4π-periodic Josephson supercurrent in HgTe-based topological Josephson junctions.

The Josephson effect describes the generic appearance of a supercurrent in a weak link between two superconductors. Its exact physical nature deeply influences the properties of the supercurrent. In recent years, considerable efforts have focused on the coupling of superconductors to the surface states of a three-dimensional topological insulator. In such a material, an unconventional induced p-wave superconductivity should occur, with a doublet of topologically protected gapless Andreev bound states, whose energies vary 4π-periodically with the superconducting phase difference across the junction. In this article, we report the observation of an anomalous response to rf irradiation in a Josephson junction made of a HgTe weak link. The response is understood as due to a 4π-periodic contribution to the supercurrent, and its amplitude is compatible with the expected contribution of a gapless Andreev doublet. Our work opens the way to more elaborate experiments to investigate the induced superconductivity in a three-dimensional insulator.

Mtss1 is a critical epigenetically regulated tumor suppressor in CML.

Chronic myeloid leukemia (CML) is driven by malignant stem cells that can persist despite therapy. We have identified Metastasis suppressor 1 (Mtss1/MIM) to be downregulated in hematopoietic stem and progenitor cells from leukemic transgenic SCLtTA/Bcr-Abl mice and in patients with CML at diagnosis, and Mtss1 was restored when patients achieved complete remission. Forced expression of Mtss1 decreased clonogenic capacity and motility of murine myeloid progenitor cells and reduced tumor growth. Viral transduction of Mtss1 into lineage-depleted SCLtTA/Bcr-Abl bone marrow cells decreased leukemic cell burden in recipients, and leukemogenesis was reduced upon injection of Mtss1-overexpressing murine myeloid 32D cells. Tyrosine kinase inhibitor (TKI) therapy and reversion of Bcr-Abl expression increased Mtss1 expression but failed to restore it to control levels. CML patient samples revealed higher DNA methylation of specific Mtss1 promoter CpG sites that contain binding sites for Kaiso and Rest transcription factors. In summary, we identified a novel tumor suppressor in CML stem cells that is downregulated by both Bcr-Abl kinase-dependent and -independent mechanisms. Restored Mtss1 expression markedly inhibits primitive leukemic cell biology in vivo, providing a therapeutic rationale for the Bcr-Abl-Mtss1 axis to target TKI-resistant CML stem cells in patients.

Novel approach to dynamic knee laxity measurement using capacitive strain gauges.

PURPOSE: Knee joint laxities are observed in patients after severe trauma to the joint, resulting in ligament tears. Specifically, injuries to the anterior cruciate ligament may cause a significant instability. The degree of these laxities is essential in diagnostics and may affect which treatment option is suggested. METHODS: Polydimethylsiloxane (PDMS) strain gauges are proposed as a non-invasive, highly accurate and easy-to-use measurement method to quantify anterolateral and rotational laxities of the knee joint during active and passive motion. In this work, proof-of-concept measurements and a prototype of the proposed device are displayed. The measurements were taken using a knee test rig, which has specifically been designed for this purpose. This apparatus allows the simulation of isolated knee joint instabilities with a motor-controlled model of a human knee. RESULTS: The absolute sensitivity [Formula: see text] of an exemplary sensor was determined to be 2.038 [Formula: see text]; the relative sensitivity [Formula: see text] was 1.121 [Formula: see text]. Optimal positions of sensors to capture bone-to-bone displacement as projected displacement on the skin were identified. CONCLUSION: PDMS strain gauges are capable of measuring bone-to-bone displacements on the skin. We present an experimental in vitro study using an artificial knee test rig to simulate knee joint laxities and display the feasibility of our novel measurement approach.

Length Changes of the Anterolateral Ligament During Passive Knee Motion: A Human Cadaveric Study.

BACKGROUND: Persistent rotatory instability after anterior cruciate ligament (ACL) reconstruction may be a result of unaddressed insufficiency of the anterolateral structures. Recent publications about the anatomy of the anterolateral ligament (ALL) have led to a renewed interest in lateral extra-articular procedures, and several authors have proposed ALL reconstruction to supplement intra-articular ACL reconstruction. However, only limited knowledge about the biomechanical characteristics of the ALL exists. PURPOSE/HYPOTHESIS: The purpose of this study was to analyze length changes of the ALL during passive knee motion. The study hypothesis was that the ALL lengthens with knee flexion and internal tibial rotation. STUDY DESIGN: Controlled laboratory study. METHODS: The ALL of 6 cadaveric knees was dissected. Specimens were mounted in a specifically designed test rig that allowed unconstrained passive flexion/extension movement between 0° and 90° as well as external/internal tibial rotation of 25° at various flexion angles. Highly elastic, capacitive polydimethylsiloxane strain gauges were attached to the insertion sites of the ALL. Length changes were recorded continuously at flexion angles between 0° and 90° and during internal/external tibial rotation at 0°, 15°, 30°, 45°, 60°, 75°, and 90°. All measurements were calculated as the relative length change (%) of the ALL compared with 0° of flexion and neutral rotation. RESULTS: The mean relative length of the ALL significantly increased with increasing knee flexion (P < .001), with an estimated mean length change of +0.15% per degree. Both internal and external tibial rotation were independent determinants for length change; internal rotation significantly increased the length of the ALL (P < .001), whereas external rotation significantly decreased its length (P < .001). The mean length change with internal rotation increased with knee flexion, with a significantly greater length change at 90° compared with 0° (P = .048), 15° (P = .033), and 30° (P = .015). The maximum mean length change was +33.77% ± 9.62%, which was observed at 25° of internal rotation and 90° of flexion. CONCLUSION: The ALL is a nonisometric structure that tensions with knee flexion and internal tibial rotation. Length changes with internal rotation were greater at higher flexion angles, with the greatest length change of the ALL observed at 90° of flexion. CLINICAL RELEVANCE: The ALL can be considered a stabilizer against internal tibial rotation, especially at deep flexion angles. With regard to ALL reconstruction procedures, tensioning and fixation of the graft should be performed near 90° of flexion because graft tensioning near extension may cause excessive ligament strain with increasing knee flexion.

A new approach to determine ligament strain using polydimethylsiloxane strain gauges: exemplary measurements of the anterolateral ligament.

A thorough understanding of ligament strains and behavior is necessary to create biomechanical models, comprehend trauma mechanisms, and surgically reconstruct those ligaments in a manner that restores a physiological performance. Measurement techniques and sensors are needed to conduct this data with high accuracy in an in vitro environment. In this work, we present a novel sensor device that is capable of continuously recording ligament strains with high resolution. The sensor principle of this biocompatible strain gauge may be used for in vitro measurements and can easily be applied to any ligament in the human body. The recently rediscovered anterolateral ligament (ALL) of the knee joint was chosen to display the capability of this novel sensor system. Three cadaver knees were tested to successfully demonstrate the concept of the sensor device and display first results regarding the elongation of the ALL during flexion/extension of the knee.

Epimutations mimic genomic mutations of DNMT3A in acute myeloid leukemia.

Mutations in the genetic sequence of the DNA de novo methyltransferase DNMT3A (DNA methyltransferase 3A) are found in many patients with acute myeloid leukemia (AML). They lead to dysfunction of DNMT3A protein and represent a marker for poor prognosis. Effects of genetic mutations can be mimicked by epigenetic modifications in the DNA methylation (DNAm) pattern. Using DNAm profiles of the Cancer Genome Atlas Research Network (TCGA), we identified aberrant hypermethylation at an internal promoter region of DNMT3A, which occurred in about 40% of AML patients. Bisulfite pyrosequencing assays designed for this genomic region validated hypermethylation specifically in a subset of our AML samples. High DNAm levels at this site are particularly observed in samples without genetic mutations in DNMT3A. Epimutations and mutations of DNMT3A were associated with related gene expression changes such as upregulation of the homeobox genes in HOXA and HOXB clusters. Furthermore, epimutations in DNMT3A were enriched in patients with poor or intermediate cytogenetic risk, and in patients with shorter event-free survival and overall survival (OS). Taken together, aberrant DNA hypermethylation within the DNMT3A gene, in analogy to DNMT3A mutations, is frequently observed in AML and both modifications seem to be useful for risk stratification or choice of therapeutic regimen.

NF-kappaB signalling in cerebral ischaemia.

In acute stroke, neuronal apoptosis and inflammation are considered to be important mechanisms on the road to tissue loss and neurological deficit. Both apoptosis and inflammation depend on gene transcription. We have identified a signalling pathway that regulates transcription of genes involved in apoptosis and inflammation. In a mouse model of focal cerebral ischaemia, there is an induction of the cytokine TWEAK (tumour necrosis factor-like weak inducer of apoptosis) and its membrane receptor Fn14. TWEAK promotes neuronal cell death and activates the transcription factor NF-kappaB (nuclear factor kappaB) through the upstream kinase IKK [IkappaB (inhibitory kappaB) kinase]. In vivo, IKK is activated in neurons. Neuron-specific deletion of the subunit IKK2 or inhibition of IKK activity reduced the infarct size and neuronal cell loss. A pharmacological inhibitor of IKK also showed neuroprotective properties. IKK-dependent ischaemic brain damage is likely to be mediated by NF-kappaB, because neuron-specific inhibition of NF-kappaB through transgenic expression of the NF-kappaB superrepressor was found to reduce the infarct size. In summary, there is evidence that IKK/NF-kappaB signalling contributes to ischaemic brain damage and may provide suitable drug targets for the treatment of stroke.

[Heparin Surface-Modified Poly(methylmethacrylate) and Foldable Hydrophobic Acrylic Intraocular Lenses in Cataract Patients with Acquired Immune Deficiency Syndrome and CMV-Retinitis]. / Heparinbeschichtete Polymethylmethacrylat- und faltbare hydrophobe Acrylatintraokularlinsen bei Kataraktpatienten mit erworbenem Immundefektsyndrom und CMV-Retinitis.

BACKGROUND: In HIV-positive patients with necrotising retinitis, well-tolerated lens material as well as minimal invasive surgery to avoid postoperative complications are imperative. Heparin surface-modified PMMA-IOLs as well as acrylic IOLs are associated with less postoperative inflammation than conventional intraocular lenses. METHODS: In this randomised prospective clinical trial 18 patients received 7 HSM-IOLs through a self-sealing scleral tunnel and 11 foldable Acrysof-IOLs through a self-sealing limbal tunnel incision by the same surgeon. 7 of the 18 eyes were silicone oil-filled before cataract surgery, one eye received oil after the IOL implantation. Visual acuity, intraocular pressure, contrast sensitivity, intraocular inflammation and posterior capsule opacification were assessed. The follow-up period was 1 year. RESULTS: Eyes with Acrysof-IOLs were associated with lower, but not statistically significant, laser flare photometry values (photon counts/ms) than those with HSM-IOLs pre- (90.18 +/- 54.7 vs. 73.92 +/- 6.44) and 3 months post-surgery (69.06 +/- 8.27 vs. 55.03 +/- 7.75). 6 of the 7 eyes with HSM-IOL and 3 eyes of the Acrysof-group developed a dense posterior capsule opacification (PCO), 2 eyes had no and 6 eyes only a distinct PCO. YAG capsulotomy did not improve visual acuity in any case but retinal examination was again possible. Eyes with Acryl-IOL showed pre- and postoperatively a better visual acuity than eyes with HSM-IOL ("hand movement" - 0.4 vs. "no light perception" - 0.1 pre- and 0.05 - 0.6 vs. "no light perception" - 0.1 3 months postoperatively. Contrast sensitivity testing (Vistech method) could be performed in the PMMA-group preoperatively only in 1 eye (A1), in the Acryl-group in 2 eyes (A4, B4, C2, D2) and revealed postoperatively "no contrast vision" - A1, B2, C1 vs. "no contrast vision" - A2, B2, C3, D1, E1. The intraocular pressure was preoperatively 13.86 mm Hg (PMMA) vs. 14.82 mm Hg (Acrysof) and 14.4 mm Hg vs. 12.89 mm Hg 3 months post surgery. CONCLUSION: In the parameters we observed there was no statistical significant difference between heparin-surface modified (Pharmacia 811 C) and hydrophobic acrylic IOLs (Alcon Acrysof MA60BM) in patients with AIDS. As foldable Acrysof-IOLs can be implanted through a self-sealing bloodless tunnel incision and are associated with less posterior capsule opacification we prefer this IOL type in cataract surgery of AIDS patients.

[Electrolyte levels in feces and urine in healthy breeding calves between the ages of 5 days to 6 months]. / Elektrolytkonzentrationen in Kot und Harn von gesunden Aufzuchtkälbern im Alter von fünf Tagen bis sechs Monaten.

In contrast to the situation in adult cattle there are high concentrations of sodium and low concentrations of potassium in the faeces of suckling calves. It was investigated in this study in which stage of the development of the ruminant these changes in electrolyte levels occur, and whether there are changes in electrolyte levels in urine as well. Samples of faeces and urine from healthy calves were examined fortnightly starting with the 5th day after birth. There was a distinct decrease in sodium concentration in faecal water within the first three weeks of life, i.e. without any relation to the intake of solid feed. However, the levels of sodium, potassium and chloride in urine samples and of potassium in faecal water increased with the development of rumination. The concentration of chloride in faeces was on a low level during the whole period of investigation.

Neoadjuvant radio-chemotherapy in advanced primarilynon-resectable carcinomas of the pancreas.

AIM: To investigate the feasibility of neoadjuvant radio-chemotherapy (RCT) in the treatment of primarily non-resectable pancreas carcinoma the parameters tumour regression, possibility of subsequent resection and tolerability were examined. METHOD: Between 1995 and 1997, 27 patients with locally inoperable (assessed by CT criteria) pancreatic carcinoma received radio-chemotherapy for 5 weeks comprising irradiation (55.8 Gy) and chemotherapy with 5-fluorouracil (5-FU, 1000 mg/m(2)/day; 120 h continuous infusion) and mitomycin C (10 mg/m(2)i.v.-bolus, day 2 and day 30) during the first and fifth week of radiotherapy. Two target volumes were irradiated with fractionated doses of 1.8 Gy up to a total of 50.4 Gy. Radiation was applied once a day five times a week and target volume 1 was irradiated with the same fractionated dose, and an additional boost of 5.4 Gy to make an overall total of 55.8 Gy. RESULTS: Sixteen patients underwent explorative laparotomy, 10 of these were resected (eight Whipple's procedures, two distal pancreatic resections), while six could not be resected due to peritoneal carcinosis (n=3), local irresectability (n=2) and liver cirrhosis (n=1). A further nine patients were found to have unresectable tumours on CT and did not undergo surgery after restaging (five of these patients were staged as <>, three patients had distant metastases and one patient refused surgery). In two patients RCT was abandoned because of progression of disease. CONCLUSIONS: The study protocol described is feasible without significant acute toxicity and when used the resectability rate was improved; the survival rate, however, was not improved. Additional intra-arterial or intraportal application of such drugs as mitomycin C or cisplatin may be necessary.

Preoperative Chemoradiation in Locally Advanced Pancreatic Carcinoma: A Phase II Study.

BACKGROUND: Effectiveness and feasibility of preoperative chemoradiation (CRT) in locally advanced adenocarcinoma of the pancreas are evaluated. MATERIAL AND METHODS: 29 eligible of 37 registered patients were treated. 3d-Conformal external radiotherapy was delivered with a 1.8-Gy single dose and a total dose of 50.4 Gy plus 5.4 Gy boost. Simultaneous chemotherapy consisted of 5-fluorouracil and mitomycin C. RESULTS: Among 27 completely treated patients, 16 (59%) underwent surgery, 6 of them being irresectable intraoperatively. Ten patients (37%) had clear resection margins at Whipple's procedure. Eleven patients were not considered for surgery (7 still irresectable at restaging, 3 distant metastases, 1 refusal of surgery). Toxicity was predominantly hematological (grade 3: 30%, grade 4: 7%); furthermore, there was nausea/vomiting (grade 3: 20%, grade 4: 0%). No patient died perioperatively. The tumor-related overall survival rate was better for resected patients than for nonresected patients (50% vs. 6%, 2-year survival, p = 0.07), median overall survival was 9 months (median follow-up, 28 months). CONCLUSIONS: Neoadjuvant CRT without significant acute toxicity produced a resectability rate of 37% (all R0), which should be confirmed by randomized phase III studies. Copyright 2000 S. Karger GmbH, Freiburg

ECG baseline wander reduction using linear phase filters.

The continuous real time reduction of baseline wander is a considerable problem in electrocardiography during exercises. Our solution consists of spectral filtering. The legitimacy of high-pass filtering of the ECG by means of digital linear phase filters with a low cut-off frequency as high as the heart rate is shown. The specifications of these filters are derived from experimental results. Special hardware is presented that simultaneously performs the desired real-time filter operation in four ECG leads.

Aggregation of meso-tetra-(p-sulphonatophenyl)porphine and its cu(II) and zn(II) complexes in aqueous solution.

The aggregation of meso-tetra(p-sulphonatophenyl)porphine, an analytical reagent for the determination of metals at low concentration, has been studied over a wide concentration range by both spectrophotometric and (1)H NMR methods. Up to a concentration of about 3 x 10(-4)M, the experimental data were satisfactorily accounted for by a monomer-dimer equilibrium. At higher concentrations, the best fit of the chemical shift data required postulation of a tetramer. Analysis of the experimental data for the Zn(II) complex indicated the occurrence of dimerization at higher concentrations.

Multielement preconcentration of trace metals with meso-tetra(p-sulphonatophenyl) porphine.

meso-tetra(p-sulphonatophenyl)porphine reacts with several metal ions in ammoniacal aqueous solution. The resulting complexes are extractable into methyl isobutyl ketone with tricaprylmethylammonium chloride. The distribution ratios for the metal ions range from 8 for Mn(II) to about 1400 for Cd(II), corresponding, respectively, to single-stage extractions of 33-99% with a phase-volume ratio V (w)V (o) = 18. A procedure has been developed for the multielement preconcentration of several trace metals (Mn, Co, Ni, Cu, Cd, Pb) from sea-water and their subsequent determination by graphite-furnace AAS.