Increased plasma levels of interleukin-6 in sepsis

Interleukin-6 (IL-6) is likely to be an important mediator of the inflammatory response. We measured levels of this cytokine in plasma samples from 37 patients with sepsis or septic shock obtained at the time of admission to the intensive care unit and related these levels to hemodynamic and biochemical parameters as well as to clinical outcome. In 32 of the 37 patients, increased levels of IL-6 were found, occasionally up to 7,500 times the normal level. The highest IL-6 levels were encountered in patients who suffered from septic shock (P value of the difference between patients with and without shock less than .0001). In addition, IL-6 significantly correlated with plasma lactate (P less than .0001), heart rate (P = .05) and, inversely, with mean arterial pressure (P = .01) and platelet counts (P = .0002). Significant correlations of IL-6 with the anaphylatoxins C3a (P = .0001) and C4a (P = .0002) and with the main inhibitor of the classical pathway of complement, C1-inhibitor (inverse correlation, P = .05), were also observed. IL-6 on admission appeared to be of prognostic significance: levels were higher in septic patients who subsequently died than in those who survived (P = .0003), in particular when only patients with septic shock were considered (P less than .0001). All nine septic patients with levels of less than 40 U/mL on admission survived, whereas 89% of the nine patients with levels exceeding 7,500 U/mL died. These data provide evidence for a role of IL-6 in the pathophysiology of septic shock. Further studies are needed to reveal whether IL-6 in sepsis is directly involved in mediating lethal complications or whether it is to be considered as an "alarm hormone" that reflects endothelial cell injury probably mediated by the anaphylatoxines.     

Prognostic value of ambulatory heart rate revisited in 6928 subjects from 6 populations

The evidence relating mortality and morbidity to heart rate remains inconsistent. We performed 24-hour ambulatory blood pressure monitoring in 6928 subjects (not on beta-blockers; mean age: 56.2 years; 46.5% women) enrolled in prospective population studies in Denmark, Belgium, Japan, Sweden, Uruguay, and China. We computed standardized hazard ratios for heart rate, while stratifying for cohort, and adjusting for blood pressure and other cardiovascular risk factors. Over 9.6 years (median), 850, 325, and 493 deaths accrued for total, cardiovascular, and noncardiovascular mortality, respectively. The incidence of fatal combined with nonfatal end points was 805, 363, 439, and 324 for cardiovascular, stroke, cardiac, and coronary events, respectively. Twenty-four-hour heart rate predicted total (hazard ratio: 1.15) and noncardiovascular (hazard ratio: 1.18) mortality but not cardiovascular mortality (hazard ratio: 1.11) or any of the fatal combined with nonfatal events (hazard ratio: < or =1.02). Daytime heart rate did not predict mortality (hazard ratio: < or =1.11) or any fatal combined with nonfatal event (hazard ratio: < or =0.96). Nighttime heart rate predicted all of the mortality outcomes (hazard ratio: > or =1.15) but none of the fatal combined with nonfatal events (hazard ratio: < or =1.11). The night:day heart rate ratio predicted total (hazard ratio: 1.14) and noncardiovascular mortality (hazard ratio: 1.12) and all of the fatal combined with nonfatal events (hazard ratio: > or =1.15) with the exception of stroke (hazard ratio: 1.06). Sensitivity analyses, in which we stratified by risk factors or from which we excluded 1 cohort at a time or the events occurring within 2 years of enrollment, showed consistent results. In the general population, heart rate predicts total and noncardiovascular mortality. With the exception of the night:day heart rate ratio, heart rate did not add to the risk stratification for fatal combined with nonfatal cardiovascular events. Thus, heart rate adds little to the prediction of cardiovascular risk.     

Headache and Epilepsy

Headache and epilepsy often co-occur. Epidemiologic studies conducted in the past few years reinforce the notion of a bi-directional association between migraine and epilepsy. Data on an association between headache (in general) and epilepsy, however, are less clear. Peri-ictal headache often presents with migraine-like symptoms and can be severe. A correct diagnosis and management are paramount. It was demonstrated that cortical hyperexcitability may underlie both epilepsy and migraine. A recent study linked spreading depolarisation, the supposed underlying pathophysiological mechanism of migraine with aura, to epilepsy. Although this study was carried out in patients who had suffered a subarachnoid haemorrhage, the finding may shed light on pathophysiological mechanisms common to epilepsy and migraine.     

Influence of rosmarinic acid on opsonization and intracellular killing of Escherichia coli and Staphylococcus aureus by porcine and human polymorphonuclear leucocytes

The influence of rosmarinic acid on the function of porcine and human polymorphonuclear leucocytes was tested. Rosmarinic acid inhibited the chemiluminescence of PMNL, induced by preopsonized Zymosan or phorbol myristate acetate. The killing of Escherichia coli was inhibited by rosmarinic acid at a concentration of 2 mM, but not that of Staphylococcus aureus. The inhibition of the killing was due to an impaired opsonization, caused by an adverse influence of rosmarinic acid on complement activation. Direct effects of rosmarinic acid on the killing mechanisms of PMNL were not observed.     

Adverse effects and compliance with mefloquine or proguanil antimalarial chemoprophylaxis

Objective: We had the impression that adverse reactions to standard antimalarial prophylaxis were reported much more often than stated by the package insert and medical drug references; and that side effects adversely affected compliance. Therefore, we evaluated adverse effects and compliance of the two standard malaria prophylactic regimens (mefloquine 250 mg per week and proguanil 100 mg twice per day) among short-term travellers. We expected that travellers who had experienced possible adverse effects on previous journeys might avoid antimalarial drugs on subsequent journeys (self-selection) and we therefore looked at adverse effects dependent on prior use. Methods: The presence of neuropsychological and gastrointestinal symptoms were assessed by telephone interviewing of 300 travellers who had visited the travel vaccination service of our regional public health institute. Symptoms, prior use and non-compliance of 104 mefloquine users and 103 proguanil users were compared with 93 non-users in order to control for travel-related symptoms. Results: Mefloquine showed the following adverse effects: depression [excess risk (ER) 7.2 per 100 users], dizziness (ER 9.3) and itching (ER 12.3). Adverse effects of proguanil were dizziness (ER 7.5) and nausea (ER 12.7). Adverse effects were mostly mild to moderate and occurred mainly during the time abroad. These results did not change when adjusting for age, sex, or destination. For almost every symptom, we found a remarkable difference between the relationship of symptoms and antimalarial drugs in first-time users and that in prior users: in the first-time users the relationship was positive, while in prior users it was absent or negative. This could be due to self-selection or adaptation to adverse effects. 22% of mefloquine users were non-compliant, whereas 35% of proguanil users were non-compliant. Adverse effects (experienced or expected) were the most often reported reason for mefloquine users to stop or even not to start taking the drug (42%). For proguanil, most of the non-compliant participants saw no point in starting or continuing its use (perceived uselessness 54%). Conclusion: We can confirm the reports by users that adverse effects of mefloquine and proguanil are common and, although mostly mild, adversely affect compliance. We suggest that a longer run-in period for mefloquine as well as counselling travellers about possible adverse effects might improve compliance. Received: 24 May 1996 / Accepted in revised form: 30 January 1997     

Production and characterisation of mouse monoclonal antibodies reacting with the lipopolysaccharide core region of gram-negative bacilli

Monoclonal antibodies to the lipopolysaccharide (LPS) core region were produced by immunising mice with Escherichia coli strain J5 (chemotype Rc). One of these bound to the deepest part of the core, i.e., Lipid A, and reacted with other heat-killed but not live gram-negative bacilli, including E. coli, Klebsiella pneumoniae and Pseudomonas aeruginosa. Eight other monoclonal antibodies, binding to the terminal glucose residue of Rc LPS, reacted with live cells of E. coli strains only. Thus, the O antigen does not necessarily render the core inaccessible to antibody. However, despite binding to live bacteria, these monoclonal antibodies neither enhanced phagocytic killing, nor protected mice from dying from gram-negative infection or endotoxaemia. It is concluded that antibodies reacting with the most immunodominant parts of the J5 core are not protective.     

Life threatening complications from a lower wisdom tooth

The case history of a 25-year-old student who developed a number of very serious complications after a simple extraction of a lower wisdom tooth is presented. A submandibular abscess was followed by septic shock with severe thrombocytopenia and transient renal insufficiency, adult respiratory distress syndrome, pneumothorax and pericarditis. From the blood, alpha-hemolytic Streptococci were cultured, while cultures from the abscess grew Bacteroides fragilis. With intensive treatment, including artificial ventilation with PEEP, the patient survived this life-threatening episode.