Integrable Atomtronic Interferometry.

High sensitivity quantum interferometry requires more than just access to entangled states. It is achieved through the deep understanding of quantum correlations in a system. Integrable models offer the framework to develop this understanding. We communicate the design of interferometric protocols for an integrable model that describes the interaction of bosons in a four-site configuration. Analytic formulas for the quantum dynamics of certain observables are computed. These expose the system's functionality as both an interferometric identifier, and producer, of NOON states. Being equivalent to a controlled-phase gate acting on 2 hybrid qudits, this system also highlights an equivalence between Heisenberg-limited interferometry and quantum information. These results are expected to open new avenues for integrability-enhanced atomtronic technologies.

[Severe caffeine poisoning with rhabdomyolysis]. / Schwere Koffeinintoxikation mit Rhabdomyolyse.

We report the case of a young man who took a large amount of caffeine powder dissolved in water in a suicide attempt. He was found comatose. The initial diagnosis was difficult. In hospital he suffered from rhabdomyolysis with renal failure and sepsis rapidly developed. After renal replacement treatment with hemodialysis, long-term artificial ventilation with tracheotomy and a 3­week stay in the intensive care unit, the patient could be discharged to a rehabilitation center.

Progression-free survival as surrogate end point for overall survival in clinical trials of HER2-targeted agents in HER2-positive metastatic breast cancer.

BACKGROUND: The gold standard end point in randomized clinical trials in metastatic breast cancer (MBC) is overall survival (OS). Although therapeutics have been approved based on progression-free survival (PFS), its use as a primary end point is controversial. We aimed to assess to what extent PFS may be used as a surrogate for OS in randomized trials of anti-HER2 agents in HER2+ MBC. METHODS: Eligible trials accrued HER2+ MBC patients in 1992-2008. A correlation approach was used: at the individual level, to estimate the association between investigator-assessed PFS and OS using a bivariate model and at the trial level, to estimate the association between treatment effects on PFS and OS. Correlation values close to 1.0 would indicate strong surrogacy. RESULTS: We identified 2545 eligible patients in 13 randomized trials testing trastuzumab or lapatinib. We collected individual patient data from 1963 patients and retained 1839 patients from 9 trials for analysis (7 first-line trials). During follow-up, 1072 deaths and 1462 progression or deaths occurred. The median survival time was 22 months [95% confidence interval (CI) 21-23 months] and the median PFS was 5.7 months (95% CI 5.5-6.1 months). At the individual level, the Spearman correlation was equal to ρ = 0.67 (95% CI 0.66-0.67) corresponding to a squared correlation value of 0.45. At the trial level, the squared correlation between treatment effects (log hazard ratios) on PFS and OS was provided by R(2) = 0.51 (95% CI 0.22-0.81). CONCLUSIONS: In trials of HER2-targeted agents in HER2+ MBC, PFS moderately correlates with OS at the individual level and treatment effects on PFS correlate moderately with those on overall mortality, providing only modest support for considering PFS as a surrogate. PFS does not completely substitute for OS in this setting.

VEGF-A acts via neuropilin-1 to enhance epidermal cancer stem cell survival and formation of aggressive and highly vascularized tumors.

We identify a limited subpopulation of epidermal cancer stem cells (ECS cells), in squamous cell carcinoma, that form rapidly growing, invasive and highly vascularized tumors, as compared with non-stem cancer cells. These ECS cells grow as non-attached spheroids, and display enhanced migration and invasion. We show that ECS cell-produced vascular endothelial growth factor (VEGF)-A is required for the maintenance of this phenotype, as knockdown of VEGF-A gene expression or treatment with VEGF-A-inactivating antibody reduces these responses. In addition, treatment with bevacizumab reduces tumor vascularity and growth. Surprisingly, the classical mechanism of VEGF-A action via interaction with VEGF receptors does not mediate these events, as these cells lack VEGFR1 and VEGFR2. Instead, VEGF-A acts via the neuropilin-1 (NRP-1) co-receptor. Knockdown of NRP-1 inhibits ECS cell spheroid formation, invasion and migration, and attenuates tumor formation. These studies suggest that VEGF-A acts via interaction with NRP-1 to trigger intracellular events leading to ECS cell survival and formation of aggressive, invasive and highly vascularized tumors.

Reconstruction of the ossicular chain with titanium implants.

OBJECTIVES: Since 1994 more than 1300 titanium implants have been used to reconstruct the ossicular chain of the middle ear for chronic otitis media. Two different types of implants were used. First, a total and a partial implant of fixed length, available in numerous different lengths. And second, a total and partial implant that has an adjustable length. The implants are commercially available from 2 different companies. Patients were followed for a postoperative term from 6 to 72 months. METHODS: A wide variety of patients aged 5 to 82 years received a tympanoplasty type III. Those patients whose ossicular chain had been reconstructed with titanium implants since 1994 were evaluated. As implants from one company are fixed in length; implants of a second company are trimmable in length. All prostheses are lightweight and made of pure titanium, fitting most anatomical situations. RESULTS: Earlier results already showed a very low complication rate. Extrusions occurred only in cases of middle ear atalectasis with resorption of interposed cartilage (<1%). No adverse reaction to the prostheses could be seen, even in histologic reviews. An average air-bone gap less than 20 dB(A) for all calculated frequencies of 0.5, 1, 2, and 4 kHz was achieved for 76% of cases; 43% of cases showed a calculated air-bone gap of less than 10 dB(A), only 10% higher than 30 dB(A). CONCLUSION: All implants used offer the proven benefits of titanium, namely high biocompatibility and high stability at a very low complication rate with excellent hearing results for the patients. Titanium implants can highly be recommended to reconstruct the ossicular chain of the middle ear.

[Replacement of ear ossicles with titanium prostheses]. / Gehörknöchelchenersatz mit Titan-Prothesen.

BACKGROUND: Titanium has been a well established implant material for many years. New material processing techniques now permit the manufacture of small implants for ossicular chain reconstruction. METHODS: Between November 1994 and September 1995, 100 titanium middle ear implants (55 PORP, 45 TORP) were used for reconstruction of the ossicular chain. A range of five different sizes for partial and total protheses suits all implantation needs. The shape of the implants can be altered by bending. Time consuming intraoperative shaping and trimming is avoided. RESULTS: At a follow-up time of three months (33 patients) and six months (17 patients), no adverse reactions or extrusions occurred. Biologic fixation between the foot of the partial prothesis and the head of the stapes was found eight months after implantation. A hearing result of 0-20 dB residual air-bone gap was achieved in 79%. CONCLUSION: Titanium middle ear implants show good bio-compatibility and are readily integrated into the ossicular chain. Although delicate in shape, they offer excellent mechanical properties in respect to sound conduction and implantation. Initial results show Titanium to be a perfect implant material for middle ear prostheses, although long-term results are not yet available.

[Simultaneous cisplatin and radiotherapy of locally advanced squamous cell carcinomas of the head and neck region. A clinical pilot study]. / Simultane Cisplatin- und Bestrahlungstherapie lokal fortgeschrittener Plattenepithelkarzinome der Kopf-Hals-Region. Eine klinische Pilotstudie.

Cisplatin (20 mg/m2 on five successive days, together with hydration and osmotic diuresis) was administered in two treatment cycles to 32 patients with locally advanced tumours (T2-4, N1-3, M0) of the head and neck region. Cisplatin-free interval was at least four weeks. At the same time there was radiotherapy with photons or electrons, daily fractions of 2 Gy four to five times weekly to a final volume dose of 60-70 Gy. Tumour resection was undertaken if there was no tumour involution of at least 50% after 40 Gy and one cisplatin cycle. Total remission rate (complete and partial) was 91%. Complete remission occurred in 22 patients (69%). Biopsies in 14 patients after 40 Gy and one cisplatin cycle indicated that in seven there was no histological evidence of tumour. There was no clinically serious rise in local toxicity. However, erythema and oedema in the radiation fields were more frequent and earlier than with radiotherapy alone. The results indicate that combined cisplatin administration and radiotherapy give the same or even better results than aggressive chemotherapy followed by radiotherapy.

[Three years of experience with titanium implants in the middle ear]. / Titan-Prothesen im Mittelohr. 3-Jahres-Erfahrungsbericht.

BACKGROUND: In continuation of our previously published report on initial experience with titanium implants in the middle ear [13], we now present the results of routine use over a three year period. METHODS: From November 1994 to November 1997, 661 titanium implants (Düsseldorf model) were implanted in the authors' clinics (355 PORP, 306 TORP). There was no preselection of patients. Five hundred eighty-two follow up examinations were performed with a medium follow up time of 11.6 months. RESULTS: The good initial results of the previous study with respect to biocompatibility and functional hearing results were confirmed in the long term follow-up. The average air-bone gap was calculated over the frequencies 0.5, 1, 2, and 4 kHz. Closure to within 20 dB was achieved in 72% of cases. The air-bone gap tended to decrease with increasing time of implantation. Adverse reaction to the prostheses did not occur. Extrusion occurred in one case of complete middle ear atelectasis with resorption of the interposed cartilage. Insufficient improvement of hearing was attributable to a short implant in 12 cases (1.8%). In three cases (0.5%) insufficient stability of the PORP was attributable to eroded stapes suprastructure, and in three others (0.5%) a dislocation was responsible for a poor hearing result. Middle ear fibrosis with impairment of sound transmission was seen in 3 patients (0.5%). CONCLUSION: The superior acoustic properties of the delicate yet rigid low-weight titanium implants combined with excellent biocompatibility lead to a good hearing result if a meticulous surgical technique is employed. The easy handling makes it a pleasure to work with these protheses.

Nitric oxide inhibits endothelial IL-1[beta]-induced ICAM-1 gene expression at the transcriptional level decreasing Sp1 and AP-1 activity.

BACKGROUND: Nitric oxide (NO) has frequently been shown to inhibit leukocyte adherence to activated endothelium thus displaying anti-adhesive and immunosuppressive activities. A molecular mechanism contributing to this effect is described. MATERIALS AND METHODS: Primary murine aortic endothelial cells were activated with interleukin (IL)-1beta to express intercellular adhesion molecule-1 (ICAM-1) mRNA in the presence or absence of the physiological spontaneous NO-donor S-nitrosocysteine. Subsequently, semiquantitative RT-PCR and gel shift assays with nuclear extracts were performed to analyse the effects of NO on ICAM-1 mRNA expression and on the activity of transcription factors involved in ICAM-1 transcription. In addition, luciferase reporter gene activity of cytokine-activated cells transiently transfected with an ICAM-1 promoter-luciferase construct and cultured in the presence of the slow-releasing NO-donor DETA/NO was determined. RESULTS: NO at subtoxic concentrations decreases IL-1beta-induced endothelial ICAM-1 mRNA expression. This inhibition occurs at the transcriptional level, as NO affects IL-1b-induced ICAM-1 promoter activity in transiently transfected cells. Using gel-shift assays and double-stranded oligonucleotide consensus sequences of the known transcription factor binding sites of the ICAM-1 promoter, Sp1 and AP-1 were identified as transcriptional activators of IL-1beta-driven ICAM-1 expression. The DNA binding of both of these transcription factors to specific binding sites of the ICAM-1 promoter was decreased in MAEC exposed to NO. CONCLUSIONS: Our studies indicate that the anti-adhesive effect of NO concentrations equivalent to high-output NO synthesis is mediated, at least in part, by inhibition of ICAM-1 expression via a concerted action of NO on the redox-sensitive transcriptional activators Sp1 and AP-1. This molecular mechanism may contribute to the anti-inflammatory actions of NO synthesized by the inducible NO synthase.