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We argue that Benenson et al. need to consider not only sex differences in the effects of care on offspring survival but also in age-specific fertility when predicting how longevity affects fitness. We review evidence that staying alive has important effects on both women's and men's fitness, and encourage consideration of alternative explanations for observed sex differences in threat responses.

Background and objectives How do new ideas spread in social groups? We apply the framework of cultural evolution theory to examine what drives change in perinatal care norms among Himba women in the Kunene region of Namibia. Access to formal medical care is on the rise in this region, and medical workers regularly visit communities to promote WHO-recommended perinatal care practices. This study investigates how various forms of social transmission affect women’s uptake of medical recommendations concerning perinatal care. Methodology Based on interviews with one hundred Himba mothers, we used Bayesian multi-level logistical regression models to examine how perceptions of group preferences, prestige ascribed to outgroup conformers, interaction with the outgroup and access to resources affect norm adoption. Results Women who perceive medical recommendations as common in their group prefer, plan and practice these recommendations more often themselves. We observed a shift toward medical recommendations regarding birth location and contraception use that was in line with conformity bias predictions. Practices that serve as cultural identity markers persist in the population. Conclusions and implications Norm changes, and the cultural evolutionary processes that can lead to them, are not uniform, either in process or pace. Empirical studies like this one provide important examples of how these changes reflect local culture and circumstance and are critical for better understanding the models that currently predominate in cultural evolution work. These cases can also help bridge the gap between evolutionary anthropology and public health by demonstrating where promotion and prevention campaigns might be most effective. Lay Summary The recent promotion of WHO-recommended perinatal care practices in Namibia provides an opportunity to empirically study norm change using a cultural evolution framework. We found women adopt medical recommendations when they believe these are common in their social group. Local norms that were not discouraged persisted in the study group.

Mit der zunehmenden Inzidenz der Vulva- und Vaginalkarzinome ist auch mit einer zunehmenden Bedeutung der Systemtherapie bei fortgeschrittenen und metastasierten Tumoren zu rechnen. In den einschlagigen Leitlinien wird der Einsatz bei mangelhafter Datenlage zuruckhaltend bewertet. Die vorliegenden Daten aus der Literatur zur Systemtherapie (ohne Radiochemotherapie) sollen dargestellt werden und auf ihre Anwendbarkeit im Einzelfall in den verschiedenen Therapiesituationen Neoadjuvanz, Adjuvanz und Palliation gewertet werden. Es wurde eine Literaturrecherche in PubMed mit den Schlagwortern „vulvar cancer“ und „systemic therapy“ oder „systemic treatment“ oder „chemotherapy“ oder „neoadjuvant chemotherapy“ sowie „vaginal cancer“ und „systemic treatment“ oder „chemotherapy“ oder „neoadjuvant chemotherapy“ von Januar 1990 bis Juli 2018 durchgefuhrt. Die Daten beschranken sich im Wesentlichen auf retrospektive, einarmige, monozentrische Untersuchungen an meist sehr kleinen Fallzahlen, bestenfalls handelt es sich um prospektive multizentrische Phase-II-Studien. Als Orientierung konnen die bei den haufigeren, biologisch ahnlichen Entitaten Zervixkarzinom und Analkarzinom verwendeten Zytostatika und -kombinationen dienen. Bei jungeren Patientinnen mit HPV(humanes Papillomvirus)-induzierten Vulva- und Vaginalkarzinomen ist mit einer besseren Wirksamkeit und Vertraglichkeit der Chemotherapie zu rechnen. Erste Ergebnisse zu zielgerichteten Therapien deuten auf eine Wirksamkeit von EGFR(„epidermal growth factor receptor“)-gerichteten Therapien. Insbesondere bei HPV-induzierten Tumoren konnte die Krebsimmuntherapie zukunftig eine Option sein. Aufgrund der sparlichen Daten ist ein Einsatz von Systemtherapien auf Einzelfalle zu beschranken, bei denen es um eine Reduzierung von Folgen anderer Therapiemodalitaten gehen muss oder andere Behandlungsoptionen nicht (mehr) zur Verfugung stehen. Die Seltenheit dieser Tumoren macht internationale Studienkooperationen und Registerstudien zur Erfassung der Therapierealitat erforderlich. Eine Chance ist moglicherweise die Ubertragbarkeit von Ergebnissen bei haufigeren Tumorentitaten mit ahnlichen biologischen Eigenschaften und Ansatzen fur zielgerichtete Therapien.

Purpose Primarily, to investigate the effect of high intake of cod (lean fish) or salmon (fatty fish) on serum concentration of total neopterin, a marker of cellular immune activation that is associated with cardiovascular disease. Second, to investigate effects of high cod/salmon intake on antioxidant vitamins and elements essential for activity of antioxidant enzymes. Methods In this randomised clinical trial, 63 participants with overweight/obesity consumed 750 g/week of either Atlantic cod (N = 22) or Atlantic salmon (N = 22) or were instructed to continue their normal eating habits but avoid fish intake (Control group, N = 19) for 8 weeks. Food intake was recorded, and fasting serum were collected at baseline and endpoint. Results Serum total neopterin concentration was reduced in the Cod group (median change − 2.65 (25th, 75th percentiles − 3.68, − 0.45) nmol/l, P = 0.018) but not in the Salmon group (median change 0.00 (25th, 75th percentiles − 4.15, 3.05) nmol/l, P = 0.59) when compared with the Control group after 8 weeks. The estimated daily intake of selenium, iron, magnesium and zinc were similar between all groups. Increased serum concentration of selenium was observed only after cod intake when compared to the Control group (P = 0.017). Changes in serum concentrations of copper, iron, magnesium, all-trans retinol, α-tocopherol and γ-tocopherol were similar between the groups. Conclusion A high intake of cod, but not of salmon, lowered serum total neopterin concentration when compared to the Control group. Clinical trial registration This trial was registered at clinicaltrials.gov as NCT02350595

PurposeTo explore whether high intake of cod or salmon would affect gut microbiota profile, faecal output and serum concentrations of lipids and bile acids.MethodsSeventy-six adults with overweight/obesity with no reported gastrointestinal disease were randomly assigned to consume 750 g/week of either cod or salmon, or to avoid fish intake (Control group) for 8 weeks. Fifteen participants from each group were randomly selected for 72 h faeces collection at baseline and end point for gut microbiota profile analyses using 54 bacterial DNA probes. Food intake was registered, and fasting serum and morning urine were collected at baseline and end point.ResultsSixty-five participants were included in serum and urine analyses, and gut microbiota profile was analysed for 33 participants. Principal component analysis of gut microbiota showed an almost complete separation of the Salmon group from the Control group, with lower counts for bacteria in theBacteroidetesphylum and theClostridialesorder of theFirmicutesphyla, and higher counts for bacteria in theSelenomonadalesorder of theFirmicutesphylum. The Cod group showed greater similarity to the Salmon group than to the Control group. Intake of fibres, proteins, fats and carbohydrates, faecal daily mass and output of fat, cholesterol and total bile acids, and serum concentrations of cholesterol, triacylglycerols, non-esterified fatty acids and total bile acids were not altered in the experimental groups.ConclusionA high intake of cod or salmon fillet modulated gut microbiota but did not affect faecal output or serum concentrations of lipids and total bile acids.Clinical trial registrationThis trial was registered at clinicaltrials.gov as NCT02350595.

Low serum concentrations of several vitamins have been linked to increased risk of diseases including insulin resistance and type 2 diabetes (T2D). Fish is a good source of several vitamins, and the prevalence of T2D is low in populations with high fish intake. The aim of the present study was to investigate the effects of high fish intake on vitamins in serum from adults in autumn in South-Western Norway at 60° north latitude. In this randomised clinical trial, sixty-three healthy participants with overweight/obesity consumed 750 g/week of either cod (n22) or salmon (n22) as five weekly dinners or were instructed to continue their normal eating habits but avoid fish intake (Control group,n19) for 8 weeks. The estimated vitamin D intake was significantly increased in the Salmon group when compared with the Cod group (P= 6·3 × 10−4) and with the Control group (P= 3·5 × 10−6), with no differences between groups for estimated intake of vitamins A, B1, B2, B3, B6, B9, C and E. Serum 25-hydroxyvitamin D3concentration was decreased in all groups after 8 weeks; however, the reduction in the Salmon group was significantly smaller compared with the Cod group (P= 0·013) and the Control group (P= 0·0060). Cod and salmon intake did not affect serum concentrations of the other measured vitamins. The findings suggest that 750 g/week of salmon was not sufficient to prevent a decrease in serum 25-hydroxyvitamin D3in autumn in South-Western Norway in adults with overweight/obesity.

Yearly, development-induced displacement affects some 20 million people, a disproportionate share of whom are indigenous. Within the diverse category of indigenous peoples, hunter-gatherers are especially vulnerable to displacement as they form the least powerful sectors of society. While displacement poses a major threat to the few remaining hunter-gatherer peoples, case studies of how this process unfolds are scarce. This ethnographic study details how two decades of indigenous land rights legislation have been ineffective in preventing displacement of indigenous communities in the Philippines, through the case of Agta hunter-gatherers of Dimasalansan. The paper demonstrates how procedural inconsistencies, institutional competition and a development paradigm focused on commodification of land have undermined the legal titling process. We argue that the ensuing land-rush that currently displaces Agta is symptomatic for how the implementation of indigenous land rights legislation is undermined by business interests, thereby creating more uncertainty than certainty for the least powerful.

The prevalence of type 2 diabetes (T2D) is low in populations with a high fish intake; however prospective studies with fish intake have shown positive, negative or no association between fish intake and the risk for T2D. The aim of this study was to investigate the effects of high intake of lean or fatty fish on glucose tolerance, leucocyte membrane fatty acid composition and leucocyte function in overweight/obese adults. In this randomised clinical trial, sixty-eight healthy overweight/obese participants consumed 750 g/week of either lean or fatty fish as dinners, or were instructed to continue their normal eating habits but to avoid fish intake (control group), for 8 weeks. Energy and macronutrient intake and physical activity were not changed within the groups during the study period. High intake of fatty fish, but not of lean fish, significantly improved glucose regulation 120 min postprandially (P=0·012), but did not affect fasting glucose concentration. A smaller increase in fasting to 120 min postprandial insulin C-peptide concentration was seen after fatty fish intake (P=0·012). Lean fish increased the DHA content in leucocyte membranes (P=0·010), and fatty fish increased the total content of n-3 PUFA (P=0·00016) and reduced the content of n-6 PUFA (P=0·00057) in leucocyte membranes. Lean and fatty fish intake did not affect phagocytosis of bacteria ex vivo. The findings suggest that high intake of fatty fish, but not of lean fish, beneficially affected postprandial glucose regulation in overweight/obese adults, and may therefore prevent or delay the development of T2D in this population.

Cadaveric tissue-perfusion models are well established in the fields of structural heart and peripheral vascular disease; however, less consideration has been given toward coronary artery disease despite comparable prevalence and morbidity. Two tissue-perfusion models were developed to address this need. The first, an intact heart model, allows simulation of percutaneous coronary interventional procedures. The second focuses upon isolated arteries, allowing quantification of simulated procedures. Both models were applied for clinical training and for investigations into medical device behavior. The manner of preparation facilitates access to clinically relevant disease, thus providing a platform to further research on coronary artery disease.

To identify biomarkers to assess participants’ compliance in an intervention study with high intake of cod or salmon, compared to a fish-free diet. In this randomised clinical trial, 62 healthy overweight/obese participants consumed 750 g/week of either cod (N = 21) or salmon (N = 22) across 5 weekly dinners, or were instructed to continue their normal eating habits but avoid fish intake (Control group, N = 19) for 8 weeks. After cod intake, serum concentrations of trimethylamine N-oxide (TMAO, p = 0.0043), creatine (p = 0.024) and 1-methylhistidine (1-MeHis, p = 0.014), and urine concentrations (relative to creatinine) of TMAO (p = 2.8 × 10−5), creatine (p = 8.3 × 10−4) and 1-MeHis (p = 0.016) were increased when compared to Control group. After salmon intake, serum concentrations of 1-MeHis (p = 2.0 × 10−6) and creatine (p = 6.1 × 10−4), and urine concentrations (relative to creatinine) of 1-MeHis (p = 4.2 × 10−6) and creatine (p = 4.0 × 10−5) were increased when compared to Control group. Serum and urine concentrations of TMAO were more increased following cod intake compared to salmon intake (p = 0.028 and 2.9 × 10−4, respectively), and serum and urine 1-MeHis concentrations were more increased after salmon intake compared to cod intake (p = 8.7 × 10−5 and 1.2 × 10−4, respectively). Cod and salmon intake did not affect serum and urine concentrations of 3-methylhistidine, and only marginally affected concentrations of free amino acids and amino acid metabolites. TMAO measured in serum or urine is a potential biomarker of cod intake, and 1-MeHis measured in serum or urine is a potential biomarker of salmon intake.

The aim of the present study was to examine whether high intake of lean or fatty fish (cod and farmed salmon, respectively) by healthy, normal-weight adults would affect risk factors of type 2 diabetes and CVD when compared with lean meat (chicken). More knowledge is needed concerning the potential health effects of high fish intake (>300 g/week) in normal-weight adults. In this randomised clinical trial, thirty-eight young, healthy, normal-weight participants consumed 750 g/week of lean or fatty fish or lean meat (as control) for 4 weeks at dinner according to provided recipes to ensure similar ways of preparations and choices of side dishes between the groups. Energy and macronutrient intakes at baseline and end point were similar in all groups, and there were no changes in energy and macronutrient intakes within any of the groups during the course of the study. High intake of fatty fish, but not lean fish, significantly reduced TAG and increased HDL-cholesterol concentrations in fasting serum when compared with lean meat intake. When compared with lean fish intake, fatty fish intake increased serum HDL-cholesterol. No differences were observed between lean fish, fatty fish and lean meat groups regarding fasting and postprandial glucose regulation. These findings suggest that high intake of fatty fish, but not of lean fish, could beneficially affect serum concentrations of TAG and HDL-cholesterol, which are CVD risk factors, in healthy, normal-weight adults, when compared with high intake of lean meat.

Orbital atherectomy (OA) is indicated for facilitating stent delivery in patients by reducing coronary plaque, but complete understanding of the therapeutic mechanism has not been established. We performed a mechanistic study using a cadaveric heart perfusion model to investigate the impact of OA on

Background Talactoferrin alfa is an oral dendritic cell (DC)-mediated immunotherapy (DCMI). We tested whether talactoferrin was superior to placebo in advanced non-small-cell lung cancer (NSCLC). Patients and methods An FORTIS-M trial was an international, multicenter, randomized, double-blind comparison of talactoferrin (1.5g p.o. BID) versus placebo BID, in patients with stage IIIB/IV NSCLC whose disease had failed two or more prior regimens. Treatment was administered for a maximum of five 14-week cycles. The primary efficacy end point was overall survival (OS); secondary end points included 6- and 12-month survival, progression-free survival (PFS), and disease control rate (DCR). Results Seven hundred and forty-two patients were randomly assigned (2:1) to talactoferrin (497) or placebo (245). The median OS in the intent-to-treat (ITT) population was 7.66 months in the placebo arm and 7.49 months in the talactoferrin arm [hazard ratio (HR), 1.04; 95% CI, 0.873–1.24; P = 0.6602]. The 6-month survival rates were 59.9% (95% CI, 53.4% to 65.8%) and 55.7% (95% CI, 51.1% to 59.9%), respectively. The 12-month survival rates were 32.2% (95% CI, 26.3% to 38.2%) and 30.9% (95% CI, 26.8% to 35%), respectively. The median PFS rates were 1.64 months and 1.68 months, respectively (HR, 0.99; 95% CI, 0.835–1.16; P = 0.8073). The DCRs were 38.4 and 37.6%, respectively [stratified odds ratio (OR), 0.96; 95% CI, 0.698–1.33; P = 0.8336]. The safety profiles were comparable between arms. Conclusions There was no improvement in efficacy with talactoferrin alfa in patients with advanced NSCLC whose disease had failed two or more previous regimens.

18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) has been investigated as a tool for monitoring response to neoadjuvant chemo- and chemoradiotherapy (CT and CRT, respectively) and as a predictor for survival in patients with esophageal cancer. In contrast to patients who undergo neoadjuvant CT, it is not known whether patients who are clinically identified as responders after neoadjuvant CRT show better disease-free survival (DFS) than patients identified as nonresponders. The aim of the study was to determine the predictive value of FDG-uptake measured prior to and early during neoadjuvant CRT. Patients treated with neoadjuvant CRT between 2004 and 2009 within a randomized trial were included. FDG-uptake was measured at baseline and after 14 days of CRT. According to the PERCIST-criteria, patients were allocated to have metabolic response, stable disease, or progression. Patients were followed until recurrence of disease or death. The predictive value of FDG-PET was determined with univariable and multivariable analysis in patients who underwent potentially curative surgery. One-hundred and six patients were included in the analysis. Minimal follow-up for surviving patients was 60 months. No significant differences in DFS were found between patients with metabolic response, stable disease, or progression, with 5-year DFS rates of 66%, 53%, and 67%, respectively (P = 0.39). Relative change in FDG uptake after 14 days of CRT is not associated with DFS in patients with esophageal cancer undergoing neoadjuvant chemoradiotherapy followed by surgery. These measurements should not be used for prognostication in this specific group of patients.

To determine activity and safety of capecitabine at a moderate dose of 2000 mg/m(2) as first-line therapy for metastatic breast cancer.In this prospective phase II trial, patients with HER2-negative metastatic breast cancer received first-line capecitabine 2000 mg/m(2) on days 1-14 every 3 weeks. The primary aim was to exclude a time to progression (TTP)6 months. Secondary end-points were overall response rate, overall survival (OS), toxicity and quality of life.Median age of the 161 included patients was 65 years. Median TTP and OS were 7.3 months [95% (confidence interval) CI: 6.2-8.4] and 17.1 months (95% CI: 14.0-20.3), respectively. An overall response rate of 26.1%, including 13 complete remissions was observed. Patients developing grade I-III hand-foot syndrome had a significantly longer TTP and OS and patients65 years also achieved a significantly longer TTP. Haematological grade I-IV toxicities were leucopenia (64.0%), anaemia (50.9%) and thrombocytopenia (28.0%). Relevant non-haematological toxicities were hand-food-syndrome (37.3%), fatigue (34.2%), nausea (29.8%) and diarrhoea (20.5%). Quality of life assessment revealed an improved emotional function, but worsening of nausea and vomiting from cycle 1-10.Capecitabine at a dose of 2000 mg/m(2) is active and safe as first-line treatment of patients with metastatic breast cancer.

Die temperaturprogrammierte O2-Desorption (O2-TPD), die N2- und Kr- Gassorption sowie die Raster-Elektronen-Mikroskopie (REM) sind bedeutende Analysemethoden in der Katalysechemie. Am Beispiel eines korund- und eines calciumhexaaluminathaltigen Tragermaterials werden die Methoden angewendet und das Potenzial der eingesetzten Katalysatoren hinsichtlich der Oberflacheneigenschaften und der damit verbundenen Aktivitat aufgezeigt. Welches der beiden getragerten Katalysatorsysteme fur die Ag-katalysierte Epoxidierung von 1,3-Butadien zu 3,4-Epoxy-1-buten vorteilhafter ist, wird im Rohrreaktor getestet. The temperature-programmed O2 desorption (O2-TPD), the N2- and Kr- sorption as well as the scanning-electron microscope (SEM) are important analysis methods in catalysis chemistry. By the example of a corundum and of a calcium hexaaluminate substrate the methods are used and the potential regarding to the surface properties and the activity of the assigned catalysts thereby pointed. Which of the two catalyst systems for the Ag-catalyzed epoxidation of 1,3-butadiene to 3,4-epoxy-1-butene is more favorable is tested in a tubular reactor.

Prior anatomic studies demonstrate frequent existence of patent microchannels in Chronic Total Occlusions (CTOs) but real-time visualization to guide Percutaneous Coronary Intervention is limited. The Scanning Fiber Endoscope (SFE) is a novel technology that provides images with significantly

Most patients with severe acute respiratory syndrome (SARS) develop antibodies against the SARS coronavirus and survive the infection. This suggests that active or passive immunisation might be an effective option in preventing or treating SARS. Therefore, the development of SARS vaccination strategies belongs to the most important targets of SARS research. The present study analyses data-bases for the current knowledge on vaccination strategies. Both, passive and active immunisation protocols are presently being developed. Passive immunisation with sera from surviving patients leads to partial success. Whereas the passive immunisation exhibits a promising therapeutic tool, only active immunisation can successfully prevent infection. A number of approaches has been used on the basis of inactivated SARS coronaviruses, recombinant subunits, recombinant DNA, and viral vectors. However, all recently developed candidates need to be evaluated critically before clinical use. The so-called "antibody-dependent enhancement" can improve viral uptake into host cells resulting in increased viral load and exacerbation of disease.

We present the results of our multicolor observations of BL Lac in the period 1999–2001. We show that the spectral energy distribution of the variable component in the range from K to B had remained unchanged for three years. The power-law spectrum is indicative of its synchrotron nature.

MgO (100) single crystals are implanted with 1.50-MeV Al+ and 3.00-MeV Al2 + ions at a fluence of 1×1015 Al atoms cm-2 under high-vacuum conditions. The surface morphology of the substrate is measured in air using atomic force microscopy and X-ray reflectometry followed by computer-simulated spectrum analysis. The ion-irradiated areas are found to protrude to different heights on the nanometre scale. Small height differences are observed in the areas irradiated by Al+ and Al2 + ions of comparable energy, dose rate and total fluence. The results indicate that protrusions are most likely caused by implantation-induced point defects (vacancies) generated in the crystal during implantation. Other possibilities for the cause of protrusions are discussed. Thermal treatment stimulates a partial recovery of the implantation damage and alters the topography of MgO surfaces.

The results of multicolor observations of the blazar 3C 66A, obtained in the course of the project OJ-94, are analyzed. It is established that the energy distribution of the variable source in the optical and IR ranges can be represented, on the average, by a power law: Fν ∝ ν-0.92. Since the blazar's emission is strongly polarized, there is no doubt of the synchrotron nature of the variable source responsible for the blazar's activity.

The color variability of BL Lac during the strong 1997 outburst was studied. It was found that the energy distribution in the spectrum of the variable source, which determines the object’s photometric behavior, did not vary during the outburst. It was a power- law spectrum and was flatter than during other, lower-power out-bursts. There is no doubt of the synchrotron nature of the variable source.

We consider an electromagnetic compatibility problem, where an electromagnetic plane wave, incident on an aperture in the wall of a cavity, is coupled to a set of enclosed metallic plates and a monopole is connected to the base of the cavity and loaded with an impedance. For an aperture of moderate dimensions, one can define an equivalent problem where the incident wave is the one radiated by electric and magnetic dipoles placed inside the cavity with the aperture short-circuited. To predict the voltage induced on the load, an integral representation of the electric field combined with the Green's function of the cavity is used to model the electric field. This reduces the set of unknowns to the values of the currents on the monopole and on the plates. A method of moments is then used to solve the related integral equation. The analysis of the variations of the average and maximum values of the voltage over a given frequency band, as a function of the parameters of the structure, is conducted in an unusual manner. We use statistical tools such as experiment design, regression, and kriging to determine the prevailing parameters and their degree of correlation and to provide a fast prediction of the average and maximum values of the voltage.

In this paper, we demonstrate that the trefoil knot has the unique property that its forward scattering for circularly polarized wa es exhibits a strong dependence on the handedness of the polarization. Both a single knot element as well as an array of these knots show this ( ) property which could be used in a polarization-selecti e surface PSS . Q 1999 John Wiley & Sons, Inc. Microwave Opt Technol Lett 21: 170]173, 1999.

The problem of the activity of extragalactic objects is one of the main problems of current astrophysics. There are many manifestations of activity but the photometric and polarimetric variability in IR, optical, UV and X-ray regions is probably one of the most important. The sources responsible for the variability are placed in the nearest neighbourhood of a central engine. Clarifying the nature of these sources might give a tool to the solution of the problem of nuclear activity in general.

Mutations in LRRK2 were first reported as causing Parkinson's disease (PD) in late 2004. Since then, approximately a dozen LRRK2 substitutions have been identified that are believed to be pathogenic mutations. The substitution of adenine for guanine at nucleotide 4541 (4541G>A) in LRRK2 was recently reported. This substitution resulted in the replacement of an arginine at position 1514 with a glutamine (R1514Q). Although this substitution was not found in a large cohort of controls, its pathogenicity could not be verified. We have now genotyped the R1514Q substitution in a sample of 954 PD patients from 429 multiplex PD families. This substitution was identified in 1.8% of the PD patients; however, the majority of the PD sibships segregating this substitution were discordant for this putative mutation. In addition, the R1514Q substitution was detected in 1.4% of neurologically evaluated, control individuals. These data suggest that the R1514Q variant is not a pathogenic LRRK2 mutation. We believe it is imperative that the causative nature of any newly identified genetic variant be determined before it is included in any panel for diagnostic testing.

Optical light curves of three blazars are analyzed by Hurst’s method of normalized range. It is shown that Hurst’s empirical relationship is satisfied for these curves, in accordance with which the Hurst parameters are found for each curve. Assuming that blazar light curves have self-affinity, they determine the fractal dimensionality of the curves to be D ≈ 1.1.

We investigated the spectroscopic, photophysical, and photochemical properties of novel caged cyclic nucleotides, the axial and equatorial (7-methoxycoumarin-4-yl)methyl esters of cGMP and of 8-Br-cGMP. The competition between fluorescence and photochemical ester cleavage results in a strong quenching of the coumarin fluorescence. This fluorescence quenching is enhanced additionally by the donor–acceptor interaction between the coumarin unit and the nucleic base, pronounced in the axial configuration. On photochemical decaging the fluorescence intensity increases up to 48-fold and more. This photochemical fluorescence enhancement can be used for the description of the temporal and local distribution of biologically active cGMP derivatives.

ML18147 evaluated continued bevacizumab with second-line chemotherapy for patients with metastatic colorectal cancer (mCRC) progressing after the standard first-line bevacizumab-containing therapy.Evaluating outcomes according to tumor Kirsten rat sarcoma virus oncogene (KRAS) status was an exploratory analysis. KRAS data were collected from local laboratories (using their established methods) and/or from a central laboratory (mutation-specific Scorpion amplification-refractory mutation system). No adjustment was made for multiplicity; analyses were not powered to detect statistically significant differences.Of 820 patients, 616 (75%) had unambiguous KRAS data; 316 (51%) had KRAS wild-type tumors and 300 (49%) had mutant KRAS tumors. The median progression-free survival (PFS) was 6.4 months for bevacizumab plus chemotherapy and 4.5 months for chemotherapy [P0.0001; HR = 0.61; 95% confidence interval (CI): 0.49-0.77] for wild-type KRAS and 5.5 and 4.1 months, respectively (P = 0.0027; HR = 0.70; 95% CI: 0.56-0.89) for mutant KRAS. The median overall survival (OS) was 15.4 and 11.1 months, respectively (P = 0.0052; HR = 0.69; 95% CI: 0.53-0.90) for wild-type KRAS and 10.4 versus 10.0 months, respectively (P = 0.4969; HR = 0.92; 95% CI: 0.71-1.18) for mutant KRAS. In both analyses, no treatment interaction by KRAS status was observed (PFS, P = 0.4436; OS, P = 0.1266).Bevacizumab beyond first progression represents an option for patients with mCRC treated with bevacizumab plus standard first-line chemotherapy, independent of KRAS status.

6-Chloro-3,4′-bipyridine-1-oxides 5 and 5-cyano-1,6-dihydro-2-methyl-6-oxo-3,4′-bipyridine-1′-oxide 7 have been prepared from the corresponding pyridine derivatives by oxidation using peracetic acid. Reaction of 5 with various amines gave the 6-substituted compounds 6 . Some of the synthesized products 6 were subsequently converted by derivation into related analogues 8, 9 and 10 . In this series 5-cyano-6-morpholino-(3,4′-bipyridine)-1′-oxide (AWD 122–239, 6a ), exhibited remarkable positive inotropic potency in spontaneously beating isolated guinea-pig atria as well as in anesthetized pigs. Additionally, 6a showed nearly no inhibition of cyclic AMP phosphodiesterase III. The molecular and crystal structures were determined together with the molecular electrostatic potential and structure-activity relationships are discussed. The obtained results clearly indicate compound 6a as a new type of cardiotonic.