The Effects of Low and High Concentrations of Luteolin on Cultured Human Endothelial Cells Under Normal and Glucotoxic Conditions: Involvement of Integrin‐Linked Kinase and Cyclooxygenase‐2

Luteolin protects against high glucose (HG)‐induced endothelial dysfunction whereas its cytotoxicity has been reported against normal endothelial cells. This study was undertaken to determine luteolin cytoprotective and cytotoxic dose ranges and to elucidate their respective mechanisms. Luteolin prevented HG‐induced human umbilical vein endothelial cell (HUVEC) death with an EC50 value of 2.0 ± 0.07 μM. The protective effect of luteolin was associated with decreased intracellular reactive oxygen species (ROS) and Ca²⁺ (Cai²⁺) levels and enhanced nitric oxide (NO) production. At high concentrations, luteolin caused HUVEC death in normal glucose (NG) and HG states (LC₅₀ 40 ± 2.23 and 38 ± 1.12 μM, respectively), as represented by increased ROS and Cai²⁺ and decreased NO. Western blots illustrated that exposure to HG increased cyclooxygenase‐2 (COX‐2) and integrin‐linked kinase (ILK) expression. Luteolin at low concentrations suppressed HG‐mediated up‐regulation of COX‐2 but maintained HG‐induced over‐expression of ILK while at high concentrations significantly increased COX‐2 and decreased ILK expression in both HG and NG states. Our data indicated that cytoprotective action of luteolin was manifested with much lower concentrations, by a factor of approximately 20, compared with cytotoxic activity under both normal or glucotoxic conditions. It appears that luteolin exerts its action, in part, by modulating ILK expression which is associated with regulation of COX‐2 expression and NO production in endothelial cells. Copyright © 2014 John Wiley & Sons, Ltd.     

Cost-Effectiveness Analysis of Adding Low Dose Ribavirin to Peginterferon Alfa-2a for Treatment of Chronic Hepatitis C Infected Thalassemia Major Patients in Iran

Background

The prevalence of hepatitis C in Iran is 1% and 18% in general population and thalassemia patients respectively. The cost effectiveness analysis of adding Ribavirin to Peginterferon alfa-2a (PEG IFN alfa-2a) as a combination treatment strategy of chronic hepatitis C in thalassemia patients in comparison with monotherapy could help clinicians and policy makers to provide the best treatment for the patients.

Objectives

In this study we aimed to assess whether adding Ribavirin to PEG IFN alfa-2a is a cost effective strategy in different genotypes and different subgroups of 280 patients with chronic hepatitis C infection from the perspective of society in Iranian setting.

Patients and Methods

A cost effectiveness analysis including all costs and outcomes of treatments for chronic hepatitis C infected thalassemia major patients was conducted. We constructed a decision tree of treatment course in which a hypothetical cohort of 100 patients received “PEG IFN alfa-2a” or “Peg IFN alfa-2a plus Ribavirin.” The cost analysis was based on cost data for 2008 and we used 9300 Iranian Rials (IR Rial) as exchange rate declared by the Iranian Central Bank on that time to calculating costs by US Dollar (USD). To evaluate whether a strategy is cost effective, one time and three times of GDP per capita were used as threshold based on recommendation of the World Health Organization.

Results

The Incremental Cost Effectiveness Ratio (ICER) for combination therapy in genotype-1 and genotypes non-1 subgroups was 2,673 and 19,211 US dollars (USD) per one Sustain Virological Response (SVR), respectively. In low viral load and high viral load subgroups, the ICER was 5,233 and 14,976 USD per SVR, respectively. The calculated ICER for combination therapy in subgroup of patients with previously resistant to monotherapy was 13,006 USD per SVR. Combination therapy in previously resistant patients to combination therapy was a dominant strategy.

Conclusions

Adding low dose of Ribavirin to PEG IFN alfa-2a for treatment of chronic hepatitis C patients with genotype-1 was “highly cost effective” and in patients with low viral load and in previous monotherapy resistant patients was “cost effective.”     

Annexin1 regulates DC efferocytosis and cross-presentation during Mycobacterium tuberculosis infection

The phagocytosis of apoptotic cells and associated vesicles (efferocytosis) by DCs is an important mechanism for both self tolerance and host defense. Although some of the engulfment ligands involved in efferocytosis have been identified and studied in vitro, the contributions of these ligands in vivo remain ill defined. Here, we determined that during Mycobacterium tuberculosis (Mtb) infection, the engulfment ligand annexin1 is an important mediator in DC cross-presentation that increases efferocytosis in DCs and intrinsically enhances the capacity of the DC antigen–presenting machinery. Annexin1-deficient mice were highly susceptible to Mtb infection and showed an impaired Mtb antigen–specific CD8⁺ T cell response. Importantly, annexin1 expression was greatly downregulated in Mtb-infected human blood monocyte–derived DCs, indicating that reduction of annexin1 is a critical mechanism for immune evasion by Mtb. Collectively, these data indicate that annexin1 is essential in immunity to Mtb infection and mediates the power of DC efferocytosis and cross-presentation.     

Body mass index is associated with risk of reoperation and revision after primary total hip arthroplasty: a study of the Swedish Hip Arthroplasty Register including 83,146 patients

Background and purpose — The prevalence of obesity is on the rise, becoming a worldwide epidemic. The main purpose of this register-based observational study was to investigate whether different BMI classes are associated with increased risk of reoperation within 2 years, risk of revision within 5 years, and the risk of dying within 90 days after primary total hip arthroplasty (THA). We hypothesized that increasing BMI would increase these risks.

Patients and methods — We analyzed a cohort of 83,146 patients who had undergone an elective THA for primary osteoarthritis between 2008 and 2015 from the Swedish Hip Arthroplasty Register (SHAR). BMI was classified according to the World Health Organization (WHO) into 6 classes: < 18.5 as underweight, 18.5–24.9 as normal weight, 25–29.9 as overweight, 30–34.9 as class I obesity, 35–39.9 as class II obesity, and ≥ 40 as class III obesity.

Results — Both unadjusted and adjusted parameter estimates showed increasing risk of reoperation at 2 years and revision at 5 years with each overweight and obesity class, mainly due to increased risk of infection. Uncemented and reversed hybrid fixations and surgical approaches other than the posterior were all associated with increased risk. Obesity class III (≥ 40), male sex, and increasing ASA class were associated with increased 90-day mortality.

Interpretation — Increasing BMI was associated with 2-year reoperation and 5-year revision risks after primary THA where obese patients have a higher risk than overweight or normal weight patients. As infection seems to be the main cause, customizing preoperative optimization and prophylactic measures for obese patients may help reduce risk.     

Association between patient survival following reoperation after total hip replacement and the reason for reoperation: an analysis of 9,926 patients in the Swedish Hip Arthroplasty Register

Background and purpose — The association between long-term patient survival and elective primary total hip replacement (THR) has been described extensively. The long-term survival following reoperation of THR is less well understood. We investigated the relative survival of patients undergoing reoperation following elective THR and explored an association between the indication for the reoperation and relative survival.

Patients and methods — In this observational cohort study we selected the patients who received an elective primary THR and subsequent reoperations during 1999–2017 as recorded in the Swedish Hip Arthroplasty Register. The selected cohort was followed until the end of the study period, censoring or death. The indications for 1st- and eventual 2nd-time reoperations were analyzed and the relative survival ratio of the observed survival and the expected survival was determined.

Results — There were 9,926 1st-time reoperations and of these 2,558 underwent further reoperations. At 5 years after the latest reoperation, relative survival following 1st-time reoperations was 0.94% (95% CI 0.93–0.96) and 0.90% (CI 0.87–0.92) following 2nd-time reoperations. At 5 years patients with a 1st-time reoperation for aseptic loosening had higher survival than expected; however, reoperations performed for periprosthetic fracture, dislocation, and infection had lower survival.

Interpretation — The relative survival following 1st- and 2nd-time reoperations in elective THR patients differs by reason for reoperation. The impact of reoperation on life expectancy is more obvious for infection/dislocation and periprosthetic fracture.     

A standardized approach to assessing physician expectations and perceptions of continuing medical education

INTRODUCTION: Rapidly expanding science and mandates for maintaining credentials place increasing demands on continuing medical education (CME) activities to provide information that is current and relevant to patient care. Quality may be seen as the perceived level of service measured against consumer expectations. Standard tools have not been developed to determine how well CME activities meet consumer expectations. METHODS: A widely used approach for evaluating perceptions of service quality in other fields, SERVQUAL, was adapted for CME by eliciting perspectives from physician consumers of CME and CME providers through nominal group techniques. These perspectives were used to develop a CMEQUAL evaluation survey instrument. Feasibility testing was conducted. Data were analyzed and items were tested for internal consistency. RESULTS: CME participants were individuals willing to complete items related to expectations before participation and perceptions after participation in a CME activity. Of the CME activity participants who provided CMEQUAL rating data for the study, 43% rated their overall perceptions of the CME activity below their overall expectations. CME activities most clearly met participant expectations in providing fair and balanced evidence-based content. Areas of lower priority for participants included opportunities for self-assessment, solving cases, and interactive learning. Two areas highly valued by participants but not adequately addressed by CME activities were (1) translating trial data to patient seen in practice and (2) addressing barriers to optimal patient management. DISCUSSION: Developing standards for evaluating physician perceptions of the quality of CME activities may assist CME providers in improving the effectiveness of CME activities in meeting physician learning needs.     

Low risk of intra-abdominal infections in rectal cancer patients treated with Hartmann’s procedure: a report from a national registry

Purpose

To describe the postoperative surgical complications in patients with rectal cancer undergoing Hartmann’s procedure (HP).

Methods

Data were retrieved from the Swedish Colorectal Cancer Registry for all patients with rectal cancer undergoing HP in 2007–2014. A retrospective analysis was performed using prospectively recorded data. Characteristics of patients and risk factors for intra-abdominal infection and re-laparotomy were analysed.

Results

Of 10,940 patients resected for rectal cancer, 1452 (13%) underwent HP (median age, 77 years). The American Society of Anesthesiologists (ASA) score was 3–4 in 43% of patients; 15% had distant metastases and 62% underwent a low HP. The intra-abdominal infection rate was 8% and re-laparotomy rate was 10%. Multivariable logistic regression analysis identified preoperative radiotherapy (OR, 1.78; 95% CI, 1.14–2.77), intra-operative bowel perforation (OR, 1.99; 95% CI, 1.08–3.67), T4 tumours (OR, 1.68; 95% CI 1.04–2.69) and female gender (OR, 1.73; 95% CI, 1.15–2.61) as risk factors for intra-abdominal infection. ASA score 3–4 (OR, 1.62; 95% CI, 1.12–2.34), elevated BMI (OR, 1.05; 95% CI, 1.02–1.09) and female gender (OR, 2.06; CI, 1.41–3.00) were risk factors for re-laparotomy after HP. The rate of intra-abdominal infection was not increased after a low HP.

Conclusions

Despite older age and co-morbidities including more advanced cancer, patients undergoing Hartmann’s procedure had low rates of serious postoperative complications and re-laparotomy. A low HP was not associated with a higher rate of intra-abdominal infection. HP seems to be appropriate for old and frail patients with rectal cancer.

     

A program encouraging early defibrillation results in improved in-hospital resuscitation efficacy

OBJECTIVES: The purpose of this study was to determine whether survival to discharge after in-hospital cardiopulmonary arrest could be improved by a program encouraging early defibrillation that included switching from monophasic to biphasic devices. BACKGROUND: In-hospital resuscitation continues to have a low success rate. Biphasic waveform devices have demonstrated characteristics that might improve survival, and outside the hospital, automated external defibrillators (AEDs) have shown promise in improving survival of patients suffering cardiopulmonary arrest. METHODS: A program including education and replacement of all manual monophasic defibrillators with a combination of manual biphasic defibrillators used in AED mode and AEDs in all outpatient clinics and chronic care units was implemented. RESULTS: With program implementation, the percentage survival of all patients with resuscitation events improved 2.6-fold, from 4.9% to 12.8%. Factors independently predicting survival included event location outside an intensive care unit, younger age, an initial rhythm of pulseless ventricular tachycardia (VT) or ventricular fibrillation (VF), pre-arrest beta-blocker, and program initiation. The outcome was independent of gender, race, work shift, number of previous resuscitation attempts, body mass index, comorbidity index, presence of diabetes, presence of hypertension, or use of angiotensin-converting enzyme inhibitors. The improvement in mortality was attributable solely to an effect on patients presenting with VT/VF. Patients with these initial rhythms were 14-fold (odds ratio = 0.07 of death, confidence interval = 0.02 to 0.3) more likely to survive to discharge after program initiation. Automated external defibrillators performed similarly to biphasic manual defibrillators in AED mode. CONCLUSIONS: A program including education and use of biphasic manual defibrillators in AED mode and selective use of AEDs improved survival to discharge in hospitalized patients suffering from cardiopulmonary arrest.     

The preventive and therapeutic potential of natural polyphenols on influenza

Influenza virus belongs to orthomyxoviridae family. This virus is a major public health problems, with high rates of morbidity and mortality. Despite a wide range of pharmacotherapeutic choices inhibiting specific sequences of pathological process of influenza, developing more effective therapeutic options is an immediate challenge. In this paper, a comprehensively review of natural polyphenolic products used worldwide for the management of influenza infection is presented. Cellular and molecular mechanisms of the natural polyphenols on influenza infection including suppressing virus replication cycle, viral hemagglutination, viral adhesion and penetration into the host cells, also intracellular transductional signaling pathways have been discussed in detail. Based on cellular, animal, and human evidence obtained from several studies, the current paper demonstrates that natural polyphenolic compounds possess potential effects on both prevention and treatment of influenza, which can be used as adjuvant therapy with conventional chemical drugs for the management of influenza and its complications.