RESUMO
Clinical management and clinical trials of patients with overt hepatic encephalopathy (OHE) are compromised by lack of standardized and reproducible tools for its clinical diagnosis or for caregiver (CG) identification of OHE manifestations which merit medical evaluation. Using an iterative Delphi method, Steering Committee and international hepatologist panel, the West Haven (WH) scale was modified to develop and operationalize a clinician tool for OHE identification and grading (HE Grading Instrument, HEGI™). Major diagnostic criteria included disorientation to time, place, and person, asterixis, lethargy, and coma. Minimum HEGI requirements for OHE diagnosis included: (1) disorientation, or (2) presence of both lethargy and asterixis, or (3) coma. Inter- and intra-rater HEGI reproducibility were 97 % and 98 %, respectively. When applied to a phase II clinical trial population of 178 patients with 388 OHE episodes, HEGI demonstrated excellent concordance with investigator judgement. Additionally, a multi-stage study was conducted to develop a daily CG e-diary, based on OHE manifestations recognizable by CG including speech difficulties, unusual behavior, forgetfulness, confusion, disorientation and level of consciousness. The e-diary was designed for use on smart phone, laptop or desktop, utilized branching logic and skip patterns, incorporated automatic daily completion reminders and real time alerts to clinical sites to facilitate daily standardized CG input and was found to be user friendly and understandable. The HEGI and e-diary, which were developed using methodology accepted by regulatory authorities, are designed to facilitate the design and interpretation of clinical trials for OHE and improve outcomes for OHE patients in clinical practice.
Assuntos
Cuidadores/psicologia , Técnica Delphi , Registros Eletrônicos de Saúde , Encefalopatia Hepática/psicologia , Prontuários Médicos , Médicos , Idoso , Cuidadores/tendências , Registros Eletrônicos de Saúde/tendências , Feminino , Encefalopatia Hepática/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Médicos/tendências , Resultado do TratamentoRESUMO
Hypomyelinating leukodystrophies (HLDs) are a group of neurodevelopmental disorders that affect proper formation of the myelin sheath in the central nervous system. They are characterized by developmental delay, hypotonia, spasticity, and variable intellectual disability. In the past various classification systems for HLDs have been used, based on imaging findings, clinical manifestation, and organelle-specific disorders. Here we present a molecular insight into HLDs based on a defect in specific gene engaged in myelination. We discuss recent findings on pathogenesis, clinical presentation, and imaging related to these disorders. We focus on HLDs that are in use in differential diagnostics of Pelizaeus-Merzbacher disease (PMD), with a special emphasis on Allan-Herndon-Dudley syndrome (AHDS), an X-linked condition with delayed myelination due to thyroid transport disturbances. On the background of previously published patients we describe a proband initially considered as presenting with a severe PMD, whose diagnosis of AHDS due to a novel nonsense SLC16A2 mutation unraveled two previously undiagnosed generations of affected males who died in infancy from unexplained reasons. Since AHDS is found to be a relatively frequent cause of X-linked intellectual disability, we emphasize the need for determining the whole thyroid profile especially in hypotonic males with a delay of psychomotor development.
Assuntos
Leucoencefalopatias/genética , Deficiência Intelectual Ligada ao Cromossomo X/genética , Hipotonia Muscular/genética , Atrofia Muscular/genética , Doença de Pelizaeus-Merzbacher/genética , Criança , Pré-Escolar , Diagnóstico Diferencial , Genes Ligados ao Cromossomo X , Humanos , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/metabolismo , Masculino , Deficiência Intelectual Ligada ao Cromossomo X/diagnóstico , Deficiência Intelectual Ligada ao Cromossomo X/metabolismo , Hipotonia Muscular/diagnóstico , Hipotonia Muscular/metabolismo , Atrofia Muscular/diagnóstico , Atrofia Muscular/metabolismo , Mutação , Bainha de Mielina/genética , Bainha de Mielina/metabolismo , Linhagem , Doença de Pelizaeus-Merzbacher/diagnóstico , Doença de Pelizaeus-Merzbacher/metabolismoRESUMO
BACKGROUND: Overt hepatic encephalopathy (OHE) is a frequent complication of decompensated cirrhosis. AIMS: A multicenter prospective observational study was performed to assess the most commonly recorded presenting manifestations of OHE and its associated health-care burden. METHODS: Qualifying patients must have experienced ≥1 OHE episode within 30 days of enrollment (qualifying OHE) and were followed for recurrence (on-study OHE). RESULTS: Two hundred and sixty-five patients were enrolled at 30 sites and followed for up to 9 months (mean 72 days). Seventy-two patients experienced 122 on-study episodes; with 72, 23, and 13 having ≥1, ≥2, or ≥3 on-study episodes with median days to occurrence of the 1st, 2nd, and 3rd episode of 34, 19, and 11, respectively. The most frequently recorded OHE manifestations included confusion (78 %), change in mental status (57 %), disorientation (48 %), lethargy (46 %), and asterixis (45 %). West Haven grade was used inconsistently and recorded for only 28 % of episodes. Most qualifying and on-study episodes occurred on rifaximin (60 and 82 %, respectively) and were associated with hospitalization (68 and 85 %, respectively). Twenty-three patients experienced ≥2 on-study episodes within 2 months of enrollment on average (median 45 days) and accounted for 60 % of on-study episodes. CONCLUSIONS: In this prospective study, OHE's most commonly recorded presenting manifestations included confusion, altered mental status, disorientation, lethargy, and asterixis. As reflected by frequent recurrence and hospitalizations, OHE, particularly the approximately 10 % of "high-resource-utilizing" patients with frequent recurrence, continues to pose a major unmet medical need and health-care burden despite the use of rifaximin.
Assuntos
Encefalopatia Hepática/patologia , Cirrose Hepática/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade , Rifamicinas/administração & dosagem , Rifamicinas/farmacologia , Rifaximina , Adulto JovemRESUMO
We have studied a solid-to-plasma transition by irradiating Al foils with the FLASH free electron laser at intensities up to 10(16) W/cm(2). Intense XUV self-emission shows spectral features that are consistent with emission from regions of high density, which go beyond single inner-shell photoionization of solids. Characteristic features of intrashell transitions allowed us to identify Auger heating of the electrons in the conduction band occurring immediately after the absorption of the XUV laser energy as the dominant mechanism. A simple model of a multicharge state inverse Auger effect is proposed to explain the target emission when the conduction band at solid density becomes more atomiclike as energy is transferred from the electrons to the ions. This allows one to determine, independent of plasma simulations, the electron temperature and density just after the decay of crystalline order and to characterize the early time evolution.
RESUMO
We investigated the damage mechanism of MoN/SiN multilayer XUV optics under two extreme conditions: thermal annealing and irradiation with single shot intense XUV pulses from the free-electron laser facility in Hamburg - FLASH. The damage was studied "post-mortem" by means of X-ray diffraction, interference-polarizing optical microscopy, atomic force microscopy, and scanning transmission electron microscopy. Although the timescale of the damage processes and the damage threshold temperatures were different (in the case of annealing it was the dissociation temperature of Mo2N and in the case of XUV irradiation it was the melting temperature of MoN) the main damage mechanism is very similar: molecular dissociation and the formation of N2, leading to bubbles inside the multilayer structure.
RESUMO
By use of high intensity XUV radiation from the FLASH free-electron laser at DESY, we have created highly excited exotic states of matter in solid-density aluminum samples. The XUV intensity is sufficiently high to excite an inner-shell electron from a large fraction of the atoms in the focal region. We show that soft-x-ray emission spectroscopy measurements reveal the electronic temperature and density of this highly excited system immediately after the excitation pulse, with detailed calculations of the electronic structure, based on finite-temperature density functional theory, in good agreement with the experimental results.
Assuntos
Alumínio/química , Elétrons , Processos Fotoquímicos , Gases em Plasma/química , Raios UltravioletaRESUMO
We investigated single shot damage of Mo/Si multilayer coatings exposed to the intense fs XUV radiation at the Free-electron LASer facility in Hamburg - FLASH. The interaction process was studied in situ by XUV reflectometry, time resolved optical microscopy, and "post-mortem" by interference-polarizing optical microscopy (with Nomarski contrast), atomic force microscopy, and scanning transmission electron microcopy. An ultrafast molybdenum silicide formation due to enhanced atomic diffusion in melted silicon has been determined to be the key process in the damage mechanism. The influence of the energy diffusion on the damage process was estimated. The results are of significance for the design of multilayer optics for a new generation of pulsed (from atto- to nanosecond) XUV sources.
Assuntos
Membranas Artificiais , Molibdênio/química , Molibdênio/efeitos da radiação , Dispositivos Ópticos , Silício/química , Silício/efeitos da radiação , Desenho de Equipamento , Análise de Falha de Equipamento , Teste de Materiais , Raios UltravioletaRESUMO
UNLABELLED: To study the effect of a new direct acting reversible P2Y(12) inhibitor, elinogrel (PRT060128), and the relation to cytochrome P450 (CYP) polymorphisms in patients with high platelet reactivity (HPR) on standard dual antiplatelet therapy. METHODS AND RESULTS: We studied the pharmacodynamic and pharmacokinetic effects of a single 60-mg oral dose of elinogrel in 20 of 45 previously stented stable patients with HPR. We also genotyped for CYP2C19*2,3,5,17 and CYP3A5*3. Platelet reactivity fell within 4 h of dosing, the earliest time point evaluated as measured by the following assays: maximum 5 and 10 microM ADP LTA (P < 0.001 for both vs. predosing); maximum 20 microM ADP LTA (P < 0.05); VerifyNow (P < 0.001); thrombelastography (P < 0.05); VASP phosphorylation (P < 0.01); and perfusion chamber assay (P < 0.05); this was reversible within 24 h in these same assays (P = ns vs. predosing for all assays). CYP2C19*2 was present in 44% of all patients but was more frequent in HPR patients (77% vs. 16%, P = 0.0004). CONCLUSIONS: HPR is reversibly overcome by a single 60-mg oral dose of elinogrel, a drug now being investigated in a phase 2 trial. CYP2C19*2 was associated with HPR during conventional dual antiplatelet therapy.
Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Aspirina/uso terapêutico , Plaquetas/efeitos dos fármacos , Doença da Artéria Coronariana/terapia , Inibidores da Agregação Plaquetária/uso terapêutico , Polimorfismo Genético , Antagonistas do Receptor Purinérgico P2 , Quinazolinonas/uso terapêutico , Sulfonamidas/uso terapêutico , Ticlopidina/análogos & derivados , Difosfato de Adenosina , Administração Oral , Idoso , Angioplastia Coronária com Balão/instrumentação , Hidrocarboneto de Aril Hidroxilases/metabolismo , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/metabolismo , Moléculas de Adesão Celular/sangue , Clopidogrel , Colágeno/uso terapêutico , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP3A/genética , Quimioterapia Combinada , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Proteínas dos Microfilamentos/sangue , Pessoa de Meia-Idade , Fenótipo , Fosfoproteínas/sangue , Fosforilação , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/farmacocinética , Quinazolinonas/administração & dosagem , Quinazolinonas/farmacocinética , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2Y12 , Stents , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Tromboelastografia , Ticlopidina/uso terapêuticoRESUMO
We present a new technique for the characterization of non-Gaussian laser beams which cannot be described by an analytical formula. As a generalization of the beam spot area we apply and refine the definition of so called effective area (A(eff)) [1] in order to avoid using the full-width at half maximum (FWHM) parameter which is inappropriate for non-Gaussian beams. Furthermore, we demonstrate a practical utilization of our technique for a femtosecond soft X-ray free-electron laser. The ablative imprints in poly(methyl methacrylate) - PMMA and amorphous carbon (a-C) are used to characterize the spatial beam profile and to determine the effective area. Two procedures of the effective area determination are presented in this work. An F-scan method, newly developed in this paper, appears to be a good candidate for the spatial beam diagnostics applicable to lasers of various kinds.
Assuntos
Lasers , Modelos Estatísticos , Simulação por Computador , Desenho Assistido por Computador , Desenho de Equipamento , Análise de Falha de Equipamento , Luz , Distribuição Normal , Espalhamento de Radiação , Raios XRESUMO
We have focused a beam (BL3) of FLASH (Free-electron LASer in Hamburg: lambda = 13.5 nm, pulse length 15 fs, pulse energy 10-40 microJ, 5 Hz) using a fine polished off-axis parabola having a focal length of 270 mm and coated with a Mo/Si multilayer with an initial reflectivity of 67% at 13.5 nm. The OAP was mounted and aligned with a picomotor controlled six-axis gimbal. Beam imprints on poly(methyl methacrylate) - PMMA were used to measure focus and the focused beam was used to create isochoric heating of various slab targets. Results show the focal spot has a diameter of < or =1 microm. Observations were correlated with simulations of best focus to provide further relevant information.
Assuntos
Lasers , Lentes , Teste de Materiais/instrumentação , Teste de Materiais/métodos , Difração de Raios X/instrumentação , Difração de Raios X/métodos , Desenho Assistido por Computador , Elétrons , Desenho de Equipamento , Análise de Falha de Equipamento , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
We report the first observation of single-shot soft x-ray laser induced desorption occurring below the ablation threshold in a thin layer of poly (methyl methacrylate)--PMMA. Irradiated by the focused beam from the Free-electron LASer in Hamburg (FLASH) at 21.7 nm, the samples have been investigated by atomic-force microscope (AFM) enabling the visualization of mild surface modifications caused by the desorption. A model describing non-thermal desorption and ablation has been developed and used to analyze single-shot imprints in PMMA. An intermediate regime of materials removal has been found, confirming model predictions. We also report below-threshold multiple-shot desorption of PMMA induced by high-order harmonics (HOH) at 32 nm. Short-time exposure imprints provide sufficient information about transverse beam profile in HOH's tight focus whereas long-time exposed PMMA exhibits radiation-initiated surface ardening making the beam profile measurement infeasible.
Assuntos
Lasers , Raios X , Compostos de Boro/efeitos da radiação , Carbono/efeitos da radiação , Elétrons , Terapia a Laser/métodos , Microscopia de Força Atômica , Polimetil Metacrilato , Espectrofotometria , Propriedades de Superfície , Raios UltravioletaRESUMO
DYT1 primary torsion dystonia is an autosomal dominant disorder caused by deletion of a GAG triplet in exon 5 of the DYT1 gene. A significant proportion of individuals with early-onset generalized dystonia is believed to be DYT1 mutation carriers. We assessed the frequency of the GAG deletion in the DYT1 gene in a group of 61 Polish probands with clinical diagnosis of primary dystonia. The deletion was identified in four probands presenting with early-onset generalized disease (7%). Further studies in probands' families revealed two symptomatic and nine asymptomatic mutation carriers. We tested all mutation-positive individuals for the presence of some common polymorphisms within the DYT1 gene. Two of the 15 mutation-positive individuals additionally carried polymorphisms in 3'-UTR of the gene. Early onset in a limb and progression toward a generalized form, but not family history of dystonia, are indicative of DYT1 dystonia in Polish dystonic individuals.
Assuntos
Distúrbios Distônicos/genética , Deleção de Genes , Chaperonas Moleculares/genética , Adolescente , Adulto , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polônia/epidemiologiaRESUMO
A linear accelerator based source of coherent radiation, FLASH (Free-electron LASer in Hamburg) provides ultra-intense femtosecond radiation pulses at wavelengths from the extreme ultraviolet (XUV; lambda<100nm) to the soft X-ray (SXR; lambda<30nm) spectral regions. 25-fs pulses of 32-nm FLASH radiation were used to determine the ablation parameters of PMMA - poly (methyl methacrylate). Under these irradiation conditions the attenuation length and ablation threshold were found to be (56.9+/-7.5) nm and approximately 2 mJ*cm(-2), respectively. For a second wavelength of 21.7 nm, the PMMA ablation was utilized to image the transverse intensity distribution within the focused beam at mum resolution by a method developed here.
RESUMO
The POU family of transcription factors plays a vital role in controlling cell-fate determination and the timing of cellular events in a number of tissues, including the nervous system. One such POU protein, SCIP, is expressed by Schwann cells in a tightly delimited developmental window termed promyelination. In the PNS, promyelination is functionally defined as the period following Schwann cell exit from the cell-cycle, but prior to the onset of myelination. Previous transgenic and gene ablation studies have shown that SCIP is a myelin-competence factor in the Schwann cell, where it is required for entry into, and the subsequent maintenance of promyelination. To further understand the molecular biology of the promyelination-to-myelination transition in the Schwann cell, we have undertaken a series of DDRTPCR studies to identify genes that are expressed during this phenotypic flux. Through these studies we have identified another POU gene, Brn-5, the expression of which has not previously been appreciated in the Schwann cell. Here we show that the developmental expression patterns of Brn-5 and SCIP are inverse, with Brn-5 stably expressed in the adult myelinating Schwann cell, but virtually absent during promyelination. Further, we show that the induction of the two genes is independent, with SCIP induction requiring activation of adenyl cyclase, whereas Brn-5 induction requires only GGF2. In addition, the induction of Brn-5 is exquisitely sensitive to neuregulin concentration, with higher levels inhibiting its expression. Following nerve injury, when GGF2 levels are elevated in the distal nerve, Brn-5 expression disappears, and SCIP is reexpressed.
Assuntos
Movimento Celular/fisiologia , Proteínas de Ligação a DNA/genética , Neuregulina-1/farmacologia , Células de Schwann/citologia , Células de Schwann/fisiologia , Fatores de Transcrição/genética , Animais , Diferenciação Celular/fisiologia , Células Cultivadas , Relação Dose-Resposta a Droga , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Camundongos , Camundongos Endogâmicos , Compressão Nervosa , Fator 6 de Transcrição de Octâmero , Fatores do Domínio POU , Nervo Isquiático/citologia , Nervo Isquiático/fisiologia , Degeneração Walleriana/fisiopatologiaRESUMO
The article refers to the bonds of the Silesian medicine with the Faculty of Medicine at the Jagiellonian University in interwar period. Fiftieth anniversary of the Silesian Academy of Medicine occurring in 1998 is a chance to recall these relationships. There is a special attention paid to graduates from the Jagiellonian University coming from historical Silesian who graduated from the University, who got doctor's certificates and University degrees. Some of them stayed at the University taking over high ranks, others came back to Silesia, where as high qualified physicians created medical personnel of manufacturing industry of Silesia.
Assuntos
Docentes de Medicina/história , Faculdades de Medicina/história , História do Século XX , PolôniaRESUMO
Together with the recently determined potential energy surface for the ground electronic state of HeH2+ [V. Spirko and W. P. Kraemer, J. Mol. Spectrosc. 172, 265-274 (1995)], the electric dipole moment components were calculated directly as expectation values with the corresponding length operators at the center of mass of the ion and using the variationally optimized configuration interaction wavefunctions. From the fitted potential energy and dipole moment functions all bound rotation-vibration energy levels and the line strengths of all dipole-allowed bound-bound transitions were evaluated variationally within the framework of the Sutcliffe-Tennyson Hamiltonian. Strong transitions, especially for the (He...H2)+ stretching motion, were obtained in the 500-800 cm-1 infrared frequency range. The present calculations demonstrate that the conditions for detecting the still unobserved rotation-vibration spectrum of HeH2+ are rather promising. Copyright 1997Academic Press