Publisher Correction: Imaging single glycans.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Imaging single glycans.

Imaging of biomolecules guides our understanding of their diverse structures and functions1,2. Real-space imaging at sub-nanometre resolution using cryo-electron microscopy has provided key insights into proteins and their assemblies3,4. Direct molecular imaging of glycans-the predominant biopolymers on Earth, with a plethora of structural and biological functions5-has not been possible so far6. The inherent glycan complexity and backbone flexibility require single-molecule approaches for real-space imaging. At present, glycan characterization often relies on a combination of mass spectrometry and nuclear magnetic resonance imaging to provide insights into size, sequence, branching and connectivity, and therefore requires structure reconstruction from indirect information7-9. Here we show direct imaging of single glycan molecules that are isolated by mass-selective, soft-landing electrospray ion beam deposition and imaged by low-temperature scanning tunnelling microscopy10. The sub-nanometre resolution of the technique enables the visualization of glycan connectivity and discrimination between regioisomers. Direct glycan imaging is an important step towards a better understanding of the structure of carbohydrates.

[Postherpetic neuralgia of the left trigeminus nerve V1 : Successful therapy with capsaicin 8% patch]. / Post-Zoster-Neuralgie des linken Trigeminusastes V1 : Erfolgreiche Therapie mit Capsaicin 8 %­Pflaster.

A 68-year-old patient suffered from postzoster neuralgia with severe pain of the left trigeminal nerve V1. Despite medication with gabapentin 1800 mg/d, oxacarbazepine 600 mg, tapentadol 500 mg/d, amitriptyline 20 mg as well as ambroxol 20% ointment and lidocaine patch topically, the pain reached an intensity of 8-10 on the numeric rating scale (NRS). Wearing a CPAP (continuous positive airway pressure) mask at night to treat a sleep apnea was impossible or the mask was leaking under lidocaine patch, only topical ambroxol 20% brought a certain pain relief. Lack of sleep, a strongly reduced quality of life and massive exhaustion followed quickly. Due to a fall the systemic medication could not be increased. Also lidocaine infusions with dexamethasone and supraorbitalis blockades were unsuccessful, and a ganglionic local opioid analgesia (GLOA) was anatomically not feasible. Therefore, 8 weeks after the onset of the disease, treatment with capsaicin 8% for 60 min on the face was performed. After only one week, 20-30% pain relief was achieved, sometimes even freedom from pain. Six weeks after application, the average pain during the day was only NRS 3/10 despite a considerable reduction in oral medication. Three months after the second treatment, the patient was almost pain-free during the day. Topical capsaicin 8% patch is, in our opinion, also safe and successful to use on the face with appropriate experience of the user.

Long- versus Short-Range Scattering in Doped Epitaxial Graphene.

Tuning the electronic properties of graphene by adatom deposition unavoidably introduces disorder into the system, which directly affects the single-particle excitations and electrodynamics. Using angle-resolved photoemission spectroscopy (ARPES) we trace the evolution of disorder in graphene by thallium adatom deposition and probe its effect on the electronic structure. We show that the signatures of quasiparticle scattering in the photoemission spectral function can be used to identify thallium adatoms, although charged, as efficient short-range scattering centers. Employing a self-energy model for short-range scattering, we are able to extract a δ-like scattering potential δ = -3.2 ± 1 eV. Therefore, isolated charged scattering centers do not necessarily act just as good long-range (Coulomb) scatterers but can also act as efficient short-range (δ-like) scatterers; in the case of thallium, this happens with almost equal contributions from both mechanisms.

Topical ambroxol for the treatment of neuropathic pain. An initial clinical observation.

BACKGROUND: Neuropathic pain is difficult to treat, and the available options are often inadequate. The expectorant ambroxol also acts as a strong local anaesthetic and blocks sodium channels about 40 times more potently than lidocaine. It preferentially inhibits the channel subtype Nav 1.8, which is expressed especially in nociceptive C-fibres. In view of the low toxicity of ambroxol, it seemed reasonable to try using it for the treatment of neuropathic pain that failed to respond to other standard options. MATERIAL AND METHODS: The medical records of seven patients with severe neuropathic pain and pain reduction following topical ambroxol treatment are reported retrospectively. As standard therapies had not proved sufficient, a topical ambroxol 20% cream was repeatedly applied by the patients in the area of neuropathic pain. RESULTS: The reasons for neuropathic pain were postherpetic neuralgia (2 ×), mononeuropathy multiplex, phantom pain, deafferentation pain, postoperative neuralgia and foot neuropathy of unknown origin. The individual mean pain intensity reported was between 4 and 6/10 (NRS), maximum pain at 6-10/10 (NRS). The pain reduction achieved individually following ambroxol cream was 2-8 points (NRS) within 5-30 min and lasted for 3-8 h. Pain attacks were reduced in all five patients presenting with this problem. Four patients with no improvement after lidocaine 5% and one patient with no response to capsaicin 8% nevertheless experienced a pain reduction with topical ambroxol. No patient reported any side effects or skin changes during a treatment that has since been continued for up to 4 years. CONCLUSION: Ambroxol acts as a strong local anaesthetic and preferentially inhibits the nociceptively relevant sodium channel subtype Nav 1.8. For the first time, we report below on a relevant pain relief following topical ambroxol 20% cream in patients with neuropathic pain. In view of the positive side effect profile, the clinical benefit in patients with pain should be investigated further.

[Topical ambroxol for the treatment of neuropathic pain: A first clinical observation. German version]. / Topisches Ambroxol zur Behandlung neuropathischer Schmerzen: Eine erste klinische Beobachtung.

BACKGROUND: Neuropathic pain is difficult to treat and available options are frequently not sufficient. The expectorant ambroxol also works as a strong local anesthetic and blocks sodium channels about 40 times more potently than lidocaine. Ambroxol preferentially inhibits the channel subtype Nav 1.8, which is expressed particularly in nociceptive C fibers. Due to the low toxicity, topical ambroxol seemed to represent a reasonable therapeutic attempt for treatment of neuropathic pain resistant to other standard options. MATERIALS AND METHODS: Medical records of 7 patients with severe neuropathic pain, in whom many attempts at treatment with approved substances were not sufficient or possible, are reported retrospectively. Patients were then treated with topical ambroxol 20% cream applied in the area of neuropathic pain. RESULTS: Causes of neuropathic pain were postherpetic neuralgia (2-×), mononeuropathy multiplex, phantom pain, deafferentation pain, postoperative neuralgia and an unclear allodynia of the foot. Mean pain intensity was reported as 4-6/10 on a numeric rating scale (NRS) and maximum pain intensity as 6-10/10. Pain reduction following ambroxol cream was 2-8 points (NRS) within 15-30 min and lasted 3-8 h. Pain attacks were reduced in all 5 patients presenting this problem. Topical ambroxol achieved pain reduction in 4 patients with no improvement after lidocaine 5% and 1 patient with no response to capsaicin 8%. No adverse events or skin changes have been observed, and the longest treatment duration is currently 4 years. CONCLUSION: Ambroxol acts as a strong local anesthetic and preferentially inhibits the nociceptive-relevant sodium channel subtype Nav 1.8. For the first time, we report relevant pain reduction following topical Ambroxol 20% cream in patients with neuropathic pain. Regarding the advantageous profile with rare side effects, the clinical benefit for pain patients should be further investigated.

A hydrodynamically optimized nano-electrospray ionization source and vacuum interface.

The coupling of atmospheric pressure ionization (API) sources like electrospray ionization (ESI) to vacuum based applications like mass spectrometry (MS) or ion beam deposition (IBD) is done by differential pumping, starting with a capillary or pinhole inlet. Because of its low ion transfer efficiency the inlet represents a major bottleneck for these applications. Here we present a nano-ESI vacuum interface optimized to exploit the hydrodynamic drag of the background gas for collimation and the reduction of space charge repulsion. Up to a space charge limit of 40 nA we observe 100% current transmission through a capillary with an inlet and show by MS and IBD experiments that the transmitted ion beams are well defined and free of additional contamination compared to a conventional interface. Based on computational fluid dynamics modelling and ion transport simulations, we show how the specific shape enhances the collimation of the ion cloud. Mass selected ion currents in the nanoampere range available further downstream in high vacuum open many perspectives for the efficient use of electrospray ion beam deposition (ES-IBD) as a surface coating method.

Uptake and depuration of gold nanoparticles in Daphnia magna.

This study presents a series of short-term studies (total duration 48 h) of uptake and depuration of engineered nanoparticles (ENP) in neonate Daphnia magna. Gold nanoparticles (Au NP) were used to study the influence of size, stabilizing agent and feeding on uptake and depuration kinetics and animal body burdens. 10 and 30 nm Au NP with different stabilizing agents [citrate (CIT) and mercaptoundecanoic acid (MUDA)] were tested in concentrations around 0.5 mg Au/L. Fast initial uptake was observed for all studied Au NP, with CIT stabilized Au NP showing similar rates independent of size and MUDA showing increased uptake for the smaller Au NP (MUDA 10 nm > CIT 10 nm, 30 nm > MUDA 30 nm). However, upon transfer to clean media no clear trend on depuration rates was found in terms of stabilizing agent or size. Independent of stabilizing agent, 10 nm Au NP resulted in higher residual whole-animal body burdens after 24 h depuration than 30 nm Au NP with residual body burdens about one order of magnitude higher of animals exposed to 10 nm Au NP. The presence of food (P. subcapitata) did not significantly affect the body burden after 24 h of exposure, but depuration was increased. While food addition is not necessary to ensure D. magna survival in the presented short-term test design, the influence of food on uptake and depuration kinetics is essential to consider in long term studies of ENP where food addition is necessary. This study demonstrates the feasibility of a short-term test design to assess the uptake and depuration of ENP in D. magna. The findings underlines that the assumptions behind the traditional way of quantifying bioconcentration are not fulfilled when ENPs are studied.

A natural topological insulator.

The earth's crust and outer space are rich sources of technologically relevant materials which have found application in a wide range of fields. Well-established examples are diamond, one of the hardest known materials, or graphite as a suitable precursor of graphene. The ongoing drive to discover novel materials useful for (opto)electronic applications has recently drawn strong attention to topological insulators. Here, we report that Kawazulite, a mineral with the approximate composition Bi2(Te,Se)2(Se,S), represents a naturally occurring topological insulator whose electronic properties compete well with those of its synthetic counterparts. Kawazulite flakes with a thickness of a few tens of nanometers were prepared by mechanical exfoliation. They exhibit a low intrinsic bulk doping level and correspondingly a sizable mobility of surface state carriers of more than 1000 cm(2)/(V s) at low temperature. Based on these findings, further minerals which due to their minimized defect densities display even better electronic characteristics may be identified in the future.

[Capsaicin 8 % cutaneous patches for phantom limb pain. Results from everyday practice (non-interventional study)]. / Das 8 %ige Capsaicin-Pflaster bei Phantomschmerz. Ergebnisse aus dem Praxisalltag (nichtinterventionelle Studie).

BACKGROUND: Post amputation pain presents a challenge for pain physicians and is often detrimental to the patient's quality of life. PATIENTS AND METHODS: A prospective 12-week non-interventional study (NIS) was conducted in Germany to obtain data on the effectiveness and safety of capsaicin 8 % cutaneous patches from real life use in patients with peripheral neuropathic pain. For the first time in a subgroup of amputees data on post amputation pain were collected. This article presents the results for patients who suffered from phantom limb pain (PLP), stump pain (SP) and combined phantom limb/stump pain (PLP/SP). RESULTS: The analyses included 21 patients with post amputation pain (PLP: n = 10, SP: n = 4, PLP/SP: n = 7). The mean duration of pain (± standard deviation) was 12.8 ± 13.0 years for PLP, 23.1 ± 29.9 years for SP and 11.0 ± 15.8 years for PLP/SP. A single treatment with capsaicin 8 % cutaneous patches significantly reduced the average pain intensity over the observational period of 12 weeks. The mean numeric pain rating scale (NPRS) baseline score changed by - 2.4 for PLP with a standard error of the mean (SEM) of 0.4 (median: - 2.9, Q1: - 3.5, Q3: - 1.0), - 1.7 for SP (SEM: 0.8, median: - 1.1, Q1: - 2.9, Q3: - 0.5) and - 1.5 for PLP/SP (SEM: 0.6, median: - 2.0, Q1: - 2.3, Q3: 0) during weeks 1-12. The 30 % responder rates (i.e. ≥ 30 % reduction in pain, day 7/14 to week 12) were 70.0 % (PLP), 50.0 % (SP) and 28.6 % (PLP/SP). PLP and PLP/SP patients in particular, benefited from improvements in pain attacks, sleep duration and sleep quality and one patient (PLP/SP) reported an adverse drug reaction (increase of pain). Physicians rated the tolerability of the patch as very good or good in 90.5 % of patients. A poor tolerability was stated for none of the 21 amputees. Of the patients 80 % for PLP and 50 % for both SP and PLP/SP expressed the wish to receive retreatment with capsaicin 8 % patches. CONCLUSION: Capsaicin 8 % cutaneous patches seem to be effective and safe for the treatment of post amputation pain, notably in patients suffering from phantom limb pain.

Superexchange-mediated ferromagnetic coupling in two-dimensional Ni-TCNQ networks on metal surfaces.

We investigate the magnetic coupling of Ni centers embedded in two-dimensional metal-coordination networks self-assembled from 7,7,8,8-tetracyanoquinodimethane (TCNQ) molecules on Ag(100) and Au(111) surfaces. X-ray magnetic circular dichroism measurements show that single Ni adatom impurities assume a spin-quenched configuration on both surfaces, while Ni atoms coordinating to TCNQ ligands recover their magnetic moment and exhibit ferromagnetic coupling. The valence state and the ferromagnetic coupling strength of the Ni coordination centers depend crucially on the underlying substrate due to the different charge state of the TCNQ ligands on the two surfaces. The results suggest a superexchange coupling mechanism via the TCNQ ligands.

[Prolonged-release tapentadol for phantom pain. A case series]. / Retardiertes Tapentadol bei Phantomschmerzen. Eine Fallserie.

OBJECTIVES: The successful therapy of phantom pain remains a major challenge, because the underlying pathophysiological mechanisms are still not fully understood. A therapeutic approach with tapentadol has not been described so far. PATIENTS AND METHODS: Five patients suffering upper and lower extremity phantom pain were successfully treated with tapentadol (prolonged release) with differing doses. RESULTS: In 4 patients, a strongly reduced pain intensity between 4 and 6.5 on the visual analog scale (VAS) was recorded. The fifth patient reported an increase in the nocturnal sleep duration from 2 to 5 h and a decrease in the number of phantom pain attacks by 30 %. In 2 patients, the additional medication could be lowered or stretched. Side effects (vertigo, fatigue) were only observed in one subject. CONCLUSION: The cases described provide preliminary evidence that the synergistic combination of µ-opioid receptor agonism (MOR) and noradrenalin re-uptake inhibition (NRI) provided by tapentadol may be beneficial in the treatment of phantom pain.

Giant ambipolar Rashba effect in the semiconductor BiTeI.

We observe a giant spin-orbit splitting in the bulk and surface states of the noncentrosymmetric semiconductor BiTeI. We show that the Fermi level can be placed in the valence or in the conduction band by controlling the surface termination. In both cases, it intersects spin-polarized bands, in the corresponding surface depletion and accumulation layers. The momentum splitting of these bands is not affected by adsorbate-induced changes in the surface potential. These findings demonstrate that two properties crucial for enabling semiconductor-based spin electronics-a large, robust spin splitting and ambipolar conduction-are present in this material.

In-plane magnetic anisotropy of Fe atoms on Bi2Se3(111).

The robustness of the gapless topological surface state hosted by a 3D topological insulator against perturbations of magnetic origin has been the focus of recent investigations. We present a comprehensive study of the magnetic properties of Fe impurities on the prototypical 3D topological insulator Bi(2)Se(3) using local low-temperature scanning tunneling spectroscopy and integral x-ray magnetic circular dichroism techniques. Single Fe adatoms on the Bi(2)Se(3) surface, in the coverage range ≈ 1% of a monolayer, are heavily relaxed into the surface and exhibit a magnetic easy axis within the surface plane, contrary to what was assumed in recent investigations on the supposed opening of a gap. Using ab initio approaches, we demonstrate that an in-plane easy axis arises from the combination of the crystal field and dynamic hybridization effects.

[Effect of botulinum toxin type B on residual limb sweating and pain. Is there a chance for indirect phantom pain reduction by improved prosthesis use?]. / Wirkung von Botulinumtoxin Typ B auf Stumpfschwitzen und Stumpfschmerzen. Besteht die Chance der indirekten Phantomschmerzreduktion durch bessere Prothesennutzung?

OBJECTIVES: Hyperhidrosis of a residual limb after amputation is one of the most common reasons for impaired prosthesis use and quality of life and affects 30-50% of all amputees causing skin irritation in about 25%. Thus the probability of residual limb pain increases in addition to an increased likelihood of phantom pain due to shorter duration of prothesis use. Development of both types of pain was studied following treatment of hyperhidrosis in 9 amputees. DESIGN: A total of 9 lower limb amputees received injections of 1750 units of botulinum toxin type B (BTX-B) for the treatment of hyperhidrosis of a residual limb (20 intracutaneous injections each). Prior to injections and 4 weeks and 3 months afterwards, patients rated the impairments regarding residual limb pain, phantom pain and sweating of the residual limb. Furthermore the duration of use of the prosthetic device and quality of life were rated on a numeric rating scale (NRS 0-10). RESULTS: Stump pain (n=9) was highly significantly reduced after 3 months (baseline: NRS 5; 4 weeks: NRS 4, p=0.109; 3 months: NRS 3, p=0.008) and also a tendency for phantom pain after 3 months (baseline NRS 5; 3 months: NRS 3; p=0.109). Sweating of the residual limb prior to BTX-B application was rated as a median 7 on the NRS scale with significant improvements after 4 weeks (NRS 3, p=0.027) and 3 months (NRS 3, p=0.020). Impaired duration of prothesis use improved from NRS 8 to NRS 2 (4 weeks; p=0.023) and NRS 3 (3 months; p=0.023) as well as the quality of life (p=0.016, p=0.023, respectively). CONCLUSIONS: Residual limb pain improved 3 months after intracutaneous, low-dose BTX-B in a trial with 9 patients and also phantom pain by tendency. Sweating of the residual limb was significantly reduced, probably thereby improving the duration of prothesis use. Larger studies should confirm these findings and conclusions.

Coronary angiographic findings for out-of-hospital cardiac arrest survivors presenting with nonshockable rhythms and no ST elevation post resuscitation.

BACKGROUND: Recent guidelines suggest that coronary angiography (CAG) should be considered for out-of-hospital cardiac arrest (OHCA) survivors, including those without ST elevation (STE) and without shockable rhythms. However, there is no prospective data to support CAG for survivors with nonshockable rhythms and no STE post resuscitation. METHODS: This was a re-analysis of the PEARL study (randomized OHCA survivors without STE to early CAG versus not). Patients were subdivided by initial rhythm as nonshockable (Nsh) vs shockable (Sh). The primary outcome was coronary angiographic evidence of acute culprit lesion, with secondary outcomes being survival to hospital discharge and neurological recovery. RESULTS: The PEARL study included 99 patients with OHCA from a presumed cardiac etiology, 24 with nonshockable and 75 with shockable rhythms. There was no difference in the frequency of CAG between the two groups [71% (Nsh) and 75% (Sh); p = 0.79], presence of CAD [81% (Nsh) and 68% (sh); p = 0.37, or culprit lesions identified in each group [50% (Nsh) and 45% (Sh); p = 0.78. Nonshockable patients had worse discharge survival [33% (Nsh) vs 57% (Sh); p = 0.04] and those survived, had worse neurological recovery [30% (Nsh) vs 54% (Sh); p = 0.02] compared to shockable patients. CONCLUSIONS: OHCA survivors presenting with nonshockable rhythms and no STE post resuscitation had similar prevalence of culprit coronary lesions to those with shockable rhythms. CAG may be considered in patients with OHCA without STE regardless of initial presenting rhythm. There was no benefit of emergent CAG both in shockable and non-shockable rhythms.

An exploratory study of sunitinib plus paclitaxel as first-line treatment for patients with advanced breast cancer.

BACKGROUND: Sunitinib has shown single-agent activity in patients with previously treated metastatic breast cancer (MBC). We investigated the safety of the combination of sunitinib and paclitaxel in an exploratory study of patients with locally advanced or MBC. METHODS: Patients received oral sunitinib 25 mg/day (with escalation to 37.5 mg/day as tolerated) on a continuous daily dosing schedule and paclitaxel 90 mg/m(2) on days 1, 8, and 15 of each 28-day cycle. Study endpoints included safety (primary endpoint), pharmacokinetics, and antitumor activity. RESULTS: Twenty-two patients were enrolled. The most frequent adverse events (AEs) were fatigue/asthenia (77%), dysgeusia (68%), and diarrhea (64%). Grade 3 AEs included neutropenia (43%), fatigue/asthenia (27%), neuropathy (18%), and diarrhea (14%). No drug-drug interaction was observed on the basis of pharmacokinetic analysis. Of 18 patients with measurable disease at baseline, 7 (38.9%) achieved objective responses (including 2 complete and 5 partial responses). Clinical responses were observed in three of nine patients with triple-negative receptor status (estrogen receptor negative, progesterone receptor negative, and human epidermal growth factor receptor-2 negative). CONCLUSIONS: These data indicate that sunitinib and paclitaxel in combination are well tolerated in patients with locally advanced or MBC. No drug-drug interaction was detected and there was preliminary evidence of antitumor activity.

[Lidocaine patch for therapy of neuropathic and non-neuropathic pain. A clinical case series of 87 patients]. / Lidocain-Pflaster zur Therapie neuropathischer und nichtneuropathischer Schmerzen. Klinische Fallstudie an 87 Patienten.

BACKGROUND: Topical lidocaine patches (LP) reduce pain in postherpetic neuralgia and other forms of focal neuropathy. The aim of this study was to determine clinical predictors of therapeutic success. MATERIAL AND METHODS: The medical histories of 87 patients with neuropathic (NS) and non-neuropathic pain (NNS) who had received LP as an add-on to their established pain medication were retrospectively analyzed. The variables assessed were gender, age, analgesic co-medication, pain localization, adverse effects and presence of dynamic allodynia. The impact of these variables on the clinical pain-relieving effect (scored on a 5-point scale) was investigated. RESULTS: A total of 24 out of 28 patients with manifest allodynia scored the therapy with LP as beneficial, patients without allodynia (n=59, 67.8%) profited significantly less frequently with only 39% (p<0.001). The probability of profiting from LP therapy in the presence of allodynia was found to be about tenfold higher compared to patients without allodynia (odds ratio 9.14). Of the 87 patients investigated 48 were female (55.2%). Allodynia was considerably more frequent in women (39.6%) compared to men (23.1%) but this was insignificant. Of the female patients 62.5% responded to LP treatment, compared to only 43.6% of men. In more than 60% of cases rated as very good pain relief allodynia was manifest and in non-responders only in less than 10%. The variables age, pain localization and analgesic co-medication were not related with the success of therapy. DISCUSSION: Patients with manifest allodynia profited significantly more frequently from LP therapy and were less frequently non-responders. Female patients showed therapeutic success more often together with a higher rate of allodynia. CONCLUSIONS: In the presence of allodynia, in especially of neuropathic origin, LP seems to be an effective and save option for add-on therapy, this being independent from pain localization and age. Gender specific effects however need more systematic investigation.

Attosecond coherent manipulation of electrons in tunneling microscopy.

Nanoelectronic devices operating in the quantum regime require coherent manipulation and control over electrons at atomic length and time scales. We demonstrate coherent control over electrons in a tunnel junction of a scanning tunneling microscope by means of precise tuning of the carrier-envelope phase of two-cycle long (<6-femtosecond) optical pulses. We explore photon and field-driven tunneling, two different regimes of interaction of optical pulses with the tunnel junction, and demonstrate a transition from one regime to the other. Our results show that it is possible to induce, track, and control electronic current at atomic scales with subfemtosecond resolution, providing a route to develop petahertz coherent nanoelectronics and microscopy.