Beneficial effects of aggressive low-density lipoprotein cholesterol lowering in women with stable coronary heart disease in the Treating to New Targets (TNT) study

OBJECTIVE: To examine by secondary analysis of the Treating to New Targets (TNT) study whether the benefits of intensive versus standard levels of lipid lowering are equally applicable to women. METHODS: A total of 10 001 patients (1902 women) with stable coronary heart disease (CHD) were randomised to double-blind treatment with atorvastatin 10 or 80 mg/day for a median follow-up of 4.9 years. RESULTS: In women and men, intensive treatment with atorvastatin 80 mg significantly reduced the rate of major cardiovascular events compared with atorvastatin 10 mg. Among women, the relative and absolute reductions were 27% and 2.7%, respectively (hazard ratio (HR) = 0.73, 95% confidence interval (CI) 0.54 to 1.00, p = 0.049). In men, the corresponding rate reductions were 21% and 2.2% (HR = 0.79, 95% CI 0.69 to 0.91, p = 0.001). The number needed to treat value (to prevent one cardiovascular event over 4.9 years compared with patients treated with atorvastatin 10 mg) for atorvastatin 80 mg was 29 for women and 30 for men. Rates of death of non-cardiovascular origin in the atorvastatin 80 mg and atorvastatin 10 mg were 3.6% and 1.6%, respectively (p = 0.004) among women, and 2.8% and 3.1% (p = 0.47) among men. CONCLUSION: Intensive lipid-lowering treatment with atorvastatin 80 mg produced significant reductions in relative risk for major cardiovascular events compared with atorvastatin 10 mg in both women and men with stable CHD.

Activation of cyclic AMP response element-binding protein (CREB) in aggressive periodontal disease

OBJECTIVES: To report a novel observation of neutrophil signal transduction abnormalities in patients with localized aggressive periodontitis (LAP) that are associated with an enhanced phosphorylation of the nuclear signal transduction protein cyclic AMP response element-binding factor (CREB). METHOD AND MATERIALS: Peripheral venous blood neutrophils of 18 subjects, 9 patients with LAP and 9 race-, sex-, and age-matched healthy controls, were isolated and prepared using the Ficoll-Hypaque density-gradient technique. Neutrophils (5.4 x 10(6)/mL) were stimulated with the chemoattractant FMLP (10(-6) mol/L) for 5 minutes and lysed. Aliquots of these samples were separated by SDS-PAGE (60 microg/lane) on 9.0% (w/v) polyacrylamide slab gels and transferred electrophoretically to polyvinyl difluoride membranes. The cell lysates were immunoblotted with a 1:1,000 dilution of rabbit-phospho-CREB antibody that recognizes only the phosphorylated form of CREB at Ser133. The activated CREB was visualized with a luminol-enhanced chemoluminescence detection system and evaluated by laser densitometry. RESULTS: In patients with LAP, the average activation of CREB displayed an overexpression for the unstimulated peripheral blood neutrophils of 80.3% (17.5-fold) compared to healthy controls (4.6%). CONCLUSION: LAP neutrophils who express their phenotype appear to be constitutively primed, as evidenced by activated CREB in resting cells compared to normal individuals. The genetically primed neutrophil phenotype may contribute to neutrophil-mediated tissue damage in the pathogenesis of LAP.

Crossover comparison of the laryngeal mask supreme and the i-gel in simulated difficult airway scenario in anesthetized patients

BACKGROUND: The single-use supraglottic airway devices LMA-Supreme (LMA-S; Laryngeal Mask Company, Henley-on-Thames, United Kingdom) and i-gel (Intersurgical Ltd, Wokingham, Berkshire, United Kingdom) have a second tube for gastric tube insertion. Only the LMA-S has an inflatable cuff. They have the same clinical indications and might be useful for difficult airway management. This prospective, crossover, randomized controlled trial was performed in a simulated difficult airway scenario using an extrication collar limiting mouth opening and neck movement. METHODS: Sixty patients were included. Both devices were placed in random order in each patient. Primary outcome was overall success rate. Other measurements were time to successful ventilation, airway leak pressure, fiberoptic glottic view, and adverse events. RESULTS: Success rate for the LMA-S was 95% versus 93% for the i-gel (P = 1.000). LMA-S needed shorter insertion time (34 +/- 12 s vs. 42 +/- 23 s, P = 0.024). Tidal volumes and airway leak pressure were similar (LMA-S 26 +/- 8 cm H20; i-gel 27 +/- 9 cm H20; P = 0.441). Fiberoptic view through the i-gel showed less epiglottic downfolding. Overall agreement in insertion outcome was 54 (successes) and 1 (failure) or 55 (92%) of 60 patients. The difference in success rate was 1.7% (95% CI -11.3% to 7.6%). CONCLUSIONS: Both airway devices had similar insertion success and clinical performance in the simulated difficult airway situation. The authors found less epiglottic downfolding and better fiberoptic view but longer insertion time with the i-gel. Our study shows that both devices are feasible for emergency airway management in patients with reduced neck movement and limited mouth opening.

Management of early aggressive rheumatoid arthritis during pregnancy and lactation

This survey outlines the problems of drug therapy in women with early aggressive rheumatoid arthritis (RA) who desire children, are pregnant, or are lactating. Solutions for treatment that benefit the mother and do not harm the fetus or the breast-fed child are discussed. The most effective immunosuppressive drugs alone or in combination are contraindicated during pregnancy and, to a lesser degree, also during lactation. Judicious timing of therapy is therefore necessary, aiming at fast remission of symptoms with the most effective therapy and maintaining quiescent disease with drugs compatible with pregnancy or lactation.

Nonsurgical treatment of aggressive periodontitis with photodynamic therapy or systemic antibiotics. Three-month results of a randomized, prospective, controlled clinical study

The aim of this randomized, controlled clinical study was to compare the short-term effects of nonsurgical periodontal therapy with the additional administration of systemic antibiotics (AB) and the same therapy with additional photodynamic therapy (PDT) in the treatment of patients with aggressive periodontitis (AP). Thirty-six patients with AP received full-mouth nonsurgical periodontal treatment (SRP) and were then randomly divided into two groups of 18 subjects each. Group AB received amoxicillin and metronidazole three times a day for 7 days. Group PDT received two applications of PDT on the day of SRP as well as at follow-up after 7 days. The following clinical parameters were measured at baseline and 3 months after therapy: plaque index (PLI), bleeding on probing (BOP), probing depth (PD), gingival recession (GR), and clinical attachment level (CAL). After 3 months, PD was significantly reduced in both groups (from 5.0±0.8 mm to 3.2±0.4 mm with AB, and 5.1±0.5 mm to 4.0±0.8 mm with PDT; both p<0.001), while AB revealed significantly lower values compared to PDT (p = 0.001). In both groups, GR was not significantly changed. CAL was significantly reduced in both groups (PDT: 5.7±0.8 mm to 4.7±1.1 mm; p=0.011; AB: 5.5±1.1 mm to 3.9±1.0 mm; p<0.001) and differed significantly between the groups (p=0.025). The number of residual pockets (PD ≥4 mm) and positive BOP was reduced by AB from 961 to 377, and by PDT from 628 to 394. Pockets with PD ≥7 mm were reduced by AB from 141 to 7, and by PDT from 137 to 61. After 3 months, both treatments led to statistically significant clinical improvements. The systemic administration of antibiotics, however, resulted in significantly higher reduction of PD and a lower number of deep pockets compared to PDT.

Loss of Raf-1 kinase inhibitor protein (RKIP) is strongly associated with high-grade tumor budding and correlates with an aggressive phenotype in pancreatic ductal adenocarcinoma (PDAC)

BACKGROUND Raf-1 kinase inhibitor protein (RKIP) has emerged as a significant metastatic suppressor in a variety of human cancers and is known to inhibit Ras/Raf/MEK/ERK signaling. By suppressing the activation of the NFkB/SNAIL circuit, RKIP can regulate the induction of epithelial-mesenchymal transition (EMT). The aim of this study was to evaluate RKIP expression and to determine its association with clinicopathological features, including EMT in form of tumor budding in pancreatic ductal adenocarcinoma (PDAC). METHODS Staining for RKIP was performed on a multipunch Tissue Microarray (TMA) of 114 well-characterized PDACs with clinico-pathological, follow-up and adjuvant therapy information. RKIP-expression was assessed separately in the main tumor body and in the tumor buds. Another 3 TMAs containing normal pancreatic tissue, precursor lesions (Pancreatic Intraepithelial Neoplasia, PanINs) and matched lymph node metastases were stained in parallel. Cut-off values were calculated by receiver operating characteristic (ROC) curve analysis. RESULTS We found a significant progressive loss of RKIP expression between normal pancreatic ductal epithelia (average: 74%), precursor lesions (PanINs; average: 37%), PDAC (average 20%) and lymph node metastases (average 8%, p<0.0001). RKIP expression was significantly lower in tumor buds (average: 6%) compared to the main tumor body (average 20%; p<0.005). RKIP loss in the tumor body was marginally associated with advanced T-stage (p=0.0599) as well as high-grade peritumoral (p=0.0048) and intratumoral budding (p=0.0373). RKIP loss in the buds showed a clear association with advanced T stage (p=0.0089). CONCLUSIONS The progressive loss of RKIP seems to play a major role in the neoplastic transformation of pancreas, correlates with aggressive features in PDAC and is associated with the presence of EMT in form of tumor budding.

Envisioning sustainable water futures in a transdisciplinary learning process: combining normative, explorative, and participatory scenario approaches

Competing water demands for household consumption as well as the production of food, energy, and other uses pose challenges for water supply and sustainable development in many parts of the world. Designing creative strategies and learning processes for sustainable water governance is thus of prime importance. While this need is uncontested, suitable approaches still have to be found. In this article we present and evaluate a conceptual approach to scenario building aimed at transdisciplinary learning for sustainable water governance. The approach combines normative, explorative, and participatory scenario elements. This combination allows for adequate consideration of stakeholders’ and scientists’ systems, target, and transformation knowledge. Application of the approach in the MontanAqua project in the Swiss Alps confirmed its high potential for co-producing new knowledge and establishing a meaningful and deliberative dialogue between all actors involved. The iterative and combined approach ensured that stakeholders’ knowledge was adequately captured, fed into scientific analysis, and brought back to stakeholders in several cycles, thereby facilitating learning and co-production of new knowledge relevant for both stakeholders and scientists. However, the approach also revealed a number of constraints, including the enormous flexibility required of stakeholders and scientists in order for them to truly engage in the co-production of new knowledge. Overall, the study showed that shifts from strategic to communicative action are possible in an environment of mutual trust. This ultimately depends on creating conditions of interaction that place scientists’ and stakeholders’ knowledge on an equal footing.

Periodontal pathogens and associated factors in aggressive periodontitis: results 5-17 years after active periodontal therapy

OBJECTIVES To assess the association between presence of periodontal pathogens and recurrence of disease in patients with aggressive periodontitis (AgP) after active periodontal therapy (APT) and further influencing factors. MATERIAL & METHODS Microbiological samples were taken from 73 patients with AgP 5-17 years after APT at 292 sites (deepest site per quadrant). Real-time polymerase chain reactions were used to detect the periodontal pathogens Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia and Treponema denticola. Uni- and multivariate analyses evaluated the associations between pathogens and recurrence of disease, smoking and adjunctive antibiotic therapy. RESULTS At re-examination A. actinomycetemcomitans could be detected in six patients (8.2%), P. gingivalis in 24 (32.9%), T. forsythia in 31 (42.5%) and T. denticola in 35 (48.0%). Increased levels of T. forsythia and T. denticola at re-examination were significantly associated with recurrence of disease in multivariate analyses (OR: 12.72, p < 0.001; OR 5.55, p = 0.002 respectively). Furthermore, high counts of T. denticola were found in patients with increased percentage of sites with clinical attachment levels (CAL) ≥ 6 mm compared to those with low counts (13.8% versus 3.2%, p = 0.005). CONCLUSION In patients with recurrence of disease T. forsythia and T. denticola were detected more frequently and in higher counts. Furthermore, T. denticola was found more frequently in patients with increased CAL.

Six-month results following treatment of aggressive periodontitis with antimicrobial photodynamic therapy or amoxicillin and metronidazole.

OBJECTIVE The use of antibacterial photodynamic therapy (aPDT) additionally to scaling and root planing (SRP) has been shown to positively influence the clinical outcomes. However, at present, it is unknown to what extent aPDT may represent a potential alternative to the use of systemic antibiotics in nonsurgical periodontal therapy in patients with aggressive periodontitis (AP). The aim of this study was to evaluate the outcomes following nonsurgical periodontal therapy and additional use of either aPDT or amoxicillin and metronidazole (AB) in patients with AP. MATERIAL AND METHODS Thirty-six patients with AP displaying at least three sites with pocket depth (PD) ≥6 mm were treated with SRP and either systemic administration of AB for 7 days or with two episodes of aPDT. The following clinical parameters were evaluated at baseline and at 6 months: plaque index (PI), bleeding on probing (BOP), PD, gingival recession (GR) and clinical attachment level (CAL). RESULTS Thirty-five patients have completed the 6-month evaluation. At 6 months, mean PD was statistically significantly reduced in both groups (from 5.0 ± 0.8 to 3.0 ± 0.6 mm with AB and from 5.1 ± 0.5 to 3.9 ± 0.8 mm with aPDT (p < 0.001)). AB yielded statistically significantly higher improvements in the primary outcome parameter PD (p < 0.001) when compared to aPDT. The number of pockets ≥7 mm was reduced from 141 to 3 after AB (p < 0.001) and from 137 to 45 after aPDT (p = 0.03). Both therapies resulted in statistically significant reductions in all parameters compared to baseline. CONCLUSION While both treatments resulted in statistically significant clinical improvements, AB showed statistically significantly higher PD reduction and lower number of pockets ≥7 mm compared to aPDT. CLINICAL RELEVANCE In patients with AP, the two times application of aPDT in conjunction with nonsurgical periodontal therapy cannot be considered an alternative to the systemic use of amoxicillin and metronidazole.

The Silencing of N-myc Downstream-Regulated Gene-1 in an Orthotopic Pancreatic Cancer Model Leads to More Aggressive Tumor Growth and Metastases

BACKGROUND: The understanding of molecular mechanisms leading to poor prognosis in pancreatic cancer may help develop treatment options. N-myc downstream-regulated gene-1 (NDRG1) has been correlated to better prognosis in pancreatic cancer. Therefore, we thought to analyze how the loss of NDRG1 affects progression in an orthotopic xenograft animal model of recurrence. METHODS: Capan-1 cells were silenced for NDRG1 (C(sil)) or transfected with scrambled shRNA (C(scr)) and compared for anchorage-dependent and anchorage-independent growth, invasion and tube formation in vitro. In an orthotopic xenograft model of recurrence tumors were grown in the pancreatic tail. The effect of NDRG1 silencing was evaluated on tumor size and metastasis. RESULTS: The silencing of NDRG1 in Capan-1 cells leads to more aggressive tumor growth and metastasis. We found faster cell growth, double count of invaded cells and 1.8-fold increase in tube formation in vitro. In vivo local tumors were 5.9-fold larger (p = 0.006) and the number of metastases was higher in animals with tumors silenced for NDRG1 primarily (3 vs. 1.1; p = 0.005) and at recurrence (3.3 vs. 0.9; p = 0.015). CONCLUSION: NDRG1 may be an interesting therapeutic target as its silencing in human pancreatic cancer cells leads to a phenotype with more aggressive tumor growth and metastasis.

Comparing three CPR feedback devices and standard BLS in a single rescuer scenario: a randomised simulation study

BACKGROUND Efficiently performed basic life support (BLS) after cardiac arrest is proven to be effective. However, cardiopulmonary resuscitation (CPR) is strenuous and rescuers' performance declines rapidly over time. Audio-visual feedback devices reporting CPR quality may prevent this decline. We aimed to investigate the effect of various CPR feedback devices on CPR quality. METHODS In this open, prospective, randomised, controlled trial we compared three CPR feedback devices (PocketCPR, CPRmeter, iPhone app PocketCPR) with standard BLS without feedback in a simulated scenario. 240 trained medical students performed single rescuer BLS on a manikin for 8min. Effective compression (compressions with correct depth, pressure point and sufficient decompression) as well as compression rate, flow time fraction and ventilation parameters were compared between the four groups. RESULTS Study participants using the PocketCPR performed 17±19% effective compressions compared to 32±28% with CPRmeter, 25±27% with the iPhone app PocketCPR, and 35±30% applying standard BLS (PocketCPR vs. CPRmeter p=0.007, PocketCPR vs. standard BLS p=0.001, others: ns). PocketCPR and CPRmeter prevented a decline in effective compression over time, but overall performance in the PocketCPR group was considerably inferior to standard BLS. Compression depth and rate were within the range recommended in the guidelines in all groups. CONCLUSION While we found differences between the investigated CPR feedback devices, overall BLS quality was suboptimal in all groups. Surprisingly, effective compression was not improved by any CPR feedback device compared to standard BLS. All feedback devices caused substantial delay in starting CPR, which may worsen outcome.