Reduction of circulating cholesterol and apolipoprotein levels during sepsis

Sepsis with multiple organ failure is frequently associated with a substantial decrease of cholesterol levels. This decrease of cholesterol is strongly associated with mortality suggesting a direct relation between inflammatory conditions and altered cholesterol homeostasis. The host response during sepsis is mediated by cytokines and growth factors, which are capable of influencing lipid metabolism. Conversely lipoproteins are also capable of modulating cytokine production during the inflammatory response. Therefore the decrease in circulating cholesterol levels seems to play a crucial role in the pathophysiology of sepsis. In this review the interaction between cytokines and lipid metabolism and its clinical consequences will be discussed

B-> D* zero-recoil formfactor and the heavy quark expansion in QCD: a systematic study

We present a QCD analysis of heavy quark mesons focussing on the B -> D* formfactor at zero recoil, F_D*(1). An advanced treatment of the perturbative corrections in the Wilsonian approach is presented. We estimate the higher-order power corrections to the OPE sum rule and describe a refined analysis of the nonresonant continuum contribution. In the framework of a model-independent approach, we show that the inelastic contribution in the phenomenological part of the OPE is related to the mQ-dependence of the hyperfine splitting and conclude that the former is large, lowering the prediction for F_D*(1) down to about 0.86. This likewise implies an enhanced yield of radial and D-wave charm excitations in semileptonic B decays and alleviates the problem with the inclusive yield of the wide excited states. We also apply the approach to the expectation values of dimension 7 and 8 local operators and to a few other issues in the heavy quark expansion.Comment: 70 pages, 13 figure

Modeling recursive RNA interference.

An important application of the RNA interference (RNAi) pathway is its use as a small RNA-based regulatory system commonly exploited to suppress expression of target genes to test their function in vivo. In several published experiments, RNAi has been used to inactivate components of the RNAi pathway itself, a procedure termed recursive RNAi in this report. The theoretical basis of recursive RNAi is unclear since the procedure could potentially be self-defeating, and in practice the effectiveness of recursive RNAi in published experiments is highly variable. A mathematical model for recursive RNAi was developed and used to investigate the range of conditions under which the procedure should be effective. The model predicts that the effectiveness of recursive RNAi is strongly dependent on the efficacy of RNAi at knocking down target gene expression. This efficacy is known to vary highly between different cell types, and comparison of the model predictions to published experimental data suggests that variation in RNAi efficacy may be the main cause of discrepancies between published recursive RNAi experiments in different organisms. The model suggests potential ways to optimize the effectiveness of recursive RNAi both for screening of RNAi components as well as for improved temporal control of gene expression in switch off-switch on experiments

Practice Models and Challenges in Teledermatology: A Study of Collective Experiences from Teledermatologists

Despite increasing practice of teledermatology in the U.S., teledermatology practice models and real-world challenges are rarely studied.The primary objective was to examine teledermatology practice models and shared challenges among teledermatologists in California, focusing on practice operations, reimbursement considerations, barriers to sustainability, and incentives. We conducted in-depth interviews with teledermatologists that practiced store-and-forward or live-interactive teledermatology from January 1, 2007 through March 30, 2011 in California.Seventeen teledermatologists from academia, private practice, health maintenance organizations, and county settings participated in the study. Among them, 76% practiced store-and-forward only, 6% practiced live-interactive only, and 18% practiced both modalities. Only 29% received structured training in teledermatology. The average number of years practicing teledermatology was 4.29 years (SD±2.81). Approximately 47% of teledermatologists served at least one Federally Qualified Health Center. Over 75% of patients seen via teledermatology were at or below 200% federal poverty level and usually lived in rural regions without dermatologist access. Practice challenges were identified in the following areas. Teledermatologists faced delays in reimbursements and non-reimbursement of teledermatology services. The primary reason for operational inefficiency was poor image quality and/or inadequate history. Costly and inefficient software platforms and lack of communication with referring providers also presented barriers.Teledermatology enables underserved populations to access specialty care. Improvements in reimbursement mechanisms, efficient technology platforms, communication with referring providers, and teledermatology training are necessary to support sustainable practices

The use of mesenchymal stem cells for cartilage repair and regeneration: a systematic review.

BACKGROUND: The management of articular cartilage defects presents many clinical challenges due to its avascular, aneural and alymphatic nature. Bone marrow stimulation techniques, such as microfracture, are the most frequently used method in clinical practice however the resulting mixed fibrocartilage tissue which is inferior to native hyaline cartilage. Other methods have shown promise but are far from perfect. There is an unmet need and growing interest in regenerative medicine and tissue engineering to improve the outcome for patients requiring cartilage repair. Many published reviews on cartilage repair only list human clinical trials, underestimating the wealth of basic sciences and animal studies that are precursors to future research. We therefore set out to perform a systematic review of the literature to assess the translation of stem cell therapy to explore what research had been carried out at each of the stages of translation from bench-top (in vitro), animal (pre-clinical) and human studies (clinical) and assemble an evidence-based cascade for the responsible introduction of stem cell therapy for cartilage defects. This review was conducted in accordance to PRISMA guidelines using CINHAL, MEDLINE, EMBASE, Scopus and Web of Knowledge databases from 1st January 1900 to 30th June 2015. In total, there were 2880 studies identified of which 252 studies were included for analysis (100 articles for in vitro studies, 111 studies for animal studies; and 31 studies for human studies). There was a huge variance in cell source in pre-clinical studies both of terms of animal used, location of harvest (fat, marrow, blood or synovium) and allogeneicity. The use of scaffolds, growth factors, number of cell passages and number of cells used was hugely heterogeneous. SHORT CONCLUSIONS: This review offers a comprehensive assessment of the evidence behind the translation of basic science to the clinical practice of cartilage repair. It has revealed a lack of connectivity between the in vitro, pre-clinical and human data and a patchwork quilt of synergistic evidence. Drivers for progress in this space are largely driven by patient demand, surgeon inquisition and a regulatory framework that is learning at the same pace as new developments take place

Effect of Iron Overload and Iron Deficiency on Liver Hemojuvelin Protein

INTRODUCTION: Hemojuvelin (Hjv) is a key component of the signaling cascade that regulates liver hepcidin (Hamp) expression. The purpose of this study was to determine Hjv protein levels in mice and rats subjected to iron overload and iron deficiency. METHODS: C57BL/6 mice were injected with iron (200 mg/kg); iron deficiency was induced by feeding of an iron-deficient diet, or by repeated phlebotomies. Erythropoietin (EPO)-treated mice were administered recombinant EPO at 50 U/mouse. Wistar rats were injected with iron (1200 mg/kg), or fed an iron-deficient diet. Hjv protein was determined by immunoblotting, liver samples from Hjv-/- mice were used as negative controls. Mouse plasma Hjv content was determined by a commercial ELISA kit. RESULTS: Liver crude membrane fraction from both mice and rats displayed a major Hjv-specific band at 35 kDa, and a weaker band of 20 kDa. In mice, the intensity of these bands was not changed following iron injection, repeated bleeding, low iron diet or EPO administration. No change in liver crude membrane Hjv protein was observed in iron-treated or iron-deficient rats. ELISA assay for mouse plasma Hjv did not show significant difference between Hjv+/+ and Hjv-/- mice. Liver Hamp mRNA, Bmp6 mRNA and Id1 mRNA displayed the expected response to iron overload and iron deficiency. EPO treatment decreased Id1 mRNA, suggesting possible participation of the bone morphogenetic protein pathway in EPO-mediated downregulation of Hamp mRNA. DISCUSSION: Since no differences between Hjv protein levels were found following various experimental manipulations of body iron status, the results indicate that, in vivo, substantial changes in Hamp mRNA can occur without noticeable changes of membrane hemojuvelin content. Therefore, modulation of hemojuvelin protein content apparently does not represent the limiting step in the control of Hamp gene expression

Oxidative stress and antioxidant defense in patients with chronic hepatitis C patients before and after pegylated interferon alfa-2b plus ribavirin therapy

BACKGROUND: Oxidative stress could play a role in pathogenesis of hepatitis C virus (HCV) infection. The aim of our study is to determine oxidant/antioxidant status of patients with chronic hepatitis C (CHC), and the effect of pegylated interferon alfa-2b plus ribavirin combination therapy on oxidative stress. METHODS: Nineteen patients with chronic HCV infection and 28 healthy controls were included in the study. In control and patient groups, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, erythrocyte malondialdehyde (MDA) levels, erythrocyte CuZn-superoxide dismutase (SOD), erythrocyte glutathione peroxidase (GSH-Px) activities were measured. After pegylated interferon alfa-2b and ribavirin combination therapy for 48 weeks, these parameters were measured again in the patient group. RESULTS: Serum MDA levels increased significantly in CHC patients (n:19), before the treatment when compared with healthy subjects (n:28) 9.28 ± 1.61, 4.20 ± 1.47 nmol/ml, p < 0.001 respectively. MDA concentration decreased significantly (p < 0.001) after the treatment as well as ALT, AST activity, in erythrocytes of these patients. Average antioxidant enzymes (superoxide dismutase and glutathione peroxidase) were significantly lower in erythrocytes of patients with CHC before treatment compared with the control group (both, p < 0.001). Chronic Hepatitis C patients after pegylated interferon alfa-2b and ribavirin therapy showed values of SOD, GSH-Px were significantly higher than pretreatment levels (both, p < 0.001). CONCLUSION: Our results show that patients with chronic HCV infection are under the influence of oxidative stress associated with lower levels of antioxidant enzymes. These impairments return to level of healthy controls after pegylated interferon alfa-2b plus ribavirin combination therapy of CHC patients. Although interferon and ribavirin are not antioxidants, their antiviral capacity might reduce viral load, and inflammation, and perhaps through this mechanism might reduce virus-induced oxidative stress

Determining the best immunization strategy for protecting African children against invasive Salmonella disease

Background The World Health Organization recently prequalified a typhoid conjugate vaccine (TCV), recommending its use in persons ≥6 months to 45 years residing in typhoid fever (TF)–endemic areas. We now need to consider how TCVs can have the greatest impact in the most vulnerable populations. Methods The Typhoid Fever Surveillance in Africa Program (TSAP) was a blood culture-based surveillance of febrile patients from defined populations presenting at healthcare facilities in 10 African countries. TF and invasive non-typhoidal Salmonella (iNTS) disease incidences were estimated for 0–10 year-olds in one-year age increments. Results Salmonella Typhi and iNTS were the most frequently isolated pathogens; 135 and 94 cases were identified, respectively. Analysis from three countries was excluded (incomplete person-years of observation (PYO) data). Thirty-seven of 123 TF cases (30.1%) and 71/90 iNTS disease cases (78.9%) occurred in children aged <5 years. No TF and 8/90 iNTS infections (8.9%) were observed in infants aged <9 months. The TF incidences (/100 000 PYO) for children aged <1 year and 1 to <2 years were 5 and 39, respectively; the highest incidence was 304 per 100 000 PYO in 4 to <5 year-olds. The iNTS disease incidence in the defined age groups ranged between 81 and 233 per 100 000 PYO, highest in 1 to <2 year-olds. TF and iNTS disease incidences were higher in West Africa. Conclusions High burden of TF detected in young children strengthens the need for TCV introduction. Given the concurrent iNTS disease burden, development of a trivalent vaccine against S. Typhi, S. Typhimurium, and S. Enteritidis may be timely in this region

Statistical Metamodeling for Revealing Synergistic Antimicrobial Interactions

Many bacterial pathogens are becoming drug resistant faster than we can develop new antimicrobials. To address this threat in public health, a metamodel antimicrobial cocktail optimization (MACO) scheme is demonstrated for rapid screening of potent antibiotic cocktails using uropathogenic clinical isolates as model systems. With the MACO scheme, only 18 parallel trials were required to determine a potent antimicrobial cocktail out of hundreds of possible combinations. In particular, trimethoprim and gentamicin were identified to work synergistically for inhibiting the bacterial growth. Sensitivity analysis indicated gentamicin functions as a synergist for trimethoprim, and reduces its minimum inhibitory concentration for 40-fold. Validation study also confirmed that the trimethoprim-gentamicin synergistic cocktail effectively inhibited the growths of multiple strains of uropathogenic clinical isolates. With its effectiveness and simplicity, the MACO scheme possesses the potential to serve as a generic platform for identifying synergistic antimicrobial cocktails toward management of bacterial infection in the future