Vascular 3D Printing with a Novel Biological Tissue Mimicking Resin for Patient-Specific Procedure Simulations in Interventional Radiology: a Feasibility Study.

Three-dimensional (3D) printing of vascular structures is of special interest for procedure simulations in Interventional Radiology, but remains due to the complexity of the vascular system and the lack of biological tissue mimicking 3D printing materials a technical challenge. In this study, the technical feasibility, accuracy, and usability of a recently introduced silicone-like resin were evaluated for endovascular procedure simulations and technically compared to a commonly used standard clear resin. Fifty-four vascular models based on twenty-seven consecutive embolization cases were fabricated from preinterventional CT scans and each model was checked for printing success and accuracy by CT-scanning and digital comparison to its original CT data. Median deltas (Δ) of luminal diameters were 0.35 mm for clear and 0.32 mm for flexible resin (216 measurements in total) with no significant differences (p > 0.05). Printing success was 85.2% for standard clear and 81.5% for the novel flexible resin. In conclusion, vascular 3D printing with silicone-like flexible resin was technically feasible and highly accurate. This is the first and largest consecutive case series of 3D-printed embolizations with a novel biological tissue mimicking material and is a promising next step in patient-specific procedure simulations in Interventional Radiology.

Sustained response to brigatinib in a patient with refractory metastatic pheochromocytoma harboring R1192P anaplastic lymphoma kinase mutation: a case report from the Austrian Group Medical Tumor Therapy next-generation sequencing registry and discussion of the literature.

Metastatic pheochromocytoma and paraganglioma (PPGL) are rare diseases with dismal prognosis and standard therapies are lacking. We herein report the first case of a germline anaplastic lymphoma kinase (ALK) mutation in a patient with chemorefractory metastatic pheochromocytoma in the absence of mutations of known PPGL-associated predisposing genes. Therapy with the ALK inhibitor (ALKi) brigatinib led to dramatic and durable disease remission, despite previous disease progression on the ALKi alectinib. This case underscores the potential clinical use of molecular profiling in rare diseases with limited treatment options and suggests that the ALK-R1192P point mutation might predict sensitivity to brigatinib.

MRI of CNS lymphoma with choroid plexus involvement in five dogs and one cat.

OBJECTIVES: To describe the clinical features, magnetic resonance imaging (MRI) findings, and outcome of dogs and cats with central nervous system (CNS) lymphoma that involved the choroid plexus. MATERIALS AND METHODS: A bi-institutional retrospective study of MRI of dogs and cats with CNS lymphoma, in which the choroid plexus was affected on MRI. Signalment, clinical, MRI, clinicopathologic and histopathologic findings were recorded and evaluated. RESULTS: CNS lymphoma with choroid plexus involvement on the MRI was identified in five dogs and one cat. MRI revealed diffuse enlargement and multifocal nodularity in the choroid plexus in most cases, with the fourth ventricle the most common site affected. Five of the cases had signs of extraneural involvement (including the cat), while the sixth case was not staged. Four of five CSF samples analysed provided a diagnosis of lymphoma. CLINICAL SIGNIFICANCE: We report MRI findings of CNS lymphoma involving the choroid plexus. These results show the importance of recognising novel imaging patterns and the potential utility of CSF collection in diagnosing CNS lymphoma involving the choroid plexus ante mortem.

Binding of a TlCl Entity by a Tetragold Tetramercaptothiacalixarene Metalloligand via Metallophilic Interactions.

The successive auration of p-tert-butyltetramercaptotetrathiacalix[4]arene, H4 (MTC[4]), with gold(I) phosphine units was investigated. Through deprotonation with NaOMe, followed by salt metathesis reactions with (PR3 )AuCl (R=Me, Ph) complexes with two and three [(PR3 )Au]+ moieties could be prepared and isolated, namely [(Ph3 PAu)2 H2 (MTC[4])] and [(Me3 PAu)3 H(MTC[4])]. In [(Me3 PAu)3 H(MTC[4])] two gold atoms already come close enough to undergo aurophilic interactions. To introduce a fourth [(PR3 )Au]+ entity TlOEt had to be used for the deprotonation, which led to the finding that four gold atoms organised by the (MTC[4])4- coordination platform are able to bind and stabilize a TlCl entity, yielding [(Me3 PAu)4 TlCl(MTC[4])]. As evidenced by structural and theoretical investigations the binding occurs through strong metallophilic interactions, which lead to photoluminescence at low temperatures.

Oral Health Effects of Combusted and Smokeless Tobacco Products.

The oral cavity is usually the first part of a consumer's body exposed to the constituents of tobacco products or their emissions. Consequently, the oral cavity is a frequent site for carcinogenic, microbial, immunologic, and clinical effects of tobacco use. This article summarizes 5 presentations on various aspects of oral health affected by combusted or noncombusted tobacco products from a recent conference, "Oral Health Effects of Tobacco Products: Science and Regulatory Policy," sponsored by the American Association for Dental Research and the Food and Drug Administration.

Uncovering the (un-)occupied electronic structure of a buried hybrid interface.

The energy level alignment at organic/inorganic (o/i) semiconductor interfaces is crucial for any light-emitting or -harvesting functionality. Essential is the access to both occupied and unoccupied electronic states directly at the interface, which is often deeply buried underneath thick organic films and challenging to characterize. We use several complementary experimental techniques to determine the electronic structure of p -quinquephenyl pyridine (5P-Py) adsorbed on ZnO(1 0 -1 0). The parent anchoring group, pyridine, significantly lowers the work function by up to 2.9 eV and causes an occupied in-gap state (IGS) directly below the Fermi level E F. Adsorption of upright-standing 5P-Py also leads to a strong work function reduction of up to 2.1 eV and to a similar IGS. The latter is then used as an initial state for the transient population of three normally unoccupied molecular levels through optical excitation and, due to its localization right at the o/i interface, provides interfacial sensitivity, even for thick 5P-Py films. We observe two final states above the vacuum level and one bound state at around 2 eV above E F, which we attribute to the 5P-Py LUMO. By the separate study of anchoring group and organic dye combined with the exploitation of the occupied IGS for selective interfacial photoexcitation, this work provides a new pathway for characterizing the electronic structure at buried o/i interfaces.

Acid-catalysed thermal cycloreversion of a diarylethene: a potential way for triggered release of stored light energy?

Upon addition of catalytic amounts of acid, a closed diarylethene derivative carrying a fluorenol moiety undergoes facile thermal ring opening. The underlying thermodynamics and kinetics of the entire system have been analysed experimentally as well as computationally. Our work suggests that general acid catalysis provides a useful tool to bypass thermal barriers, by opening new reaction pathways, and to efficiently trigger the release of light energy stored in photoswitches.

Connectivity pattern modifies excited state relaxation dynamics of fluorophore-photoswitch molecular dyads.

In order to modulate the emission of BODIPY fluorophores, they were connected to a diarylethene (DAE) photoswitch via phenylene-ethynylene linkers of different lengths and orientations. The latter allowed for modulation of the electronic coupling in the prepared four BODIPY-DAE dyads, which were compared also to appropriate BODIPY and DAE model compounds by steady state as well as time-resolved spectroscopies. In their open isomers, all dyads show comparable luminescence behavior indicative of an unperturbed BODIPY fluorophore. In strong contrast, in the closed isomers the BODIPY emission is efficiently quenched but the deactivation mechanism depends on the nature of the linker. The most promising dyad was rendered water-soluble by means of micellar encapsulation and aqueous suspensions were investigated by fluorescence spectroscopy and microscopy. Our results (i) illustrate that the electronic communication between the BODIPY and DAE units can indeed be fine-tuned by the nature of the linker to achieve fluorescence modulation while maintaining photoswitchability and (ii) highlight potential applications to image and control biological processes with high spatio-temporal resolution.

Pituitary Macrotumor Causing Narcolepsy-Cataplexy in a Dachshund.

Familial narcolepsy secondary to breed-specific mutations in the hypocretin receptor 2 gene and sporadic narcolepsy associated with hypocretin ligand deficiencies occur in dogs. In this report, a pituitary mass is described as a unique cause of narcolepsy-cataplexy in a dog. A 6-year-old male neutered Dachshund had presented for acute onset of feeding-induced cataplexy and was found to have a pituitary macrotumor on magnetic resonance imaging (MRI). Cerebral spinal fluid hypocretin-1 levels were normal, indicating that tumor effect on the ventral lateral nucleus of the hypothalamus was not the cause of the dog's narcolepsy-cataplexy. The dog was also negative for the hypocretin receptor 2 gene mutation associated with narcolepsy in Dachshunds, ruling out familial narcolepsy. The Dachshund underwent stereotactic radiotherapy (SRT), which resulted in reduction in the mass and coincident resolution of the cataplectic attacks. Nine months after SRT, the dog developed clinical hyperadrenocorticism, which was successfully managed with trilostane. These findings suggest that disruptions in downstream signaling of hypocretin secondary to an intracranial mass effect might result in narcolepsy-cataplexy in dogs and that brain MRI should be strongly considered in sporadic cases of narcolepsy-cataplexy.

Repeated Famotidine Administration Results in a Diminished Effect on Intragastric pH in Dogs.

BACKGROUND: Famotidine is an acid suppressant commonly administered to dogs. Prolonged famotidine use in people results in decreased efficacy, but the effect in dogs is unknown. HYPOTHESIS/OBJECTIVES: To compare the effect of repeated oral administration of famotidine or placebo on intragastric pH and serum gastrin in dogs. We hypothesized that famotidine would have a diminished effect on intragastric pH on day 13 compared to day 1. ANIMALS: Six healthy adult colony Beagles. METHODS: Randomized, 2-factor repeated-measures crossover design. All dogs received oral placebo or 1.0 mg/kg famotidine q12h for 14 consecutive days. Intragastric pH monitoring was used to continuously record intragastric pH on treatment days 1-2 and 12-13. Mean pH as well as mean percentage time (MPT) that intragastric pH was ≥3 or ≥4 were compared between and within groups by analysis of variance. Serum gastrin was measured on days 0, 3, and 12 for each treatment. RESULTS: Continued administration of famotidine resulted in a significant decrease in mean pH, MPT ≥3, and MPT ≥4 (P < .0001) on day 12 and 13. This resulted in a mean decrease in pH by 1.63 on days 12 and 13 compared to days 1 and 2. Furthermore, a mean decrease of MPT ≥3 and MPT ≥4 by 33 and 45% was observed for the same time period, respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: Continued administration of famotidine results in a diminished effect on intragastric pH in dogs. Caution is advised when recommending long-term, daily oral administration of famotidine to dogs.

Two-Photon-Induced versus One-Photon-Induced Isomerization Dynamics of a Bistable Azobenzene Derivative in Solution.

We report on a bistable azobenzene derivative with sufficiently high 2-photon absorption to induce its photochemical isomerization and measurable excited state dynamics. Broadband transient absorption spectra were recorded and compared upon 1-photon (331 nm) and 2-photon (640 nm) excitation of the S0 → S2 transition. The spectra are different at early (t ∼ 1 ps) and late (t ∼ 100 ps) time but show similar photoisomerization behavior on a 10 ps time scale. With 2-photon excitation, strong population transfer S2 → Sn occurs due to resonance absorption of a third pump photon. Subsequent internal conversion Sn → S1 results in a very hot S1 population causing extra-broadening of the transient spectra. The resonance pump absorption is common with nonlinear excitation and should be taken into account when considering photochemical applications. The 2-photon excitation cross-section σ((2)) at 640 nm was measured to be 7 GM for the specific tetra-ortho-fluorinated azobenzene derivative and 1 GM for unsubstituted parent azobenzene. The direct 2-photon induced trans-to-cis isomerization, described herein, provides an unprecedented potential for spatially addressing P-type (bistable) azobenzene photoswitches in 3D.

Lumbar paraspinal muscle transverse area and symmetry in dogs with and without degenerative lumbosacral stenosis.

OBJECTIVES: To investigate whether dogs with degenerative lumbosacral stenosis have decreased lumbar paraspinal muscle transverse area and symmetry compared with control dogs. MATERIALS AND METHODS: Retrospective cross-sectional study comparing muscles in transverse T2-weighted magnetic resonance images for nine dogs with and nine dogs without degenerative -lumbosacral stenosis. Mean transverse area was measured for the lumbar multifidus and sacrocaudalis dorsalis lateralis muscles bilaterally and the L7 vertebral body at the level of the caudal endplate. Transverse areas of both muscle groups relative to L7 and asymmetry indices were compared between study populations using independent t tests. RESULTS: Mean muscle-to-L7 transverse area ratios were significantly smaller in the degenerative lumbosacral stenosis group compared with those in the control group in both lumbar multifidus (0·84 ±0·26 versus 1·09 ±0·25; P=0·027) and sacrocaudalis dorsalis lateralis (0·5 ±0·15 versus 0·68 ±0·12; P=0·005) muscles. Mean asymmetry indices were higher for both muscles in the group with degenerative lumbosacral stenosis than in the control group, but highly variable and the difference was not statistically significant. CLINICAL SIGNIFICANCE: These findings suggest that dogs with degenerative lumbosacral stenosis have decreased lumbar paraspinal muscle mass that may be a cause or consequence of the -syndrome. Understanding altered paraspinal muscle characteristics may improve understanding of the -pathophysiology and management options for degenerative lumbosacral stenosis.

Broadband transient absorption spectroscopy with 1- and 2-photon excitations: Relaxation paths and cross sections of a triphenylamine dye in solution.

1-photon (382 nm) and 2-photon (752 nm) excitations to the S1 state are applied to record and compare transient absorption spectra of a push-pull triphenylamine (TrP) dye in solution. After 1-photon excitation, ultrafast vibrational and structural molecular relaxations are detected on a 0.1 ps time scale in nonpolar hexane, while in polar acetonitrile, the spectral evolution is dominated by dipolar solvation. Upon 2-photon excitation, transient spectra in hexane reveal an unexpected growth of stimulated emission (SE) and excited-state absorption (ESA) bands. The behavior is explained by strong population transfer S1 → Sn due to resonant absorption of a third pump photon. Subsequent Sn → S1 internal conversion (with τ1 = 1 ps) prepares a very hot S1 state which cools down with τ2 = 13 ps. The pump pulse energy dependence proves the 2-photon origin of the bleach signal. At the same time, SE and ESA are strongly affected by higher-order pump absorptions that should be taken into account in nonlinear fluorescence applications. The 2-photon excitation cross sections σ(2) = 32 ⋅ 10(-50) cm(4) s at 752 nm are evaluated from the bleach signal.

Efficient light emission from inorganic and organic semiconductor hybrid structures by energy-level tuning.

The fundamental limits of inorganic semiconductors for light emitting applications, such as holographic displays, biomedical imaging and ultrafast data processing and communication, might be overcome by hybridization with their organic counterparts, which feature enhanced frequency response and colour range. Innovative hybrid inorganic/organic structures exploit efficient electrical injection and high excitation density of inorganic semiconductors and subsequent energy transfer to the organic semiconductor, provided that the radiative emission yield is high. An inherent obstacle to that end is the unfavourable energy level offset at hybrid inorganic/organic structures, which rather facilitates charge transfer that quenches light emission. Here, we introduce a technologically relevant method to optimize the hybrid structure's energy levels, here comprising ZnO and a tailored ladder-type oligophenylene. The ZnO work function is substantially lowered with an organometallic donor monolayer, aligning the frontier levels of the inorganic and organic semiconductors. This increases the hybrid structure's radiative emission yield sevenfold, validating the relevance of our approach.

Controlling the growth mode of para-sexiphenyl (6P) on ZnO by partial fluorination.

We report on the impact of partial fluorination of para-sexiphenyl (6P) on the growth mode when deposited on the non-polar ZnO(101̄0) surface. The evolution of the thin film structure and morphology is monitored by in situ atomic force microscopy and in situ real-time X-ray scattering. Both 6P and its symmetrical, terminally fluorinated derivative (6P-F4) grow in a highly crystalline mode, however, with a distinctly different morphology. While 6P films are characterised by the formation of two different phases with three-dimensional nanocrystallites and consequently a rather rough surface morphology, layer-by-layer growth and phase purity in case of 6P-F4 prevails leading to smooth terraced thin films. We relate the different growth behaviour to specifics of the thin film structure.

Impact of structural and metabolic variations on the toxicity and carcinogenicity of hydroxy- and alkoxy-substituted allyl- and propenylbenzenes.

The metabolic fate of a compound is determined by numerous factors including its chemical structure. Although the metabolic options for a variety of functional groups are well understood and can often provide a rationale for the comparison of toxicity based on structural analogy, at times quite minor structural variations may have major consequences for metabolic outcomes and toxicity. In this perspective, the effects of structural variations on metabolic outcomes is detailed for a group of related hydroxy- and alkoxy-substituted allyl- and propenylbenzenes. These classes of compounds are naturally occurring constituents of a variety of botanical-based food items. The classes vary from one another by the presence or absence of alkylation of their para-hydroxyl substituents and/or the position of the double bond in the alkyl side chain. We provide an overview of how these subtle structural variations alter the metabolism of these important food-borne compounds, ultimately influencing their toxicity, particularly their DNA reactivity and carcinogenic potential. The data reveal that detailed knowledge of the consequences of subtle structural variations for metabolism is essential for adequate comparison of structurally related chemicals. Taken together, it is concluded that predictions in toxicological risk assessment should not be performed on the basis of structural analogy only but should include an analogy of metabolic pathways across compounds and species.

Magnetic resonance imaging (MRI) spinal cord and canal measurements in normal dogs.

The goal of this study was to establish Magnetic resonance imaging (MRI) reference ranges for spinal measurements in normal dogs. Forty dogs (1-10 kg, 11-20 kg, 21-30 kg, > 30 kg; 10 dogs per category) underwent spinal MRI. Measurements were performed on sagittal T2-W images at the level of the 4th thoracic vertebra (T4), the 9th thoracic vertebra (T9) and the 3rd lumbar vertebra (L3). Spinal canal diameter (mm) ranged from 6.07 ± 0.63 (1-10 kg) to 8.27 ± 1.15 (> 30 kg) at the level of T4; 6.55 ± 0.61 (1-10 kg) to 9.04 ± 1.26 (> 30 kg) at the level of T9; and 6.80 (6.47-7.00; 1-10 kg) to 9.00 (7.90-9.73; > 30 kg) at the level of L3. There were significant differences (P < 0.05) in spinal canal diameter between groups. Mean spinal cord diameter (mm) ranged from 4.46 ± 0.51 (11-20 kg) to 4.70 ± 0.35 (1-10 kg) at the level of T4; 4.41 ± 0.50 (> 30 kg) to 4.85 ± 0.57 (1-10 kg) at the level of T9; and 4.52 ± 0.51 (> 30 kg) to 5.14 ± 0.68 (1-10 kg) at the level of L3. There were no significant differences in spinal cord diameter between groups. Spinal cord-to-spinal canal ratio varied significantly, ranging from 0.51 ± 0.08 (> 30 kg at L3) to 0.78 (0.69-0.80; 1-10 kg at T4) (P < 0.05). These findings are important when using MRI to evaluate patients with suspected diffuse spinal cord disease.

Dopamine in human follicular fluid is associated with cellular uptake and metabolism-dependent generation of reactive oxygen species in granulosa cells: implications for physiology and pathology.

STUDY QUESTION: Is the neurotransmitter dopamine (DA) in the human ovary involved in the generation of reactive oxygen species (ROS)? SUMMARY ANSWER: Human ovarian follicular fluid contains DA, which causes the generation of ROS in cultured human granulosa cells (GCs), and alterations of DA levels in follicular fluid and DA uptake/metabolism in GCs in patients with polycystic ovary syndrome (PCOS) are linked to increased levels of ROS. WHAT IS KNOWN ALREADY: DA is an important neurotransmitter in the brain, and the metabolism of DA results in the generation of ROS. DA was detected in human ovarian homogenates, but whether it is present in follicular fluid and plays a role in the follicle is not known. STUDY DESIGN, SIZE AND DURATION: We used human follicular fluid from patients undergoing in vitro fertilization (IVF), GCs from patients with or without PCOS and also employed mathematical modeling to investigate the presence of DA and its effects on ROS. PARTICIPANTS/MATERIALS, SETTING AND METHODS: DA in follicular fluid and GCs was determined by enzyme-linked immunosorbent assay. GC viability, apoptosis and generation of ROS were monitored in GCs upon addition of DA. Inhibitors of DA uptake and metabolism, an antioxidant and DA receptor agonists, were used to study cellular uptake and the mechanism of DA-induced ROS generation. Human GCs were examined for the presence and abundance of transcripts of the DA transporter (DAT; SLC6A3), the DA-metabolizing enzymes monoamine oxidases A/B (MAO-A/B) and catechol-O-methyltransferase and the vesicular monoamine transporter. A computational model was developed to describe and predict DA-induced ROS generation in human GCs. MAIN RESULTS AND ROLE OF CHANCE: We found DA in follicular fluid of ovulatory follicles of the human ovary and in GCs. DAT and MAO-A/B, which are expressed by GCs, are prerequisites for a DA receptor-independent generation of ROS in GCs. Blockers of DAT and MAO-A/B, as well as an antioxidant, prevented the generation of ROS (P < 0.05). Agonists of DA receptors (D1 and D2) did not induce ROS. DA, in the concentration range found in follicular fluid, did not induce apoptosis of cultured GCs. Computational modeling suggested, however, that ROS levels in GCs depend on the concentrations of DA and on the cellular uptake and metabolism. In PCOS-derived follicular fluid, the levels of DA were higher (P < 0.05) in GCs, the transcript levels of DAT and MAO-A/B in GCs were 2-fold higher (P < 0.05) and the DA-induced ROS levels were found to be more than 4-fold increased (P < 0.05) compared with non-PCOS cells. Furthermore, DA at a high concentration induced apoptosis in PCOS-derived GCs. LIMITATIONS, REASONS FOR CAUTION: While the results in IVF-derived follicular fluid and in GCs reveal for the first time the presence of DA in the human follicular compartment, functions of DA could only be studied in IVF-derived GCs, which can be viewed as a cellular model for the periovulatory follicular phase. The full functional importance of DA-induced ROS in small follicles and other compartments of the ovary, especially in PCOS samples, remains to be shown. WIDER IMPLICATIONS OF THE FINDINGS: The results identify DA as a factor in the human ovary, which, via ROS generation, could play a role in ovarian physiology and pathology. The results obtained in samples from women with PCOS suggest the involvement of DA, acting via ROS, in this condition. STUDY FUNDING/COMPETING INTERESTS: This work was supported by a grant from DFG MA1080/17-3 and in part MA1080/19-1. There are no competing interests.

In vitro-in vivo evaluation of nanosuspension release from subcutaneously implantable osmotic pumps.

Utilizing poorly soluble drug candidates in pharmacokinetic studies remains challenging in preclinical drug development. We investigated a nanosuspension-based delivery system to achieve constant drug plasma levels by applying the nanoparticles via subcutaneously implanted micro-osmotic pumps. Various nanosuspension formulations were characterized in vitro prior to Alzet® pump release by means of dynamic light scattering (DLS), scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and rheological measurements. In vitro formulation release was checked by HPLC/UV. The in vivo experiments compared plasma-concentration time profiles of subcutaneously injected nanosuspensions with those of formulations delivered by pumps. Two Poloxamer 338 containing nanosuspensions with different viscosities were found to be stable over observation time, physically resistant against biorelevant media and showed only a low amorphous part after preparation. The more viscous nanosuspension with 31.65 mPas revealed in vitro the expected zero-order release, while the low viscous formulation with 2.18 mPas showed first order release. In in vivo experiments, the higher viscous nanosuspension released from osmotic pumps exhibited elevated plasma levels compared to the lower viscous formulation. Compared to bolus injected nanosuspensions constant plasma levels could be maintained by adapting the viscosity of the nanosuspension. Subcutaneously implanted osmotic pumps prove to be a valuable delivery system for nanosuspensions in pharmacokinetic studies by consideration of the key parameter viscosity in release kinetics.