Continuous monitoring of ScvO<Subscript>2</Subscript> by a new fibre-optic technology compared with blood gas oximetry in critically ill patients: a multicentre study

Objective The aim of this study was to compare the accuracy of the CeVOX monitor measuring continuous central venous saturation (ScvO₂) with laboratory blood gas oximetry under clinical circumstances. Design Prospective, multicentre, observational study. Setting Five adult general intensive care units. Patients and participants Fifty-three critically ill patients. Interventions The fibre-optic probe was inserted into an ordinary central venous catheter's distal lumen. Blood samples were taken from this line via a Y-adapter every 8 h and ScvO₂ was measured with a laboratory co-oximeter. Patients were observed for a maximum of 5 days. Results were compared using linear regression and the Bland and Altman plots. Measurements and results The 526 matched pairs of ScvO₂ showed a significant correlation between the two methods (r = 0.79, p< 0.001). Bland–Altman plots showed an overall mean bias of –0.3% and moderate agreement (lower and upper levels of agreement: –13.2% and 12.5%). Correlation for the first time point, and for differences between the first two time points for each method revealed good correlation: (n = 53): r = 0.79, p< 0.001; (n = 50): r = 0.58, p< 0.001, respectively. Conclusion These results in a heterogeneous group of critically ill patients show that continuous ScvO₂ monitoring by the CeVOX technology yielded results comparable with those obtained by laboratory co-oximetry and therefore can be relied on in everyday clinical practice. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Seroreactivity to microbial components in Crohn's disease is associated with ileal involvement, noninflammatory disease behavior and NOD2/CARD15 genotype, but not with risk for surgery in a Hungarian cohort of IBD patients

BACKGROUND: Antibodies directed against Saccharomyces cerevisiae (ASCA), perinuclear components of neutrophils (pANCA), and porin protein C of Escherichia coli (anti-OmpC) are reported to be associated with disease phenotype and may be of diagnostic importance in inflammatory bowel disease (IBD). Since limited data are available from Eastern Europe, we assessed the above antibodies in Hungarian IBD patients. METHODS: In all, 653 well-characterized, unrelated consecutive IBD patients (Crohn's disease [CD]: 558, m/f: 263/295, duration: 8.1 +/- 10.7 years; ulcerative colitis [UC]: 95, m/f: 44/51, duration: 8.9 +/- 9.8 years) and 100 healthy subjects were investigated. Sera were assayed for anti-Omp and ASCA by enzyme-linked immunosorbent assay (ELISA) and ANCA by indirect immunofluorescence assay (IIF). TLR4 and NOD2/CARD15 variants were tested by polymerase chain reaction/restriction fragment length polymorphism (PCR-RFLP). Detailed clinical phenotypes were determined by reviewing the medical charts. RESULTS: Anti-Omp, ASCA, and atypical pANCA antibodies were present in 31.2%, 59.3%, and 13.8% of CD, 24.2%, 13.7%, and 48.5% of UC patients, and in 20%, 16%, and 5.6% of controls, respectively. ASCA and anti-Omp positivity were associated with increased risk for CD (odds ratio [OR](ASCA) = 7.65, 95% confidence interval [CI]: 4.37-13.4; OR(Omp) = 1.81, 95% CI: 1.08-3.05). In a logistic regression analysis, anti-Omp and ASCA were independently associated with ileal and noninflammatory disease, but not with a risk for surgery or response to steroids or infliximab. A serology dosage effect was also observed. ASCA and anti-Omp antibodies were associated with NOD2/CARD15, in addition to a gene dosage effect. No associations were found in UC. CONCLUSIONS: Serological markers were useful in the differentiation between CD and UC in an Eastern European IBD cohort. Reactivity to microbial components was associated with disease phenotype and NOD2/CARD15 genotype, further supporting the role of altered microbial sensing in the pathogenesis of CD.     

When metformin is not enough: Pros and cons of SGLT2 and DPP‐4 inhibitors as a second line therapy

The newer oral therapies for type 2 diabetes mellitus, dipeptidyl peptidase‐4 (DPP‐4) inhibitors and sodium glucose cotransporter 2 (SGLT2) inhibitors, have advantages over older agents. Dipeptidyl peptidase‐4 inhibitors are weight neutral and have few adverse effects. Sodium glucose cotransporter 2 inhibitors have additional benefits: weight loss, blood pressure reduction, cardiovascular risk reduction, and renoprotective effects. Sodium glucose cotransporter 2 inhibitors have increased risk of urogenital infections and possible risk of “euglycaemic” diabetic ketoacidosis. It is important to balance the benefits over the older‐oral therapies as these agents are more expensive; yet some analyses suggest that they are within the limits of what is considered cost‐effective in health care. We discuss the relative merits and drawbacks of these 2 classes and consider their roles in the treatment of type 2 diabetes mellitus. We suggest a number of patient profiles where early use of these agents could be used. We favour the use of SGLT2 inhibitors over DPP‐4 inhibitors as add on therapy to metformin when glycaemic targets have not been achieved given their similar glycaemic efficacy and the additional benefits of SGLT2 inhibitors. We particularly favour SGLT2 inhibitors in those where additional weight loss and blood pressure reductions are desired, and in patients with heart failure or cardiovascular disease. Care should be taken to warn patients about genital fungal infections and to avoid use in people with risk factors for SGLT2 associated ketoacidosis. We favour DPP‐4 inhibitors in those where side effects of other agents are of concern, the frail elderly population, and those with renal disease precluding SGTL2 inhibitor use.     

The combination of granulocyte colony-stimulating factor and stem cell factor significantly increases the number of bone marrow-derived endothelial cells in brains of mice following cerebral ischemia

Granulocyte colony-stimulating factor (G-CSF) induces proliferation of bone marrow–derived cells. G-CSF is neuroprotective after experimental brain injury, but the mechanisms involved remain unclear. Stem cell factor (SCF) is a cytokine important for the survival and differentiation of hematopoietic stem cells. Its receptor (c-kit or CD117) is present in some endothelial cells. We aimed to determine whether the combination of G-CSF/SCF induces angiogenesis in the central nervous system by promoting entry of endothelial precursors into the injured brain and causing them to proliferate there. We induced permanent middle cerebral artery occlusion in female mice that previously underwent sex-mismatched bone marrow transplantation from enhanced green fluorescent protein (EGFP)–expressing mice. G-CSF/SCF treatment reduced infarct volumes by more than 50% and resulted in a 1.5-fold increase in vessel formation in mice with stroke, a large percentage of which contain endothelial cells of bone marrow origin. Most cells entering the brain maintained their bone marrow identity and did not transdifferentiate into neural cells. G-CSF/SCF treatment also led to a 2-fold increase in the number of newborn cells in the ischemic hemisphere. These findings suggest that G-CSF/SCF treatment might help recovery through induction of bone marrow–derived angiogenesis, thus improving neuronal survival and functional outcome.     

Targeted vascular delivery of antisense molecules using intravenous microbubbles.

OBJECTIVE: Perfluorocarbon-exposed sonicated dextrose albumin (PESDA) microbubbles bind the antisense to the c-myc protooncogene (anti-c-myc) which prevents neointimal hyperplasia following vascular endothelial injury. The microbubbles also adhere to sites of damaged vascular endothelium and thus may be a method of systemically targeting delivery of anti-c-myc. METHODS: Laser scanning microscopy was performed on the aorta of 10 mice (five which were complement depleted) that received intravenous FITC-PESDA following aortic endothelial injury. C-myc expression was quantified following selective intracoronary injury in nine pigs that received intravenous (IV) anti-c-myc bound to PESDA. Finally, neointimal formation was measured following intracoronary stent deployment in 30 pigs that received either IV anti-c-myc alone or the same dose bound to PESDA. RESULTS: Fluorescent microscopy confirmed selective PESDA microbubble adherence to aortic endothelium in all mice with aortic injury. This binding was nearly abolished when serum complement was depleted prior to injury. C-myc expression at the site of coronary endothelial injury was significantly lower in pigs treated with systemic anti-c-myc bound to PESDA. There was a 33% reduction in % stenosis and a 28% reduction in intimal area at 45 days post-stent deployment in pigs that received IV antisense plus PESDA. The stent margins also had reduced neointimal formation. CONCLUSION: Systemic administration of anti-c-myc bound to PESDA microbubbles may be a good method for preventing coronary neointimal formation within and around implanted stents.     

Human SHPRH is a ubiquitin ligase for Mms2-Ubc13-dependent polyubiquitylation of proliferating cell nuclear antigen

Human SHPRH gene is located at the 6q24 chromosomal region, and loss of heterozygosity in this region is seen in a wide variety of cancers. SHPRH is a member of the SWI/SNF family of ATPases/helicases, and it possesses a C(3)HC(4) RING motif characteristic of ubiquitin ligase proteins. In both of these features, SHPRH resembles the yeast Rad5 protein, which, together with Mms2-Ubc13, promotes replication through DNA lesions via an error-free postreplicational repair pathway. Genetic evidence in yeast has indicated a role for Rad5 as a ubiquitin ligase in mediating the Mms2-Ubc13-dependent polyubiquitylation of proliferating cell nuclear antigen. Here we show that SHPRH is a functional homolog of Rad5. Similar to Rad5, SHPRH physically interacts with the Rad6-Rad18 and Mms2-Ubc13 complexes, and we show that SHPRH protein is a ubiquitin ligase indispensable for Mms2-Ubc13-dependent polyubiquitylation of proliferating cell nuclear antigen. Based on these observations, we predict a role for SHPRH in promoting error-free replication through DNA lesions. Such a role for SHPRH is consistent with the observation that this gene is mutated in a number of cancer cell lines, including those from melanomas and ovarian cancers, which raises the strong possibility that SHPRH function is an important deterrent to mutagenesis and carcinogenesis in humans.     

The effect of baseline characteristics on clinical efficacy of liraglutide in patients treated with high‐dose insulin

In patients requiring high‐dose insulin treatment, a randomized, double‐blind, placebo‐controlled study showed that liraglutide improved glycaemic control and treatment satisfaction while promoting weight loss. We performed a post hoc analysis to evaluate if patients’ baseline characteristics impact the efficacy of liraglutide, and which outcomes correlate with treatment satisfaction. We used regression analysis to model the change in HbA1c and weight, with treatment assignment and baseline characteristics [HbA1c, age, body mass index (BMI), total daily dose (TDD) of insulin, duration of insulin treatment, and type of insulin regimen] as independent variables. Improvement in HbA1c was best predicted by treatment with liraglutide, followed by higher baseline HbA1c, BMI and age. Changes in weight were only associated with liraglutide treatment, independent of all baseline characteristics. Improvement in HbA1c was the only significant predictor of improvement in treatment satisfaction, while weight loss, change in TDD of insulin and rate of hypoglycaemia did not influence treatment satisfaction. In patients treated with high‐dose insulin, liraglutide significantly improved glycaemic control and led to weight loss regardless of patients’ baseline characteristics. Improvement in HbA1c was the most important predictor of patients’ treatment satisfaction.     

Acoustic Properties of Cries in 12-Month Old Infants at High-Risk of Autism Spectrum Disorder

There is preliminary evidence that infant siblings of children with Autism Spectrum Disorder (ASD) have an atypical pattern of cry, characterized by higher fundamental frequency and increased dysphonation. This prospective study collected multiple cry samples of 12-month old siblings of children with ASD (n?=?22, ‘high-risk’ group) and 12-month olds with no family history of ASD (n?=?27, ‘low risk’ group). While there was no difference between groups in the fundamental frequency or degree of phonation of the cry samples, the duration of each cry unit was significantly shorter in the high-risk siblings (p?<?.05). The six infant siblings who received a diagnosis of ASD at age two had amongst the shortest recorded cry durations.