The effect of emergency department delay on outcome in critically ill medical patients: evaluation using hospital mortality and quality of life at 6 months.

OBJECTIVE: To assess the impact of delay in emergency department (ED) on outcome of critically ill patients admitted to the medical intensive care unit (MICU). Outcome was defined as hospital mortality and as health-related quality of life (HRQoL) at 6 months after intensive care assessed by the 15D measure. The 15D is a generic, 15-dimensional, standardized measure of HRQoL. We hypothesized that prolonged stay in the ED is related to worse outcome. DESIGN AND SETTING: A prospective follow-up cohort study in university hospital. SUBJECTS: All consecutive 1675 patients admitted to the MICU between July 2002 and June 2004. RESULTS: The 15D questionnaire was mailed to all patients alive at 6 months after admission. Of all MICU patients, 64% were admitted from ED. The mean length of stay in the ED was 6.2 h (95%CI 5.9-6.5 h). The hospital mortality rate was 24.4% (20.0% in the ED vs. 33.0% in the non-ED cohort, P < 0.001) and it was associated with higher age and degree of physiological derangement at admission. Neither the length of ED stay was associated with hospital mortality (P = 0.82) nor with HRQoL at 6 months after MICU admission (P = 0.34). Altogether, HRQoL at 6 months was significantly lower compared with the age- and sex-matched general population (P < 0.001). CONCLUSIONS: In a university hospital, the length of ED stay was not associated with the outcome of critically ill medical patients. However, we feel that the effect of ED treatment and delay on outcome and outcome prediction in the critically ill patients deserves further evaluation.

Thalidomide therapy and polyneuropathy in myeloma patients.

Thalidomide is today an increasingly used therapy in advanced and refractory myeloma patients, especially in patients relapsing after high dose therapy. One important and well-known side effect of thalidomide is polyneuropathy (PNP). The purpose of this study was to investigate 1) how severe the thalidomide-induced PNP is in patients treated for myeloma 2) which neurophysiological tests and parameters are most sensitive in detecting the thalidomide-induced PNP and 3) how neuropathic symptoms correlate with neurophysiological changes. Twelve patients received thalidomide for treatment of relapsed multiple myeloma for at least 5 months. Prior to the thalidomide treatment, all patients had been treated with chemotherapy including vincristine, and seven patients had also received cisplatin. PNP symptoms, clinical findings and neurophysiological tests before and after the therapy were evaluated. Prior to thalidomide treatment, 7 patients had minimal and one patient slight PNP. After thalidomide treatment, 4 patients had minimal, 4 patients slight, and 3 patients moderate PNP. Thalidomide-induced PNP mainly affected sensory myelinated axons, but also alpha motor neuron axons were affected to some extent. Thermal thresholds were not altered, indicating that thin myelinated and unmyelinated axons are spared. The most sensitive parameter for detecting thalidomide-induced PNP was the sensory nerve compound action potential amplitude. The neuropathic symptoms deteriorated significantly during the therapy, but clinically, no patient developed a disabling PNP that would have required interrupting the therapy. The neuropathic side effects of thalidomide seem to be acceptable in myeloma patients.

Improved early risk stratification and diagnosis of myocardial infarction, using a novel troponin I assay concept.

BACKGROUND: We evaluated the clinical performance of a novel cardiac troponin I (cTnI) assay specifically designed to improve the very early risk stratification in acute coronary syndromes. SUBJECTS AND METHODS: Serum and plasma samples (taken 0, 6-12 h and 24 h after admission) from 531 patients with suspected acute coronary syndrome were studied using a novel investigational cTnI assay, reference cTnI assay and myoglobin. The lowest cTnI concentration giving a total assay imprecision of 10% was used as the positive myocardial infarction (MI) cut-off value. RESULTS: At the time of admission, the investigational assay was positive in 27.9% of the patients, the reference cTnI assay was positive in only 17.5% (P < 0.001) and myoglobin in 24.1% (P = 0.067). Receiver operating characteristic (ROC) curve analysis for the detection of myocardial injury on admission gave area-under-curve (AUC) values of 0.937, 0.775 and 0.762, respectively (P < 0.001). Of those MI patients who presented within 3 h of symptom onset, 50.0% were identified by the investigational assay at the time of presentation, compared with 44.2% by myoglobin (P = 0.791) but only 11.5% by the reference assay (P < 0.001). CONCLUSIONS: The novel cTnI assay considerably improves the performance of cTnI as an early rule-in biomarker for MI.

Increased pulse pressure is associated with reduced baroreflex sensitivity.

Although pulse pressure (PP), heart rate variability (HRV) and baroreflex sensitivity (BRS) have been shown to predict cardiovascular events and mortality in various populations, their relationships have not been clarified. We examined these associations in two separate population-based samples of healthy middle-aged subjects. In population 1, data were obtained from 149 subjects (71 men and 78 women) aged 35-64 (mean 47.7) years, and in population 2, from 214 subjects (88 men and 126 women) aged 40-62 (mean 50.5) years. Increased 24-h ambulatory PP was related to decreased cross-spectral BRS independent of age and gender (beta=-0.28, P<0.001 for population 1; beta=-0.22, P=0.003 for population 2). This association remained significant when 24-h ambulatory diastolic blood pressure, body mass index, smoking and alcohol intake were added as covariates in the multivariate analysis. Increased ambulatory PP was also associated with increased beat-to-beat systolic arterial pressure variability. Associations between ambulatory PP and HRV were not significant after controlling for age and gender. Our results suggest that elevated PP does not affect overall HRV, but it interferes with baroreflex-mediated control of the heart rate. This association may be due to a common denominator, such as arterial stiffness, for PP and BRS.

Glutathione depletion and cardiomyocyte apoptosis in viral myocarditis.

BACKGROUND: The course of viral myocarditis is highly variable. Oxidative stress and Bcl-2 family genes may play a role in its pathogenesis by regulating the amount of cardiomyocyte apoptosis. Apoptosis is difficult to detect and quantify in vivo. Therefore, we set to look for indicators of this potentially preventable form of cell death during various phases of experimental murine coxsackievirus B3 myocarditis. METHODS: BALB/c mice were infected with the cardiotropic coxsackievirus B3 variant. Glutathione (HPLC), cardiomyocyte apoptosis (TUNEL and caspase-3 cleavage), Bax and Bcl-X(L) mRNA expression (real time RT-PCR), histopathology and viral replication (plaque assay and real time RT-PCR) were measured from day 3 to day 20 after infection. RESULTS: Infection caused severe myocarditis and led to progressive decrease of plasma glutathione levels. Myocardial mRNA levels of pro-apoptotic Bax and antiapoptotic Bcl-X(L) were significantly increased from day 3 onwards. Bax mRNA and ratio of Bax to Bcl-X(L) correlated with cardiomyocyte apoptosis (r = 0.77, P = < 0.001 and r 0.51, P < 0.01, respectively). Cardiomyocyte apoptosis was highest on day 5, coinciding with a rapid decline in plasma glutathione (r = -0.52, P = 0.003). CONCLUSIONS: Systemic oxidative stress as indicated by decreased plasma glutathione levels coincides with cardiomyocyte apoptosis in experimental coxsackievirus myocarditis. Decreased plasma glutathione levels and changes in cardiac Bax and Bcl-X(L) mRNA expression identify a phase of myocarditis in which the potentially preventable cardiomyocyte apoptosis is mostly observed.

Sustained cardiomyocyte apoptosis and left ventricular remodelling after myocardial infarction in experimental diabetes.

AIMS/HYPOTHESIS: Diabetes is known to reduce survival after myocardial infarction. Our aim was to examine whether diabetes is associated with enhanced cardiomyocyte apoptosis and thus interferes with the post-infarction remodelling process in myocardium in rat. METHODS: Four weeks after intravenous streptozotocin (diabetic groups) or citrate buffer (controls) injection, myocardial infarction was produced by ligation of left descending coronary artery. Level of cardiomyocyte apoptosis was quantified by TUNEL and caspase-3 methods. Collagen volume fraction and connective tissue growth factor were determined under microscope. Left ventricular dimensions were evaluated by echocardiography and planimetry. RESULTS: The number of apoptotic cardiomyocytes was equally high in diabetic and non-diabetic rats after 1 week from infarction. At 12 weeks after infarction the number of apoptotic cells was higher in the diabetic as compared to non-diabetic rats both in the border zone of infarction and in non-infarcted area. Correspondingly, left ventricular end diastolic diameter, relative cardiac weight, connective tissue growth factor-expression and fibrosis were increased in diabetic compared with non-diabetic rats with myocardial infarction. CONCLUSION/INTERPRETATION: Sustained cardiomyocyte apoptosis, left ventricular enlargement, increased cardiac fibrosis and enhanced profibrogenic connective tissue growth factor expression were detected after myocardial infarction in experimental diabetes. Apoptotic myocyte loss could be an important mechanism contributing to progressive dilatation of the heart and poor prognosis after myocardial infarction in diabetes.

Reduced heart rate variability in hypertension: associations with lifestyle factors and plasma renin activity.

Limited information exists on the relations between heart rate variability, hypertension, lifestyle factors and renin-angiotensin-aldosterone system. A total of 191 newly diagnosed yet untreated hypertensive men and women, 35-54 years of age, were compared with an age- and gender-stratified random population sample of 105 normotensive men and women to find out independent determinants of heart rate variability. Heart rate variability was computed from 5-min ECG time series using the standard deviation of normal-to-normal RR intervals (SDNN), the square root of the mean of squared differences between adjacent normal RR intervals (RMSSD) and the fast Fourier transform spectral analysis. All absolute measures of heart rate variability were reduced in hypertension (P<0.001 for each, ANOVA). In multivariate regression analyses, reduced heart rate variability was independently associated with higher heart rate (P<0.001 for all absolute measures of heart rate variability), higher age (P=0.001 for SDNN, total and LF powers; P<0.001 for RMSSD and HF power) and higher mean arterial pressure (P<0.05 for total power, P<0.01 for the other absolute measures) but not with sodium and alcohol intakes, body mass index and smoking. Increased plasma renin activity (PRA) was an independent attributor of reduced HF power (P<0.05) and reduced RMSSD (P<0.01). Increased blood pressure and heart rate are associated with decreased heart rate variability without any direct effects on heart rate variability of lifestyle factors. High PRA is an independent determinant of diminished modulation of vagal activity.

Cardiomyocyte apoptosis and ventricular remodeling after myocardial infarction in rats.

We investigated the role of cardiomyocyte apoptosis in the remodeling of the left ventricle from 24 h to 12 wk after myocardial infarction in the rat. Infarct size planimetry, quantification of cardiomyocyte apoptosis, terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) methodology, and echocardiography (left ventricular diastolic diameter and ejection fraction) were performed. Sham-operated animals showed low rates of cardiomyocyte apoptosis (0.03%) and no change in diastolic diameter or ejection fraction during the study. Twenty-four hours after infarction, TUNEL positivity was high in the infarct areas (1.4%) and border zones (4.9%). It declined to 0.34% (P < 0.01 vs. sham) at 4 wk and 0.10% at 12 wk in the border zones. In the remote myocardium, cardiomyocyte apoptosis increased to 0.07% (P = 0.03 vs. sham) on day 1 and remained on the same level up to 4 wk. The increase in diastolic diameter 1-4 wk after infarction correlated (r = 0.60, P < 0.01) with cardiomyocyte apoptosis in the noninfarcted myocardium, which quantitatively contributed most (>50%) to the apoptotic cell loss by 4 wk.

Use of [11C]acetate and [15O]O2 PET for the assessment of myocardial oxygen utilization in patients with chronic myocardial infarction.

Carbon-11 acetate positron emission tomography (PET) has been widely used to assess regional oxidative metabolism of the heart. However, the accuracy of [11C]acetate PET in assessing oxidative metabolism in infarcted myocardium remains controversial. Thirteen patients with stable coronary artery disease and old myocardial infarction were studied. The 15O-based PET studies yielded regional blood flow (rMBF, ml/min/g) and oxygen consumption (rMMRO2, ml/min/g), which was compared with the myocardial clearance rate constant (kmono) of [11C]acetate in segments with rMBF > or = 75% (group A), 50%-74% (group B) or < 50% (group C) of the normal reference segment. Mean MBF was 0.96 +/- 0.08 ml/g/min in group A, 0.67 +/- 0.06 ml/g/min in group B and 0.42 +/- 0.07 ml/g/min in group C segments. The segmental rMMRO2 correlated linearly with kmono (r = 0.89, P < 0.001, y = 0.61x + 0.026). The kmono/rMMRO2 ratio was comparable in the group A and B segments (0.99 +/- 0.19 vs 1.07 +/- 0.21, P = NS). However, the ratio was significantly higher in the group C segments (1.28 +/- 0.35, P = 0.037). It is concluded that kmono of [11C]acetate correlates linearly with rMMRO2 determined by [15O]O2 inhalation. However, kmono appears to yield higher rMMRO2 estimates than the [15O]O2 method in low-flow areas.

Reduced myocardial carbon-11 hydroxyephedrine retention is associated with poor prognosis in chronic heart failure.

Abnormalities of the autonomic nervous system are known to be of prognostic significance in chronic heart failure (CHF). The prognostic value of positron emission tomography (PET) imaging of cardiac autonomic innervation in CHF has not been explored previously. We retrospectively studied the survival data of 46 NYHA class II-III CHF patients (mean LVEF 35% +/- 8%) who had undergone carbon-11 hydroxyephedrine (11C-HED) studies at the Turku PET Centre between August 1992 and March 1996. The origin of CHF was dilated cardiomyopathy in 13 of the 46 patients and coronary artery disease with at least one prior myocardial infarction in the remaining 33. Data on causes of death and heart transplantation were collected, and the statistically significant predictors of prognosis were analysed using Cox's proportional hazards regression. During the mean follow-up period of 55 +/- 19 months, 11 deaths occurred and two patients underwent heart transplantation successfully. Eleven end-points were classified as cardiac (nine sudden cardiac deaths and two deaths due to progressive heart failure) and two as non-cardiac. When divided into two groups based on the median of 11C-HED retention (mean 0.184 +/- 0.061, median 0.183), eight end-points (death or cardiac transplantation) were reached in the group with 11C-HED retention below the median and three in the group with 11C-HED retention above the median (P < 0.02). In proportional hazards regression analysis, only peak oxygen uptake (peak VO2), left ventricular end-diastolic volume and HED retention were found to be statistically significant. It is concluded that 11C-HED PET provides independent prognostic information in patients with CHF.

Adenosine in myocardial protection given through three windows of opportunity. An experimental study with pigs.

OBJECTIVE: Adenosine (ADO) has been shown to have beneficial effects against tissue injury after myocardial ischemia. However, the timing and dose of ADO administration have not been defined. This study was designed to determine the cardioprotective effect of exogenous ADO in an experimental open heart surgery model in pigs. DESIGN: The animals were openly divided into two groups both undergoing 30 min of total cardiac arrest. In the control group animals received cold crystalloid cardioplegic solution. In the ADO group ADO was added to cardioplegic solution and in addition ADO was infused to the superior vena cava for 2 h starting 30 min before cardiac arrest. The pumping function of the heart was measured with echocardiography and myocardial blood flow was measured with microspheres and positron emission tomography (PET). Cardiomyocyte apoptosis was detected and tumor necrosis factor (TNF) levels were measured. RESULTS: Better post-ischemic pumping function was found in the ADO group (relative decrease 43.7% vs 55.4%, p = 0.20 between the groups). The cardiac output decreased significantly from the baseline values (p < 0.05 in both groups). There was a temporary decrease in myocardial blood flow post-ischemically, followed by a compensatory increase during the later reperfusion period. The cardiomyocyte apoptosis was induced significantly in both groups. CONCLUSIONS: In this experiment two important details were noticed. Firstly, cardiomyocyte apoptosis is involved in ischemia-reperfusion injury associated with open heart surgery. Secondly, PET is a comparable method with the microsphere technique when coronary flow is studied. No significant effects of ADO against ischemia-reperfusion injury could be shown. However, there were some signsof positive outcome, even though statistical significance could not be reached.

Level of circulating phospholipase A2 in prediction of the prognosis of patients with suspected myocardial infarction.

OBJECTIVES: Atherosclerotic lesions result from inflammatory-proliferative responses of the endothelium and smooth muscle of the arterial wall. Poor prognosis of acute myocardial infarction (AMI) patients has been associated with elevated levels of acute phase proteins including C-reactive protein. We investigated the significance of circulating phospholipase A2 in the long-term prognosis of suspected AMI patients. METHODS: The concentration of phospholipase A2 was measured by an immunoassay in sera of 100 suspected AMI patients. Admission phospholipase A2 95 % fractile outliers were excluded to eliminate the effect of acute infectious diseases. The total and atherosclerotic mortalities were followed for a 4-year period. RESULTS: The most powerful prognostic limit for both admission (p = 0.02, RR = 2.6 and 95% CI = 1.2 to 5.6) and maximal (p = 0.06, RR = 2.4 and 95% CI = 0.96 to 5.9) phospholipase A2 groups was > or =8 microg/l. The admission phospholipase A2 level had an independent prognostic significance for atherosclerotic mortality (p = 0.04, RR = 2.4 and CI = 1.02 to 5.8) in multivariate analysis with CK-MB and age. CONCLUSIONS: The elevated serum phospholipase A2 level at admission is an independent predictor of long-term atherosclerotic mortality in patients with suspected AMI. The prognostic significance of phospholipase A2 weakens during hospitalisation concomitant to the onset of the acute inflammatory response to myocardial injury.

Myocardial efficiency during levosimendan infusion in congestive heart failure.

AIMS: Levosimendan, a novel calcium-dependent calcium sensitizer of the myocardial contractile proteins, also enhances diastolic relaxation and induces peripheral vasodilation by opening potassium channels. To assess the combined energetical effects of levosimendan infusion in vivo, we performed positron emission tomography in patients with decompensated chronic heart failure. METHODS AND RESULTS: Eight hospitalized patients with New York Heart Association functional class III or IV heart failure received levosimendan or placebo intravenously in a randomized double-blind cross-over study. During steady-state, dynamic positron emission tomography with [11C]acetate was used to assess myocardial oxygen consumption and [15O]H2O to measure myocardial blood flow. Cardiac performance and dimensions were assessed by pulmonary artery catheterization and echocardiography. Compared with healthy volunteers, myocardial oxygen consumption during placebo was elevated in the right ventricle but comparable in the left ventricle. During administration of levosimendan, cardiac output increased by 32% (P = .002) mainly because of higher stroke volume. Coronary, pulmonary, and systemic vascular resistance values were significantly reduced. Mean myocardial blood flow increased from 0.76 to 1.02 mL/min/g (P = .033). Levosimendan was neutral on myocardial oxygen consumption and left ventricular efficiency, but it improved right ventricular mechanical efficiency by 24% (P = .012). CONCLUSIONS: Levosimendan has an energetically favorable short-term profile in the treatment of congestive heart failure. It enhances cardiac output without oxygen wasting, particularly by improving efficiency in the right ventricle.

Multimodality MR imaging assessment of myocardial viability: combination of first-pass and late contrast enhancement to wall motion dynamics and comparison with FDG PET-initial experience.

PURPOSE: To combine three magnetic resonance (MR) imaging modalities-dobutamine stress cine, first pass, and late contrast material-enhanced T1-weighted imaging-and to compare the results with 2-[fluorine 18]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) in the assessment of unviable myocardium in coronary artery disease. MATERIALS AND METHODS: Ten patients with multivessel coronary artery disease underwent MR imaging before and 6 months after bypass surgery. Left ventricular cine MR imaging was performed at rest and during dobutamine infusion. Inversion-recovery gradient-echo images were obtained to study myocardial contrast enhancement at first pass and 5 minutes later. FDG PET was performed with orally administered acipimox before surgery. RESULTS: With dobutamine cine MR imaging, unviable myocardium was detected with a sensitivity of 79% and a specificity of 93%; postoperative wall thickening was the standard. First-pass analysis increased these values to 97% and 96%; analysis of late enhancement with T1-weighted imaging, to 62% and 98%. FDG PET had a sensitivity of 81% and a specificity of 86%. CONCLUSION: The combination of first-pass enhancement analysis and wall motion assessment with stress significantly increases the specificity of MR imaging in the detection of unviable sectors.

Bactericidal/permeability-increasing protein (BPI) in sepsis correlates with the severity of sepsis and the outcome.

OBJECTIVE: To compare the prognostic significance of bactericidal/permeability-increasing protein (BPI), group II phospholipase A2 (PLA2-II), C-reactive protein (CRP), tumour necrosis factor-alpha (TNF), interleukin-8 (IL-8) and interferon-gamma (IFN) in terms of predicting severity of sepsis and outcome. DESIGN: A prospective study. SETTING: Medical intensive care unit (ICU) of a university hospital. PATIENTS: Thirty-four patients with severe sepsis requiring ICU treatment. MEASUREMENTS AND RESULTS: The levels of BPI, PLA2-II, CRP, TNF, IL-8 and IFN were measured in these 34 patients. High levels of BPI were associated particularly with Gram-negative sepsis. BPI and BPI/neutrophil ratios correlated positively with PLA2-II, CRP, TNF and IL-8 and negatively with blood pressure. At 24 h, BPI/neutrophil ratios, IL-8 and Simplified Acute Physiology Scores II (SAPS II) scores were higher in non-survivors than in survivors. No such associations were noted in the levels of CRP, PLA2-II, TNF or IFN. The areas under the curve (AUC(ROC)s) of SAPS II scores and IL-8 were higher than AUC(ROC) of BPI/neutrophil ratio. CONCLUSION: The BPI and BPI/neutrophil ratios may serve as adjunctive tools to illustrate the severity of sepsis. However, their predictive power for sepsis-related death was not comparable to that of SAPS II scores and IL-8.

Comparison of autonomic withdrawal in men with obstructive sleep apnea syndrome, systemic hypertension, and neither condition.

Obstructive sleep apnea syndrome is characterized by obesity, nocturnal breathing abnormalities, arterial hypertension, and an increased number of cardiovascular events. Sympathetic activity is increased during nocturnal apneic episodes, which may mediate the cardiovascular complications of sleep apnea. We studied 15 male subjects with obstructive sleep apnea syndrome and associated hypertension, 54 subjects with mild to moderate essential hypertension, and 25 healthy normotensive men. Cardiovascular autonomic control was assessed using frequency domain measures of heart rate variability (HRV) during a controlled breathing test and during orthostatic maneuver. Compared with normotensive and hypertensive groups, total power and low- and high-frequency components of HRV during controlled breathing were significantly (analysis of variance, p<0.0001) lower in the obstructive sleep apnea syndrome. During the orthostatic maneuver, the change in total power of HRV was different between the 3 groups (analysis of variance, p = 0.004). The total power of HRV tended to increase in the normotensive (4.11+/-12.29 ms2) and in hypertensive (2.31+/-12.65 ms2) groups, but decreased (1.13+/-1.23 ms2) in the hypertensive group with obstructive sleep apnea syndrome. According to multivariate regression analysis, age and sleep apnea were the major independent determinants of HRV. This study found that an abnormal response to autonomic nervous tests characterizes hypertension in overweight subjects with obstructive sleep apnea syndrome. This could be due to autonomic withdrawal or supersaturation of the end-organ receptors by excessive and prolonged sympathetic stimulation. Our results also show the reduced response of orthostatic maneuver and controlled breathing in the hypertensive group compared with the normotensive group.

Protein C substitution in sepsis-associated purpura fulminans.

OBJECTIVE: To assess the effect of protein C (PC) substitution on imminent peripheral necroses and overall outcome in patients with sepsis-associated purpura fulminans. DESIGN: Case series. SETTING: Intensive care units of two university hospitals. PATIENTS: A total of 12 patients with purpura fulminans, disseminated intravascular coagulation and imminent peripheral necroses in association with sepsis caused by Neisseria meningitidis (n = 5), Streptococcus pneumoniae (n = 2), Capnocytophaga canimorsus (n = 2), and Staphylococcus aureus (n = 1). In two patients, no pathogens were identified. INTERVENTIONS: Intravenous administration of PC concentrate (100 IU/kg every 6 hrs). In addition, antithrombin III substitution, antimicrobial therapy, hemodynamic support, and mechanical ventilation in all patients and hemodiafiltration in 10 patients. MAIN RESULTS: After the onset of PC, progressive peripheral ischemia was reversed irrespective of the etiology of infection. Laboratory variables reflecting disseminated intravascular coagulation improved rapidly, although the recovery of the platelet count was retarded in the patients who subsequently died. No drug-related adverse events were noted. Amputations were necessary in two patients, and necrotic tips of fingers and toes were macerated in a third. The hospital mortality was 42%. Of the five lethal cases, two were caused by S. pneumoniae, one by N. meningitidis, one by C. canimorsus, and one by an unknown pathogen. CONCLUSIONS: This article provides encouraging results on the use of PC substitution in meningococcal purpura and presents new data on the administration of this drug to patients with septic purpura caused by other bacterial species. By clinical judgment, PC limited the extent of tissue necrosis. The small number of patients does not allow for any conclusions on the potential effect of PC on mortality. A controlled and randomized study with a larger number of patients is needed before any recommendations can be given on the use of PC in sepsis-related purpura fulminans and shock.

In vivo detection of vascular adhesion protein-1 in experimental inflammation.

Vascular adhesion protein-1 (VAP-1) is an inflammation-inducible endothelial glycoprotein which mediates leukocyte-endothelial cell interactions. To study the pathogenetic significance of VAP-1 in inflammatory disorders, an in vivo immunodetection method was used to detect the regulation of luminally expressed VAP-1 in experimental skin and joint inflammation in the pig and dog. Moreover, VAP-1 was studied as a potential target to localize inflammation by radioimmunoscintigraphy. Up-regulation of VAP-1 in experimental dermatitis and arthritis could be visualized by specifically targeted immunoscintigraphy. Moreover, the translocation of VAP-1 to the functional position on the endothelial surface was only seen in inflamed tissues. These results suggest that VAP-1 is both an optimal candidate for anti-adhesive therapy and a potential target molecule for imaging inflammation.

Vascular adhesion protein-1, intercellular adhesion molecule-1 and P-selectin mediate leukocyte binding to ischemic heart in humans.

OBJECTIVES: The expression of endothelial adhesion molecules and their functional significance in leukocyte adhesion to human myocardial blood vessels in acute myocardial infarction (AMI) were studied. BACKGROUND: Leukocyte extravasation, mediated by specific adhesion molecules, exacerbates tissue injury after restoration of blood supply to an ischemic tissue. Experimental myocardial reperfusion injury can be alleviated with antibodies that block the function of adhesion molecules involved in leukocyte emigration, but the relevant molecules remain poorly characterized in human AMI. METHODS: Semiquantitative immunohistochemistry and in vitro adhesion assays were used to study the expression and granulocyte binding abilities of different endothelial adhesion molecules in human AMI. Changes in the molecular nature of vascular adhesion protein-1 (VAP-1) were evaluated using immunoblotting. RESULTS: Certain endothelial adhesion molecules (intercellular adhesion molecule [ICAM-2], CD31 and CD73) were expressed in myocardial blood vessels homogeneously in normal and ischemic hearts, whereas others (E-selectin and peripheral lymph node addressin) were completely absent from all specimens. The synthesis of ICAM-1 was locally, and that of P-selectin regionally, upregulated in the infarcted hearts when compared with nonischemic controls. Vascular adhesion protein-1 showed ventricular preponderance in expression and alterations in posttranslational modifications during ischemia-reperfusion. Importantly, P-selectin, ICAM-1 and VAP-1 mediated granulocyte binding to blood vessels in the ischemic human heart. CONCLUSIONS: Human P-selectin, ICAM-1 and VAP-1 appear to be the most promising targets when antiadhesive interventions preventing leukocyte-mediated tissue destruction after myocardial ischemia are planned.