coronary syndrome (ACS), particularly non-ST elevation (NSTE)-ACS. However, the functional properties as well as homeostasis of Tregs are mainly unknown in coronary artery disease (CAD). Here, we investigated the composition and functional properties of naïve (n) and memory (m)Tregs in patients with NSTE-ACS and in patients 6-12 months post-ACS. METHODS: Based on the expression of CD25, FOXP3, CD127, CD45RA, CD39 and CTLA-4, Treg subsets were defined by flow cytometry in whole blood or isolated CD4(+) T cells. The functional properties of nTregs and mTregs were examined in terms of proliferative capacity and modulation of cytokine secretion. To understand the potential consequences of Treg defects, we also investigated correlations with lipopolysaccharide (LPS)-induced cytokine secretion and ultrasound-defined carotid atherosclerosis. RESULTS: Both NSTE-ACS and post-ACS patients exhibited reduced levels of nTregs (P < 0.001) compared with healthy control subjects, but without compensatory increases in mTregs. Both nTregs and mTregs from patients showed significantly lower replicative rates and impaired capacity to modulate T-cell proliferation and secretion of interferon-gamma and IL-10. The Treg defect was also associated with LPS-induced cytokine secretion and increased burden of carotid atherosclerosis. CONCLUSION: Our results demonstrate a functional and homeostatic Treg defect in patients with NSTE-ACS and also in stabilized patients 6-12 months after ACS. Moreover, this defect was associated with a subclinical proinflammatory and atherogenic state. We believe that the failure to preserve Treg function and homeostasis reflects a need for immune-restoring strategies in CAD.

pT4 stage II and III colon cancers carry the worst prognosis in a nationwide survival analysis. Shepherd's local peritoneal involvement revisited.

The aim of this study is to clarify the prognostic importance of several well-known but still debated pathological variables related to the survival of colon cancer patients. The study focuses on the definition and survival carried by the pT4 category and stage II where the presence of high-risk variables may determine whether or not adjuvant chemotherapy is administered. A retrospective nationwide study was carried out including all colon cancer patients that underwent resection in Iceland between 1990 and 2004 (n = 889). All histopathology was reassessed. Cancer-specific survival (CSS) and overall survival were analysed using Kaplan-Meier and Cox regression analysis. In stage II, the five-year CSS for pT4 was 50% (95% CI, 32-69%), which was the lowest survival observed in that stage. In stage III the five-year CSS was 30% (95% CI, 18-41%) and 37% (95% CI, 26-48%) for pT4 and pN2 tumors, respectively. Lymphatic invasion and differentiation had no prognostic value in stage II. The survival associated with pT4a versus pT4b depends on how these categories are defined with regard to Shepherd's local peritoneal involvement (LPI). In the present series, pT4 is a major indicator of poor prognosis in patients with stage II and III colon carcinoma. Four-tiered TNM or Dukes staging systems are insufficient by not taking this variable into account. Only Shepherd's LPI4 and a subgroup of LPI3 (i.e., borderline LPI3/LPI4) should qualify for the pT4a subcategory. The results do not support lymphatic invasion or poor differentiation as high-risk stage II variables.

Natural killer (NK) cell deficit in coronary artery disease: no aberrations in phenotype but sustained reduction of NK cells is associated with low-grade inflammation.

Although reduced natural killer (NK) cell levels have been reported consistently in patients with coronary artery disease (CAD), the clinical significance and persistence of this immune perturbation is not clarified. In this study we characterized the NK cell deficit further by determining (i) differentiation surface markers and cytokine profile of NK cell subsets and (ii) ability to reconstitute NK cell levels over time. Flow cytometry was used to analyse NK cell subsets and the intracellular cytokine profile in 31 patients with non-ST elevation myocardial infarction (non-STEMI), 34 patients with stable angina (SA) and 37 healthy controls. In blood collected prior to coronary angiography, the proportions of NK cells were reduced significantly in non-STEMI and SA patients compared with controls, whereas NK cell subset analyses or cytokine profile measurements did not reveal any differences across groups. During a 12-month follow-up, the proportions of NK cells increased, although not in all patients. Failure to reconstitute NK cell levels was associated with several components of metabolic syndrome. Moreover, interleukin (IL)-6 levels remained high in patients with sustained NK cell deficit, whereas a decline in IL-6 (P < 0·001) was seen in patients with a pronounced increase in NK cells. In conclusion, we found no evidence that reduction of NK cells in CAD patients was associated with aberrations in NK cell phenotype at any clinical stage of the disease. Conversely, failure to reconstitute NK cell levels was associated with a persistent low-grade inflammation, suggesting a protective role of NK cells in CAD.

Provitamin A carotenoids are independently associated with matrix metalloproteinase-9 in plasma samples from a general population.

BACKGROUND AND AIM: Carotenoids in plasma are inversely associated with cardiovascular risk. Low levels can be explained by low dietary intake but also by a number of other factors including inflammatory activity. Given that matrix metalloproteinase (MMP)-9 has an important role in inflammation and cardiovascular disease, we hypothesized that circulating MMP-9 levels would be inversely related to total or single carotenoids in a general population cohort. METHODS: A well-characterized population-based cohort of 285 Swedish men and women (45-69 years) was used for the present study. The intake of carotenoid-rich fruits and vegetables was estimated from a food frequency questionnaire. Levels of MMP-9, C-reactive protein (CRP), interleukin (IL)-6 and six major carotenoids [ß-cryptoxanthine, α-carotene, ß-carotene, lutein (+zeaxanthin) and lycopene] were determined in plasma. RESULTS: Lower plasma levels of total and single carotenoids were associated with lower dietary intake of carotenoids, older age, male sex, lower physical activity, higher alcohol consumption, higher body mass index (BMI), higher systolic and diastolic blood pressures, lower levels of total cholesterol and HDL cholesterol and higher levels of CRP, IL-6 and MMP-9. After multivariate adjustments, plasma levels of total carotenoids and provitamin A carotenoids (ß-cryptoxanthine, α-carotene and ß-carotene) remained independently associated with sex, dietary intake of carotenoids, BMI, HDL cholesterol and MMP-9, whilst associations with CRP and IL-6 were not maintained. Neither dietary intake of carotenoid-rich fruits and vegetables, nor vitamin supplement use was associated with MMP-9, CRP or IL-6 levels. CONCLUSION: Plasma carotenoids were associated with a variety of factors including age, sex, dietary intake and metabolic variables. A new finding was the independent relationship in plasma between low provitamin A carotenoids and high MMP-9, suggesting a link between these carotenoids, matrix turnover and arterial remodelling.

Effects of simvastatin on carotenoid status in plasma.

BACKGROUND AND AIMS: Carotenoids are potent antioxidants mainly transported in the low density lipoprotein (LDL) fraction. They may also influence the immune response and inverse associations with inflammatory markers have been reported. We investigated whether simvastatin, by exerting both lipid-lowering and anti-inflammatory effects, altered the carotenoid status in plasma. METHODS AND RESULTS: A randomized, double-blind, placebo-controlled study design was applied. Eighty volunteers with mild to moderate hypercholesterolemia received either simvastatin 40 mg or placebo for 6 weeks. Lipids, oxidized LDL (ox-LDL), C-reactive protein (CRP), interleukin (IL)-6, oxygenated carotenoids (lutein, zeaxanthin, ß-cryptoxanthin) and hydrocarbon carotenoids (α-carotene, ß-carotene, lycopene) were measured in plasma. Simvastatin use was associated with significant reductions in total cholesterol, LDL, ox-LDL and CRP. Simvastatin therapy also resulted in reduced plasma levels of both oxygenated and hydrocarbon carotenoids. However, when adjusted for lipids, all carotenoids except ß-cryptoxanthin showed significant increases after simvastatin therapy. Both crude and lipid-adjusted carotenoids were inversely correlated with CRP and IL-6 in plasma but the change in carotenoid status during simvastatin therapy was not specifically related to any changes in inflammatory markers. CONCLUSIONS: To summarize, the change in carotenoid status during simvastatin therapy was mainly attributed to the lowering of cholesterol and not to the suppression of inflammatory activity. After adjustment for lipids, the levels of lutein, lycopene, α-carotene and ß-carotene were significantly increased by simvastatin suggesting an increased ratio of carotenoids per particle.

Elevated levels of circulating matrix metalloproteinase-9 are associated with a dysregulated cortisol rhythm--A case-control study of coronary artery disease.

A dysregulated cortisol pattern has been found to be associated with systemic inflammatory activity in patients with coronary artery disease (CAD). Matrix metalloproteinase (MMP)-9 is involved in both inflammation and matrix degradation and considered a main contributor to coronary plaque rupture. In this study, we hypothesized that a dysfunctional cortisol response also involved a failure to regulate systemic MMP-9 levels in CAD patients. Total MMP-9, active MMP-9 and the endogenous inhibitor TIMP-1 were measured in 30 CAD patients and 30 healthy controls. Morning and evening cortisol was measured in repeated saliva samples. Patients had higher levels of total and active MMP-9 (both p<0.01) and increased 24-h cortisol output (p<0.05) characterized by higher levels of evening cortisol (p=0.011). MMP-9 was associated with evening cortisol (p<0.001) independent of smoking and inflammatory markers. Compared with controls, patients also showed a blunted cortisol response to stress. After stress, the levels of MMP-9 became significantly reduced in controls whereas they remained unchanged in patients. The data indicate that MMP-9 is differently regulated in patients due to a dysfunctional hypothalamic-pituitary-adrenal (HPA) axis and emphasize the role of MMP-9 as a possible link between stress and cardiovascular disease.

Impaired cortisol response to acute stressors in patients with coronary disease. Implications for inflammatory activity.

OBJECTIVES: Inflammation is assumed to play a major role in the progress of atherosclerotic disease. We hypothesized that an altered hypothalamic-pituitary adrenal (HPA) axis activity was linked to a disinhibited inflammatory activity in patients with coronary artery disease (CAD). METHODS: Thirty CAD patients were assessed 12-14 weeks after a first-time acute coronary syndrome. Serum samples were assayed for C-reactive protein (CRP) and interleukin-6. Free cortisol was measured in a 24-h urine sample and in repeated saliva samples 30 min after awakening and at bedtime. The levels of inflammatory markers and cortisol were also determined before and after standardized physical and psychological stress tests. RESULTS: The CAD patients had a higher 24-h cortisol secretion and a flattened diurnal slope, resulting from significantly higher cortisol levels at bedtime, compared to clinically healthy controls. The levels of evening cortisol were strongly related to inflammatory markers in serum. When exposed to acute physical and psychological stressors, the CAD patients showed a significantly blunted cortisol response compared to controls. In addition, a stress-induced increase in CRP was only observed in the patient group. CONCLUSIONS: Patients with CAD exhibited a cortisol pattern that markedly differed from controls. The data indicate that a dysfunctional HPA axis response involves a failure to contain inflammatory activity in CAD patients, thus providing a possible link between stress and inflammation in disease.

Estradiol increases proteinuria and angiotensin II type 1 receptor in kidneys of rats receiving L-NAME and angiotensin II.

Prospective, placebo-controlled clinical trials suggest that estrogen may have adverse effects on the vascular system in women. The goal of this study was to determine if 17beta-estradiol (E2) would have adverse effects on the renovasculature in a rat model of renal injury characterized by low nitric oxide (NO) and high angiotensin II (AngII). We studied female Wistar rats that were sham-operated (sham), ovariectomized (OVX), or ovariectomized and replaced with E2 (OVX/E2). All rats were maintained on a high salt diet and renovascular injury was caused by treating rats with an inhibitor of NO synthase, N(omega)-nitro-L-arginine-methyl-ester (L-NAME), for 14 days, plus AngII on days 11 through 14. L-NAME/AngII treatment, as compared to placebo, caused proteinuria, glomerular injury, and fibrinoid necrosis of renal arterioles in sham-operated rats. Ovariectomy reduced L-NAME/AngII-induced renal damage, whereas E2 treatment increased L-NAME/AngII-induced damage in OVX rats. In rats treated with L-NAME/AngII, levels of AngII type 1 receptor (AT(1)R) protein were higher in the renal cortex of sham and OVX/E2 rats than in OVX rats. AT(1)R protein correlated with renal injury. E2 treatment also increased expression of AT(1)R mRNA. Thus, under conditions of low NO and high AngII, E2 exacerbated renal injury. E2-mediated increases in renal cortical AT(1)R expression may represent a novel mechanism for the adverse renovascular effects of estrogen.

Mitochondrial abnormalities in inclusion-body myositis.

Mitochondrial changes are frequently encountered in sporadic inclusion-body myositis (s-IBM). Cytochrome c oxidase (COX)-deficient muscle fibers and large-scale mitochondrial DNA (mtDNA) deletions are more frequent in s-IBM than in age-matched controls. COX deficient muscle fibers are due to clonal expansion of mtDNA deletions and point mutations in segments of muscle fibers. Such segments range from 75 microm to more than 1,000 microm in length. Clonal expansion of the 4977 bp "common deletion" is a frequent cause of COX deficient muscle fiber segments, but many other deletions also occur. The deletion breakpoints cluster in a few regions that are similar to what is found in human mtDNA deletions in general. Analysis in s-IBM patients of three nuclear genes associated with multiple mtDNA deletions, POLG1, ANT1 and C10orf2, failed to demonstrate any mutations. In s-IBM patients with high number of COX-deficient fibers, the impaired mitochondrial function probably contribute to muscle weakness and wasting. Treatment that has positive effects in mitochondrial myopathies may be tried also in s-IBM.

Expansion of peripheral CD8+ T cells in patients with coronary artery disease: relation to cytomegalovirus infection.

OBJECTIVES: The nature of the immune response in coronary artery disease (CAD) is not fully defined. One pathogen that has been linked to atherogenesis, cytomegalovirus (CMV), is known to exert strong and long-lasting effects on peripheral T cells. In the present study, we investigated the effect of prior CMV infection on the immune system in CAD patients. SUBJECTS: Patients with stable angina and angiographically verified CAD (n=43) and clinically healthy controls (n=69) were included. METHODS: The expression of CD57 and CD28 on peripheral CD4+ and CD8+ T cells was evaluated with three-colour flow cytometry. The findings were related to serological markers of inflammation, T-cell activation and CMV seropositivity. RESULTS: An expansion of CD8+ T cells expressing CD57 but lacking CD28 was seen in the patient group. The numbers of CD8+ CD57+ and CD8+ CD28-T-cell subsets were independently related to CMV seropositivity (P<0.001) but also to CAD per se (P<0.05). Serum concentrations of C-reactive protein (CRP) and soluble interleukin-2 receptor (sIL-2R) were elevated in the patients but not related to CMV or CD8+ T-cell subsets. CONCLUSION: A pronounced shift in peripheral T-cell homeostasis was observed in CAD patients. Primarily CMV infection but also CAD per se contributed to the expansion of CD8+ T-cell subsets. The T-cell changes were not related to a systemic inflammatory response but should rather be considered as markers of a chronic antigen exposure and/or immunosenescence in CAD.

Low serum beta-carotene reflects immune activation in patients with coronary artery disease.

BACKGROUND AND AIM: Low serum levels of antioxidant vitamins are associated with coronary artery disease (CAD). An immunomodulatory effect of antioxidants has been proposed. The aim of the study was to investigate whether an increased immune response in CAD patients was associated with suppressed circulating levels of antioxidant vitamins. METHODS AND RESULTS: Forty-four men with stable angina and angiographically verified CAD were included as well as 69 healthy controls. T cell subsets in peripheral blood were quantified by 3-colour flow cytometry. C-reactive protein (CRP), soluble interleukin-2 receptor (sIL-2R) and the lipophilic antioxidants alpha-tocopherol, beta-carotene and lycopene were determined in serum. Compared with controls, patients had signs of an enhanced inflammatory activity assessed by significantly increased levels of CRP, sIL-2R and CD4+CD25+T cell subsets. Patients also had significantly lower beta-carotene and lycopene levels whereas a-tocopherol levels did not differ. The increased inflammatory/immune parameters in patients showed a significant inverse relationship to serum beta-carotene but not to lycopene or alpha-tocopherol. CONCLUSIONS: Low serum beta-carotene in CAD patients reflects activation of the immune system. Inflammation should be considered as an important confounding factor when analysing data on beta-carotene and CAD.

DTI mapping of human brain connectivity: statistical fibre tracking and virtual dissection.

Several approaches have been used to trace axonal trajectories from diffusion MRI data. If such techniques were first developed in a deterministic framework reducing the diffusion information to one single main direction, more recent approaches emerged that were statistical in nature and that took into account the whole diffusion information. Based on diffusion tensor MRI data coming from normal brains, this paper presents how brain connectivity could be modelled globally by means of a random walk algorithm. The mass of connections thus generated was then virtually dissected to uncover different tracts. Corticospinal, corticobulbar, and corticothalamic tracts, the corpus callosum, the limbic system, several cortical association bundles, the cerebellar peduncles, and the medial lemniscus were all investigated. The results were then displayed in the form of an in vivo brain connectivity atlas. The connectivity pattern and the individual fibre tracts were then compared to known anatomical data; a good matching was found.

Are early clinical effects of cholesterol lowering mediated through effects on inflammation?

In a randomized, double-blind trial in 3086 patients with unstable angina pectoris or non-Q wave myocardial infarction we investigated if 80 mg of atorvastatin daily could improve outcome of cardiovascular events during a short period of time (16 weeks) compared with placebo. Baseline LDL cholesterol was 3.2 mmol L-1 (124 mg dL-1) and decreased by 40% to 1.9 mmol L-1 (72 mg dL-1) during atorvastatin treatment. The primary endpoint, which was a composite of death, non-fatal acute myocardial infarction, cardiac arrest with resuscitation or recurrent symptomatic myocardial ischaemia with objective evidence and requiring emergency rehospitalization occurred in 228 patients (14.8%) in the atorvastatin group and 269 patients (17.4%) in the placebo group. The relative risk was 0.84 and 95% confidence interval was 0.70-1.00 (P = 0.048). Thus for patients with acute coronary syndromes, lipid-lowering therapy with high dose atorvastatin reduces recurrent ischaemic events in the short-term. A possible mechanism behind this rapid clinical effect induced by statin treatment is on inflammatory processes. Recent studies strongly suggest that acute T-cell activation is involved in the pathogenesis of unstable angina. In another study we investigated whether circulating T cells showed signs of activation in patients with stable angina pectoris (SA). Systemic venous blood samples were taken from 38 men with SA and 42 healthy controls. The T-cell receptor expression was assessed by three-colour flow cytometry using monoclonal antibodies against CD3,CD4, CD8, CD25 and human leucocyte antigen (HLA)-DR. Soluble interleukin-2 receptor (sIL-2R) was measured as the circulating form in serum. Levels of circulating CD3+ and CD4+ T cells tended to be higher in patients compared with controls. Patients were also shown to have a significant increase in CD4+ T cells expressing the activation markers CD25 (P < 0.05) and HLA-DR (P < 0.01). Furthermore, serum levels of sIL-2R were significantly higher (P < 0.001) in patients than in controls. We also observed that the T-cell response was more pronounced in patients without simvastatin treatment (n = 18) compared with simvastatin-treated patients (n = 20). In conclusion, our findings indicate that a continuous immune system activation takes place in patients with chronic angina pectoris, predominantly involving proliferation of CD4+ T cells. Statin treatment seems to be able to decrease this inflammatory response.

Apolipoprotein A-I-derived amyloid in atherosclerosis. Its association with plasma levels of apolipoprotein A-I and cholesterol.

Wild-type apolipoprotein A-I (apo A-I)-derived amyloid commonly occurs in atherosclerotic plaques. To clarify apo A-I amyloid formation, plasma levels of apo A-I and cholesterol were related to the presence of amyloid in atherosclerotic plaques in 15 patients with peripheral atherosclerosis, subjected to arterial reconstruction. Plasma levels of apo A-I and high-density lipoprotein (HDL) cholesterol were slightly higher in patients with apo A-I-derived amyloid than in those without, but the difference was not significant. Levels of low-density lipoprotein cholesterol and total cholesterol were significantly higher in the group with amyloid. High concentrations of apo A-I in the arterial intima are probably of greater importance to amyloid formation than high plasma levels of the protein. During atherosclerosis, the acute phase reactant serum amyloid A may displace apo A-I from HDL, leading to increased concentration of lipid-free apo A-I in the intima and conformational changes of apo A-I, which make it more fibrillogenic. Some forms of amyloid fibrils have been shown to be cytotoxic. Apo A-I-derived amyloid is possibly a pathogenically important factor in atherosclerosis.

[Carcinoma of the colon in Iceland 1955-1989. A study on pathology.].

OBJECTIVE: The objective of this study was to investigate various pathological parameters of colon carcinoma in Iceland in the 35 year time period from 1955-1989, and changes in these parameters during the study period. MATERIAL AND METHODS: Information on all patients diagnosed with colon carcinoma in the study period was obtained from the Icelandic Cancer Registry. All pathology reports and autopsy reports were checked. All pathology samples were reviewed and the tumours reevaluated, reclassified, tumour location determined, the tumours graded and Dukes staged and age standardized incidence was calculated according to revised diagnosis. Cancers in polyps are included in the study. The study period was separated into seven five year periods and changes in pathological parameters investigated according to time periods. RESULTS: After reevaluation of the tumours 1205 fulfilled the criteria for the diagnosis of colon carcinoma, 572 in men and 633 in women. The incidence increased in the study period for men from 8.2 to 21.5/105 and for women from 7.9 to 15.8/105. The pathological parameters were determined for 1109 tumours. Adenocarcinoma NOS was the most common diagnosis or 90.1% of the tumours and mucinous carcinomas came second. Most of the tumours were located in the sigmoid colon (38.6%), 19.1% in the coecum and 14.5% in the ascending colon. No significant observed changes occurred in tumour location in the study period. The mucinous histological type and signet ring tumour type were more common in the right colon. In Dukes staging of the tumours 9.1% were in stage A, 32.1% in stage B, 24.6% in stage C and 22.7% in stage D, whereas 11.5% proved indeterminate. A minimal trend to increase in Dukes A tumours was observed in the latter half of the study period, overall no significant changes in Dukes classification could be pinpointed in the time period. Most of the tumours were of intermediate tumour grade or 70.1%, but 16.5% were well differentiated and 13.4% were poorly differentiated. A much higher percentage of poorly differentiated tumours were present in the right colon in comparison to the left colon. A poorer differentiation of the tumours went hand in hand with worse Dukes stage of tumours. CONCLUSIONS: We conclude that: 1. the incidence of colon carcinoma has much increased during the study period for both sexes, 2. observed changes in studied pathological parameters over the study period were minimal. Of interest is the minimal change in Dukes stages of colon cancer in the study period.

Lipoprotein(a) and HLA-DRB1 and -DQB1 genes in coronary artery disease.

In some respects, atherosclerosis resembles autoimmune disease. Since many autoimmune diseases are associated with certain histocompatibility leukocyte antigen (HLA) class II alleles, we have looked for a similar HLA association with atherosclerosis. In the first phase, genomic typing was performed in 52 men with coronary artery disease. In the second phase, 50 men with early onset (before 50 years of age) coronary artery disease were studied. 12 DRB1 and 4 DQB1 alleles were determined by restriction fragment length polymorphism analysis. No significant difference in frequency of the examined alleles was observed in any of the patient groups compared to healthy controls. The plasma level of lipoprotein(a) (Lp(a)) is considered an important risk factor for early coronary heart disease. A linkage between inherited high levels of Lp(a) and certain HLA class II genotypes has been suggested. In the present study, Lp(a) levels were measured in men with early onset of coronary artery disease. 11 (23%) Study patients and 3 (7%) control subjects had Lp(a) levels above 450 mg/l. However, no correlation between high Lp(a) levels and certain HLA genotypes was found. Summarized, these findings indicate that atherosclerosis, especially early onset coronary atherosclerosis, is not a disease associated with particular HLA alleles.