Cancer spectrum and frequency among children with Noonan, Costello, and cardio-facio-cutaneous syndromes.

BACKGROUND: Somatic mutations affecting components of the Ras-MAPK pathway are a common feature of cancer, whereas germline Ras pathway mutations cause developmental disorders including Noonan, Costello, and cardio-facio-cutaneous syndromes. These 'RASopathies' also represent cancer-prone syndromes, but the quantitative cancer risks remain unknown. METHODS: We investigated the occurrence of childhood cancer including benign and malignant tumours of the central nervous system in a group of 735 individuals with germline mutations in Ras signalling pathway genes by matching their information with the German Childhood Cancer Registry. RESULTS: We observed 12 cases of cancer in the entire RASopathy cohort vs 1.12 expected (based on German population-based incidence rates). This corresponds to a 10.5-fold increased risk of all childhood cancers combined (standardised incidence ratio (SIR)=10.5, 95% confidence interval=5.4-18.3). The specific cancers included juvenile myelomonocytic leukaemia=4; brain tumour=3; acute lymphoblastic leukaemia=2; rhabdomyosarcoma=2; and neuroblastoma=1. The childhood cancer SIR in Noonan syndrome patients was 8.1, whereas that for Costello syndrome patients was 42.4. CONCLUSIONS: These data comprise the first quantitative evidence documenting that the germline mutations in Ras signalling pathway genes are associated with increased risks of both childhood leukaemia and solid tumours.

Alanate anion, AlH4(-): photoelectron spectrum and computations.

The alanate anion, AlH4(-), was generated in the gas phase using a pulsed arc cluster ionization source. Its photoelectron spectrum was then measured with 193 nm photons. The spectrum consists of a broad feature, spanning electron binding energies from 3.8 eV to over 5.3 eV. This band reflects the photodetachment transitions between the ground state of the AlH4(-) anion and the ground state of its thermodynamically unstable neutral counterpart, AlH4. The vertical detachment energy (VDE) of AlH4(-) was measured to be 4.4 eV. Additionally, VDE values were also computed in a comprehensive theoretical study and compared both with the previously computed value and with our experimentally determined value.

Comment on "Intensifying weathering and land use in Iron Age Central Africa".

Bayon et al. (Reports, 9 March 2012, p. 1219) interpreted unusually high aluminum-potassium ratio values in an Atlantic sediment core as indicating anthropogenic deforestation around 2500 years before the present (B.P.). We argue that there is no terrestrial evidence for forest destruction by humans and that the third millennium B.P. rainforest crisis can be clearly attributed mostly to climatic change.

The function of alpha- and beta-adrenoceptors of the saphenous artery in caveolin-1 knockout and wild-type mice.

BACKGROUND AND PURPOSE: Adrenoceptors can associate with cardiac caveolae. To investigate the function of vascular caveolae, adrenoceptor-mediated effects were compared in the saphenous artery of caveolin-1 knockout (cav-1KO) and wild-type (WT) mice. EXPERIMENTAL APPROACH: Electronmicroscopy was used to detect caveolae. Real-Time quantitative PCR was used for adrenoceptor subtypes. Catecholamine-evoked contractions and relaxations were studied in arterial segments. KEY RESULTS: Caveolae were found in arterial smooth muscle from WT but not from cav-1KO mice. Arterial mRNA levels for the adrenoceptors alpha1A, alpha1B, alpha1D, beta1, beta2 and beta3 were similar in cav-1KO and WT. (-)-Noradrenaline contracted cav-1KO (-log EC50M=7.1) and WT (-log EC50M=7.3) arteries through prazosin-sensitive receptors. Maximum (-)-noradrenaline-evoked contractions were greater in cav-1KO than WT arteries. (-)-Isoprenaline relaxed WT arteries (-log EC50M=7.3) more potently than cav-1KO arteries (-log EC50M=6.8); the effects were antagonized partially and similarly by the beta2-selective antagonist ICI118551 (50 nM). The (-)-isoprenaline-evoked relaxation was partially antagonized by the beta1-adrenoceptor-selective antagonist CGP20712 (300 nM) in WT but not cav-1KO arteries. The beta3-adrenoceptor-selective antagonist L748337 (100 nM) partially antagonized the relaxant effects of (-)-isoprenaline in cav-1KO but not in WT arteries. BRL37344 partially relaxed arteries through beta3-adrenoceptors in cav-1KO but not WT. The relaxant effects of BRL37344 were decreased by the NO synthase inhibitor OmegaL-nitroarginine. CONCLUSIONS AND IMPLICATIONS: The function of arterial alpha1- and beta2-adrenoceptors is similar in cav-1KO and WT mice. beta1-adrenoceptor-mediated relaxation in WT is lost in cav-1KO and replaced by the appearance of beta3-adrenoceptors.

Topochemical anion metathesis routes to the Zr2N2S phases and the Na2S and ACl derivatives (A = Na, K, Rb).

Anion metathesis reactions between ZrNCl and A(2)S (A = Na, K, Rb) in the solid state follow three different pathways depending on reaction temperature and reactant stoichiometry: (1) the reaction of ZrNCl with A(2)S in the 2:1 stoichiometry at 800 degrees C/72 h/in vacuo yields alpha-Zr(2)N(2)S with the expected layered structure of La(2)O(2)S. Above 850 degrees C, alpha-Zr(2)N(2)S (P3 macro m1; a = 3.605(1) A, c = 6.421(3) A) neatly transforms to beta-Zr(2)N(2)S (P6(3)/mmc: a = 3.602(1) A, c = 12.817(1) A). The structures of the alpha- and beta-forms are related by an a/2 shift of successive Zr(2)N(2) layers. (2) The same reaction at low temperatures (300-400 degrees C) yields ACl intercalated phases of the formula A(x)Zr(2)N(2)SCl(x) (0 < x < approximately 0.15), where alkali ions are inserted between the S/Cl.S/Cl van der Waals gap of a ZrNCl-type structure. The S and Cl ions are disordered and the c lattice parameters are alkali dependent (R3 macro m, a approximately 3.6 A, c approximately 28.4 (Na), 28.9 (K), and 30.5 A (Rb). A(x)Zr(2)N(2)SCl(x) phases are hygroscopic and reversibly absorb water to give monohydrates. (3) Reaction of ZrNCl with excess A(2)S at 400-1000 degrees C gives A(2)S intercalated phases of the formula A(2)(x)Zr(2)N(2)S(1+)(x) (0 < x < 0.5), where the alkali ions reside between the S.S van der Waals gap of a ZrNCl type structure (R3 macro m, a approximately 3.64 A, c approximately 29.48 A). Structural characterization of the new phases and implications of the results are described.

Pharmacokinetics and tissue distribution of the anticholinergics tiotropium and ipratropium in the rat and dog.

Ipratropium, a current treatment for chronic obstructive pulmonary disease (COPD) and tiotropium, a longer acting anticholinergic bronchodilator currently being developed for COPD are structurally related to atropine. In this study, the intravenous (i.v.), oral (p.o.) and intratracheal (i.tr.) single dose pharmacokinetics (PK) of tiotropium and ipratropium were determined in rat and dog. In rats, concentration-time profiles of tiotropium and ipratropium after single i.v. bolus administration of 7-8 mg kg(-1) are similar. Both drugs are highly cleared (Cl between 87 and 150 ml min(-1) kg(-1)) and extensively distributed into tissues (volume of distribution V(ss) between 3 and 15 l kg(-1)). In dogs, this holds also true for both drugs (Cl between 34 and 42 ml min(-1) kg(-1), V(ss) between 2 and 10 l kg(-1)), although different dose regimen were applied (i.v. bolus of 0.08 mg kg(-1) vs. infusion of 0.1 mg kg(-1) h(-1) for 3 h). Tiotropium plasma concentrations increased linearly in rats over a wide dose range following single i.v. administration. Both ipratropium and tiotropium showed a comparable terminal elimination half-life in rat urine (21-24 h) after single i.v. administration, which was much longer than the corresponding half-life in plasma (6-8 h). Whole body autoradiography in rats revealed a broad and rapid tissue distribution of [(14)C]tiotropium radioactivity after single i.v. administration. A comparable distribution pattern has also been reported earlier for ipratropium.

Structurally modulated magnetic properties in the A(3)MnRu(2)O(9) phases (A = Ba, Ca): the role of metal-metal bonding in perovskite-related oxides.

Ca(3)MnRu(2)O(9) and Ba(3)MnRu(2)O(9) were synthesized from transition metal dioxides and alkaline earth metal carbonates at 1100-1300 degrees C. Ca(3)MnRu(2)O(9) adopts the prototypical GdFeO(3)-type perovskite structure with Mn and Ru statistically disordered over the single metal atom site. The susceptibility shows Curie-Weiss behavior above 240 K with mu(eff) = 3.14 micro(B)/metal atom, which is in excellent agreement with the expected spin-only moment of 3.20 micro(B). Below 150 K, the compound shows spin-glass-like short-range ferrimagnetic correlations. The high-temperature region of the electrical resistivity reveals a small activation energy of 17(1) meV whereas the low-temperature region is nonlinear and does not fit a variable range hopping model. Ba(3)MnRu(2)O(9) crystallizes in the 9-layer BaRuO(3)-type structure containing M(3)O(12) face-shared trioctahedral clusters in which Mn and Ru are statistically disordered. Ba(3)MnRu(2)O(9) shows nonlinear reciprocal susceptibility at all temperatures and is described by a variable-spin cluster model with an S = (1)/(2) ground state with thermally populated excited states. The low spin value of this system (S = (1)/(2)) is attributed to direct metal-metal bonding. Below 30 K, the compound shows short-range magnetic correlations and spin-glass-like behavior. The high-temperature region of the electrical resistivity indicates a small activation energy of 8.8(1) meV whereas the low-temperature region is nonlinear. The importance of metal-metal bonding and the relationships to other related compounds are discussed.

Coordination trends in alkali metal crown ether uranyl halide complexes: the series [A(crown)]2[UO(2)X(4)] where A=Li, Na, K and X=Cl, Br.

UO(2)(C(2)H(3)O(2))(2).2H(2)O reacts with AX or A(C(2)H(3)O(2) or ClO(4)) (where A = Li, Na, K; X = Cl, Br) and crown ethers in HCl or HBr aqueous solutions to give the sandwich-type compounds [K(18-crown-6)](2)[UO(2)Cl(4)] (1), [K(18-crown-6)](2)[UO(2)Br(4)] (2), [Na(15-crown-5)](2)[UO(2)Cl(4)] (3), [Na(15-crown-5)](2)[UO(2)Br(4)] (4), [Li(12-crown-4)](2)[UO(2)Cl(4)] (5), and [Li(12-crown-4)](2)[UO(2)Br(4)] (6). The compounds have been characterized by single-crystal X-ray diffraction, powder diffraction, elemental analysis, IR, and Raman spectroscopy. The [UO(2)X(4)](2-) ions coordinate to two [A(crown)](+) cations through the four halides only (2), through two halides only (3), through the two uranyl oxygens and two halides (3, 4), or through the two uranyl oxygen atoms only (5, 6). Raman spectra reveal nu(U-O) values that correlate with expected trends. The structural trends are discussed within the context of classical principles of hard-soft acid-base theory.

Hydrothermal synthesis of the first organically templated open-framework uranium phosphate.

[(C2H5)2NH2]2[(UO2)5(PO4)4] was prepared from U3O8, HONEt2 and phosphoric acid under hydrothermal conditions (180 degrees C, 5 days) and represents the first three-dimensional open-framework uranium phosphate prepared to date.

Pharmacokinetics of pinokalant, a new nonselective cation channel blocker in the rat.

The pharmacokinetics of 1-isoquinolineacetamide, 3,4-dihydro-6,7-dimethoxy-alpha-phenyl-N,N-bis [2-(2,3,4-trimethoxyphenyl)ethyl]-, monomethanesulfonate (pinokalant, salt form of the active entity LOE 908 BS, CAS 143482-63-7), a nonselective cation channel blocker, was studied in rats. Drug plasma levels declined rapidly in a polyphasic manner after intravenous bolus administration of 8.8 mg/kg LOE 908 BS. The disposition of LOE 908 BS was governed by a rapid elimination (clearance Cl = 47.7 ml/min/kg) and an extensive distribution into tissues (volume of distribution Vss = 7.21 l/kg). A dose-proportional increase of AUC and steady state concentration up to doses of 194 mg/kg (6 h infusion) was observed suggesting linear pharmacokinetics. The protein binding was very high with 99.4% to 99.7% bound to plasma proteins in the concentration range 0.26 to 2.6 micrograms/ml. The LOE 908 BS concentration-time profile in brain tissue after intravenous infusion (4.4 mg/kg/h over 4 h) paralleled those measured in plasma indicating a rapid but also low penetration of the blood-brain-barrier. The concentration-time profile of drug-related radioactivity after intravenous (bolus) administration of [14C]LOE 908 BS dropped also rapidly to approximately 16% within the first hour compared to the initial 2-min value. The drug exhibited a high biliary excretion (84% during 5 h) and, accordingly, faecal excretion was the main route of excretion (> 90%). The mass balance was complete after 96 h indicating no persistence of radioactivity in the animals. The relevance of these findings with respect to results obtained with LOE 908 BS in animal models for stroke and traumatic brain injury is discussed.

The closo-[Sn9M(CO)314- Zintl ion clusters where M = Cr, Mo, W: two structural isomers and their dynamic behavior.

The closo-[Sn9M(CO)3]4-ions where M = Cr (1), Mo (2), W (3) were prepared from [LM(CO)3] precursors (L=mesitylene, cycloheptatriene), K4Sn9. and 2,2,2-cryptand in ethylenediamine/toluene solvent mixtures. The [K(2,2,2-cryptand)]+ salts are very air and moisture sensitive and have been characterized by IR, 119Sn, and 13C NMR spectroscopy and single-crystal X-ray diffraction studies. Complexes 1-3 form bicapped square-antiprismatic 10-vertex 22-electron closo structures in which the [M(CO)3] units occupy cluster vertices. For 1 and 2, the clusters have C4. symmetry in the solid state in which the [M(CO)A] fragments occupy capping positions with Sn9(4-) ions that are bound to the metal in an 4 fashion. For 3, the [M(CO)3] fragment occupies a position in the square plane with an eta/5-Sn9(4-) ion and C(s) point symmetry. For 1-3, a dynamic equilibrium exists between the eta4 and eta5 structures yielding three 119Sn NMR signals that reflect the three chemically distinct Sn environments of the higher symmetry C(4v) structure. The 119Sn NMR chemical shifts and coupling constants show solvent and temperature dependencies due to the equilibrium process. A triangular-face rotation mechanism is proposed to describe the dynamic behavior.

Synthesis and magnetic and transport properties of Sr6V9S22O2: "AM2S5" phases revisited.

The compound Sr6V9S22O2 was prepared from SrS, sulfur, vanadium metal, and V2O5 at 950 degrees C in an evacuated quartz tube. The compound is rhombohedral, R3, with a = 8.7538(6) A, c = 34.934(3) A, and Z = 3, and shows strong preferred orientation in its XRD profiles (00l) due to the layered nature of the structure. The compound contains charged CdI2 type VS2 layers of formula [V7S14]4- separated by [Sr6(VOS3)2(S2)]4+ layers. The latter has VOS3(3-) tetrahedra and S2(2-) disulfide units linked by Sr2+ ions. Magnetic susceptibility and four-probe resistivity studies show essentially temperature-independent paramagnetism above 80 K and small gap semiconductor behavior, respectively. The compound has a positive Hall coefficient at room temperature. The relationship among Sr6V9S22O2, "SrV2S5" (J. Solid State Chem. 1996, 126, 189), and other AM2S5 phases is discussed.

[Intraoperative facial nerve monitoring in parotid surgery]. / Intraoperatives Fazialisnervmonitoring in der Parotischirurgie.

Neurophysiological monitoring of cranial motor nerves has proved to be of value in cerebellopontine and skull base surgery. Unfortunately, facial nerve monitoring has been used infrequently for routine parotid gland surgery because suspicion of expense, possible unreliability and the requirement for extra personnel. This study presents clinical experience at the University of Erlangen with facial nerve monitoring during parotid gland surgery done by residents. Advantages are also emphasized for the experienced ENT-surgeon for use during revision parotidectomy. In 35 consecutive patients with benign parotid gland tumors intraoperative monitoring of the facial nerve was done using two different two-channel electromyography units. Bipolar coaxial electrical stimulation was superior to the monopolar stimulation mode. The average operative time and postoperative functional results were compared with those of a control group consisting of 24 patients without monitoring. Findings demonstrated a reduction is operative time and better functional outcome in the patient group with monitoring. Additionally four patients had to undergo total revision parotidectomy because of recurrent benign tumors, while one patient suffered from chronic parotitis due to sialolithiasis and required complete parotidectomy for relief of symptoms. No patient developed permanent facial paresis and nerve monitoring proved to be very helpful for identification and protection of the facial nerve in scar tissue.

Reduction of nightwork by re-designing of shift-rotas.

The reduction of nightwork is an important preventive measure to limit possible negative effects of night shifts on well-being, health and social life. An example of a gradual reduction of nightwork in a group of transport workers at an airport is presented. After having carefully analysed the real number of persons needed during nighttime for loading and unloading aircrafts the number of shiftworkers who had to work between 02.00 and 06.00 h was reduced in a first step from 104 to 66 and in a second step to 38 persons.

[The mixing index in the argon breath holding test for the demonstration of pharmacologically induced airways reactions. A comparison with other methods (author's transl)]. / Der Mischungsindex in der Argon-Breath-Holding-Methode zur Objektivierung pharmakologisch ausgelöster Atemwegsreaktionen im Vergleich mit anderen Untersuchungsmethoden.

In 42 patients with obstructive airways diseases the behavior of the mixing index (delta argon %/1 during phase III of the argon-volume diagram) was studied after beta2 stimulation or after provocation by acetylcholine. Changes in airways resistance resp. conductance (GAW), FEV1.0 and residual volume (RV) were also determined for comparison. In an inhomogeneous subgroup with obstructive airways disease of various aetiology the mixing index (MI) and FEV1.0 indicated changes in the airways system with about equal frequency. Distinct discrepancies between the two tests, observed in a few cases, suggest that the two methods register different pathophysiological reactions. These differences could be confirmed statistically in a more homogeneous subgroup with extrinsic bronchial asthma. A correlation could be established between MI and RV on the one hand and between FEV1.0 or GAW and RV on the other hand. The results indicate that the mixing index as a test of distribution of ventilation reflects mainly the reactions of the small airways. Its use offers the possibility of a more differentiated pharmacodynamic evaluation.