Grouping of PFAS for human health risk assessment: Findings from an independent panel of experts.

An expert panel was convened to provide insight and guidance on per- and polyfluoroalkyl substances (PFAS) grouping for the purposes of protecting human health from drinking water exposures, and how risks to PFAS mixtures should be assessed. These questions were addressed through multiple rounds of blind, independent responses to charge questions, and review and comments on co-panelists responses. The experts agreed that the lack of consistent interpretations of human health risk for well-studied PFAS and the lack of information for the vast majority of PFAS present significant challenges for any mixtures risk assessment approach. Most experts agreed that "all PFAS" should not be grouped together, persistence alone is not sufficient for grouping PFAS for the purposes of assessing human health risk, and that the definition of appropriate subgroups can only be defined on a case-by-case manner. Most panelists agreed that it is inappropriate to assume equal toxicity/potency across the diverse class of PFAS. A tiered approach combining multiple lines of evidence was presented as a possible viable means for addressing PFAS that lack analytical and/or toxicological studies. Most PFAS risk assessments will need to employ assumptions that are more likely to overestimate risk than to underestimate risk, given the choice of assumptions regarding dose-response model, uncertainty factors, and exposure information.

PSMA PET/CT with Glu-urea-Lys-(Ahx)-[68Ga(HBED-CC)] versus 3D CT volumetric lymph node assessment in recurrent prostate cancer.

PURPOSE: PET/CT with the PSMA ligand is a powerful new method for the early detection of nodal metastases in patients with biochemical relapse. The purpose of this retrospective investigation was to evaluate the volume and dimensions of nodes identified by Glu-urea-Lys-(Ahx)-[(68)Ga(HBED-CC)] ((68)Ga-PSMA-11) in the setting of recurrent prostate cancer. METHODS: All PET/CT images were acquired 60 ± 10 min after intravenous injection of (68)Ga-PSMA-11 (mean dose 176 MBq). In 21 patients with recurrent prostate cancer and rising PSA, 49 PSMA-positive lymph nodes were identified. Using semiautomated lymph node segmentation software, node volume and short-axis and long-axis dimensions were measured and compared with the maximum standardized uptake values (SUVmax). Round nodes greater than or equal to 8 mm were considered positive by morphological criteria alone. The percentage of nodes identified by elevated SUVmax but not by conventional morphological criteria was determined. RESULTS: The mean volume of (68)Ga-PSMA-11-positive nodes was 0.5 ml (range 0.2 - 2.3 ml), and the mean short-axis diameter was 5.8 mm (range 2.4 - 13.3 mm). In 7 patients (33.3 %) with 31 PSMA-positive nodes only 11 (36 %) were morphologically positive based on diameters >8 mm on CT. In the remaining 14 patients (66.7 %), 18 (37 %) of PSMA positive lymph nodes had short-axis diameters <8 mm with a mean short-axis diameter of 5.0 mm (range 2.4 - 7.9 mm). Thus, in this population, (68)Ga-PSMA-11 PET/CT detected nodal recurrence in two-thirds of patients who would have been missed using conventional morphological criteria. CONCLUSION: (68)Ga-PSMA-11 PET/CT is more sensitive than CT based 3D volumetric lymph node evaluation in determining the node status of patients with recurrent prostate cancer, and is a promising method of restaging prostate cancers in this setting.

[The embolisation of venous malformations]. / Die Rolle der Embolisation bei venösen Malformationen.

BACKGROUND: The treatment of congenital, vascular malformations is a challenge for physicians and patients. Although different therapeutic options have been described to date, their individual relevance has still to be defined.  METHODS: We performed a retrospective study of 61 patients with a venous malformation (VM, mean age 22  years), who were referred to our depart-ment during the last 5 years. The size of the VM was larger than 5  cm in 41 patients (66 %). The lower extremities were involved in 45  cases (73 %). The most frequent clinical manifestations were recurrent swelling (80 %), pain (63 %), varicosis (60 %) and thrombophlebitis (39 %). MR angiography with venous sequences was always performed before treatment. Depending on the localisation and the extension of the VM, different techniques of embolisation were selected: foam sclerotherapy or application of synthetic glue by direct punction, coiling of pelvic veins or arterial embolisation with glue. RESULTS: 42  patients (69 %) underwent a procedure because of the complaints or the extension of the VM. An embolisation was performed in 25  patients with 65  interventional sessions. The most frequent technique was foam sclerotherapy (45 ×), followed by glue injection (13 ×), pelvic -venous coiling (6 ×) and arterial embolisation with glue (1 ×). Fifteen patients (60 %) reported a very good and 8  patients a marked improvement (32 %). In two cases there was no change of the complaints. The postinterventional complications were severe pain (n = 3) and skin/fat necrosis at the toe of one patient. CONCLUSIONS: The embolisation of venous malformations is an effective therapeutic tool. Different techniques can be used to address specific localisations and morphological patterns. The com-plication rate is very low when a step-by-step -approach is used, so that a repeat intervention is feasible. However, a more specific documentation of the post-interventional changes of the VM is needed before a general recommendation can be given.

Nano-fin based mercury-sensor for environmental surveillance.

This Nano-Fin-Sensor bases on a lithography-independent technology-process, enabling research on Nano-Sensors without cost-intensive technology-equipment. Background for the sensor described within this paper is the high pollution with mercury of the environment and the lack of cheap, easy to use and portable sensors. The lithography-independent process is based on a "deposition and etch-back" technique defining Nano-Fins. Active sensor-material is a gold-layer, deposited on the fin, increasing resistance being exposed to mercury-vapor due to the process of amalgamation. Regeneration is done by heating-up the gold-layer using the poly-silicon fin as resistance-heating-device driving out the adsorbed mercury. To increase the measurement-accuracy, the sensor is made up of four Nano-Fin-Sensors, connected as Wheatstone-bridge. Two sensors have to be passivated by a mercury diffusion barrier, here a silicon-nitride-layer.

A new cost effective method of planarisation for multiple metal layers in the sub-100 nm-region.

The availability of multiple metal layers has become essential for high-density layouts and economic chip size. The presented paper describes an efficient and low-cost alternative to Chemical-Mechanical-Polishing (CMP). The method uses an auxiliary wafer as a sort of plunger. Starting with a preprocessed wafer, for example from a Complementary-Metal-Oxide-Semiconductor (CMOS) technology, a spin-on glass is applied before the deposition of the first metal layer. Afterwards a second silicon wafer will be covered homogeneously with photo resist and subsequentially coated with aluminum or titanium. This wafer serves as a plunger, while the metal layer protects the photo resist against impression. Whilst the plunger is pressed down on the spin-on glass, the first wafer is cooled down bonding the two wafers together. Separation of the wafers is accomplished by removing the photo resist layer. After the separation step any remaining photo resist as well as the aluminum layer are removed by etching. This process results in a planar surface which is optimally suited for the deposition and structuring of further metal layers which lead to more freedom concerning the complex interconnects in modern analog and digital circuits.

[Origin, structure and distribution of dioxins]. / Entstehung, Struktur und Verbreitung von Dioxinen.

Polychlorinated dibenzo-para-dioxins (PCDD) and polychlorinated dibenzofurans (PCDF) are generated as unintentional by-products in a number of thermal and chemical-industrial processes. Biogenic formation through dimerization of chlorinated precursors, such as chlorophenols, is know but does not play a major role in national dioxin release inventories and in most cases is not quantified. PCDD/PCDF are semi-volatile substances and undergo long-range transport; they are persistent and accumulate in the environment and organismus; and they are toxic. They have become a global environmetnal problem. At the international level this issue is addressed by the Stockholm Convention on Persistent Organic Pollutants, a legally binding instrument to eliminate PCDD/PCDF through step-wise implementation of reduction measures. Within the Stockholm Convention, Parties have to develop national or regional dioxin inventories. First results show that in most industrialized countries, incineration of municipal solid waste does no longer represent the largest dioxin source; instead, certain processes in the metallurgical industry have become largest emitters. In developing countries, the situation is very different: open burning processes such as forest and grassland fires, burning of agricultural residues either before or after harvest as well as fires in waste dumps or the private fires to dispose of municipal waste represent the largest dioxin sources. First steps for a global environmental monitoring program under the Stockholm Convention have been initiated.

[Beak trimming in turkeys]. / Schnabelkürzen bei Puten.

In Germany, Bio-beaker and infra-red irradiation (PSP) are used for beak trimming in turkey chicks as routine methods to prevent feather pecking and cannibalism. By both procedures the animals suffer from extensive damage and considerable continuous pain. Beak trimming is allowed by animal welfare legislation, but the operation requires an official permission and must be carried out under anesthesia. The official intention, due to animal welfare reasons, to decrease this operation and to question it permanently fails because beak trimming without anesthesia is tolerated. Elaboration of alternative programs has been demanded for a long time. Therefore selection of stocks tending less to cause feather pecking and cannibalism as well as adequate keeping and housing conditions during hatching and rearing are proposed.

Crystal structure of the antibiotic albomycin in complex with the outer membrane transporter FhuA.

One alternative method for drug delivery involves the use of siderophore-antibiotic conjugates. These compounds represent a specific means by which potent antimicrobial agents, covalently linked to iron-chelating siderophores, can be actively transported across the outer membrane of gram-negative bacteria. These "Trojan Horse" antibiotics may prove useful as an efficient means to combat multi-drug-resistant bacterial infections. Here we present the crystallographic structures of the natural siderophore-antibiotic conjugate albomycin and the siderophore phenylferricrocin, in complex with the active outer membrane transporter FhuA from Escherichia coli. To our knowledge, this represents the first structure of an antibiotic bound to its cognate transporter. Albomycins are broad-host range antibiotics that consist of a hydroxamate-type iron-chelating siderophore, and an antibiotically active, thioribosyl pyrimidine moiety. As observed with other hydroxamate-type siderophores, the three-dimensional structure of albomycin reveals an identical coordination geometry surrounding the ferric iron atom. Unexpectedly, this antibiotic assumes two conformational isomers in the binding site of FhuA, an extended and a compact form. The structural information derived from this study provides novel insights into the diverse array of antibiotic moieties that can be linked to the distal portion of iron-chelating siderophores and offers a structural platform for the rational design of hydroxamate-type siderophore-antibiotic conjugates.

Isolation of CF0CF1 from Chlamydomonas reinhardtii cw15 and the N-terminal amino acid sequences of the CF0CF1 subunits.

CF0CF1 was isolated from chloroplasts of the cell wall-deficient Chlamydomonas reinhardtii strain cw15. The subunit pattern was analyzed by SDS-gel electrophoresis and the N-terminal amino acid sequences of all nine subunits were determined by microsequencing. The amino acid sequences of subunits alpha, beta, gamma and epsilon match with those derived from the corresponding Chlamydomonas DNA sequences. In variance with the previously assumed N-terminus of beta; however, it was found that the first 11 amino acids are lacking. The subunits delta, I, II, III and IV were identified by comparison with known sequences of homologous polypeptides of higher plant chloroplasts and cyanobacteria, respectively.

Dose comparison of tropisetron (Navoban) 5 mg and 10 mg orally in the prophylaxis of dacarbazine-induced nausea and emesis.

In this double-blind, randomized trial performed at five study centers, the prophylactic, antiemetic effect of two different dosages of tropisetron (Navoban; Sandoz Pharma Ltd, Basel, Switzerland) was investigated in dacarbazine-treated patients with melanoma. Patients received tropisetron 5 mg or 10 mg orally (as one capsule) once daily (minimum 3 days) on each day of chemotherapy. No significant differences were found in the effects of tropisetron 5 mg and 10 mg. During the first 24 hours, total control of vomiting was seen in 93% and 98% of patients receiving tropisetron 5 mg and 10 mg, respectively. Total control of nausea was achieved in 84% and 80% of patients receiving tropisetron at these dosages. Over days 2 to 7 of chemotherapy, total control of vomiting and nausea remained high. Patients reported that quality of life remained good throughout chemotherapy, as did mood; only a small decrease in food intake occurred. Tropisetron was well tolerated. Constipation was the most common adverse event, occurring in 13% of patients. Headache (4%), diarrhea (4%), and anorexia (2%) also were observed.

Tryptanthrins: a novel class of agonists of the aryl hydrocarbon receptor.

2,3,7,8-Tetrachlorodibenzo-p-dioxin and related environmental pollutants exert most of their adverse effects such as immunosuppression, induction of endocrine dysfunction, tumor promotion, and teratogenicity via the aryl hydrocarbon or dioxin receptor. While most potent agonists of the aryl hydrocarbon receptor are of synthetic origin, an increasing number of natural compounds are now recognized as receptor agonists. Our findings demonstrated that some tryptanthrin derivatives biosynthesized in incubations of Candida lipolytica with tryptophan and anthranilic acid or its derivatives were agonists of the aryl hydrocarbon receptor. The biosynthetic products 8-methyltryptanthrin, 8-chlorotryptanthrin, and 8-bromotryptanthrin induced cytochrome P4501A1 mRNA and protein in rat hepatocytes in primary culture, characteristic features of aryl hydrocarbon receptor agonists. Log-probit analysis of the catalytic activity of cytochrome P4501A1, 7-ethoxyresorufin O-deethylase (EROD), revealed EC50 induction values of 1.7, 0.25, and 0.17 microM for 8-methyltryptanthrin, 8-chlorotryptanthrin, and 8-bromotryptanthrin, respectively. Interestingly, the nonsubstituted tryptanthrin molecule, biosynthesized from the common physiological precursors tryptophan and anthranilic acid, was also active as an inducer. The specificity of the inducing effect of tryptanthrins was demonstrated in gel retardation experiments in Hepa-1 mouse hepatoma cells, showing the characteristic interaction of the activated aryl hydrocarbon receptor with an oligonucleotide containing a xenobiotic-responsive element. It is suggested that the receptor may be part of a defense system protecting higher organisms from secondary metabolites formed by the microflora of the host or its environment.

Novel bioactive compounds from actinomycetes.

Actinomycetes form an enormous reservoir of secondary metabolites and enzymes. The potential for exploiting rare actinomycetes is highlighted by the discovery of novel compounds from strains of Spirillospora and Nocardioides. Novel compounds of well known classes of antibiotics, such as polyenes, continue to be discovered. For compounds containing a chromophore, the analysis by high-performance liquid chromatography coupled with a diode-array detector enables the elimination of producers of known compounds and facilitates the discovery of novel compounds or derivatives. The complexity of the regulatory mechanisms is illustrated by glutamine synthetase. The characterization of thermostable amylolytic, lignolytic, peroxidase and neuramidase activities, and the isolation of novel cellulolytic actinomycetes clearly demonstrate the potential of Actinomycetes as producers of enzymes.

Course of serum-Ig concentrations in B12 chickens of the UM line.

The University of Munich chicken line ("UM") is isogenic in respect to the MHC and divides into normogammaglobulinemic, permanent and transient dysgammaglobulinemic individuals. Hence the immune defect is independent of the MHC. Continual analysis of the immunoglobulins until the 50th week of life revealed: one group of dysgammaglobulinemic individuals showed an initial IgG peak between the third and sixth week of life. Unusually high IgM and IgA levels occur in permanent and transient dysgammaglobulinemic individuals previous to the appearance of the IgG deficit and previous to a possible initial IgG peak. These high levels remain throughout the life of the chicken, possibly due to a missing negative feedback mechanism. Transient dysgammaglobulinemic chickens also exhibited increased IgM and IgA values after IgG normalization. Based upon our results, we postulate that the dysgammaglobulinemia defect is already preprogrammed during late embryonic development. The prevalence of a B or T-cell defect is still under discussion.

Kinetics of delayed-type hypersensitivity (DTH) reactions and Ig levels in FCA-induced dysgammaglobulinemic B 12 chickens.

Kinetic studies on delayed-type hypersensitivity (DTH) to Freund's complete adjuvant (FCA) have been done in spontaneous dysgammaglobulinemic chickens, which have drastically reduced serum IgG levels and highly elevated IgM and IgA levels - in comparison to chickens with normal immunoglobulin (Ig) levels. For a period of five weeks, serum Ig levels, leukocyte migration inhibition (LMIT), and wattle reaction were examined once a week. In normal chickens, FCA treatment resulted in stimulation of IgG, but did not affect IgM synthesis, whereas in spontaneous dysgammaglobulinemic chickens, FCA stimulated only IgM synthesis. Spontaneous dysgammaglobulinemic chickens could produce LMIT and wattle reactions as well as normal birds. Whereas in normal birds, both types of DTH reactions declined continuously about the third or fourth week, in immunodeficient chickens, further increments of LMIT and wattle reactions up to the fifth week persisted as evidenced by LMIT and wattle reactions even 15 weeks after sensitization. In contrast, only minimal signs of reactivity were seen in normal birds. Spontaneous dysgammaglobulinemic chickens, nearly unable to synthesize IgG even after FCA stimulation in vivo, lack suppressive mechanisms regulating the course of DTH reaction to FCA. The possible B-cell nature of the regulatory cell population is discussed.

Enterobactin: the characteristic catecholate siderophore of Enterobacteriaceae is produced by Streptomyces species.(1).

Enterobactin is described in the literature as the typical iron-chelating compound (siderophore) produced by bacteria of the family Enterobacteriaceae. In the course of a HPLC with diode array detection screening programme for detection of novel secondary metabolites, enterobactin, its biosynthetic precursor 2,3-dihydroxy-N-benzoylserine and its linear dimer and trimer condensation products were found to be produced by two Streptomyces strains besides the trihydroxamate-type siderophores desferri-ferrioxamine B and E.

Isolation and characterization of staphyloferrin A, a compound with siderophore activity from Staphylococcus hyicus DSM 20459.

A highly hydrophilic compound was isolated from low iron culture broth of Staphylococcus hyicus DSM 20459 which exhibits siderophore activity to the producer and 37 other staphylococci. The previously unknown metabolite was designated staphyloferrin A and consists of two molecules of citric acid, each linked to D-ornitine by an amide bond. Using an ion-pair HPLC-system we detected staphyloferrin A and a second iron regulated compound (staphyloferrin B) in the culture fluid of several Staphylococcus strains. We found no evidence that staphylococci synthesize catecholor hydroxamate-type siderophores.

Isolation and biological characterization of staphyloferrin B, a compound with siderophore activity from staphylococci.

A highly hydrophilic compound with siderophore activity has been isolated from the supernatant of Staphylococcus hyicus DSM 20459 grown under iron-restricted conditions. The metabolite, named staphyloferrin B, is strictly iron-regulated and produced by a large variety of staphylococci strains. In vivo iron transport measurements and the growth-promoting activity in a bioassay establish staphyloferrin B as the second siderophore for staphylococci besides the previously described staphyloferrin A. The structure elucidation revealed 2,3-diaminopropionic acid, citrate, ethylenediamine and 2-ketoglutaric acid as structural components of the compound. Thus, staphyloferrin B is a structurally new siderophore of the complexone type.

Improved secondary metabolite production in the genus Streptosporangium by optimization of the fermentation conditions.

The cultivation of strains of the genus Streptosporangium in batch fermentations demonstrated that the optimal conditions for secondary metabolite production are completely different to those of the closely related genus Streptomyces. The dissolved oxygen tension (pO(2)) was identified as an important parameter for optimal production of secondary metabolites in submerged cultures. Extreme variations of this parameter by changes in aeration (gas flow), agitation system and stirrer speed showed a tremendous impact in production yields of all investigated strains. Finally, a 20-fold increase in productivity was observed by conditions of controlled oxygen excess compared to optimal fermentation conditions for Streptomyces strains.

Acid volatile sulfide determination in sediments using elemental analyzer with thermal conductivity detector.

A method for the determination of acid volatile sulfides (AVS) in sediments, using a common elemental analyzer with thermal conductivity detector, is proposed. The method uses a mixture of Sn and V(2)O(5) for pyrolysis and combustion to determine total sulfur (TS), and non volatile sulfur (NVS), after an acidic attack. AVS is calculated as the difference between TS and NVS. The method for TS is validated by analyzing a certified reference material. The recovery in the determination of acid volatile sulfide is determined by spiking a river sediment with ZnS. The method is accurate and gives a good reproducibility, recovering 97.7-99.6% of the sulfur in the 0-3% total sulfur content, with SD of approximately 0.015%.

Streptocidins A-D, novel cyclic decapeptide antibiotics produced by Streptomyces sp. Tü 6071. I. Taxonomy, fermentation, isolation and biological activities.

Four novel cyclic homodecapetide antibiotics, streptocidins A-D were detected in the mycelium extract of Streptomyces sp. Tü 6071 by HPLC-diode-array and HPLC-electrospray-mass-spectrometry screening. The peptides which were closely related in structure to the tyrocidines and gramicidins of Bacillus brevis show antibiotic activities against Gram-positive bacteria.