Tatu Juvonen

Elevated Circulating Levels of Inflammatory Cytokines in Patients With Abdominal Aortic Aneurysm

The basic feature in the pathogenesis of abdominal aortic aneurysm (AAA) is the degradation of extracellular matrix components. This process is induced partly by cytokines secreted from inflammatory and mesenchymal cells. Circulating levels of inflammatory cytokines were studied in AAA patients and compared with subjects suffering from atherosclerotic disease only. Furthermore, the predictive value of cytokine concentrations was evaluated for aneurysm expansion rate. Circulating levels of interleukin 1 beta (IL-1 beta), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) were measured in 50 AAA patients (40 men, 10 women), 42 patients with coronary heart disease (CHD) (23 men, 19 women), and 38 controls whose angiogram was normal (17 men, 21 women). No differences in cytokine concentrations were found between the CHD patients and the controls. AAA disease was found to be associated with significantly higher IL-1 beta and IL-6 concentrations in both male patients (median concentrations of 19.40 pmol/L and 6.45 pmol/L, respectively) and female patients (19.26 pmol/L and 7.99 pmol/L) than in either the CHD patients or the controls (P < .005). TNF-alpha levels were slightly higher in the AAA patients (1.64 pmol/L in the males and 1.59 pmol/L in the females) than in the other groups (P < .05). IFN-gamma levels were elevated significantly in the female AAA patients (3.75 pmol/L) compared with levels found in the other female (P < .05) or male (P < .01) patient groups. The measured cytokine concentrations were not related to the size of the aneurysm or the maximal thickness of the thrombus within the aneurysm. IFN-gamma concentration showed a significant positive correlation to the aneurysm expansion (R = .37, P < .02) and negative correlation to the concentration of aminoterminal propeptide of type III procollagen during 6-month follow up (R = -.42, P < .005). The results show that circulating levels of inflammatory cytokines are elevated in patients with AAA disease, suggesting that the production of these cytokines is increased in these patients compared with CHD patients and controls. Elevated INF-gamma concentrations seem to predict an increased rate of expansion in AAA.

Demonstration of Chlamydia pneumoniae in the walls of abdominal aortic aneurysms

BACKGROUND Seroepidemiologic studies have indicated an association between chronic Chlamydia pneumoniae infection and coronary heart disease. The organism, which is a common respiratory pathogen, has been demonstrated in atherosclerotic lesions of the aorta and coronary arteries. Abdominal aortic aneurysms are frequently associated with atherosclerosis, and inflammation may actually be an important factor in aneurysmal dilatation. Hence it could be assumed that C. pneumoniae may play a role in maintaining an inflammation and triggering the development of aortic aneurysms. METHODS AND RESULTS Specimens from abdominal aortic aneurysm were examined for the presence of C. pneumoniae by immunohistochemical analysis, the polymerase chain reaction amplifying omp 1 gene, transmission electron microscopy, and culture methods with histologically atherosclerosis-negative human aortic tissues used as a control group. Chlamydial lipopolysaccharide and C. pneumoniae specific antigens were found by immunohistochemistry in 12 and 8 of 12 aneurysm specimens, respectively, and C. pneumoniae DNA could be demonstrated in 6 of 6 aneurysm specimens studied. Furthermore electron microscopy revealed the presence of Chlamydia-like elementary bodies in three of four aneurysm specimens tested. None of the control samples gave positive reaction in the polymerase chain reaction, and C. pneumoniae antigens were not detected in any of them. CONCLUSIONS C. pneumoniae is frequently found in the vessel wall of abdominal aortic aneurysm. The potential etiopathogenetic role of C. pneumoniae in the development of these aneurysms remains to be studied.

Factors influencing wound dehiscence after midline laparotomy

PURPOSE To identify patients who have high risk of wound dehiscence and who might benefit from the use of internal retention sutures. PATIENTS AND METHODS Forty-eight patients with midline abdominal wound dehiscence were compared with 48 control patients standardized by sex, age, and operative indication. RESULTS The mean hospital stay was significantly prolonged in the dehiscence group, resulting in a higher total cost of hospital treatment. The variables that were significantly associated with wound dehiscence included hypoalbuminemia, anemia, malnutrition, chronic lung disease, and emergency procedure. The additional postoperative factors that were found to be significant were vomiting, prolonged intestinal paralysis, repeated urinary retention, and increased coughing. Obesity, chronic heart disease, diabetes, alcoholism, preoperative intestinal obstruction, jaundice, systemic and local infection, use of steroids, type of incision, operating time, and type of wound closure were nonsignificant variables. The number of wound dehiscences increased significantly (P = 0.0001) when the number of risk factors increased from zero to five. CONCLUSION We recommend using internal retention sutures for patients who have three or more risk factors.

Detection of Chlamydia pneumoniae–Reactive T Lymphocytes in Human Atherosclerotic Plaques of Carotid Artery

Linkage between Chlamydia pneumoniae infection and atherosclerosis has been confirmed in several studies, but the precise role of this organism in the disease process is not known. We investigated the relation and reactivity of T lymphocytes of human carotid plaques to C pneumoniae antigens. Tissue specimens were obtained from 17 patients who underwent carotid endarterectomy. Immunohistological staining and/or in situ hybridization revealed the presence of C pneumoniae in 11 (64%) of the 17 of the cases. Inflammatory infiltration seen in the vessel walls consisted primarily of CD45RO+ T-memory lymphocytes (median 80%, range 50% to 90%), whereas CD20+ B cells and monocytes were in minor proportion. In vivo activated T lymphocytes were propagated from the specimens with interleukin-2, and the antigen specificity of the established T-cell lines (TLLs) was analyzed against C pneumoniae elementary body antigen. TLLs were established from all 17 carotid tissues but none from the control specimens of ascending aorta. C pneumoniae was recognized as a specific T-cell-stimulating antigen in 7 (41%) of 17 cases. Further analyses of the C pneumoniae-reactive TLLs showed that chlamydial 60-kDa heat-shock protein induced specific proliferation in 5 (71%) of 7 cases and revealed 2 haplotype (DRB1*1502 and DQB1*06) binding motifs in human 60-kDa heat-shock protein. C pneumoniae was identified as a specific microbial antigen recognized by 41% of TLLs propagated from in vivo activated plaque T cells. Our results suggests that cell-mediated immunity to C pneumoniae plays a role in the atherosclerotic process and that this response may involve autoimmunity.

Remote Ischemic Preconditioning Protects the Brain Against Injury After Hypothermic Circulatory Arrest

Background— Ischemic preconditioning (IPC) is a mechanism protecting tissues from injury during ischemia and reperfusion. Remote IPC (RIPC) can be elicited by applying brief periods of ischemia to tissues with ischemic tolerance, thus protecting vital organs more susceptible to ischemic damage. Using a porcine model, we determined whether RIPC of the limb is protective against brain injury caused by hypothermic circulatory arrest (HCA). Methods and Results— Twelve piglets were randomized to control and RIPC groups. RIPC was induced in advance of cardiopulmonary bypass by 4 cycles of 5 minutes of ischemia of the hind limb. All animals underwent cardiopulmonary bypass followed by 60 minutes of HCA at 18°C. Brain metabolism and electroencephalographic activity were monitored for 8 hours after HCA. Assessment of neurological status was performed for a week postoperatively. Finally, brain tissue was harvested for histopathological analysis. Study groups were balanced for baseline and intraoperative parameters. Brain lactate concentration was significantly lower (P<0.0001, ANOVA) and recovery of electroencephalographic activity faster (P<0.05, ANOVA) in the RIPC group. RIPC had a beneficial effect on neurological function during the 7-day follow-up (behavioral score; P<0.0001 versus control, ANOVA). Histopathological analysis demonstrated a significant reduction in cerebral injury in RIPC animals (injury score; mean [interquartile range]: control 5.8 [3.8 to 7.5] versus RIPC 1.5 [0.5 to 2.5], P<0.001, t test). Conclusions— These data demonstrate that RIPC protects the brain against HCA-induced injury, resulting in accelerated recovery of neurological function. RIPC might be neuroprotective in patients undergoing surgery with HCA and improve long-term outcomes. Clinical trials to test this hypothesis are warranted.

Increased turnover of collagen in abdominal aortic aneurysms, demonstrated by measuring the concentration of the aminoterminal propeptide of type III procollagen in peripheral and aortal blood samples

PURPOSE The pathogenesis of abdominal aortic aneurysm (AAA) involves many factors; elastin degradation is believed to lead to initial dilation, whereas changes in the collagen structure predispose the aneurysm to rupture. The major collagens in the aortic wall are types I and III. We set out here to determine whether changes in serum propeptide of type III procollagen (PIIINP), a biologically relevant marker of type III collagen turnover, could be associated with the characteristics of AAA. METHODS The aminoterminal PIIINP and the carboxyterminal propeptide of type I collagen were measured by radioimmunoassay in 87 patients with AAA and 90 control subjects with aortodistal arteriosclerosis. The samples were taken from the peripheral blood and from the abdominal aorta at the levels of the diaphragm and the common iliac artery. RESULTS Mean PIIINP concentrations were higher in patients with AAA than in control subjects (3.47 micrograms/L vs 2.73 micrograms/L, p < 0.0001), correlating positively with aneurysm diameter in the former (r = 0.27, p = 0.04) and with the maximum thickness of the intraluminal thrombus (r = 0.39, p = 0.003). The gradient in PIIINP between the upper and lower end of the abdominal aorta was significant in the AAA group (-0.30 microgram/L, range -0.20 to -0.50 vs -0.10 micrograms/L, range -0.20 to 0.30, p = 0.002). CONCLUSIONS These studies indicate that the turnover of type III collagen is increased in patients with AAA.

Automatic analysis and monitoring of burst suppression in anesthesia

Objective.We studied the spectral characteristics of the EEGburst suppression patterns (BSP) of two intravenous anesthetics,propofol and thiopental. Based on the obtained results, we developed amethod for automatic segmentation, classification and compactpresentation of burst suppression patterns. Methods.The spectralanalysis was performed with the short time Fourier transform and withautoregressive modeling to provide information of frequency contents ofbursts. This information was used when designing appropriate filters forsegmentation algorithms. The adaptive segmentation was carried out usingtwo different nonparametric methods. The first one was based on theabsolute values of amplitudes and is referred to as the ADIF method. Thesecond method used the absolute values of the Nonlinear Energy Operator(NLEO) and is referred to as the NLEO method. Both methods have beendescribed earlier but they were modified for the purposes of BSPdetection. The signal was classified to bursts, suppressions andartifacts. Automatic classification was compared with manualclassification. Results.The NLEO method was more accurate,especially in the detection of artifacts. NLEO method classifiedcorrectly 94.0% of the propofol data and 92.8% of thethiopental data. With the ADIF method, the results were 90.5% and88.1% respectively. Conclusions.Our results show thatburst suppression caused by the different anesthetics can be reliablydetected with our segmentation and classification methods. The analysisof normal and pathological EEG, however, should include information ofthe anesthetic used. Knowledge of the normal variation of the EEG isnecessary in order to detect the abnormal BSP of, for instance, seizurepatients.

Chronic inflammation and elastin degradation in abdominal aortic aneurysm disease: an immunohistochemical and electron microscopic study

OBJECTIVES To investigate (i) elastin degradation and the possible association between proteolysis and inflammation in abdominal aortic aneurysm disease (AAA), and (ii) the presence of cytomegalovirus (CMV) infection in the walls of AAA. MATERIALS Specimens from 12 infrarenal AAAs, eight aortas with occlusive disease (AOD) and two normal aortas were studied by conventional light microscopy, immunohistochemistry using a monoclonal anti-elastin antibody BA-4 and anti-CMV antibody and transmission electron microscopy (TEM). MAIN RESULTS In AAA the decrease in elastin immunoreactivity and the presence of elastin degradation was associated with increased mononuclear inflammatory cell infiltrates (p = 0.004 and p = 0.00002, respectively). The CMV immunostainings of the normal aortic wall and all the AAA and AOD samples were negative, nor could any CMV particles be demonstrated by TEM. CONCLUSIONS The chronic inflammation and degradation of elastin in AAA suggests a possible immune-mediated mechanism. The inflammation may be induced by the chemotactic properties of elastin-derived peptides.

Gallstone cholesterol content is related to apolipoprotein E polymorphism

BACKGROUND The genetically determined phenotypes of apolipoprotein E are related to variations in lipoprotein levels and in the enterohepatic metabolism of cholesterol and bile acids. The present study was designed to elucidate the role of apolipoprotein E polymorphism in gallstone formation. METHODS Apolipoprotein E phenotype was determined in 169 consecutive cholecystectomy patients and in 200 controls. The cholesterol content of the gallstones (n = 169), the presence of cholesterol monohydrate crystals of fresh gallbladder bile (n = 142), and the nucleation time (n = 35) were also analyzed. RESULTS The median cholesterol content of the gallstones was higher in the apolipoprotein E4 category (phenotypes E4/4 and E4/3, 97%) than in the E3 (E3/3, 78%) and E2 patients (E2/2 and E2/3, 76%, P = 0.0003). In E4 patients, cholesterol crystals were found immediately after surgery in 27 of 40 (68%), whereas in E3 and E2 groups in 36 of 88 (41%), and 4 of 14 (29%) of the patients (P = 0.0001). The median nucleation time in E4 patients (2.5 days) was shorter than in patients with E3 (5.5 days) or E2 (6.0 days) (P = 0.0016). CONCLUSIONS These data indicate that apolipoprotein E polymorphism affects cholesterol content of cholelithiasis. We suggest that this phenomenon is mediated by the altered formation of cholesterol monohydrate crystals in different apolipoprotein E phenotypes.

Angiosome-targeted lower limb revascularization for ischemic foot wounds: systematic review and meta-analysis.

OBJECTIVE The efficacy of angiosome-targeted revascularization to achieve healing of ischemic tissue lesions of the foot and limb salvage is controversial. This issue has been investigated in this meta-analysis. METHODS A systematic review of the literature and meta-analysis of data on angiosome-targeted lower limb revascularization for ischemic tissue lesions of the foot were performed. RESULTS Nine studies reported on data of interest. No randomized controlled study was available. There were 715 legs treated by direct revascularization according to the angiosome principle and 575 legs treated by indirect revascularization. The prevalence of diabetes was >70% in each study group and three studies included only patients with diabetes. The risk of unhealed wound was significantly lower after direct revascularization (HR 0.64, 95% CI: 0.52-0.8, I2 0%, four studies included) compared with indirect revascularization. Direct revascularization was also associated with significantly lower risk of major amputation (HR 0.44, 95% CI: 0.26-0.75, I2 62%, eight studies included). Pooled limb salvage rates after direct and indirect revascularization were at 1 year 86.2% vs. 77.8% and at 2 years 84.9% vs. 70.1%, respectively. The analysis of three studies reporting only on patients with diabetes confirmed the benefit of direct revascularization in terms of limb salvage (HR 0.48, 95% CI: 0.31-0.75, I2 0%). CONCLUSIONS The results of the present meta-analysis suggest that, when feasible, direct revascularization of the foot angiosome affected by ischemic tissue lesions may improve wound healing and limb salvage rates compared with indirect revascularization. Further studies of better quality and adjusted for differences between the study groups are needed to confirm the present findings.