Early activation of the cardiac CX3CL1/CX3CR1 axis delays ß-adrenergic-induced heart failure.

We recently highlighted a novel potential protective paracrine role of cardiac myeloid CD11b/c cells improving resistance of adult hypertrophied cardiomyocytes to oxidative stress and potentially delaying evolution towards heart failure (HF) in response to early ß-adrenergic stimulation. Here we characterized macrophages (Mφ) in hearts early infused with isoproterenol as compared to control and failing hearts and evaluated the role of upregulated CX3CL1 in cardiac remodeling. Flow cytometry, immunohistology and Mφ-depletion experiments evidenced a transient increase in Mφ number in isoproterenol-infused hearts, proportional to early concentric hypertrophy (ECH) remodeling and limiting HF. Combining transcriptomic and secretomic approaches we characterized Mφ-enriched CD45+ cells from ECH hearts as CX3CL1- and TNFα-secreting cells. In-vivo experiments, using intramyocardial injection in ECH hearts of either Cx3cl1 or Cx3cr1 siRNA, or Cx3cr1-/- knockout mice, identified the CX3CL1/CX3CR1 axis as a protective pathway delaying transition to HF. In-vitro results showed that CX3CL1 not only enhanced ECH Mφ proliferation and expansion but also supported adult cardiomyocyte hypertrophy via a synergistic action with TNFα. Our data underscore the in-vivo transient protective role of the CX3CL1/CX3CR1 axis in ECH remodeling and suggest the participation of CX3CL1-secreting Mφ and their crosstalk with CX3CR1-expressing cardiomyocytes to delay HF.

Aspects of transition cow metabolomics-Part I: Effects of a metaphylactic butaphosphan and cyanocobalamin treatment on the metabolome in liver, blood, and urine in cows with different liver metabotypes.

Dairy cows in modern production systems are at risk to develop metabolic disorders during the transition period. Reasons for individual differences in susceptibility, as well as the underlying pathomechanisms, are still only partially understood. The development of metaphylactic treatment protocols is needed. In this context, an on-farm prospective 3-fold blinded randomized study involving 80 German Holstein cows was performed throughout 1 yr. The trial involved a thorough recording of the production and clinical traits, clinical chemistry, and liver biopsies and blood and urine sampling at d 14 (mean: 12 d, range: 1-26 d) antepartum (AP), and d 7 (7, 4-13) and 28 (28, 23-34) postpartum (PP) for metabolomics analyses. Two groups received a treatment with butaphosphan and cyanocobalamin (BCC) at either the dosage recommended by the manufacturer or the double dosage (5 or 10 mL/100 kg of body weight 10% butaphosphan and 0.005% cyanocobalamin (Catosal, Bayer Animal Health), n = 20 in each group, parity: 4.2 ± 2.0 and 3.4 ± 1.3, respectively (mean ± SD)] and one group a placebo treatment (NaCl 0.9%, n = 40, parity: 4.0 ± 1.9). The animals were treated at 6 time points (7, 6, and 5 d AP, and 1, 2, and 3 d PP) via intravenous injection. Mass spectroscopy-based targeted metabolomics analysis of blood plasma and liver samples were performed using the AbsoluteIDQ p180 kit (Biocrates Life Sciences), whereas the urine samples were analyzed by nuclear magnetic resonance spectroscopy. Statistical analysis was performed using multivariate [partial least squares discriminant analysis (PLS-DA)] and univariate methods (linear mixed model). Multivariate data analysis (PLS-DA plots) of the liver metabolome revealed 3 different metabotypes (A = medium, B = minor, C = large alterations in liver metabolome profile between AP and PP status). Metabotype B animals were characterized by higher PP lipomobilization (stronger PP body condition decrease and higher blood bilirubin, fatty acids, gamma-glutamyltransferase, and triglyceride levels) and a higher occurrence of transition cow diseases, compared with the animals in metabotype C. Analysis of the feeding data showed that the period of metabotype B animals (calving in a distinct time frame) was characterized by a decreased grass silage quality. The PP liver metabolome of the metabotype C animals was characterized by higher concentrations of AA, acylcarnitines, lysoPC and sphingomyelins compared with metabotype B. For the metaphylactic treatment with BCC a dose-dependent effect was confirmed, differing between the metabotypes. In all matrices and metabotypes at various time points significant treatment effects were observed, with different profiles in clinical chemistry and as well in metabolomics data. The most clear-cut treatment effect was observed in metabotype B in the liver at 7 d PP, characterized by an increase in several acylcarnitines and phosphatidylcholines, indicating a more efficient influx and oxidation of fatty acids in mitochondria and thereby an increase in energy supply and more efficient triglyceride export in the liver. The results from the liver metabolomics analysis support the application of an indication-based metaphylactic treatment with BCC.

Aspects of transition cow metabolomics-Part III: Alterations in the metabolome of liver and blood throughout the transition period in cows with different liver metabotypes.

The liver plays a central role in the postpartum (PP) energy metabolism of the transition dairy cow; however, studies describing the liver metabolome during this period were lacking. The aim of the presented study was therefore to compare the alterations in the liver and blood metabolome of transition dairy cows. For this purpose, an on-farm trial with 80 German Holstein cows (mean lactation number: 3.9; range: 2-9) was performed, with thorough documentation of clinical traits and clinical chemistry, as well as production data. Liver biopsies and blood samples were collected at d 14 (mean: 12 d, range: 1-26 d) antepartum (AP), d 7 (7, 4-13) and 28 (28, 23-34; mean, earliest-latest) PP for targeted mass spectroscopy-based metabolomics analysis using the AbsoluteIDQ p180 kit (Biocrates Life Sciences). Statistical analysis was performed using multivariate (partial least squares discriminant analysis) as well as univariate methods (linear mixed model). Multivariate data analysis of the liver metabolome revealed 3 different metabotypes (A = medium, B = minor, C = large alterations in the liver metabolome profile between AP and PP). In metabotype C, an increase of almost all acylcarnitines, lysophosphatidylcholines (lysoPC), sphingomyelins, and some phosphatidylcholines (PC, mainly at 7 d PP) was observed after calving. In contrast to metabotype C, the clinical data of the metabotype B animals indicated a higher PP lipomobilization and occurrence of transition cow diseases. The liver metabolome profile of these animals most likely mirrors a failure of adaptation to the PP state. This strong occurrence of metabotypes was much less pronounced in the blood metabolome. Additionally, differences in metabolic patterns were observed across the transition period when comparing liver and blood matrices (e.g., in different biogenic amines, acylcarnitines and sphingolipids). In summary, the blood samples at 7 d PP showed lower acylcarnitines and PC, with minor alterations and a heterogeneous pattern in AA, biogenic amines, and sphingomyelins compared with 14 d AP. In contrast to 7 d PP, the blood samples at 28 PP revealed an increase in several AA, lysoPC, PC, and sphingomyelins in comparison to the AP state, irrespective of the metabotype. In the liver biopsies metabotype B differed from metabotype C animals ante partum by following metabolites: higher α aminoadipic acid, lower AA, serotonin, taurine, and symmetric dimethylarginine levels, lower or higher concentrations of certain acylcarnitines (higher: C2, C3, C5, C4:1; lower: C12:1, C14:1-OH, C16:2), and lower lysoPC (a C16:0, C18:0, C20:3, C20:4) and hexose levels. In blood samples, fewer differences were observed, with lower serotonin, acylcarnitine C16:2, lysoPC (a C16:0, C17:0, C18:0 and C18:1), PC aa C38:0, and PC ae C42:2. The results show that the use of only the blood metabolome to assess liver metabolism may be hampered by the fact that blood profiles are influenced by the metabolism of many organs, and metabolomics analysis from liver biopsies is a more suitable method to identify distinct metabotypes. Future studies should investigate the stability and reproducibility of the metabotype and phenotypes observed, and the possible predictive value of the metabolites already differing AP between metabotype B and C.

Antibiotic treatment and prophylaxis of periprosthetic infections: Evaluation of 666 consecutive breast implant removals.

Periprosthetic infections are feared complications in esthetic and reconstructive breast surgery. The purpose of our study is to evaluate our institution's specific culture data and to identify most common organisms and suitable antibiotics for prophylaxis and first-line treatment. We evaluated all patients with a change or removal of breast implants from 01.01.2012 to 31.12.2017 retrospectively. Based on the medical records, the surgical indications were identified and specifically analyzed for signs of infection, reasons for primary and secondary surgery, and all available microbiological data of these interventions. A total of 666 implant removals or exchanges were performed in 431 patients. Microbiological smears were gathered from 291 patients (449 implants). Bacteria were cultured from 63 implants (56 patients). In six additional patients (ten implants), a periprosthetic infection was seen, without bacteria detection. Advanced capsular contracture correlated with a higher proportion of positive swabs (p<0.05). In 11.5% of smears, bacterial contamination was found despite absence of clinical signs of infection. Coagulase-negative staphylococci were the dominant pathogen in clinical inapparent infections, while Staphylococcus aureus was when there was clinical evidence of infection. All pathogens were sensitive to vancomycin. In the majority of cases, bacterial contamination was an incidental finding, which was more common in the presence of advanced capsular contracture. In our institution, cefuroxime and amoxicillin/clavulanic acid have been proven to be reasonable choices for prevention and treatment of periprosthetic infections. In the treatment of fulminant infections and for the prophylaxis during implant replacement due to advanced capsular contracture, vancomycin became our first choice.

TRPV4 inhibition attenuates stretch-induced inflammatory cellular responses and lung barrier dysfunction during mechanical ventilation.

Mechanical ventilation is an important tool for supporting critically ill patients but may also exert pathological forces on lung cells leading to Ventilator-Induced Lung Injury (VILI). We hypothesised that inhibition of the force-sensitive transient receptor potential vanilloid (TRPV4) ion channel may attenuate the negative effects of mechanical ventilation. Mechanical stretch increased intracellular Ca2+ influx and induced release of pro-inflammatory cytokines in lung epithelial cells that was partially blocked by about 30% with the selective TRPV4 inhibitor GSK2193874, but nearly completely blocked with the pan-calcium channel blocker ruthenium red, suggesting the involvement of more than one calcium channel in the response to mechanical stress. Mechanical stretch also induced the release of pro-inflammatory cytokines from M1 macrophages, but in contrast this was entirely dependent upon TRPV4. In a murine ventilation model, TRPV4 inhibition attenuated both pulmonary barrier permeability increase and pro-inflammatory cytokines release due to high tidal volume ventilation. Taken together, these data suggest TRPV4 inhibitors may have utility as a prophylactic pharmacological treatment to improve the negative pathological stretch-response of lung cells during ventilation and potentially support patients receiving mechanical ventilation.

A high-spin square planar iron(ii)-siloxide and its tetrahedral allogon - structural and spectroscopic models of Fe-zeolite sites.

The famous α-Fe active sites in Fe-zeolites have recently been revealed to correspond to mononuclear high-spin iron(ii) centres in square planar coordination environments. Here we report a first iron siloxide complex which represents a faithful structural and spectroscopic model of such sites. Notably, also an allogon with a distorted structure exists and could be crystallised.

A Hexanuclear Iron(II) Layer with Two Square-Planar FeO4 Units Spanned by Tetrasiloxide Ligands: Mimicking of Minerals and Catalysts.

A hexanuclear iron(II) siloxide complex has been prepared by reacting an incompletely condensed silsesquioxane first with NaOMe and then with Fe(OTf)2. In the process of product formation, the siloxane framework undergoes a transformation and it was shown that this happens already upon addition of base: Treatment of the ligand precursor with NaOMe leads to a completely condensed silsesquioxane cage with 12 Si atoms that is composed of 2 equiv of the tetrasiloxide ligands found in the product complex. Its iron centers form a two-dimensional array reminiscent of the situations found in minerals and two-dimensional oxide films caused by segregation of FeOx and silica. As the hexairon(II) assembly contains two high-spin square-planar FeO4 units-suggested to represent the active sites in Fe-zeolites, which react with N2O to generate strongly oxidizing sites-it was treated with Me3NO. This led to the oxidation of two of the iron centers to the oxidation state +III and elimination of one iron ion, so that a pentanuclear, mixed valent iron siloxide was formed. All complexes were fully characterized.

Colistin, an Old Drug in a New Territory, Solid Organ Transplantation.

BACKGROUND: The clinical experience with colistin therapy for multidrug-resistant Gram-negative pathogens in solid organ transplantation is limited. METHODS: Patients transplanted from January 2003 to July 2011 and treated with intravenous or nebulized colistin were included. Descriptive statistics were used to summarize patients' characteristics and Kaplan-Meier curves for survival analysis. RESULTS: Fifteen patients were included: 10 adults (median age, 54.6 y; range, 32.2-79.6 y) and 5 children (median age, 3.3 y; range, 1.1-10.4 y). Eight patients had intra-abdominal infections, 3 had pneumonia, and 4 had bacteremia. The infections were diagnosed at a median of 5.9 months (range, 0.8-49.8 mo) after transplantation. Eight patients had coinfections, mainly with enteric pathogens. Pseudomonas aeruginosa was isolated in 13 cases and ESBL Klebsiella oxytoca and ESBL Escherichia coli were isolated in 1 case each. Thirteen patients received concomitant antibiotics with colistin. The median dose of intravenous colistin (13 patients) was 2.7 mg/kg/d (range, 1-4.9 mg/kg/d) and nebulized colistin (2 patients) was 241.7 mg/d (range, 150-333.3 mg/d). Clinical cure was achieved in 9 patients (60%). Four-week survival rate after infection was 86.7% (95% confidence interval, 56.4%-96.5%). There was no difference in the median creatinine clearance in adults (P = .38) or children (P = .88) before and after colistin. One patient had both neurotoxicity and nephrotoxicity, and 1 patient had neurotoxicity only. CONCLUSIONS: Colistin might be used as an alternate therapy for transplant patients with multidrug-resistant Gram-negative pathogens.

Viability of five different pre- and intraoperative imaging methods for autologous breast reconstruction.

BACKGROUND: Autologous breast reconstruction is an integral part in the treatment of breast cancer. While computed tomography angiography (CTA) is an established preoperative diagnostic tool for microsurgeons, no study has so far evaluated and compared five different imaging methods and their value for the reconstructive team. In order to determine the feasibility of each of the tools for routine or specialized diagnostic application, the methods' efficiency and informative value were analyzed. METHODS: We retrospectively analyzed imaging data of 41 patients used for perforator location and assessment for regional perfusion and vessel patency in patients undergoing autologous breast reconstruction with deep inferior epigastric perforator flap (DIEP), transverse rectus abdominis muscle flap (TRAM), or transverse myocutaneous gracilis flap (TMG). Five different imaging techniques were used: hand held Doppler (HHD), CT angiography (CTA), macroscopic indocyanine green (ICG) video angiography, microscope-integrated ICG video angiography, and laser Doppler imaging (LDI). RESULTS: CTA proved to be the best tool for preoperative determination of the highly variable anatomy of the abdominal region, whereas HHD showed the same information on perforator localization with some false-positive results. Intraoperative HHD was an excellent tool for dissection and vessel patency judgment. Microscope-integrated ICG was an excellent tool to document the patency of microanastomoses. In our series, macroscopic perfusion measurement with ICG or LDI was only justified in special situations, where information on perfusion of abdominal or mastectomy flaps was required. LDI did not add any additional information. CONCLUSION: Preoperative assessment should be performed by CTA with verification of the perforator location by HHD. Intraoperative HHD and microscope-integrated ICG contribute most toward the evaluation of vessel patency. ICG and LDI should only be used for special indications.

Botulinum toxin A and lidocaine have an impact on adipose-derived stem cells, fibroblasts, and mature adipocytes in vitro.

Lipofilling with autologous fat tissue is widely used in plastic and reconstructive surgery to treat soft-tissue deficiency. Unfortunately, implanted cells disappear gradually and make it difficult to predict the resorption rate. Several adjuvants are used to improve the success of fat tissue grafting. In this study, the effect of botulinum toxin (BoNT) on mature adipocytes, as well as adipose-derived stem cells (ASC) and fibroblasts was evaluated. As lidocaine is the most prevalent drug to anesthetize the donor site as well as the area to be treated with autologous fat, this local anesthetic was examined too. Primary ASCs, fibroblasts, and mature adipocytes were exposed to 1, 10, and 20 IU/ml BoNT A and 1% lidocaine. Cells were tested on proliferation, viability, and LDH release. Adipogenic differentiation potential was evaluated by quantitative real-time PCR analyzing the expression of FABP4. BoNT had no significant influence on the proliferation or viability of tested cells. By trend, low concentrations of BoNT improved adipogenic potential of ASCs. Lidocaine had a strong diminishing effect on the proliferation of ASCs and fibroblasts and on the viability of these cells. Mature adipocytes show no significant inferior viability after BoNT or lidocaine treatment. BoNT has no negative effect on ASCs, mature adipocytes, or fibroblasts in vitro. Lidocaine (1%) negatively influences the proliferation and viability of fibroblasts and partly of ASCs but not of mature adipocytes.

Skin graft fixation in severe burns: use of topical negative pressure.

Over the last 50 years, the evolution of burn care has led to a significant decrease in mortality. The biggest impact on survival has been the change in the approach to burn surgery. Early excision and grafting has become a standard of care for the majority of patients with deep burns; the survival of a given patient suffering from major burns is invariably linked to the take rate and survival of skin grafts. The application of topical negative pressure (TNP) therapy devices has demonstrated improved graft take in comparison to conventional dressing methods alone. The aim of this study was to analyze the impact of TNP therapy on skin graft fixation in large burns. In all patients, we applied TNP dressings covering a %TBSA of >25. The following parameters were recorded and documented using BurnCase 3D: age, gender, %TBSA, burn depth, hospital length-of-stay, Baux score, survival, as well as duration and incidence of TNP dressings. After a burn depth adapted wound debridement, coverage was simultaneously performed using split-thickness skin grafts, which were fixed with staples and covered with fatty gauzes and TNP foam. The TNP foam was again fixed with staples to prevent displacement and finally covered with the supplied transparent adhesive film. A continuous subatmospheric pressure between 75-120 mm Hg was applied (VAC®, KCI, Vienna, Austria). The first dressing change was performed on day 4. Thirty-six out of 37 patients, suffering from full thickness burns, were discharged with complete wound closure; only one patient succumbed to their injuries. The overall skin graft take rate was over 95%. In conclusion, we consider that split thickness skin graft fixation by TNP is an efficient method in major burns, notably in areas with irregular wound surfaces or subject to movement (e.g. joint proximity), and is worth considering for the treatment of aged patients.

Au cours des 50 dernières années, l'évolution des soins de brûlure a conduit à une diminution significative de la mortalité. Le plus grand impact sur la survie a été le changement dans l'approche de la chirurgie. L'excision précoce et la greffe sont devenues une norme de soins pour la majorité des patients atteints de brûlures profondes; la survie chez les grands brûlés est invariablement liée à la taux de prise et à la survie des greffes de peau. L'application de la pression négative topique (PNT) a démontré une amélioration dans la prise des greffes par rapport aux méthodes conventionnelles. Le but de cette étude était d'analyser l'impact du traitement de PNT sur la prise des greffes de peau dans les grandes brûlures. Chez tous les patients, nous avons appliqué des pansements PNT, couvrant à moins 25% de la SCT. Les paramètres suivants ont été enregistrés et documentés via "BurnCase 3D" : âge, sexe, % de la SCT, profondeur de brûlure, durée de séjour à l'hôpital, le score Baux, survie, ainsi que la durée et la fréquence des pansements PNT. Après le débridement des plaies, la couverture était simultanément réalisée à l'aide de greffes de peau de demi-épaisseur, qui ont été fixées avec des agrafes et couvertes de toiles gras et de mousse de PNT. La mousse PNT a été de nouveau fixée avec des agrafes pour empêcher le déplacement et finalement recouverte avec le film adhésif transparent. Une pression atmosphérique continue entre 75 à 120 mm Hg a été appliquée (VAC®, KCI, Vienne, Autriche). Le premier changement de pansement a été effectué pendant le quatrième jour. Trente-six des 37 patients, souffrant de brûlures au troisième degré, ont obtenu leur congé avec la fermeture complète de la plaie ; un seul patient a succombé à ses blessures. Le taux de la prise des greffes de peau était supérieur à 95%. La greffe de peau mince par PNT est une méthode efficace dans les grandes brûlures, notamment dans les zones avec des surfaces irrégulières et des zones soumises à un mouvement (par exemple, de proximité joint), et est à considérer pour le traitement des patients âgés.

Oral cavity tumors in younger patients show a poor prognosis and do not contain viral RNA.

BACKGROUND: Oral cavity and in particular oral tongue cancers occur with a rising incidence in younger patients often lacking the typical risk factors of tobacco use, alcohol use, and human papilloma virus (HPV) infection. Their prognosis when treated with chemoradiation has not been well studied and responsible risk factors remain elusive. A viral etiology (other than HPV) has been hypothesized. METHODS: First we analyzed outcomes from 748 head and neck cancer patients with locoregionally advanced stage tumors treated with curative-intent chemoradiation by anatomic site. Second, we analyzed seven oral tongue (OT) tumors from young, non-smokers/non-drinkers for the presence of viral mRNA using short-read massively-parallel sequencing (RNA-Seq) in combination with a newly-developed digital subtraction method followed by viral screening and discovery algorithms. For positive controls we used an HPV16-positive HNC cell line, a cervical cancer, and an EBV-LMP2A transgene lymphoma. RESULTS: Younger patients with oral cavity tumors had worse outcomes compared to non-oral cavity patients. Surprisingly none of the seven oral tongue cancers showed significant presence of viral transcripts. In positive controls the expected viral material was identified. CONCLUSION: Oral cavity tumors in younger patients have a poor prognosis and do not appear to be caused by a transcriptionally active oncovirus.

Tissue expansion for correction of scars due to burn and other causes: a retrospective comparative study of various complications.

BACKGROUND: Tissue expansion is associated with a relatively high complication rate. The aim of this study was to quantify the complication risk of burn scar patients who underwent tissue expansion in comparison to patients with other indications such as skin tumors. Furthermore it was attempted to compare the complication rates in children and adults. METHODS: A retrospective analysis was performed on 148 expanders implanted in 73 patients during the years 1994-2011. Two patient cohorts (burn scar cohort n=31 and other indication cohort n=42) were identified and analyzed. RESULTS: 27 male and 46 female patients with a median age of 21 years were included. No statistically significant difference for complication risk between the burn and other indication cohorts could be found (p=0.1412). Statistical analyses revealed a higher complication rate (52%) in the lower limb compared to all other anatomic sites (29%) (p=0.1746). In addition, statistical analyses revealed a significantly higher total complication rate in children younger than 10 years (p=0.0043). Moreover a greater TBSA was accompanied by a higher complication rate (p=0.0258). CONCLUSION: This set of data suggests that the burn scar patient is at no greater risk to suffer complications from tissue expansion. Other factors like age, TBSA and anatomical site have far more influence on the expander complication rate than the initial indication for tissue expansion.

Severe obesity increases adipose tissue expression of interleukin-33 and its receptor ST2, both predominantly detectable in endothelial cells of human adipose tissue.

OBJECTIVE: Obesity is associated with chronic inflammation of the adipose tissue, which contributes to obesity-associated complications such as insulin resistance and type 2 diabetes. Interleukin (IL)-33 acts via its receptor ST2 and is involved in the pathogenesis of inflammatory disorders including atherosclerosis and heart disease. IL-33 has been demonstrated to promote endothelial cell inflammatory response, but also anti-inflammatory and protective actions such as TH2 and M2 polarization of T cells and macrophages, respectively. IL-33 and ST2 have been shown to be expressed in human and murine adipose tissue. Our objective was to investigate alterations in obesity and a possible role of IL-33 in adipose tissue inflammation. SUBJECTS AND METHODS: We investigated severely obese patients (BMI>40 kg m(-2), n=20) and lean to overweight controls (BMI<30 kg m(-2); n=20) matched for age and sex, as well as diet-induced obese and db/db mice, in order to determine the impact of obesity on IL-33 and ST2 gene and protein expression levels in adipose tissue and blood, and their correlation with inflammatory and metabolic parameters. Furthermore, we examined the cellular source and location of IL-33 and ST2 in situ. RESULTS: IL-33 and ST2 expression levels were markedly elevated in omental and subcutaneous adipose tissue of severely obese humans and in diet-induced obese mice, but not in leptin receptor-deficient db/db mice. In addition, soluble ST2, but not IL-33 serum levels, were elevated in obesity. The main source for IL-33 in adipose tissue were endothelial cells, which, in humans, exclusively expressed ST2 on their surface. IL-33 expression strongly correlated with leptin expression in human adipose tissue. CONCLUSIONS: Expression of IL-33 and its receptor ST2 in human adipose tissue is predominantly detectable in endothelial cells and increased by severe obesity indicating an autocrine action. Thus, the adipose tissue microvasculature could participate in obesity-associated inflammation and related complications via IL-33/ST2.

Gamma-ray energies in the decay of 38Cl.

In order to resolve a long-standing discrepancy of some 30 standard deviations between the two most precise previously reported values of the γ-ray energies in the (38)Cl decays, we have undertaken a new precision measurement of the decay energies using a variety of different sources for energy calibration. The deduced energies from the present work are 1642.668 ± 0.010 and 2167.395 ± 0.010 keV. These results agree very well with one of the previous reports and disagree with the other.

The use of Suprathel(®) in deep dermal burns: first results of a prospective study.

INTRODUCTION: While autologous skin grafting has been the standard for coverage of full-thickness areas, several options for deep-partial-thickness defects exist. With regard to economising donor sites, we compared a copolymer based on DL-lactid acid (Suprathel(®)) as temporary wound dressing with autologous skin, and analysed time to healing and scar quality in matched areas of deep-partial-thickness burn. METHODS: We recruited 18 patients with a median age of 45 years (range: 25-83 years), for this prospective, non-blinded controlled non-inferiority study, suffering from deep-partial-thickness burns from November 2009 to July 2010. After early tangential excision, matched deep-partial-thickness areas were covered with 1:1.5 meshed autologous skin grafts and the copolymer for direct intra-individual comparison. Scars were evaluated by means of the Vancouver Scar Scale (VSS), the Patient and Observer Scar Assessment Scale (POSAS) and suction cutometry (MPA 580, Courage and Khazaka Electronic GmbH, Cologne, Germany) on days 30 and 90, postoperatively. RESULTS: Fifteen days after surgery, complete wound closure was present in 44.4% (8/18) of all areas covered with copolymer and 88.9% (16/18) in the split-thickness skin graft (STSG) area (p=0.008). Evaluation of the total VSS, POSAS and cutometry satisfied the criterion of non-inferiority for Suprathel(®) on day 30. Ninety days after surgery, only the Observer Scar Scale showed that Suprathel is non-inferior to STSG, albeit the mean total VSS and Patient Scar Scale were better in Suprathel(®) areas. CONCLUSION: Suprathel(®) represents a solid, reliable epidermal skin substitute with longer healing times in comparison to skin grafts but comparable results concerning early scar formation. Suprathel(®) can serve as a tool in treatment portfolio for adult patients suffering from deep dermal burns. Especially in patients with extensive burns, Suprathel(®) can be used to cover the deep dermal burn wounds to save STSGs and its donor sites for the coverage of full-thickness burned areas.

TMEM132D, a new candidate for anxiety phenotypes: evidence from human and mouse studies.

The lifetime prevalence of panic disorder (PD) is up to 4% worldwide and there is substantial evidence that genetic factors contribute to the development of PD. Single-nucleotide polymorphisms (SNPs) in TMEM132D, identified in a whole-genome association study (GWAS), were found to be associated with PD in three independent samples, with a two-SNP haplotype associated in each of three samples in the same direction, and with a P-value of 1.2e-7 in the combined sample (909 cases and 915 controls). Independent SNPs in this gene were also associated with the severity of anxiety symptoms in patients affected by PD or panic attacks as well as in patients suffering from unipolar depression. Risk genotypes for PD were associated with higher TMEM132D mRNA expression levels in the frontal cortex. In parallel, using a mouse model of extremes in trait anxiety, we could further show that anxiety-related behavior was positively correlated with Tmem132d mRNA expression in the anterior cingulate cortex, central to the processing of anxiety/fear-related stimuli, and that in this animal model a Tmem132d SNP is associated with anxiety-related behavior in an F2 panel. TMEM132D may thus be an important new candidate gene for PD as well as more generally for anxiety-related behavior.

Two differentially expressed MATE factor genes from apple complement the Arabidopsis transparent testa12 mutant.

Proanthocyanidins (PAs) are a class of flavonoids with numerous functions in plant ecology and development, including protection against microbial infection, animal foraging and damage by UV light. PAs are also beneficial in the human diet and livestock farming, preventing diseases of the cardiovascular system and lowering the risk of cancer, asthma and diabetes. Apples (Malus x domestica Borkh.) are naturally rich in flavonoids, but the flavonoid content and composition varies significantly between cultivars. In this work, we applied knowledge from the model plant Arabidopsis thaliana, for which the main features of flavonoid biosynthesis have been elucidated, to investigate PA accumulation in apple. We identified functional homologues of the Multidrug And Toxic compound Extrusion (MATE) gene TRANSPARENT TESTA12 from A. thaliana using a comparative genomics approach. MdMATE1 and MdMATE2 were differentially expressed, and the function of the encoded proteins was verified by complementation of the respective A. thaliana mutant. In addition, MdMATE genes have a different gene structure in comparison to homologues from other species. Based on our findings, we propose that MdMATE1 and MdMATE2 are vacuolar flavonoid/H(+) -antiporters, active in PA accumulating cells of apple fruit. The identification of these flavonoid transporter genes expands our understanding of secondary metabolite biosynthesis and transport in apple, and is a prerequisite to improve the nutritional value of apples and apple-derived beverages.

Long-term anxiolytic and antidepressant-like behavioural effects of tiagabine, a selective GABA transporter-1 (GAT-1) inhibitor, coincide with a decrease in HPA system activity in C57BL/6 mice.

Gamma-aminobutyric acid (GABA) system plays a pivotal role in the pathophysiology of anxiety and mood disorders. This study was aimed to assess the anxiolytic and antidepressant-like properties of tiagabine, an inhibitor of the GABA transporter-1 (GAT-1), after acute and chronic administration in C57BL/6JOlaHsD mice with paroxetine as a positive control. In first experiments, the acute administration of tiagabine (7.5 mg/kg, orally [PO]) and paroxetine (10 mg/kg PO) induced anxiolytic effects in the elevated plus maze test and the modified hole board test and an antidepressant-like effect in the forced swim test. Chronic application of tiagabine (7.5 mg/kg PO) and paroxetine (10 mg/kg PO) for 22 days revealed an anxiolytic and antidepressant-like efficacy of tiagabine only. In a further experiment, we analysed the impact of chronic tiagabine versus paroxetine treatment on the hypothalamic-pituitary-adrenocortical (HPA) system regulation. GAT-1 blockade induced a setpoint-shift of the stress hormone system toward lower levels as indicated by decreased plasma corticosterone concentrations and attenuated gene expression levels of corticotropin-releasing factor in the paraventricular nucleus of the hypothalamus and of hippocampal steroid receptors. This data indicate that both acute and long-term anxiolytic and antidepressant-like properties of brain GAT-1 inhibition coincide with a reduction in HPA system activity in mice.