[The new GOÄ and its pitfalls]. / Die neue GOÄ und ihre Fallstricke.

The German Medical Association is working out a new fee scale for medical invoicing, which has to be reformed because the contents and the ratings are not up to date. The secretary of state for health in Germany demands that the new draft be coordinated with private insurance companies; as a result, they can influence indirectly the relationship between physicians and their patients. The new specifications will narrow the gap between private and social insurance in Germany. We discuss the consequences for the physician-patient relationship and the implications for the political plans to reform the whole insurance system in Germany.

[Flight and migration : A challenge for medicine in Germany]. / Flucht und Migration : Eine Herausforderung für die Medizin in Deutschland.

In 2015 about 1.1 million refugees came to Germany. As a consequence public health authorities as well as physicians in hospitals and surgeries were faced with considerable challenges and problems. Between January and March 2016 the German Society of Internal Medicine (DGIM) and the Professional Organisation of German Internists (BDI) initiated a survey among their members in order to ascertain which diseases and problems physicians were confronted with. A total of 28,063 members of the DGIM and BDI participated in the survey of which 3626 members answered all questions. This equals a response rate of 11.31 %. Of the respondents, 1865 (51.9 %) stated holding employment positions and 987 (27.4 %) were self-employed. The predominant number of physicians were under the impression that the composition of diseases needing treatment did not change within the time period under survey (55.7 % of employed and 73.7 % of self-employed physicians). Typical disease patterns of internal medicine were mentioned here. Most significant problems when treating migrants and refugees were linguistic communication, cultural affiliation, and psychological traumatic experiences. Little or nothing is known about the modalities of reimbursement for the respective health care areas, especially by physicians in employed positions (84.6 %). In agreement with the vote of the 119th Deutscher Ärztetag, DGIM and BDI recommend the introduction of a nationwide health insurance card for migrants and refugees.

Plasma nitriding monitoring reactor: A model reactor for studying plasma nitriding processes using an active screen.

A laboratory scale plasma nitriding monitoring reactor (PLANIMOR) has been designed to study the basics of active screen plasma nitriding (ASPN) processes. PLANIMOR consists of a tube reactor vessel, made of borosilicate glass, enabling optical emission spectroscopy (OES) and infrared absorption spectroscopy. The linear setup of the electrode system of the reactor has the advantages to apply the diagnostic approaches on each part of the plasma process, separately. Furthermore, possible changes of the electrical field and of the heat generation, as they could appear in down-scaled cylindrical ASPN reactors, are avoided. PLANIMOR has been used for the nitriding of steel samples, achieving similar results as in an industrial scale ASPN reactor. A compact spectrometer using an external cavity quantum cascade laser combined with an optical multi-pass cell has been applied for the detection of molecular reaction products. This allowed the determination of the concentrations of four stable molecular species (CH4, C2H2, HCN, and NH3). With the help of OES, the rotational temperature of the screen plasma could be determined.

Semiochemicals of the Scarabaeinae VIII. Identification of active constituents of the abdominal sex-attracting secretion of the male dung beetle, Kheper bonellii, using gas chromatography with flame ionization and electroantennographic detection in parallel.

Using gas chromatography with flame ionization detection and electroantennographic detection in parallel (GC-FID/EAD), the active constituents of the sex attractant of male dung beetles of Kheper bonellii were located in the gas chromatogram of an extract of the secretion. These constituents were identified as propanoic acid, butanoic acid, indole, 3-methylindole (skatole) and methyl cis-cascarillate (methyl cis-2-2'-hexylcyclopropylacetate) by, inter alia, GC-MS, (1)H and (13)C NMR analysis, and synthesis. These compounds elicited EAD responses in male as well as female antennae. Racemic methyl cis-cascarillate was synthesized for comparison with the natural methyl ester. Enantioselective GC-FID/EAD using a capillary column coated with OV-1701-OH containing 10% heptakis(2,3-di-O-methyl-6-O-tert-butyldimethylsilyl)-beta-cyclodextrin showed that the natural compound co-eluted with the first-eluting enantiomer of the racemic methyl cis-cascarillate, which was the only enantiomer that elicited EAD responses in the antennae of male and female K. bonellii. The absolute configuration of this enantiomer was established by a stereoselective synthesis, which gave methyl (R,R)-cascarillate [methyl (1'R,2'R)-2-2'-hexylcyclopropylacetate] in an enantiomeric excess of 69%.

Dramatic effect of the tridentate ligand on the stability of 99mTC "3 + 1" oxo complexes bearing arylpiperazine derivatives.

Mixed-ligand model complexes of general formula [(99m)Tc(O)(kappa(3)-PNX)(kappa(1)-SPh))] [X = O (1a), S (2a)] were prepared in a one-step procedure from [(99m)TcO(4)(-)] using stannous chloride as reducing agent. Stability studies and challenge experiments with glutathione showed that complex 2a presented promising features for pursuing animal studies. The activity in the brain (% dose injected/organ) at 5 min (0.14% +/- 0.03) and 120 min (0.11% +/- 0.02) pi encouraged the synthesis of several mixed-ligand "3 + 1" oxo complexes of general formula [M(O)(kappa(3)-PNS)(kappa(1)-SL))] (M = (99m)Tc, 3a-6a, Re, 3-6), in which the tridentate ligand is the heterofunctionalized phosphine 2-(diphenylphosphanyl)-N-(2-thioethyl)benzamide (PNS) and the co-ligands are different arylpiperazine derivatives (HSL1-HSL4). The (99m)Tc complexes have been characterized by comparison of their retention times in the HPLC chromatogram (gamma-detection) with the retention times of the analogous Re complexes (UV detection at 254 nm). The (99m)Tc complexes, obtained with radiochemical purity higher than 95%, after HPLC purification, are stable in saline, 0.01 M PBS (pH 7.4), rat plasma (4 h, 37 degrees C), and glutathione (10 mM solutions, 2h, 37 degrees C). Binding affinity and selectivity for 5-HT(1A) receptors (relative to the 5-HT(2A) receptor) were determined, complex 5 demonstrating the best values (IC(50) for the 5-HT(1A) 2.35 +/- 0.02 nM; competitor 5-HT(2A) 372 +/- 11 nM). Biodistribution and stability studies in mice indicated a preferred hepatobiliary excretion, a high in vivo stability, but a poor brain uptake.

Novel procedures for preparing 99mTc(III) complexes with tetradentate/monodentate coordination of varying lipophilicity and adaptation to 188Re analogues.

Improved methods are presented for the preparation of 99mTc and 188Re mixed-ligand complexes with tetradentate and monodentate ligands of the general formula [MIII(Lm)(Ln)] (M = Tc, Re; Lm = NS3 or NS3COOH; Ln = isocyanide or phosphine). To avoid the undesired formation of reduced-hydrolyzed species of both metals, the preparation of complexes is performed in a two-step procedure. At first the Tc(III)- or Re(III)-EDTA complex is formed which reacts in a second step with the tripodal ligand 2,2',2' '-nitrilotris(ethanethiol) (NS3) or its carboxyl derivative NS3COOH (a) and the monodentate phosphine ligands (triphenylphosphine L1, dimethylphenylphosphine L2) or isocyanides (tert-butyl isonitrile L3, methoxyisobutyl isonitrile L4, 4-isocyanomethylbenzoic acid-L-arginine L5, 4-isocyanomethylbenzoic acid-L-arginyl-L-arginine L6, 4-isocyanomethylbenzoic acid-neurotensin(8-13) L7) to the so-called '4+1' complex. Copper(I) isocyanide complexes are used for preparing the '4+1' complexes. That facilitates storage stability and allows kit formulations, and, moreover, enables the formation of 188Re complexes in acidic solution. Only micromolar amounts of the monodentate ligand are needed, and that results in high specific activity labeling of interesting molecules. The lipophilicity of complexes can be controlled by introducing a carboxyl group into the tetradentate ligand and/or derivatization of the monodentate ligands. Furthermore, the carboxyl group enables the conjugation of biomolecules. As an example, the neurotensin derivative CN-NT(8-13) was prepared and labeled with 99mTc according to the '4+1' approach, and its behavior in vivo was studied.

Synthesis and biological evaluation of silylated mixed-ligand 99mTc complexes with the [PNS/S] donor atom set.

New oxotechnetium complexes of general formula [99mTc(O)(PNS)(S(CH2)nOSiR3)] (4-6) were synthesized by direct reduction of [99mTcO4]- with stannous chloride, in the presence of the tridentate heterofunctionalized phosphine H2PNS and of the monodentate silylated thiols [HS(CH2)nOSiR3] (n = 2, R = Ph (1); n = 3, R = Ph (2); n = 3, R = Et (3)). The mixed-ligand rhenium and technetium complexes of general formula [M(O)(PNS)(S(CH2)nOH)] (n = 2: M = 99mTc, (7), M = Re, (7a); n = 3: M = 99mTc, (8), M = Re, (8a)) were also prepared. All the 99mTc complexes were obtained with high radiochemical purity (> 95%), after purification by HPLC, and were characterized by comparison of their HPLC profiles with the ones obtained for the corresponding Re compounds. The silylated compounds 4-6 are stable in phosphate saline buffer (PBS) pH 7.4, rat plasma, human serum and whole blood, and do not bind to plasmatic proteins, and also do not challenge with glutathione. The biological behavior of [99mTc(O)(PNS)(S(CH2)nOH)] (7, 8) and [99mTc(O)(PNS)(S(CH2)nOSiR3)] (4-6) was studied. The effect of the pH on the cleavage of the O-Si bond in complexes 4-6 was also evaluated.

Novel tumortropic ester derivatives of 99mTc(V) mesodimercapto succinic acid with low affinity for bone tissue.

Starting from our previous finding that 99mTc(V) dimercaptosuccinic acid (99mTc(V)-DMSA), a useful agent for the localization of osteosarcoma and bone metastases, loses its bone affinity when one ester group is introduced into the complex we studied the impact of esterification in more detail. This paper reports on the evaluation of various ester complexes of 99mTc(V)-DMSA in rats and tumour-bearing nude mice with regard to their tumour retention and improvement of the tumour to tissue ratios. The distribution patterns of the complexes [99mTcO(DMSA)2]- (A), [99mTcO(DMSA/DMSEt)]- (B) and [99mTcO(DMSEt)2]- (C) are gradually changed with the number of ester groups in the anionic complex. However, the asymmetric diester complex [99mTcO(DMSA/DMSEt2)]- (D) is very slowly cleared, especially from the blood of nude mice. Moreover, this complex differs significantly from the symmetrical complex C in its elimination behaviour from the liver and kidneys. The tumour uptake is maintained with complexes that contain one or two non-hydrolysable ester functions. Preliminary biodistribution studies of the monoethyl and diethyl ester complexes B, C and D in comparison with A in tumour-bearing nude mice showed similar uptake into the human squamous cell carcinoma (FaDu) as well as into the human colonic cell carcinoma (HT29) of nude mice. The low bone accumulation of B, C and D results in excellent tumour-to-bone ratios, e.g., approx. 3:1 for the ester complex B compared to approx. 1:2 for complex A. Differences were observed in the accumulation and elimination behaviour of the complexes A and B in various bone structures of rats. The age-dependent uptake of A and B was compared in long bone (femur) and in cranial bone of rats. The results suggest that 99mTc(V)-DMSA complexes that contain a functional ester, and their 188Re analogues, may be superior to 99mTc(V)/188Re(V)-DMSA in diagnostic and therapeutic nuclear medicine.

Tc and Re chelates of 8alpha-amino-6-methyl-ergoline: synthesis and affinity to the dopamine D2 receptor.

The influence of structural changes at the 8alpha-amino position of 8alpha-amino-6-methyl-ergoline on the lipophilicity and affinity to the D2 receptor was studied. 8alpha-amino-6-methyl-ergoline (1) was converted into the derivatives (2a-f) by mercaptoacetylation of the amino group to make it possible to prepare the rhenium and technetium complexes (3, 4a,b). Binding tests on cloned human dopamine D2 receptors show that the affinities of the coordination compounds (IC50 values between 50 and 240 nM) are less than those of the derivatives 2a-f (IC50=3-50 nM) but more than those of the parent compound 1. Biodistribution studies of the Tc complexes 4a,b performed on Wistar rats show a slow blood clearance with substantial accumulation and retention in the liver and kidneys and low brain uptake.

Synthesis and biological evaluation of technetium(III) mixed-ligand complexes with high affinity for the cerebral 5-HT(1A) receptor and the alpha1-adrenergic receptor.

Tc(III) and Re(III) complexes [M(NS(3))(CNR)] (M = Re, 99mTc, NS(3) = 2,2',2"-nitrilotris(ethanethiol), CNR = functionalized isocyanide bearing a derivative of WAY 100635) have been synthesized and characterized. Re was used as Tc surrogate for chemical characterization and in vitro receptor-binding studies. For two representatives subnanomolar affinities for the 5-HT(1A) as well as for the alpha1-adrenergic receptor were reached. Biodistribution studies in rats of the 99mTc complexes showed brain uptakes between 0.3 and 0.5% ID/organ (5 min p.i.). In vitro autoradiography of one 99mTc representative in sections of post mortem human brain indicate its accumulation in 5-HT(1A) receptor-rich brain regions. However, addition of the specific 5-HT(1A) receptor agonist 8-OH-DPAT as well as the alpha1-adrenoceptor antagonist prazosin could not substantially block this tracer accumulation. A preliminary SPET study in a monkey showed negligible brain uptake.

Spatio-temporal dynamics of expansion growth in roots: automatic quantification of diurnal course and temperature response by digital image sequence processing.

A newly developed technique based on image sequence analysis allows automatic and precise quantification of the dynamics of the growth velocity of the root tip, the distribution of expansion growth rates along the entire growth zone and the oscillation frequencies of the root tip during growth without the need of artificial landmarks. These three major parameters characterizing expansion growth of primary roots can be analysed over several days with high spatial (20 microm) and temporal resolution (several minutes) as the camera follows the growing root by an image-controlled root tracking device. In combination with a rhizotron set up for hydroponic plant cultivation the impact of rapid changes of environmental factors can be assessed. First applications of this new system proved the absence of diurnal variation of root growth in Zea mays under constant temperature conditions. The distribution profile of relative elemental growth rate (REGR) showed two maxima under constant and varying growth conditions. Lateral oscillatory movements of growing root tips were present even under constant environmental conditions. Dynamic changes in velocity- and REGR-distribution within 1 h could be quantified after a step change in temperature from 21 degrees C to 26 degrees C. Most prominent growth responses were found in the zone of maximal root elongation.

The biosynthesis of ovothiol A (N-methyl-4-mercaptohistidine). Identification of S-(4'-L-histidyl)-L-cysteine sulfoxide as an intermediate and the products of the sulfoxide lyase reaction.

Crude extracts of Crithidia fasciculata catalyse the formation of 4-mercapto-L-histidine, an intermediate in the biosynthesis of ovothiol A (N1-methyl-4-mercaptohistidine), in the presence of histidine, cysteine, Fe2+ and pyridoxal phosphate. This activity was present in a 35-55% ammonium sulfate fraction that was shown to produce a transsulfuration intermediate in the absence of pyridoxal phosphate. The transsulfuration intermediate was isolated and identified as S-(4'-L-histidyl)-L-cysteine sulfoxide. The synthase activity, partially purified by anion-exchange chromatography, was shown to require oxygen and could be used to synthesize a number of isotopically labeled S-(4'-L-histidyl)-L-cysteine sulfoxides. Sulfoxide lyase activity was partially resolved from the synthase by anion-exchange chromatography. The phenylhydrazone of the product derived from the cysteine moiety of the sulfoxide coeluted with the phenylhydrazone of pyruvate on HPLC, but this assignment could not be confirmed by mass spectral analysis. S-(4'-[14C]L-histidyl)-[U-13C3,15N]L-cysteine sulfoxide was synthesized and converted to products of the lyase reaction in the presence of lactate dehydrogenase and NADH. The 13C-labeled product was identified by 13C-NMR spectroscopy as lactate and the primary product of the lyase reaction is therefore pyruvate. With S-(4'[3H]L-histidyl)-[14C]L-cysteine sulfoxide as the substrate [14C]lactate, [14C]cysteine and [3H]4-mercaptohistidine could be detected as products of the lyase reaction, but the sum of the two thiol species exceeded the amount of sulfoxide substrate used. Evidence is presented that this anomaly was due to the utilization of sulfur from dithiothreitol for the formation of cysteine.

Mammalian exocrine secretions XV. Constituents of secretion of ventral gland of male dwarf hamster, Phodopus sungorus sungorus.

In a study aimed at the chemical characterization of constituents of the ventral gland secretion of the male dwarf hamster, Phodopus sungorus sungorus, 48 compounds, including saturated alcohols, saturated and unsaturated ketones, saturated and unsaturated straight-chain carboxylic acids, iso- and anteisocarboxylic acids, 3-phenylpropanoic acid, hydroxyesters, 2-piperidone, and some steroids were identified in the secretion. The position of the double bonds in gamma-icosadienyl-gamma-butyrolactone and gamma-henicosadienyl-gamma-butyrolactone, and the position of methylbranching in seven C16-C21 saturated ketones could not be established. Several constituents with typically steroidal mass spectra also remained unidentified. The female dwarf hamster's ventral gland either does not produce secretion or produced so little secretion that it was impossible to collect enough material for analysis.

Mammalian exocrine secretions XVI. Constitutents of secretion of supplementary sacculi of dwarf hamster, Phodopus sungorus sungorus.

As a first step in a study of the role of the secretion of the supplementary sacculi (buccal secretion) of the dwarf hamster, Phodopus sungorus sungorus, almost complete chemical characterization of the secretion was achieved. The 35 compounds identified include carbon dioxide, hydrogen sulfide, a large number of carboxylic acids (representing the bulk of the organic volatile fraction of the secretion), phenol, 2-piperidone, indole, two long-chain hydroxyesters, cholestrol, desmosterol, and lanosterol. The position of the double bonds in gamma-icosadienyl-gamma-butyrolactone and gamma-henicosadienyl-gamma-butyrolactone could not be determined, and these two compounds remained only partially characterized. Large variations were found in the relative concentrations in which the short-chain carboxylic acids are present in the secretions of individual animals, and although this aspect was not investigated in sufficient detail in the present investigation, the difference in the carboxylic acid profiles of the secretions of individual animals could play a role in individual recognition in this animal.

Mixed-ligand technetium(III) complexes with tetradendate/monodendate NS(3)/isocyanide coordination: a new nonpolar technetium chelate system for the design of neutral and lipophilic complexes stable in vivo.

Starting from the tripodal ligand 2,2',2' '-nitrilotris(ethanethiol) (NS(3)) and isocyanides (CNR) as co-ligands, neutral mixed-ligand technetium(III) complexes of the general formulation [Tc(NS(3))(CNR)] have been synthesized and characterized. The (99)Tc complexes can be( )()obtained by a two-step reduction/substitution procedure starting from [TcO(4)](-) via the phosphine-containing precursor complex [Tc(NS(3))(PMe(2)Ph)]. As shown by X-ray structural analyses, the complexes adopt a nearly ideal trigonal-bipyramidal geometry with the trigonal plane formed by the three thiolate sulfurs of the tripodal ligand. The central nitrogen atom of the chelate ligand and the monodendate isocyanides occupy the apical positions. The no-carrier-added preparation of the corresponding (99m)Tc complexes was performed by a one-step procedure starting from (99m)[TcO(4)](-) with stannous chloride as reducing agent. Biodistribution studies in the rat demonstrated for the nonpolar, lipophilic compounds a significant initial brain uptake. In vitro challenge experiments with glutathione clearly indicated that no transchelation reaction occurs. Furthermore, there were no indications for reoxidation of Tc(III) to Tc(V) species or pertechnetate. We propose this type of complexes as a useful tool in the design of lipophilic (99m)Tc or (186)Re/(188)Re radiopharmaceuticals.

Ligand-exchange reaction of labile "3 + 1"99mTc(V) complexes with SH group-containing proteins.

The reactivity of labile 3 + 1 mixed-ligand 99mTc complexes of the type [99mTcO(SES)(RS)] with SES being a tridentate dithiol ligand and glutathione or dimethylcysteamine as monodentate ligands RSH towards proteins was investigated in vitro and in vivo. It was found that the complexes undergo reversible transchelation reactions with SH group-containing components of blood such as albumin or haemoglobin. High labelling yields were obtained when 3 + 1 complexes with the tridentate SSS ligand were used. The biodistribution of blood proteins labelled by ligand-exchange reaction with the [99TcO(SSS)] or [99mTcO(SNMeS)] core was studied and compared with the in vivo distribution of the labile 3 + 1 complexes containing glutathione as monodentate ligand.

Synthesis and characterization of novel trigonal bipyramidal technetium(III) mixed-ligand complexes with SES/S/P coordination (E = O, N(CH3), S).

Five-coordinate oxotechnetium(V) mixed-ligand complexes [TcO(SES)(S-p-C6H4-OMe)], where SES is a tridentate dithiolato fragment of the type -S(CH2)2E(CH2)2S- (E = O, 1; E = S, 2; E = NMe, 3) are converted via reduction-substitution reactions in the presence of PMe2Ph into the corresponding five-coordinate Tc(III) complexes [Tc(SES)(S-p-C6H4-OMe)(PMe2Ph)] (E = O, 4; E = S, 5; E = NMe, 6). Rearrangement of the original square pyramidal "3 + 1" oxo species to the trigonal bipyramidal "3 + 1 + 1" Tc(III) complexes occurs by placing the three thiolate donors on the basal plane, the phosphine phosphorus, and the heteroatom of the tridentate ligand at the apexes of the bipyramid. These Tc(III) complexes are diamagnetic species, thereby allowing multinuclear NMR characterization in solution, which confirm their structures to be identical to those observed in the solid state via X-ray determinations.