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• Objective:Several pressure ulcer (PU) risk factors including paralysis and age greater than 70 have been identified, while others such as nutrition are debated. The object of this study is to identify perioperative risk factors that may predict improved outcomes and reduced complications in primary and recurrent PU reconstructions.• Method:A retrospective chart review of patients treated surgically for PUs from 2004 to 2013 at the University of Toledo Medical Center, Toledo, Ohio, US, was completed. Data collected included ulcer and medical history, as well as risk factors, complications and postoperative outcome. Data were statistically analysed for perioperative variances between primary and recurrent ulcers and closure status.• Results:A total of 49 patients with 102 reconstructions were reviewed. Spinal cord injured patients accounted for 90% receiving flap coverage of ulcers. Numerous differences between primary and recurrent ulcers were identified, including ulcer location, patient nutritional status, wound infection, postoperative course and recurrence. Multivariate analysis revealed a flap reconstruction prediction model using creatinine, haematocrit, haemoglobin, and prealbumin that is able to successfully predict closure outcome in 83.6% of cases.• Conclusion:Many factors play a role in the development, course and treatment of PUs. It is vital to understand the role of patient risk factors in the development of PUs, to direct subsequent management and reconstruction, and to prevent future recurrences.

Facet syndrome is a condition that may cause 15–45 % of chronic lower back pain. It is commonly diagnosed and treated using facet joint injections. This needle technique demands high accuracy, and ultrasound (US) is a potentially useful modality to guide the needle. US-guided injections, however, require physicians to interpret 2-D sonographic images while simultaneously manipulating an US probe and needle. Therefore, US-guidance for facet joint injections needs advanced training methodologies that will equip physicians with the requisite skills.We used Perk Tutor—an augmented reality training system for US-guided needle insertions—in a configuration for percutaneous procedures of the lumbar spine. In a pilot study of 26 pre-medical undergraduate students, we evaluated the efficacy of Perk Tutor training compared to traditional training.The Perk Tutor Trained group, which had access to Perk Tutor during training, had a mean success rate of 61.5 %, while the Control group, which received traditional training, had a mean success rate of 38.5 % ($$p = 0.031$$). No significant differences in procedure times or needle path lengths were observed between the two groups.The results of this pilot study suggest that Perk Tutor provides an improved training environment for US-guided facet joint injections on a synthetic model.

We examine 150 volcanoes and geothermal areas in the central, southern and austral Andes for thermal anomalies between the years 2000 and 2010 from two different spaceborne sensors: (1) those automatically detected by the MODVOLC algorithm from MODIS; and (2) manually identified hotspots in night-time images from ASTER (Advanced Spaceborne Thermal Emission and Reflection Radiometer). Based on previous work, we expected to find eight volcanoes displaying thermal anomalies (Ubinas, Villarrica, Copahue, Láscar, Llaima, Chaitén, Lonquimay and Chiliques). We document 35 volcanic areas with pixel-integrated temperatures of 4 up to more than 100 K above background in at least two images, and another 16 areas that have questionable hotspots with either smaller anomalies or a hotspot identified in only one image. Most of the thermal anomalies are related to known activity (i.e. lava and pyroclastic flows, growing lava domes, fumaroles, and lakes) while others are of unknown origin or reflect activity at volcanoes that were not thought to have surface activity. A handful of volcanoes exhibit temporal variations in the magnitude and location of their temperature anomalies that can be related to both documented and undocumented pulses of activity. Our survey reveals that low-amplitude volcanic hotspots detectable from space are more common than expected, based on lower spatial resolution data, and that these features could be more widely used to monitor changes in the activity of remote volcanoes. We find no evidence from ASTER or MODVOLC that the thermal anomalies were affected by six earthquakes with Mwabove 7 in our study area from 2000 to 2010, although the observations may not have been optimal to detect such anomalies.Supplementary material:Supplementary tables of data and figures for the volcanoes studied are available at http://www.geolsoc.org.uk/SUP18581.

It is unclear whether patients age 65 years and over with a recent stroke or TIA benefit from statin treatment to a similar degree as younger patients.

Amido ansa 3‐substituted indenyl complex precursors can be activated with methylaluminoxane and used for prepolymerization with ethylene to give a heterogeneous catalyst for olefin polymerization. Homo polymerization of ethylene with 1‐(3‐pent‐4‐enylindenylidene) dimethylsilyl'butylamidotitaniumdichloride (1), 1‐(3‐hex‐5‐enylindenylidene)dimethylsilyl'butylamidotitanium‐dichloride (2), and 1‐(3‐pent‐4‐enylindenylidene) (oct‐7‐enyl)methylsilyl'butylamidotitaniumdichloride (3) produces polyethylenes that contain ethyl branches. The ethyl branching in the polymers made with complexes 1 and 2 is barely above the 13C NMR detection limit, but the level observed in the polymer made with complex 3 is 17 times greater. Copolymerization of ethylene and 1‐hexene using prepolymerized 3 yields copolymers containing both ethyl and butyl branches. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 100: 734–739, 2006

A number of isatin sulfonamide analogues were prepared and their potencies for inhibiting caspase-1, -3, -6, -7, and -8 were evaluated in vitro. Several compounds displaying a nanomolar potency for inhibiting the executioner caspases, caspase-3 and caspase-7, were identified. These compounds were also observed to have a low potency for inhibiting the initiator caspases, caspase-1 and caspase-8, and caspase-6. Molecular modeling studies provided further insight into the interaction of this class of compounds with activated caspase-3. The results of the current study revealed a number of non-peptide-based caspase inhibitors that may be useful in assessing the role of inhibiting the executioner caspases in minimizing tissue damage in disease conditions characterized by unregulated apoptosis.

Estrogen receptor β (ERβ), a less active ER subtype that appears to have a restraining effect on the more active ERα, could be a factor that determines the level of estrogen action in certain estrogen target tissues. ERβ is found in breast cancer, and its levels relative to ERα decline with disease progression. Thus, the independent quantification of ERα and ERβ levels in breast cancer by imaging might be predictive of responses to different hormone therapies. To develop an imaging agent for ERβ, we synthesized a fluoroethyl analogue of DPN (2,3-bis(4-hydroxyphenyl)propanonitrile), a known ERβ-selective ligand. This analogue, FEDPN (5-fluoro-(2R*,3S*)-2,3-bis(4-hydroxyphenyl)pentanenitrile), has an 8.3-fold absolute affinity preference for ERβ. [¹⁸F]Fluoride-labeled FEDPN was prepared from a toluenesulfonate precursor, which provided [¹⁸F]FEDPN with a specific activity greater than 3100 Ci/mmol after HPLC purification. Biodistribution studies in immature female rats using estradiol as a blocking agent revealed specific uptake of [¹⁸F]FEDPN in the uterus and ovaries. Experiments using ERα- and ERβ-knockout mice demonstrated the expected ERα-subtype dependence in the tissue uptake of the known 16α-[¹⁸F]fluoro-17β-estradiol ([¹⁸F]FES), which has a 6.3-fold preference for ERα. The tissue uptake of [¹⁸F]FEDPN in the ER knockout mice showed some evidence of mediation by ERβ, but the levels of specific uptake of this agent were relatively modest. Based on our results, imaging of ERα can be done effectively with [¹⁸F]FES, but imaging of ERβ will likely require agents with more optimized ERβ binding affinity and selectivity than [¹⁸F]FEDNP.

Infection of the central nervous system by Taenia solium cysticerci is the cause of human neurocysticercosis, a major neurological infection in the Third World and an emerging infectious disease in the United States. We previously isolated a cysteine proteinase from cysticerci of Taenia crassiceps and demonstrated that it degrades human IgG in vitro. We have now isolated a 48 kDa thiol-dependent proteinase from T. solium. The T. solium enzyme also degrades human IgG, but does not significantly degrade albumin. IgG degradation was inhibited by cysteine proteinase inhibitors, but not significantly by inhibitors of aspartic, serine, or metalloproteinases. The peptide substrate specificity and pH optimum resemble cathepsin L. The Km for the peptide substrate Z-Phe-Arg-AFC was calculated to be 7·0×10−6M, the Kcat was 1·98×105 s−1, and the Kcat/Km 2·84×109M−1 s−1, a value which is within the diffusion control limit for highly catalytic enzymes. We propose that immunoglobulin degradation by the T. solium cysteine proteinase may play a key role in the host-parasite interface and could be employed as a target for chemotherapy.

AbstractKingstonite, ideally Rh3S4, is a new mineral from the Bir Bir river, Yubdo District, Wallaga Province, Ethiopia. It occurs as subhedral, tabular elongate to anhedral inclusions in a Pt-Fe nugget with the associated minerals isoferroplatinum, tetraferroplatinum, a Cu-bearing Pt-Fe alloy, osmium, enriched oxide remnants of osmium, laurite, bowieite, ferrorhodsite and cuprorhodsite. It is opaque with a metallic lustre, has a black streak, is brittle and has a subconchoidal fracture and a good cleavage parallel to [001]. VHN25is 871–920 kg/mm2. In plane-polarized reflected light, kingstonite is a pale slightly brownish grey colour. It is weakly pleochroic and displays a weak bireflectance. It does not possess internal reflections. The anisotropy is weak to moderate in dull greys and browns. Reflectance data and colour values are tabulated. Average results of twenty electron microprobe analyses on four grains give Rh 46.5, Ir 16.4, Pt 11.2, S 25.6, total 99.7 wt.%. The empirical formula is (Rh2.27Ir0.43Pt0.29)S2.99S4.01, based on 7 atoms per formula unit (a.p.f.u.). Kingstonite is monoclinic (C2/m) with a= 10.4616(5), b= 10.7527(5), c= 6.2648(3) Å, ß = 109.000(5)°, V= 666.34(1) Å3(Z = 6). The calculated density is 7.52 g/cm3(on the basis of the empirical formula and unit-cell parameters refined from powder data). The seven strongest X-ray powder-diffraction lines [d in Å(I) (hkl)] are: 3.156 (100) (310), 3.081 (100) (1¯31), 2.957 (90) (002), 2.234 (60) (202), 1.941 (50) (2¯23), 1.871 (80) (4¯41) and 1.791 (90) (060, 1¯33). The structure of kingstonite was solved and refined to Rp = 3.8%. There are four distinct metal sites with Rh occupancies of 0.64–0.89. Two metal sites are regular RhS6octahedra that share edges to form a ribbon running parallel to c. The other two metal sites are coordinated by 4 S + 2 Rh and 5 S + 2 Rh and define a puckered Rh6ring. The ribbons of regular RhS6octahedra alternate with the columns of Rh6rings linked by S atoms. S–S bridges also connect the ribbons and columns. As such, the kingstonite structure is essentially that of synthetic Rh3S4. Minor differences in the unit-cell parameters, atom coordinates and displacement parameters of kingstonite and synthetic Rh3S4arise from the considerable substitution of Ir for Rh. The mineral name honours Gordon Kingston (formerly of Cardiff University) in recognition of his contributions to platinum group element mineralogy and the geology of their mineral deposits.

Genetic algorithms (GA) were used to develop specific copper metal−ligand force field parameters for the MM3 force field, from a combination of crystallographic structures and ab initio calculations. These new parameters produced results in good agreement with experiment and previously reported copper metal−ligand parameters for the AMBER force field. The MM3 parameters were then used to develop several quantitative structure−activity relationship (QSAR) models. A successful QSAR for predicting the lipophilicity (log Pow) of several classes of Cu(II)-chelating ligands was built using a training set of 32 Cu(II) radiometal complexes and 6 simple molecular descriptors. The QSAR exhibited a correlation between the predicted and experimental log Pow with an r² = 0.95, q² = 0.92. When applied to an external test set of 11 Cu(II) complexes, the QSAR preformed with great accuracy; r² = 0.93 and a q² = 0.91 utilizing a leave-one-out cross-validation analysis. Additional QSAR models were developed to predict the biodistribution of a smaller set of Cu(II) bis(thiosemicarbazone) complexes.

AbstractThe octahedral-framework mineral bernalite, Fe(OH)3, provides a rare opportunity to examine directly the effects of a vacant Asite upon the physical properties of perovskite-like structures. Here, we report the effect upon compressibility. Bernalite has been reported previously as having space group Immm(Birch et al., 1993), but numerous reflections violating I-centering were observed in the present study. A case is presented for bernalite having orthorhombic space group Pmmn. Lattice parameters were refined using the Le Bail method for a metrically tetragonal cell and their variation with pressure at room temperature was determined from 17 measurements at pressures from 10–4to 9.3 GPa using synchrotron X-ray powder diffraction. No discontinuities in the compression curves of lattice parameters were observed. Fitting to a second-order Birch-Murnaghan equation-of-state (KT0'= 4) gives V0= 438.51±0.06 Å3and KT0= 78.2±0.4 GPa. Second-order fits of (a/a0)3and (c/c0)3give elastic moduli KT0a= 82.0(6) GPa and KT0c= 71.6(4) GPa: the shorter cation–cation distance is the more compressible. These values are very close to those of stottite, FeGe(OH)6, which has tilt system a+a+c–. The difference in the elastic moduli KT0aand KT0cof bernalite and their close similarity to the stottite values support the revised Pmmn structure (tilt system a+b+c–) for bernalite proposed here. The compressional anisotropy observed in bernalite may reflect its highly anisotropic and directional H-bonding topology.

Abstract The behaviour of the ammonium ion in synthetic buddingtonite, N(D,H)4AlSi3O8, has been studied by infrared (IR) spectroscopy from 20 K to 298 K and by 2H NMR spectroscopy from 120 K to 298 K. IR spectra were collected from 500 to 3500 cm-1. Static 2H NMR spectra collected at 298 K and 120 K are very similar, consisting of a single sharp isotropic resonance, indicating complete averaging of quadrupolar interactions and implying that at these temperatures the ammonium ion is in rapid (<1 µs) randomised motion within the M-site cavity of the feldspar framework. NMR spectroscopy indicates that the splitting of the internal modes of the ammonium ion observed by IR spectroscopy is not due to “freezing in” of the ammonium ion. This observation rules out the formation of a preferred N–H...O hydrogen bond, with precession of the ion about it, as proposed by Kimball and Megaw (1978), because any N–H...O hydrogen bond must be very weak and transient in nature. Contraction of the cavity site upon cooling imposes a distortion upon the ammonium ion that affects vibrational modes. This distortion does not affect the motion of the ammonium ion as observed on the NMR time-scale.

Early detection of melanoma is essential, since a patient's prognosis with metastatic melanoma is poor. Previous studies showed that ¹¹¹In−DOTA−ReCCMSH(Arg¹¹), a cyclic analogue of α-melanocyte stimulating hormone (α-MSH), exhibited high tumor concentration and rapid clearance from nontarget tissue. The goal of this current study was to label DOTA−ReCCMSH(Arg¹¹) with β⁺-emitting radionuclides, to determine if the high sensitivity of positron emission tomography (PET) imaging would aid in the detection of malignant melanoma. DOTA−ReCCMSH(Arg¹¹) was labeled with ⁶⁴Cu and ⁸⁶Y. Biodistribution and small animal PET imaging were carried out in mice implanted with B16/F1 murine melanoma tumor and compared with data obtained in the same animal model with [¹⁸F]FDG. In both cases a subset of animals were co-injected with 20 μg of DOTA−ReCCMSH(Arg¹¹) to determine if tumor concentration was receptor mediated. Tumor concentration for both the ⁸⁶Y- and ⁶⁴Cu-complexes reached a maximum at 30 min, while coadministering 20 μg of unlabeled complex reduced tumor uptake significantly. Nontarget organ concentration was considerably lower with ⁸⁶Y−DOTA−ReCCMSH(Arg¹¹) than its ⁶⁴Cu analogue, except in the kidneys, where the ⁶⁴Cu complex had lower accumulation at all time points. Small animal PET images for both complexes showed the tumor could be visualized after 30 min, with the standardized uptake value (SUV) analysis following a similar trend as the biodistribution data. The data obtained suggests that DOTA−ReCCMSH(Arg¹¹), when labeled with β⁺-emitting radionuclides, has the potential for early detection of malignant melanoma by exploiting the sensitivity and high resolution of PET.

As more becomes known about the expression profiles of normal and cancerous cells, it should become possible to design antisense-based imaging agents for the early detection of cancer noninvasively. In this report, we rationally designed and synthesized three antisense and one sense hybrid PNA (peptide nucleic acid) to the unr mRNA that is highly overexpressed in a breast cancer cell line (MCF-7). The conjugates had a four-lysine tail at the carboxy terminus for cell permeation and a DOTA (1,4,7,10-tetraazacyclododecane-N,N‘,N‘ ‘,N‘ ‘‘-tetraacetic acid) chelating moiety at the amino terminal end for chelating ⁶⁴Cu for biodistribution and microPET imaging studies. Biodistribution of two ⁶⁴Cu-labeled conjugates with antisense and sense sequences (PNA50 and PNA50S) showed high uptake and long retention in kidney and low uptake and efficient clearance in blood and muscle in normal balb/c mice when administered intravenously or intraperitoneally. Intraperitoneal administration, however, gave a much slower release rate. MCF-7 tumors (100−320 mg) in CB-17 SCID mice were imaged with all four ⁶⁴Cu-labeled PNA conjugates by microPET, but the image contrast varied with different time points and different conjugates. Of the conjugates studied, ⁶⁴Cu-DOTA-Y-PNA50-K4 showed the best tumor image quality at all time points with a tumor/muscle ratio of 6.6 ± 1.1 at 24 h postinjection, which is among the highest reported for radiolabeled oligonucleotides. Our work further strengthens the potential of antigene and antisense PNAs to be utilized as specific molecular probes for early detection of cancer and ultimately for patient specific radiotherapy.

Cyclopentadienyl tricarbonylmetal (CpTM, M = Re, ^94mTc) complexes, some based on a typical nonsteroidal estrogen, were prepared with the aim of developing technetium- and rhenium-labeled imaging agents for estrogen receptor (ER) positive breast tumors. CpT[^94mTc] compounds with simple cyclopentadienyl substituents were first synthesized using a modified double ligand transfer reaction. The in vivo biodistribution of one of these CpT[^94mTc] complexes was determined by tissue dissection and microPET imaging. Novel C-ring substituted analogues of cyclofenil, a nonsteroidal compound known to bind the ER, were also prepared, and their ER binding was measured. Because of their low ER affinity, however, labeling and imaging studies of these compounds were not pursued. It is notable that the highest ER binding analogue, a CpTRe cyclofenil derivative, could be synthesized from the corresponding ferrocenyl cyclofenil analogue by the double ligand transfer reaction. This further demonstrates the versatility of the double ligand transfer reaction and indicates that the synthesis of technetium and rhenium radiolabeled agents for breast tumor imaging and therapy is also likely to be successful.

AbstractThe [4]Al/Si and [6]Al/Mg order-disorder behaviour of minerals in the tremolite-tschermakite solid solution (namely, end-member tschermakite and the 50:50 composition, magnesiohornblende) has been investigated by Monte Carlo simulation, using a model Hamiltonian in which atomic interaction parameters Jiwere derived from empirical lattice energy calculations, and chemical potential terms µj(to express the preferences of cations for particular crystallographic sites) were derived from ab initiomethods. The simulations performed were increasingly complex. Firstly, ordering in one tetrahedral double chain with Al:Si = 1:3 (tschermakite) was simulated. Although the low-temperature cation distribution in this system was ordered, there was no phase transition (due to the quasi-one-dimensional nature of the system). Next, interactions between tetrahedral Al:Si = 1:3 double chains were included, and a phase transition was observed, with the cation distribution in one double chain lining up with respect to that in the next. Finally, interactions between tetrahedral and octahedral sites were incorporated, to model the whole unit cell, and compositions corresponding to tschermakite and magnesiohornblende were investigated. The whole-cell simulation results compare favourably with experimental conclusions for magnesiohornblende, in that Al at T1 is preferred over Al at T2, and Al at M2 is favoured over that at M1 and M3, but the significant amount of Al at M1 is at odds with experimental observation.

Amphiphilic core−shell nanoparticles have drawn considerable interest in biomedical applications. The precise control over their physicochemical parameters and the ability to attach various ligands within specific domains suggest shell cross-linked (SCK) nanoparticles may be used as multi-/polyvalent scaffolds for drug delivery. In this study, the biodistribution of four SCKs, differing in size, core composition, and surface PEGylation, was evaluated. To facilitate in-vivo tracking of the SCKs, the positron-emitting radionuclide copper-64 was used. By using biodistribution and microPET imaging approaches, we found that small diameter (18 nm) SCKs possessing a polystyrene core showed the most favorable biological behavior in terms of prolonged blood retention and low liver accumulation. The data demonstrated that both core composition, which influenced the SCK flexibility and shape adaptability, and hydrodynamic diameter of the nanoparticle play important roles in the respective biodistributions. Surface modification with poly(ethylene glycol) (PEG) had no noticeable effects on SCK behavior.

The in vivo behavior of copper(II)−cyclen complexes was modified via substitution of the parent ligand with two different substituents, 4-tert-butylbenzyl and acetate. This was achieved by using same synthetic strategy (regioselective protection/first alkylation/deprotection/second alkylation) to give nine cyclen derivatives. The X-ray structure of [Cu(2c)Cl]⁺ (2c = 1-(4-tert-butylbenzyl)-1,4,7,10-tetraazacyclododecane) showed that the chlorine ion from the reaction mixture occupied the remaining apical position of a square pyramidal coordination environment of these Cu−cyclen complexes. Eight out of nine compounds were labeled with ⁶⁴Cu in high radiochemical purity. log P measurements showed that the lipophilicities of the copper complexes were increased dramatically by attaching hydrophobic substituents on the nitrogen atoms of cyclen. Conversely, as the number of acetate groups increased, the lipophilicity was decreased. The biodistribution of Cu−cyclen complexes was found to be influenced mostly by the overall charge of the complexes rather than their lipophilicity. Positively charged (+2) complexes showed high blood retention at early time points with sluggish clearance from liver by 24 h. The attachment of even one acetate group onto cyclen accelerated blood and liver clearance dramatically compared to +2 charged Cu(II) complexes. Neutral trans-substituted Cu−4 showed the best clearance and lowest retention of doses from all organs most time, followed by −1 charged complex Cu−2. Trans-substituted complexes structure isomers Cu−3 and Cu−4 showed better clearance and lower retention from all organs than their cis-counterparts Cu−5 and Cu−6.

This paper reports results from a stress, acoustics and vibration investigation of the ride and driveline components of a new 2-seater sports car. The work was aimed at giving design assurance information to designers and vehicle engineers working to compressed timescales. The paper focuses on two particular areas: design of the power train for NVH refinement, and design analysis of a suspension wishbone. In the first case, a dynamic model of drive shaft torsion effects was created to understand design relationships needed for high power, high torque performance car. In the second case, an investigation was made into the integrity of a suspension wishbone component when gauge thickness was reduced from 3 mm to 2 mm. The work described was carried out in a joint industry academic venture sponsored by Knowledge Transfer Partnership (KTP). It is from this background that the authors give some perspectives on vehicle development.

The formation of new blood vessels (angiogenesis) is a feature common to all solid tumors. The integrin receptor αVβ3, which is found on endothelial cells lining newly growing blood vessels at a higher density than on mature blood vessels, is being explored as a marker for tumor angiogenesis. Bitistatin, a member of the disintegrin family of polypeptides, has affinity for αVβ3 integrins. To determine whether radiolabeled bitistatin could target tumors, its biodistribution was tested in tumor-bearing mice. For initial validation studies, ¹²⁵I-bitistatin was injected into BALB/c mice bearing EMT-6 mouse mammary carcinoma tumors, a model that is highly vascular but which lacks αVβ3 directly on tumor cells. Tumor uptake reached maximal values (11.7 ± 4.6 %ID/g) at 2 h. Co-injection of 200 μg of unlabeled bitistatin reduced tumor uptake 62%, suggesting that the binding of ¹²⁵I-bitistatin is receptor-mediated. This work was extended to include the β⁺-emitting radionuclide ⁶⁴Cu, which was attached to bitistatin via 1,4,7,10-tetraazacyclododecane-N,N‘,N‘ ‘,N‘ ‘‘-tetraacetic acid (DOTA). This modification did not significantly alter receptor binding in vitro. MicroPET images obtained with ⁶⁴Cu-DOTA-bitistatin showed that the tumor could easily be identified 4 h after administering the radiopharmaceutical. The biodistribution of ⁶⁴Cu-DOTA-bitistatin differed from the ¹²⁵I analogue, in that maximum tumor uptake was nearly 8-fold lower and took at least 6 h to reach maximal binding (1.6 ± 0.2 %ID/g). As with ¹²⁵I-labeled bitistatin, the ⁶⁴Cu conjugate showed a 50% reduction in tumor uptake with the co-injection of 200 μg of unlabeled bitistatin (0.8 ± 0.2 %ID/g). Competition studies with integrin-specific peptides indicated that the tumor uptake was related to both αvβ3 and αIIbβ3 integrin binding. To see if tumor uptake could be improved upon, ⁶⁴Cu was tethered to bitistatin using bromoacetamidobenzyl-1,4,7,10-tetraazacyclododecane-N,N‘,N‘ ‘,N‘ ‘‘-tetraacetic acid (BAD). Tumor uptake for ⁶⁴Cu-BAD-2IT-bitistatin was higher than the DOTA conjugate at all time points, reaching a maximum at least 6 h postinjection (5.2 ± 0.6 %ID/g); however, this was accompanied by higher uptake in nontarget organs at all time points. Radiolabeled ligands of this type may be useful in the targeting of tumor angiogenesis, but the choice of radiolabeling approach has a significant impact on the in vivo properties of the radioligand.

1. This study aims (1) to determine whether secretin is synthesized centrally, specifically by the HPA axis and (2) to discuss, on the basis of the findings in this and previous studies, secretin's possible neuroregulatory role in autism. 2. An immunocytochemical technique with single-cell resolution was performed in 12 age/weight-matched male rats pretreated with stereotaxic microinjection of colchicine (0.6 μg/kg) or vehicle into the lateral ventricle. Following 2-day survival, rats were anesthetized and perfused for immunocytochemistry. Brain segments were blocked and alternate frozen 30-μm sections incubated in rabbit antibodies against secretin, vasoactive intestinal peptide, glucagon, or pituitary-adenylate-cyclase-activating peptide. Adjacent sections were processed for Nissl stain. Preadsorption studies were performed with members of the secretin peptide family to demonstrate primary antibody specificity. 3. Specificity of secretin immunoreactivity (ir) was verified by clear-cut preadsorption control data and relatively high concentrations and distinct topographic localization of secretin ir to paraventricular/supraoptic and intercalated hypothalamic nuclei. Secretin levels were upregulated by colchicine, an exemplar of homeostatic stressors, as compared with low constitutive expression in untreated rats. 4. This study provides the first direct immunocytochemical demonstration of secretinergic immunoreactivity in the forebrain and offers evidence that the hypothalamus, like the gut, is capable of synthesizing secretin. Secretin's dual expression by gut and brain secretin cells, as well as its overlapping central distribution with other stress-adaptation neurohormones, especially oxytocin, indicates that it is stress-sensitive. A neuroregulatory relationship between the peripheral and central stress response systems is suggested, as is a dual role for secretin in conditioning both of those stress-adaptation systems. Colchicine-induced upregulation of secretin indicates that secretin may be synthesized on demand in response to stress, a possible mechanism of action that may underlie secretin's role in autism.

AbstractThe original structure determination of asisite, nominally Pb7SiO8Cl2, has been re-evaluated in the light of electron-diffraction data (TEM) on the original sample material. Electron diffraction patterns indicate a super-structure based upon a metrically tetragonal 26-cation-site super-sheet motif (14x14x23 Å). Given the strong ordering of elements substituting for Pb in closely-related litharge-based oxychlorides (parkinsonite, symesite, kombatite, schwartzembergite), the asisite superstructure is inferred to be due to strong ordering of Si within the PbO sheet. The original chemical analyses of asisite given by Rouse et al. (1988) are shown to be consistent with such a super-structure, which has a 12Pb:1Si cation ratio. A new formula for asisite is proposed that is based upon this superstructure: Pb12(SiO4)O8Cl4(Z= 8). The structure of asisite determined by Rouse et al. (1988) is that of the average Pb/Si-disordered tetragonal sub-cell (I4/mmm: 4x4x23 Å) and belies the highly ordered real state. The structure of the tetragonal sub-cell has been re-determined here: R= 5.6% for 178 unique Fo > 4sFo and an anisotropic model. A significantly reduced 72% occupancy of the Pb(2) site was found that implies the nominal formula Pb7SiO8Cl2, thus confirming the findings of Rouse et al. (1988). Comparisons with kombatite and symesite support the assignment of Si to Pb(2) and imply that Si in asisite is also likely to be in tetrahedral coordination, with the apical oxygen cross-linking PbO sheets. However, because most of the key information relating to the location of Si is provided by the super-lattice reflections, the inability of X-ray diffraction to register these reflections introduces a significant ambiguity into the interpretation of Pb/Si ordering behaviour in this mineral.

Inhibition of the biosynthesis of proinflammatory cytokines such as tumor necrosis factor and interleukin-1 via p38 has been an approach toward the development of a disease modifying agent for the treatment of chronic inflammation and autoimmune diseases. The development of a new core structure of p38 inhibitors, 3-(4-fluorophenyl)-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b] pyridine, is described. X-ray crystallographic data of the lead bound to the active site of p38 was used to guide the optimization of the series. Specific focus was placed on modulating the physical properties of the core while maintaining potent inhibition of p38. These efforts identified 42c as a potent inhibitor of p38, which also possessed the required physical properties worthy of advanced studies.

Approximately 1–2% of the UK population suffers from venous ulcers. Incompetent perforator leg veins are thought to be a major contributory factor. Subfascial endoscopic perforator surgery treats incompetent perforators in a minimally invasive fashion with significant improvement in wound healing and reduction in ulcer recurrence rates.

The gastrin-releasing peptide receptor (GRPR) is overexpressed on a variety of carcinomas and has been the target for detection and treatment of these neoplasms in animals. In particular, analogues of the tetradecapeptide bombesin (BN) have been radiolabeled with ^99mTc and ¹¹¹In for detection of GRPR-positive tumors by gamma ray scintigraphy. The goal of this study was to evaluate the potential of the bombesin analogue, DOTA-Aoc-BN(7−14), for positron-emission tomographic (PET) imaging after radiolabeling with the positron-emitter ⁶⁴Cu. A saturation binding assay on PC-3 human prostate cancer cells showed that ⁶⁴Cu-DOTA-Aoc-BN(7−14) had an equilibrium binding constant (Kd) of 6.1 ± 2.5 nM and a receptor concentration (Bmax) of 2.7 ± 0.6 × 10⁵ receptors/cell. The radiolabeled analogue also showed rapid internalization with 18.2% internalized into 10⁵ PC-3 cells by 2 h. The tumor localization of ⁶⁴Cu-DOTA-Aoc-BN(7−14) was 5.5% injected dose per gram in athymic nude mice bearing PC-3 xenografts at 2 h postinjection. The tumor retention with respect to the 2 h value was 76% and 45% at 4 and 24 h, respectively, and was GRPR-mediated as shown by inhibition with a coinjection of excess peptide. MicroPET imaging of ⁶⁴Cu-DOTA-Aoc-BN(7−14) in athymic nude mice bearing subcutaneous PC-3 tumors showed good tumor localization. Further studies with ⁶⁴Cu-pyruvaldehyde-bis(N⁴-methylthiosemicarbazone) (⁶⁴Cu-PTSM) suggested that low blood flow to the PC-3 tumors may have limited the localization of ⁶⁴Cu-DOTA-Aoc-BN(7−14). This study demonstrates that ⁶⁴Cu-DOTA-Aoc-BN(7−14) can be used to detect GRPR-positive tumors by PET imaging.

The synthesis of iron(II) complexes with various tridentate di(imino)pyridine ligands and their potential as ethene oligomerization catalysts are described. The ligands are characterized by ¹H- and ¹³C-NMR spectroscopy and the complexes only by mass spectrometry due to their paramagnetism. After activation either with methylalumoxane (MAO) or with a heterogeneous cocatalyst consisting of partially hydrolyzed trimethylaluminum and silica gel, the prepared complexes proved to be good catalysts for the oligomerization of ethene. 1-Octene, 1-hexene, and 1-decene were the major products, formed in very high isomeric purity (99.9 %). © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 88: 476–482, 2003

Abstract:  The partitioning of Fe and Mn between the large M(4) site and the octahedral sites, M(1,2,3) in the amphibole structure has been investigated in two natural manganogrunerites of compositions Ca0.1Mn1.9 Mg1.25Fe2+3.56Fe3+0.38Si7.81O22(OH)2 and Ca0.24Mn1.57 Mg2.27 Fe2+2.76Fe3+0.32Si7.84O22(OH)2. The long-range cation distribution in the two samples has been elucidated by in situ neutron powder diffraction revealing that Mn is preferentially ordered onto M(4) ≫ M(2) >M(1) >M(3) in both samples. Partitioning of Mn from M(4) into the octahedral sites begins at 350 °C, with site exchange energies of −16.6 kJ mol−1 and −14.9 kJ mol−1, in samples containing 1.90 and 1.57 Mn apfu, respectively. Mössbauer and infrared spectroscopy have been used to study the samples at room temperature, and Mössbauer data agree well with the diffraction results, confirming that high-temperature cation distributions are retained during cooling. The fine structure in the hydroxyl-stretching region of the IR absorption spectra has been used to discuss qualitatively the site occupancies of the coordinating M(1)M(3)M(1) triplet, linked by O(3). On the basis of such modelling, we conclude that a degree of local clustering is present in both samples.

Human obesity may be caused by a resistance to circulating leptin. Evidence from rodents and humans suggests that a major component of this resistance is an impairment in the ability of the blood-brain barrier (BBB) to transport leptin from the blood to the brain. One potential way to bypass the BBB is by administering leptin into the intrathecal (i.t.) space. To be effective, i.t. leptin would have to move caudally from the site of injection, enter the cranium, and reach the hypothalamic arcuate nucleus at the base of the pituitary fossa. However, many substances, especially small, lipid-soluble molecules, do not diffuse far from the site of i.t. injection but are resorbed back into blood. To determine whether i.t. leptin can move caudally, we injected leptin conjugated to diethylenetriaminepentaacetic acid (DTPA) and labeled with (68)Ga (G-Ob) into the lumbar space of three baboons. We also studied unconjugated DTPA labeled with (68)Ga, which did not move up the spinal cord but rapidly appeared in blood after i.t. injection. In contrast, G-Ob steadily moved toward the cranium and had reached the hypothalamus 91 and 139 min after i.t. injection in two baboons. We estimated the concentration of leptin in the hypothalamic region to be at least 8 ng/ml, which is about 40 times higher than cerebrospinal fluid levels in normal weight humans and about 4 times higher than the highest level ever recorded after the peripheral administration of leptin. In a third baboon, the leptin neither moved caudally nor appeared in the blood. We conclude that leptin administered i.t. can reach the hypothalamus in therapeutic concentrations, although there is considerable individual variation.

AbstractThe equation of state of synthetic deuterated burtite, CaSn(OD)6, has been determined to 7.25 GPa at 298 K by synchrotron X-ray powder diffraction. Fitting to a third-order Birch-Murnaghan equation of state gives K0= 44.7(9) GPa and K0' = 5.3(4). A second-order fit gives K0= 47.4(4) GPa. Within experimental error the two fits are indistinguishable over the pressure range studied. The decrease in the aparameter with pressure is smooth and no phase transitions were observed. Burtite is much more compressible (by a factor of three or four) than CaSnO3and CdSnO3perovskites, indicating that the absence of a cavity cation has a major effect upon the compressibility of the octahedral framework. Burtite is also markedly more compressible than the closely-related mineral stottite FeGe(OH)6(K0= 78 GPa). Their different compressibilities correlate with the relative compressibilities of stannate and germanate perovskites. Although different octahedral compressions are likely to be the primary reason for the different compressibilities of burtite and stottite, we also consider the possible secondary role of hydrogen-bonding topology in affecting the compressibilities of protonated octahedral frameworks. Burtite and stottite have different hydrogen-bonding topologies due to their different octahedral-tilt system. Burtite, space group Pn3¯ and tilt system a+a+a+, has a hydrogen-bonded network of linked four-membered rings of O-H…O linkages, whereas stottite, space group P42/nand tilt system a+a+c-, has <100> O-H…O crankshafts and isolated four-membered rings. These different hydrogen-bonded configurations lead to different bracing of the empty cavity sites by the O-H…O linkages and very different hydrogen-bonding connectivities in these two minerals that may also enhance the difference between their compressibilities.

Macrocyclic chelators and their metal complexes have widespread applications in the biomedical sciences, including radiopharmaceutical chemistry. The use of copper radionuclides in radiopharmaceuticals is increasing. Macrocyclic chelators have been found to have enhanced in vivo stability over acyclic chelators such as ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA). The currently used chelators of choice for labeling copper radionuclides to biological molecules are analogues of TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid); however, recent reports have demonstrated evidence of in vivo instability of the radio-Cu(II)−TETA complexes. A new class of structurally reinforced macrocycles, the “cross-bridged” cyclam derivatives, form highly stable complexes with Cu(II) that are resistant to dissociation in strong acid. Here, we evaluate a series of ⁶⁴Cu(II) cross-bridged macrocyclic complexes for biological stability and in vivo behavior. The ligands evaluated include the parent ligand, 1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (1), and three 4,11-di-pendant arm derivatives:  4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (2); 4,11-bis(N,N-diethyl-amidomethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (3); and 4,11-bis(amidoethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (4). Copper-64 formed complexes with ligands 1−4 in high radiochemical yields. The ⁶⁴Cu−2 complex was neutral, while ⁶⁴Cu complexes of 1, 3, and 4 were positively charged. All complexes showed no decomposition in rat serum out to 24 h. Biodistribution experiments in Sprague−Dawley rats indicated that ⁶⁴Cu−1, −3, and −4 were taken up by the liver and kidney and cleared slowly over 24 h, whereas ⁶⁴Cu−2 cleared rapidly from all tissues. The rapid clearance of the ⁶⁴Cu−2 complex from the blood and liver, as well as liver metabolism experiments in rats, suggests that it is highly stable in vivo. A bifunctional chelator of 2 is a significant candidate for labeling copper radionuclides to biological molecules for diagnostic imaging and targeted radiotherapy.

AbstractThe commissioning and operation of apparatus for neutron diffraction at simultaneous high temperatures and pressures is reported. The basic design is based on the Paris-Edinburgh cell using opposed anvils, with internal heating. Temperature is measured using neutron radiography. The apparatus has been shown in both on-line and off-line tests to operate to a pressure of 7 GPa and temperature of 1700°C. The apparatus has been used in a neutron diffraction study of the crystal structure of deuterated brucite, and results for 520°C and 5.15 GPa are presented. The diffraction data that can be obtained from the apparatus are of comparable quality to previous high-pressure studies at ambient temperatures, and are clearly good enough for Rietveld refinement analysis to give structural data of reasonable quality.