Anthropometric measurements and vertebral deformities. European Vertebral Osteoporosis Study (EVOS) Group

BACKGROUND: Plasma levels of B-type natriuretic peptide (BNP) are markedly increased in patients with heart failure and acute myocardial infarction. The changes in plasma BNP levels in the treatment of acute myocardial infarction with angiotensin-converting enzyme inhibitors have not been examined well. This study was designed to examine the effects of early angiotensin-converting enzyme inhibitor therapy on plasma BNP levels in patients with acute myocardial infarction. METHODS AND RESULTS: We measured the plasma levels of B-type natriuretic peptide over the time course for 2 weeks in 30 patients with acute myocardial infarction in whom either imidapril (n = 15) or placebo (n = 15) was given at random immediately after admission. Plasma BNP levels increased and reached a peak of 192 +/- 28 pg/ML 16 hours after administration; thereafter, the levels decreased and then again increased, forming the second peak of 217 +/- 38 pg/ML on the fifth day (biphasic pattern). On the other hand, plasma BNP levels increased and reached a peak level of 190 +/- 22 pg/ML 16 hours after admission and then decreased from 2 days after admission until the second week in the imidapril group (monophasic pattern). Left ventricular ejection fraction measured in the second week was significantly higher in the imidapril group than in the control group (62.2 +/- 1.1% vs 51.2 +/- 3.6%, P < .01). CONCLUSION: It is concluded that plasma BNP levels followed a monophasic pattern after imidapril treatment, whereas a biphasic pattern was followed after placebo, and that plasma BNP levels constitute a marker of ventricular dysfunction in the treatment of acute myocardial infarction with angiotensin-converting enzyme inhibitors.     

Changes in plasma erythropoietin and interleukin-6 concentrations in patients with septic shock after hemoperfusion with polymyxin B-immobilized fiber

OBJECTIVE: To find out whether polymyxin B-immobilized fiber (PMX-F) treatment affects the clinical parameters and plasma concentrations of erythropoietin (EPO) and interleukin (IL)-6. DESIGN: A prospective case series study. SETTING: Intensive care unit of the Department of Internal Medicine, Misato Junshin Hospital, Saitama, and Koto Hospital, Tokyo, Japan. PATIENTS: 17 consecutive patients (10 men, 7 women; mean age 54.6 years) with clinically defined septic shock and 20 healthy volunteers (12 men, 8 women; mean age 52.2 years). MAIN RESULTS: Of the 17 patients with septic shock, 9 (53 %) survived. The systolic blood pressure increased significantly from 78+/-6 to 106+/-8 mm Hg 2 h after PMX-F treatment in patients with septic shock. Plasma endotoxin levels decreased significantly after treatment, from 40+/-6 to 12+/-4 pg/ml. The pretreatment plasma concentrations of EPO and IL-6 were significantly higher in the 8 nonsurviving patients with septic shock (EPO: 400+/-36 mlU/ml; IL-6: 6260+/-1180 pg/ml) than in the 9 surviving patients (EPO: 120+/-22 mlU/ml; IL-6: 680+/-138 pg/ml) and the 20 control subjects (EPO, 12+/-6 mlU/ml; IL-6, 8+/-2 pg/ml). Plasma concentrations of EPO and IL-6 in patients with septic shock decreased significantly after PMX-F treatment (EPO, nonsurviving: 320+/-28 mlU/ml, p < 0.05; survivors: 26+/-8 mlU/ ml, p < 0.001; IL-6, nonsurviving: 3860+/-840 pg/ml, p < 0.01; survivors: 84+/-20 pg/ml, p < 0.001). CONCLUSIONS: Plasma concentrations of EPO and IL-6 may be prognostic indicators in patients with septic shock: PMX-F treatment may be effective in reducing the plasma concentrations of EPO and IL-6 in patients with septic shock.     

Measuring the quality of outpatient treatment for schizophrenia

OBJECTIVE: Usually it is not possible to study the initial systemic response in patients with acute pancreatitis in the first hours after onset of the disease. We used postendoscopic retrograde pancreatography (ERP) pancreatitis as a model to study cytokine and anticytokine release in the early phase of human acute pancreatitis. METHODS: Post-ERP pancreatitis was defined as a threefold increase in serum amylase and at least two of the following clinical symptoms: abdominal pain, nausea, vomiting or peritonism 24 h after ERP. Serum levels of pro-inflammatory cytokines interleukin-1beta (IL-1beta), interleukin-6 (IL-6), interleukin-8 (IL-8), tumour necrosis factor alpha (TNF), as well as endogenous antagonistic mediators of the systemic inflammatory response such as soluble tumour necrosis factor alpha receptors p55 (TNFR p55) and p75 (TNFR p75), and IL-1-receptor antagonist (IL-1-RA) and interleukin-2-receptor (IL-2R) as indicators of lymphocyte activation were measured before and 0, 1, 4, 12, 24 and 48 h after ERP. In nine patients with acute post-ERP pancreatitis, these parameters were monitored daily until C-reactive protein (CRP) was within normal ranges and were compared to patients without pancreatitis after ERP. RESULTS: IL-1beta was not detectable in five patients with and four patients without post-ERP pancreatitis. The values of the remaining patients in both groups were lower than 3.9 pg/ml. IL-8 and IL-1-RA serum concentrations peaked 12 h after ERP (132.9 and 3245.0 pg/ml respectively) compared to patients without post-ERP pancreatitis (25.8 and 389.9 pg/ml respectively). The IL-6 concentration increased to 81.6 pg/ml (8.0 pg/ml in control patients) 24 h after ERP, while the peak values for CRP were measured 72 h after ERP (164.0 versus 7.7 mg/l). IL-2R content was maximally elevated 144 h after ERP (688.8 versus 255.9 U/ml), while concentrations of TNF and its receptors showed no significant change over time. CONCLUSION: The initial response of the cytokine network to damage of the human pancreas leading to acute pancreatitis includes the release of IL-8 and the IL-1 antagonist IL-1-RA, while IL-1beta is not found in the systemic circulation. The TNF system does not seem to be involved as indicated by the lack of detectable changes in TNF and the soluble TNFR p55 and p75 serum concentrations. Lymphocyte activation as indicated by elevated IL-2R levels occurred days after the initial trauma. Even mild post-ERP pancreatitis leads to significant systemic release of cytokines and their biological counterparts.     

Clinical significance of serum cytokine patterns during start of fever in patients with neutropenia

Serum concentrations of tumour necrosis factor alpha (TNF-alpha), interleukin-1 receptor antagonist (IL-1ra), interferon gamma (IFN-gamma), interleukin-6 (IL-6) and interleukin-10 (IL-10) were studied in 31 patients with haematological malignancies during febrile neutropenia. Samples were obtained when blood cultures were performed (time 0) and, when possible, after 2, 4, 6, 12 and 24 h. Increased levels of all cytokines were detected after start of fever with peak values in gram-negative (Gr-) bacteraemias after 2 h (TNF-alpha, IL-1ra and IFN-gamma), 4 h (IL-6) and 6 h (IL-10), respectively. At time 0 the median TNF-alpha value was higher in the Gr- group (80 pg/ml; range 54-516 pg/ml) as compared to both gram-positive bacteraemias (Gr+, 14 pg/ml; range 7-60 pg/ml; P < 0.05) and blood culture negative episodes (BCN, 8 pg/ml; range 0-87 pg/ml; P < 0.05). Furthermore, the peak values of TNF-alpha, IL-1ra, IL-6 and IL-10 during the 24 h study period were significantly and/or numerically higher in the Gr- group in comparison to the Gr+ and BCN groups, respectively. It may be concluded that neutropenic patients have increased levels of both pro- and anti-inflammatory cytokines at start of fever, with the highest values recorded during the first hours in Gr- bacteraemias. Prospective studies will show whether monitoring of serum cytokines may be used as an early diagnostic tool before results of blood cultures are available, which may have important therapeutic implications.     

Myoglobin concentration in serum as an early marker of reperfusion in patients with acute myocardial infarction after thrombolytic therapy

Detection of coronary artery reperfusion in patients after thrombolytic therapy because of acute myocardial infarction includes, except angiography, disappearance of anginal pain, regression of electrocardiographic and echocardiographic myocardial ischaemia symptoms, increased activity of creatine kinase (CPK) and its isoenzyme CK-MB. The aim of the study was to check whether changes in myoglobin serum concentration could be an early marker of coronary artery reperfusion after thrombolysis in patients with acute myocardial infarction. The studies comprised 50 patients treated by thrombolysis due to threatening myocardial infarction, including 29 men and 21 women aged 43-84 years. The patients were divided into 2 groups: the first (i)-patients without symptoms of coronary artery reperfusion and the second (ii)-those with symptoms of coronary artery reperfusion. It was assumed that the basis for successful reperfusion would be the reduction of total elevations of the ST segment 70% or more in electrocardiographic recording performed 3 hours after the start of thrombolytic treatment. Reperfusion was considered completely unsuccessful when reduction of total elevations was less than 30%. In patients with reperfusion after thrombolysis the concentrations of myoglobin were much higher and the activity of CPK and CK-MB significantly more intensive in comparison with patients without reperfusion symptoms in electrocardiographic assay. The evaluation of myoglobin concentration, CPK and CK-MB activity in the 3rd hour after the start of thrombolytic treatment in relation to maximum values is characterised by high sensitivity and specificity in the prediction of reperfusion onset Maximum myoglobin concentration in serum appears significantly earlier than maximum CPK and CK-MB activity and this marker is characterised by higher sensitivity and specificity in the evaluation of coronary artery reperfusion than the activity of CPK and CK-MB.     

Reproducibility and diagnostic sensitivity of ultrasonometry of the phalanges to assess osteoporosis

To investigate the relation between plasma brain natriuretic peptide (BNP) and progressive ventricular remodeling, we measured plasma BNP and atrial natriuretic peptide (ANP) in 30 patients with acute myocardial infarction on days 2, 7, 14, and 30 after the onset. Left ventricular end-diastolic volume index (EDVI), end-systolic volume index (ESVI), and ejection fraction (EF) on admission and 1 month after the onset were assessed by left ventriculography. Changes in EDVI (deltaEDVI), ESVI (deltaESVI), and EF (deltaEF) were obtained by subtracting respective acute-phase values from corresponding chronic-phase values. Plasma ANP on days 2 and 7 showed only weak correlations with deltaEDVI (r = 0.48 and 0.54; both p < 0.01), whereas plasma BNP on day 7 more closely correlated with deltaEDVI (r = 0.77; p < 0.001). When study patients were divided into two groups according to plasma BNP on day 7, the group with BNP higher than 100 pg/ml showed greater increases in left ventricular volume and less improvement in EF compared with the other group with BNP lower than 100 pg/ml (deltaEDVI = 10.4 +/- 8 vs -3.4 +/- 9 ml/m2, deltaESVI = 6.2 +/- 7 vs -4.9 +/- 5 ml/m2, and deltaEF = 1.0% +/- 4% vs 4.9% +/- 5%; p < 0.05, respectively). Multiple regression analysis revealed that only plasma BNP on day 7, but not ANP, peak creatine phosphokinase level, left ventricular end-diastolic pressure, or acute-phase EF, correlated independently with deltaEDVI (p < 0.01). These results suggest that plasma BNP may be a simple and useful biochemical marker for the prediction of progressive ventricular remodeling within the first 30 days of acute myocardial infarction.     

A bioluminescent method of determining antibiotic sensitivity of microbial cells in septic blood]

Previous studies have shown that adhesion molecules play a crucial role in leukocyte-endothelium interactions that occur during myocardial ischemia and reperfusion. We assessed the plasma levels of the soluble form of E-selectin (sE-selectin) and intercellular adhesion molecule-1 (sICAM-1) in 15 patients with acute myocardial infarction (AMI) and in 15 controls with chronic stable angina. In patients with AMI, the levels of sE-selectin and sICAM-1 increased significantly during the first 8 h after infarction and subsequently decreased. Soluble E-selectin levels were inversely related to the peak plasma levels of creatine kinase-MB (CK-MB), and the time course of their appearance in plasma correlated with that of neutrophil count and plasma D-dimer. In individual patients, peak and mean sICAM-1 levels correlated respectively with plasma D-dimer concentrations and monocyte count, but no correlation were found when their time courses were analyzed. Eight hours after symptom onset, the mean plasma sE-selectin levels were higher in patients with AMI than in those with stable angina, whereas no significant differences were found in mean plasma sICAM-1 levels between the two groups at every time analyzed. In the acute phase of MI (a) sE-selectin and sICAM-1 levels increase during the first 8 h and subsequently decrease; (b) the increase in sE-selectin probably reflects activation of endothelial cells, correlates with other inflammatory and coagulation parameters, and is inversely related to the degree of myocardial damage; and (c) sICAM-1 plasma levels do not represent a good marker of "cell activation" because they reflect activation of different cells and may be affected by different conditions.     

Acute toxicity of synthetic Gymnodinium breve toxin metabolite and its analogues in mice

Accidental and operative trauma are able to induce a systemic reaction of the organism characterized by fever, leukocytosis, catabolism, and an activation of the coagulation system. Interleukin-6 (IL-6) has been found to be an important mediator of this acute-phase response. In this study the influence of elective craniotomy on IL-6 plasma levels was evaluated. Blood samples were obtained from 20 patients undergoing elective craniotomy for vascular or tumorous diseases of the brain. IL-6 increased significantly (p < 0.05) from the pre-operative (0(0-5.4) pg/ml) to the intraoperative (180 min after beginning of surgery) time-point (10.6 (0-18.5) pg/ml). The maximum was reached on the first postoperative morning (13.9(4.3-45.0) pg/ml). Interleukin-10 (IL-10) is an anti-inflammatory cytokine which suppresses IL-6 synthesis in vitro in various cell lines. IL-10 plasma concentrations showed no alterations throughout the study period. Epinephrine plasma concentrations increased significantly from pre-operative values (15 (0-74) pg/ml) to the postoperative time-point (57(9-459) pg/ml). A 4.5-fold increase (p < 0.05) of norepinephrine plasma concentrations was found when comparing the data obtained 60 min after beginning of surgery with the data of the first postoperative morning. In monocytes, which are a major source of plasma IL-6, an elevation of intracellular cAMP stimulates the IL-6 synthesis. The postoperative maximum of IL-6 in plasma could be due to a release of catecholamines. In conclusion this study demonstrated an elevation of IL-6 plasma concentrations during and after elective craniotomy. Increased plasma catecholamine concentrations as well as a damage in the blood-brain barrier due to the surgical trauma with a spill-over of IL-6 from brain tissue into plasma could have contributed to this result.     

Stimulatory effect of melanin-concentrating hormone on luteinising hormone release

We investigated the cytokine profile and peak levels of interleukin (IL) -6, IL-8, IL-10 and tumour necrosis factor (TNF) -alpha levels in 42 patients after allogeneic bone marrow transplantation (BMT). Eleven of them developed veno-occlusive disease (VOD) of the liver. Fourteen patients had moderate-to-severe acute graft-versus-host disease (aGvHD), 10 isolated bacteraemia and 7 had no major complication. Those who developed severe VOD (n=6) showed a short, very high IL-8 peak (median: 6632 pg/ml, range: 5546-10,000 vs. 280 pg/ml, 0-2042 in controls, p<0.01) 1-4 d after diagnosis of the liver disease. Five of these patients had high peak levels of IL-6. Five patients with mild VOD showed a lower increase in the cytokines tested. Bilirubin levels, at day of IL-8 peak, did not differ statistically between mild and severe VOD. The highest levels of IL-10 were found in those with aGvHD. IL-8 levels were also increased, but not to the same extent as in patients with severe VOD (p=0.01 vs. VOD). In patients with bacteraemia, very high levels of IL-6 were seen. In patients without major complications, the levels of cytokines were low. In conclusion, high levels of IL-8 occurred in severe VOD of the liver, which may be of value to determine prognosis.     

Arteriovenous fistula of the jugular vein: detection and follow-up with color-coded duplex ultrasound]

Increased levels of interleukin-6 (IL-6) and interleukin-8 (IL-8) have been reported in various diseases, including lung cancer. The role of the soluble form of the IL-6 receptor (sIL-6R) remains to be explored. We therefore measured IL-6, IL-8 and sIL-6R in effusion fluid and blood serum of 10 lung cancer patients with carcinomatous pleurisy (5 men, 5 women, age 64.3 +/- 4.4 years) by enzyme-linked immunosorbent assays. Serum levels of healthy individuals served as control. Concentrations of sIL-6R were much higher in serum compared to pleural effusion fluids of tumor patients (25,698 +/- 1,993 vs. 9,438 +/- 1,407 pg/ml: p < 0.0001). In contrast, IL-6 and IL-8 were found at high concentrations in carcinomatous pleural effusions in comparison to serum (IL-6: 964 +/- 176 vs. 10.2 +/- 1.3 pg/ml, p < 0.0001; IL-8: 319 +/- 85 vs. 9.6 +/- 9.6 pg/ml, p < 0.0001). The serum concentrations of IL-6 were not significantly increased in lung cancer patients (10.2 +/- 1.3 pg/ml) in comparison to controls (7.3 +/- 1.0 pg/ml). IL-8 was detected in the serum of only 1 patient and in low levels in the serum of controls (8.0 +/- 1.5 pg/ml; all values are mean +/- SEM). We conclude from this study that decreased levels of sIL-6R, but increased levels of IL-6 and IL-8, are found in pleural effusion fluid of patients with lung cancer and carcinomatous pleurisy. The low sIL-6R levels in the presence of high IL-6 levels in pleural effusions and the high sIL-6R levels in the presence of low IL-6 levels in serum may suggest a downregulation of sIL-6R expression of sIL-6R shedding in the presence of excessive amounts of IL-6.     

Role of interleukin 8 in the genesis of acute respiratory distress syndrome through an effect on neutrophil apoptosis

OBJECTIVE: To evaluate the role of interleukin 8 (IL-8) in the regulation of neutrophil (PMN) apoptosis in normal plasma and plasma from patients with early, fulminant acute respiratory distress syndrome (ARDS). DESIGN: Experimental study using cultured human PMNs. SETTING: University hospital, level I trauma center. PARTICIPANTS: Plasma was obtained from 6 patients with early, fulminant posttraumatic ARDS (mean Injury Severity Score, 26). All samples were drawn within 24 hours after injury. Plasma was also taken from 13 healthy control subjects. These controls were also used as sources of PMNs. MAIN OUTCOME MEASURES: Effect of early, fulminant ARDS and normal plasma on spontaneous apoptosis, CD16, and CD11-b expression in PMNs in vitro; levels of IL-8 in plasma; correlation of extracellular IL-8 concentration with rate of PMN apoptosis; and effect of IL-8 blockade on PMN apoptosis, CD16, and CD11-b expression in ARDS and normal plasma. RESULTS: Plasma from patients with early, fulminant ARDS inhibited spontaneous PMN apoptosis at 24 hours (35%+/-5% vs 54%+/-5%; P=.01). Neither CD16 nor CD1l-b differed significantly between the 2 groups. The mean plasma level of IL-8 in patients with early, fulminant ARDS was 359+/-161 pg/mL vs 3.0+/-0.4 pg/mL in healthy controls (P<.05). Interleukin 8 inhibited apoptosis in plasma-free medium at low doses (1-50 pg/mL) but had no significant effect at higher doses (100-5000 pg/mL) (P<.05). Interleukin 8 blockade with monoclonal antibody suppressed apoptosis in normal plasma (28%+/-5% with monoclonal antibody vs 51%+/-5% without monoclonal antibody; P=.008) but not in plasma from patients with early, fulminant ARDS (29%+/-5% with monoclonal antibody vs 34%+/-6% without monoclonal antibody; P=.67). It had no effect on CD16 or CD11-b expression in either plasma. CONCLUSIONS: Plasma from patients with early, fulminant ARDS contains soluble factors that inhibit PMN apoptosis in vitro. Low levels of IL-8 inhibit PMN apoptosis in normal plasma. Although plasma levels of IL-8 are markedly elevated in early, fulminant ARDS, IL-8 is not directly responsible for the antiapoptotic effect of plasma from patients with early, fulminant ARDS.     

An experimental model for infiltration of malignant lymphoma to the eye and brain

For troponin T a characteristic biphasic change in the plasma time-concentration curve has been described, especially in patients with early reperfusion after thrombolytic therapy. As troponin T is bound to myofibrillar structures, treatment strategy or treatment outcome could influence the cumulative plasma release of this protein in a different way compared to the cumulative release of free cytoplasmic cardiac enzymes. The present study is the first study comparing the total quantity of troponin T released by the heart during the first 168 hours after acute myocardial infarction, both in patients treated with thrombolytic therapy (n = 16) and in patients not treated with thrombolytic therapy (n = 7). On the basis of clinical symptoms and coronary arteriogram within 24 hours, the patients treated with thrombolytic therapy were divided into two groups, reperfused (n = 9) and non-reperfused (n = 7). In the patients not treated with thrombolytic therapy, absence of spontaneous early reperfusion was judged only from clinical symptoms. Cumulative troponin T release into plasma was compared to the cumulative release of the cytoplasmic cardiac enzymes creatine kinase (EC 2.7.3.2) and hydroxybutyrate dehydrogenase (EC 1.1.1.27). Cumulative release, i. e., infarct size, was calculated using a two-compartment model for circulating proteins. Mean tissue contents, per gram wet weight, of 156 U/g for hydroxybutyrate dehydrogenase, 2.163 U/g for creatine kinase and 234 microg/g for troponin T, were used to express infarct size in gram-equivalents of healthy myocardium per litre plasma (g-eq/l). Release rates were represented by the ratio of cumulative quantities released in 10 hours and 72 hours for creatine kinase and hydroxybutyrate dehydrogenase and in 10 hours and 168 hours for troponin T. CONCLUSIONS: - Plasma time-concentration curves and release rates of troponin T in patients treated with thrombolytic therapy showing reperfusion differ significantly from those of patients not treated with thrombolytic therapy, showing no reperfusion. - Creatine kinase and hydroxybutyrate dehydrogenase release is completed within 72-100 hours in all patients, whereas troponin T release still continues after 168 hours. - Cumulative troponin T release at 168 hours is only a fraction (around 8%) of cumulative cytoplasmic enzyme release and the percentage released is not influenced by the treatment strategy or outcome, i. e., vessel patency. - Although troponin T release is only a fraction of the cumulative enzyme release (infarct size) there is a highly significant correlation between both, independent of the treatment strategy or treatment outcome.     

Interleukin-6, gamma interferon, and tumor necrosis factor receptors in typhoid fever related to outcome of antimicrobial therapy

To study mechanisms of antibiotic effects in typhoid fever, levels of interleukin-6 (IL-6), gamma interferon (IFN-gamma), and cytokine receptors (tumor necrosis factor receptor [TNF-R] p55 and TNF-R p75) were measured in the plasma of 29 adult Nepalese with culture-positive typhoid fever before therapy and on days 4 and 15 after start of therapy with either ceftriaxone at 2 g/day for 3 days or chloramphenicol at 50 mg/kg of body weight per day for 14 days. Bacteriologic cure was defined as blood cultures testing negative on days 4 and 15 after start of therapy; clinical cure was defined as symptomatic improvement within 5 days after start of therapy and absence of relapse. Clinical and bacteriologic cures occurred in 24 patients. There were two clinical failures, two patients who failed to complete therapy because of leukopenia, and one relapse. Mean levels before therapy were elevated compared with those in healthy controls (IL-6, 11.4 pg/ml; IFN-gamma, 1.3 ng/ml; TNF-R p55, 3.8 ng/ml; and TNF-R p75, 6.1 ng/ml) and fell progressively during and after therapy. For six patients (three in each treatment group) who showed prolonged fever (> 5 days) or relapse, mean levels of IL-6 and TNF-R p55 before therapy (29.5 pg/ml and 6.1 ng/ml, respectively) and on day 4 (17.7 pg/ml and 4.0 ng/ml) were significantly greater than corresponding means for 23 patients who showed early defervescence (on admission, 6.7 pg/ml and 3.3 ng/ml, and on day 4, 1.8 pg/ml and 2.7 ng/ml, P < .05). These results indicate that the concentrations of plasma cytokines and their receptors are elevated in typhoid fever and that these concentrations can be useful in predicting outcome.     

Chronic sinusitis refractory to standard management in patients with humoral immunodeficiencies

Chronic refractory sinusitis is a common feature in patients with primary immunodeficiencies. The efficacy of standard therapeutic strategies is questionable. In an open trial we evaluated the efficacy of azithromycin, N-acetylcysteine and topical intranasal beclomethasone (100 microg twice daily for 6 weeks) in 16 patients with primary immunodeficiencies (median age 13.5 years, range 5-32 years). All patients suffered from chronic sinusitis despite regular immunoglobulin replacement therapy every 3 weeks. Magnetic resonance imaging (MRI) scans were performed before and after 6 weeks of treatment to evaluate morphological changes in the paranasal sinuses. Nasal swabs and washings were taken for microbial analysis and measurement of inflammatory mediators (IL-8, tumour necrosis factor-alpha (TNF-alpha), eosinophilic cationic protein (ECP)) before and post therapy. Inflammatory mediators in nasal secretions were significantly elevated in patients: IL-8 median 2436 pg/ml (range 441-5435 pg/ml), TNF-alpha 37.3 pg/ml (3.75-524 pg/ml) and ECP 33 ng/ml (1.5-250 ng/ml) versus age-matched healthy controls: IL-8 median 212 pg/ml (99-825 pg/ml), TNF-alpha 3.77 pg/ml (2.8-10.2 pg/ml) and ECP 1.5 ng/ml (1.5-14.8 ng/ml) (P < 0.0001). Inflammation of the maxillary sinuses was confirmed by MRI scans in all patients, additionally infection of the ethmoidal and frontal sinuses was recorded in five patients. Bacterial growth appeared in 11 out of 16 cultures. In spite of therapy, no improvement in sinal inflammation visualized by MRI was achieved. Moreover, no significant decrease in pathogens and levels of inflammatory mediators could be detected (IL-8 1141 pg/ml, 426-4556 pg/ml; TNF-alpha 13.9 pg/ml, 4.1-291.6 pg/ml; ECP 32.3 ng/ml, 3.7-58.4 ng/ml). Our results demonstrate that conventional management of sinusitis is of little benefit in patients with chronic refractory sinusitis with an underlying immunodeficiency. More studies are needed to test antibiotic regimens, probably combined with surgical drainage and anti-inflammatory agents.     

Serum levels of basic fibroblast growth factor in acute myocardial infarction

As it has been reported that basic fibroblast growth factor (bFGF) is a circulating peptide and bFGF gene expression is increased after myocardial ischemia, this study was designed to investigate the serum levels of bFGF in patients with acute myocardial infarction (AMI). Using a bFGF enzyme-linked immunoassay, bFGF levels were determined in venous blood of 15 patients with AMI on admission, at 10 days, and 30 days after infarction, and of 15 age-matched healthy volunteers who were used as controls. bFGF serum levels on admission were similar to normal values (7.48 +/- 2.3 vs 8.14 +/- 2.9 pg/ml). However, they significantly increased (16.82 +/- 3.4 pg/ml; p <0.05) 10 days after the onset of AMI, and at 30 days they returned to baseline (7.07 +/- 2.9 pg/ml). The increased bFGF levels at the second week post AMI suggest that bFGF plays an important role in mediating the development of coronary collateral circulation after myocardial ischemia in humans.     

Cytokines in vitreous humor: interleukin-6 is elevated in proliferative vitreoretinopathy

PURPOSE: To measure the levels of interleukins (IL) 1 beta, 6, and 8, and tumor necrosis factor-alpha (TNF alpha) in the vitreous of patients with proliferative vitreoretinopathy (PVR), proliferative diabetic retinopathy (PDR), vitreous hemorrhage, and macular pucker. METHODS: Vitreous samples were collected, undiluted, from patients with PVR, PDR of varying severity, and miscellaneous lesions (vitreous hemorrhage from trauma, macular degeneration, vein occlusion, and non-PVR patients with giant tear, retinal detachment, and macular pucker). Immunoreactive levels of the cytokines, IL-1 beta, IL-6, IL-8, and TNF alpha were determined by enzyme-linked immunoadsorbent assays, and samples were analyzed for protein and hyaluronic acid content using standard assays. RESULTS: The levels of TNF alpha were below detection limits of the assay (< 3 pg/ml). In 45 of the 47 samples tested, IL-1 beta levels also were below detection limits of the assay (< 3 pg/ml). IL-6 levels ranged from < 30 to 5487 pg/ml, with the highest values observed in the PVR patients. IL-8 levels ranged from < 20 to 1900 pg/ml, and were consistently high in the miscellaneous group. Some of the PVR patients with C2 and C3 level severity also exhibited IL-8 levels exceeding 100 pg/ml. In a second study, IL-6 content of vitreous from miscellaneous and PVR patients was compared. In this study, significantly elevated levels of IL-6 were observed in the PVR patients (91.5 +/- 18 pg/ml) compared to the miscellaneous group (10.3 +/- 3.7 pg/ml) CONCLUSIONS: Elevated levels of IL-6 in the vitreous occur in PVR, implicating a role for this cytokine in the pathogenesis of this ocular disorder.     

Detection of urinary interleukin-8 in glomerular diseases

To clarify the mechanism of neutrophil infiltration in glomerulonephritis, both urinary and plasma levels of a potent neutrophil chemotactic cytokine, interleukin-8 (IL-8), were measured in 40 healthy volunteers and 96 patients with various renal diseases. The plasma IL-8 levels were less than 16 pg/ml. The urinary IL-8 levels were elevated in several renal diseases including IgA nephropathy (17 of 43), acute glomerulonephritis (4 of 6), lupus nephritis (11 of 15), purpura nephritis (2 of 4), membranoproliferative glomerulonephritis (1 of 1), and cryoglobulinemia (2 of 2). IL-8 was detected immunohistochemically in diseased glomeruli, suggesting its local production. Elevated urinary IL-8 levels during the acute phase or exacerbations were found to be decreased during spontaneous or steroid pulse therapy-induced convalescence in all patients examined. The urinary IL-8 levels were higher in patients with glomerular leukocyte infiltration than in those without infiltration. Collectively, local production of IL-8 in diseased glomeruli might be involved in the pathogenesis of the glomerular diseases and measurement of IL-8 in the urine might be useful for monitoring the glomerular diseases.     

Enhanced shear-induced platelet aggregation in acute myocardial infarction

BACKGROUND: Experiments under controlled flow conditions indicate that the binding of von Willebrand factor (vWF) to platelet glycoprotein (GP) Ibalpha and integrin alphaIIbbeta3 (GP IIb/IIIa complex) is crucial for aggregation at elevated shear rates. We have tested how the plasma of patients with acute myocardial infarction affects this process. METHODS AND RESULTS: Citrated plasma was obtained from 18 patients with acute myocardial infarction within 6 hours from the onset of symptoms and from 26 control subjects with chest pain syndrome without evidence of ischemia. Aggregation of normal platelets at high shear rates was significantly greater in the presence of patient than control plasma and was inhibited by both anti-GP Ibalpha and anti-alphaIIbbeta3 monoclonal antibodies. The observed values (mean+/-SD) were 47.6+/-17.8% versus 30.1+/-9.9% at 10 800 s-1 (P<0.01) and 32.9+/-14.1% versus 17.5+/-9.5% at 7200 s-1 (P<0.01), respectively, and were positively correlated with plasma vWF antigen levels and ristocetin cofactor activities. In contrast, at the lower shear rate of 1200 s-1, aggregation was similar in the presence of control or patient plasma and was not inhibited by the anti-GP Ibalpha antibody. Both vWF antigen and platelet aggregation decreased 2 weeks after the onset of myocardial infarction. CONCLUSIONS: Shear-induced platelet aggregation is enhanced in plasma in the presence of acute myocardial infarction, apparently as a result of increased vWF concentration. This may contribute to the onset of acute coronary artery thrombosis and early reocclusion after reperfusion treatment.     

Release of interleukin-12 in experimental Escherichia coli septic shock in baboons: relation to plasma levels of interleukin-10 and interferon-gamma

Interleukin (IL)-12 is thought to be a key factor for the induction of interferon gamma (IFN-gamma), a cytokine essential for the lethal effects of endotoxin. We report here on the release of the nonfunctional subunit of IL-12, p40, as well as biologically active heterodimeric IL-12, p70, after administration of a lethal (n = 5) or sublethal (n = 8) dose of live Escherichia coli to baboons. Remarkably, on lethal challenge, peak levels of p40 were observed at 3 hours that were about twofold lower than those elicited after sublethal challenge (2,813 +/- 515 pg/mL v 4,972 +/- 732 pg/mL, P < .05). This disparity was also observed, although to a lesser extent, for IL-12 p70 antigen, of which maximum levels of 91 +/- 47 pg/mL and 151 +/- 41 pg/mL were measured 6 hours after a lethal or sublethal dose of E coli, respectively. Circulating p70 antigen correlated with IL-12 biologic activity (r = 0.869; P < .001). When comparing lethal to sublethal conditions, lower peak levels of IL-12 on lethal E coli sharply contrasted with higher levels of other proinflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, IL-1beta, IL-6, and IL-8 observed in these animals. Lower IL-12 concentrations in the lethal group may have resulted in part from the enhanced production of IL-10, a known inhibitor of IL-12 synthesis in vitro, as peak levels of this cytokine 3 hours postchallenge inversely correlated with peak levels of IL-12, in particular p40 (r = -0.802; P < .01). Contrary to what might be expected if IFN-gamma were solely induced by IL-12, lethally challenged baboons generated threefold more IFN-gamma at 6 hours than those receiving a sublethal dose (P < .05). Moreover, higher levels of IFN-gamma were associated with lower p40/p70 ratios, suggesting that, in agreement with observations in vitro, IFN-gamma may have preferentially upregulated the release of p70 over p40. These data show that IL-12 is released in experimental septic shock in nonhuman primates and suggest that IL-10 and IFN-gamma are involved in the regulation of this release. Furthermore, this study indicates that the systemic release of IL-12 might be essential, but is not likely sufficient, to promote lethal production of IFN-gamma in sepsis.     

Codon 219 Lys allele of PRNP is not found in sporadic Creutzfeldt-Jakob disease

OBJECTIVE: To determine the prevalence of hypergastrinemia in cats with naturally developing chronic renal failure (CRF) and the correlation between gastrin concentration in plasma and severity of CRF. DESIGN: Cohort study. ANIMALS: 30 cats with naturally developing CRF and 12 clinically normal control cats. PROCEDURE: Gastrin concentrations in plasma were determined by double-antibody radioimmunoassay of blood samples obtained from cats after food was withheld 8 hours. Concentrations were compared, using a nonparametric Kruskal-Wallis ANOVA. RESULTS: 18 cats with CRF had high gastrin concentrations (median, 45 pg/ml; range, < 18 to > 1,333 pg/ml), compared with those for control cats (< 18 pg/ml). Prevalence of hypergastrinemia increased with severity of renal insufficiency. Three of 9 cats with mild CRF, 6 of 11 cats with moderate CRF, and 9 of 10 cats with severe CRF had high gastrin concentrations. Gastrin concentrations were significantly different between control cats and cats with CRF, regardless of disease severity. CLINICAL IMPLICATIONS: The potential role of high concentrations of gastrin on gastric hyperacidity, uremic gastritis, bleeding from the gastrointestinal tract, and associated clinical signs of hypergastrinemia (e.g., anorexia and vomiting) may justify use of histamine2-receptor antagonists or proton pump inhibitors to suppress gastric acid secretion in cats with CRF that have these clinical signs.