[Antibiotic therapy in diabetic foot ulcers].
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Anti-Bacterial Agents↗
Biomedical subjects
R W Sauerwein
Publications and source records attributed to R W Sauerwein.
Soluble interleukin 6 receptor in biological fluids from human origin.
OBJECTIVE: measurement of baseline soluble interleukin 6 receptor (sIL-6R) and interleukin 6 (IL-6) levels in biological fluids in non-pathological conditions. SUBJECTS AND MATERIALS: Blood and urine were obtained from healthy volunteers. Cerebrospinal fluid (CSF) and synovial fluid (SF) were obtained from patients during spinal puncture and athroscopy, respectively. Only CSF and SF of patients with proven non-pathological conditions were used in this study. Both sIL-6R and IL-6 were measured using ELISAs. It was shown that neither did sIL-6R interfere with the IL-6 ELISA nor did IL-6 interfere in the sIL-6R ELISA. Moreover, addition of recombinant sIL-6R to the IL-6 bio-assay (B9) did not influence IL-6 recovery. RESULTS: using our sIL-6R ELISA we found baseline levels for sIL-6R in serum of 76.6 +/- 19.3 ng/ml in serum and 3.7 +/- 1.3 ng/ml in urine. In non-pathological conditions sIL-6R concentrations in CSF are 1.6 +/- 0.4 ng/ml, and in SF 11.6 +/- 3.3 ng/ml, while IL-6 concentrations are below detectable ranges in these fluids. CONCLUSIONS: sIL-6R levels are detectable in serum, urine, CSF and SF during non-pathological conditions. sIL-6R levels in serum outrange levels in CSF, urine and SF and large interindividual differences in baseline concentrations for sIL-6R exist.
Biological Assay↗
Differential expression of proinflammatory cytokines and their inhibitors during the course of meningococcal infections.
Circulating concentrations of tumor necrosis factor-alpha (TNF), interleukin (IL)-1 beta, IL-6, IL-1 receptor antagonist (IL-1ra), and soluble TNF receptors p55 (sTNFr-55) and p75 (sTNFr-75) and ex vivo production of TNF, IL-1, IL-6, and IL-1ra using a whole blood culture system were measured during the acute and convalescent stages of meningococcal infection. Circulating TNF and IL-1 were below detection level, whereas IL-6 and IL-1ra, sTNFr-55, and sTNFr-75 were increased at admission. The ex vivo production of proinflammatory cytokines TNF, IL-1, and IL-6 was suppressed at admission and restored gradually during recovery. On the contrary, the production of the antiinflammatory IL-1ra was increased at admission. The elevated concentrations of both IL-1ra and sTNFr early in the course of infection suggest a regulatory role for these antiinflammatory compounds. The observed down-regulation of the ex vivo production of TNF, IL-1, and IL-6 and up-regulation of the production of IL-1ra in the acute stage may indicate a protective regulation mechanism.
Acute Disease↗
Interference of circulating azathioprine but not methotrexate or sulfasalazine with measurements of interleukin-6 bioactivity.
Bioassays are currently used to measure the presence of functionally active cytokines in biological fluids. These assays may be influenced by the presence of other substances, either cytokine specific or not, in such fluids. In the present study, we analyzed whether some currently used disease-modifying antirheumatic drugs (DMARDs) could interfere with the measurements of circulating interleukin-6 (IL-6) bioactivity in the B9 hybridoma assay. When sera from healthy controls and patients treated with various DMARDs, such as azathioprine (AZA), methotrexate (MTX), intramuscular gold, and sulfasalazine (SASP), were tested in the IL-6 bioassay, an inhibitory effect was observed only with sera from patients treated with AZA. Addition of exogenous AZA, 6-mercaptopurine (6-MP), and MTX to the IL-6 bioassay resulted in a dose-dependent inhibition of the B9 cell proliferation induced by IL-6, AZA being most potent on a molar basis. Concentrations of AZA and 6-MP compatible with serum concentrations achieved in RA patients were able to inhibit the bioassay, but this was not the case for MTX. Exogenous SASP and its metabolites did not modify the IL-6-induced B9 cell proliferation. This study shows that circulating AZA (or its metabolites) exert an inhibitory effect in the IL-6 bioassay. This method is therefore not suitable to measure IL-6 concentrations in patients treated with AZA. Interference of drugs must be ruled out when bioassays are used to evaluate cytokine levels in biological fluids.
Arthritis, Rheumatoid↗
Circulating soluble tumor necrosis factor receptors, interleukin-2 receptors, tumor necrosis factor alpha, and interleukin-6 levels in rheumatoid arthritis. Longitudinal evaluation during methotrexate and azathioprine therapy.
OBJECTIVE: To assess whether circulating concentrations of soluble tumor necrosis factor receptors (sTNFR; p55 and p75), soluble interleukin-2 receptors (sIL-2R), tumor necrosis factor alpha (TNF alpha), and interleukin-6 (IL-6) reflect clinical response and whether changes are dependent on the drug used in rheumatoid arthritis (RA) patients taking methotrexate (MTX) or azathioprine (AZA). METHODS: These cytokines and soluble receptors were assessed in 20 control subjects and serially for up to 48 weeks in 61 RA patients, by bioassay (IL-6) and immunoassays (sTNFR, sIL-2R, TNF alpha, and IL-6). RESULTS: Concentrations of p55 and p75, sIL-2R, and TNF alpha (but not IL-6) were significantly higher in RA patients than in controls. Significant decreases in sIL-2R and p55 concentrations were associated with clinical improvement and were observed in patients treated with MTX, but not AZA. Both treatments induced decreases in IL-6 concentrations, but circulating AZA (or its metabolites) appears to interfere with the measurement of IL-6 bioactivity. TNF alpha and p75 levels did not show significant changes. CONCLUSION: Measurement of circulating sIL-2R, p55, and IL-6 may be useful in the evaluation of RA disease activity and response to therapy. Interference by circulating levels of drugs must be ruled out when bioassays are used to evaluate cytokine levels.
Arthritis, Rheumatoid↗
Failure of clindamycin to influence the course of severe oromucositis associated with streptococcal bacteraemia in allogeneic bone marrow transplant recipients.
33 consecutive allogeneic bone marrow transplant recipients who were likely to develop streptococcal bacteraemia were treated for 5 days with clindamycin (900 mg i.v. t.d.s) and ceftazidime (2 g t.d.s.) for the initial management of fever associated with severe oral mucositis. Bacteraemia due to 'viridans' streptococci was encountered in 23 cases (70%) as mucositis progressed to peak severity and occurred a day before fever in 8 cases. At the end of treatment with clindamycin only 2 patients had defervesced although the streptococci were successfully eradicated. C-reactive protein (CRP) levels continued to rise in 18 cases and declined by more than 10% in only 7 cases. Severe oromucositis rather than infection appeared to induce an acute phase response with fever suggesting bacteraemia due to 'viridans' streptococci to have been a consequence of mucosal damage. Indeed, oromucositis was the only primary focus of inflammation in 22 patients and only after its resolution did both fever and CRP levels diminish. By then, patients had also begun to recover from granulocytopenia. These data indicate that rather than including a specific antimicrobial like clindamycin in an empirical regimen, it would be more beneficial to evolve strategies that minimise mucosal damage in this patient population.
Adolescent↗
Cytokine patterns in patients after major vascular surgery, hemorrhagic shock, and severe blunt trauma. Relation with subsequent adult respiratory distress syndrome and multiple organ failure.
OBJECTIVE: This study investigates the course of serum cytokine levels in patients with multiple trauma, patients with a ruptured abdominal aortic aneurysm (AAA), and patients undergoing elective AAA repair and the relationship of these cytokines to the development of adult respiratory distress syndrome (ARDS) and multiple organ failure (MOF). SUMMARY BACKGROUND DATA: Severe tissue trauma, hemorrhagic shock, and ischemia-reperfusion injury are pathophysiologic mechanisms that may result in an excessive uncontrolled activation of inflammatory cells and mediators. This inflammatory response is thought to play a key role in the development of (remote) cell and organ dysfunction, which is the basis of ARDS and MOF. METHODS: The study concerns 28 patients with multiple trauma, 20 patients admitted in shock because of a ruptured AAA, and 18 patients undergoing elective AAA repair. Arterial blood was serially sampled from admission (or at the start of elective operation) to day 13 in the intensive care unit, and the serum concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 beta, and IL-6 were determined. RESULTS: Twenty-two patients died, 15 within 48 hours and 7 after several weeks, as a result of ARDS/MOF. At hospital admission and after 6 hours, these nonsurvivors had significantly higher plasma TNF-alpha and IL-1 beta levels than did the survivors. At the same measuring points, TNF-alpha and IL-1 beta were significantly more elevated in patients with ruptured AAA than in traumatized patients. However, IL-6 was significantly higher in the traumatized patients. In 10 patients, ARDS/MOF developed, and 41 had an uncomplicated course in this respect. Those with ARDS/MOF exhibited significantly different cytokine patterns in the early postinjury phase. TNF-alpha and IL-1 beta levels were higher mainly on the first day of admission; IL-6 concentrations were significantly elevated in patients with ARDS/MOF from the second day onward. The latter cytokine showed a good correlation with the daily MOF score during the whole 2-week observation period. CONCLUSIONS: In the early postinjury phase, higher concentrations of these cytokines are associated, not only with an increased mortality rate, but also with an increased risk for subsequent ARDS and MOF. These data therefore support the concept that these syndromes are caused by an overwhelming autodestructive inflammatory response.
Aged↗
Kupffer cell elimination enhances development of liver schizonts of Plasmodium berghei in rats.
We investigated the development of exoerythrocytic forms (EEF) of Plasmodium berghei in livers of normal and macrophage-depleted Brown Norway rats. Macrophages were depleted by use of liposome-encapsulated dichloromethylene diphosphonate. Upon inoculation of sporozoites, macrophage-depleted rats had significantly larger numbers of EEF than untreated rats. We also investigated the effect of macrophage impairment by silica treatment on the development of EEF and confirmed that silica induces a significant reduction of EEF development. Intravenous administration of silica induced high levels of interleukin-6 in plasma within a few hours. The seemingly contradictory results for EEF development may be explained by our previous observation that interleukin-6 strongly inhibits sporozoite penetration and EEF development in vivo. We conclude that in experimental infections with sporozoites, Kupffer cells inhibit rather than enhance EEF development.
Animals↗
High-dose meropenem in meningitis due to Pseudomonas aeruginosa.
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Adult↗
Cytokines inhibit the development of liver schizonts of the malaria parasite Plasmodium berghei in vivo.
The effect of induction of an acute-phase response and its mediators on the development of liver schizonts of the rodent malaria parasite Plasmodium berghei was investigated in Brown Norway rats. Subcutaneous injection of turpentine oil 24 h or 5 min before inoculation of sporozoites resulted in 80% and 35% reduction of schizont development, respectively. Turpentine oil induced high plasma levels of interleukin-6 (IL-6). Intraperitoneal administration of IL-1, IL-6 or both, significantly reduced liver schizont development. This reduction was also present if IL-6 had been administered 24 h after sporozoite inoculation. Inhibition induced by IL-1 could be prevented by simultaneous administration of polyclonal anti-IL-6. Administration of polyclonal anti-IL-6 without IL-1 resulted in a 40% increase of liver schizonts compared to control animals. We conclude that induction of an acute-phase response during experimental Plasmodium berghei infections in Brown Norway rats, strongly inhibits liver schizont development and that IL-6 is a key mediator in this process.
Acute-Phase Reaction↗
Plasma and whole blood exchange in meningococcal sepsis.
The present study describes the effect of plasma exchange or whole blood exchange (PEBE) on the survival rate among patients with fulminant meningococcal sepsis and on the level of circulating endotoxin. Since 1989 all patients with meningococcal disease and hypotension who were admitted to our intensive care unit were treated with PEBE. Results for our patients were compared with those for a historical control group conventionally treated between 1984 and 1989 (n = 10; mortality rate, 60%); the expected mortality rate, which was based on the Niklasson prognostic score and was calculated for seven patients in this control group, was 73%. A total of 15 patients were treated with PEBE, three (20%) of whom died, whereas the prognostic score (calculated for 14 patients) for this group was 62%. In two of the fatal cases, PEBE was started after a delay of greater than or equal to 40 hours. In the remaining 13 patients, PEBE was started within 5-30 hours after the first hospital admission. The mortality rate among this group was 8% (one of 13 patients); this rate was significantly different from that among the control group (P = .025). For seven patients treated with PEBE, plasma endotoxin concentrations were sequentially measured. The overall half-life (+/- SEM) of endotoxin was 181 +/- 18 minutes. This is approximately the same as reported values for patients who were not treated with PEBE. It is concluded that early initiation of PEBE may improve the rate of survival among patients with meningococcal infection and hypotension but that the mechanism of the beneficial effect is most likely not based on the elimination of endotoxin.
Adolescent↗
Kingella kingae intervertebral diskitis in an adult.
Kingella kingae rarely causes infection and is mainly associated with endocarditis and septic arthritis in adults. The organism is also capable of causing intervertebral diskitis in children, but thus far, no reports of this infection occurring in adults have been published. A case of diskitis due to K. kingae in an adult is reported for the first time, and the literature on this infection in children is reviewed.
Adult↗
Ceftazidime monotherapy for pulmonary melioidosis in a traveler returning from Thailand.
A patient with deteriorating pulmonary melioidosis rapidly recovered after treatment with ceftazidime. To prevent possible relapses, an oral maintenance regimen of amoxicillin and clavulanic acid was prescribed for a period of three months. Melioidosis is caused by Pseudomonas pseudomallei. It is an insidious disease because of its variable clinical presentation, possible long-term asymptomatic carriage, broad-spectrum resistance to first-line antibiotics, and high mortality rate. As in our patient, the diagnosis should be particularly considered when there is reduced immunologic resistance and previous exposure in endemic areas, such as Southeast Asia.
Ceftazidime↗
Serum interleukin-6 and C reactive protein responses in patients after laparoscopic or conventional cholecystectomy.
OBJECTIVE: To investigate the acute phase inflammatory response to surgical trauma after laparoscopic and conventional cholecystectomy. DESIGN: Prospective open study. SETTING: University Hospital in The Netherlands. SUBJECTS: 21 patients with symptomatic cholelithiasis admitted for elective cholecystectomy who had had no previous upper abdominal operations. INTERVENTIONS: 12 patients underwent conventional, and 9 patients laparoscopic, cholecystectomy. Circulating interleukin-6 (IL-6) and C reactive protein concentrations were measured 6, 12, 24 and 48 hours after operation. MAIN OUTCOME MEASURE: Changes in IL-6 and C reactive protein concentrations, and comparison of operative blood loss and length of stay in hospital. RESULTS: Those treated by laparoscopic cholecystectomy lost significantly less blood (median 60 compared to 100 ml) and spent significantly fewer days in hospital (median 2 compared with 7 days), (p < 0.01 in each case). The only changes in circulating IL-6 concentrations were seen in patients over the age of 60 years who underwent conventional cholecystectomy. There were significant differences in C reactive protein concentrations between the two operations at both 24 and 48 hours after the operation (p < 0.01 in each case). CONCLUSION: We conclude that laparoscopic cholecystectomy reduces the acute phase inflammatory response compared with the conventional operation; there seems to be no relevant correlation between plasma concentrations of IL-6 and C reactive protein; the presence of IL-6 does not affect the response of C reactive protein to trauma; and the response of IL-6 to trauma is age dependent.
Adult↗
Phase I clinical trial of a recombinant malaria vaccine consisting of the circumsporozoite repeat region of Plasmodium falciparum coupled to hepatitis B surface antigen.
R16HBsAg is an experimental recombinant malaria vaccine consisting of 16 repeats of a four amino acid sequence (Asn-Ala-Asn-Pro or NANP) of the circumsporozoite (CS) protein of Plasmodium falciparum expressed as a fusion protein with the recombinant hepatitis B virus surface antigen (HBsAg) produced by yeast cells. Twenty male volunteers were experimentally vaccinated with the product, as well as with two doses of the commercial recombinant HBsAg vaccine Engerix B (Smith Kline Beecham Biologicals, Rixensart, Belgium) at intervals during a period of 18 months. No serious side effects were observed. Circulating antibodies to recombinant CS antigen (R32tet32) developed in all volunteers and persisted in most cases over ten months. Anti-HBs antibody production was poor initially, but a single dose of the commercial hepatitis B vaccine was sufficient to elevate these titers to high levels in all but two volunteers.
Adult↗
Low dosages of interleukin 1 protect mice against lethal cerebral malaria.
In cerebral malaria, pathological changes can be found in the brain of infected people and in the brain of Plasmodium berghei-infected mice. The pathogenesis of cerebral malaria in mice is believed to be due to an immunopathological reaction giving rise to an excessive production of cytokines such as interferon gamma (IFN-gamma) and tumor necrosis factor (TNF). We find that low doses of interleukin 1 (IL-1) protect mice against cerebral malaria; IL-1 also inhibits parasitemia. The IL-1 effect on parasitemia was not observed in nude mice and was at least partly reversed in mice treated with IL-1 in combination with antibody to IFN-gamma, indicating the involvement of T cells. Mice protected against development of cerebral malaria by IL-1 treatment developed the syndrome when TNF was given as observed in control infected mice or infected mice treated with inactivated IL-1.
Animals↗
Identification of a peptide sequence of the 25 kD surface protein of Plasmodium falciparum recognized by transmission-blocking monoclonal antibodies: implications for synthetic vaccine development.
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Amino Acid Sequence↗
Anti-CD3 antibodies induce T helper function for human B cell differentiation in vitro by an interleukin 2-independent pathway.
Previously we have shown that interleukin 2 (IL 2) is an essential mediator in T cell-dependent B cell differentiation induced by pokeweed mitogen. Here we show that activation with monoclonal anti-CD3 antibodies of peripheral blood T cells led to the induction of helper activity for IgM secretion by human B cells from a prolymphatic leukemia. With the use of monoclonal antibodies against the IL 2 receptor and CD3+CD4+CD8- chronic lymphatic leukemia T cells with a strongly reduced capacity to produce IL 2, it was demonstrated that the anti-CD3-driven Ig secretion was obtained by an IL 2-independent pathway. The T cell help in this system is mediated by soluble factors.
Antibodies, Monoclonal↗