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The original version of this Article contained an error in the fifth sentence of the first paragraph of the 'Application on H2' section of the Results, which incorrectly read 'The role of electron correlation is quite apparent in this presentation: Fig. 1a is empty for the uncorrelated Hartree-Fock wave function, since projection of the latter wave function onto the 2pσu orbital is exactly zero, while this is not the case for the fully correlated wave function (Fig. 1d); also, Fig. 1b, c for the uncorrelated description are identical, while Fig. 1e, f for the correlated case are significantly different.' The correct version replaces 'Fig. 1e, f' with 'Fig. 2e and f'.
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The toolbox for imaging molecules is well-equipped today. Some techniques visualize the geometrical structure, others the electron density or electron orbitals. Molecules are many-body systems for which the correlation between the constituents is decisive and the spatial and the momentum distribution of one electron depends on those of the other electrons and the nuclei. Such correlations have escaped direct observation by imaging techniques so far. Here, we implement an imaging scheme which visualizes correlations between electrons by coincident detection of the reaction fragments after high energy photofragmentation. With this technique, we examine the H2 two-electron wave function in which electron-electron correlation beyond the mean-field level is prominent. We visualize the dependence of the wave function on the internuclear distance. High energy photoelectrons are shown to be a powerful tool for molecular imaging. Our study paves the way for future time resolved correlation imaging at FELs and laser based X-ray sources.
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We investigate the photodouble ionization of H_{2} molecules with 400 eV photons. We find that the emitted electrons do not show any sign of two-center interference fringes in their angular emission distributions if considered separately. In contrast, the quasiparticle consisting of both electrons (i.e., the "dielectron") does. The work highlights the fact that nonlocal effects are embedded everywhere in nature where many-particle processes are involved.
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Electron motion in chemical bonds occurs on an attosecond timescale. This ultrafast motion can be driven by strong laser fields. Ultrashort asymmetric laser pulses are known to direct electrons to a certain direction. But do symmetric laser pulses destroy symmetry in breaking chemical bonds? Here we answer this question in the affirmative by employing a two-particle coincidence technique to investigate the ionization and fragmentation of H2 by a long circularly polarized multicycle femtosecond laser pulse. Angular streaking and the coincidence detection of electrons and ions are employed to recover the phase of the electric field, at the instant of ionization and in the molecular frame, revealing a phase-dependent anisotropy in the angular distribution of H⺠fragments. Our results show that electron localization and asymmetrical breaking of molecular bonds are ubiquitous, even in symmetric laser pulses. The technique we describe is robust and provides a powerful tool for ultrafast science.
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A 9-year-old cynomolgus monkey (Macaca fascicularis) infected orally with bovine spongiform encephalopathy (BSE) was presented for necropsy following euthanasia 4 years post infection (p.i.). This macaque R984 was exposed to a BSE dose that causes a simian form of variant Creutzfeldt-Jakob disease (vCJD) within 5 years p.i. in other macaques. All orally BSE-infected macaques developed a significant weight gain within the first 2 years p.i. compared with non-BSE-infected age- and sex-matched control animals, suggesting increased risk of type 2 diabetes (T2D). In contrast, macaque R984 developed rapid weight loss, hyperglycemia, and glucosuria and had to be euthanatized 4 years p.i. before clinical signs of vCJD. Pancreas histopathological evaluation revealed severe islet degeneration but, remarkably, no islet amyloid deposits were present. Immunostaining of pancreas sections for insulin and glucagon confirmed the loss of endocrine cells. In addition, prions were present in the adenohypophysis but not in other areas of the brain, indicating centripetal prion spread from the gut during the preclinical phase of BSE infection. Plasma glucose and insulin concentrations of macaque R984 became abnormal with age and resembled T2D. This unusual case of spontaneous T2D in the absence of islet amyloid deposits could have been due to early prion spread from the periphery to the endocrine system or could have occurred spontaneously.
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Diabetes Mellitus Tipo 2/patologia , Encefalopatia Espongiforme Bovina/complicações , Macaca fascicularis , Doenças dos Macacos/patologia , Obesidade/complicações , Animais , Glicemia/metabolismo , Peso Corporal , Bovinos , Diabetes Mellitus Tipo 2/etiologia , Feminino , Técnicas Histológicas/veterinária , Insulina/sangue , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Pâncreas/patologia , Fatores SexuaisRESUMO
We simultaneously measured the momentum transferred to a free-floating molecular double slit and the momentum change of the atom scattering from it. Our experimental results are compared to quantum mechanical and semiclassical models. The results reveal that a classical description of the slits, which was used by Einstein in his debate with Bohr, provides a surprisingly good description of the experimental results, even for a microscopic system, if momentum transfer is not ascribed to a specific pathway but shared coherently and simultaneously between both.
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Pandemic influenza vaccines have to fulfill specific requirements. In contrast to seasonal influenza vaccines, they have to be effective even in an immunologically naïve population. In addition, they should be available in a relatively short period of time and should be produced at an unprecedented speed in huge amounts. For this reason, they need a specific design which has to be different from that of seasonal vaccines. With the given technological possibilities, antigen-sparing adjuvanted vaccines most closely fulfill the requirements of an ideal pandemic vaccine.
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Desenho de Fármacos , Vírus da Influenza A Subtipo H1N1 , Vacinas contra Influenza/biossíntese , Vacinas contra Influenza/uso terapêutico , Influenza Humana/prevenção & controle , Pandemias/prevenção & controle , Alemanha/epidemiologia , Humanos , Influenza Humana/epidemiologia , Pandemias/estatística & dados numéricosRESUMO
In April 2009 the first pandemic of the 21st century developed within a few weeks starting from Mexico. Its first wave reached Germany in autumn 2009 and was responsible for 1.8-3.5 million additional medical consultations. For the public health sector, this pandemic was one of the largest challenges of the last few decades. As a contribution to broader evaluations on national and international level, the Robert Koch Institute invited representatives from different professions involved in the pandemic response to participate in a workshop on 22-23 March 2010. This workshop was structured in short presentations, group work, and plenary discussions. Main experiences were that (a) pandemic preparedness was helpful, (b) the early warning systems were reliable, (c) vaccines were available within a few months, however, in limited amounts. Need for improvement was discussed for (a) effectiveness of vaccination logistics, (b) mechanisms for the reimbursement of the cost of vaccination, (c) availability of surveillance and monitoring systems, (d) integration of physicians in decision-making processes and health education, and (e) proactive communication strategies. Investments in the above mentioned areas can help to improve public health protection in the future.
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Surtos de Doenças , Vírus da Influenza A Subtipo H1N1 , Influenza Humana/epidemiologia , Comportamento Cooperativo , Estudos Transversais , Previsões , Alemanha , Necessidades e Demandas de Serviços de Saúde/tendências , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/provisão & distribuição , Influenza Humana/prevenção & controle , Comunicação Interdisciplinar , Programas Nacionais de Saúde/tendências , Vigilância da População , Encaminhamento e Consulta/estatística & dados numéricos , Mecanismo de ReembolsoRESUMO
We present fully differential state-resolved experimental data for the dissociative ionization of molecular hydrogen induced through electron impact. Molecular-frame ionization cross sections are derived for transitions from the X{1}Sigma{g}{+} molecular ground state to the 1ssigma{g}, 2psigma{u}, 2ssigma{g}, and 2ppi{u} states of H2+. For transitions to the 2ssigma{g} and 2ppi{u} states, a strong orientation dependence in the cross sections is revealed, with "side-on" preferred to "end-on" collisions and a propensity for the fragment proton to emerge along the normal to the scattering plane.
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Highly pathogenic avian influenza viruses of the H5N1 subtype are responsible for an increasing number of infections in humans since 2003. More than 60% of the infections is lethal and new infections are reported frequently. In the light of the pandemic threat caused by these events the rapid availability of safe and effective vaccines is desirable. Modified vaccinia virus Ankara (MVA) expressing the HA gene of an influenza A/H5N1 virus is a promising candidate vaccine that induced protective immunity against infection with homologous and heterologous influenza A/H5N1 viruses in mice. We also evaluated the recombinant MVA vector expressing the HA of influenza A/H5N1 virus A/Vietnam/1194/04 (MVA-HA-VN/04) in non-human primates. Cynomolgus macaques were immunized twice and then challenged with influenza virus A/Vietnam/1194/04 (clade 1) or A/Indonesia/5/05 (clade 2.1) to assess the level of protective immunity. Immunization with MVA-HA-VN/04 induced (cross-reactive) antibodies and prevented virus replication in the upper and lower respiratory tract and the development of severe necrotizing bronchointerstitial pneumonia. Therefore MVA-HA-VN/04 is a promising vaccine candidate for the induction of protective immunity against highly pathogenic avian influenza A/H5N1 viruses.
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Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Virus da Influenza A Subtipo H5N1/imunologia , Vacinas contra Influenza/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Animais , Anticorpos Antivirais/sangue , Feminino , Macaca fascicularis , Camundongos , Camundongos Endogâmicos C57BL , Vaccinia virus/imunologiaRESUMO
BACKGROUND: Highly pathogenic avian influenza viruses of the H5N1 subtype have been responsible for an increasing number of infections in humans since 2003. More than 60% of infected individuals die, and new infections are reported frequently. In light of the pandemic threat caused by these events, the rapid availability of safe and effective vaccines is desirable. Modified vaccinia virus Ankara (MVA) expressing the hemagglutinin (HA) gene of H5N1 viruses is a promising candidate vaccine that induced protective immunity against infection with homologous and heterologous H5N1 influenza virus in mice. METHODS: In the present study, we evaluated a recombinant MVA vector expressing the HA gene of H5N1 influenza virus A/Vietnam/1194/04 (MVA-HA-VN/04) in nonhuman primates. Cynomolgus macaques were immunized twice and then were challenged with influenza virus A/Vietnam/1194/04 (clade 1) or A/Indonesia/5/05 (clade 2.1) to assess the level of protective immunity. RESULTS: Immunization with MVA-HA-VN/04 induced (cross-reactive) antibodies and prevented virus replication in the upper and lower respiratory tract and the development of severe necrotizing bronchointerstitial pneumonia. CONCLUSION: Therefore, MVA-HA-VN/04 is a promising vaccine candidate for the induction of protective immunity against highly pathogenic H5N1 avian influenza viruses in humans.
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Hemaglutininas/imunologia , Virus da Influenza A Subtipo H5N1/imunologia , Vacinas contra Influenza , Infecções por Orthomyxoviridae/prevenção & controle , Vaccinia virus/genética , Animais , Anticorpos Antivirais/sangue , Encéfalo/virologia , Hemaglutininas/genética , Hemaglutininas/metabolismo , Imuno-Histoquímica , Virus da Influenza A Subtipo H5N1/isolamento & purificação , Pulmão/patologia , Pulmão/virologia , Macaca fascicularis , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/patologia , Recombinação Genética , Sistema Respiratório/virologia , Baço/virologia , Vacinas Sintéticas , Vaccinia virus/classificação , Vaccinia virus/metabolismoRESUMO
This article presents a new type of low-energy crossed-beam electron spectrometer for measuring angular differential cross sections of electron-impact excitation of atomic and molecular targets. Designed for investigations at energies close to excitation thresholds, the spectrometer combines a pulsed electron beam with the time-of-flight technique to distinguish between scattering channels. A large-area, position-sensitive detector is used to offset the low average scattering rate resulting from the pulsing duty cycle, without sacrificing angular resolution. A total energy resolution better than 150 meV (full width at half maximum) at scattered energies of 0.5-3 eV is achieved by monochromating the electron beam prior to pulsing it. The results of a precision measurement of the differential cross section for electron-impact excitation of helium, at an energy of 22 eV, are used to assess the sensitivity and resolution of the spectrometer.
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The development of blood products as medicines initially took place on the national level in various countries, which resulted in considerable diversity of mechanisms and stringency of regulatory oversight. The scenario changed dramatically with the catastrophic experience that severe virus infections had been transmitted by blood products world-wide. Blood products, which had been regulated differently in the member states, became subject to the European pharmaceutical legislation in 1989. A specialized directive regulating the blood transfusion sector and the collection of plasma for fractionation was enacted in 2002. The European Community, particularly the Commission and the European Medicines Agency, is continuously refining the requirements, providing detailed technical and scientific guidance. In addition, institutions of the Council of Europe play an important role in the transfusion sector, the elaboration of the European Pharmacopoeia prescriptions, and the co-ordination of Official Medicines Control Laboratory or Laboratories batch release. However, further and sustained efforts towards international harmonization are needed. There are already important mechanisms in place, such as the International Conference on Harmonization initiative, which is producing internationally recognized guidelines on central issues. Another important achievement is the common technical document format, which enables the use of uniform applications for marketing authorization. However, there is still room for progress, for example, questions regarding regulatory requirements for licensing of in vitro diagnostic devices, or mutual recognition of inspections. The World Health Organization continues to play an important role in harmonization, both substantially by the production of high-level guidance documents or the establishment of physical international standard preparations, and in a more general sense by providing a platform for international collaboration. A very important aspect is the transparency of the creation and refinement of regulatory requirements. It is currently the rule that draft legal texts, monographs and guidelines are published for a consultation period before adoption. Effort and attention are required to keep track of the developments. However, in the era of modern electronic communication tools, the necessary information can be found on websites and comments can easily be submitted. Networking and exchange of information will continue to be crucial for development and maintenance of sound and balanced regulatory requirements.
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Transfusão de Componentes Sanguíneos/legislação & jurisprudência , Cooperação Internacional , Programas de Rastreamento/normas , Remoção de Componentes Sanguíneos/normas , Transfusão de Componentes Sanguíneos/efeitos adversos , Qualidade de Produtos para o Consumidor , Europa (Continente) , Humanos , Programas de Rastreamento/métodos , Farmacopeias como Assunto , Controle de Qualidade , Testes Sorológicos/métodosRESUMO
A new spectrometer is described for measuring the momentum distributions of scattered electrons arising from electron-atom and electron-molecule ionization experiments. It incorporates and builds on elements from a number of previous designs, namely, a source of polarized electrons and two high-efficiency electrostatic electron energy analyzers. The analyzers each comprise a seven-element retarding-electrostatic lens system, four toroidal-sector electrodes, and a fast position-and-time-sensitive two-dimensional delay-line detector. Results are presented for the electron-impact-induced ionization of helium and the elastic scattering of electrons from argon and helium which demonstrate that high levels of momentum resolution and data-collection efficiency are achieved. Problematic aspects regarding variations in collection efficiency over the accepted momentum phase space are addressed and a methodology for their correction presented. Principles behind the present design and previous designs for electrostatic analyzers based around electrodes of toroidal-sector geometry are discussed and a framework is provided for optimizing future devices.
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This review summarizes scientific, ethical and regulatory aspects of Phase I clinical trials with monoclonal antibodies. The current standard requirements for pre-clinical testing and for clinical study design are presented. The scientific considerations discussed herein are generally applicable, the view on legal requirements for clinical trials refer to the German jurisdiction only. The adverse effects associated with the TGN1412 Phase I trial indicate that the predictive value of pre-clinical animal models requires reevaluation and that, in certain cases, some issues of clinical trial protocols such as dose fixing may need refinement or redesign. Concrete safety measures, which have been proposed as a consequence of the TGN1412 event include introduction of criteria for high-risk antibodies, sequential inclusion of trial participants and implementation of pre-Phase I studies where dose calculation is based on the pre-clinical No Effect Level instead of the No Observed Adverse Effect Level. The recently established European clinical trials database (EUDRACT Database) is a further safety tool to expedite the sharing of relevant information between scientific authorities.
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Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Ensaios Clínicos Fase I como Assunto/legislação & jurisprudência , Aprovação de Drogas/legislação & jurisprudência , Experimentação Humana/legislação & jurisprudência , Legislação de Medicamentos , Projetos de Pesquisa , Sistemas de Notificação de Reações Adversas a Medicamentos , Animais , Anticorpos Monoclonais/toxicidade , Anticorpos Monoclonais Humanizados , Antineoplásicos/toxicidade , Ensaios Clínicos Fase I como Assunto/ética , Ensaios Clínicos Fase I como Assunto/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Revisão Ética , Alemanha , Guias como Assunto , Experimentação Humana/ética , Humanos , Nível de Efeito Adverso não Observado , Valores de Referência , Medição de Risco , Testes de ToxicidadeRESUMO
We present high-precision (e,2e) measurements and calculations for the e-He four-body Coulomb breakup problem. Cross-section ratios for ionization and excitation of the first three excited states of He+ relative to the ground state have been measured for incident energies between 112 and 319 eV. Comparing the data with predictions from a state-of-the-art hybrid distorted-wave+convergent R matrix with pseudostates (close coupling) approach shows that treating the projectile-target interaction at least to second order is crucial to obtain reasonable agreement between theory and experiment. Nevertheless, our benchmark studies reveal significant theoretical problems for the symmetric energy-sharing cases, thus indicating the need for further improvement.
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Simultaneous ionization and excitation of helium atoms by 500 eV electron impact is observed by a triple coincidence of an ionized slow electron, the recoiling He+ ion, and the radiated vacuum ultraviolet photon (lambda< or =30.4 nm). Kinematically complete differential cross sections are presented for the He+(2p)2P final ionic state, demonstrating the feasibility of a quantum mechanically complete experiment. The experimental data are compared to predictions from state-of-the-art numerical calculations. For large momentum transfers, a first-order treatment of the projectile-target interaction can reproduce the experimental angular dependence, but a second-order treatment is required to obtain consistent magnitudes.
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Jaagsiekte retrovirus (JSRV) causes ovine pulmonary adenomatosis (OPA) that resembles bronchioloalveolar carcinoma (BAC) in humans. To test the possible role of JSRV in human diseases, DNA specimens from 103 individuals either healthy or suffering from lung carcinomas were analyzed for JSRV sequences. orf-x sequences were detected in 19 of 64 samples and gag-prt sequences in 4 of 38 samples, predominantly in individuals from Africa. Sequences obtained from orf-x amplimers varied in-between each other and differed from control endogenous ovine JSRV sequence. No association with lung cancer was found. This is the first report of JSRV-like sequences detected in humans.
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Adenocarcinoma Bronquioloalveolar/virologia , Sequência de Bases , Betaretrovirus/genética , Retrovirus Jaagsiekte de Ovinos/genética , Neoplasias Pulmonares/virologia , Ovinos/virologia , Animais , Camarões , Carcinoma de Células Pequenas/virologia , Humanos , Dados de Sequência Molecular , Nigéria , Adenomatose Pulmonar Ovina/virologia , Alinhamento de Sequência , Análise de Sequência de DNARESUMO
The principle of live attenuated influenza vaccines has been known for many decades. However, the pharmaceutical and clinical development according to current regulations, of modern live influenza vaccines based on cold adapted influenza viruses (CAIV) started only recently and these vaccines will most probably become an alternative within the next couple of years to licensed inactivated influenza vaccines that have been used routinely since the early 1940s. In contrast to contemporary trivalent inactivated influenza vaccines, which are administered intramuscularly, trivalent CAIV-based vaccines will be administered intranasally as a spray. Quality, safety and efficacy aspects related to CAIV vaccines as well as possible risks linked to the widespread use of these vaccines will be discussed in the following overview and compared to established influenza vaccines. Moreover, issues of practicality of CAIV vaccines focusing on the necessity of an annual update of influenza vaccines are addressed.