The complement factor H R1210C mutation is associated with atypical hemolytic uremic syndrome

Mutations in the gene encoding complement factor H (CFH) that alter the C3b/polyanions-binding site in the C-terminal region impair the capacity of factor H to protect host cells. These mutations are also strongly associated with atypical hemolytic uremic syndrome (aHUS). Although most of the aHUS-associated CFH mutations seem "unique" to an individual patient or family, the R1210C mutation has been reported in several unrelated aHUS patients from distinct geographic origins. Five aHUS pedigrees and 7 individual aHUS patients were analyzed to identify potential correlations between the R1210C mutation and clinical phenotype and to characterize the origins of this mutation. The clinical phenotype of aHUS patients carrying the R1210C mutation was heterogeneous. Interestingly, 12 of the 13 affected patients carried at least one additional known genetic risk factor for aHUS. These data are in accord with the 30% penetrance of aHUS in R1210C mutation carriers, as it seems that the presence of other genetic or environmental risk factors significantly contribute to the manifestation and severity of aHUS in these subjects. Genotype analysis of CFH and CFHR3 polymorphisms in the 12 unrelated carriers suggested that the R1210C mutation has a single origin. In conclusion, the R1210C mutation of complement factor H is a prototypical aHUS mutation that is present as a rare polymorphism in geographically separated human populations.     

The use of medication after laparoscopic antireflux surgery

Background  Laparoscopic antireflux surgery (LARS) significantly improves symptoms of gastro-esophageal reflux disease (GERD) and quality of life. Nevertheless, 14–62% of patients report using antisecretory medication after surgery, although only a tiny percentage has proven recurrence of GERD. We sought to determine symptoms of GERD, quality of life, and use of medication before and after LARS, and to compare our findings with those from previous studies. Methods  Five hundred fifty-three patients with GERD who underwent LARS were evaluated before and at 1 year after surgery. After surgery, multidisciplinary follow-up care was provided for all patients by surgeons, psychologists, dieticians, and speech therapists. Results  Symptoms of GERD and quality of life improved significantly and only 4.2% of patients still required medication after surgery [proton pump inhibitors (PPI) (98.4 vs. 2.2%; p < 0.01), prokinetics (9.6 vs. 1.1%; p < 0.01), and psychiatric medication (8 vs. 1.6%; p < 0.01)]. Conclusion  LARS significantly reduced medication use at 1-year follow-up. However, these effects might be attributed, in part, to the multidisciplinary follow-up care. Further studies are therefore required to investigate which patients may benefit from multidisciplinary follow-up care and whether its selective application may reduce the need for medication after LARS.     

Electroporation-enhanced nonviral gene transfer for the prevention or treatment of immunological, endocrine and neoplastic diseases

Nonviral gene transfer is markedly enhanced by the application of in vivo electroporation (also denoted electro-gene transfer or electrokinetic enhancement). This approach is safe and can be used to deliver nucleic acid fragments, oligonucleotides, siRNA, and plasmids to a wide variety of tissues, such as skeletal muscle, skin and liver. In this review, we address the principles of electroporation and demonstrate its effectiveness in disease models. Electroporation has been shown to be equally applicable to small and large animals (rodents, dogs, pigs, other farm animals and primates), and this addresses one of the major problems in gene therapy, that of scalability to humans. Gene transfer can be optimized and tissue injury minimized by the selection of appropriate electrical parameters. We and others have applied this approach in preclinical autoimmune and/or inflammatory diseases to deliver either cytokines, anti-inflammatory agents or immunoregulatory molecules. Electroporation is also effective for the intratumoral delivery of therapeutic vectors. It strongly boost DNA vaccination against infectious agents (e.g., hepatitis B virus, human immunodeficiency virus-1) or tumor antigens (e.g., HER-2/neu, carcinoembryonic antigen). In addition, we found that electroporation-enhanced DNA vaccination against islet-cell antigens ameliorated autoimmune diabetes. One of the most likely future applications, however, may be in intramuscular gene transfer for systemic delivery of either endocrine hormones (e.g., growth hormone releasing hormone and leptin), hematopoietic factors (e.g., erythropoietin, GM-CSF), antibodies, enzymes, or numerous other protein drugs. In vivo electroporation has been performed in humans, and it seems likely it could be applied clinically for nonviral gene therapy.     

Methanol extract of the ethnopharmaceutical remedy Smilax spinosa exhibits anti-neoplastic activity

Plants have been the source of several effective drugs for the treatment of cancer and over 60% of anticancer drugs originate from natural sources. Therefore, extracts of the rhizome of Smilax spinosa, an ethnomedicinal plant from Guatemala which is used for the treatment of inflammatory conditions, were investigated regarding their anti-neoplastic activities. By using several solvents the methanol extract was by far the most potent against HL60 cell proliferation (50% inhibition at 60 μg/ml). Furthermore, fractionation of this extract yielded fraction F2, which exhibited enforced pro-apoptotic activity, and activated CYP1A1. Proteins that are relevant for cell cycle progression and apoptosis, as well as proto-oncogenes were investigated by western blotting. This revealed that the methanol extract increased the levels of p21 and this may have caused cell cycle attenuation. The derivative fraction F2 induced apoptosis through the intrinsic pathway, which correlated with the inhibition of Stat3 phosphorylation and concomitant induction of caspase 9, then caspase 8 and caspase 3. In summary, the methanol extract and the derivative fraction F2 of S. spinosa showed anti-neoplastic effects in HL-60 cells and CYP1A1 activation in estrogen receptor-positive MCF-7 breast cancer cells but not in estrogen-negative MDA-MB231 breast cancer cells. Based on our data Smilax spinosa may be a promising source for novel anticancer agents.     

Early massive transfusion in trauma patients: Canadian single-centre retrospective cohort study

Purpose

To determine associations between red blood cell (RBC) transfusion and early and late clinical outcomes in massively transfused adult trauma patients.

Methods

A retrospective cohort study (1992–2001) including 260 patients receiving ≥10 RBC units ≤24 hr after admission to a university-affiliated trauma centre. We extracted demographic and clinical data and used multivariable regression to determine independent effects of RBC transfusion on clinical outcomes.

Results

Patients had a high (mean [standard deviation]) injury severity score (ISS) (42.5 [15.1]), a high admission sequential organ failure assessment (SOFA) score (8.4 [3.8]), and a high hospital mortality (58.5%). They received 38 (25–64) (median [interquartile range]) blood components within 48 hr, including 19 (14–28) RBC units. For 143 patients surviving ≥48 hr, the maximum SOFA score was associated with RBC units transfused before 48 hr (linear regression beta coefficient 0.075, P < 0.0001), lower nadir hemoglobin before 48 hr (0.034, P = 0.03), age (0.032, P = 0.015), and admission SOFA (0.59, P < 0.0001). The RBC units transfused by 48 hr were not associated with either hospital mortality (n = 35) among patients surviving ≥48 hr (independent predictors, age [logistic regression odds ratio (OR) 1.06, 95% confidence interval 1.03–1.10], ISS [OR 1.07, 1.02–1.13], and maximum SOFA score [OR 1.56, 1.27–1.93]) or 48-hr mortality (n = 117) (independent predictors, admission SOFA [1.65, 1.45–1.88] and later year of hospital admission [OR 1.15, 1.02–1.29]).

Conclusions

Hospital mortality is high among massively transfused trauma patients. Among early survivors, 48-hr RBC transfusion volume is associated with increased organ dysfunction, but not hospital mortality. Also, it is not associated with 48-hr mortality. Future research should continue to explore methods to improve hemostasis and minimize the need for RBC transfusion.     

Neurogenesis in the adult spinal cord in an experimental model of multiple sclerosis

Multiple sclerosis is an inflammatory disease of the central nervous system characterized by inflammation, demyelination, axonal degeneration and accumulation of neurological disability. Previously, we demonstrated that stem cells constitute a possible endogenous source for remyelination. We now addressed the question of whether neurogenesis can occur in neuroinflammatory lesions. We demonstrated that, in experimental autoimmune encephalomyelitis, induced in rats 1,1'-dioctadecyl-6,6'-di(4sulphopentyl)-3,3,3',3'tetramethylindocarbocyanin(DiI)-labelled ependymal cells not only proliferated but descendants migrated to the area of neuroinflammation and differentiated into cells expressing the neuronal markers beta-III-tubulin and NeuN. Furthermore, these cells were immunoreactive for bromodeoxyuridine and PCNA, markers for cells undergoing cell proliferation. Using the whole-cell patch-clamp technique on freshly isolated 1, DiI-labelled cells from spinal cord lesions we demonstrated the ability of these cells to fire overshooting action potentials similar to those of immature neurones. We thus provide the first evidence for the initiation of neurogenesis in neuroinflammatory lesions in the adult spinal cord.     

Fluid balance,intradialytic hypotension,and outcomes in critically ill patients undergoing renal replacement therapy: a cohort study

Introduction

In this cohort study, we explored the relationship between fluid balance, intradialytic hypotension and outcomes in critically ill patients with acute kidney injury (AKI) who received renal replacement therapy (RRT).

Methods

We analysed prospectively collected registry data on patients older than 16 years who received RRT for at least two days in an intensive care unit at two university-affiliated hospitals. We used multivariable logistic regression to determine the relationship between mean daily fluid balance and intradialytic hypotension, both over seven days following RRT initiation, and the outcomes of hospital mortality and RRT dependence in survivors.

Results

In total, 492 patients were included (299 male (60.8%), mean (standard deviation (SD)) age 62.9 (16.3) years); 251 (51.0%) died in hospital. Independent risk factors for mortality were mean daily fluid balance (odds ratio (OR) 1.36 per 1000 mL positive (95% confidence interval (CI) 1.18 to 1.57), intradialytic hypotension (OR 1.14 per 10% increase in days with intradialytic hypotension (95% CI 1.06 to 1.23)), age (OR 1.15 per five-year increase (95% CI 1.07 to 1.25)), maximum sequential organ failure assessment score on days 1 to 7 (OR 1.21 (95% CI 1.13 to 1.29)), and Charlson comorbidity index (OR 1.28 (95% CI 1.14 to 1.44)); higher baseline creatinine (OR 0.98 per 10 μmol/L (95% CI 0.97 to 0.996)) was associated with lower risk of death. Of 241 hospital survivors, 61 (25.3%) were RRT dependent at discharge. The only independent risk factor for RRT dependence was pre-existing heart failure (OR 3.13 (95% CI 1.46 to 6.74)). Neither mean daily fluid balance nor intradialytic hypotension was associated with RRT dependence in survivors. Associations between these exposures and mortality were similar in sensitivity analyses accounting for immortal time bias and dichotomising mean daily fluid balance as positive or negative. In the subgroup of patients with data on pre-RRT fluid balance, fluid overload at RRT initiation did not modify the association of mean daily fluid balance with mortality.

Conclusions

In this cohort of patients with AKI requiring RRT, a more positive mean daily fluid balance and intradialytic hypotension were associated with hospital mortality but not with RRT dependence at hospital discharge in survivors.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-014-0624-8) contains supplementary material, which is available to authorized users.     

No evidence of tocilizumab treatment efficacy for severe to critical SARS-CoV2 infected patients: Results from a retrospective controlled multicenter study

To assess tocilizumab (TCZ) efficacy associated to standard of care (SOC) compared to SOC alone in severe coronavirus associated disease 2019 (COVID-19) patients. In a matched case-control study from 3 French Hospital COVID-19 Departments, 27 patients with severe COVID-19 treated with TCZ and SOC were matched for baseline epidemiological and clinical features and compared to 27 severe COVID-19 patients treated with SOC alone. Baseline characteristics of the study population were comparable between groups. Eleven patients (20%) died. TCZ was not associated with clinical improvement as compared to SOC regarding oxygen-free status (44% vs 63%) and death (18.5% vs 22%), despite a higher decrease of the C-reactive protein at Day 7 (10.7 vs 52 mg/L; P < 10⁻³). Compared to the 43 patients alive at the end-of follow-up, patients who died were older (78 vs 64 years; P < 10⁻³), with 82% of them older than 72 years vs only 23% of live patients (P < 10⁻³). Age (OR = 1.15; 95%CI = 1.04–1.3; P = .008) and age over 72 years (OR) = 14.85; 95%CI = 2.7–80; P = .002) were independently associated with mortality. TCZ in addition to SOC for severe COVID-19 patients did not reduce mortality, subsequent need for invasive mechanical ventilation nor did it shorten the time of oxygen support, despite better control of the inflammatory response. More powerful and randomized controlled trials are warranted to determine if TCZ is effective in the management of COVID-19.