Protective DNA vaccination against myelin oligodendrocyte glycoprotein is overcome by C3d in experimental autoimmune encephalomyelitis

Complement receptor 2 (CR2) and its physiological ligand, C3d, known for its molecular adjuvant property on the immune response, exhibit opposite effects with regard to autoimmunity. Although CR2 has been implicated in maintaining self-tolerance, recent studies reported a role for C3d signaling to CR2 in tolerance breakdown to self-antigens and the initiation of inflammatory autoimmune pathologies. In the present study, we have investigated the effect of C3d in a model of tolerogenic DNA vaccination encoding the myelin oligodendrocyte glycoprotein (MOG-DNA) which protected mice from the induction of an experimental autoimmune encephalomyelitis (EAE). We show that fusing two or three copies of C3d to MOG overcomes the protective effect of DNA vaccination. Multimeric C3d was able to revert the unresponsiveness state of specific T cells induced by MOG-DNA, independently of a modification in the Th1/Th2 cytokine pattern. Interestingly, the adjuvant effect of C3d was not sufficient to boost the anti-MOG antibody response after DNA vaccination. These findings suggest that C3d might be involved in self-tolerance breakdown and could contribute to the pathogenesis of central nervous system autoimmune disorders.     

Diesel engine exhaust exposure in underground mines: Comparison between different surrogates of particulate exposure

Exposure to diesel particulate matter (DPM) is frequently assessed by measuring indicators of carbon speciation, but these measurements may be affected by organic carbon (OC) interference. Furthermore, there are still questions regarding the reliability of direct-reading instruments (DRI) for measuring DPM, since these instruments are not specific and may be interfered by other aerosol sources. This study aimed to assess DPM exposure in 2 underground mines by filter-based methods and DRI and to assess the relationship between the measures of elemental carbon (EC) and the DRI to verify the association of these instruments to DPM. Filter-based methods of respirable combustible dust (RCD), EC, and total carbon (TC) were used to measure levels of personal and ambient DPM. For ambient measurements, DRI were used to monitor particle number concentration (PNC; PTrak), particle mass concentration (DustTrak DRX and DustTrak 8520), and the submicron fraction of EC (EC_1;Airtec). The association between ambient EC and the DRI was assessed by Spearman correlation. Geometric mean concentrations of RCD, respirable TC (TC_R) and respirable elemental EC (EC_R) were 170 µg/m³, 148 µg/m³, and 83 µg/m³ for personal samples, and 197 µg/m³, 151 µg/m³, and 100 µg/m³ for ambient samples. Personal measurements had higher TC_R:EC_R ratios compared to ambient samples (1.8 vs. 1.50) and weaker association between EC_R and TC_R. Among the DRI, the measures of EC₁ by the Airtec (ρ = 0.86; P < 0.001) and the respirable particles by the DustTrak 8520 (ρ = 0.74; P < 0.001) showed the strongest association with EC, while PNC showed a weak and non-significant association with EC. In conclusion, this study provided important information about the concentrations of DPM in underground mines by measuring several indicators using filter-based methods and DRI. Among the DRI, the Airtec proved to be a good tool for estimating EC concentrations and, although the DustTrak showed good association with EC, interferences from other aerosol sources should be considered when using this instrument to assess DPM.     

Epidemiology and economic evaluation of severe sepsis in France: age, severity, infection site, and place of acquisition (community, hospital, or intensive care unit) as determinants of workload and cost

PURPOSE: Severe sepsis is a leading cause of death in critically ill patients. We evaluated cost and workload according to infection site, place and time of acquisition, and severity. MATERIAL AND METHOD: We used a prospective 3-year database from 6 intensive care units (ICUs) including 1698 patients. RESULTS: Of the 1698 patients, 713 (42%) had severe sepsis at admission and 339 during the ICU stay (211 had both). Mortality was twice as high in patients with than those without ICU-acquired infection, independent of the presence of severe sepsis at admission. The mean (SD; median) cost of severe sepsis was 22 800 (21 400 ; 15 800 ). Among patients with severe sepsis at admission, workload and cost were higher for pneumonia, peritonitis, and multiple-site infections and for hospital-acquired (17,400 [14,700; 17,400]) vs community-acquired infection (12,600 [12,100 ; 8900 ]). Intensive care unit-acquired severe sepsis was associated with greater than 3-fold increases in workload and costs. By multiple linear regression, older age, emergency surgery, septic shock, Acute Physiological and Chronic Health Evaluation II score, and hospital or ICU-acquired severe sepsis were independently associated with higher costs. CONCLUSIONS: The wide variations in cost and workload invite efforts to identify patient subgroups most likely to benefit from high-cost treatments and from prevention, particularly targeting severe nosocomial infections.     

Real-world outcomes following 12 months of intravitreal aflibercept monotherapy in patients with diabetic macular edema in France: results from the APOLLON study

Graefe's Archive for Clinical and Experimental Ophthalmology - To report the effectiveness of intravitreal aflibercept (IVT-AFL) treatment for diabetic macular edema (DME) in French clinical...     

Neoadjuvant targeted molecular therapies in patients undergoing nephrectomy and inferior vena cava thrombectomy: is it useful?

Objective

To assess the effect of neoadjuvant targeted molecular therapies (TMTs) on size and level of inferior vena cava tumor thrombi and to evaluate their impact on surgical management.

Methods

We retrospectively analyzed the data of 14 patients treated for a clear cell renal cell carcinoma with inferior vena cava thrombi by neoadjuvant TMT before nephrectomy. Clinical, pathological and perioperative data were gathered retrospectively at each institution. The primitive tumor size and the thrombus size were defined by computed tomography before TMT. The tumor thrombus level was defined according to the Novick’s classification.

Results

Before TMT, thrombus level was staged I for 1 (7 %), II for 10 (72 %) and III (21 %) for 3 patients. First-line therapy was sunitinib in 11 cases and sorafenib in 3 cases. Median therapy duration was two cycles (1–5). Three patients experienced major adverse effects (grade III) during TMT. Following TMT, 6 (43 %) patients had a measurable decrease, 6 (43 %) had no change, and 2 (14 %) had an increase in the thrombus. One patient (7 %) had a downstage of thrombus level, 12 (85 %) had stable thrombi, and 1 (7 %) had an upstage. Regarding primary tumor, 7 (50 %), 5 (36 %) and 2 (14 %) patients had a decrease, stabilization and an increase in tumor size, respectively.

Conclusion

Neoadjuvant TMT appears to have limited effects on renal tumor thrombi. This retrospective study failed to demonstrate a significant impact of neoadjuvant TMT on surgical management of clear cell renal cell carcinoma with inferior vena cava tumor thrombi.     

Male Inmate Profiles and Their Biological Correlates

Objective:

Borderline and antisocial personality disorders (PDs) share common clinical features (impulsivity, aggressiveness, substance use disorders [SUDs], and suicidal behaviours) that are greatly overrepresented in prison populations. These disorders have been associated biologically with testosterone and cortisol levels. However, the associations are ambiguous and the subject of controversy, perhaps because these heterogeneous disorders have been addressed as unitary constructs. A consideration of profiles of people, rather than of exclusive diagnoses, might yield clearer relationships.

Methods:

In our study, multiple correspondence analysis and cluster analysis were employed to identify subgroups among 545 newly convicted inmates. The groups were then compared in terms of clinical features and biological markers, including levels of cortisol, testosterone, estradiol, progesterone, and sulfoconjugated dehydroepiandrosterone (DHEA-S).

Results:

Four clusters with differing psychiatric, criminal, and biological profiles emerged. Clinically, one group had intermediate scores for each of the tested clinical features. Another group comprised people with little comorbidity. Two others displayed severe impulsivity, PD, and SUD. Biologically, cortisol levels were lowest in the last 2 groups and highest in the group with less comorbidity. In keeping with previous findings reported in the literature, testosterone was higher in a younger population with severe psychiatric symptoms. However, some apparently comparable behavioural outcomes were found to be related to distinct biological profiles. No differences were observed for estradiol, progesterone, or DHEA-S levels.

Conclusions:

The results not only confirm the importance of biological markers in the study of personality features but also demonstrate the need to consider the role of comorbidities and steroid coregulation.     

Nephropathy and Elevated BP in Mice with Podocyte-Specific NADPH Oxidase 5 Expression

NADPH oxidase (Nox) enzymes are a significant source of reactive oxygen species, which contribute to glomerular podocyte dysfunction. Although studies have implicated Nox1, -2, and -4 in several glomerulopathies, including diabetic nephropathy, little is known regarding the role of Nox5 in this context. We examined Nox5 expression and regulation in kidney biopsies from diabetic patients, cultured human podocytes, and a novel mouse model. Nox5 expression increased in human diabetic glomeruli compared with nondiabetic glomeruli. Stimulation with angiotensin II upregulated Nox5 expression in human podocyte cultures and increased reactive oxygen species generation. siRNA-mediated Nox5 knockdown inhibited angiotensin II–stimulated production of reactive oxygen species and altered podocyte cytoskeletal dynamics, resulting in an Rac-mediated motile phenotype. Because the Nox5 gene is absent in rodents, we generated transgenic mice expressing human Nox5 in a podocyte-specific manner (Nox5^pod+). Nox5^pod+ mice exhibited early onset albuminuria, podocyte foot process effacement, and elevated systolic BP. Subjecting Nox5^pod+ mice to streptozotocin-induced diabetes further exacerbated these changes. Our data show that renal Nox5 is upregulated in human diabetic nephropathy and may alter filtration barrier function and systolic BP through the production of reactive oxygen species. These findings provide the first evidence that podocyte Nox5 has an important role in impaired renal function and hypertension.Albuminuria is a clinical marker of kidney dysfunction that arises in most glomerulopathies and is associated with poor prognoses for ESRD, hypertension, and cardiovascular mortality. Changes to the podocyte (e.g., foot process effacement, hypertrophy, detachment, and loss) underlie the development and progression of albuminuria and thereby highlight the critical role for these cells in upholding the glomerular filtration barrier.^1,2 Therefore, identifying factors that induce podocyte injury and loss is essential to understanding the mechanisms of filtration barrier dysfunction.Of the many factors implicated in podocyte dysfunction, excessive production of reactive oxygen species (ROS; oxidative stress) may be particularly important.^3–6 Although sources of ROS are numerous, the NADPH oxidase (Nox) family of enzymes yields significant superoxide production in the kidney.^7–10 Nox-induced ROS production has been closely linked to various glomerular pathologies. In animal models of minimal change disease, membranous nephropathy, and FSGS, inhibition of Nox activity is associated with decreased podocyte effacement and amelioration of albuminuria.^11–14 In models of diabetic nephropathy, treatment with the Nox inhibitor apocynin, as well the antioxidant vitamin E, reduces oxidative stress, podocyte effacement and loss, and albuminuria.^6,15,16 Noxs are regulated by many factors, including the renin angiotensin aldosterone system.^5,9 Several studies have linked increased renin angiotensin aldosterone system activity to enhanced renal Nox activity and ROS generation.^5,17 Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers slow progression of proteinuria in models of diabetes, and these effects may be, in part, independent of their effects on systemic BP,^17–20 because direct activation of Nox enzymes through the angiotensin II (AngII)/AT1 receptor (AT1R) pathway leads to oxidative stress. In vitro studies in both human and rodent cell lines have also shown that Nox family member expression and activity are regulated by disease-associated factors, including AngII, ET-1, TGF-β, high glucose, mechanical stretch, and PDGF (factors that are upregulated in the diabetic milieu).^3,21–23The roles of Nox4, and to a lesser extent, Nox1 and -2, in the kidney have been examined, but nothing is known regarding the role of the most recently identified member of the Nox family, Nox5. The Nox5 gene is absent from the mouse and rat genomes, making the use of conventional animal models unfeasible. Unlike other Nox family members, Nox5 does not require membrane-bound or cytosolic components, such as p22phox or p47phox, for its activity, but is tightly regulated by changes in intracellular calcium levels.^24,25 Nox5 has a large amino terminal EF hand-containing domain that plays a critical role in its calcium-dependent activation along with several phosphorylation sites that alter the sensitivity of Nox5 to intracellular calcium.^26–29 Because AngII increases intracellular calcium concentrations, it seems to induce renal Nox5-dependent ROS generation, which was shown in human endothelial cells.²³ Here, we show that (1) Nox5 is upregulated in human diabetic glomeruli; (2) AngII stimulates ROS generation in human podocytes in a Nox5-dependent manner, a process associated with actin cytoskeletal reorganization and activation of Rac GTPase, which promotes podocyte motility in vitro; (3) mice that express human Nox5 in a podocyte-specific manner (Nox5β^pod+ mice) exhibit renal dysfunction, including albuminuria, podocyte effacement, glomerular basement membrane (GBM) thickening, interstitial fibrosis, and hypertension; and (4) Nox5^pod+ mice subjected to streptozotocin (STZ)-induced diabetes develop a more severe kidney phenotype than nontransgenic littermates. These novel data indicate the potential importance of podocyte Nox5 in human renal pathologies, such as diabetic nephropathy.     

Survival Benefit of Hyperthermic Intraperitoneal Chemotherapy for Recurrent Ovarian Cancer: A Multi-institutional Case Control Study

Background

Hyperthermic intraperitoneal chemotherapy (HIPEC) and complete surgical removal of the tumor, in relapsing patients may provide a clinical benefit. There is no consensus considering the place of HIPEC for patients who had first ovarian cancer relapse. To assess for possible efficacy of HIPEC on overall survival (OS) rates in this situation, we performed a multi-institutional study.

Methods

The current study was a retrospective case control multi-institutional study comparing a group of patients treated with HIPEC to a group of patients treated without HIPEC. Inclusion criteria were first relapse of a serous ovarian carcinoma and >6 months after the end of initial treatment. Exclusion criteria were another pathological subtype of ovarian cancer, a relapse at <6 months after initial treatment, and a second relapse or more. We aimed to assess OS, morbidity, and mortality rates and prognostic factors.

Results

From June 1997–July 2011, 42 patients were included, 23 in the HIPEC group and 19 in the control group. Each patient from the two groups had a complete secondary surgery at the time of the first relapse. At 4 years OS was 75.6 % in the HIPEC group and 19.4 % in the control group (p = 0.013). In a multivariate analysis, HIPEC and interval-free before the end of initial treatment were both independent prognostic factors.

Conclusion

When compared to the control group, complete secondary surgery and HIPEC appear to afford a better OS rate than complete secondary surgery alone, in case of first ovarian cancer relapse. Further randomized trials are warranted to confirm these results.