Repetitive transcranial magnetic stimulation: a putative add-on treatment for major depression in elderly patients.

Repetitive transcranial magnetic stimulation (rTMS) is a recent putative treatment for affective disorders. Several studies have demonstrated antidepressant effects of rTMS in younger patients; we aimed to assess its effect in older outpatients with treatment-resistant major depression. Twenty-four outpatients (mean age=62 years, S.D.=12) with major depression were randomized for sham or real stimulation and received 10 daily rTMS sessions (20 Hz, 2-s trains, 28-s intertrain intervals, 100% of motor threshold) in addition to the antidepressant medication. For sham stimulation, the coil was tilted 90 degrees. Depression severity was assessed using the Hamilton Depression Rating Scale, the Beck Depression Inventory, items from the NIMH self-rated symptom scale, and a visual analog depression scale. Mini-Mental Status Examination performance, memory, and executive and attentional functions were measured to control for cognitive side effects. Depression ratings revealed significant antidepressant effects within 2 weeks in both sham and real stimulation groups; however, there were no between-group differences. Treatment with rTMS was safe; adverse events were rare and not more prevalent in either group, and cognitive assessment did not show any deterioration. We were unable to demonstrate any additional antidepressant effects of real stimulation in elderly patients with treatment-resistant major depression. Therapeutic effects of rTMS in this clinically challenging patient group remain to be demonstrated.

Mood effects of repetitive transcranial magnetic stimulation of left prefrontal cortex in healthy volunteers.

This study investigated the effect of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) of the left prefrontal cortex (LPFC) on mood in a sham-controlled crossover design. Twenty-five healthy male subjects received HF-rTMS of the LPFC in real and sham conditions. Forty trains (frequency 20 Hz, stimulation intensity 100% of individual motor threshold, train duration 2 s, intertrain interval 28 s) were applied in each session. Mood change from baseline was measured with five visual analog scales (VAS) for sadness, anxiety, happiness, tiredness and pain/discomfort. We were unable to demonstrate significant mood changes from baseline on visual analog scales after either sham or real stimulation of LPFC. There is insufficient evidence to support the general conclusion that HF-rTMS of LPFC has mood effects in healthy volunteers. Future studies should be sham-controlled, have larger sample sizes, and strictly stimulate one single region per session in order to exclude interaction effects with the previous stimulation.

Differences in Time to Disease Progression Do Not Predict for Cancer-specific Survival in Patients Receiving Immediate or Deferred Androgen-deprivation Therapy for Prostate Cancer: Final Results of EORTC Randomized Trial 30891 with 12 Years of Follow-up

BACKGROUND Trials assessing the benefit of immediate androgen-deprivation therapy (ADT) for treating prostate cancer (PCa) have often done so based on differences in detectable prostate-specific antigen (PSA) relapse or metastatic disease rates at a specific time after randomization. OBJECTIVE Based on the long-term results of European Organization for Research and Treatment of Cancer (EORTC) trial 30891, we questioned if differences in time to progression predict for survival differences. DESIGN, SETTING, AND PARTICIPANTS EORTC trial 30891 compared immediate ADT (n=492) with orchiectomy or luteinizing hormone-releasing hormone analog with deferred ADT (n=493) initiated upon symptomatic disease progression or life-threatening complications in randomly assigned T0-4 N0-2 M0 PCa patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Time to first objective progression (documented metastases, ureteric obstruction, not PSA rise) and time to objective castration-resistant progressive disease were compared as well as PCa mortality and overall survival. RESULTS AND LIMITATIONS After a median of 12.8 yr, 769 of the 985 patients had died (78%), 269 of PCa (27%). For patients receiving deferred ADT, the overall treatment time was 31% of that for patients on immediate ADT. Deferred ADT was significantly worse than immediate ADT for time to first objective disease progression (p<0.0001; 10-yr progression rates 42% vs 30%). However, time to objective castration-resistant disease after deferred ADT did not differ significantly (p=0.42) from that after immediate ADT. In addition, PCa mortality did not differ significantly, except in patients with aggressive PCa resulting in death within 3-5 yr after diagnosis. Deferred ADT was inferior to immediate ADT in terms of overall survival (hazard ratio: 1.21; 95% confidence interval, 1.05-1.39; p [noninferiority]=0.72, p [difference] = 0.0085). CONCLUSIONS This study shows that if hormonal manipulation is used at different times during the disease course, differences in time to first disease progression cannot predict differences in disease-specific survival. A deferred ADT policy may substantially reduce the time on treatment, but it is not suitable for patients with rapidly progressing disease.

Update as Evidence: Belief Expansion

We introduce a justification logic with a novel constructor for evidence terms, according to which the new information itself serves as evidence for believing it. We provide a sound and complete axiomatization for belief expansion and minimal change and explain how the minimality can be graded according to the strength of reasoning. We also provide an evidential analog of the Ramsey axiom.

Small aliquot and single grain IRSL and post-IR IRSL dating of fluvial and alluvial sediments from the Pativilca valley, Peru

Infrared stimulated luminescence (IRSL) and post-IR IRSL are applied to small aliquots and single grains to determine the equivalent dose (De) of eleven alluvial and fluvial sediment samples collected in the Pativilca valley, Central Peru at ca. 10°S latitude. Small aliquot De distributions are rather symmetric and display over-dispersion values between 15 and 46%. Small aliquot g-values range between 4 and 8% per decade for the IRSL and 1 and 2% per decade for the post-IR IRSL signal. The single grain De distributions are highly over-dispersed with some of them skewed to higher doses, implying partial bleaching; this is especially true for the post-IR IRSL. Measurements of a modern analog reveal that residuals due to partial bleaching are present in both the IRSL as well as the post-IR IRSL signal. The g-values of individual grains exhibit a wide range with high individual uncertainties and might contribute significantly to the spread of the single grain De values, at least for the IRSL data. Electron Microprobe Analysis performed on single grains reveal that a varying K-content can be excluded as the origin of over-dispersion. Final ages for the different approaches are calculated using the Central Age Model and the Minimum Age Model (MAM). The samples are grouped into well-beached, potentially well-bleached and partially bleached according to the evaluation of the single grain distributions and the agreement of age estimates between methods. The application of the MAM to the single grain data resulted in consistent age estimates for both the fading corrected IRSL and the post-IR IRSL ages, and suggests that both approaches are suitable for dating these samples. Keywords

Islam als Problem der Gesellschaft

Die Blicke, die die Wissenschaft auf Islam und Muslime in der Schweiz wirft, sind in den meisten Fällen entweder auf Subjekte gerichtet, oder sie behandeln die soziale und kommunikative Konstruktion jener Phänomene nur mit Blick auf einzelne Teilsysteme der Gesellschaft wie Politik und Massenmedien (respektive öffentliche Diskurse) ohne gesellschaftstheoretische und funktionalistische Rückbindung. Die vorliegende Arbeit positioniert sich in dieser Beobachtungslücke und nimmt die vielfältigen Beobachter der Gesellschaft von Islam und Muslimen in der Schweiz in den Blick. Fragt man danach, welche Strukturen sich wie irritieren lassen, treten die Phänomene Islam und Muslime in den Hintergrund, und auf dem analytischen Schirm erscheint die Gesellschaft selbst. In der Folge werden die umfangreichen Kommunikationsleistungen sichtbar, die eine Irritation in verschiedenen Teilsystemen – nicht nur in der Politik oder den Massenmedien, sondern genauso im Recht, der Religion, der Kunst oder der Wirtschaft – auslöst. Sei es, dass Eltern ihre Kinder aus religiösen Gründen nicht am gemischtgeschlechtlich erteilten Schwimmunterricht an öffentlichen Primarschulen in Basel teilnehmen lassen wollen, oder dass ein muslimischer Verein im Zuge des Um- und Ausbaus ihres Vereinslokals in Langenthal ein Minarett auf dem Dach desselben errichten will: diese und andere Gesuche, (teil-)öffentlich soziale Vielfalt in der Form religiöser Differenz auszudrücken, regen eine Fülle von Beobachtungs- und Kommunikationsleistungen an. Den Hauptteil der vorliegenden Studie bildet denn auch die Analyse der vielfältigen Reaktionen in zwei Konfliktfällen zur Nichtteilnahme am gemischtgeschlechtlich erteilten Schwimmunterricht in Primarschulen Basel-Stadts und dem Baugesuch für ein Minarett und eine Kuppel als Teil des Ausbaus eines Vereinslokals in Langenthal. Die beiden Fälle wurden deshalb ausgewählt, weil ihre anfängliche Irritation quer durch die gesellschaftlichen Teilsysteme hindurch und über mehrere Jahre hinweg Antwortversuche auslöste und die empirische Analyse deshalb über mehr und aussagekräftigeres Material verfügen konnte, als es in anderen, ansonsten für eine Analyse prinzipiell auch denkbaren, Konfliktfällen, beispielsweise zur Einrichtung eines muslimischen Grabfeldes auf einem Friedhof oder dem Tragen eines Kopftuchs an der Schule, bei der Arbeit oder beim Sport, möglich gewesen wäre. Die Beobachtung des Umgangs mit diesen beiden Instanzen sozialer Vielfalt (aber auch in inhaltlich anders gelagerten Fällen der Differenzbearbeitung) macht sichtbar, dass und wie Erwartungen verunsichert und Lösungen für die Aufhebung dieser Unsicherheiten gefunden und ausprobiert werden. Die zentrale Einsicht der Studie lautet, dass selbstreproduzierende und selbstorganisierende Systeme, wie es Recht, Politik, Massenmedien, Kunst und Religion unter den Bedingungen einer funktional differenzierten, modernen Gesellschaft sind, aufgrund ihrer spezifischen Funktionsweise in der Gesellschaft ihre eigenen Zugänge zu religiöser Vielfalt entwickeln, die sich nur schwer miteinander vereinbaren lassen. In anderen Worten interessiert sich das Rechtssystem für die rechtlichen Folgen des Auftauchens islamischer Normativitäten, die Politik für daraus resultierende Machtansprüche, oder die Massenmedien für das aus der Vielfalt resultierende Konfliktpotenzial. Um gleichzeitig diese Einsicht in kürzeste Form zu bringen und die Wahl des Titels der vorliegenden Studie zu erläutern, sind Islam und Muslime kommunikativ konstruierte Artefakte. Sie werden jeweils dazu, was die Gesellschaft – respektive die sozialen Systeme, aus denen diese besteht – aus ihnen vermittels ihrer eigenen Beobachtungsleistungen macht. Dies schliesst natürlich die im vorliegenden Text kommunizierten Beschreibungen mit ein, da auch sie nichts anderes als einen Vollzug von Gesellschaft darstellen. Die Analyse von Konfliktfällen zu muslimisch-religiöser Diversität in den folgenden Kapiteln will dementsprechend keine Aussagen über Islam, Muslime und ihre Hintergründe und Motivlagen, die zu Konflikten führen könnten, treffen. Jenseits dieser subjektorientierten Beschreibungen genügt es dem Anspruch der vorliegenden Arbeit jedoch auch nicht, nur das Kursieren von Differenzsemantiken oder Diskursen über Islam und Muslime festzustellen – obwohl dies einen Teil der Analyse bildet. Diese gesellschaftlichen Problematisierungen von und die mannigfaltigen „Umgangsformen“ gegenüber Islam und Muslimen, oder allgemeiner: gegenüber Fremdheit, Differenz, Vielfalt – sollen zudem auf ihre funktionalen und gesellschaftsstrukturellen Ermöglichungsbedingungen und Grenzen hin untersucht werden. Wenn die vorliegende Studie Konfliktfälle analysiert, die als muslimisch bezeichnete Personen in die Kommunikation miteinbeziehen, liegt ihr Forschungsinteresse also auf einer Beobachtungsebene zweiter Ordnung und in den Formen des kommunikativen Umgangs mit Kontingenz und Vielfalt in der Form von „Islam“ und „Muslimen“ – und dafür, wo die Grenzen dieses Umgangs liegen. Dementsprechend sind die beiden fallanalytischen Kapitel (4 und 5) nach systemspezifischen Problemlösungen des Rechts, der Politik, der Massenmedien, der Kunst und der Religion strukturiert. Der Einsatz eines systemtheoretischen Analyserahmens, wie in Kapitel 2 dargestellt, in Kombination mit einer adaptierten Methode (in Kapitel 3 diskutiert) ermöglicht es dabei,spezifische, system- oder beobachterspezifische Unterscheidungsleistungen zu erkennen, die den jeweiligen Problemlösungsstrategien zu Grunde liegen. Die Bezeichnung „systemtheoretisch“ deutet dabei bereits an, dass sich der Analysefokus von individuellen Akteuren mit Motiven und Handlungen weg und in Richtung überindividueller, also sozialer, Kommunikationsstrukturen verschiebt. Die erkenntnistheoretischen Grundlagen der alltäglichen und wissenschaftlichen Beschäftigung mit dem, was gemeinhin „Realität“ genannt wird, werden gleich in Kapitel 2 diskutiert, um die Basis für die darauffolgenden konstruktivistischen, kommunikations-, system- und differenztheoretischen sowie funktionalistischen Überlegungen der hier verwendeten Methodologie zu schaffen (Kapitel 3). Der empirischen Erforschung der kommunikativen Mechanismen des Umgangs mit (sozialer Vielfalt, hier: Islamität zugeschriebener) Kontingenz widmet sich die vorliegende Arbeit daraufhin anhand der beiden obengenannten Fallstudien des Schwimmunterrichts in Basel-Stadt (Kapitel 4) und des Minarettbaugesuchs in Langenthal (Kapitel 5). Eine Analyse der kommunikativen Unterscheidungsleistungen, die Objekte durch sprachlichen Ein- und Ausschluss (und blinde Flecken) konstruiert, fördert die Schlüsselstellung von System- und Gesellschaftsstrukturen, tradierten Gesellschaftsbildern, Integrationsvorstellungen und dem ungebrochenen Vertrauen in die Möglichkeit gesellschaftlicher Steuerung für die Grenzen des Umgangs mit sozialer Vielfalt zu Tage. In der Fallstudie zum Schwimmunterricht in Basel (Kapitel 4) treten einander die Beobachtungsperspektiven des Rechts, der Politik, der Erziehung und der Massenmedien gegenüber, und ihre verschiedenen Funktionslogiken werden sichtbar. Angesichts dieses Befunds gesellschaftlicher Ausdifferenzierung zeichnet sich die Schwierigkeit ab, noch vom Nichtbesuch des Schwimmunterrichts aus religiösen Gründen als einem Problem zu sprechen. Im Gegenteil: in der funktional differenzierten, modernen Gesellschaft stellt der Widerspruch, das „Nein“ der Absage an den Besuch des gemischtgeschlechtlich erteilten Schwimmunterrichts, ein Mehrfachproblem dar. Er wird von mehreren Systemen gleichzeitig, aber aufgrund ihrer Funktion und Strukturen unterschiedlich beobachtet. Darüber hinaus lassen sich auch innerhalb politischer Kommunikation von Seiten der Integrations-, Erziehungs- und Ausländerpolitik drei unterschiedliche „Lösungsansätze“ feststellen. Das Kapitel beschreibt diese funktionale Differenzierung für das Rechtssystem, die Politik und die Massenmedien anhand empirischer Daten wie Gerichtsurteilen, Verwaltungsakten und -publikationen, politischen Vorstössen, massenmedialen Produkten und Interviews. Der Aufbau des Kapitels orientiert sich an jenen systemischen Zugängen. Der Befund der funktionalen Differenzierung wird in einem zweiten Schritt den Selbstbeschreibungen der Systeme gegenüber gestellt, um in den jeweiligen Erwartungsstrukturen die semantischen Grenzen des Umgangs mit Fremdheit respektive Vielfalt aufzudecken und den Weg für Alternativen zu ebnen. Die Fallanalyse zum Minarettbaugesuch in Langenthal (Kapitel 5) ermöglicht eine Überprüfung der Ergebnisse aus der Analyse zum Schwimmunterricht. Im Fall Langenthal bestätigt sich der Befund der systemisch differenzierten Zugänge zum Konfliktfall, wobei zusätzlich zum Recht, der Politik und den Massenmedien in diesem Fall auch die Systeme Religion und Kunst kommunikativ beteiligt sind. Auch dieses Kapitel ist analog zur Fallanalyse dees Schwimmunterrichts entlang der systemischen Zugänge aufgebaut. Durch die Vergleichsmöglichkeiten mit dem Fall Basel können im Fall Langenthal empirische Befunde zu den Formen und Grenzen gesellschaftlicher Selbstbeschreibungen und dem Umgang mit sozialer Vielfalt noch vertieft werden, und um die religiöse und künstlerische Dimension erweitert werden. Das Schlusskapitel (Kapitel 6) rollt die Befunde zur zentralen Bedeutung von Gesellschaftsstruktur und -bildern, Integrations- und Steuerungskonzepten für den Umgang mit islamischer und anderen Formen sozialer Vielfalt – und seine Beschränkungen – noch einmal auf. In der Folge setzt es sich auf der Grundlage der bisher erarbeiteten Erkenntnisse mit einem alternativen Ansatz des Umgangs mit Differenz, der Selbstreflektion, auseinander. Und schliesslich werden die Implikationen dieser Art von Analysen für die Islamwissenschaft sowie wissenschaftliche Anschlussmöglichkeiten diskutiert.

Ultracold Quantum Gases and Lattice Systems: Quantum Simulation of Lattice Gauge Theories

Abelian and non-Abelian gauge theories are of central importance in many areas of physics. In condensed matter physics, AbelianU(1) lattice gauge theories arise in the description of certain quantum spin liquids. In quantum information theory, Kitaev’s toric code is a Z(2) lattice gauge theory. In particle physics, Quantum Chromodynamics (QCD), the non-Abelian SU(3) gauge theory of the strong interactions between quarks and gluons, is nonperturbatively regularized on a lattice. Quantum link models extend the concept of lattice gauge theories beyond the Wilson formulation, and are well suited for both digital and analog quantum simulation using ultracold atomic gases in optical lattices. Since quantum simulators do not suffer from the notorious sign problem, they open the door to studies of the real-time evolution of strongly coupled quantum systems, which are impossible with classical simulation methods. A plethora of interesting lattice gauge theories suggests itself for quantum simulation, which should allow us to address very challenging problems, ranging from confinement and deconfinement, or chiral symmetry breaking and its restoration at finite baryon density, to color superconductivity and the real-time evolution of heavy-ion collisions, first in simpler model gauge theories and ultimately in QCD.

Future prospects for SPECT imaging using the radiolanthanide terbium-155 — production and preclinical evaluation in tumor-bearing mice

We assessed the suitability of the radiolanthanide 155 Tb (t1/2 = 5.32 days, Eγ = 87 keV (32%), 105 keV (25%)) in combination with variable tumor targeted biomolecules using preclinical SPECT imaging. Methods 155Tb was produced at ISOLDE (CERN, Geneva, Switzerland) by high-energy (~ 1.4 GeV) proton irradiation of a tantalum target followed by ionization and on-line mass separation. 155 Tb was separated from isobar and pseudo-isobar impurities by cation exchange chromatography. Four tumor targeting molecules – a somatostatin analog (DOTATATE), a minigastrin analog (MD), a folate derivative (cm09) and an anti-L1-CAM antibody (chCE7) – were radiolabeled with 155 Tb. Imaging studies were performed in nude mice bearing AR42J, cholecystokinin-2 receptor expressing A431, KB, IGROV-1 and SKOV-3ip tumor xenografts using a dedicated small-animal SPECT/CT scanner. Results The total yield of the two-step separation process of 155 Tb was 86%. 155 Tb was obtained in a physiological l-lactate solution suitable for direct labeling processes. The 155 Tb-labeled tumor targeted biomolecules were obtained at a reasonable specific activity and high purity (> 95%). 155 Tb gave high quality, high resolution tomographic images. SPECT/CT experiments allowed excellent visualization of AR42J and CCK-2 receptor-expressing A431 tumors xenografts in mice after injection of 155 Tb-DOTATATE and 155 Tb-MD, respectively. The relatively long physical half-life of 155 Tb matched in particular the biological half-lives of 155 Tb-cm09 and 155 Tb-DTPA-chCE7 allowing SPECT imaging of KB tumors, IGROV-1 and SKOV-3ip tumors even several days after administration. Conclusions The radiolanthanide 155 Tb may be of particular interest for low-dose SPECT prior to therapy with a therapeutic match such as the β--emitting radiolanthanides 177Lu, 161 Tb, 166Ho, and the pseudo-radiolanthanide 90Y.

MECHANISM-BASED STRATEGIES TO ENHANCE THE ACTIONS OF A

Heat shock protein 90 (HSP90) is an abundant molecular chaperone that regulates the functional stability of client oncoproteins, such as STAT3, Raf-1 and Akt, which play a role in the survival of malignant cells. The chaperone function of HSP90 is driven by the binding and hydrolysis of ATP. The geldanamycin analog, 17-AAG, binds to the ATP pocket of HSP90 leading to the degradation of client proteins. However, treatment with 17-AAG results in the elevation of the levels of antiapoptotic proteins HSP70 and HSP27, which may lead to cell death resistance. The increase in HSP70 and HSP27 protein levels is due to the activation of the transcription factor HSF-1 binding to the promoter region of HSP70 and HSP27 genes. HSF-1 binding subsequently promotes HSP70 and HSP27 gene expression. Based on this, I hypothesized that inhibition of transcription/translation of HSP or client proteins would enhance 17-AAG-mediated cytotoxicity. Multiple myeloma (MM) cell lines MM.1S, RPMI-8226, and U266 were used as a model. To test this hypothesis, two different strategies were used. For the first approach, a transcription inhibitor was combined with 17-AAG. The established transcription inhibitor Actinomycin D (Act D), used in the clinic, intercalates into DNA and blocks RNA elongation. Stress inducible (HSP90á, HSP70 and HSP27) and constitutive (HSP90â and HSC70) mRNA and protein levels were measured using real time RT-PCR and immunoblot assays. Treatment with 0.5 µM 17-AAG for 8 hours resulted in the induction of all HSP transcript and protein levels in the MM cell lines. This induction of HSP mRNA levels was diminished by 0.05 µg/mL Act D for 12 hours in the combination treatment, except for HSP70. At the protein level, Act D abrogated the 17-AAG-mediated induction of all HSP expression levels, including HSP70. Cytotoxic evaluation (Annexin V/7-AAD assay) of Act D in combination with 17-AAG suggested additive or more than additive interactions. For the second strategy, an agent that affected bioenergy production in addition to targeting transcription and translation was used. Since ATP is necessary for the proper folding and maturation of client proteins by HSP90, ATP depletion should lead to a decrease in client protein levels. The transcription and translation inhibitor 8-Chloro-Adenosine (8-Cl-Ado), currently in clinical trials, is metabolized into its cytotoxic form 8-Cl-ATP causing a parallel decrease of the cellular ATP pool. Treatment with 0.5 µM 17-AAG for 8 hours resulted in the induction of all HSP transcript and protein levels in the three MM cell lines evaluated. In the combination treatment, 10 µM 8-Cl-Ado for 20 hours did not abrogate the induction of HSP mRNA or protein levels. Since cellular bioenergy is necessary for the stabilization of oncoproteins by HSP90, immunoblot assays analyzing for expression levels of client proteins such as STAT3, Raf-1, and Akt were performed. Immunoblot assays detecting for the phosphorylation status of the translation repressor 4E-BP1, whose activity is modulated by upstream kinases sensitive to changes in ATP levels, were also performed. The hypophosphorylated state of 4E-BP1 leads to translation repression. Data indicated that treatment with 17-AAG alone resulted in a minor (<10%) change in STAT3, Raf-1, and Akt protein levels, while no change was observed for 4E-BP1. The combination treatment resulted in more than 50% decrease of the client protein levels and hypophosphorylation of 4E-BP1 in all MM cell lines. Treatment with 8-Cl-Ado alone resulted in less than 30% decrease in client protein levels as well as a decrease in 4E-BP1 phosphorylation. Cytotoxic evaluation of 8-Cl-Ado in combination with 17-AAG resulted in more than additive cytotoxicity when drugs were combined in a sequential manner. In summary, these data suggest that the mechanism-based combination of agents that target transcription, translation, or decrease cellular bioenergy with 17-AAG results in increase cytotoxicity when compared to the single agents. Such combination strategies may be applied in the clinic since these drugs are established chemotherapeutic agents or currently in clinical trials.

Application of Signal Advance Technology to Electrophysiology

Medical instrumentation used in diagnosis and treatment relies on the accurate detection and processing of various physiological events and signals. While signal detection technology has improved greatly in recent years, there remain inherent delays in signal detection/ processing. These delays may have significant negative clinical consequences during various pathophysiological events. Reducing or eliminating such delays would increase the ability to provide successful early intervention in certain disorders thereby increasing the efficacy of treatment. In recent years, a physical phenomenon referred to as Negative Group Delay (NGD), demonstrated in simple electronic circuits, has been shown to temporally advance the detection of analog waveforms. Specifically, the output is temporally advanced relative to the input, as the time delay through the circuit is negative. The circuit output precedes the complete detection of the input signal. This process is referred to as signal advance (SA) detection. An SA circuit model incorporating NGD was designed, developed and tested. It imparts a constant temporal signal advance over a pre-specified spectral range in which the output is almost identical to the input signal (i.e., it has minimal distortion). Certain human patho-electrophysiological events are good candidates for the application of temporally-advanced waveform detection. SA technology has potential in early arrhythmia and epileptic seizure detection and intervention. Demonstrating reliable and consistent temporally advanced detection of electrophysiological waveforms may enable intervention with a pathological event (much) earlier than previously possible. SA detection could also be used to improve the performance of neural computer interfaces, neurotherapy applications, radiation therapy and imaging. In this study, the performance of a single-stage SA circuit model on a variety of constructed input signals, and human ECGs is investigated. The data obtained is used to quantify and characterize the temporal advances and circuit gain, as well as distortions in the output waveforms relative to their inputs. This project combines elements of physics, engineering, signal processing, statistics and electrophysiology. Its success has important consequences for the development of novel interventional methodologies in cardiology and neurophysiology as well as significant potential in a broader range of both biomedical and non-biomedical areas of application.

Real-life results of balloon kyphoplasty for vertebral compression fractures from the SWISSspine registry

BACKGROUND CONTEXT The Swiss Federal Office of Public Health mandated a nationwide health technology assessment-registry for balloon kyphoplasty (BKP) for decision making on reimbursement of these interventions. The early results of the registry led to a permanent coverage of BKP by basic health insurance. The documentation was continued for further evidence generation. PURPOSE This analysis reports on the 1 year results of patients after BKP treatment. STUDY DESIGN Prospective multicenter observational case series. PATIENT SAMPLE The data on 625 cases with 819 treated vertebrae were documented from March 2005 to May 2012. OUTCOME MEASURES Surgeon-administered outcome instruments were primary intervention form for BKP and the follow-up form; patient self-reported measures were EuroQol-5D questionnaire, North American Spine Society outcome instrument /Core Outcome Measures Index (including visual analog scale), and a comorbidity questionnaire. Outcome measures were back pain, medication, quality of life (QoL), cement extrusions, and new fractures within the first postoperative year. METHODS Data were recorded preoperatively and at 3 to 6-month and 1-year follow-ups. Wilcoxon signed-rank test was used for comparison of pre- with postoperative measurements. Multivariate logistic regression was used to identify factors with a significant influence on the outcome. RESULTS Seventy percent of patients were women with mean age of 71 years (range, 18-91 years); mean age of men was 65 years (range, 15-93 years). Significant and clinically relevant reduction of back pain, improvement of QoL, and reduction of pain killer consumption was seen within the first postoperative year. Preoperative back pain decreased from 69.3 to 29.0 at 3 to 6-month and remained unchanged at 1-year follow-ups. Consequently, QoL improved from 0.23 to 0.71 and 0.75 at the same follow-up intervals. The overall vertebra-based cement extrusion rates with and without extrusions into intervertebral discs were 22.1% and 15.3%, respectively. Symptomatic cement extrusions with radiculopathy were five (0.8%). A new vertebral fracture within a year from the BKP surgery was observed in 18.4% of the patients. CONCLUSIONS The results of the largest observational study for BKP so far are consistent with published randomized trials and systematic reviews. In this routine health care setting, BKP is safe and effective in reducing pain, improving QoL, and lowering pain_killer consumption and has an acceptable rate of cement extrusions. Postoperative outcome results show clear and significant clinical improvement at early follow-up that remain stable during the first postoperative year.

Sexual function after vaginal and abdominal fistula repair

OBJECTIVE The purpose of this study was to compare clinical outcomes and sexual function between transvaginal and transabdominal repairs of vesicovaginal fistulae (VVF). STUDY DESIGN Participants (99 women with VVF at a tertiary referral center) were treated with urinary catheterization for 12 weeks and, if the procedure was unsuccessful, underwent repair either the transvaginal (Latzko) or transabdominal technique. Objective clinical parameters were analyzed; subjective outcomes were recorded prospectively at the 6-month follow-up examination with the use of the female sexual function index to evaluate sexual function and the visual analogue scale to measure general disturbance by the fistula. RESULTS After bladder drainage for 12 weeks, 8 patients had spontaneous fistula closure. Demographic variables were similar in the transvaginal (n = 60) and transabdominal (n = 31) repair groups. The transvaginal procedure showed significantly shorter operation times, less blood loss, and shorter hospital stay. Continence rates 6 months after surgery were 82% (transvaginal) and 90% (transabdominal). Sexual function in the 64 sexually active patients was significantly improved, and overall disturbance by the fistula was reduced with both operative techniques. Neither surgical intervention was superior to the other regarding any domain of sexual function or visual analog scale. CONCLUSION Fistula repair improves sexual function and quality of life with no difference attributable to surgical route. Given this and that operating time, blood loss and length of stay are less with the transvaginal approach, the transvaginal approach is preferred in VVF repair if fistula and patient characteristics are suitable.

Neural analogs of associative learning in {\it Aplysia\/}: Experimental and theoretical approaches

A change in synaptic strength arising from the activation of two neuronal pathways at approximately the same time is a form of associative plasticity and may underlie classical conditioning. Previously, a cellular analog of a classical conditioning protocol has been demonstrated to produce short-term associative plasticity at the connections between sensory and motor neurons in Aplysia. A similar training protocol produced long-term (24 hour) enhancement of excitatory postsynaptic potentials (EPSPs). EPSPs produced by sensory neurons in which activity was paired with a reinforcing stimulus were significantly larger than unpaired controls 24 hours after training. To examined whether the associative plasticity observed at these synapses may be involved in higher-order forms of classical conditioning, a neural analog of contingency was developed. In addition, computer simulations were used to analyze whether the associative plasticity observed in Aplysia could, in theory, account for second-order conditioning and blocking. ^

Molecular and biochemical analysis of the {\it Drosophila\/} segmentation gene {\it runt\/}

Genetic evidence has indicated that the segmentation gene runt plays a key role in regulating gene expression of the pair-rule genes hairy, even-skipped, and fushi tarazu. In contrast to other pair-rule genes, sequence data of the runt open reading frame did not reveal homologies to DNA-binding motifs of known transcriptional regulatory proteins. This thesis project examined several properties of the runt gene based on the sequence of the transcription unit, including the subcellular localization of the protein in vivo, its ability to bind DNA, and the functionality of a putative nucleotide binding domain.^ A runt-specific antibody was generated and used to demonstrate that runt is localized in the nucleus. Since the precise overlap of the pair-rule stripes is thought to be critical for the determination of cellular identity along the anterior-posterior axis, phasing of early runt expression in the blastoderm was examined with regard to the segmentation genes hairy, even-skipped, and fushi tarazu. runt was also expressed at later stages of embryogenesis, including expression in neuroblasts, and ganglion mother cells of the developing nervous system. Expression at this stage was required for the subsequent formation of specific neurons and runt was extensively expressed in the central and peripheral nervous systems.^ Several experiments were done to address the biochemical function of the runt protein. A direct interaction of runt with DNA was first examined. Although bacterial expressed runt was found to bind dsDNA-cellulose, subsequent experiments failed to detect sequence-specific interactions with DNA. Inter-species conservation of the putative nucleotide binding domain suggested that this region was functionally important, and runt protein bound a labeled ATP analog with high affinity in vitro. Finally, the effect of substitution of a critical residue of the nucleotide binding domain on runt activity was examined in vivo. Ectopic expression of the mutant protein indicated that this conserved substitution altered, but did not eliminate, runt activity as evaluated by segmentation phenotype and viability. ^

p75 receptor-mediated neurotrophism: A new mechanism of melanoma cell survival and invasion

Trophism as a "clonal dominance" support mechanism for tumor cells is an unexplored area of tumor progression. This report presents evidence that the human melanoma low-affinity neurotrophin receptor (p75) can signal independently of its high-affinity tyrosine kinase counterparts, the TRK family of kinases. Signaling may be accomplished by a p75-associated purine-analog-sensitive kinase and results in enhanced invasion into a reconstituted basement membrane with a corresponding stimulation of matrix metalloproteinase-2 expression. Additionally, a "stress culture" survival assay was developed to mimic the growth limiting conditions encountered by melanoma cells in a rapidly growing primary tumor or metastatic deposit prior to neoangiogenesis. Under these conditions, p75, promotes the survival of high p75 expressing brain-colonizing melanoma cells. Extensive 70W melanoma cell-cell contact, which downregulates p75, immediately precedes the induction of cell death associated with diminished production of two key cell survival factors, bcl-2 and the p85 subunit of phosphoinositol-3-kinase, and an elevation in apoptosis promoting intracellular reactive oxygen species (ROSs). Since one function of bcl-2 may be to control the generation of ROSs via the antioxidant pathway, these cells may receive a apoptosis-prompting "double hit". 70W melanoma cell death occurred by an apoptotic mechanism displaying classical morphological changes including plasma membrane blebbing, loss of microvilli and redistribution of ribosomes. 70W apoptosis could be pharmacologically triggered following anti-p75 monoclonal antibody-mediated clustering of p75 receptors. 70W cells fluorescently sorted for high-p75 expression (p75$\sp{\rm H}$ cells) exhibited an augmented survival potential and a predilection to sort with the S + G2/M growth phase, relative to their low p75 expressing, p75$\sp{\rm L}$ counterparts. Apoptosis is significantly delayed by p75$\sp{\rm H}$ cells, whereas p75$\sp{\rm L}$ cells are exquisitely prone to initiate apoptosis. Importantly, the p75$\sp{\rm L}$ cells that survive apoptosis, highly re-expressed p75 and were remarkably responsive to exogenous NGF.^ These are the first data to implicate p75-mediated neurotrophism as an invasion and survival support mechanism employed by brain-metastatic cells. In particular, these results may have implications in little understood phenomena of tumor progression, such as the emergence of "clonal dominance" and tumor dormancy. ^