A case-control study of sporadic Creutzfeldt-Jakob disease in Switzerland: analysis of potential risk factors with regard to an increased CJD incidence in the years 2001-2004

BACKGROUND: In 2001, the observed annual mortality from Creutzfeldt-Jakob disease (CJD) in Switzerland increased from less than 1.5 to 2.6 per million inhabitants. An underlying cause could not be identified. METHODS: To analyse potential risk factors for sCJD in Switzerland, close relatives of 69 sCJD-patients and 224 frequency age-matched controls were interviewed in a case-control study using a standardised questionnaire. 135 potential risk factors including socio-demographics, medical history, occupation and diet were analysed by logistic regression adjusting for age, sex and education. RESULTS: sCJD patients were more likely to have travelled abroad, worked at an animal laboratory, undergone invasive dental treatment, orthopaedic surgery, ophthalmologic surgery after 1980, regular GP visits, taken medication regularly, and consumed kidney. No differences between patients and controls were found for residency, family history, and exposure to environmental and other dietary factors. CONCLUSION: Although some factors were significantly more frequent among sCJD-cases, this study did not reveal specific explanations for the increased incidence of deaths due to sporadic CJD observed in Switzerland since 2001. Results have to be interpreted with caution due to multiple testing and possible recall bias in association with a long incubation period. The most plausible reason for the increase in Swiss sCJD cases after 2000 is an improved case ascertainment. Therefore, underreporting of cases might well have occurred before the year 2001, and the "real" yearly incidence of sCJD might not be lower than, but rather above 2 per million inhabitants.

Synthesis of substituted 1H- and 3H-1-benzazepines: Rearrangement of 2-alkoxycarbonyl-1H-1-benzazepines to isoquinolines

The SnCl2-mediated reduction of nitro groups in 2-nitro-4-(2-nitro-benzylidene)-alkanoates and 4-nitro-2-(2-nitro-alkylidene)-alkanoates afforded via SN2′ reaction of ethyl nitroacetate and nitroethane with the acetyl derivatives of Baylis-Hillman adducts afforded by 2-nitro-substituted benzaldehydes leads to facile synthesis of substituted 1H-1-benzazepine and 3H-1-benzazepine. During the study an unprecedented rearrangement of 2-alkoxycarbonyl-1H-benzazepine to substituted isoquinoline has been observed.

Studies on the reduction of the nitro group in 3-aryl-2-methylene-4-nitro-alkanoates afforded by the Baylis-Hillman adducts: Synthesis of 4-aryl-3-methylene-2-pyrrolidinones and 3-(1-alkoxycarbonyl-vinyl)-1H-indole-2-carboxylates

The formation of substituted 2-pyrrolidinones and indoles by the reduction of the secondary nitro group in appropriate 3-aryl-2-methylene-4-nitroalkanoates afforded by Baylis-Hillman chemistry via different reducing agents is described. The 3-aryl-2-methylene-4-nitroalkanoate obtained from SN2 nucleophilic reaction between the acetate of Baylis-Hillman adducts and ethyl nitroacetate upon reduction with indium-HCl furnishes a mixture of cis and trans substituted phenyl-3-methylene-2-pyrrolidinones. In contrast, similar reductions of analogous substrates derived from nitroethane stereoselectively furnished only the trans substituted phenyl-3-methylene-2-pyrrolidinones. On the other hand the SnCl2.2H2O-promoted reductions of substrates derived from nitro ethylacetate give oxime derivatives while the ones obtained from nitroethane yield a mixture of cis and trans 4-aryl-3-methylene-2-pyrrolidinones. Alternatively, the SnCl2.2H2O-promoted reduction of substituted 2-nitrophenyl-2-methylene-alkanoate furnished from ethyl nitroacetate yields 3-(1-alkoxycarbonyl-vinyl)-1H-indole-2-carboxylate while indium-promoted reaction of this substrate leads to a complex mixture. Analogous reactions with SnCl2.2H2O of substituted 2-nitrophenyl-2-methylene-alkanoate obtained from nitroethane yield 4-alkyl-3-methylene-2-quinolones in moderate yields

Catheter removal versus retention in the management of catheter-associated enterococcal bloodstream infections

BACKGROUND Enterococci are an important cause of central venous catheter (CVC)-associated bloodstream infections (CA-BSI). It is unclear whether CVC removal is necessary to successfully manage enterococcal CA-BSI. METHODS A 12-month retrospective cohort study of adults with enterococcal CA-BSI was conducted at a tertiary care hospital; clinical, microbiological and outcome data were collected. RESULTS A total of 111 patients had an enterococcal CA-BSI. The median age was 58.2 years (range 21 to 94 years). There were 45 (40.5%) infections caused by Entercoccus faecalis (among which 10 [22%] were vancomycin resistant), 61 (55%) by Enterococcus faecium (57 [93%] vancomycin resistant) and five (4.5%) by other Enterococcus species. Patients were treated with linezolid (n=51 [46%]), vancomycin (n=37 [33%]), daptomycin (n=11 [10%]), ampicillin (n=2 [2%]) or quinupristin/dalfopristin (n=2 [2%]); seven (n=6%) patients did not receive adequate enterococcal treatment. Additionally, 24 (22%) patients received adjunctive gentamicin treatment. The CVC was retained in 29 (26.1%) patients. Patients with removed CVCs showed lower rates of in-hospital mortality (15 [18.3%] versus 11 [37.9]; P=0.03), but similar rates of recurrent bacteremia (nine [11.0%] versus two (7.0%); P=0.7) and a similar post-BSI length of hospital stay (median days [range]) (11.1 [1.7 to 63.1 days] versus 9.3 [1.9 to 31.8 days]; P=0.3). Catheter retention was an independent predictor of mortality (OR 3.34 [95% CI 1.21 to 9.26]). CONCLUSIONS To the authors' knowledge, the present article describes the largest enterococcal CA-BSI series to date. Mortality was increased among patients who had their catheter retained. Additional prospective studies are necessary to determine the optimal management of enterococcal CA-BSI.

High-resolution glacial and deglacial record of atmospheric methane by continuous-flow and laser spectrometer analysis along the NEEM ice core

The Greenland NEEM (North Greenland Eemian Ice Drilling) operation in 2010 provided the first opportunity to combine trace-gas measurements by laser spectroscopic instruments and continuous-flow analysis along a freshly drilled ice core in a field-based setting. We present the resulting atmospheric methane (CH4) record covering the time period from 107.7 to 9.5 ka b2k (thousand years before 2000 AD). Companion discrete CH4 measurements are required to transfer the laser spectroscopic data from a relative to an absolute scale. However, even on a relative scale, the high-resolution CH4 data set significantly improves our knowledge of past atmospheric methane concentration changes. New significant sub-millennial-scale features appear during interstadials and stadials, generally associated with similar changes in water isotopic ratios of the ice, a proxy for local temperature. In addition to the midpoint of Dansgaard–Oeschger (D/O) CH4 transitions usually used for cross-dating, sharp definition of the start and end of these events brings precise depth markers (with ±20 cm uncertainty) for further cross-dating with other palaeo- or ice core records, e.g. speleothems. The method also provides an estimate of CH4 rates of change. The onsets of D/O events in the methane signal show a more rapid rate of change than their endings. The rate of CH4 increase associated with the onsets of D/O events progressively declines from 1.7 to 0.6 ppbv yr−1 in the course of marine isotope stage 3. The largest observed rate of increase takes place at the onset of D/O event #21 and reaches 2.5 ppbv yr−1.

The effect of abrupt climatic warming on biogeochemical cycling and N2O emissions in a terrestrial ecosystem

The large, rapid increase in atmospheric N2O concentrations that occurred concurrent with the abrupt warming at the end of the Last Glacial period might have been the result of a reorganization in global biogeochemical cycles. To explore the sensitivity of nitrogen cycling in terrestrial ecosystems to abrupt warming, we combined a scenario of climate and vegetation composition change based on multiproxy data for the Oldest Dryas–Bølling abrupt warming event at Gerzensee, Switzerland, with a biogeochemical model that simulates terrestrial N uptake and release, including N2O emissions. As for many central European sites, the pollen record at the Gerzensee is remarkable for the abundant presence of the symbiotic nitrogen fixer Hippophaë rhamnoides (L.) during the abrupt warming that also marks the beginning of primary succession on immature glacial soils. Here we show that without additional nitrogen fixation, climate change results in a significant increase of N2O emissions of approximately factor 3.4 (from 6.4 ± 1.9 to 21.6 ± 5.9 mg N2O–N m− 2 yr− 1). Each additional 1000 mg m− 2 yr− 1 of nitrogen added to the ecosystem through N-fixation results in additional N2O emissions of 1.6 mg N2O–N m− 2 yr− 1 for the time with maximum H. rhamnoides coverage. Our results suggest that local reactions of emissions to abrupt climate change could have been considerably faster than the overall atmospheric concentration changes observed in polar ice. Nitrogen enrichment of soils due to the presence of symbiotic N-fixers during early primary succession not only facilitates the establishment of vegetation on soils in their initial stage of development, but can also have considerable influence on biogeochemical cycles and the release of reactive nitrogen trace gases to the atmosphere.

Validation of the DRAGON score in 12 stroke centers in anterior and posterior circulation

BACKGROUND AND PURPOSE The DRAGON score predicts functional outcome in the hyperacute phase of intravenous thrombolysis treatment of ischemic stroke patients. We aimed to validate the score in a large multicenter cohort in anterior and posterior circulation. METHODS Prospectively collected data of consecutive ischemic stroke patients who received intravenous thrombolysis in 12 stroke centers were merged (n=5471). We excluded patients lacking data necessary to calculate the score and patients with missing 3-month modified Rankin scale scores. The final cohort comprised 4519 eligible patients. We assessed the performance of the DRAGON score with area under the receiver operating characteristic curve in the whole cohort for both good (modified Rankin scale score, 0-2) and miserable (modified Rankin scale score, 5-6) outcomes. RESULTS Area under the receiver operating characteristic curve was 0.84 (0.82-0.85) for miserable outcome and 0.82 (0.80-0.83) for good outcome. Proportions of patients with good outcome were 96%, 93%, 78%, and 0% for 0 to 1, 2, 3, and 8 to 10 score points, respectively. Proportions of patients with miserable outcome were 0%, 2%, 4%, 89%, and 97% for 0 to 1, 2, 3, 8, and 9 to 10 points, respectively. When tested separately for anterior and posterior circulation, there was no difference in performance (P=0.55); areas under the receiver operating characteristic curve were 0.84 (0.83-0.86) and 0.82 (0.78-0.87), respectively. No sex-related difference in performance was observed (P=0.25). CONCLUSIONS The DRAGON score showed very good performance in the large merged cohort in both anterior and posterior circulation strokes. The DRAGON score provides rapid estimation of patient prognosis and supports clinical decision-making in the hyperacute phase of stroke care (eg, when invasive add-on strategies are considered).

NGRIP CH4 concentration from 120 to 10 kyr before present and its relation to a δ15N temperature reconstruction from the same ice core

During the last glacial cycle, Greenland temperature showed many rapid temperature variations, the so-called Dansgaard–Oeschger (DO) events. The past atmospheric methane concentration closely followed these temperature variations, which implies that the warmings recorded in Greenland were probably hemispheric in extent. Here we substantially extend and complete the North Greenland Ice Core Project (NGRIP) methane record from the Preboreal Holocene (PB) back to the end of the last interglacial period with a mean time resolution of 54 yr. We relate the amplitudes of the methane increases associated with DO events to the amplitudes of the local Greenland NGRIP temperature increases derived from stable nitrogen isotope (δ15N) measurements, which have been performed along the same ice core (Kindler et al., 2014). We find the ratio to oscillate between 5 parts per billion (ppb) per °C and 18 ppb °C−1 with the approximate frequency of the precessional cycle. A remarkably high ratio of 25.5 ppb °C−1 is reached during the transition from the Younger Dryas (YD) to the PB. Analysis of the timing of the fast methane and temperature increases reveals significant lags of the methane increases relative to NGRIP temperature for DO events 5, 9, 10, 11, 13, 15, 19, and 20. These events generally have small methane increase rates and we hypothesize that the lag is caused by pronounced northward displacement of the source regions from stadial to interstadial. We further show that the relative interpolar concentration difference (rIPD) of methane is about 4.5% for the stadials between DO events 18 and 20, which is in the same order as in the stadials before and after DO event 2 around the Last Glacial Maximum. The rIPD of methane remains relatively stable throughout the full last glacial, with a tendency for elevated values during interstadial compared to stadial periods.

Increment thickness versus dentin bond strength of bulk fill flowables

Objectives: The aim was to investigate the influence of increment thickness on shear bond strength (SBS) to dentin of a conventional and two bulk fill flowable composites. Methods: A total of 135 specimens of ground human dentin were produced (n=15/group; 3 increment thicknesses; 3 flowable composites) and the dentin surfaces were treated with the adhesive system OptiBond FL (Kerr) according to manufacturer’s instructions. Split Teflon molds (inner diameter: 3.6 mm) of 2 mm, 4 mm, or 6 mm height allowing three increment thicknesses were clamped on the dentin surfaces and filled with either the conventional flowable Filtek Supreme XTE ((XTE); 3M ESPE) or the bulk fill flowables Filtek Bulk Fill ((FBF); 3M ESPE) or SDR ((SDR); DENTSPLY Caulk). The flowable composites were light-cured for 20 s (Demi LED; Kerr) and the specimens stored for 24 h (37°C, 100% humidity). Specimens were then subjected to a SBS-test in a universal testing machine at a cross-head speed of 1 mm/min (Zwick Z010; Zwick GmbH & Co.). SBS-values were statistically analysed with a nonparametrical ANOVA followed by exact Wilcoxon rank sum tests (α=0.05). Failure mode of the specimens was determined under a stereomicroscope at 25× magnification. Results: SBS-values (MPa) at 2 mm/4 mm/6 mm increment thicknesses (mean value [standard deviation]) were for XTE: 18.8 [2.6]/17.6 [1.6]/16.7 [3.1], for FBF: 20.6 [2.7]/17.8 [2.7]/18.7 [2.9], and for SDR: 21.7 [2.6]/18.5 [2.6]/20.3 [3.0]. For all three flowable composites, 2 mm increments yielded the highest SBS-values whereas for increments of 4 mm and 6 mm no differences were detected. All specimens presented failure modes involving cohesive failure in dentin. Conclusion: The influence of increment thickness on dentin SBS was less pronounced than expected. However, the high number of cohesive failures in dentin, reflecting the efficiency of the adhesive system, suggests a limited discriminatory power of the SBS-test.

Sono-Electro-Magnetic Therapy for Treating Chronic Pelvic Pain Syndrome in Men: A Randomized, Placebo-Controlled, Double-Blind Trial.

OBJECTIVE To assess the efficacy and safety of sono-electro-magnetic therapy compared to placebo in men with refractory CPPS. PATIENTS AND METHODS In a randomized, placebo-controlled, double-blind single center trial, we assessed the effect of sono-electro-magnetic therapy in men with treatment refractory CPPS. Sixty male patients were randomly assigned to treatment with either sono-electro-magnetic (n = 30) or placebo therapy (n = 30) for 12 weeks. The primary outcome was a change in the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) from baseline to 12 weeks. RESULTS The 12-week difference between sono-electro-magnetic and placebo therapy in changes of the NIH-CPSI total score was -3.1 points (95% CI -6.8 to 0.6, p = 0.11). In secondary comparisons of NIH-CPSI sub-scores, we found differences between groups most pronounced for the quality-of-life sub-score (difference at 12 weeks -1.6, 95% CI -2.8 to -0.4, p = 0.015). In stratified analyses, the benefit of sono-electro-magnetic therapy appeared more pronounced among patients who had a symptom duration of 12 months or less (difference in NIH-CPSI total score -8.3, 95% CI -14.5 to 2.6) than in patients with a longer symptom duration (-0.8, 95% CI -4.6 to 3.1; p for interaction = 0.023). CONCLUSIONS Sono-electro-magnetic therapy did not result in a significant improvement of symptoms in the overall cohort of treatment refractory CPPS patients compared to placebo treatment. Subgroup analysis indicates, however, that patients with a symptom-duration of 12 months or less may benefit from sono-electro-magnetic therapy, warranting larger randomized controlled trials in this subpopulation. TRIAL REGISTRATION ClinicalTrials.gov NCT00688506.

Usefulness of electrocardiographic parameters for risk prediction in arrhythmogenic right ventricular dysplasia

The value of electrocardiographic findings predicting adverse outcome in patients with arrhythmogenic right ventricular dysplasia (ARVD) is not well known. We hypothesized that ventricular depolarization and repolarization abnormalities on the 12-lead surface electrocardiogram (ECG) predict adverse outcome in patients with ARVD. ECGs of 111 patients screened for the 2010 ARVD Task Force Criteria from 3 Swiss tertiary care centers were digitized and analyzed with a digital caliper by 2 independent observers blinded to the outcome. ECGs were compared in 2 patient groups: (1) patients with major adverse cardiovascular events (MACE: a composite of cardiac death, heart transplantation, survived sudden cardiac death, ventricular fibrillation, sustained ventricular tachycardia, or arrhythmic syncope) and (2) all remaining patients. A total of 51 patients (46%) experienced MACE during a follow-up period with median of 4.6 years (interquartile range 1.8 to 10.0). Kaplan-Meier analysis revealed reduced times to MACE for patients with repolarization abnormalities according to Task Force Criteria (p = 0.009), a precordial QRS amplitude ratio (∑QRS mV V1 to V3/∑QRS mV V1 to V6) of ≤ 0.48 (p = 0.019), and QRS fragmentation (p = 0.045). In multivariable Cox regression, a precordial QRS amplitude ratio of ≤ 0.48 (hazard ratio [HR] 2.92, 95% confidence interval [CI] 1.39 to 6.15, p = 0.005), inferior leads T-wave inversions (HR 2.44, 95% CI 1.15 to 5.18, p = 0.020), and QRS fragmentation (HR 2.65, 95% CI 1.1 to 6.34, p = 0.029) remained as independent predictors of MACE. In conclusion, in this multicenter, observational, long-term study, electrocardiographic findings were useful for risk stratification in patients with ARVD, with repolarization criteria, inferior leads TWI, a precordial QRS amplitude ratio of ≤ 0.48, and QRS fragmentation constituting valuable variables to predict adverse outcome.