Respiratory chain dysfunction associated with multiple mitochondrial DNA deletions in antiretroviral therapy-related lipodystrophy.

Highly-active antiretroviral therapy (HAART) can induce a characteristic lipodystrophy syndrome characterized by peripheral fat wasting and central adiposity, usually associated with hyperlipidaemia and insulin resistance [1,2]. Indirect data have led some authors to propose that mitochondrial dysfunction could play a role in this syndrome [3,4].To date, as recently outlined by Kakuda et al. [5] in this journal, HIV-infected patients developing lipodystrophy have not been studied for mitochondrial changes or respiratory chain capacity...

Risk perception by healthcare professionals related to drug use during pregnancy: a Swiss survey.

PRINCIPLE: Healthcare professionals' (HCPs') perception of risk associated with drug use in pregnancy may have an impact on the pharmacological treatment of some women. The aim of this study was to examine this risk perception in a sample of Swiss HCPs with a special focus on their knowledge and use of available specialised information sources. METHOD: An online, French and German, questionnaire was e-mailed to 7,136 members of four Swiss professional societies (gynaecologists, paediatricians, midwives and pharmacists). The questionnaire was designed (a) to collect demographic characteristics, (b) to evaluate the frequency of use of several specialised sources of information on drugs in pregnancy in their daily practice, and (c) to examine the perception of risk associated with drug use during pregnancy. RESULTS: A total of 1,310 questionnaires were collected (response rate of 18.4%). More than 80% of the respondent HCPs use the Swiss Drug Reference Book (Compendium) to assess the risk associated with drugs during pregnancy and are not aware of available specialised information sources (books, websites or information centres). Despite some disparities between HPCs, the risk related to drug intake was overall highly misperceived. Blinded reading of three product monographs in the Compendium was associated with an overestimated perception of risk (e.g., after reading the "paracetamol" monograph, 38% of the participants stated they would probably not advise the use of this drug to a pregnant patient). CONCLUSION: Overall, an overestimation of the risk associated with drug use during pregnancy has been observed in our sample of HCPs, which might be related to the underuse of specialised information source among other factors. These findings evidenced the need for increased training for HCPs in order to optimise medication use during pregnancy. Further studies are needed to confirm these results and identify causes.

A novel mucosal orthotopic murine model of human papillomavirus-associated genital cancers.

Cervical cancer results from infection with high-risk type human papillomaviruses (HPV). Therapeutic vaccines aiming at controlling existing genital HPV infections and associated lesions are usually tested in mice with HPV-expressing tumor cells subcutaneously implanted into their flank. However, effective vaccine-induced regression of these ectopic tumors strongly contrasts with the poor clinical results of these vaccines produced in patients with HPV-associated genital neoplasia. To assess HPV therapeutic vaccines in a more relevant setting, we have, here, established an orthotopic mouse model where tumors in the genital mucosa (GM) develop after an intravaginal instillation of HPV16 E6/E7-expressing tumor cells transduced with a luciferase-encoding lentiviral vector for in vivo imaging of tumor growth. Tumor take was 80-90% after nonoxynol-9 induced damage of the epithelium. Tumors remained localized in the genital tract, and histological analysis showed that most tumors grew within the squamous epithelium of the vaginal wall. Those tumors induced (i) E7-specific CD8 T cells restricted to the GM and draining lymph nodes, in agreement with their mucosal location and (ii) high Foxp3+ CD4+ infiltrates, similarly to those found in natural non-regressing HPV lesions. This novel genital HPV-tumor model by requiring GM homing of vaccine-induced immune responses able to overcome local immuno-suppression may be more representative of the situation occurring in patients upon therapeutic vaccination.

MyD88 and TLR9 dependent immune responses mediate resistance to Leishmania guyanensis infections, irrespective of Leishmania RNA virus burden.

Infections with Leishmania parasites of the Leishmania Viannia subgenus give rise to both localized cutaneous (CL), and metastatic leishmaniasis. Metastasizing disease forms including disseminated (DCL) and mutocutaneous (MCL) leishmaniasis result from parasitic dissemination and lesion formation at sites distal to infection and have increased inflammatory responses. The presence of Leishmania RNA virus (LRV) in L. guyanensis parasites contributes to the exacerbation of disease and impacts inflammatory responses via activation of TLR3 by the viral dsRNA. In this study we investigated other innate immune response adaptor protein modulators and demonstrated that both MyD88 and TLR9 played a crucial role in the development of Th1-dependent healing responses against L. guyanensis parasites regardless of their LRV status. The absence of MyD88- or TLR9-dependent signaling pathways resulted in increased Th2 associated cytokines (IL-4 and IL-13), which was correlated with low transcript levels of IL-12p40. The reliance of IL-12 was further confirmed in IL12AB-/- mice, which were completely susceptible to infection. Protection to L. guyanensis infection driven by MyD88- and TLR9-dependent immune responses arises independently to those induced due to high LRV burden within the parasites.

Host genetics of invasive Aspergillus and Candida infections.

Invasive candidiasis and aspergillosis are major complications in surgical and onco-hematological patients, and still associated with an important morbidity and mortality. A large number of studies highlighted the potential role of host genetic polymorphisms that may influence susceptibility to fungal pathogens, but many were limited by insufficient statistical power, problematic design, and/or lack of replication. However, some relevant polymorphisms are now emerging from well-conducted studies whose associations have been replicated and/or are supported by strong biological evidence. Such polymorphisms together with other biomarkers may play a role in the prediction, diagnosis, and management of severe fungal infections in high-risk patients in the coming years.

Polymorphisms in fibronectin binding protein A of Staphylococcus aureus are associated with infection of cardiovascular devices.

Medical implants, like cardiovascular devices, improve the quality of life for countless individuals but may become infected with bacteria like Staphylococcus aureus. Such infections take the form of a biofilm, a structured community of bacterial cells adherent to the surface of a solid substrate. Every biofilm begins with an attractive force or bond between bacterium and substratum. We used atomic force microscopy to probe experimentally forces between a fibronectin-coated surface (i.e., proxy for an implanted cardiac device) and fibronectin-binding receptors on the surface of individual living bacteria from each of 80 clinical isolates of S. aureus. These isolates originated from humans with infected cardiac devices (CDI; n = 26), uninfected cardiac devices (n = 20), and the anterior nares of asymptomatic subjects (n = 34). CDI isolates exhibited a distinct binding-force signature and had specific single amino acid polymorphisms in fibronectin-binding protein A corresponding to E652D, H782Q, and K786N. In silico molecular dynamics simulations demonstrate that residues D652, Q782, and N786 in fibronectin-binding protein A form extra hydrogen bonds with fibronectin, complementing the higher binding force and energy measured by atomic force microscopy for the CDI isolates. This study is significant, because it links pathogenic bacteria biofilms from the length scale of bonds acting across a nanometer-scale space to the clinical presentation of disease at the human dimension.

Absence of BK viremia clearance after low-dose cidofovir therapy in kidney transplant recipients with BK virus associated nephropathy

Background: BK virus associated nephropathy occurs in 1-10% of kidney transplant recipients and may be a cause of graft loss. This infection is difficult to manage because of the absence of specific therapy. Cidofovir, a DNA polymerase inhibitor approved for the treatment of CMV retinitis, has shown in vitro activity against BK virus and some clinical efficacy when used at low-dose in uncontrolled series. Objective: To assess the efficacy of low-dose Cidofovir in the treatment of BK virus associated nephropathy. Method: Two adult kidney transplant recipients with biopsy-proven BK nephropathy and persistent high viremia (>10,000 copies/ml) despite 3-month reduction of immunosuppressive therapy were treated by Cidofovir 0.5 mg/kg fortnightly for a total of 16 weeks (8 doses). Clinical response was assessed by following BK viremia. Results: No decrease in BK viremia was observed at any point during cidofovir therapy (see figure). Creatinine clearance remained stable during therapy and no side-effects of Cidofovir were observed. Conclusions: Low-dose Cidofovir therapy was not associated with a clearance or with a significant decrease of BK viremia. This pilot study does not confirm previous reports suggesting clinical efficacy of Cidofovir for BK virus associated nephropathy.

Methicillin-susceptible Staphylococcus aureus endocarditis isolates are associated with clonal complex 30 genotype and a distinct repertoire of enterotoxins and adhesins.

BACKGROUND: Using multinational collections of methicillin-susceptible Staphylococcus aureus (MSSA) isolates from infective endocarditis (IE) and soft tissue infections (STIs), we sought to (1) validate the finding that S. aureus in clonal complex (CC) 30 is associated with hematogenous complications and (2) test the hypothesis that specific genetic characteristics in S. aureus are associated with infection severity. METHODS: IE and STI isolates from 2 cohorts were frequency matched by geographic origin. Isolates underwent spa typing to infer CC and multiplex polymerase chain reaction for presence of virulence genes. RESULTS: 114 isolate pairs were genotyped. IE isolates were more likely to be CC30 (19.5% vs 6.2%; P = .005) and to contain 3 adhesins (clfB, cna, map/eap; P < .0001 for all) and 5 enterotoxins (tst, sea, sed, see, and sei; P ≤ .005 for all). CC30 isolates were more likely to contain cna, tst, sea, see, seg, and chp (P < .05 for all). CONCLUSIONS: MSSA IE isolates were significantly more likely to be CC30 and to possess a distinct repertoire of virulence genes than MSSA STI isolates from the same region. The genetic basis of this association requires further study.

CD160-Associated CD8 T-Cell Functional Impairment Is Independent of PD-1 Expression.

Expression of co-inhibitory molecules is generally associated with T-cell dysfunction in chronic viral infections such as HIV or HCV. However, their relative contribution in the T-cell impairment remains unclear. In the present study, we have evaluated the impact of the expression of co-inhibitory molecules such as 2B4, PD-1 and CD160 on the functions of CD8 T-cells specific to influenza, EBV and CMV. We show that CD8 T-cell populations expressing CD160, but not PD-1, had reduced proliferation capacity and perforin expression, thus indicating that the functional impairment in CD160+ CD8 T cells may be independent of PD-1 expression. The blockade of CD160/CD160-ligand interaction restored CD8 T-cell proliferation capacity, and the extent of restoration directly correlated with the ex vivo proportion of CD160+ CD8 T cells suggesting that CD160 negatively regulates TCR-mediated signaling. Furthermore, CD160 expression was not up-regulated upon T-cell activation or proliferation as compared to PD-1. Taken together, these results provide evidence that CD160-associated CD8 T-cell functional impairment is independent of PD-1 expression.

Sternal wound infection after heart operations in pediatric patients associated with nasal carriage of Staphylococcus aureus.

A cluster of six pediatric cases of deep-seated Staphylococcus aureus infection after heart operations prompted us to perform molecular typing of the S. aureus isolates by pulsed-field gel electrophoresis. This revealed the presence of genotypically distinct isolates in four of the six patients. Isolates of two patients were genotypically identical. All patients carried S. aureus in the anterior nares. In each patient, the banding pattern of deoxyribonucleic acid in these isolates was indistinguishable from that in strains isolated from blood or wound cultures. Molecular typing with pulsed-field gel electrophoresis ruled out nosocomial transmission of S. aureus between four patients; at the same time, it provided evidence for an association between nasal colonization and postoperative wound infection. Epidemiologic investigation of potential links between two patients with identical isolates did not provide any evidence for nosocomial transmission of S. aureus between these patients. Because nasal colonization with S. aureus may be a risk factor for surgical wound infection in pediatric patients undergoing heart operations, preoperative decolonization appears to be warranted.

Diagnosis of periprosthetic joint infections.

Advances in implant design, surgical technique, peri-operative antimicrobial prophylaxis and laminar airflow operating room environment have made total joint arthroplasty one of the most successful surgical procedures of all times. Orthopaedic implants, however, remain prone to microbial contamination resulting in persistent risk of implant-associated infection. Treatment of infections associated with orthopaedic devices usually requires appropriate surgical intervention combined with a prolonged antimicrobial therapy. The choice of the best possible treatment regimen depends on duration and pathogenesis of infection, stability of the implant, antimicrobial susceptibility of the pathogen and condition of the surrounding soft tissue. In addition towell known diagnostic procedures new promising tools for rapid and correct microbial diagnosis are being developed as correct diagnosis of the responsible micro-organism and this is paramount for successful treatment of prosthetic joint infection.

Abdominal infections in the intensive care unit: characteristics, treatment and determinants of outcome.

BACKGROUND: Abdominal infections are frequent causes of sepsis and septic shock in the intensive care unit (ICU) and are associated with adverse outcomes. We analyzed the characteristics, treatments and outcome of ICU patients with abdominal infections using data extracted from a one-day point prevalence study, the Extended Prevalence of Infection in the ICU (EPIC) II. METHODS: EPIC II included 13,796 adult patients from 1,265 ICUs in 75 countries. Infection was defined using the International Sepsis Forum criteria. Microbiological analyses were performed locally. Participating ICUs provided patient follow-up until hospital discharge or for 60 days. RESULTS: Of the 7,087 infected patients, 1,392 (19.6%) had an abdominal infection on the study day (60% male, mean age 62 ± 16 years, SAPS II score 39 ± 16, SOFA score 7.6 ± 4.6). Microbiological cultures were positive in 931 (67%) patients, most commonly Gram-negative bacteria (48.0%). Antibiotics were administered to 1366 (98.1%) patients. Patients who had been in the ICU for ≤ 2 days prior to the study day had more Escherichia coli, methicillin-sensitive Staphylococcus aureus and anaerobic isolates, and fewer enterococci than patients who had been in the ICU longer. ICU and hospital mortality rates were 29.4% and 36.3%, respectively. ICU mortality was higher in patients with abdominal infections than in those with other infections (29.4% vs. 24.4%, p < 0.001). In multivariable analysis, hematological malignancy, mechanical ventilation, cirrhosis, need for renal replacement therapy and SAPS II score were independently associated with increased mortality. CONCLUSIONS: The characteristics, microbiology and antibiotic treatment of abdominal infections in critically ill patients are diverse. Mortality in patients with isolated abdominal infections was higher than in those who had other infections.

Continuous electroencephalographic monitoring in critically ill patients with central nervous system infections.

OBJECTIVES: To determine the prevalence, predictors, and clinical significance of electrographic seizures (ESz) and other continuous electroencephalographic monitoring findings in critically ill patients with central nervous system infections. DESIGN: Retrospective cohort study. SETTING: Eighteen-bed neurocritical care unit. PATIENTS: We identified 42 consecutive patients with primary central nervous system infection (viral, 27 patients [64%]; bacterial, 8 patients [18%]; and fungal or parasitic, 7 patients [17%]) who underwent continuous electroencephalographic monitoring between January 1, 1996, and February 28, 2007. MAIN OUTCOME MEASURES: Presence of ESz or periodic epileptiform discharges (PEDs). RESULTS: Electrographic seizures were recorded in 14 patients (33%), and PEDs were recorded in 17 patients (40%). Twenty patients (48%) had either PEDs or ESz. Of the 14 patients with ESz, only 5 (36%) had a clinical correlate. Periodic epileptiform discharges (odds ratio=13.4; P=.001) and viral cause (odds ratio=13.0; P=.02) were independently associated with ESz. Both ESz (odds ratio=5.9; P=.02) and PEDs (odds ratio=6.1; P=.01) were independently associated with poor outcome at discharge (severe disability, vegetative state, or death). CONCLUSIONS: In patients with central nervous system infections undergoing continuous electroencephalographic monitoring, ESz and/or PEDs were frequent, occurring in 48% of our cohort. More than half of the ESz had no clinical correlate. Both ESz and PEDs were independently associated with poor outcome. Additional studies are needed to determine whether prevention or treatment of these electrographic findings improves outcome.

Group motivational intervention in overweight/obese patients in primary prevention of cardiovascular disease in the primary healthcare area

Background The global mortality caused by cardiovascular disease increases with weight. The Framingham study showed that obesity is a cardiovascular risk factor independent of other risks such as type 2 diabetes mellitus, dyslipidemia and smoking. Moreover, the main problem in the management of weight-loss is its maintenance, if it is achieved. We have designed a study to determine whether a group motivational intervention, together with current clinical practice, is more efficient than the latter alone in the treatment of overweight and obesity, for initial weight loss and essentially to achieve maintenance of the weight achieved; and, secondly, to know if this intervention is more effective for reducing cardiovascular risk factors associated with overweight and obesity. Methods This 26-month follow up multi-centre trial, will include 1200 overweight/obese patients. Random assignment of the intervention by Basic Health Areas (BHA): two geographically separate groups have been created, one of which receives group motivational intervention (group intervention), delivered by a nurse trained by an expert phsychologist, in 32 group sessions, 1 to 12 fortnightly, and 13 to 32, monthly, on top of their standard program of diet, exercise, and the other (control group), receiving the usual follow up, with regular visits every 3 months. Discussion By addressing currently unanswered questions regarding the maintenance in weight loss in obesity/overweight, upon the expected completion of participant follow-up in 2012, the IMOAP trial should document, for the first time, the benefits of a motivational intervention as a treatment tool of weight loss in a primary care setting.

Nouveau spectre des troubles cognitifs liés à l'infection par le VIH à l'ère des trithérapies [New spectrum of HIV-associated cognitive disorders in the HAART era]

Highly active anti-retroviral therapy (HAART) has almost abolished HIV-related mortality and serious opportunistic diseases; among them, AIDS-related dementia. However, minor forms of cognitive dysfunction, have not disappeared, and even increased in frequency. Ageing of HIV+ patients, insufficient penetration of anti-viral drugs into the brain with continuous low-grade viral production and inflammation may play a role. Minor cognitive dysfunction in HIV infection shares some clinical and pathophysiological features with neuro-degenerative diseases, in particular Alzheimers disease. It can thus be postulated that, such in Alzheimer disease, anti-cholinesterase drugs might also be efficacious in AIDS-related minor cognitive dysfunction. This hypothesis has not been tested yet however A clinical trial using ravistigmine is starting this spring in patients with HIV-associated cognitive dysfunction in Geneva and Lausanne.