Steering of the Skyrmion Hall Angle by Gate Voltages.

Magnetic skyrmions can be driven by an applied spin-polarized electron current that exerts a spin-transfer torque on the localized spins constituting the skyrmion. However, the longitudinal dynamics is plagued by the skyrmion Hall effect, which causes the skyrmions to acquire a transverse velocity component. We show how to use spin-orbit interaction to control the skyrmion Hall angle and how the interplay of spin-transfer and spin-orbit torques can lead to a complete suppression of the transverse motion. Since the spin-orbit torques can be controlled all electronically by a gate voltage, the skyrmion motion can be steered all electronically on a broad racetrack at high speed and conceptually new writing and gating operations can be realized.

Perceptions of risk and therapy among patients with Barrett's esophagus: a patient survey study.

Nondysplastic Barrett's esophagus has a risk of progression to esophageal adenocarcinoma as low as 0.18-0.3% per person per year, and low-grade dysplasia as low as 0.5%. While adherence to guidelines and selection of management options varies, little is known about what modifies patient decision-making. This study aims to evaluate and identify factors that influence patient perceptions of risk and decisions about management. An independently developed and piloted survey was administered to patients at an academic hospital. Risk perception and desire for therapy were assessed using a standard reference gamble paradigm, and responses were stratified based on patient and disease characteristics. Data were analyzed with Student's t and chi-squared tests. A total of 42 of 50 patients with Barrett's esophagus and no prior endoscopic therapy participated (84% response; 76% nondysplastic Barrett's esophagus, 22% low-grade dysplasia, 2% indeterminate for dysplasia; mean age 61 years, 29% female). On average, patients perceived their risk of developing esophageal adenocarcinoma in the next year, 10 years and lifetime as 6, 14, and 19%, respectively. Nearly half viewed their lifetime risk of developing esophageal adenocarcinoma to be the same or higher than diabetes, heart disease, or colon cancer. Although 92% of patients felt surveillance beneficial, only 54% believed endoscopic therapy to be effective in most or all cases. As many as 83% of patients were willing to undergo endoscopic therapy with a hypothetical success rate as low as 70%, and a majority (64%) accepted complication rates up to 30%. Compared to patients with low risk perception of developing esophageal adenocarcinoma, those with high risk perception more often believed their risk for developing esophageal adenocarcinoma was greater than diabetes (p = 0.04) or colon cancer (p = 0.002). Those with lifetime low risk perception were less likely to accept modest complication rates (<10%) of therapy (P < 0.05). Age, gender, degree of dysplasia, lifetime endoscopies and duration of symptoms had no impact on perceived effectiveness of surveillance or therapy, and did not correlate with desire for treatment at varying levels of risk and effectiveness. Patients with Barrett's esophagus overestimate their risk of developing esophageal adenocarcinoma and will accept low success rates and high risk of complications to undergo endoscopic therapy. Baseline risk perception correlates with the desire for endoscopic therapy.

[Biologism controversy: ethical implications for psychiatry]. / Biologismus-Kontroversen: Ethische Implikationen für die Psychiatrie.

Current biological psychiatry, it is frequently claimed by its opponents, is "biologistic" and unduly narrows psychological disorders to neurobiology and molecular biology. They deem a complete neuroscientific reduction of the mental phenomena to be impossible because of the impossibility of reducing certain phenomena, such as the individual subjective experience. If such a reduction is nevertheless undertaken it is ultimately to the disadvantage of the patients. We argue in this article that the very term "biologism" has to be put under scrutiny in the first place. As a result it becomes obvious that "biologism", as a subclass of "philosophical naturalism", is ultimately quite unproblematic. Biologism is dangerous only if it implies an eliminative rejection or an inappropriate underestimation of the relevance of the psyche. On closer examination it gets evident that such implications do not follow necessarily from biologism but cannot be precluded either. To better identify and possibly prevent such dangers, a more differentiated terminology seems helpful.

The ground state phase diagram of the diluted ferromagnetic Kondo-lattice model.

We investigate the existence of several (anti-)ferromagnetic phases in the diluted ferromagnetic Kondo-lattice model, i.e. ferromagnetic coupling of local moment and electron spin. To do this we use a coherent potential approximation (CPA) with a dynamical alloy analogy. For the CPA we need effective potentials, which we obtain first from a mean-field approximation. To improve this treatment we use in the next step a more appropriate moment conserving decoupling approach and compare the two methods. The different magnetic phases are modeled by defining two magnetic sub-lattices. As a result we present zero-temperature phase diagrams according to the important model parameters and different dilutions.

[Mandatory elective course in emergency medicine with instructions by paramedics improves practical training in undergraduate medical education]. / Praktikum im Rettungsdienst mit Anleitung durch Rettungsassistenten.

BACKGROUND: Due to the complexity of medical emergencies undergraduate medical training in the integrative course on emergency medicine requires education combining knowledge, practical skills, algorithm-driven behavior and soft skills. New State board regulations on education and licensing of physicians demand a practical implementation of these objectives. MATERIALS AND METHODS: The medical faculty of Frankfurt medical school has implemented an obligatory prehospital elective course. A retrospective questionnaire assessed the organization, instructional competence of the paramedics and integration of students in the emergency medical teams. RESULTS: Out of a total of 486 students the majority rated the longitudinal curriculum as positive (66% very good and 28% good). The practical experience at a scene was evaluated to be reasonable by 86% and 95% of the students stated that integration into the emergency team was rendered without any difficulties. CONCLUSION: A prehospital experience supported by paramedics can serve as a valuable tool in an emergency medicine curriculum.

[Training in emergency sonography for trauma. Concept of a 1-day course program]. / Schulung in Notfallsonographie bei Trauma. Konzept eines eintägigen Kursprogramms.

In the last decade prehospital focused abdominal sonography for trauma (P-FAST) could be established as a valid on-site diagnostic tool for both air and ground rescue medical services in Germany. An appropriate use of P-FAST demands a standardized training concept. Therefore a 1-day training program was developed by the working group "emergency ultrasound" in Frankfurt/Main and was introduced in 2003. The training consists of lectures on general and specific aspects of emergency ultrasound techniques with demonstrations of numerous pathological findings, intensive hands-on training with patients and volunteers, as well as simulated on-site training. After completing the P-FAST course the participants gained competency to perform prehospital emergency ultrasound with high accuracy. Strict application of the exact technique as well as appropriate integration of the adjunct into the algorithm of prehospital care are the most important prerequisites for successful use of P-FAST. From February 2003 to March 2008 540 participants were trained in P-FAST in the 1-day course.

[Pre-hospital emergency sonography of trauma patients]. / Präklinische Notfallsonographie bei traumatologischen Patienten.

Besides severe cerebral trauma, abdominal bleeding is the most frequent cause of death after multiple trauma. Abdominal bleeding is difficult to diagnose because initially at the scene a multiply injured patient with a stable circulation is often encountered. Ultrasound diagnostics have played a central role in the diagnostics of emergency patients for many years. This technique is used both in the emergency room and in the intensive care unit, in the operation center and to an increasing extent in emergency diagnostics during the pre-hospital setting. The following article deals with the ultrasound investigation of injured patients, the indications and examination technique are described, as well as the specific characteristics of using ultrasound at the scene. Finally, device-specific characteristics and the state of development in Germany are presented.

2,2'-Dithiobisbenzamides derived from alpha-, beta- and gamma-amino acids possessing anti-HIV activities: synthesis and structure-activity relationship.

Nucleocapsid protein (NCp7), which contains highly conserved retroviral zinc fingers, is essential in the early as well as the late phase of human immunodeficiency virus (HIV) life cycle and constitutes a novel target for AIDS therapy. HIV-1 NCp7 is a basic 55 amino acid protein containing two C(X)2C(X)4H(X)4C motif zinc fingers flanked by basic amino acids on each side. 2,2'-dithiobisbenzamides have previously been reported to release zinc from these NCp7 zinc fingers and also to inhibit HIV replication. Specifically, 2,2'-dithiobisbenzamides derived from simple amino acids showed good antiviral activities. The benzisothiazolone 3, the cyclic derivative of 2, was selected for clinical trials as an agent for AIDS therapy. Herein we report the syntheses and antiviral activities, including therapeutic indices, of 2,2'-dithiobisbenzamides derived from alpha-, beta- and gamma-amino acids. Electrospray ionization mass spectrometry was used to study the zinc-ejection activity of these compounds. Among the alpha-amino acid derived 2,2'-dithiobisbenzamides, analogues containing alkyl side chains were found to be antivirally active with good therapeutic indices. 2,2'-Dithiobisbenzamides, derived from beta- and gamma-amino acids, were found to possess better antiviral and therapeutic efficacies than the alpha-amino acid analogues. Thus compound 59 was found to possess an EC50 of 1.9 microM with a therapeutic index of > 50. Interestingly, 2,2'-dithiobisbenzamides derived from alpha-amino acids containing a protected acid function and polar side chains also exhibited very good antiviral activity.

2,2'-Dithiobisbenzamides and 2-benzisothiazolones, two new classes of antiretroviral agents: SAR and mechanistic considerations.

Substituted 2,2'-dithiobisbenzamides and 2-benzisothiazolones were prepared and shown to possess low microM activity with high therapeutic indices against HIV-1, HIV-2 and SIV in cell culture. The mechanism of antiviral action was determined to be directed toward the nucleocapsid protein (NCp7), which contains two zinc fingers and plays vital roles in the viral life cycle. The "active sulfides" of this study cause the extrusion of zinc from these zinc fingers. Structure-activity relationships of the 2,2'-dithiobisbenzamides reveal that the disulfide bond and the ortho benzamide functional groups are essential for activity, with the best compounds having a carboxylic acid, carboxamide, or sulfonamide substituent. The 2-benzisothiazolones are formed from the disulfides both chemically and in vivo and their SAR mimics that of the 2,2'-dithiobisbenzamides. The antiviral activity of the disulfides may require cyclization to the isothiazolones. Two agents, PD 159206 and PD 161374, which showed good antiviral activity, physical properties, and excellent pharmacokinetics in mice, were selected for advanced studies.

A new class of anti-HIV-1 agents targeted toward the nucleocapsid protein NCp7: the 2,2'-dithiobisbenzamides.

As part of the National Cancer Institute's Drug Screening Program, a new class of antiretrovirals active against the human immunodeficiency virus HIV-1 has been identified, and the HIV-1 nucleocapsid protein NCp7 was proposed as the target of antiviral action. The 2,2'-dithiobis-[4'-(sulfamoyl)benzanilide] (3x) and the 2,2'-dithiobis(5-acetylamino)benzamide (10) represented the prototypic lead structures. A wide variety of 2,2'-dithiobisbenzamides were prepared and tested for anti-HIV-1 activity, cytotoxicity, and their ability to extrude zinc from the zinc fingers for NCp7. The structure-activity relationships demonstrated that the ability to extrude zinc from NCp7 resided in the 2,2'-dithiobisbenzamide core structure. The 3,3' and the 4,4' isomers were inactive. While many analogs based upon the core structure retained the zinc extrusion activity, the best overall anti-HIV-1 activity was only found in a narrow set of derivatives possessing carboxylic acid, carboxamide, or phenylsulfonamide functional groups. These functional groups were more important for reducing cytotoxicity than improving antiviral potency or activity vs NCp7. All of the compounds with antiviral activity also extruded zinc from NCp7. From this study several classes of low microM anti-HIV agents with simple chemical structures were identified as possible chemotherapeutic agents for the treatment of AIDS.

Synthesis and antibacterial activity of new quinolones containing a 7-[3-(1-amino-1-methylethyl)-1-pyrrolidinyl] moiety. Gram-positive agents with excellent oral activity and low side-effect potential.

A series of the R and S isomers of 7-[3-(1-amino-1-methylethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxoquinoline- and 1,8-naphthyridine-3-carboxylic acids was prepared to determine the effect on potency of the two methyl groups adjacent to the distal nitrogen in the pyrrolidinyl moiety. The antibacterial efficacy of these dimethylated derivatives was compared to the relevant 7-[3-(aminomethyl)-1-pyrrolidinyl] parent compounds and, to a lesser extent, the 7-[3-(1-aminoethyl)-1-pyrrolidinyl] analogues. The activity of the title and reference compounds was assayed in vitro using an array of Gram-negative and Gram-positive organisms and in vivo using a mouse infection model. Selected derivatives were then screened for potential side effects in a phototoxicity mouse model and an in vitro mammalian cell cytotoxicity protocol. The results showed that the R isomer displayed a 2-20-fold advantage in activity in vitro and a 2-15-fold advantage in vivo over the S isomer. Although equipotent to the 7-[3-(aminomethyl)-1-pyrrolidinyl] parent compounds in vitro, the R isomers of the 7-[3-(1-amino-1-methylethyl)-1-pyrrolidinyl] analogues showed a dramatic increase in in vivo potency, especially via the oral route of administration. These same R isomers also appeared to possess a reduced risk of phototoxicity and cytotoxicity. This combination of superior in vivo performance with a low degree of phototoxicity and mammalian cell cytotoxicity recommends these agents for further study. Of these agents, naphthyridine 16-R represents the optimal blend of potency and safety.

Pharmacologic/pharmacokinetic evaluation of emesis induced by analogs of RSU 1069 and its control by antiemetic agents.

RB 6145, the ring-opened analog of RSU 1069, and PD 130908, the desoxy ring-opened analog of RSU 1069, were compared to RSU 1069 for their emetic potential in dogs. When RB 6145 and PD 130908 were administered intravenously at doses ranging from 20% to 50% of the mouse equivalent maximum tolerated dose (MTD), both analogs were less emetic than RSU 1069 on a molar basis. Furthermore, the 5HT3 antagonist ondansetron prevented emesis at doses as high as 75% of the MTD. The reactivity, and hence the emetic liability of these compounds, is thought to be mediated by formation of the corresponding aziridine intermediate. In mouse plasma, both analogs rapidly converted to two products, the reactive aziridine and a stable oxiazolidinone species formed upon reaction with bicarbonate in the blood. A positive correlation exists between the amounts of aziridine formed by these analogs and their emetic potential.

Synthesis and evaluation of a series of 3,5-disubstituted benzisoxazole-4,7-diones. Potent radiosensitizers in vitro.

A series of 3,5-disubstituted-2,1-benzisoxazole-4,7-diones was synthesized and evaluated as radiosensitizers both in vitro and in vivo. These compounds were designed as non-nitro electron-affinic agents in an effort to alleviate some of the toxicities seen with the 2-nitroimidazole radiosensitizers evaluated in the clinic. Several compounds in this series were potent radiosensitizers in vitro, with sensitizer enhancement ratios of 2.0-2.3 at concentrations less than 0.5 mM. Compounds with potent in vitro activity were also evaluated in vivo. However, none of these compounds showed radiosensitizing activity in vivo. The reduction potentials of these compounds were determined by cyclic voltammetry and compared to other electron-affinic radiosensitizers. In general, the reduction potentials of this series of compounds was slightly more positive than the 2-nitroimidazoles, but they fell within the range postulated as acceptable to yield in vivo activity. The results suggest that factors other than reduction potential may be responsible for the lack of in vivo radiosensitizing activity observed for this class of radiosensitizers.

A new class of analogues of the bifunctional radiosensitizer alpha-(1-aziridinylmethyl)-2-nitro-1H-imidazole-1-ethanol (RSU 1069): the cycloalkylaziridines.

A series of compounds related to alpha-(1-aziridinylmethyl)-2-nitro-1H-imidazole-1-ethanol (RSU 1069, 1) were synthesized and evaluated as selective hypoxic cell cytotoxic agents and as radiosensitizers. The aziridine moiety was replaced with a number of other potential alkylating groups including cycloalkylaziridines and azetidines. The data indicated that modification of the aziridine of 1 resulted in a substantial decrease in the ability of the compounds to selectively kill hypoxic cells. However, these modifications did not affect the compounds' in vitro radiosensitizing activity since many of the derivatives were as potent as 1. All of the compounds that were evaluated in vivo were less toxic than 1, and several members of this series had significant activity. The best compound was trans-alpha-[[(4-bromotetrahydro-2H-pyran-3-yl) amino]methyl]-2-nitro-1H-imidazole-1-ethanol (18), which, due to its activity and log P value, is a candidate for additional in vivo studies.

Dual-function radiosensitizers. Alpha-[[(2-bromoethyl)amino]methyl]-2-nitro-1H-imidazole-1-ethanol and related compounds: preparation via an aziridine equivalent.

An improved synthesis of the dual-function radiosensitizer alpha-[[(2-bromoethyl)amino]methyl]-2-nitro-1H-imidazole-1-ethanol (2, RB 6145) has been developed. Previously, the synthetic difficulties associated with this compound limited its attractiveness as a clinical candidate, although its radiosensitizing activity in preclinical models warranted its further development. The synthesis described uses a 2-oxazolidinone as an aziridine equivalent and provides 2 in 47% yield.

Single-step purification and biological activity of human nerve growth factor produced from insect cells.

Human nerve growth factor (NGF) was cloned and engineered for expression in a baculovirus-infected Spodoptera frugiperda (SF-9) insect cell system. Culture supernatants contained 2-3 mg/L of recombinant human NGF. The human NGF produced by this system was purified to apparent homogeneity with a single-step affinity chromatography procedure using a high-affinity monoclonal antibody originally raised against murine NGF. The purification procedure yielded 1-2 mg of pure, human NGF per liter of culture supernatant; i.e., approximately 60% recovery of the human NGF originally released into the culture medium. Although the gene transfected into the SF-9 cells coded for pro-NGF, the NGF recovered after purification was greater than 95% fully processed, mature protein. The KD for the affinity of the pure, recombinant human NGF for NGF receptor in PC12 membranes is 0.20 +/- 0.05 nM. Activation of neurite outgrowth in PC12 cells occurs with ED50 values of 85 +/- 20 pM and 9.6 +/- 1.5 pM for a 3-day primary response and a 1-day secondary response, respectively. The pure, recombinant human NGF also stimulates a significant increase in dopamine content of PC12 cells with an ED50 of 5.8 +/- 2.7 pM. These binding and biological activation properties are consistent with values observed using murine NGF purified from submaxillary glands.

Health resources management and physician control in a San Francisco, California, hospital.

The continued escalation in health care spending has caused money to become an increasingly limited resource, which may eventually affect the ability of health professionals to provide complete health care services. Health care payers have stressed efficiency and the appropriateness of health care measures and are putting greater financial pressures on health professionals by making them more accountable for services provided. Hospitals and physicians must take a more active role in monitoring health care delivery and work together to improve performance efficiency. Efficiency can be gained through a comprehensive program that emphasizes high-quality care and the effective use of health care resources. The Health Resource Management Program is a model for carrying out this function that integrates data analysis and physician input and education.

Scrutiny of resource use can increase efficiency.

In their attempts to control costs and increase net revenue, hospitals may overlook a key strategy: improved efficiency in delivering care. An analysis of each department's clinical and financial data, however, may provide only a rough framework for decreasing a hospital's expenses. focusing on areas of high resource consumption can yield the greatest benefit. Ultimately, communication between a hospital's administrators and its medical staff is the vital link in improving efficiency.

Synthesis and evaluation of alpha-[[(2-haloethyl)amino]methyl]-2- nitro-1H-imidazole-1-ethanols as prodrugs of alpha-[(1-aziridinyl)methyl]-2- nitro-1H-imidazole-1-ethanol (RSU-1069) and its analogues which are radiosensitizers and bioreductively activated cytotoxins.

alpha-[(1-Aziridinyl)methyl]-2-nitro-1H-imidazole-1-ethanols, of general formula ImCH2CH(OH)CH2NCR1R2CR3R4, where Im = 2-nitroimidazole and R1, R2, R3, R4 = H, Me, are radiosensitizers and selective bioreductively activated cytotoxins toward hypoxic tumor cells in vitro and in vivo. Treatment of the aziridines with hydrogen halide in acetone or aqueous acetone gave the corresponding 2-haloethylamines of general formula ImCH2CH(OH)CH2(+)-NH2CR1R2CR3R4X X-, where R1, R2, R3, R4 = H, Me, and X = F, Cl, Br, I. These 2-haloethylamines were evaluated as prodrugs of the parent aziridines. The rates of ring closure in aqueous solution at pH approximately 6 were found to increase with increasing methyl substitution and to depend on the nature of the leaving group (I approximately Br greater than Cl much greater than F). A competing reaction of ImCH2CH(OH)CH2+NH2CH2CH2X X- (X = Cl, Br) with aqueous HCO3- ions gives 3-[2-hyroxy-3-(2-nitro-1H-imidazol-1-yl)propyl]-2-oxazolidinone. The activities of these prodrugs as radiosensitizers or as bioreductively activated cytotoxins were consistent with the proportion converted to the parent aziridine during the course of the experiment. alpha-[[(2-Bromoethyl)amino]methyl]-2-nitro-1H-imidazole-1- ethanol (RB 6145, 10), the prodrug of alpha-[(1-aziridinyl)methyl]-2-nitro-1H-imidazole-1-ethanol (RSU-1069, 3), is identified as the most useful compound in terms of biological activity and rate of ring closure under physiological conditions.

Renin inhibitors containing isosteric replacements of the amide bond connecting the P3 and P2 sites.

Renin inhibitors having 13 different isosteres connecting the P3 and P2 positions have been prepared. Synthetic routes and in vitro activity exhibited by these compounds are discussed. The two most potent compounds, 47 and 48, contained the hydroxyethylene isostere, psi [CHOHCH2], and had IC50 values of 61 and 22 nM, respectively.