Persistent infection with Staphylococcus pseudintermedius in an adult oncology patient with transmission from a family dog.

Staphylococcus pseudintermedius is a well known commensal organism of dogs but also a canine opportunistic pathogen. Reports of this organism being recovered from specimens from humans might suggest an increase prevalence in human infections and/or improved diagnostic leading to more accurate identification. Here we report a case of persistent S. pseudintermedius infection in an adult female oncology patient including colonization of the tip of an indwelling catheter. Diligence by laboratories in correctly isolating and identifying this pathogen (including susceptibility testing) is essential for optimal patient care.

In silico Design, Virtual Screening and Synthesis of Novel Electrolytic Solvents.

We report the building, validation and release of QSPR (Quantitative Structure Property Relationship) models aiming to guide the design of new solvents for the next generation of Li-ion batteries. The dataset compiled from the literature included oxidation potentials (Eox ), specific ionic conductivities (κ), melting points (Tm ) and boiling points (Tb ) for 103 electrolytes. Each of the resulting consensus models assembled 9-19 individual Support Vector Machine models built on different sets of ISIDA fragment descriptors.(1) They were implemented in the ISIDA/Predictor software. Developed models were used to screen a virtual library of 9965 esters and sulfones. The most promising compounds prioritized according to theoretically estimated properties were synthesized and experimentally tested.

Randomized Trial Based on the Common-Sense Model of Self-regulation to Increase Child Dental Visits.

INTRODUCTION: School screening and the note home (pinned to a backpack) informing parents/caregivers that their child needs to see a dentist have not been effective. OBJECTIVES: The Family Access to a Dentist Study (FADS) evaluated the effectiveness of school interventions based on the common-sense model of self-regulation (CSM) among K-4 children needing restorative treatment. METHODS: FADS was a multisite double-blind randomized controlled trial with 5 arms. FADS tested a CSM-driven referral letter and dental information guide (DIG) to move caregivers from inaccurate to accurate perceptions of dental caries. Six school districts from Ohio and Washington (14 schools) participated in school years 2015 to 2016 and 2016 to 2017. A total of 611 caregivers were randomized, and 86% (n = 597 children) completed the exit examination. The primary outcome was receipt of care based on a change in oral health status determined clinically within 1 school year. RESULTS: In accordance with our primary aims, 5 arms were collapsed into 3: CSM letter and reduced CSM letter (combined), CSM letter + DIG and reduced CSM letter + reduced DIG (combined), and standard letter. Among all sites, 39.7% received restorative care (237 of 597). Combined analysis of sites revealed that the CSM referral letter (with and without the DIG) did not increase dental visits when compared with the standard letter. However, for combined sites (East Cleveland, Ohio; Washington), the CSM + DIG increased dental visits when compared with standard letter in univariate analysis (51.3% vs. 40.9%), indicating 1.6-times increased odds of a dental visit (95% CI, 0.97 to 2.58) after imputation and adjustment for covariates. The CSM + DIG group had 1.9-times increased odds (95% CI, 1.21 to 3.08) of care when compared the CSM letter alone. CONCLUSION: A CSM-driven approach to informing caregivers of the chronic nature of caries with resources in an illustrative manner can increase the benefit of school oral health screening (ClinicalTrials.gov NCT02395120). KNOWLEDGE TRANSFER STATEMENT: A school dental referral (note home) that tells a parent that the child has cavities has not been effective. In this trial, a referral based on the common-sense model of self-regulation increased follow-up care for children with restorative needs.

Class of cooperative stochastic models: Exact and approximate solutions, simulations, and experiments using ionic self-assembly of nanoparticles.

We present exact and approximate results for a class of cooperative sequential adsorption models using matrix theory, mean-field theory, and computer simulations. We validate our models with two customized experiments using ionically self-assembled nanoparticles on glass slides. We also address the limitations of our models and their range of applicability. The exact results obtained using matrix theory can be applied to a variety of two-state systems with cooperative effects.

[Extended coronary dissection caused by severe polytrauma with contusio cordis : Venoarterial ECMO-assisted percutaneous coronary intervention]. / Komplexe Koronardissektion bei Contusio cordis nach Polytrauma : Venoarterielle ECMO-unterstützte interventionelle Versorgung.

Treatment of a patient with acute cardiac failure due to a contusio cordis after polytrauma by an interdisciplinary team is reported. Shortly after admission to our shock room, the patient developed cardiogenic shock caused by an extended coronary dissection. After interim cardiopulmonary resuscitation, the patient was stabilized by venoarterial extracorporeal membrane oxygenation (ECMO) and subsequent complex coronary artery intervention in the heart catheter laboratory. Despite the increased left ventricular function which enabled partial weaning from the ECMO, the patient died of multiple organ failure 10 days after admission.

[Professional image of anesthetists in the general public. Influence of provision of information and previous experience with the discipline]. / Berufsbild des Anästhesisten in der Öffentlichkeit. Einfluss von Vorinformation und Vorerfahrungen mit dem Fach.

BACKGROUND: The profession of the anesthetist in Germany includes the disciplines anesthesia, intensive care, emergency and pain medicine. Despite the versatility and competence of the profession, patients do not appear to have recognized anesthesiology as a medical discipline or anesthetists as medical doctors. AIM: This study was conducted with the aim of estimating how previous experience and information gathered before contact with the anesthetist for premedication have influenced and changed the perception of patients with regards to the professional fields and the characteristics of anesthetists. MATERIAL AND METHODS: A total of 3,950 patients from 3 German hospitals were asked to answer a questionnaire handed out by the assistance nurse in the premedication area prior to the medical consultation with the duty anesthetist. The questions involved the patient perception of the discipline, the characteristics of anesthetists and also evaluated the patient previous experience and provision of information. According to the answers 1,753 patients were considered eligible for the study and were categorized into subgroups I-IV (group I interested and experienced with operations, group II interested but inexperienced, group III uninterested but experienced and group IV neither interested nor experienced) for statistical analysis. RESULTS: Of the respondents 56.2 % had obtained previous information from a general practitioner followed by acquaintances (21.4 %) and the internet (19.9 %), which significantly differed with age. Interested and experienced patients showed the best perception of the profession. Often, the knowledge of interested and uninterested persons did not significantly differ. Interested patients and those with experience of anesthesiology had the best knowledge of anesthesiology. Performing anesthesia was most often identified by all groups (50.9-95.3 %) as a function of anesthetists while the other professional fields were recognized correctly by only 5.8-26.6 %. Depending on the group 41.0-84.4 % regarded anesthetists as medical doctors. Only 15.0-78.3 % of other attributes were associated with anesthetists. CONCLUSION: Unfortunately, the perception of patients on the versatility and characteristics of anesthetists are poorly developed. However, the knowledge differs significantly depending on previous experience and gathered information. Interestingly patients with previous experience mostly showed better knowledge compared to interested patients. Results suggest that personal interaction, patient-physician communication in general and improved collaboration between general practitioners and anesthetists are the key elements for better patient knowledge, which could lead to increased patient satisfaction.

Ambulatory blood pressure monitoring: Is 24 hours necessary?

BACKGROUND: The variability of blood pressure (BP) makes any single measurement a poor indicator of a patient's true BP. Multiple studies have confirmed the superiority of ambulatory BP measurements over clinic BP measurements in predicting cardiovascular risk; however, this method presents the problem of patient acceptance as it causes frequent arm discomfort and sleep disturbance. We hypothesized that 6 h of daytime BP measurements would result in slightly higher BP readings, yet reveal similar clinical decision making when compared to 24 h of BP measurements. METHODS: The source for writing this article was a retrospective analysis of 30 patients who underwent ambulatory BP monitoring. Data obtained included: age, sex, ethnicity, baseline medical problems, medications, laboratory values, reason given for ordering 24-h ambulatory BP measurements, ambulatory BP measurements, and a subsequent decision to change medication. RESULTS: The average BP of the 24-h measurements was 127/75 mm Hg and the average BP of the 6-h daytime measurements was 131/79 mm Hg (SD 15, p = 0.009). Twenty-six out of 30 patients were at goal or pre-hypertensive. Two out of 30 patients had stage 1 hypertension and 2 out of 30 patients had stage 2 hypertension. Thirteen out of 30 patients had nocturnal dipping. Twelve out of 30 patients had a change in medication, but those changes were not associated with the presence or absence of nocturnal dipping (p = 0.5) or other factors beyond mean BP. CONCLUSIONS: Although there was a statistically significant, 4 mm Hg systolic difference between 24-h and 6-h average BP readings, there was no evidence that this difference led to changes in clinical management. The presence or absence of nocturnal dipping was not associated with a change in medication. We conclude that 6-h daytime ambulatory BP measurements provide sufficient information to guide clinical decision making without the problems of patient acceptance, arm discomfort, and sleep disturbance associated with 24-h BP measurements.

Civilian injuries due to unexploded ordnance in military training areas in southern Israel.

BACKGROUND: The problem of unexploded ordnance (UXO) is global and is usually associated with active or former war zones. Civilian injuries due to UXO in military training areas are not common. METHODS: This is a retrospective case series study based on prospectively collected data on patients who sustained injuries from UXO explosions and were admitted to the Soroka University Trauma Center during a five-year period. RESULTS: Twelve patients were included in this series. All patients were Bedouin and the distribution of injuries was concentrated around the head and upper and lower extremities, with sparing of the torso. CONCLUSION: Awareness and implementation of preventive measures are expected to reduce the incidence of this type of injury.

A randomised controlled trial comparing sugammadex and neostigmine at different depths of neuromuscular blockade in patients undergoing laparoscopic surgery.

Deep neuromuscular blockade during certain surgical procedures may improve operating conditions. Sugammadex can be used to reverse deep neuromuscular blockade without waiting for spontaneous recovery. This randomised study compared recovery times from neuromuscular blockade induced by rocuronium 0.6 mg.kg(-1), using sugammadex 4 mg.kg(-1) administered at 1-2 post-tetanic count (deep blockade) or neostigmine 50 µg.kg(-1) (plus atropine 10 µg.kg(-1)) administered at the re-appearance of the second twitch of a train-of-four stimulation (moderate blockade), in patients undergoing laparoscopic surgery. The primary efficacy variable was the time from the start of sugammadex/neostigmine administration to recovery of the train-of-four ratio to 0.9. Patients receiving sugammadex recovered 3.4 times faster than patients receiving neostigmine (geometric mean (95% CI) recovery times of 2.4 (2.1-2.7) and 8.4 (7.2-9.8) min, respectively, p<0.0001). Moreover, 94% (62/66) of sugammadex-treated patients recovered within 5 min, vs 20% (13/65) of neostigmine-treated patients, despite the difference in the depth of neuromuscular blockade at the time of administration of both drugs. The ability to provide deep neuromuscular blockade throughout the procedure but still permit reversal at the end of surgery may enable improved surgical access and an enhanced visual field.

A collaboratively-derived science-policy research agenda.

The need for policy makers to understand science and for scientists to understand policy processes is widely recognised. However, the science-policy relationship is sometimes difficult and occasionally dysfunctional; it is also increasingly visible, because it must deal with contentious issues, or itself becomes a matter of public controversy, or both. We suggest that identifying key unanswered questions on the relationship between science and policy will catalyse and focus research in this field. To identify these questions, a collaborative procedure was employed with 52 participants selected to cover a wide range of experience in both science and policy, including people from government, non-governmental organisations, academia and industry. These participants consulted with colleagues and submitted 239 questions. An initial round of voting was followed by a workshop in which 40 of the most important questions were identified by further discussion and voting. The resulting list includes questions about the effectiveness of science-based decision-making structures; the nature and legitimacy of expertise; the consequences of changes such as increasing transparency; choices among different sources of evidence; the implications of new means of characterising and representing uncertainties; and ways in which policy and political processes affect what counts as authoritative evidence. We expect this exercise to identify important theoretical questions and to help improve the mutual understanding and effectiveness of those working at the interface of science and policy.

Aerosolized semifluorinated alkanes as excipients are suitable for inhalative drug delivery--a pilot study.

Semifluorinated alkanes (SFAs) have been described as potential excipients for pulmonary drug delivery, but proof of their efficacy is still lacking. We tested whether SFA formulations with the test drug ibuprofen can be nebulised and evaluated their pharmacokinetics. Physico-chemical properties of five different ibuprofen formulations were evaluated: an aqueous solution (H2O), two different SFAs (perfluorohexyloctane (F6H8), perfluorobutylpentane (F4H5)) with and without ethanol (SFA/EtOH). Nebulisation was performed with a jet catheter system. Inhalative characteristics were evaluated by laser diffraction. A confirmative animal study with an inhalative single-dose (6 mg/kg) of ibuprofen with each formulation was performed in anaesthetised healthy rabbits. Plasma samples at defined time points and lung tissue harvested after the 6-h study period were analyzed by HPLC-MS/MS. Pharmacokinetics were calculated using a non-compartment model. All formulations were nebulisable. No differences in aerodynamic diameters (MMAD) were detected between SFA and SFA/EtOH. The ibuprofen plasma concentration-time curve (AUC) was highest with F4H5/EtOH. In contrast, F6H8/EtOH had the highest deposition of ibuprofen into lung tissue but the lowest AUC. All tested SFA and SFA/EtOH formulations are suitable for inhalation. F4H5/EtOH formulations might be used for rapid systemic availability of drugs. F6H8/EtOH showed intrapulmonary deposition of the test drug.

The effects of frequent nocturnal home hemodialysis: the Frequent Hemodialysis Network Nocturnal Trial.

Prior small studies have shown multiple benefits of frequent nocturnal hemodialysis compared to conventional three times per week treatments. To study this further, we randomized 87 patients to three times per week conventional hemodialysis or to nocturnal hemodialysis six times per week, all with single-use high-flux dialyzers. The 45 patients in the frequent nocturnal arm had a 1.82-fold higher mean weekly stdKt/V(urea), a 1.74-fold higher average number of treatments per week, and a 2.45-fold higher average weekly treatment time than the 42 patients in the conventional arm. We did not find a significant effect of nocturnal hemodialysis for either of the two coprimary outcomes (death or left ventricular mass (measured by MRI) with a hazard ratio of 0.68, or of death or RAND Physical Health Composite with a hazard ratio of 0.91). Possible explanations for the left ventricular mass result include limited sample size and patient characteristics. Secondary outcomes included cognitive performance, self-reported depression, laboratory markers of nutrition, mineral metabolism and anemia, blood pressure and rates of hospitalization, and vascular access interventions. Patients in the nocturnal arm had improved control of hyperphosphatemia and hypertension, but no significant benefit among the other main secondary outcomes. There was a trend for increased vascular access events in the nocturnal arm. Thus, we were unable to demonstrate a definitive benefit of more frequent nocturnal hemodialysis for either coprimary outcome.

Outcomes after simultaneous pancreas and kidney transplantation and the discriminative ability of the C-peptide measurement pretransplant among type 1 and type 2 diabetes mellitus.

BACKGROUND: Earlier studies reporting outcomes after pancreas transplantation have included a combination of C-peptide cutoffs and clinical criteria to classify type 2 diabetes mellitus (T2DM). However, because the kidney is the major site for C-peptide catabolism, C-peptide is unreliable to discriminate the type of diabetes in patients with kidney disease. METHODS: To improve the discriminative power and better classify the type of diabetes, we used a composite definition to identify T2DM: presence of C-peptide, negative glutamic acid decarboxylase antibody, absence of diabetic ketoacidosis, and use of oral hypoglycemics. Additionally among T2DM patients with end-stage renal disease (ESRD), body mass index of <30 kg/m(2) and use of <1 u/kg of insulin per day were selection criteria for suitablity for simultaneous pancreas and kidney transplantation (SPKT). We compared graft and patient survival between T1DM and T2DM after SPKT. RESULTS: Our study cohort consisted of 80 patients, 10 of whom were assigned as T2DM based on our study criteria. Approximately 15% of patients with T1DM had detectable C-peptide. Cox regression survival analyses found no significant differences in allograft (pancreas and kidney) or patient survival between the 2 groups. The mean creatinine clearance at 1 year estimated by the modification of Diet in Renal Disease (MDRD) equation was not significantly different between the 2 groups. Among those with 1 year of follow-up, all patients with T2DM had glycosylate hemoglobin of <6.0 at 1 year versus 92% of those with T1DM. CONCLUSION: SPKT should be considered in the therapeutic armamentarium for renal replacement in selected patients with T2DM and ESRD. Use of C-peptide measurements for ESRD patients can be misleading as the sole criterion to determine the type of diabetes.

Semifluorinated alkanes--a new class of excipients suitable for pulmonary drug delivery.

INTRODUCTION: Semifluorinated alkanes (SFAs) are considered as diblock molecules with fluorocarbon and hydrocarbon segments. Unlike Perfluorocarbons (PFCs), SFAs have the potential to dissolve several lipophilic or water-insoluble substances. This makes them possibly suitable as new excipients for inhalative liquid drug carrier systems. PURPOSE: The aim of the study was to compare physico-chemical properties of different SFAs and then to test their respective effects in healthy rabbit lungs after nebulisation. METHODS: Physico-chemical properties of four different SFAs, i.e. Perfluorobutylpentane (F4H5), Perfluorohexylhexane (F6H6), Perfluorohexyloctane (F6H8) and Perfluorohexyldodecane (F6H12) were measured. Based on these results, aerosol characteristics of two potential candidates suitable as excipients for pulmonary drug delivery, i.e. F6H8 and F4H5, were determined by laser light diffraction. Tracheotomised and ventilated New Zealand White rabbits were nebulised with either a high- or a low dose of SFAs (F6H8(low/high) and F4H5(low/high)) or saline (NaCl). Ventilated healthy animals served as controls (Sham). Arterial blood gases, lung mechanics, heart rate and blood pressure were recorded prior to nebulisation and in 30 min intervals during the 6-h study period. RESULTS: Out of the four SFAs studied initially, no satisfactory behaviour as a solvent has to be expected because of low lipophilicity for F6H6. Output rate during aerosolisation was very low for F6H12. F6H8 and F4H5 presented comparable aerosolisation characteristics and lipophilicity and were therefore tested in the in vivo model. Aerosol therapy, either SFAs or saline, impaired paO2/FiO2 ratio, dynamic lung compliance and respiratory mechanics in all groups, except for F4H5(low) group which behaved like the control group (Sham). F4H5(low) had no adverse effects on gas exchange or pulmonary mechanics. CONCLUSIONS: Perfluorobutylpentane (F4H5) in a low-dose application may be suitable as a new inhalable excipient in SFA-based pulmonary drug delivery systems for lipophilic or water-insoluble substances.

Influence of high dose tumescent local anaesthesia with prilocaine on systemic interleukin (IL)-6, IL-8 and tumour necrosis factor-α.

BACKGROUND AND OBJECTIVE: Tumescent local anaesthesia (TLA) with high prilocaine doses leads to formation of methemoglobin (MHb) which is known to be a potent activator of pro-inflammatory endothelial cell response in vitro. As TLA is widely used for large dermatological resections, the aim of this study was to investigate the effects of high prilocaine doses on the systemic inflammatory response in vivo and its clinical relevance. METHODS: This prospective study examines the influence of MHb on serum interleukin (IL)-6, IL-8 and tumour necrosis tumour necrosis (TNF)-α levels up to 72 h after application of TLA with prilocaine in doses higher than 600 mg. RESULTS: A total of 30 patients received prilocaine in a median dose of 1500 mg (range: 880-4160 mg) for large resections. Peak prilocaine serum concentration was reached 4 h (0.72 ± 0.07 µg/mL), the maximum concentration of MHb (7.43 ± 0.87%) and IL-6 (28.4 ± 4.1 U/L) 12 h after TLA application. TNF-α and IL-8 release were not found significantly increased. Three patients developed MHb concentrations >15%. CONCLUSIONS: This clinical study shows for the first time that a high prilocaine serum concentration leads in vivo to elevated systemic levels of IL-6 but not of IL-8 and TNF-α because of initial high MHb levels. Because of possible and unpredictable high MHb concentrations, TLA should only be performed with prilocaine in doses of 2.5 mg/kg. In general, new solutions of TLA are necessary to achieve adequate anaesthesia for large dermatological resections to decrease the risk of methemoglobinaemia.

The role of continuous positive airway pressure in the treatment of hypertension in patients with obstructive sleep apnea-hypoapnea syndrome: a review of randomized trials.

Obstructive sleep apnea-hypoapnea syndrome (OSA) is a disorder that results in repetitive occlusion of the airway and hypoxemia during sleep. Epidemiologic studies have associated this disorder with increased cardiovascular morbidity and mortality. Systemic hypertension is prevalent among patients with OSA and has been recognized as a common identifiable cause of hypertension. Nasal continuous positive airway pressure (nCPAP) ventilation is an effective therapy for OSA and it may additionally reduce blood pressure. The use of nCPAP ventilation to treat hypertension in patients with OSA has been studied extensively. However, whether it is effective in treating hypertension in this population remains unclear. This review evaluates the recent literature that investigates the effects of nCPAP ventilation on hypertension in patients with OSA.

Hydrocortisone aceponate activity and benefit/risk ratio in relation to reference topical glucocorticoids.

The evaluation of the benefit/risk ratio (BRR) for topical glucocorticoids (TGC) allows the comparison of active ingredients and thereby includes aspects of dosage (blanching response, BR) as well as adverse effects (skin atrophy). In the present study, the BRR of hydrocortisone aceponate, prednicarbate and betamethasone valerate was investigated according to an adapted procedure for investigating the BR. The main difference is the longer application period of the investigational substance without occlusion. Thus, the pharmacokinetic characteristics of all of the systems are considered more intensely and the penetration conditions are designed in a realistic way, namely oriented towards the preparation in order to improve the significance and relevance of the BRR for practical use. The results demonstrate that the investigated substances also show differences in the extent of the BR, but on the other hand they show that the improved penetration characteristics of the double-esterified compounds are clearly less effective. In comparison to the BRR, this results to a large extent in a balanced picture without relevant advantages for single preparations. Nevertheless, the already mentioned positive characteristics of the investigated TGC and the positive practical clinical experiences have been approved. Further investigations have to show whether the method presented here for investigating the BR offers advantages in the comparative assessment of TGC.

Modulation of brain dead induced inflammation by vagus nerve stimulation.

Because the vagus nerve is implicated in control of inflammation, we investigated if brain death (BD) causes impairment of the parasympathetic nervous system, thereby contributing to inflammation. BD was induced in rats. Anaesthetised ventilated rats (NBD) served as control. Heart rate variability (HRV) was assessed by ECG. The vagus nerve was electrically stimulated (BD + STIM) during BD. Intestine, kidney, heart and liver were recovered after 6 hours. Affymetrix chip-analysis was performed on intestinal RNA. Quantitative PCR was performed on all organs. Serum was collected to assess TNFalpha concentrations. Renal transplantations were performed to address the influence of vagus nerve stimulation on graft outcome. HRV was significantly lower in BD animals. Vagus nerve stimulation inhibited the increase in serum TNFalpha concentrations and resulted in down-regulation of a multiplicity of pro-inflammatory genes in intestinal tissue. In renal tissue vagal stimulation significantly decreased the expression of E-selectin, IL1beta and ITGA6. Renal function was significantly better in recipients that received a graft from a BD + STIM donor. Our study demonstrates impairment of the parasympathetic nervous system during BD and inhibition of serum TNFalpha through vagal stimulation. Vagus nerve stimulation variably affected gene expression in donor organs and improved renal function in recipients.

The carbon monoxide releasing molecule (CORM-3) inhibits expression of vascular cell adhesion molecule-1 and E-selectin independently of haem oxygenase-1 expression.

BACKGROUND AND PURPOSE: Although carbon monoxide (CO) can modulate inflammatory processes, the influence of CO on adhesion molecules is less clear. This might be due to the limited amount of CO generated by haem degradation. We therefore tested the ability of a CO releasing molecule (CORM-3), used in supra-physiological concentrations, to modulate the expression of vascular cell adhesion molecule (VCAM)-1 and E-selectin on endothelial cells and the mechanism(s) involved. EXPERIMENTAL APPROACH: Human umbilical vein endothelial cells (HUVECs) were stimulated with tumour necrosis factor (TNF)-alpha in the presence or absence of CORM-3. The influence of CORM-3 on VCAM-1 and E-selectin expression and the nuclear factor (NF)-kappaB pathway was assessed by flow cytometry, Western blotting and electrophoretic mobility shift assay. KEY RESULTS: CORM-3 inhibited the expression of VCAM-1 and E-selectin on TNF-alpha-stimulated HUVEC. VCAM-1 expression was also inhibited when CORM-3 was added 24 h after TNF-alpha stimulation or when TNF-alpha was removed. This was paralleled by deactivation of NF-kappaB and a reduction in VCAM-1 mRNA. Although TNF-alpha removal was more effective in this regard, VCAM-1 protein was down-regulated more rapidly when CORM-3 was added. CORM-3 induced haem oxygenase-1 (HO-1) in a dose- and time-dependent manner, mediated by the transcription factor, Nrf2. CORM-3 was still able to down-regulate VCAM-1 expression in HUVEC transfected with siRNA for HO-1 or Nrf2. CONCLUSIONS AND IMPLICATIONS: Down-regulation of VCAM and E-selectin expression induced by CORM-3 was independent of HO-1 up-regulation and was predominantly due to inhibition of sustained NF-kappaB activation.

Results of the Avonex Combination Trial (ACT) in relapsing-remitting MS.

OBJECTIVE: To assess the safety, tolerability, and efficacy of interferon beta-1a (IFNbeta-1a) combined with methotrexate (MTX), i.v. methylprednisolone (IVMP), or both in patients with relapsing-remitting multiple sclerosis (RRMS) with continued disease activity on IFNbeta-1a monotherapy. METHODS: Eligibility criteria included RRMS, Expanded Disability Status Scale score 0-5.5, and > or = 1 relapse or gadolinium-enhancing MRI lesion in the prior year on IFNbeta-1a monotherapy. Participants continued weekly IFNbeta-1a 30 microg i.m. and were randomized in a 2 x 2 factorial design to adjunctive weekly placebo or MTX 20 mg p.o., with or without bimonthly IVMP 1,000 mg/day for 3 days. The primary endpoint was new or enlarged T2 lesion number at month 12 vs baseline. The study was industry-supported, collaboratively designed, and governed by an investigator Steering Committee with independent Advisory and Data Safety Monitoring committees. Study operations, MRI analyses, and aggregated data were managed by an academic coordinating center. RESULTS: The 313 participants had clinical and MRI characteristics typical of RRMS. Combinations of IFNbeta-1a with MTX or IVMP were generally safe and well tolerated. Although trends suggesting modest benefit were seen for some outcomes for IVMP, the results did not demonstrate significant benefit for either adjunctive therapy. The data suggested IVMP reduced anti-IFNbeta neutralizing antibody titers. CONCLUSIONS: This trial did not demonstrate benefit of adding low-dose oral methotrexate or every other month IV methylprednisolone to interferon beta-1a in relapsing-remitting multiple sclerosis.