Poly-N-acetyl glucosamine fibers are synergistic with vacuum-assisted closure in augmenting the healing response of diabetic mice.

BACKGROUND: Vacuum-assisted closure (VAC) has become the preferred modality to treat many complex wounds but could be further improved by methods that minimize bleeding and facilitate wound epithelialization. Short fiber poly-N-acetyl glucosamine nanofibers (sNAG) are effective hemostatic agents that activate platelets and facilitate wound epithelialization. We hypothesized that sNAG used in combination with the VAC device could be synergistic in promoting wound healing while minimizing the risk of bleeding. METHODS: Membranes consisting entirely of sNAG nanofibers were applied immediately to dorsal excisional wounds of db/db mice followed by application of the VAC device. Wound healing kinetics, angiogenesis, and wound-related growth factor expression were measured. RESULTS: The application of sNAG membranes to wounds 24 hours before application of the VAC device was associated with a significant activation of wounds (expression of PDGF, TGFβ, EGF), superior granulation tissue formation rich in Collagen I as well as superior wound epithelialization (8.6% ± 0.3% vs. 1.8% ± 1.1% of initial wound size) and wound contraction. CONCLUSIONS: The application of sNAG fiber-containing membranes before the application of the polyurethane foam interface of VAC devices leads to superior healing in db/db mice and represents a promising wound healing adjunct that can also reduce the risk of bleeding complications.

Issuance of patient reminders for influenza vaccination by US-based primary care physicians during the first year of universal influenza vaccination recommendations.

To estimate the number of physician-reported influenza vaccination reminders during the 2010-2011 influenza season, the first influenza season after universal vaccination recommendations for influenza were introduced, we interviewed 493 members of the Physicians Consulting Network. Patient vaccination reminders are a highly effective means of increasing influenza vaccination; nonetheless, only one quarter of the primary care physicians interviewed issued influenza vaccination reminders during the first year of universal vaccination recommendations, highlighting the need to improve office-based promotion of influenza vaccination.

Artifact-free coronary magnetic resonance angiography and coronary vessel wall imaging in the presence of a new, metallic, coronary magnetic resonance imaging stent.

BACKGROUND: Coronary in-stent restenosis cannot be directly assessed by magnetic resonance angiography (MRA) because of the local signal void of currently used stainless steel stents. The aim of this study was to investigate the potential of a new, dedicated, coronary MR imaging (MRI) stent for artifact-free, coronary MRA and in-stent lumen and vessel wall visualization. METHODS AND RESULTS: Fifteen prototype stents were deployed in coronary arteries of 15 healthy swine and investigated with a double-oblique, navigator-gated, free-breathing, T2-prepared, 3D cartesian gradient-echo sequence; a T2-prepared, 3D spiral gradient-echo sequence; and a T2-prepared, 3D steady-state, free-precession coronary MRA sequence. Furthermore, black-blood vessel wall imaging by a dual-inversion-recovery, turbo spin-echo sequence was performed. Artifacts of the stented vessel segment and signal intensities of the coronary vessel lumen inside and outside the stent were assessed. With all investigated sequences, the vessel lumen and wall could be visualized without artifacts, including the stented vessel segment. No signal intensity alterations inside the stent when compared with the vessel lumen outside the stent were found. CONCLUSIONS: The new, coronary MRI stent allows for completely artifact-free coronary MRA and vessel wall imaging.

Importance of IL28B gene polymorphisms in hepatitis C virus genotype 2 and 3 infected patients.

BACKGROUND & AIMS: Genetic variation in the interleukin 28B (IL28B) gene has been associated with the response to interferon-alfa/ribavirin therapy in hepatitis C virus (HCV) genotype 1-infected patients. The importance of three IL28B single nucleotide polymorphisms (rs8099917, rs12980275 and rs12979860) for HCV genotype 2/3-infected patients is unknown. METHODS: In patients with chronic hepatitis C genotype 2/3 (n=267), IL28B host genotypes (rs8099917, rs12980275 and rs12979860) were analyzed for associations with sustained virologic response (SVR) to antiviral therapy with (pegylated) interferon-alfa and ribavirin and with respect to epidemiological, biochemical, and virological parameters. For comparison, hepatitis C genotype 1 patients (n=378) and healthy controls (n=200) were included. RESULTS: The rs12979860 CC genotype, lower age, and genotype 2 were significantly associated with SVR in HCV genotype 2/3-infected patients (p=0.01, p=0.03 and p=0.03, respectively). No association was observed for rs8099917 and rs12980275. In addition, an SVR in patients with rapid virologic response (RVR) was associated with the rs12979860 CC genotype (p=0.05), while for non-RVR no association was found. Furthermore, a significant association with a higher baseline viral load was observed for all three IL28B genotypes in genotype 1/2/3-infected patients. Finally, increasing frequencies of the rs12979860 CC genotypes were observed in genotype 1- (33.9%), genotype 3- (38.9%), and genotype 2-infected (51.9%) patients in comparison with healthy controls (49.0%) (p<0.01). CONCLUSIONS: In genotype 2/3-infected patients, rs12979860 was significantly associated with SVR. The frequency of the rs12979860 CC genotype is lower in HCV genotype 1 vs. genotype 2/3 patients. All major IL28B genotypes are associated with HCV-RNA concentration.

Achievement of at least very good partial response is a simple and robust prognostic factor in patients with multiple myeloma treated with high-dose therapy: long-term analysis of the IFM 99-02 and 99-04 Trials.

PURPOSE: The prognostic impact of complete response (CR) achievement in multiple myeloma (MM) has been shown mostly in the context of autologous stem-cell transplantation. Other levels of response have been defined because, even with high-dose therapy, CR is a relatively rare event. The purpose of this study was to analyze the prognostic impact of very good partial response (VGPR) in patients treated with high-dose therapy. PATIENTS AND METHODS: All patients were included in the Intergroupe Francophone du Myelome 99-02 and 99-04 trials and treated with vincristine, doxorubicin, and dexamethasone (VAD) induction therapy followed by double autologous stem-cell transplantation (ASCT). Best post-ASCT response assessment was available for 802 patients. RESULTS: With a median follow-up of 67 months, median event-free survival (EFS) and 5-year EFS were 42 months and 34%, respectively, for 405 patients who achieved at least VGPR after ASCT versus 32 months and 26% in 288 patients who achieved only partial remission (P = .005). Five-year overall survival (OS) was significantly superior in patients achieving at least VGPR (74% v 61% P = .0017). In multivariate analysis, achievement of less than VGPR was an independent factor predicting shorter EFS and OS. Response to VAD had no impact on EFS and OS. The impact of VGPR achievement on EFS and OS was significant in patients with International Staging System stages 2 to 3 and for patients with poor-risk cytogenetics t(4;14) or del(17p). CONCLUSION: In the context of ASCT, achievement of at least VGPR is a simple prognostic factor that has importance in intermediate and high-risk MM and can be informative in more patients than CR.

Thyroid hormone enhances transected axonal regeneration and muscle reinnervation following rat sciatic nerve injury.

Improvement of nerve regeneration and functional recovery following nerve injury is a challenging problem in clinical research. We have already shown that following rat sciatic nerve transection, the local administration of triiodothyronine (T3) significantly increased the number and the myelination of regenerated axons. Functional recovery is a sum of the number of regenerated axons and reinnervation of denervated peripheral targets. In the present study, we investigated whether the increased number of regenerated axons by T3-treatment is linked to improved reinnervation of hind limb muscles. After transection of rat sciatic nerves, silicone or biodegradable nerve guides were implanted and filled with either T3 or phosphate buffer solution (PBS). Neuromuscular junctions (NMJs) were analyzed on gastrocnemius and plantar muscle sections stained with rhodamine alpha-bungarotoxin and neurofilament antibody. Four weeks after surgery, most end-plates (EPs) of operated limbs were still denervated and no effect of T3 on muscle reinnervation was detected at this stage of nerve repair. In contrast, after 14 weeks of nerve regeneration, T3 clearly enhanced the reinnervation of gastrocnemius and plantar EPs, demonstrated by significantly higher recovery of size and shape complexity of reinnervated EPs and also by increased acetylcholine receptor (AChRs) density on post synaptic membranes compared to PBS-treated EPs. The stimulating effect of T3 on EP reinnervation is confirmed by a higher index of compound muscle action potentials recorded in gastrocnemius muscles. In conclusion, our results provide for the first time strong evidence that T3 enhances the restoration of NMJ structure and improves synaptic transmission.

Test of four colon cancer risk-scores in formalin fixed paraffin embedded microarray gene expression data.

BACKGROUND: Prognosis prediction for resected primary colon cancer is based on the T-stage Node Metastasis (TNM) staging system. We investigated if four well-documented gene expression risk scores can improve patient stratification. METHODS: Microarray-based versions of risk-scores were applied to a large independent cohort of 688 stage II/III tumors from the PETACC-3 trial. Prognostic value for relapse-free survival (RFS), survival after relapse (SAR), and overall survival (OS) was assessed by regression analysis. To assess improvement over a reference, prognostic model was assessed with the area under curve (AUC) of receiver operating characteristic (ROC) curves. All statistical tests were two-sided, except the AUC increase. RESULTS: All four risk scores (RSs) showed a statistically significant association (single-test, P < .0167) with OS or RFS in univariate models, but with HRs below 1.38 per interquartile range. Three scores were predictors of shorter RFS, one of shorter SAR. Each RS could only marginally improve an RFS or OS model with the known factors T-stage, N-stage, and microsatellite instability (MSI) status (AUC gains < 0.025 units). The pairwise interscore discordance was never high (maximal Spearman correlation = 0.563) A combined score showed a trend to higher prognostic value and higher AUC increase for OS (HR = 1.74, 95% confidence interval [CI] = 1.44 to 2.10, P < .001, AUC from 0.6918 to 0.7321) and RFS (HR = 1.56, 95% CI = 1.33 to 1.84, P < .001, AUC from 0.6723 to 0.6945) than any single score. CONCLUSIONS: The four tested gene expression-based risk scores provide prognostic information but contribute only marginally to improving models based on established risk factors. A combination of the risk scores might provide more robust information. Predictors of RFS and SAR might need to be different.

A randomized crossover study to compare efavirenz and etravirine treatment.

BACKGROUND: Efavirenz (EFV) causes neuropsychiatric side-effects and an unfavourable blood lipid profile. We investigated the effect of replacing EFV with etravirine (ETR) on patient preference, sleep, anxiety and lipid levels. METHOD: Study participants did not complain of side-effects, had tolerated EFV for at least 3 months, with less than 50 copies/ml HIV-RNA. After randomization, the ETR-first group started with ETR (400 mg daily) [DOSAGE ERROR CORRECTED] with EFV-placebo and the EFV-first group with EFV with ETR-placebo. After 6 weeks, both groups switched to the alternate regimen. Nucleoside reverse transcriptase inhibitors were continued without any change. The primary end point was patient preference for the first or the second regimen, assessed after 12 weeks. RESULTS: Fifty-eight patients were enrolled with a median CD4 cell count of 589 cells/μl and the duration of previous EFV therapy was 3.9 years. Fifty-five patients completed the study. When asked about treatment preference after 12 weeks, 16 preferred EFV and 22 preferred ETR, whereas 17 did not express a preference (P = NS). Patients who continued EFV during the first phase of the trial preferred EFV (15/21, 71%), whereas patients who started with ETR were more likely to prefer ETR (n = 16/17, 94%). This order effect was strongly significant (P < 0.0001). Quality of sleep, depression, anxiety and stress scores did not differ significantly between groups. Median plasma cholesterol levels decreased by 0.7 mmol (29 mg/100 ml) after replacing EFV with ETR (P < 0.002). CONCLUSION: After substitution of EFV by ETR, patients did not express a significant preference for ETR. There was no measurable effect on neuropsychiatric symptoms and sleep. Cholesterol decreased.

Efficacy of daptomycin in implant-associated infection due to methicillin-resistant Staphylococcus aureus: importance of combination with rifampin.

Limited treatment options are available for implant-associated infections caused by methicillin (meticillin)-resistant Staphylococcus aureus (MRSA). We compared the activity of daptomycin (alone and with rifampin [rifampicin]) with the activities of other antimicrobial regimens against MRSA ATCC 43300 in the guinea pig foreign-body infection model. The daptomycin MIC and the minimum bactericidal concentration in logarithmic phase and stationary growth phase of MRSA were 0.625, 0.625, and 20 microg/ml, respectively. In time-kill studies, daptomycin showed rapid and concentration-dependent killing of MRSA in stationary growth phase. At concentrations above 20 microg/ml, daptomycin reduced the counts by >3 log(10) CFU/ml in 2 to 4 h. In sterile cage fluid, daptomycin peak concentrations of 23.1, 46.3, and 53.7 microg/ml were reached 4 to 6 h after the administration of single intraperitoneal doses of 20, 30, and 40 mg/kg of body weight, respectively. In treatment studies, daptomycin alone reduced the planktonic MRSA counts by 0.3 log(10) CFU/ml, whereas in combination with rifampin, a reduction in the counts of >6 log(10) CFU/ml was observed. Vancomycin and daptomycin (at both doses) were unable to cure any cage-associated infection when they were given as monotherapy, whereas rifampin alone cured the infections in 33% of the cages. In combination with rifampin, daptomycin showed cure rates of 25% (at 20 mg/kg) and 67% (at 30 mg/kg), vancomycin showed a cure rate of 8%, linezolid showed a cure rate of 0%, and levofloxacin showed a cure rate of 58%. In addition, daptomycin at a high dose (30 mg/kg) completely prevented the emergence of rifampin resistance in planktonic and adherent MRSA cells. Daptomycin at a high dose, corresponding to 6 mg/kg in humans, in combination with rifampin showed the highest activity against planktonic and adherent MRSA. Daptomycin plus rifampin is a promising treatment option for implant-associated MRSA infections.

Appropriateness of therapy for fistulizing Crohn's disease: findings from a national inflammatory bowel disease cohort.

BACKGROUND: About 30-50% of patients with Crohn's disease (CD) develop fistulae, implying significant disease burden and complicated clinical management. AIM: To assess appropriate use of therapy for fistulizing CD patients enrolled in the Swiss Inflammatory Bowel Disease Cohort using criteria developed by the European Panel on the Appropriateness of Crohn's disease Therapy. METHODS: Specific questionnaires were used to gather information on disease and its management. We assessed appropriateness of therapy at enrolment for adult CD patients with one or several fistulae. RESULTS: Two hundred and eighty-eight CD patients had fistulizing disease, of which 80% had complex fistulae and 32% currently had active draining fistulae. Mean age (s.d.) at diagnosis was 27 years (11), 51% males. Of the patients, 78% were judged as having globally an appropriate therapy, which was more often given for complex fistulae (87%) than for simple fistulae (67%). Antibiotics, azathioprine/MP, methotrexate and conservative surgery were almost always appropriate. Anti-tumor necrosis factor α was considered globally appropriate (91%), although most often with an uncertain indication. The 5ASA compounds, steroids and aggressive surgery were most often inappropriate (84%, 58% and 86% respectively). CONCLUSIONS: Formal appropriateness criteria for CD therapy were applied to a national cohort of IBD patients. For more than three-quarters of the patients with fistulizing CD, therapy was globally appropriate.

MGMT promoter methylation in malignant gliomas: ready for personalized medicine?

The DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) antagonizes the genotoxic effects of alkylating agents. MGMT promoter methylation is the key mechanism of MGMT gene silencing and predicts a favorable outcome in patients with glioblastoma who are exposed to alkylating agent chemotherapy. This biomarker is on the verge of entering clinical decision-making and is currently used to stratify or even select glioblastoma patients for clinical trials. In other subtypes of glioma, such as anaplastic gliomas, the relevance of MGMT promoter methylation might extend beyond the prediction of chemosensitivity, and could reflect a distinct molecular profile. Here, we review the most commonly used assays for evaluation of MGMT status, outline the prerequisites for standardized tests, and evaluate reasons for difficulties in reproducibility. We critically discuss the prognostic and predictive value of MGMT silencing, reviewing trials in which patients with different types of glioma were treated with various chemotherapy schedules, either up-front or at recurrence. Standardization of MGMT testing requires comparison of different technologies across laboratories and prospectively validated cut-off values for prognostic or predictive effects. Moreover, future clinical trials will need to determine, for each subtype of glioma, the degree to which MGMT promoter methylation is predictive or prognostic, and whether testing should become routine clinical practice.

Predictive value of the MGMT promoter methylation status in metastatic melanoma patients receiving first-line temozolomide plus bevacizumab in the trial SAKK 50/07.

The O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status is a predictive parameter for the response of malignant gliomas to alkylating agents such as temozolomide. First clinical trials with temozolomide plus bevacizumab therapy in metastatic melanoma patients are ongoing, although the predictive value of the MGMT promoter methylation status in this setting remains unclear. We assessed MGMT promoter methylation in formalin-fixed, primary tumor tissue of metastatic melanoma patients treated with first-line temozolomide and bevacizumab from the trial SAKK 50/07 by methylation-specific polymerase chain reaction. In addition, the MGMT expression levels were also analyzed by MGMT immunohistochemistry. Eleven of 42 primary melanomas (26%) revealed a methylated MGMT promoter. Promoter methylation was significantly associated with response rates CR + PR versus SD + PD according to RECIST (response evaluation criteria in solid tumors) (p<0.05) with a trend to prolonged median progression-free survival (8.1 versus 3.4 months, p>0.05). Immunohistochemically different protein expression patterns with heterogeneous and homogeneous nuclear MGMT expression were identified. Negative MGMT expression levels were associated with overall disease stabilization CR+PR+SD versus PD (p=0.05). There was only a poor correlation between MGMT methylation and lack of MGMT expression. A significant proportion of melanomas have a methylated MGMT promoter. The MGMT promoter methylation status may be a promising predictive marker for temozolomide therapy in metastatic melanoma patients. Larger sample sizes may help to validate significant differences in survival type endpoints.

Azithromycin versus Sulfadiazine and Pyrimethamine for non-vision-threatening toxoplasmic retinochoroiditis: a pilot study.

BACKGROUND: The purpose of this pilot study is to compare the efficacy and tolerance of azithromycin alone as opposed to standard treatment with sulfadiazine and pyrimethamine for active, non-vision-threatening toxoplasmic retinochoroiditis. MATERIAL/METHODS: We conducted a prospective, randomized, institutional clinical study comparing azithromycin to sulfadiazine and pyrimethamine for active, non-vision-threatening toxoplasmic retinochoroiditis. Nineteen out of 75 patients fulfilled inclusion criteria and were randomized into 2 treatment regimens. Nine patients were treated with sulfadiazine and pyrimethamine and 10 patients with azithromycin at a dose of 500 mg qd. Main outcome measures assessed were time to sharpening of lesion borders, time to lesion scarring, time to disease inactivity, and treatment tolerance. RESULTS: Azithromycin monotherapy achieved lesion scarring and disease inactivity in all but 1 patient. Although no statistically significant difference was found between the 2 patient groups as regards main outcome measures for treatment efficacy, all median times to endpoints (days) were longer for the azithromycin group - time to sharpening of lesion borders on clinical evaluation (25.5 vs. 24) and masked evaluation of photographs (30.5 vs. 24), time to lesion scarring on clinical evaluation (73 vs. 47) and masked evaluation of photographs (71.5 vs. 36) and time to disease inactivity (73 vs. 49). Treatment tolerance was significantly better for the azithromycin group (p=0.0005). ConcluSIONS: Azithromycin monotherapy at a dose of 500 mg per day was shown to be effective and well-tolerated for the treatment of active, non-vision-threatening toxoplasmic retinochoroiditis. Duration of treatment was clinically longer for the azithromycin group.