Coherent beam combining of high power quasi continuous wave tapered amplifiers.

We demonstrate coherent beam combining of four high brightness tapered amplifiers in pulsed, quasi continuous wave (QCW) operation, seeded by a 976 nm laser diode. The maximum power of 22.7 W was achieved with > 64% combining efficiency in a close to diffraction limited beam. We discuss turn-on dynamics of tapered amplifiers operated in pulsed mode in detail.

Insulin degludec results in lower rates of nocturnal hypoglycaemia and fasting plasma glucose vs. insulin glargine: A meta-analysis of seven clinical trials.

BACKGROUND AND AIMS: Basal insulin analogues have a reduced risk of hypoglycaemia compared with NPH insulin, but hypoglycaemia still remains a major impediment to achieving recommended fasting plasma glucose (FPG) targets in patients with diabetes. Insulin degludec (IDeg) is a new basal insulin that forms soluble multihexamers after subcutaneous injection resulting in an ultra-long duration of action and stable glucose-lowering effect. The aim of this analysis was to compare the effect of IDeg on FPG and nocturnal confirmed hypoglycaemia as compared to insulin glargine (IGlar). METHODS AND RESULTS: Data were included from seven phase 3a, randomised, open-label, treat-to-target clinical trials in which once-daily IDeg was compared with once-daily IGlar. Two trials included a total of 957 patients with type 1 diabetes (T1D) and five trials included a total of 3360 patients with type 2 diabetes (T2D); all trials were 26 or 52 weeks in duration. Confirmed hypoglycaemia was defined as plasma glucose <3.1 mmol/L or severe episodes requiring assistance, and nocturnal hypoglycaemia occurred between 00:01 and 05:59. In all trials, the mean end-of-trial FPG was lower for IDeg than IGlar, reaching statistical significance in three trials. Similarly, IDeg was associated with a lower rate of nocturnal confirmed hypoglycaemia vs. IGlar, which was statistically significant in three trials, regardless of type of diabetes or background therapy. CONCLUSION: This analysis shows that the lower rate of nocturnal confirmed hypoglycaemia seen with IDeg relative to IGlar is accompanied by a reduced mean FPG, in particular in patients with T2D.

Magnetic moments of chromium-doped gold clusters: the Anderson impurity model in finite systems.

The magnetic moment of a single impurity atom in a finite free electron gas is studied in a combined x-ray magnetic circular dichroism spectroscopy, charge transfer multiplet calculation, and density functional theory study of size-selected free chromium-doped gold clusters. The observed size dependence of the local magnetic moment can be understood as a transition from a local moment to a mixed valence regime. This shows that the Anderson impurity model essentially describes finite systems even though the discrete density of states introduces a significant deviation from a bulk metal, and the free electron gas is only formed by less than 10 electrons. Electronic shell closure in the gold host minimizes the interaction of localized impurity states with the confined free electron gas and preserves the magnetic moment of 5 µ_{B} fully in CrAu_{2}^{+} and almost fully in CrAu_{6}^{+}. Even for open-shell species, large local moments are observed that scale with the energy gap of the gold cluster. This indicates that an energy gap in the free electron gas stabilizes the local magnetic moment of the impurity atom.

Insulin degludec improves long-term glycaemic control similarly to insulin glargine but with fewer hypoglycaemic episodes in patients with advanced type 2 diabetes on basal-bolus insulin therapy.

The aim of the present study was to compare the long-term safety and efficacy of insulin degludec with those of insulin glargine in patients with advanced type 2 diabetes (T2D) over 78 weeks (the 52-week main trial and a 26-week extension). Patients were randomized to once-daily insulin degludec or insulin glargine, with mealtime insulin aspart ± metformin ± pioglitazone, and titrated to pre-breakfast plasma glucose values of 3.9-4.9 mmol/l (70-88 mg/dl). After 78 weeks, the overall rate of hypoglycaemia was 24% lower (p = 0.011) and the rate of nocturnal hypoglycaemia was 31% lower (p = 0.016) with insulin degludec in the extension trial set, while both groups of patients achieved similar glycaemic control. Rates of adverse events and total insulin doses were similar for both groups in the safety analysis set. During 18 months of treatment, insulin degludec + mealtime insulin aspart ± oral antidiabetic drugs in patients with T2D improves glycaemic control similarly, but confers lower risks of overall and nocturnal hypoglycaemia than with insulin glargine treatment.

Efficacy and safety of insulin degludec given as part of basal-bolus treatment with mealtime insulin aspart in type 1 diabetes: a 26-week randomized, open-label, treat-to-target non-inferiority trial.

AIMS: The efficacy and safety of insulin degludec (IDeg) was compared with insulin detemir (IDet), both administered once daily (OD) as basal treatment in participants with type 1 diabetes mellitus (T1DM). The primary outcome was non-inferiority of IDeg to IDet in glycated haemoglobin (HbA1c) reduction after 26 weeks. METHODS: This multinational, 26-week, controlled, open-label, parallel-group trial randomized adults with T1DM to IDeg or IDet as OD basal insulin treatment combined with mealtime bolus insulin aspart (IAsp). Participants with T1DM treated with any basal-bolus insulin regimen for ≥ 12 months prior to the trial, a mean HbA1c ≤ 10.0% (85.8 mmol/mol) and body mass index (BMI) ≤ 35.0 kg/m(2) at screening participated in the trial (IDeg: N = 302; IDet: N = 153). RESULTS: After 26 weeks, HbA1c decreased 0.73% (8.0 mmol/mol) (IDeg) and 0.65% (7.1 mmol/mol) (IDet) [estimated treatment difference (ETD) IDeg-IDet: -0.09% (-0.23; 0.05)95% CI (-10.0 mmol/mol [-2.6; 0.6]95% CI ); confirming non-inferiority]. Mean fasting plasma glucose improved in both groups, and was lower with IDeg than IDet [ETD IDeg-IDet: -1.66 mmol/l (-2.37; -0.95)95% CI , p < 0.0001]. The rate of confirmed hypoglycaemia was similar with IDeg and IDet [45.83 vs. 45.69 episodes per patient-year of exposure (PYE); estimated rate ratio (RR) IDeg/IDet: 0.98 (0.80; 1.20)95% CI , p = 0.86]. The rate of nocturnal confirmed hypoglycaemia was lower with IDeg than IDet [4.14 vs. 5.93 episodes per PYE; RR IDeg/IDet: 0.66 (0.49; 0.88)95% CI , p = 0.0049]. Adverse event profiles were similar between groups. CONCLUSION: IDeg administered OD in basal-bolus therapy effectively improved long-term glycaemic control in participants with T1DM with a lower risk of nocturnal confirmed hypoglycaemia than IDet.

Spin coupling and orbital angular momentum quenching in free iron clusters.

Magnetic spin and orbital moments of size-selected free iron cluster ions Fe{n}{+} (n=3-20) have been determined via x-ray magnetic circular dichroism spectroscopy. Iron atoms within the clusters exhibit ferromagnetic coupling except for Fe{13}{+}, where the central atom is coupled antiferromagnetically to the atoms in the surrounding shell. Even in very small clusters, the orbital magnetic moment is strongly quenched and reduced to 5%-25% of its atomic value while the spin magnetic moment remains at 60%-90%. This demonstrates that the formation of bonds quenches orbital angular momenta in homonuclear iron clusters already for coordination numbers much smaller than those of the bulk.

[Novel uses of afterbirth tissues in regenerative medicine]. / Neue Verwendungsmöglichkeiten von Nachgeburtsgewebe für die Regenerative Medizin.

INTRODUCTION: Afterbirth tissues, which include the umbilical cord, placenta, amnion, and cord blood, are usually discarded. Recent progress in regenerative medicine suggests that we re-evaluate these tissues and assess their therapeutic potential. METHODS: Firstly the unique properties of afterbirth tissues and their current use in regenerative medicine are summarised. Then we introduce the cooperation of our institutions and our experiences regarding the collection and utilisation of afterbirth tissues. RESULTS: A literature survey suggests that besides the well-known transplantation of hematopoietic stem cells from cord blood, afterbirth tissues were also used as a source of stem cells, progenitor cells, differentiated cells, and blood vessels for tissue engineering purposes. According to our own experience, the two participating OB/GYN departments and the blood donation service were able to organise a sufficient supply of umbilical cords for research purposes. The yield correlated with incentives for the midwives. A total of more than 4,300 cords was collected for experiments designed to create small caliber vessel grafts. The contamination rate was low. Birth mode significantly affected umbilical vein function, whereas ischaemia for up to 40 h did not have any deleterious effects. Umbilical veins were cryopreserved with a moderate loss of function. Fresh umbilical veins were endothelium-denuded and reseeded with endothelial cells harvested from coronary artery disease patients to generate an autologous surface. CONCLUSIONS: Afterbirth tissues have unique properties which make them ideally suited for regenerative medicine. These tissues can be procured and utilised in research facilities even in the absence of an in-house birthing centre.

Bubbles in live-stranded dolphins.

Bubbles in supersaturated tissues and blood occur in beaked whales stranded near sonar exercises, and post-mortem in dolphins bycaught at depth and then hauled to the surface. To evaluate live dolphins for bubbles, liver, kidneys, eyes and blubber-muscle interface of live-stranded and capture-release dolphins were scanned with B-mode ultrasound. Gas was identified in kidneys of 21 of 22 live-stranded dolphins and in the hepatic portal vasculature of 2 of 22. Nine then died or were euthanized and bubble presence corroborated by computer tomography and necropsy, 13 were released of which all but two did not re-strand. Bubbles were not detected in 20 live wild dolphins examined during health assessments in shallow water. Off-gassing of supersaturated blood and tissues was the most probable origin for the gas bubbles. In contrast to marine mammals repeatedly diving in the wild, stranded animals are unable to recompress by diving, and thus may retain bubbles. Since the majority of beached dolphins released did not re-strand it also suggests that minor bubble formation is tolerated and will not lead to clinically significant decompression sickness.

Self-assessment and objective determination of dexterity in patients with type 1 or type 2 diabetes mellitus.

OBJECTIVE: Insulin-treated patients perform complex treatment activities during daily routine, such as blood glucose measurements and insulin injections. We aimed to identify suitable dexterity and cognitive function tests for diabetes patients, and to compare the patient self-assessment of their dexterity skills with the test results (Jebsen-Taylor hand function test, (JHFT), motoric performance test (MLS), number connection test). METHOD: We enrolled 90 diabetes patients (36 females, 54 males): 15 type 1 with clinically suspected dexterity impairment (A: age: 60 ± 9 years), 30 type 2 with clinically suspected dexterity impairment (B: 61 ± 10 years), 30 type 1 or type 2 patients with visual impairment (C: 64 ± 6 years), and 15 type 1 or type 2 patients without obvious impairment (control group: D: 64 ± 5 years). RESULTS: There were no differences regarding neuropathy and slight impairments in the number connection test in all groups. Patient self-assessment revealed that 33.4% in group A, 33.3% in group B, 36.7% in group C and 13.7% in group D, considered themselves to have dexterity impairment. However in the JHFT test, all patients from A (100%) and B (100%), 33% from C, and 0% from D presented with dexterity impairment by only passing less than four subtests. CONCLUSIONS: Impairment of dexterity was much more frequent than believed by the patients themselves. It may be worthwhile to consider these findings when classifying patients regarding their capabilities to perform certain treatments or when assessing diabetes technology with human subjects.

Usability and preference evaluation of a prefilled insulin pen with a novel injection mechanism by people with diabetes and healthcare professionals.

OBJECTIVE: This cross-over usability study assessed the perceptions of, and preference for, FT (FlexTouch*), a new prefilled insulin pen, compared with KP (KwikPen†) another widely available prefilled insulin pen, among people with diabetes and healthcare professionals (physicians and nurses). RESEARCH DESIGN AND METHODS: Participants were randomly assigned to start with either FT or KP. Following instruction on how to operate the pen, the participant performed several injections at different doses into a foam cushion and then answered written questions on ease of use, confidence and preference. RESULTS: Seventy-nine people with diabetes and 81 healthcare professionals (40 physicians and 41 nurses) took part. Overall, most respondents preferred using FT (86%) to KP (7%; p < 0.001), found FT (85%) the easier pen to use versus KP (4%; p < 0.001), and would recommend FT (88%) rather than KP (6%; p < 0.001). Ratings for FT were also significantly higher than for KP on questions relating to the injection process, including ease of depressing the push-button and ease of injecting at three dose levels (20 International Units [IU], 40 IU and 60 IU [p < 0.001 for all]). Significantly more respondents chose FT as the pen that gave them most confidence in correct and complete insulin delivery (73% vs. 6% for KP; p < 0.001). CONCLUSIONS: FT was rated significantly higher (all p < 0.001) for ease of use and confidence, and was preferred over KP by people with diabetes, physicians and nurses. The features of FT may improve the insulin injection experience for a wide range of users. A limitation of the usability questionnaire employed in this study is that it did not assess the factors that influence preference. Additional analyses could be conducted using multivariate regression to help elucidate the features of FT that appeal to different users.

TMEM16 proteins: the long awaited calcium-activated chloride channels?

Currents mediated by calcium-activated chloride channels (CaCCs), observed for the first time in Xenopus oocytes, have been recorded in many cells and tissues ranging from different types of neurons to epithelial and muscle cells. CaCCs play a role in the regulation of excitability in neurons including sensory receptors. In addition, they are crucial mediators of chloride movements in epithelial cells where their activity regulates electrolyte and fluid transport. The roles of CaCCs, particularly in epithelia, are briefly reviewed with emphasis on their function in secretory epithelia. The recent identification by three independent groups, using different strategies, of TMEM16A as the molecular counterpart of the CaCC is discussed. TMEM16A is part of a family that has 10 other members in mice. The discovery of the potential TMEM16 anion channel activity opens the way for the molecular investigation of the role of these anion channels in specific cells and in organ physiology and pathophysiology. The identification of TMEM16A protein as a CaCC chloride channel molecule represents a great triumph of scientific perseverance and ingenuity. The varied approaches used by the three independent research groups also augur well for the solidity of the discovery.

TMEM16 proteins: the long awaited calcium-activated chloride channels?

Currents mediated by calcium-activated chloride channels (CaCCs), observed for the first time in Xenopus oocytes, have been recorded in many cells and tissues ranging from different types of neurons to epithelial and muscle cells. CaCCs play a role in the regulation of excitability in neurons including sensory receptors. In addition, they are crucial mediators of chloride movements in epithelial cells where their activity regulates electrolyte and fluid transport. The roles of CaCCs, particularly in epithelia, are briefly reviewed with emphasis on their function in secretory epithelia. The recent identification by three independent groups, using different strategies, of TMEM16A as the molecular counterpart of the CaCC is discussed. TMEM16A is part of a family that has 10 other members in mice. The discovery of the potential TMEM16 anion channel activity opens the way for the molecular investigation of the role of these anion channels in specific cells and in organ physiology and pathophysiology. The identification of TMEM16A protein as a CaCC chloride channel molecule represents a great triumph of scientific perseverance and ingenuity. The varied approaches used by the three independent research groups also augur well for the solidity of the discovery.

Ultrastructure of human placental tissue after 6 h of normoxic and hypoxic dual in vitro placental perfusion.

The dual in vitro perfusion model of human placental tissue allows the study of different aspects of placental function, such as metabolism, transport and secretion of proteohormones, cytokines and prostaglandins. The integrity of the perfused placental tissue is an important parameter to validate the perfusion system. Using light and electron microscopy, the morphology of villous tissue was examined before and after six hours of normoxic (n=10) vs. hypoxic (n=10) perfusion. An apical shift of the rough endoplasmic reticulum and occasional vacuoles were found in the syncytiotrophoblast of the terminal villi, the exchange area of the placenta. No unexpected pathological findings were seen before the perfusion experiments and only slight changes with moderate distension of the endoplasmic reticulum after 6 h of normoxic perfusion. After hypoxic perfusions, distinct ultrastructural alterations, such as oedematous villous stroma, swollen or completely destroyed cell organelles (e.g., mitochondria and endoplasmic reticulum), multiple vacuoles inside syncytio- and cytotrophoblasts as well as the microvilli were seen, which leads to an impairment of the placental barrier and other functions. The ultrastructural examination of placental tissue before and after dual in vitro perfusion broadens the knowledge of physiological and pathophysiological processes in the perfused placenta and may be a beneficial part of regular validation.

[Intravitreal bevacizumab for recurring choroidal neovascularisation]. / Intravitreales Bevacizumab bei rezidivierender idiopathischer chorioidaler Neovaskularisation.

We administered bevacizumab intravitreally to treat a recurrence of CNV after confocal laser coagulation and photodynamic therapy in a 32-year-old female patient with a single functional eye. Before and after treatment the vision in the affected eye was stable at 1.0. Before administration of the VEGF antibody leakage was distinctly seen on fluorescein angiography, which did not appear on examination after the treatment. Despite the entailed measure of risk we decided in favour of intravitreal application because it seemed promising in view of earlier positive clinical experience with it in exsudative AMD and macular oedema following central retinal vein occlusion. Intravitreal bevacizumab is an alternative that should also be considered for the treatment of idiopathic CNV. Careful clinical studies will follow.

Gating of two-pore domain K+ channels by extracellular pH.

Potassium channels have a conserved selectivity filter that is important in determining which ions are conducted and at what rate. Although K+ channels of different conductance characteristics are known, they differ more widely in the way their opening and closing, the gating, is governed. TASK and TALK subfamily proteins are two-pore region KCNK K+ channels gated open by extracellular pH. We discuss the mechanism for this gating in terms of electrostatic effects on the pore changing the occupancy and open probability of the channels in a way reminiscent of C-type inactivation gating at the selectivity filter. Essential to this proposed mechanism is the replacement of two highly conserved aspartate residues at the pore mouth by asparagine or histidine residues in the TALK and TASK channels.

[The STEMMAT-project as part of health initiative BayernAktiv: adult stem cells from umbilical cord and cord blood as alternative to embryonic stem cell research]. / Das STEMMAT-Projekt als Teil der Gesundheitsinitiative BayernAktiv: Adulte Stammzellen aus Nabelschnur und -blut als Alternative zur embryonalen Stammzellforschung.

Adult stem cells from umbilical cord and cord blood are an interesting alternative to embryonic stem cells because such research is commonly recognized as ethical undisputed and many aspects are still insufficiently investigated. In the context of the STEMMAT research project (STEM = Stem Cell and MAT = Material) different aspects of stem cells from umbilical cord and cord blood are investigated, to improve basic science understanding and potentially leading someday to a clinical application.

[Private umbilical cord blood banking does not reduce the number of samples for scientific stem cell research]. / Privates Nabelschnurblutbanking reduziert nicht die Probenanzahl für wissenschaftliche Stammzellforschung.

OBJECTIVE: Private umbilical cord blood (UCB) banking after delivery has increased over the last decade. For adult/somatic stem cell research UCB is an essential source of stem cells and researchers question if the number of UCB samples for research might be reduced by private banking. METHODS: A survey among seven private blood banks in Germany and analysis and comparison of the number of UCB samples donated for research within the STEMMAT project with private blood banking were performed from 03/2003 to 06/2005 at the Frauenklinik (OB/GYN), Technical University Munich, Germany. RESULTS: Within 27.5 months 1,551 UCB samples were collected for research purposes; the effective recruitment rate was higher than expectations at an effective 66.2 %. Private UCB banking [n = 24] was distributed among three cord blood banks [n = 16, 6 and 4]. The rate of private blood banking was 0.99 % for all deliveries, thus reducing the effective rate for research purpose by only 1.5 %. CONCLUSION: Under the assumption of active and successful recruitment of scientific UCB samples, private blood banking does not significantly reduce this rate and therefore is a negligible rival in the competition for sufficient numbers of UCB samples for research.

[Umbilical cord stromal cells (UCSC). Cells featuring osteogenic differentiation potential]. / Umbilical Cord Stromal Cells (UCSC). Zellen mit osteogenem Differenzierungspotenzial.

The identification of appropriate cell types is necessary to establish cell-based therapies in regenerative medicine. These cell types must (1) be available in an appropriate amount, (2) be easy to obtain, (3) be sufficiently expandable in vitro, and (4) fit to or at least be able to differentiate into the required cell type. Since the umbilical cord is available without any intervention and represents a notable amount of tissue, we consider it to be a promising source for isolating cells for cell-based therapies. This study demonstrates that umbilical cord stromal cells (UCSC), the connective tissue cells of the umbilical cord, can be isolated in sufficient quantities and be well expanded. UCSC feature phenotypic plasticity and thus are functionally similar to stem cells. UCSC can be differentiated into cells with osteoblastic properties (expression of alkaline phosphatase, formation of bone nodules). It is concluded that the umbilical cord should no longer be regarded as valueless tissue and be unthinkingly discarded. Instead, it should be considered a valuable resource for the isolation of potent cells for cell-based therapies, especially for treatment of bone defects.

Biocorrosion of magnesium alloys: a new principle in cardiovascular implant technology?

OBJECTIVES: To develop and test a new concept of the degradation kinetics of newly developed coronary stents consisting of magnesium alloys. METHODS: Design of a coronary stent prototype consisting of the non-commercial magnesium based alloy AE21 (containing 2% aluminium and 1% rare earths) with an expected 50% loss of mass within six months. Eleven domestic pigs underwent coronary implantation of 20 stents (overstretch injury). RESULTS: No stent caused major problems during implantation or showed signs of initial breakage in the histological evaluation. There were no thromboembolic events. Quantitative angiography at follow up showed a significant (p < 0.01) 40% loss of perfused lumen diameter between days 10 and 35, corresponding to neointima formation seen on histological analysis, and a 25% re-enlargement (p < 0.05) between days 35 and 56 caused by vascular remodelling (based on intravascular ultrasound) resulting from the loss of mechanical integrity of the stent. Inflammation (p < 0.001) and neointimal plaque area (p < 0.05) depended significantly on injury score. Planimetric degradation correlated with time (r = 0.67, p < 0.01). CONCLUSION: Vascular implants consisting of magnesium alloy degradable by biocorrosion seem to be a realistic alternative to permanent implants.

Paradoxical pressor effects of beta-blockers in standing elderly patients with mild hypertension: a beneficial side effect.

BACKGROUND: Baroreflex sensitivity declines with age, creating a fall in systolic blood pressure and pulse pressure when standing. If, in addition, blood pressure is reduced as a result of antihypertensive medication, compensatory mechanisms may be inadequate and orthostatic problems may occur. This may be less true in patients on beta-blockers. beta-blockers cause pressor effects in standing patients with autonomic neuropathy, but their effects on standing pulse pressures in elderly subjects with mild hypertension have not been systematically studied. METHODS AND RESULTS: We studied 3741 patients with mild hypertension for 6 months who were being treated with the beta-blocker nebivolol 5 mg daily. Blood pressures were measured after 10 minutes in the supine position and after 1 minute in the standing position. Overall, systolic and diastolic blood pressures rose slightly while standing, whereas pulse pressures remained unchanged. When previously untreated patients (n=2085) >60 and <60 years of age were assessed separately, supine pulse pressures were consistently higher in the elderly group compared with those of the younger subjects by 6 to 11 mm Hg (P<0.001 to 0.0001). However, while standing, pulse pressures rose in the younger subjects, whereas they tended to fall in the elderly group. After 6 months of beta-blockade, this pattern was unchanged in the younger subjects but reversed into significant rise of pulse pressures in the elderly group by 4 (SD 1) mm Hg (P<0.001). In the patients previously treated with other classes of antihypertensive drugs (n=712), the effects were essentially the same. CONCLUSIONS: In elderly patients with mild hypertension, a depressor trend of pulse pressure while standing can be turned into a significant pressor response by treatment with a beta-blocker.