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Objective Although most patients recover from acute Q fever, around 20% develop Q fever fatigue syndrome (QFS), a debilitating fatigue syndrome that lasts at least 6 months. This study investigated transcriptional profiles of circulating monocytes and circulating cytokines as a subsequent mirror of myeloid cell function, 1 and 6 months after an acute Q fever infection. Methods Total RNA of circulating monocytes was collected from 11 acute Q fever patients and 15 healthy controls, matched for age (±5 years) and sex. Samples were collected at a median of 27 days (baseline, interquartile range, 15–35 days) after the infection and again 6 months thereafter. Transcriptome analysis was performed using RNA sequencing. Additionally, concentrations of circulating interleukin (IL)-10, IL-1β, IL-1Ra, and IL-6 were measured in serum. Results At baseline, acute Q fever patients clearly show a differential transcriptional program compared with healthy controls. This is still the case at follow-up, albeit to a lesser extent. At baseline, a significant difference in levels of circulating IL-10 (P = .0019), IL-1β (P = .0067), IL-1Ra (P = .0008), and IL-6 (P = .0003) was seen. At follow-up, this difference had decreased for IL-10 (P = .0136) and IL-1Ra (P = .0017) and had become nonsignificant for IL-1β (P = .1139) and IL-6 (P = .2792). Conclusions We show that an acute Q fever infection has a long-term effect on the transcriptional program of circulating monocytes and, therefore, likely their myeloid progenitor cells, as well as concentrations of circulating IL-10, IL-1β, IL-1Ra, and IL-6., This study shows that an acute Q fever infection has a long-lasting effect on the transcriptional program of circulating monocytes and, therefore, likely their myeloid progenitor cells as well as concentrations of circulating interleukin (IL)-10, IL-1β, IL-1Ra, and IL-6.

Item does not contain fulltext Patients with sepsis in the intensive care unit (ICU) are prone to develop Candida infections. Here, we investigated Candida-induced T-helper 17 (Th17) responses during experimental human endotoxemia and in patients with sepsis admitted to the ICU. Peripheral blood mononuclear cells were stimulated with Candida albicans. The Th17 response was significantly lower during endotoxemia, compared with baseline. Patients with gram-negative sepsis had a significantly lower Th17 response as compared to healthy controls. These data demonstrate that the Th17 response is deficient during endotoxin-related systemic inflammation, which likely represents an important risk factor for increased susceptibility to develop Candida infection in patients with sepsis.

Contains fulltext : 87209.pdf (Publisher’s version ) (Closed access) Infections caused by Candida spp. continue to be a substantial cause of disease burden, especially in immunocompromised patients. New approaches are needed to improve the outcome of patients suffering from Candida infections, because it seems unlikely that the established standard treatment will drastically lower the morbidity of mucocutaneous Candida infections and the high mortality associated with invasive candidiasis. New insights into the mechanisms of the anti-Candida host response have contributed to the design of novel immunotherapeutic approaches that have been proposed as adjuvant therapy in Candida infections. This review presents an overview of novel strategies in the prevention and treatment of Candida infections, with a special focus on adjuvant immunotherapy. 01 november 2010

Contains fulltext : 80198.pdf (Publisher’s version ) (Closed access) Differences in host immune genes may predispose to tuberculosis caused by particular Mycobacterium tuberculosis genotypes. We examined this hypothesis in Indonesia by spoligotyping M. tuberculosis isolates recovered from 336 patients with pulmonary tuberculosis and typing the patients' SLC11A1 gene (formerly known as "NRAMP1"), which is involved in susceptibility to tuberculosis. The M. tuberculosis Beijing genotype, which comprised 29.8% of all isolates, was strongly associated with 2 polymorphisms in SLC11A1: the D543N G allele (odds ratio [OR], 2.15; P=.005) and the 3' untranslated region (3'UTR) insertion/insertion genotype (OR, 2.5; P=.001). This finding supports the hypothesis of coevolution of M. tuberculosis and the human immune system.

Contains fulltext : 41703.pdf (Publisher’s version ) (Closed access) OBJECTIVES: To develop effective and targeted interventions to improve care for patients with community-acquired pneumonia (CAP), insight is needed into the factors that influence the quality of antibiotic use. Therefore, we measured the performance of nine quality indicators and studied determinants of variation in the quality of antibiotic use. PATIENTS AND METHODS: Data on 498 prospectively included patients with CAP from eight medium-sized Dutch hospitals were extracted from the medical charts. Outcomes of nine indicators were calculated using previously constructed algorithms. Multilevel logistic regression analysis was performed to explain differences in performance rates at the patient, doctor and hospital level. RESULTS: Performance indicators were generally moderate. Markers of severe illness were found to be positive predictors of timely administration of antibiotics (low oxygen saturation on admission OR 1.11; 95% CI: 1.04--1.19) and obtaining blood samples for culture (low sodium concentration on admission OR 1.10; 95% CI: 1.03--1.16). Recent outpatient antibiotic therapy (OR 0.46; 95% CI: 0.26--0.80) and presence of a hospital antibiotic committee (OR 0.27; 95% CI: 0.08--0.90) were negatively associated with guideline-adherent empirical therapy. The main positive predictor of timely administration of antibiotics (within 4 h) was antibiotic administration in the Emergency Department (ED) (OR 3.9; 95% CI: 1.96--8.73). CONCLUSIONS: We gained new insights into factors that determine quality of antibiotic prescription in hospitals. Treatment in the ED, rather than in the ward, will result in earlier administration of antibiotics. Guidelines should clarify preferred antibiotic management of patients who have received antibiotics prior to admission. Hospital-based structures aimed at quality improvement, such as antibiotic committees, do not necessarily lead to better adherence to national standards. Efforts should be made to encourage these committees to implement national guidelines at a local level.

Post-traumatic stress disorder (PTSD) is sometimes put forward as an explanation for unexplained somatic symptoms in military personnel who have been deployed in war or peace missions. Using a cross-sectional postal survey, we investigated whether PTSD symptoms can account for fatigue in Dutch (ex-)servicemen who returned from the peace operation United Nations Transitional Authority for Cambodia and what features distinguish veterans with and without presumptive PTSD diagnoses. Increased PTSD scores were found in 1.3% of 1,698 veterans. There was no concordance between increased PTSD scores and fatigue, as defined in previous studies. Respondents with presumptive PTSD had more often left service, had more often been exposed to severe and potentially traumatic events, and more often reported a greater impact of the mission. Furthermore, they reported more mental problems that they perceived to be service related and they held a stronger causal attribution to post-traumatic stress. In conclusion, presumptive PTSD cannot offer an explanation for fatigue in Cambodia veterans.

Contains fulltext : 208279.pdf (Publisher’s version ) (Closed access) Toll-like receptors (TLRs) represent the main class of pattern-recognition receptors involved in sensing pathogenic microorganisms. The aim of the present study was to assess the role of TLR4 in the defense against Candida albicans infection. The outgrowth of C. albicans was 10-fold higher in TLR4-defective C3H/HeJ mice, compared with that in control C3H/HeN mice (P

Item does not contain fulltext Despite the importance of interferon (IFN)-gamma, tumor necrosis factor (TNF), and interleukin (IL)-18 for host defense against candidiasis, the pathways leading to their stimulation by Candida albicans are unclear. In a whole-blood model, IL-18 neutralization by IL-18 binding protein decreased C. albicans-induced IFN-gamma synthesis by 72%. Similarly, neutralization of IL-12 or IL-1beta by either neutralizing antibodies or IL-1 receptor antagonist also reduced (by 65%) IFN-gamma production. Neutralization of TNF by TNF binding proteins resulted in only a 36% reduction of IFN-gamma synthesis. In contrast, production of TNF and IL-8 was largely unaffected by these cytokine inhibitors. Thus, C. albicans stimulates IFN-gamma production in an IL-18-, IL-12-, and IL-1beta-dependent manner, whereas production of TNF and IL-8 is independent of these cytokines. Blocking the biologic activities of IL-18, IL-12, and IL-1beta in patients (e.g., for treatment of autoimmune diseases) may result in increased susceptibility to C. albicans infection.

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.

Sir, We thank Tom Kindlon for his letter, in which he raises several important issues. We will respond to all the issues in the same order as they appear in his letter. First, Tom Kindlon points out that cognitive behavioural therapy (CBT) is not a panacea for the chronic fatigue syndrome (CFS). It should be obvious from all previous meta-analyses that CBT does not lead to a full recovery in all CFS patients (while the exact numbers on improvement rates depend on a host of experimental factors like the exact type of therapy given, inclusion criteria of the study, as well as other factors …