The sexual dimorphism of anticardiolipin autoantibodies in acute Q fever patients.

OBJECTIVES: Q fever is a zoonotic disease caused by Coxiella burnetii which affects men more than women (sex ratio men/women: 2.2). Acute Q fever complications are associated with elevation of anticardiolipin (aCL) antibodies. Here, we investigate the sexual dimorphism of aCL antibodies during acute C. burnetii infection. METHODS: IgG aCL antibodies were evaluated at the time of Q fever serological diagnosis with enzyme-linked immunosorbent assay. Results were analysed according to sex. RESULTS: Among the 1323 patients with Q fever tested for aCL, 1013 had acute Q fever (692 men/321 women) and 310 had persistent focalized infection (226 men/84 women). In cases of acute Q fever, men presented a significantly higher proportion of positive aCL antibodies (351/692, 50.7%) than women (113/321, 35.2%) (p <0.05). In addition, men had significantly higher aCL antibodies levels than women (p <0.001). CONCLUSIONS: We highlight a relationship between sex and markers of autoimmunity during Q fever. Further investigations are necessary to better understand the mechanisms of this sexual dimorphism.

Sex and bacterial infectious diseases.

Most infectious diseases are unequally distributed between male and female subjects. This sex dimorphism is confirmed by epidemiologic studies which suggest an increased number of male septic patients, while, due to the class age of septic patients, an overrepresentation of female patients would be expected. Lifestyle, recreational activities, professional exposition and access to care are plausible reasons for this dimorphism. However, biological differences should be carefully considered, particularly the weight of X-linked variability and the role of sex hormones. Animal models clearly show that clinical response to infection is more exuberant in males than in females. This is partly explained by an attenuation of the inflammatory response by female sex hormones. However, the translation from experimental studies to the bedside remains challenging as a result of confounding factors like age, hormone changes and response to treatment.

Higher education at the Institut Hospitalo-Universitaire Méditerranée Infection.

Since its creation in 2011, the Institut Hospitalo-Universitaire Méditerranée Infection (IHU MI) has devoted a major part of its funding to support higher education programs. In 2017, on a recurrent budget of 5.8 million Euros per year, 2.9 (50%) were spent on infrastructure, mostly for maintenance and equipment of our new building. Among the remaining 2.9 million Euros, 2.3 (80%) have been dedicated to support higher education programs.

Aspergillus fumigatus in cystic fibrosis: An update on immune interactions and molecular diagnostics in allergic bronchopulmonary aspergillosis.

A wide spectrum of pathological conditions may result from the interaction of Aspergillus fumigatus and the immune system of its human host. Allergic bronchopulmonary aspergillosis is one of the most severe A. fumigatus-related diseases due to possible evolution toward pleuropulmonary fibrosis and respiratory failure. Allergic bronchopulmonary aspergillosis occurs almost exclusively in cystic fibrosis or asthmatic patients. An estimated 8%-10% of patients with cystic fibrosis experience this condition. The diagnosis of allergic bronchopulmonary aspergillosis relies on criteria first established in 1977. Progress in the understanding of host-pathogen interactions in A. fumigatus and patients with cystic fibrosis and the ongoing validation of novel laboratory tools concur to update and improve the diagnosis of allergic bronchopulmonary aspergillosis.

Involvement of matrix metalloproteinases in chronic Q fever.

OBJECTIVES: Chronic Q fever is a persistent infection with the intracellular Gram-negative bacterium Coxiella burnetii, which can lead to complications of infected aneurysms. Matrix metalloproteinases (MMPs) cleave extracellular matrix and are involved in infections as well as aneurysms. We aimed to study the role of MMPs in the pathogenesis of chronic Q fever. METHODS: We investigated gene expression of MMPs through microarray analysis and MMP production with ELISA in C. burnetii-stimulated peripheral blood mononuclear cells (PBMCs) of patients with chronic Q fever and healthy controls. Twenty single nucleotide polymorphisms (SNPs) of MMP and tissue inhibitor of MMP genes were genotyped in 139 patients with chronic Q fever and 220 controls with similar cardiovascular co-morbidity. Additionally, circulating MMPs levels in patients with chronic Q fever were compared with those in cardiovascular controls with and without a history of past Q fever. RESULTS: In healthy controls, the MMP pathway involving four genes (MMP1, MMP7, MMP10, MMP19) was significantly up-regulated in C. burnetii-stimulated but not in Escherichia coli lipopolysaccharide -stimulated PBMCs. Coxiella burnetii induced MMP-1 and MMP-9 production in PBMCs of healthy individuals (both p<0.001), individuals with past Q fever (p<0.05, p<0.01, respectively) and of patients with chronic Q fever (both p<0.001). SNPs in MMP7 (rs11568810) (p<0.05) and MMP9 (rs17576) (p<0.05) were more common in patients with chronic Q fever. Circulating MMP-7 serum levels were higher in patients with chronic Q fever (median 33.5 ng/mL, interquartile range 22.3-45.7 ng/mL) than controls (20.6 ng/mL, 15.9-33.8 ng/mL). CONCLUSION: Coxiella burnetii-induced MMP production may contribute to the development of chronic Q fever.

Intact interferon-γ response against Coxiella burnetii by peripheral blood mononuclear cells in chronic Q fever.

OBJECTIVES: Q fever is caused by Coxiella burnetii, an intracellular bacterium that infects phagocytes. The aim of the present study was to investigate whether the C. burnetii-induced IFN-γ response is defective in chronic Q fever patients. METHODS: IFN-γ was measured in supernatants of C. burnetii-stimulated peripheral blood mononuclear cells (PBMCs) of 17 chronic Q fever patients and 17 healthy individuals. To assess IFN-γ responses, expression profiles of IFN-γ-induced genes in C. burnetii-stimulated PBMCs were studied in six patients and four healthy individuals. Neopterin was measured in PBMC supernatants (of eight patients and four healthy individuals) and in sera (of 21 patients and 11 healthy individuals). In a genetic association study, polymorphisms in genes involved in the Th1-cytokine response were analysed in a cohort of 139 chronic Q fever patients and a cohort of 220 control individuals with previous exposition to C. burnetii. RESULTS: IFN-γ production by C. burnetii-stimulated PBMCs from chronic Q fever patients was significantly higher than in healthy controls. Many IFN-γ response genes were strongly upregulated in PBMCs of patients. Neopterin levels were significantly higher in PBMC supernatants and sera of patients. The IL12B polymorphisms rs3212227 and rs2853694 were associated with chronic Q fever. CONCLUSIONS: IFN-γ production, as well as the response to IFN-γ, is intact in chronic Q fever patients, and even higher than in healthy individuals. Polymorphisms in the IL-12p40 gene are associated with chronic Q fever. Thus, a deficiency in IFN-γ responses does not explain the failure to clear the infection. The genetic data suggest, however, that the IL-12/IFN-γ pathway does play a role.

Cytomegalovirus reactivation enhances the virulence of Staphylococcus aureus pneumonia in a mouse model.

OBJECTIVES: Cytomegalovirus (CMV) reactivation in intensive care unit patients may increase mortality and favour bacterial pneumonia. We developed a murine model to compare the severity of staphylococcal pneumonia after CMV reactivation and in CMV-negative mice. METHODS: Balb/c mice were primo-infected with murine cytomegalovirus (MCMV n=90) or received saline (control n=90). After latency, all mice underwent caecal ligation and puncture to trigger MCMV reactivation in MCMV primary-infected mice. Surviving animals received an intra-nasal inoculation with methicillin-susceptible Staphylococcus aureus (MSSA) to induce pneumonia. Mortality, lung bacterial count, histology and interferon-alpha and gamma serum levels were compared in MCMV reactivated and control mice 2, 5 and 15 days after pneumonia. RESULTS: After MSSA pneumonia, MCMV mice showed a trend towards a higher mortality (9.4% versus 0%; p 0.09) and a higher weight loss (2.2 (0.6-4.1 g) versus 0.7 (-0.3 to 1.3 g); p 0.005). The lung bacterial count was higher in MCMV mice 2 days (5×103 (103 to 3×105) versus 102 (0 to 4×102) CFU/lung; p 0.007) and 5 days (2.5×104 (1.6×104 to 6.5×105) versus 15 (10-40) CFU/lung; p 0.005) after MSSA pneumonia. 8/40 (20%) MCMV mice developed lung abscesses compared to 0% in control (p 0.011). Interferon-alpha serum levels 2 days after staphylococcal pneumonia were higher in MCMV mice. CONCLUSIONS: MCMV reactivation decreased lung bacterial clearance and favoured the development of staphylococcal abscessing pneumonia. CMV reactivation may be responsible for a higher susceptibility to bacterial sepsis.

Aspergillus fumigatus components distinguish IgE but not IgG4 profiles between fungal sensitization and allergic broncho-pulmonary aspergillosis.

Aspergillus fumigatus is the causative agent of allergic broncho-pulmonary aspergillosis. Prompt and accurate diagnosis may be difficult to achieve with current clinical and laboratory scores, which do not include immune responses to recombinant A. fumigatus allergens. We measured specific immunoglobulin E and G4 directed to recombinant A. fumigatus allergens in 55 cystic fibrosis patients without allergic broncho-pulmonary aspergillosis but sensitized to A. fumigatus and in nine patients with allergic broncho-pulmonary aspergillosis (two with cystic fibrosis and seven with asthma). IgG4 responses to recombinant A. fumigatus allergens were detected in all patients, but neither prevalence nor levels were different between the two patient groups. On the other hand, both prevalence and levels of IgE responses to Asp f 3, Asp f 4, and Asp f 6 helped distinguish allergic broncho-pulmonary aspergillosis from A. fumigatus sensitization with good negative and positive predictive values.

[Use of MRI before biopsy in diagnosis of prostate cancer: Single-operator study]. / Utilité de l'IRM pré-biopsique dans la détection du cancer de prostate: étude mono-opérateur.

UNLABELLED: The diagnostic for prostate cancer is changing. To improve the detection of this cancer, urologists expect a lot from the contribution of magnetic resonance imaging (MRI). What is the role of this imaging in prostate cancer detection? This is a retrospective study, from 2011 to 2013, mono-centric and single-operator. Of the 464 needle biopsy of the prostate (BP), we excluded those with PSA>20 ng/mL or digital rectal examination (DRE)>T3. The remaining 430 BP were submitted or not to a 1.5 tesla MRI with pelvic antenna. The primary aim is the overall detection of prostate cancer. Secondary aim was the detection rate during the first series of BP and repeat BP, between the two groups in the MRI group. MRI and MRI without populations are comparable for age (63.3 vs 64.6), PSA (6.10 vs 6.13), DRE>T1c, prostate volume (55.4 cm(3) vs 51.7 cm(3)). There is no significant difference in overall detection between the two groups (P=0.12). There is no significant difference in cancer detection between the first BP (P=0.13) and the repeat BP (P=0.07). There is a significant difference in the early detection of BP MRI group (P=0.03) but not for the BP repeat MRI group (P=0.07). For 108 BP iterative MRI group, there were 67 BP targeted "mentally" with MRI: 18 cancers were detected, making a 25% detection rate. This study helps to highlight the value of MRI in the early rounds of BP but we can ask the value of this imaging during repeat biopsies. Targeted biopsies "mentally" do not have the expected detection sensitivity and seems to require a three-dimensional reconstruction to be more effective. LEVEL OF EVIDENCE: 5.

The standard tangential fields used for breast irradiation do not allow optimal coverage and dose distribution in axillary levels I-II and the sentinel node area.

BACKGROUND: Recent data from ACOSOG Z0011 and NSABP B32 trials suggested no need for axillary lymph node dissection (ALND) in patients with micrometastatic involvement of the sentinel lymph node (SLN). The low rate of axillary recurrence was attributed to the axilla coverage by the tangential fields (TgFs) irradiation and systemic therapy. This study aimed to evaluate dose distribution and coverage of the axilla levels I-II and the SLN area. PATIENTS AND METHODS: One hundred and nine patients were analyzed according to three groups: group 1 (50 Gy; n = 18), group 2 (60 Gy; n = 34) and group 3 (66 Gy; n = 57). Patients were treated using the standard (STgF; n = 22) or high (HTgF; n = 87) TgF. RESULTS: The median doses delivered to level I using HTgF versus STgF were 33 and 20 Gy (P = 0.0001). The mean dose delivered to the SLN area was only 28 Gy. Additionally, the SLN area was totally included in the HTgF in 1 out of 12 patients who had intraoperative clip placement in the SNL area. CONCLUSIONS: TgFs provide a limited coverage of the axilla and the SNLB area. This information should be considered when only TgFs are planned to target the axilla in patients with a positive SLN without ALND. Standardization of locoregional radiotherapy in this situation is urgently needed.

Reduced interleukin-12 release from stimulated monocytes in patients with sepsis after major cancer surgery.

BACKGROUND: Major cancer surgery is a high-risk situation for sepsis in the post-operative period. The aim of this study was to assess the relation between the monocyte production of IL-12 and the development of post-operative sepsis in patients undergoing major cancer surgery. METHODS: In 19 patients undergoing major cancer surgery, the production of cytokines by basal and lipolysaccharide (LPS)-stimulated monocytes was measured before and after (from day 1 to day 3 and day 7) surgery. Seven of them developed a post-operative sepsis. Ten healthy volunteers were used as controls for the assessment of pre-operative values. RESULTS: Before surgery, the production of interleukin (IL)-12 p40 by LPS-stimulated monocytes was similar in the patients and the healthy volunteers. The production of IL-12 p40 by unstimulated monocytes was higher in the patients than in the healthy volunteers. IL-12 production did not differ between the septic and the non-septic patients. After surgery, the production of IL-12 p40 was dramatically reduced in the LPS-stimulated monocytes of the septic patients from day 1 to day 3, as compared with that of the non-septic patients. Before surgery, the production of IL-6, IL-10, and IL-1 receptor antagonist (IL-1ra) in the patients was significantly higher than that of the healthy volunteers for both stimulated and unstimulated monocytes. After surgery, the production of these cytokines by both stimulated and unstimulated monocytes of the septic patients was similar to that of the non-septic patients. Intragroup analysis showed significant changes for IL-6, IL-10, and IL-1ra under all conditions, with the exception of changes in unstimulated monocytes of septic patients that were not significant for IL-10 release. CONCLUSION: After surgery, the septic patients showed drastic failure to up-regulate monocyte LPS-stimulated production of IL-12 p40.

Tropheryma whipplei, the Whipple's disease bacillus, induces macrophage apoptosis through the extrinsic pathway.

Tropheryma whipplei, the etiological agent of Whipple's disease, is an intracellular bacterium that infects macrophages. We previously showed that infection of macrophages results in M2 polarization associated with induction of apoptosis and interleukin (IL)-16 secretion. In patients with Whipple's disease, circulating levels of apoptotic markers and IL-16 are increased and correlate with the activity of the disease. To gain insight into the understanding of the pathophysiology of this rare disease, we examined the molecular pathways involved in T. whipplei-induced apoptosis of human macrophages. Our data showed that apoptosis induction depended on bacterial viability and inhibition of bacterial protein synthesis reduced the apoptotic program elicited by T. whipplei. Induction of apoptosis was also associated with a massive degradation of both pro- and anti-apoptotic mediators. Caspase-specific inhibition experiments revealed that initiator caspases 8 and 10 were required for apoptosis, in contrast to caspases 2 and 9, in spite of cytochrome-c release from mitochondria. Finally, the effector caspases 3 and 6 were mandatory for apoptosis induction. Collectively, these data suggest that T. whipplei induces apoptosis through the extrinsic pathway and that, beside M2 polarization of macrophages, apoptosis induction contributes to bacterial replication and represents a virulence trait of this intracellular pathogen.

[Prostate radiation therapy: in vivo measurement of the dose delivered by kV-CBCT]. / Radiothérapie des cancers de la prostate : évaluation in vivo de la dose délivrée par tomographie conique de basse énergie (kV).

PURPOSE: To investigate if the regular use of kV-CBCT notably increases the dose delivered to tumor and surrounding healthy tissues. MATERIAL AND METHODS: Images were obtained using a Varian equipment (OBI version 1.3, 645 to 650 projections in 370 degrees to acquire image), and patients were irradiated at source-tumor distance: 100cm. In vivo measurements were performed using radio-thermoluminescent dosimeters Harshaw-TLD700H (TLD) at skin (anterior-posterior and lateral axis crossing the rotation axis), with a fourth TLD group under the table thanks to a retrolaser. TLD's were calibrated at the kV-CBCT effective energy (64 keV), and the method validated using an anthropomorphic phantom, in which Gafchromic EBT films were also inserted. RESULTS: The phantom study showed that the dose distribution depends on the phantom position relative to the axis and that the doses measured at the phantom surface using TLD and films (good agreement) were maximum at the entrance of the anterior-posterior axis. Their arithmetic mean was equal, or a slightly greater than doses measured at mid-thickness of the phantom and at the level of the rectum (OAR). In vivo measurements performed on the five first patients (125 kV-CBCT) yield a mean skin dose per kV-CBCT varying from 5.8+/-0.1 to 7.3+/-0.2 cGy on the anterior-posterior axis. Lateral skin doses vary from 3.4+/-0.2 to 4.5+/-0.2 cGy. CONCLUSION: Doses delivered by repeated kV-CBCT are not negligible. They should be taken into account, but questions about the RBE to be applied to kilovoltage X-rays are raised.

[Description and results of a prospective study on a new physiotherapy method in the management of postprostatectomy urinary incontinence]. / Description et résultat d'une étude prospective portant sur une nouvelle méthode de kinésithérapie dans la prise en charge de l'incontinence urinaire postprostatectomie.

OBJECTIVE: Prospective evaluation of the short-, medium- and long-term efficacy of the "ABDO-MG concept" technique in the rehabilitation of urinary incontinence following radical prostatectomy (abdominal or laparoscopic approach). METHODOLOGY: Fifty-three patients suffering from clinical urinary stress or triple incontinence (pure stress incontinence, incontinence due to bladder instability or sphincteric insufficiency) took part in the study. Rehabilitation treatment, begun six weeks before the operation, continued during the immediate postoperative period, at home and at the physiotherapist's office for three to 12 months until the urinary incontinence had disappeared or was considered to be minimal and acceptable, therefore tolerated. The exercises were performed according to a strict protocol defined by the inventor of the concept, involving expiration into a specific end-piece (called "sound end-piece") and connection with an abdominal neurostimulator for which the current is triggered and maintained by the sound of the patient's breathing into the sound end-piece. The efficacy of this concept was confirmed by a comparative trial before and during rehabilitation and then at the end of treatment. There was triple monitoring: evaluation by LFT noting, for each breath, the flowrate/volume curve and FEV1/s, clinical abdominal testing with monitoring of abdominal movement both vertically and horizontally during coughing and a "pad test" at home, assessing the quantity of nocturnal and diurnal urinary leakage relative to each patient's activity. RESULTS: The results were meaningful and significant. The improvement of the flowrate/volume curve and FEV1/s varied between 1.4436 and 1.1209 L. Abdominal testing showed constant positive evolution in the correction of abdominal incompetence under stress (test improved by one point on a negative graduation of -1 to -3). The home "pad test" confirmed a highly significant result with leakage virtually disappearing, sometimes falling from nearly 800 cc to just a few drops at the end of treatment. The subjective results were marked by the improvement in various dysfunctions within the context of abdominal incompetence increased by the abdominal surgery. CONCLUSION: This prospective study was the first to provide an evaluation of the abdominal motor score and the relationship between expiration thrust and pelviperitoneal protection.

Early postoperative compensatory anti-inflammatory response syndrome is associated with septic complications after major surgical trauma in patients with cancer.

BACKGROUND: Patients who undergo major surgery for cancer are at high risk of postoperative infection. Postoperative immunosuppression may be due to dysregulation of cytokine production. The aim of this study was to investigate the association between changes in serum proinflammatory and anti-inflammatory cytokine concentrations and postoperative septic complications after major surgery. METHODS: Serial blood samples were collected from 30 consecutive patients for determination of serum cytokine levels. Healthy volunteers were used as the control group. RESULTS: Eleven patients developed no complications (group 1), 14 developed sepsis or severe sepsis (group 2), and five developed septic shock (group 3). On day 1 the patients in groups 2 and 3 had significantly higher levels of interleukin (IL) 6 than those in group 1. IL-6 levels remained high until day 5. Tumour necrosis factor (TNF), IL-1, interferon (IFN) gamma and IL-12 levels were not affected by surgical trauma or by the occurrence of septic complications. After operation the circulating IL-1 receptor antagonist (IL-1ra) concentration was increased in all groups, but patients in group 3 had significantly higher levels of IL-1ra than those in group 1. IL-1ra levels correlated with IL-6 levels. The pattern of IL-10 levels was similar to that of IL-1ra levels. CONCLUSION: Serum concentrations of proinflammatory cytokines (TNF, IL-1, IFN-gamma and IL-12) were not affected by operation or the occurrence of septic complications. The postoperative increase in IL-6 concentration was associated with septic morbidity, while raised IL-1ra concentration was associated with postoperative septic shock.