Importance of IL-6 trans-signaling and high autocrine IL-6 production in human osteoarthritic chondrocyte metabolism.

OBJECTIVE: Neutralization of Interleukin (IL)-6-signaling by antibodies is considered a promising tool for the treatment of osteoarthritis (OA). To gain further insight into this potential treatment, this study investigated the effects of IL-6-signaling and IL-6 neutralization on chondrocyte metabolism and the release of IL-6-signaling-related mediators by human chondrocytes. DESIGN: Chondrocytes were collected from 49 patients with advanced knee/hip OA or femoral neck fracture. Isolated chondrocytes were stimulated with different mediators to analyze the release of IL-6, soluble IL-6 receptor (sIL-6R) and soluble gp130 (sgp130). The effect of IL-6 and IL-6/sIL-6R complex as well as neutralization of IL-6-signaling on the metabolism was analyzed. RESULTS: OA chondrocytes showed high basal IL-6 production and release, which was strongly negatively correlated with the production of cartilage-matrix-proteins. Chondrocytes produced and released sIL-6R and sgp130. The IL-6/sIL-6R complex significantly increased nitric oxide, prostaglandin E2 and matrix metalloproteinase 1 production, decreased Pro-Collagen Type II and mitochondrial ATP production, and increased glycolysis in OA chondrocytes. Neutralization of IL-6-signaling by antibodies did not significantly affect the metabolism of OA chondrocytes, but blocking of glycoprotein 130 (gp130)-signaling by SC144 significantly reduced the basal IL-6 release. CONCLUSION: Although IL-6 trans-signaling induced by IL-6/sIL-6R complex negatively affects OA chondrocytes, antibodies against IL-6 or IL-6R did not affect chondrocyte metabolism. Since inhibition of gp130-signaling reduced the enhanced basal release of IL-6, interfering with gp130-signaling may ameliorate OA progression because high cellular release of IL-6 correlates with reduced production of cartilage-matrix-proteins.

Biomechanical Comparison of Cannulated Screw Osteosynthesis With Tension-Band Wiring for Proximal Fractures of the Fifth Metatarsal (Jones Fracture).

Jones fractures, which lie at the junction of the diaphysis to the metaphysis of the fifth metatarsal, are a well-described clinical issue. There are various surgical approaches, including the commonly performed cannulated screw osteosyntheses, and the less frequently used tension-band approach. The aim is to compare the biomechanical stability of these osteosyntheses. We performed an osteotomy on 16 fresh frozen fifth metatarsal bones from body donors representing a Jones fracture. The fractures were treated pairwise with screw osteosynthesis or tension-band wiring. This was followed by cyclic axial bending until osteosynthesis failure. Stability under axial bending force was higher in the screw osteosynthesis (mean: 70.0 ± 66.5 N) compared to the tension-band wiring (mean: 35.7 ± 23.3 N) group although not reaching statistical significance (p = .116). The study shows no statistically significant difference in biomechanical stability under axial loading between screw osteosynthesis and tension band wiring. Based on the data obtained, no differences can be observed from a biomechanical point of view. The study supports the established method of treating Jones fractures primarily with screw osteosynthesis. In addition, the data suggest that tension band wiring may be a good alternative osteosynthesis, for example, after failed casting treatment or failure of primary osteosynthesis.

Limits to Crystallization Pressure.

Crystallization pressure drives deformation and damage in monuments, buildings, and the Earth's crust. Even though the phenomenon has been known for 170 years, there is no agreement between theoretical calculations of the maximum attainable pressure and experimentally measured pressures. We have therefore developed a novel experimental technique to image the nanoconfined crystallization process while controlling the pressure and applied it to calcite. The results show that displacement by crystallization pressure is arrested at pressures well below the thermodynamic limit. We use existing molecular dynamics simulations and atomic force microscopy data to construct a robust model of the disjoining pressure in this system and thereby calculate the absolute distance between the surfaces. On the basis of the high-resolution experiments and modeling, we formulate a novel mechanism for the transition between damage and adhesion by crystallization that may find application in Earth and materials sciences and in conservation of cultural heritage.

Rab6 regulates cell migration and invasion by recruiting Cdc42 and modulating its activity.

Rab proteins are master regulators of intracellular membrane trafficking, but they also contribute to cell division, signaling, polarization, and migration. The majority of the works describing the mechanisms used by Rab proteins to regulate cell motility involve intracellular transport of key molecules important for migration. Interestingly, a few studies indicate that Rabs can modulate the activity of Rho GTPases, important regulators for the cytoskeleton rearrangements, but the mechanisms behind this crosstalk are still poorly understood. In this work, we identify Rab6 as a negative regulator of cell migration in vitro and in vivo. We show that the loss of Rab6 promotes formation of actin protrusions and influences actomyosin dynamics by upregulating Cdc42 activity and downregulating myosin II phosphorylation. We further provide the molecular mechanism behind this regulation demonstrating that Rab6 interacts with both Cdc42 and Trio, a GEF for Cdc42. In sum, our results uncover a mechanism used by Rab proteins to ensure spatial regulation of Rho GTPase activity for coordination of cytoskeleton rearrangements required in migrating cells.

Cavity Formation in Confined Growing Crystals.

Growing crystals form a cavity when placed against a wall. The birth of the cavity is observed both by optical microscopy of sodium chlorate crystals (NaClO_{3}) growing in the vicinity of a glass surface, and in simulations with a thin film model. The cavity appears when growth cannot be maintained in the center of the contact region due to an insufficient supply of growth units through the liquid film between the crystal and the wall. We obtain a nonequilibrium morphology diagram characterizing the conditions under which a cavity appears. Cavity formation is a generic phenomenon at the origin of the formation of growth rims observed in many experiments, and is a source of complexity for the morphology of growing crystals in natural environments. Our results also provide restrictions for the conditions under which compact crystals can grow in confinement.

Analyzing candidemia guideline adherence identifies opportunities for antifungal stewardship.

Candidemia epidemiology varies significantly by region; thus, local data are essential for evidence-based decision-making in prophylaxis and treatment. Current management strategies are derived from large randomized controlled trials mostly executed in large high-volume tertiary care centers. Results may not be entirely transferable to smaller hospitals. This study investigates epidemiology, diagnosis, and treatment standards in six hospitals in the Cologne metropolitan area (number of inhabitants approx. one million). We assessed adherence to the current guideline of the European Society for Clinical Microbiology and Infectious Diseases (ESCMID) and the Infectious Diseases Society of America (IDSA) using the EQUAL Candida Score of the European Confederation of Medical Mycology (ECMM). Data were documented by trained medical students as part of an integrated research and teaching concept at the University of Cologne. Between January 2014 and June 2017, 77 patients had candidemia, corresponding to an incidence of 0.2 cases/1000 admissions. While 55 patients were enrolled, 22 patients were excluded due to incompletely retrievable health records. Fluconazole monotherapy was the preferred first-line treatment in cases with Candida albicans infection (21/29). A central vascular catheter was present in 40 patients and was removed in 17 (43%) during treatment. Overall mortality at 30 days was 44%. Patients reached a mean EQUAL Candida Score of 9.9 (range 8-14), which was well below the maximum score of 22 for perfect guideline adherence. In summary, management of candidemia differed from current European recommendations. It remains unclear to what extent enhanced adherence would improve patient outcome. Larger prospective studies need to answer that question.

Monocytic angiotensin-converting enzyme 2 relates to atherosclerosis in patients with chronic kidney disease.

Background: Increased levels of monocytic angiotensin-converting enzyme (ACE) found in haemodialysis (HD) patients may directly participate in the pathogenesis of atherosclerosis. We demonstrated recently that uremia triggers the development of highly pro-atherogenic monocytes via an angiotensin II (AngII)­dependent mechanism. Opposing actions of the AngII-degrading ACE2 remain largely unknown. We examined the status of both ACEs and related receptors in circulating leukocytes of HD, not-dialyzed CKD and healthy individuals. Furthermore, we tested the possible impact of monocytic ACEs on atherogenesis and behaviour of the cells under conditions mimicking chronic renal failure. Methods: Expression of ACE, ACE2, AT1R, AT2R and MASR was investigated on circulating leukocytes from 71 HD (62 ± 14 years), 24 CKD stage 3­5 (74 ± 10 years) patients and 37 healthy control subjects (53 ± 6 years) and isolated healthy monocytes treated with normal and uremic serum. Analyses of ACE, ACE2, ICAM-1, VCAM-1, MCSF and endothelial adhesion were tested on ACE-overexpressing THP-1 monocytes treated with captopril or losartan. ACE2-overexpressing monocytes were subjected to transmigration and adhesion assays and investigated for MCP-1, ICAM-1, VCAM-1, MCSF, AT1R and AT2R expression. Results: The ACE mRNA level was significantly increased in HD and CKD stage 3­5 leukocytes. Correspondingly, ACE2 was downregulated and AngII as well as MAS receptor expression was upregulated in these cells. Healthy monocytes preconditioned with uremic serum reflected the same expressional regulation of ACE/ACE2, MAS and AngII receptors as those observed in HD and CKD stage 3­5 leukocytes. Overexpression of monocytic ACE dramatically decreased levels of ACE2 and induced a pro-atherogenic phenotype, partly reversed by AngII-modifying treatments, leading to an increase in ACE2. Overexpression of ACE2 in monocytes led to reduced endothelial adhesion, transmigration and downregulation of adhesion-related molecules. Conclusions: HD and not-dialyzed CKD stage 3­5 patients show enhanced ACE and decreased ACE2 expression on monocytes. This constellation renders the cells endothelial adhesive and likely supports the development of atherosclerosis.

Surfing along Filopodia: A Particle Transport Revealed by Molecular-Scale Fluctuation Analyses.

Filopodia perform cellular functions such as environmental sensing or cell motility, but they also grab for particles and withdraw them leading to an increased efficiency of phagocytic uptake. Remarkably, withdrawal of micron-sized particles is also possible without noticeable movements of the filopodia. Here, we demonstrate that polystyrene beads connected by optical tweezers to the ends of adherent filopodia of J774 macrophages, are transported discontinuously toward the cell body. After a typical resting time of 1-2 min, the cargo is moved with alternating velocities, force constants, and friction constants along the surface of the filopodia. This surfing-like behavior along the filopodium is recorded by feedback-controlled interferometric three-dimensional tracking of the bead motions at 10-100 kHz. We measured transport velocities of up to 120 nm/s and transport forces of ∼ 70 pN. Small changes in position, fluctuation width, and temporal correlation, which are invisible in conventional microscopy, indicate molecular reorganization of transport-relevant proteins in different phases of the entire transport process. A detailed analysis implicates a controlled particle transport with fingerprints of a nanoscale unbinding/binding behavior. The manipulation and analysis methods presented in our study may also be helpful in other fields of cellular biophysics.

Measuring Local Viscosities near Plasma Membranes of Living Cells with Photonic Force Microscopy.

The molecular processes of particle binding and endocytosis are influenced by the locally changing mobility of the particle nearby the plasma membrane of a living cell. However, it is unclear how the particle's hydrodynamic drag and momentum vary locally and how they are mechanically transferred to the cell. We have measured the thermal fluctuations of a 1 µm-sized polystyrene sphere, which was placed in defined distances to plasma membranes of various cell types by using an optical trap and fast three-dimensional (3D) interferometric particle tracking. From the particle position fluctuations on a 30 µs timescale, we determined the distance-dependent change of the viscous drag in directions perpendicular and parallel to the cell membrane. Measurements on macrophages, adenocarcinoma cells, and epithelial cells revealed a significantly longer hydrodynamic coupling length of the particle to the membrane than those measured at giant unilamellar vesicles (GUVs) or a plane glass interface. In contrast to GUVs, there is also a strong increase in friction and in mean first passage time normal to the cell membrane. This hydrodynamic coupling transfers a different amount of momentum to the interior of living cells and might serve as an ultra-soft stimulus triggering further reactions.

Electronic decoupling of a cyclophane from a metal surface.

Electronic self-decoupling of an organic chromophore from a metal substrate is achieved using a naphtalenediimide cyclophane to spatially separate one chromophore unit of the cyclophane from the substrate. Observations of vibronic excitations in scanning tunneling spectra demonstrate the success of this approach. These excitations contribute a significant part of the tunneling current and give rise to clear structure in scanning tunneling microscope images. We suggest that this approach may be extended to implement molecular functions at metal surfaces.

Standardized analysis of syndesmosis stability in ankle trauma with an innovative syndesmosis-test-tool: a biomechanical study.

When treating ankle fractures, the question of syndesmosis complex involvement often arises. So far, there is no standardized method to reliably detect syndesmosis injuries in the surgical treatment of ankle fractures. For this reason, an intraoperative syndesmosis-test-tool (STT) was developed and compared to the recommended and established hook-test (HT). Tests were performed on cadaveric lower legs (n = 20) and the diastasis was visualized by 3D camera. Tests were performed at 50, 80, and 100 N in native conditions and four instability levels. Instability was induced from anterior to posterior and the reverse on the opposite side. The impact on diastasis regarding the direction, the force level, the instability level, and the device used was checked using a general linear model for repeated measurement. The direction of the induced instability showed no influence on the diastasis during the stability tests. The diastasis measured with the STT increased from 0.5 to 3.0 mm depending on the instability, while the range was lower with the HT (1.1 to 2.3 mm). The results showed that the differentiation between the instability levels was statistically significantly better for the developed STT. The last level of maximum instability was significantly better differentiable with the STT compared to the HT. An average visualizable diastasis of more than 2 mm could only be achieved at maximum instability. In conclusion, the newly developed STT was superior to the commonly used HT to detect instability.

Fibula Nail versus Locking Plate Fixation-A Biomechanical Study.

In the treatment of ankle fractures, complications such as wound healing problems following open reduction and internal fixation are a major problem. An innovative alternative to this procedure offers a more minimally invasive nail stabilization. The purpose of this biomechanical study was to clarify whether this method was biomechanically comparable to the established method. First, the stability (range of motion, diastasis) and rotational stiffness of the native upper ankle were evaluated in eight pairs of native geriatric specimens. Subsequently, an unstable ankle fracture was created and fixed with a locking plate or a nail in a pairwise manner. The ankles showed significantly less stability and rotational stiffness properties after nail and plate fixations than the corresponding native ankles (p < 0.001 for all parameters). When comparing the two methods, both showed no differences in their range of motion (p = 0.694) and diastasis (p = 0.166). The nail also presented significantly greater rotational stiffness compared to the plate (p = 0.001). However, both fixations remained behind the native stability and rotational stiffness. Due to the comparable biomechanical properties of the nail and plate fixations, an early weight-bearing following nail fixation should be assessed on a case-by-case basis considering the severity of fractures.

Objective Assessment of Syndesmosis Stability Using the Hook Test.

The hook test is a widely used intraoperative method for assessing syndesmosis stability. However, there are no recommendations regarding the force required to perform this test. Furthermore, the reliability of the test is unclear. Ten experienced surgeons performed hook tests on a cadaver bone model. The applied forces were recorded in a blinded manner. In addition, standardized hook tests with defined forces (50, 80, and 100 N) were performed on 10 pairs of cadaver lower legs and the syndesmosis was sequentially destabilized. Diastasis of the syndesmosis was recorded using an optical 3D camera system. A median force of 81 N (Range: 50 N-145 N) was applied. A proportion of 82% of the tests showed a force < 100 N. The data showed good intraraterreliability and poor interraterreliability. In the standardized investigation of the hook test on the cadaver bone model, both the force and the instability of the syndesmosis had a significant influence on the syndesmosis diastasis. Nevertheless, even with maximum instability of the syndesmosis, diastasis > 2 mm could only be measured in 12 of the 19 evaluable specimens. The widely used hook test shows a high variability when performed in practice. Even in a standardized manner, the hook test cannot detect a relevant syndesmosis injury.

Biomechanical Comparison of Medio-Plantar and Plantar Plate Fixation for First Tarsometatarsal Joint Arthrodesis.

Plantar plate positioning has been demonstrated as biomechanically superior. However, some operators remain resentful about the morbidity of the surgical approach. To provide improved plate fixation for first tarsometatarsal joint arthrodesis with respect to the tibialis anterior tendon, a medio-plantar plate was developed. The purpose of this biomechanical study was to compare its construct stability to that of a plantar plate construct. Twelve pairs of fresh frozen human specimens were used in a matched pair test. Each pair was fixed with a 4 mm compression screw and either a plantar locking plate or a medio-plantar locking plate. A cantilever beam test was performed in dorsiflexion. Before and after cyclic loading (5000 cycles; 40 N), bending stiffness and relative movements at the joint space were monitored in a quasi-static test including optical motion tracking. Maximum load and bending moment to failure were investigated in a load-to-failure ramp test. The bending stiffness of both groups did not significantly differ before (plantar 49.9 N/mm ± 19.2; medio-plantar 53.9 N/mm ± 25.4, p = 0.43) or after (plantar 24.4 N/mm ± 9.7; medio-plantar 35.3 N/mm ± 22.0, p = 0.08) cyclic loading but decreased significantly in both groups (p < 0.01) after cyclic loading. Relative movement increased significantly during cyclic testing in both groups (p < 0.01) but did not differ significantly between the groups before (p = 0.29) or after (p = 0.16) cyclic loading. Neither load nor bending moment to failure were significantly different (plantar 225 N ± 78, 10.8 Nm; medio-plantar 210 N ± 86, 10.1 Nm, p = 0.61). Both plate constructs provided equivalent construct stability, both being well suited for Lapidus arthrodesis.

Staphylococcus aureus surgical site infection rates in 5 European countries.

OBJECTIVE: To determine the overall and procedure-specific incidence of surgical site infections (SSI) caused by Staphylococcus aureus (S. aureus) as well as risk factors for such across all surgical disciplines in Europe. METHODS: This is a retrospective cohort of patients with surgical procedures performed at 14 European centres in 2016, with a nested case-control analysis. S. aureus SSI were identified by a semi-automated crossmatching bacteriological and electronic health record data. Within each surgical procedure, cases and controls were matched using optimal propensity score matching. RESULTS: A total of 764 of 178 902 patients had S. aureus SSI (0.4%), with 86.0% of these caused by methicillin susceptible and 14% by resistant pathogens. Mean S. aureus SSI incidence was similar for all surgical specialties, while varying by procedure. CONCLUSIONS: This large procedure-independent study of S. aureus SSI proves a low overall infection rate of 0.4% in this cohort. It provides proof of principle for a semi-automated approach to utilize big data in epidemiological studies of healthcare-associated infections. Trials registration The study was registered at clinicaltrials.gov under NCT03353532 (11/2017).

Light-driven coordination-induced spin-state switching: rational design of photodissociable ligands.

The bistability of spin states (e.g., spin crossover) in bulk materials is well investigated and understood. We recently extended spin-state switching to isolated molecules at room temperature (light-driven coordination-induced spin-state switching, or LD-CISSS). Whereas bistability and hysteresis in conventional spin-crossover materials are caused by cooperative effects in the crystal lattice, spin switching in LD-CISSS is achieved by reversibly changing the coordination number of a metal complex by means of a photochromic ligand that binds in one configuration but dissociates in the other form. We present mathematical proof that the maximum efficiency in property switching by such a photodissociable ligand (PDL) is only dependent on the ratio of the association constants of both configurations. Rational design by using DFT calculations was applied to develop a photoswitchable ligand with a high switching efficiency. The starting point was a nickel-porphyrin as the transition-metal complex and 3-phenylazopyridine as the photodissociable ligand. Calculations and experiments were performed in two iterative steps to find a substitution pattern at the phenylazopyridine ligand that provided optimum performance. Following this strategy, we synthesized an improved photodissociable ligand that binds to the Ni-porphyrin with an association constant that is 5.36 times higher in its trans form than in the cis form. The switching efficiency between the diamagnetic and paramagnetic state is efficient as well (72% paramagnetic Ni-porphyrin after irradiation at 365 nm, 32% paramagnetic species after irradiation at 440 nm). Potential applications arise from the fact that the LD-CISSS approach for the first time allows reversible switching of the magnetic susceptibility of a homogeneous solution. Photoswitchable contrast agents for magnetic resonance imaging and light-controlled magnetic levitation are conceivable applications.

Crystal growth in confinement.

The growth of crystals confined in porous or cellular materials is ubiquitous in Nature and forms the basis of many industrial processes. Confinement affects the formation of biominerals in living organisms, of minerals in the Earth's crust and of salt crystals damaging porous limestone monuments, and is also used to control the growth of artificial crystals. However, the mechanisms by which confinement alters crystal shapes and growth rates are still not elucidated. Based on novel in situ optical observations of (001) surfaces of NaClO3 and CaCO3 crystals at nanometric distances from a glass substrate, we demonstrate that new molecular layers can nucleate homogeneously and propagate without interruption even when in contact with other solids, raising the macroscopic crystal above them. Confined growth is governed by the peculiar dynamics of these molecular layers controlled by the two-dimensional transport of mass through the liquid film from the edges to the center of the contact, with distinctive features such as skewed dislocation spirals, kinetic localization of nucleation in the vicinity of the contact edge, and directed instabilities. Confined growth morphologies can be predicted from the values of three main dimensionless parameters.

Osteoarthritis-Induced Metabolic Alterations of Human Hip Chondrocytes.

Osteoarthritis (OA) alters chondrocyte metabolism and mitochondrial biology. We explored whether OA and non-OA chondrocytes show persistent differences in metabolism and mitochondrial function and different responsiveness to cytokines and cAMP modulators. Hip chondrocytes from patients with OA or femoral neck fracture (non-OA) were stimulated with IL-1ß, TNF, forskolin and opioid peptides. Mediators released from chondrocytes were measured, and mitochondrial functions and glycolysis were determined (Seahorse Analyzer). Unstimulated OA chondrocytes exhibited significantly higher release of IL-6, PGE2 and MMP1 and lower production of glycosaminoglycan than non-OA chondrocytes. Oxygen consumption rates (OCR) and mitochondrial ATP production were comparable in unstimulated non-OA and OA chondrocytes, although the non-mitochondrial OCR was higher in OA chondrocytes. Compared to OA chondrocytes, non-OA chondrocytes showed stronger responses to IL-1ß/TNF stimulation, consisting of a larger decrease in mitochondrial ATP production and larger increases in non-mitochondrial OCR and NO production. Enhancement of cAMP by forskolin prevented IL-1ß-induced mitochondrial dysfunction in OA chondrocytes but not in non-OA chondrocytes. Endogenous opioids, present in OA joints, influenced neither cytokine-induced mitochondrial dysfunction nor NO upregulation. Glycolysis was not different in non-OA and OA chondrocytes, independent of stimulation. OA induces persistent metabolic alterations, but the results suggest upregulation of cellular mechanisms protecting mitochondrial function in OA.

Open versus minimally invasive fixation of thoracic and lumbar spine fractures in patients with ankylosing spinal diseases.

PURPOSE: Posterior multilevel fixation of traumatic instability in ankylosing spinal disease (ASD) can be performed by open surgery (OS) or minimally invasive surgery (MIS). We investigated whether both methods differ based on the reduction results and perioperative parameters. METHODS: In this retrospective cohort study, OS and MIS groups were investigated. The bisegmental Cobb angles and dislocation angles were measured using pre- and postoperative CT images, and the initial malalignment and achieved reduction were calculated. Cut-seam time, calculated blood loss, transfusion number, fluoroscopy time, pedicle screw placement accuracy, duration of ICU stay, in-patient stay, and complications (bleeding, postoperative thrombosis and embolism, and postoperative mortality) were recorded. RESULTS: Seventy-five ASD patients with spine fractures (Ø 75 ± 11 years, male: 52, female: 23) (MIS: 48; OS: 27) were included in this study. The extent of reduction did not differ in the OS and MIS groups (p = 0.465; MIS:- 1 ± 3°, OS:-2 ± 6°). The residual postoperative malalignment angle was not significantly different (p = 0.283). Seventy-eight of the implanted screws (11%) showed malpositioning. No difference was found between OS and MIS (MIS, 37 [7%]; OS, 41 [16%]; p = 0.095). MIS was associated with less blood loss (OS: 1.28 ± 0.78 l, MIS: 0.71 ± 0.57 l, p = 0.001), cut-seam time (MIS: 98 ± 44 min, OS: 166 ± 69 min, p < 0.001), and hospital stay (MIS: Ø14 ± 16 d, OS: Ø38 ± 49 d, p = 0.02) than OS. CONCLUSION: OS and MIS show equally limited performance in terms of the fracture reduction achieved. The MIS technique was superior to OS based on the perioperative outcome. Therefore, MIS should be preferred over OS for unstable spinal injuries, excluding C-type fractures, in ASD patients without neurological impairment.

Stability and aromaticity of charged Möbius[4n]annulenes.

A number of parent aromatic Möbius annulenes that violate the Hückel rule have been proposed theoretically. Unfortunately, these species are thermodynamically and kinetically unstable and probably impossible to synthesize. We therefore systematically screened a large number of annulene anions, dianions, and dications and predict that a Möbius [14]annulene dication is not only the most stable isomer among these monocyclic structures but also the global minimum on the (CH)(14)(2+) hypersurface including bicyclic and tricyclic isomers. Thus, under stable ion conditions the Möbius [14]annulene dication should be stable toward cis-trans isomerizations and electrocyclic reactions which are the most probable pathways limiting the lifetime of Möbius annulenes.