Validation of putative biomarkers of furan exposure through quantitative analysis of furan metabolites in urine of F344 rats exposed to stable isotope labeled furan.

Humans are chronically exposed to furan, a potent liver toxicant and carcinogen that occurs in a variety of heat-processed foods. Assessment of human exposure based on the furan content in foods is, however, subject to some uncertainty due to the high volatility of furan. Biomarker monitoring is thus considered an alternative or complementary approach to furan exposure assessment. Previous work suggested that urinary furan metabolites derived from the reaction of cis-2-butene-1,4-dial (BDA), the reactive intermediate of furan, with glutathione (GSH) or amino acids may serve as potential biomarkers of furan exposure. However, some metabolites were also reported to occur in urine of untreated animals, indicating either background contamination via animal feed or endogenous sources, which may limit their suitability as biomarkers of exposure. The overall aim of the present study was to accurately establish the correlation between external dose and concentration of furan metabolites in urine over time and to discriminate against endogenous formation and furan intake via feed. To this end, the furan metabolites GSH-BDA (N-[4-carboxy-4-(3-mercapto-1H-pyrrol-1-yl)-1-oxobutyl]-L-cysteinylglycine), NAcLys-BDA (R-2-(acetylamino)-6-(2,5-dihydro-2-oxo-1H-pyrrol-1-yl)-1-hexanoic acid), NAcCys-BDA-NAcLys (N-acetyl-S-[1-[5-(acetylamino)-5-carboxypentyl]-1H-pyrrol-3-yl]-L-cysteine) and NAcCys-BDA-NAcLys sulfoxide (N-acetyl-S-[1-[5-(acetylamino)-5-carboxypentyl]-1H-pyrrol-3-yl]-L-cysteine sulfoxide) were simultaneously analyzed by stable isotope dilution ESI-LC-MS/MS as unlabeled and [13C4]-furan dependent metabolites following oral administration of a single oral dose of isotopically labelled [13C4]-furan (0.1, 1, 10, 100 and 1000 µg/kg bw) to male and female F344/DuCrl rats. Although a linear correlation between urinary excretion of [13C4]-furan-dependent metabolites was observed, analysis of unlabeled NAcLys-BDA, NAcCys-BDA-NAcLys and NAcCys-BDA-NAcLys sulfoxide revealed substantial, fairly constant urinary background levels throughout the course of the study. Analysis of furan in animal feed excluded feed as a source for these background levels. GSH-BDA was identified as the only furan metabolite without background occurrence, suggesting that it may present a specific biomarker to monitor external furan exposure. Studies in humans are now needed to establish if analysis of urinary GSH-BDA may provide reliable exposure estimates.

Characterizing Social Functioning in School-Age Children with Sensory Processing Abnormalities.

Children with sensory abnormalities (SAs) have a variety of social problems resulting in poorer social functioning than children with typical development (TD). We describe the relationship between SAs and social functioning in school-age children with SAs, children with TD and a clinical comparison sample of children with autism spectrum disorder (ASD). Children with SAs demonstrated impaired social functioning on standardized measures. Children with SAs demonstrated worse social functioning than children with TD and equivalent social functioning to children with ASD. Increased SAs were associated with poorer social functioning across all groups. The results suggest that children with SAs experience clinically significant problems with social functioning and future research is needed to develop interventions to support social functioning in this population.

Precision Mass Measurements of Neutron-Rich Scandium Isotopes Refine the Evolution of N=32 and N=34 Shell Closures.

We report high-precision mass measurements of ^{50-55}Sc isotopes performed at the LEBIT facility at NSCL and at the TITAN facility at TRIUMF. Our results provide a substantial reduction of their uncertainties and indicate significant deviations, up to 0.7 MeV, from the previously recommended mass values for ^{53-55}Sc. The results of this work provide an important update to the description of emerging closed-shell phenomena at neutron numbers N=32 and N=34 above proton-magic Z=20. In particular, they finally enable a complete and precise characterization of the trends in ground state binding energies along the N=32 isotone, confirming that the empirical neutron shell gap energies peak at the doubly magic ^{52}Ca. Moreover, our data, combined with other recent measurements, do not support the existence of a closed neutron shell in ^{55}Sc at N=34. The results were compared to predictions from both ab initio and phenomenological nuclear theories, which all had success describing N=32 neutron shell gap energies but were highly disparate in the description of the N=34 isotone.

GDF15 reflects beta cell function in obese patients independently of the grade of impairment of glucose metabolism.

BACKGROUND AND AIMS: Growth differentiation factor 15 (GDF15) is a strong predictor of cardiovascular morbidity and mortality found to be both marker and target of impaired glucose metabolism. GDF15 increases following glucose administration and is up-regulated in obesity and diabetes. We investigate here the relationship between GDF15 and beta cell function. METHODS AND RESULTS: In this cross-sectional study we evaluated GDF15 concentrations in 160 obese subjects (BMI 35-63 kg/m2, age 39.4 ± 18.6 years, m/f 38/122) who underwent a 75 g oral glucose tolerance test (OGTT). Based on the OGTT results, the cohort was divided into two groups: 1) normal fasting glucose and normal glucose tolerance (n = 80), 2) impaired fasting glucose, impaired glucose tolerance or type 2 diabetes (n = 80). The relationship of GDF15 to fasting and OGTT-based dynamic insulin sensitivity and insulin secretion parameters was evaluated. GDF15 was higher in the prediabetes and diabetes groups and correlated with HbA1c, glucose, insulin as well as baseline and dynamic indices of insulin sensitivity and estimated beta cell function. Multiple regression analysis revealed that age, waist-to-height ratio, glomerular filtration rate and prehepatic beta cell function, but not the grade of impairment of glucose metabolism, were independent predictors of GDF15. Subgroup analysis showed that of all parameters of glucose metabolism only C-peptide, fasting prehepatic beta cell function and insulinogenic index remained significantly related to GDF15 in both groups. CONCLUSION: We conclude that in patients with severe obesity, GDF15 strongly relates to beta cell function and should be further investigated as a potential therapeutic target and biomarker guiding treatment options.

Dawning of the N=32 Shell Closure Seen through Precision Mass Measurements of Neutron-Rich Titanium Isotopes.

A precision mass investigation of the neutron-rich titanium isotopes ^{51-55}Ti was performed at TRIUMF's Ion Trap for Atomic and Nuclear science (TITAN). The range of the measurements covers the N=32 shell closure, and the overall uncertainties of the ^{52-55}Ti mass values were significantly reduced. Our results conclusively establish the existence of the weak shell effect at N=32, narrowing down the abrupt onset of this shell closure. Our data were compared with state-of-the-art ab initio shell model calculations which, despite very successfully describing where the N=32 shell gap is strong, overpredict its strength and extent in titanium and heavier isotones. These measurements also represent the first scientific results of TITAN using the newly commissioned multiple-reflection time-of-flight mass spectrometer, substantiated by independent measurements from TITAN's Penning trap mass spectrometer.

A Lewis acid ß-diiminato-zinc-complex as all-rounder for co- and terpolymerisation of various epoxides with carbon dioxide.

A ß-diiminato-zinc-N(SiMe3)2 complex (1) was synthesised and fully characterised, including an X-ray diffraction study. The activity of catalyst 1 towards the coupling reaction of CO2 and various epoxides, including propylene oxide (PO), cyclohexene oxide (CHO), styrene oxide (SO), limonene oxide (LO), octene oxide (OO) and epichlorohydrin (ECH), was investigated. Terpolymerisation of CO2, PO and LO, as well as CO2, CHO and PO, was successfully realised, resulting in polymers with adjustable glass transition temperatures and transparencies. Reaction conditions such as temperature, pressure and catalyst concentration were varied to find the optimal reaction values, especially regarding LO/CO2. In situ IR experiments hinted that at 60 °C and a critical LO concentration, polymerisation and depolymerisation are in an equilibrium (ceiling effect). Pressurising catalyst 1 with carbon dioxide resulted in a dimeric catalyst (2) with a OSiMe3 group as a new initiator. Homopolymerisation of different epoxides was carried out in order to explain the reactivity concerning copolymerisation reaction of CO2 and epoxides.

Lost in plasmids: next generation sequencing and the complex genome of the tick-borne pathogen Borrelia burgdorferi.

BACKGROUND: Borrelia (B.) burgdorferi sensu lato, including the tick-transmitted agents of human Lyme borreliosis, have particularly complex genomes, consisting of a linear main chromosome and numerous linear and circular plasmids. The number and structure of plasmids is variable even in strains within a single genospecies. Genes on these plasmids are known to play essential roles in virulence and pathogenicity as well as host and vector associations. For this reason, it is essential to explore methods for rapid and reliable characterisation of molecular level changes on plasmids. In this study we used three strains: a low passage isolate of B. burgdorferi sensu stricto strain B31(-NRZ) and two closely related strains (PAli and PAbe) that were isolated from human patients. Sequences of these strains were compared to the previously sequenced reference strain B31 (available in GenBank) to obtain proof-of-principle information on the suitability of next generation sequencing (NGS) library construction and sequencing methods on the assembly of bacterial plasmids. We tested the effectiveness of different short read assemblers on Illumina sequences, and of long read generation methods on sequence data from Pacific Bioscience single-molecule real-time (SMRT) and nanopore (Oxford Nanopore Technologies) sequencing technology. RESULTS: Inclusion of mate pair library reads improved the assembly in some plasmids as did prior enrichment of plasmids. While cp32 plasmids remained refractory to assembly using only short reads they were effectively assembled by long read sequencing methods. The long read SMRT and nanopore sequences came, however, at the cost of indels (insertions or deletions) appearing in an unpredictable manner. Using long and short read technologies together allowed us to show that the three B. burgdorferi s.s. strains investigated here, whilst having similar plasmid structures to each other (apart from fusion of cp32 plasmids), differed significantly from the reference strain B31-GB, especially in the case of cp32 plasmids. CONCLUSION: Short read methods are sufficient to assemble the main chromosome and many of the plasmids in B. burgdorferi. However, a combination of short and long read sequencing methods is essential for proper assembly of all plasmids including cp32 and thus, for gaining an understanding of host- or vector adaptations. An important conclusion from our work is that the evolution of Borrelia plasmids appears to be dynamic. This has important implications for the development of useful research strategies to monitor the risk of Lyme disease occurrence and how to medically manage it.

Buried free flaps in head and neck reconstruction: higher risk of free flap failure?

Thrombosis of the pedicle is central to free flap failure, and early revision of a compromised flap is the key to successfully salvage a flap. Therefore, the majority of free flaps in reconstructive head and neck surgery are used with the ability to visually examine the flap. Sometimes, due to intra-operative circumstances, it is necessary to use a flap that cannot be monitored externally. These flaps are called buried flaps and have the reputation of being put at risk. The current literature provides only limited data to support or disprove this position. A single institution retrospective review of patient charts between 2007 and 2015 was performed. Flap monitoring was carried out with hand-held Doppler of the pedicle hourly for the first 72 h in all cases. Additional duplex ultrasound was performed in the majority of buried flaps. A total of 437 flaps were included into the study. 37 flaps (7.8 %) were identified to fulfill the criteria of a buried free flap. In total, four patients had complications, three of which required operative reexploration. All interventions were successful, resulting in no flap loss in our series. An accurate operation technique combined with meticulous monitoring protocols supported by duplex ultrasound can result in satisfactory outcome of buried flaps. No enhanced risk of flap loss of buried flaps was found in our cohort.

Measurement of Excitation Spectra in the

Excitation spectra of ^{11}C are measured in the ^{12}C(p,d) reaction near the η^{'} emission threshold. A proton beam extracted from the synchrotron SIS-18 at GSI with an incident energy of 2.5 GeV impinges on a carbon target. The momenta of deuterons emitted at 0° are precisely measured with the fragment separator (FRS) operated as a spectrometer. In contrast to theoretical predictions on the possible existence of deeply bound η^{'}-mesic states in carbon nuclei, no distinct structures are observed associated with the formation of bound states. The spectra are analyzed to set stringent constraints on the formation cross section and on the hitherto barely known η^{'}-nucleus interaction.

Clinical impact of malnutrition on complication rate and length of stay in elective ENT patients: a prospective cohort study.

Malnutrition is considered as an independent risk factor for morbidity, mortality and a prolonged hospital stay for in-hospital patients. While most available data on the impact of malnutrition on health-related and financial implications refer to gastroenterologic or abdominal surgery patients, little is known about the impact of malnutrition on Ear Nose Throat (ENT)/head and neck surgery patients. The objective of this study was to investigate the impact of malnutrition on morbidity and length of hospital stay in an elective ENT/head and neck surgery patient cohort. The study was performed as a single-center, prospective cohort study at a tertiary referral centre. Nutritional risk at admission was assessed using the NRS-2002 screening tool. Multivariate regression models were used to determine independent risk factors for complications and a prolonged hospitalization. Three hundred fifty one participants were included in the study. A malignant disease was found in 62 participants (17.7 %). 62 patients (17.7 %) were at a moderate to severe risk of malnutrition. A bad general health condition and complications during hospital stay could be identified as independent risk factors for a prolonged hospitalization. Patients with a malignant tumor showed a more than fourfold higher risk of developing at least one complication. Malnutrition, however, was not statistically associated with a higher complication rate or a prolonged hospital stay. Our data suggests that malnutrition does not seem to play such an important role as a risk factor for complications and a prolonged hospital stay in ENT patients as it does in other disciplines like abdominal surgery or gastroenterology.

[Renal cell carcinoma: Drug therapy and prognostic models]. / Nierenzellkarzinom : Medikamentöse Therapie und prognostische Modelle.

Renal cell carcinoma (RCC) represents the sixth-leading cancer-specific cause of death worldwide. This is mainly caused by metastatic or locally advanced RCC. Approximately 25-30% of patients present with metastasis during the initial diagnosis. Furthermore, 20-30% of patients develop metastatic disease following initial curative surgery. Metastatic RCC is characterized by a poor prognosis with a median overall survival of less than 2 years. Today, targeted therapies such as VEGF receptor inhibitors and antagonists as well as mTOR inhibitors represent the standard of care in metastatic RCC. Conventional chemotherapies or cytokine-based medications have been abandoned due to inferior clinical efficacy compared with targeted therapies. In Germany, sunitinib, pazopanib, temsirolimus, and bevacizumab have been approved for first-line treatment and sorafenib, axitinib, and everolimus for second-line treatment. Prognostic models, assessing individual risk profiles, have been developed in the last 15 years, which are crucial for the design of trials, patient counseling, and initiation of goal-directed therapies.

Strong association of serum- and glucocorticoid-regulated kinase 1 with peripheral and adipose tissue inflammation in obesity.

OBJECTIVE: The serum- and glucocorticoid-regulated kinase 1 (SGK1) is an early transcriptional target of glucocorticoids and is activated via insulin. Here we investigate the regulation of SGK1 expression in human obesity, diet-induced murine obesity and human monocytic cell line THP-1 monocytes. SUBJECTS AND METHODS: SGK1 expression was studied in subcutaneous and omental adipose tissue (AT) of 20 morbidly obese and 20 age- and gender-matched non-obese controls in murine diet-induced obesity and the THP-1 cell line. The regulation of SGK1 by inflammatory signals was tested in THP-1 cells. RESULTS: Murine diet-induced obesity is associated with a significant upregulation of Sgk1 in gonadal AT. Sgk1 expression is highest in the macrophage-rich stromal vascular fraction and lower in adipocytes. In humans, AT SGK1 is predominantly expressed in CD14(+) macrophages and significantly upregulated in omental and subcutaneous AT of obese subjects. SGK1 mRNA expression in both omental and subcutaneous AT correlates with body mass index, circulating leptin and C-reactive protein, and the local expression of inflammatory markers including monocyte chemotactic protein-1 and macrophage inflammatory protein-1α. The expression of SGK1 in THP-1 cells is upregulated by inflammatory signals, such as lipopolysaccharide and tumour necrosis factor-α, as well as during the induction of monocyte-to-macrophage maturation. CONCLUSIONS: Our data present the first link between SGK1 and obesity-associated inflammation. SGK1 expression is stimulated in response to inflammatory signals and increased in AT macrophages. The characterisation of SGK1 functions in obesity and immunity may help identify potential therapeutic targets in the treatment of obesity.

Dinuclear zinc catalysts with unprecedented activities for the copolymerization of cyclohexene oxide and CO2.

A variety of new dinuclear zinc catalysts was developed and tested for the copolymerization of cyclohexene oxide and carbon dioxide. Electron-withdrawing groups thereby led to unprecedented activities with turnover frequencies up to 155,000 h(-1). These are by far the highest polymerization rates ever reported for the copolymerization of cyclohexene oxide and CO2.

[The supraclavicular flap for reconstruction of the head and neck]. / Der supraclaviculäre Lappen zur Rekonstruktion im Kopf-Hals-Bereich.

The complex anatomy of the head and neck region requires the ability to raise a wide spectrum of pedicled and free flaps, to ensure optimal reconstruction of various defects by the reconstructive surgeon. The supraclavicular (island) flap, which has almost been buried in oblivion, provides excellent potential to reconstruct even bigger defects of the head and neck region, while causing minimal donor site morbidity at the same time. Its benefits lie in the reliable skin island and its wide arc of rotation, resulting in excellent cosmetic and functional outcomes.

Googling caesarean section: a survey on the quality of the information available on the Internet.

OBJECTIVE: To examine the quality and completeness of information on caesarean section in web pages used by laypersons in Brazil, a country with very high rates of caesarean delivery. DESIGN: Cross-sectional study. SETTING: Brazil. SAMPLE: A total of 176 Internet websites. METHODS: The term 'caesarean delivery' and 25 synonyms were entered into the most popular search engines in Brazil. The first three pages of hits were downloaded and assessed by two independent investigators using the DISCERN instrument and a content checklist. MAIN OUTCOME MEASURES: Quality and completeness of information on caesarean section. RESULTS: A total of 3900 web pages were retrieved and 176 fulfilled the selection criteria. The overall average DISCERN score was 43.6 (±8.9 SD), of a maximum score of 75; 30% of the pages were of poor or very poor quality and 47% were of moderate quality. Most pages scored low, especially in questions related to reliability of the information. The most frequently covered topics were: indications for caesarean section (80% of websites), which did not reflect clinical practice; short-term maternal risks (80%); and potential benefits of caesarean section (56%), including maternal and doctor convenience. Less than half of the websites mentioned perinatal risks and less than one-third mentioned long-term maternal risks associated with caesarean section, such as uterine rupture (17%) or placenta praevia/accreta (12%) in future pregnancies. CONCLUSIONS: The quality and completeness of web-based resources in Portuguese about caesarean section were poor to moderate. Pending improvement of these resources, obstetricians should warn pregnant women about these facts and encourage them to discuss what they have read on the Internet about caesarean section. TWEETABLE ABSTRACT: The quality and completeness of information about caesareans is poor in 176 websites used by Brazilians.

[Prevention of postprostatectomy incontinence: etiology and risk factors]. / Verhinderung der Postprostatektomieinkontinenz: Ätiologie und Risikofaktoren.

The prevention of postprostatectomy incontinence has always been a challenge for urologists. Improved understanding of male continence and changes in pelvic anatomy after radical prostatectomy and the implementation of new surgical techniques raised hope of reduced incontinence rates. Despite using the full potential of continence-sparing techniques and atraumatic robot-assisted surgery, postprostatectomy incontinence still occurs in 5-20 % of cases. Recently published data showed a trend of improved early return to continence using anterior suspension or posterior reconstruction in robot-assisted prostatectomy. Postprostatectomy incontinence has a negative impact on quality of life and causes high costs of treatment. Therefore, further research in the amelioration of postoperative continence is mandatory.

[Tract sealing techniques in percutaneous nephrolitholapaxy]. / Versiegelungstechniken bei der perkutanen Nephrolitholapaxie.

Since the introduction of the percutanous nephrolitholapaxy (PNL), the instruments as well as the technique have experienced a tremendous modification. The miniaturisation of the instruments has led to a decreased hospital stay, reduced analgetic use as well as an extension of the indication for PNL. A nephrostomy tube was normally inserted to prevent urinoma and to provoke renal haemostasis. In 1997, the necessity for the regular use of a nephrostomy tube was first questioned. In a prospective study, the nephrostomy tube was successfully omitted in 50 selected patients. Since then, increasingly, the nephrostomy tube is omitted. Alternatively, different haemostatic substances are used for renal tract closure. The necessity for the use of these agents is still unclear.

[Traditional Chinese medicine in urology]. / Traditionelle chinesische Medizin in der Urologie.

Traditional Chinese medicine (TCM) is an ancient holistic medicine based on the doctrine of Tao and Qi. Tao represents an alteration from which the polarity of Yin and Yang arises and Qi is the vitality which circulates through the body. Therapeutic concepts of TCM include acupuncture, herbal therapy, nutrition and Tuina, a form of manual therapy. TCM is now gaining increased acceptance in the Western society as a complementary therapy. Acupuncture and herbal therapy are the main forms of implementation of TCM in urology.

Diabetes and thrombolysis for acute stroke: a clear benefit for diabetics.

BACKGROUND AND PURPOSE: Diabetes is a predictor for poor outcome after thrombolysis in stroke patients, and early post-stroke glycaemia is associated with higher rates of post-thrombolytic symptomatic intracerebral haemorrhages (SICHs). Diabetic stroke patients may nevertheless profit from thrombolysis. Here, we compared outcome data of matched thrombolysed and non-thrombolysed diabetic and non-diabetic stroke patients from a national database. METHODS: The outcomes of 1079 matched quadruples, each consisting of a thrombolysed diabetic, a non-thrombolysed diabetic, a thrombolysed non-diabetic and a non-thrombolysed non-diabetic case (a total of 4316 cases), enrolled in the Austrian Stroke Unit Registry (2004-2013), were compared. Patients were matched according to sex, age, stroke severity, pre-stroke disability and prior stroke. RESULTS: A regression model with improvement as depending variable found no effect of diabetes (P = 0.158) or the interaction diabetes × thrombolysis (P = 0.507), whereas the effect of thrombolysis itself was highly significant (P < 0.001). Functional outcome (modified Rankin Scale) was significantly better in thrombolysed than in non-thrombolysed diabetic patients at discharge from the stroke-unit (P < 0.001) and 3 months later (P = 0.006). No significant differences were found in the number of SICHs after thrombolytic treatment between diabetic (4.9%) and non-diabetic strokes (3.5%). Both groups had a higher risk of SICH compared with the non-thrombolysed groups (diabetics 2.6%, non-diabetics 2.5%). Due to lack of documentation, the effect of admission blood glucose on SICH was not investigated. CONCLUSIONS: Data from this nationwide survey show that diabetic stroke patients receive a substantial benefit from thrombolysis, and therefore diabetic strokes should not be excluded from thrombolytic treatment.