Infective endocarditis in the Netherlands: current epidemiological profile and mortality : An analysis based on partial ESC EORP collected data.

INTRODUCTION: Infective endocarditis (IE) is associated with a high in-hospital and long term mortality. Although progress has been made in diagnostic approach and management of IE, morbidity and mortality of IE remain high. In the latest European guidelines, the importance of the multi-modality imaging in diagnosis and follow up of IE is emphasized. AIM: The aim was to provide information regarding mortality and adverse events of IE, to determine IE characteristics and to assess current use of imaging in the diagnostic workup of IE. METHODS: This is a prospective observational cohort study. We used data from the EURO-ENDO registry. Seven hospitals in the Netherlands have participated and included patients with IE between April 2016 and April 2018. RESULTS: A total of 139 IE patients were included. Prosthetic valve endocarditis constituted 32.4% of the cases, cardiac device related IE 7.2% and aortic root prosthesis IE 3.6%. In-hospital mortality was 14.4% (20 patients) and one-year mortality was 21.6% (30 patients). The incidence of embolic events under treatment was 16.5%, while congestive heart failure or cardiogenic shock occurred in 15.1% of the patients. Transthoracic and transoesophageal echocardiography were performed most frequently (97.8%; 81.3%) and within 3 days after IE suspicion, followed by 18F­fluorodeoxyglucose positron emission tomography/computed tomography (45.3%) within 6 days and multi-slice computed tomography (42.4%) within 7 days. CONCLUSION: We observed a high percentage of prosthetic valve endocarditis, rapid and extensive use of imaging and a relatively low in-hospital and one-year mortality of IE in the Netherlands. Limitations include possible selection bias.

The (re)generation of splenic tissue.

A 48-year-old man with a history of a traumatic splenic rupture followed by splenectomy at the age of 5 years was referred to the outpatient clinic with markedly elevated liver enzymes. He was diagnosed with alcoholic liver cirrhosis. Ultrasound of the upper abdomen revealed hepatomegaly and suggested a central mass in the liver. Subsequent MRI of the abdomen did not show a hepatic mass, but revealed multiple intraperitoneal and retroperitoneal ovoid structures with a maximum diameter of 3 cm. A peripheral blood smear did not reveal Howell-Jolly bodies suggesting intact splenic function. The diagnosis splenosis-that is, autotransplantation of splenic tissue after iatrogenic/traumatic rupture of the spleen-was considered and confirmed by SPECT-CT with technetium-99m ((99m)Tc) labelled heat-denatured autologous red blood cells.

A retrospective, cohort-based survey of patients using twice-daily indinavir + ritonavir combinations: pharmacokinetics, safety, and efficacy.

OBJECTIVE: To describe the pharmacokinetics, safety, and efficacy of twice-daily indinavir + ritonavir regimens DESIGN: A cohort-based survey of HIV-infected patients who either used indinavir 800 mg + ritonavir 100 mg twice daily or indinavir 400 mg + ritonavir 400 mg twice daily. METHODS: Data were extracted from a database of samples sent to our laboratory for measurement of indinavir + ritonavir plasma concentrations. Patient characteristics, safety, and efficacy measurements were collected by retrospective chart review. RESULTS: 100 Patients using 800-mg indinavir + 100-mg ritonavir twice daily and 32 patients using 400-mg indinavir + 400-mg ritonavir twice daily were eligible. Median peak and trough concentrations of indinavir were 6.8 and 0.77 mg/L in the 800/100 group and 2.6 and 0.45 mg/L in the 400/400 group. The most frequently found side effects were nausea and vomiting, which occurred in 22.1% and 34.9% of the patients in the 800/100 and the 400/400 groups, respectively. Viral load data were analyzed for patients who switched from 800-mg indinavir three times daily to one of the indinavir + ritonavir twice daily regimens. At the time of switch 63% (800/100 group) and 60% (400/400 group) had an undetectable viral load and this increased to 77% and 70%, respectively, during follow-up. Patients who switched to the 400/400 group discontinued treatment more frequently than patients who switched to the 800/100 group (70% vs. 26%, p =.008). CONCLUSIONS: Indinavir + ritonavir regimens show improved pharmacokinetic properties, allowing twice-daily dosing with food. Clinical data suggest that safety and efficacy is at least as good as with indinavir three-times-daily regimens without ritonavir. Prospective, comparative trials are needed to properly assess the role in HIV therapy of these twice-daily indinavir + ritonavir regimens.

Interleukin 1 beta, tumour necrosis factor-alpha and interleukin 1 receptor antagonist in newly diagnosed insulin-dependent diabetes mellitus: comparison to long-standing diabetes and healthy individuals.

Interleukin 1 beta (IL-1) and tumour necrosis factor alpha (TNF) are important for the beta cell lysis in insulin-dependent diabetes mellitus (IDDM), while IL-1 receptor antagonist (IL-1ra) is considered protective by blocking the effects of IL-1. Serum concentrations and ex-vivo production of IL-1, TNF and IL-1ra were examined in 10 newly diagnosed IDDM (ND-IDDM) patients, and compared with 11 long-standing IDDM (LS-IDDM) patients and 14 healthy volunteers. Ex-vivo LPS-stimulated production of IL-1 in ND-IDDM patients was significantly increased compared with LS-IDDM patients and healthy controls, while TNF and IL-1ra synthesis did not differ significantly. IL-1ra/IL-1 ratio was significantly decreased in ND-IDDM, and returned to normal values in the LS-IDDM group. Circulating concentrations of IL-1ra in LS-IDDM patients were increased. These data suggest a proinflammatory imbalance in ND-IDDM patients and this may play an important role in beta cell loss.

The role of hyperuricemia in the increased cytokine production after lipopolysaccharide challenge in neutropenic mice.

Patients with severe granulocytopenia are more susceptible to severe infections and sepsis. Proinflammatory cytokines such as tumor necrosis factor-alpha (TNF), interleukin-1 alpha (IL-1 alpha), and IL-1 beta play an important role in the pathophysiology of sepsis. The profile of these proinflammatory cytokines after lipopolysaccharide (LPS) challenge in cyclophosphamide-induced neutropenic mice was assessed, and possible mechanisms responsible for the modified cytokine production were studied. After LPS, both circulating concentrations of TNF and IL-1 alpha in neutropenic mice were 50% to 200% higher than those of controls, whereas IL-1 beta concentrations were not modified. The kinetics of cytokine production were similar in neutropenic and control animals. The susceptibility of neutropenic mice to an LPS challenge was increased. The observed overproduction of TNF and IL-1 alpha was not due to a direct effect of cyclophosphamide treatment. Because circulating concentrations of uric acid were increased in the neutropenic mice, the effect of hypouricemic treatment with allopurinol and sodium bicarbonate was investigated; such treatment in neutropenic mice challenged with LPS was followed by an improved survival and a reduced proinflammatory cytokine production towards the concentrations in control mice. Hyperuricemia induced by repeated administrations of uric acid in normal mice led to an increased TNF production after LPS. In conclusion, neutropenic mice respond with enhanced cytokine production and increased susceptibility to an LPS challenge, and hyperuricemia probably plays an important role in this phenomenon.

Pro- and anti-inflammatory cytokines in healthy volunteers fed various doses of fish oil for 1 year.

Dietary supplementation with n-3 fatty acids from fish oil alleviates inflammation in various chronic inflammatory disease states. Reductions in the production of pro-inflammatory cytokines interleukin 1 beta (IL-1 beta), tumour necrosis factor alpha (TNF-alpha), and interleukin 6 (IL-6) have been seen in humans after short-term n-3 fatty acid supplementation. We investigated long-term effects of dietary n-3 fatty acids on circulating cytokine concentrations and on ex vivo stimulated whole-blood production of IL-1 beta, TNF-alpha and interleukin 1 receptor antagonist (IL-1Ra), the naturally occurring antagonist of IL-1. A total of 58 monks with a mean age of 56 years were randomized into four groups and their diets were supplemented with 0, 3, 6, or 9 g of fish oil, providing 0, 1.06, 2.13 or 3.19 g of n-3 fatty acids per day. Subjects received equal amounts of saturated fatty acids, vitamin E and cholesterol. Compliance was excellent and erythrocyte fatty acid profiles closely reflected the amounts of n-3 fatty acids ingested. In the group receiving 9 g of fish oil per day, no influence of n-3 fatty acids on circulating cytokine concentrations was observed relative to placebo. Endotoxin-stimulated whole-blood cytokine production was measured at 26 and 52 weeks after the start and at 4, 8 and 26 weeks after cessation of supplementation. In all groups, the production of IL-1 beta and IL-1Ra was higher during supplementation than afterwards. However, no differences in cytokine production were noted between the placebo group and the various treatment groups at any point in time. Our results suggest that long-term supplementation of fish oil does not affect ex vivo cytokine production in man.

Implementation of an educational program and an antibiotic order form to optimize quality of antimicrobial drug use in a department of internal medicine.

In a study designed to evaluate the effects of an educational program and an antibiotic order form on the quality of antimicrobial drug use, a prospective analysis was conducted in the department of internal medicine of a 948-bed university hospital. Following a quality-of-use review of all consecutive courses of antimicrobial drugs prescribed during four weeks, an educational program was conducted and an antibiotic order form introduced. After four years, an identical review was performed. In the first review, 109 (31%) of 347 patients were prescribed antimicrobial drugs. Only 40% of the prescriptions were considered definitely appropriate, and 13% were considered unjustified. There was a certain degree of underutilization, and only 67% of clinical isolates were susceptible to empirical therapy. In the review performed after intervention, 164 (21%) of 796 patients were given antimicrobial drugs. Defined daily doses per 100 bed days increased from 59.8 to 72.6. Fifty-three percent of the prescriptions were judged optimal, and only 9% were judged unjustified. Ninety percent of the clinical isolates were susceptible to empirical therapy. After one year, compliance with the antibiotic order forms on a voluntary basis reached 77%, documenting 86% of antimicrobial drug costs. As a result, the antibiotic order form will be useful for surveillance, if logistic support is provided by the pharmacy. The combination of several measures leads to improved quality of use. As correctly predicted by the first evaluation, improvement in quality resulted in increased drug consumption by fewer patients and a higher cost per bed day.

Dietary n-3 fatty acids increase spleen size and postendotoxin circulating TNF in mice; role of macrophages, macrophage precursors, and colony-stimulating factor-1.

In experimental studies in mice, dietary supplementation with n-3 fatty acids (FA) alleviates inflammation and increases resistance to infection. Nevertheless, TNF production capacity was found to be increased in n-3 FA-fed mice. We previously found increased relative spleen weights in n-3 FA-fed mice. In this study, the nature of this increased spleen size was further investigated. Spleen cellularity was increased significantly in mice fed n-3 FA (fish oil 15% w/w), compared with controls fed corn oil (15%) or normal lab chow (p < 0.05). Experiments with T cell-deficient nude mice and experiments using macrophage depletion through liposomal dichloromethylene-biphosphonate revealed that the increase in spleen cellularity is T cell independent and largely due to macrophage accumulation in the spleen. Accumulation of marginal zone and red pulp macrophages was histologically and immunohistochemically confirmed. n-3 FA induced peripheral blood monocytosis and an aspecific increase in bone marrow cellularity. Postendotoxin circulating TNF concentrations were increased significantly in n-3 FA-fed mice compared with controls. Splenectomy did not abolish this increase in circulating TNF. However, after macrophage depletion through liposomal dichloromethylene-biphosphonate, circulating TNF was not detectable after endotoxin challenge. Circulating concentrations of CSF-1 did not differ between the various experimental groups. It is suggested that the cellular changes observed relate to increased constitutive production of TNF.

Feasibility of an antibiotic order form. First experience in the department of internal medicine of a university hospital.

Inadequate control of antimicrobial drug use may lead to excessive expenditure for antimicrobial drugs and improper prescribing it may also result in the emergence of multiresistant bacteria. An antibiotic order form may improve the quality of prescriptions by increasing the awareness of the physician of the antimicrobial spectrum needed (i.e. which microorganism is expected in a given patient), the desired duration of treatment, the potential need to adjust dosage, and the potential allergy of the patient to the drug. Furthermore, such an antibiotic order form facilitates prospective evaluation of both the quantity and the quality of prescribing practice. However, the introduction of yet another form to fill in may be met with opposition from prescribers. We have developed an easy-to-use antibiotic order form that incorporated the conventional medication order that was already in use in our hospital. Compliance (percentage of antimicrobial drug prescriptions for which an order form was used) was on average 58% in the first two weeks after introduction, and remained thereafter between 60% and 90%, varying between the different wards. Data retrieved from the antibiotic order forms could be used for surveillance We conclude that this antibiotic order form was feasible in a large department of internal medicine of a university hospital. Future usefulness will depend on compliance and on personnel support for data processing and intervention.

Modulation of inflammation and cytokine production by dietary (n-3) fatty acids.

The production of pro-inflammatory cytokines, such as interleukin-1 and tumor necrosis factor, is pivotal in the response to infection. However, overproduction of these cytokines might be detrimental. It has been suggested that (n-3) fatty acids suppress inflammation and ameliorate the course of infection by decreasing the production of pro-inflammatory cytokines. We here, review these effects. Use of (n-3) fatty acids induced moderate clinical improvements in rheumatoid arthritis, psoriasis and colitis, but not in systemic lupus erythematosus. Data on critically ill burn or postoperative cancer patients are still inconclusive. The (n-3) fatty acids markedly inhibited sterile inflammation in animal studies and improved survival in some experimental infections. T cell responses decreased in healthy volunteers but remained unchanged or increased in certain patient groups. The production of pro-inflammatory cytokines decreased in most human studies. The (n-3) fatty acids increased cytokine production capacity in mice. Differences in cytokine-producing cell types studied may account for these paradoxical responses in humans and mice. Although the increased cytokine production in mice is partly mediated by effects on prostaglandins, mechanisms of action in other species remain to be elucidated. The (n-3) fatty acids may be of moderate benefit in some chronic inflammatory diseases. Their therapeutic value and possible hazards in critically ill patients remain to be established.

Inhibition of Plasmodium berghei liver schizont development and reduction of cytokine production capacity in rats by dietary fish oil supplementation.

Experimental primary infection with Plasmodium berghei in rats is known to be influenced by several cytokines. Dietary supplementation of n-3 fatty acids has been shown to influence cytokine production capacity and to protect mice from cerebral malaria. We investigated the effect of dietary fish oil (FO) supplementation on cytokine and nitric oxide production and liver schizont development in male brown Norway rats. Control groups were fed either a corn oil-supplemented diet (CO) or standard lab chow (LC). After six weeks on either diet, rats given supplementary FO had a significantly lower production of interleukin-1 (IL-1) and IL-6 after stimulation with lipopolysaccharide, and also had significantly lower numbers of liver schizonts compared with CO- or LC-fed animals. We conclude that in rats, an FO-supplemented diet reduces the production capacity of IL-1 and IL-6 and inhibits schizont development after intravenous inoculation of P. berghei sporozoites. Fish oil did not influence nitric oxide production by peritoneal macrophages.

Pharmacologic inhibitors of tumor necrosis factor production exert differential effects in lethal endotoxemia and in infection with live microorganisms in mice.

Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) are principal mediators of septic shock; inhibition of TNF-alpha production may ameliorate outcome in severe infections. Pentoxifylline, chlorpromazine, and thalidomide inhibit TNF-alpha production. Their effects were tested in lethal endotoxemia in sensitized mice. Only chlorpromazine significantly improved survival. Chlorpromazine and pentoxifylline significantly reduced postendotoxin circulating TNF-alpha, by 89% and 76%, respectively. Chlorpromazine also significantly reduced IL-1 beta and soluble TNF receptor-P75. No drug improved survival in Klebsiella pneumoniae-infected mice despite significantly lower circulating TNF-alpha concentrations in chlorpromazine- or pentoxifylline-treated animals. The three compounds decreased circulating TNF-alpha in Candida albicans-infected mice, but survival was not influenced. In neutropenic mice, chlorpromazine had no influence on candida in organs, but in normal mice, Candida counts in kidneys were higher in chlorpromazine-treated mice. Thus, inhibition of TNF-alpha production was of no benefit in K. pneumoniae infection and worsened outcome in C. albicans infection.

[Postanginal sepsis caused by Fusobacterium necrophorum: Lemierre syndrome]. / Postangineuze sepsis door Fusobacterium necrophorum: het syndroom van Lemierre.

Postanginal sepsis or Lemierre's syndrome is characterised by septic thrombophlebitis of the jugular vein, metastatic abscesses in the lungs, soft tissues, joints or elsewhere, occurring several days to two weeks after tonsillitis or pharyngitis. The primary pathogen is a Gram-negative anaerobic rod, mostly Fusobacterium necrophorum. Previously healthy, young adults are affected mainly and the syndrome was seen more frequently in the pre-antibiotic era than it is nowadays. In the three young patients described here, a girl aged 15 and two boys aged 18 and 16, F. necrophorum was isolated from blood or pus. Histories and examinations were suggestive of Lemierre's syndrome. Ultrasound and CT scanning of the neck and other localisations proved to be important diagnostic tools in assessing the diagnosis. Response to therapy was slow and depended in at least one case on adequate drainage of abscesses. If the syndrome is suspected, initial antibiotic treatment should provide adequate coverage of anaerobic bacteria. In previously healthy patients with chills and fever occurring several days after a sore throat, Lemierre's syndrome should be considered.

[Chorea and primary antiphospholipid syndrome]. / Chorea en het primaire antifosfolipidensyndroom.

Primary antiphospholipid syndrome or PAPS is characterised by antiphospholipid antibodies and arterial and/or venous thromboses. Numerous other clinical features have been shown to be related to this syndrome. Chorea is a well known but rare phenomenon in systemic lupus erythematosus; it has been shown to be strongly related to the presence of antiphospholipid antibodies. We describe two patients with chorea that appeared to be caused by the PAPS.

Dietary fish-oil supplementation in experimental gram-negative infection and in cerebral malaria in mice.

Dietary fish-oil supplementation interferes with eicosanoid production and appears to decrease production of interleukin-1 (IL-1) and tumor necrosis factor (TNF). The effect of fish oil was investigated in an intramuscular Klebsiella pneumoniae infection in Swiss mice and in cerebral malaria induced by Plasmodium berghei in C57B1/6 mice. After a low inoculum of K. pneumoniae, 90% of fish oil-fed mice survived; survival in control mice fed equal amounts of corn or palm oil or normal chow was 30%, 40%, and 0, respectively. Cerebral malaria occurred in only 23% of fish oil-fed mice; in the controls, cerebral malaria developed in 61%, 81%, and 78%, respectively. Contrary to what was expected, lipopolysaccharide-induced ex vivo production of IL-1 alpha and TNF alpha by peritoneal cells was significantly enhanced in fish oil-fed mice compared with controls. Indomethacin treatment did not alter the outcome in these two infections, thus arguing against reduced prostaglandin synthesis as an explanation for the increase in resistance to infection.