RESUMEN
Wolfram syndrome (WS) is an ultra-rare progressive neurodegenerative disorder defined by early-onset diabetes mellitus and optic atrophy. The majority of patients harbour recessive mutations in the WFS1 gene, which encodes for Wolframin, a transmembrane endoplasmic reticulum protein. There is limited availability of human ocular and brain tissues, and there are few animal models for WS that replicate the neuropathology and clinical phenotype seen in this disorder. We, therefore, characterised two wfs1 zebrafish knockout models harbouring nonsense wfs1a and wfs1b mutations. Both homozygous mutant wfs1a-/- and wfs1b-/- embryos showed significant morphological abnormalities in early development. The wfs1b-/- zebrafish exhibited a more pronounced neurodegenerative phenotype with delayed neuronal development, progressive loss of retinal ganglion cells and clear evidence of visual dysfunction on functional testing. At 12 months of age, wfs1b-/- zebrafish had a significantly lower RGC density per 100 µm2 (mean ± standard deviation; 19 ± 1.7) compared with wild-type (WT) zebrafish (25 ± 2.3, p < 0.001). The optokinetic response for wfs1b-/- zebrafish was significantly reduced at 8 and 16 rpm testing speeds at both 4 and 12 months of age compared with WT zebrafish. An upregulation of the unfolded protein response was observed in mutant zebrafish indicative of increased endoplasmic reticulum stress. Mutant wfs1b-/- zebrafish exhibit some of the key features seen in patients with WS, providing a versatile and cost-effective in vivo model that can be used to further investigate the underlying pathophysiology of WS and potential therapeutic interventions.
Asunto(s)
Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Síndrome de Wolfram/genética , Síndrome de Wolfram/fisiopatología , Animales , Codón sin Sentido , Modelos Animales de Enfermedad , Técnicas de Inactivación de Genes , Mutación , Atrofia Óptica , Respuesta de Proteína Desplegada , Síndrome de Wolfram/metabolismo , Pez CebraRESUMEN
OBJECTIVES: Involvement of people living with HIV (PLHIV) in the design of HIV cure studies is important, given the potential risks to participants. We present results of an international survey of PLHIV to define these issues and inform cure research. METHODS: PLHIV were recruited in June-November 2014 through HIV websites, advocacy forums, social media and 12 UK HIV clinics. The survey included questions concerning demographics, HIV disease history, the desirability of types of cure and the patient's willingness to accept potential toxicity and treatment interruption (TI). We examined factors associated with TI and willingness to accept substantial risks. RESULTS: A total of 982 PLHIV completed the survey; 87% were male, 79% white and 81% men who have sex with men (MSM). Fifty-one per cent were aged 25-44 years and 69% were UK residents. The median time since diagnosis was 7 years [interquartile range (IQR) 2-17 years]. Eighty-eight per cent were receiving antiretrovirals (91% reported undetectable viral load). Health/wellbeing improvements (96%) and an inability to transmit HIV (90%) were more desirable cure characteristics than testing HIV-negative (69%). Ninety-five per cent were interested in participating in cure studies, and 59% were willing to accept substantial risks. PLHIV with a low CD4 count [201-350 cells/µL vs. ≥ 350 cells/µL; odds ratio (OR) 2.11; 95% confidence interval (CI) 1.11-4.00] were more likely to accept risks, whereas those with limited knowledge of HIV treatments vs. excellent/good knowledge and those aged ≥ 65 years vs. 45-64 years were less likely to accept risks [OR 0.58 (95% CI 0.37-0.90) and OR 0.18 (95% CI 0.07-0.45), respectively]. TI was acceptable for 62% of participants, with the main concerns being becoming unwell (82%), becoming infectious (76%) and HIV spreading through the body (76%). CONCLUSIONS: Cure research was highly acceptable to the PLHIV surveyed. Most individuals would accept risks, including TI, even in the absence of personal benefit. An optimal cure would improve health and minimize onward transmission risk.
Asunto(s)
Actitud , Ensayos Clínicos como Asunto , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/psicología , Aceptación de la Atención de Salud/psicología , Participación del Paciente/psicología , Adolescente , Adulto , Anciano , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reino Unido , Adulto JovenRESUMEN
(1) H MRS measurements of lactate are often confounded by overlapping lipid signals. Double-quantum (DQ) filtering eliminates lipid signals and permits single-shot measurements, which avoid subtraction artefacts in moving tissues. This study evaluated a single-voxel-localized DQ filtering method qualitatively and quantitatively for measuring lactate concentrations in the presence of lipid, using high-grade brain tumours in which the results could be compared with standard acquisition as a reference. Paired standard acquisition and DQ-filtered (1) H MR spectra were acquired at 3T from patients receiving treatment for glioblastoma, using fLASER (localization by adiabatic selective refocusing using frequency offset corrected inversion pulses) single-voxel localization. Data were acquired from 2 × 2 × 2 cm(3) voxels, with a repetition time of 1 s and 128 averages (standard acquisition) or 256 averages (DQ-filtered acquisition), requiring 2.15 and 4.3 min respectively. Of 37 evaluated data pairs, 20 cases (54%) had measureable lactate (fitted Cramér-Rao lower bounds ≤ 20%) in either the DQ-filtered or the standard acquisition spectra. The measured DQ-filtered lactate signal was consistently downfield of lipid (1.33 ± 0.03 ppm vs 1.22 ± 0.08 ppm; p = 0.002), showing that it was not caused by lipid breakthrough, and that it matched the lactate signal seen in standard measurements (1.36 ± 0.02 ppm). In the absence of lipid, similar lactate concentrations were measured by the two methods (mean ratio DQ filtered/standard acquisition = 1.10 ± 0.21). In 7/20 cases with measurable lactate, signal was not measureable in the standard acquisition owing to lipid overlap but was quantified in the DQ-filtered acquisition. Conversely, lactate was undetected in seven DQ-filtered acquisitions but visible using the standard acquisition. In conclusion, the DQ filtering method has proven robust in eliminating lipid and permits uncontaminated measurement of lactate. This is important validation prior to use in tissues outside the brain, which contain large amounts of lipid and which are often susceptible to motion.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Ácido Láctico/metabolismo , Imagen Molecular/métodos , Espectroscopía de Protones por Resonancia Magnética/métodos , Procesamiento de Señales Asistido por Computador , Algoritmos , Humanos , Imagen por Resonancia Magnética/métodos , Clasificación del Tumor , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Experiments to measure the hydrogen uptake kinetics of DEB getter/Pd catalyst/activated carbon pellets have been performed under isothermal isobaric conditions. The extracted kinetics were then used to predict the performance of the getter pellets under different temperatures and pressures, including nonisobaric situations. For isothermal isobaric uptake at higher H2 pressure (666.6-2666.5 Pa), H2 solubility in the getter matrix is responsible for the uptake observed up to a 40-60% reacted fraction. Once the hydrogenated product becomes thicker, the diffusions of the reactants (atomic hydrogen and getter molecules) toward the reaction front become the rate limiting step. However, in a dynamic but very low H2 pressure, encountered in many vacuum electronic applications, the hydrogen spillover effect, over micrometer scale, becomes the dominant reaction mechanism. Despite such a complex dependence of the rate limiting mechanisms on the experimental environment, there is good agreement between kinetic prediction models and experiments. The investigation also reveals that the ultimate uptake capacity in the getter pellets scales inversely with the free volume of the vacuum vessel in which the DEB getter pellets are used, and that DEB getter pellets' performance greatly deteriorates during the final 10-15% capacity (as evidenced by the sharp bend in the slopes of the reacted fraction vs time curves at 85-90% reacted fraction).
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/prevención & control , Fármacos Anti-VIH/uso terapéutico , Seropositividad para VIH/tratamiento farmacológico , Seropositividad para VIH/transmisión , Condones , Composición Familiar , Femenino , Heterosexualidad , Humanos , Masculino , Cumplimiento de la Medicación , Educación del Paciente como Asunto , Factores de Riesgo , Reino Unido/epidemiología , Carga ViralRESUMEN
Computerised videokeratography is increasing in sophistication and accuracy. The Orbscan II Videokeratographer combines the advantages of Placido derived and slit-scanning derived topography, to acquire shape information on the posterior surface of the cornea. The purpose of this paper is to construct a model of slit-scanning elevation topography and highlight potential sources of variation in this methodology. Ray tracing calculations were performed on a defined, theoretical, spherical model to obtain a pachymetric measurement. These calculations were tested by comparing the pachymetry measurement derived from the model, over a refractive index shift from 1.376 to 1.400 with the pachymetry measurement obtained by Orbscan II, of a human eye, with an identical alteration in refractive index. The two methods of measurement differed by only 0.157 microm, suggesting that the model is a good representation of slit-scanning elevation topography, and that refractive index variations have only a minimal effect on Orbscan II pachymetry measurement.
Asunto(s)
Enfermedades de la Córnea/diagnóstico , Topografía de la Córnea/métodos , Topografía de la Córnea/instrumentación , Humanos , Modelos Biológicos , Refracción Ocular , Sensibilidad y EspecificidadRESUMEN
To investigate the potential usefulness of u.v. germicidal irradiation (UVGI) in preventing the spread of Burkholderia cepacia, an important pathogen in cystic fibrosis (CF), the in-vitro susceptibility of B. cepacia to UVGI was determined. Five strains were exposed to UVGI from a 7.2-W source. Burkholderia cepacia was less susceptible to UVGI than other important CF-related pathogens, namely Staphylococcus aureus and Pseudomonas aeruginosa, but was more susceptible than Stenotrophomonas maltophilia. No strain of B. cepacia survived longer than an 8 s exposure to UVGI, with doses required to achieve 1 log reduction in bacterial numbers ranging from 28.3 to 57.5 J m(-2).
Asunto(s)
Burkholderia cepacia/efectos de la radiación , Fibrosis Quística/microbiología , Rayos Ultravioleta , Infecciones por Burkholderia/microbiología , Relación Dosis-Respuesta en la Radiación , Humanos , Pseudomonas aeruginosa/efectos de la radiación , Dosis de Radiación , Staphylococcus aureus/efectos de la radiaciónRESUMEN
The world-wide occurrence of tuberculosis (TB) is very high, and in many parts of the world prevalence has reached epidemic proportions. While the WHO's global 'directly observed therapy short-course' (DOTS) programme has yielded some notable successes, it has reached only 12% of the world's TB cases (1996 data). This suggests that the use of drug therapy alone is not enough to solve the global TB problem and that prevention using public health engineering techniques may provide a complementary solution. There are a number of engineering control strategies, such as the use of ultraviolet germicidal irradiation (UVGI) and advanced ventilation techniques, which can be used to combat the spread of Mycobacterium tuberculosis and other airborne pathogens. This paper describes a pilot study currently being undertaken at the Leeds General Infirmary in the UK, which is investigating the use of UVGI to disinfect air in ward spaces.
Asunto(s)
Control de Infecciones/métodos , Tuberculosis Pulmonar/prevención & control , Microbiología del Aire , Infección Hospitalaria/prevención & control , Desinfección/métodos , Humanos , Modelos Teóricos , Mycobacterium tuberculosis , Proyectos Piloto , Tuberculosis Pulmonar/microbiología , Rayos Ultravioleta , VentilaciónRESUMEN
Results from simulations of weight perturbation as an on-chip learning scheme for analogue VLSI neural networks are presented. The limitations of analogue hardware are modelled as realistically as possible. Thus synaptic weight precision is defined according to the smallest change in the weight setting voltage which gives a measurable change at the output of the corresponding neuron. Tests are carried out on a hard classification problem constructed from mobile robot navigation data. The simulations show that the degradation in classification performance on a 500-pattern test set caused by the introduction of realistic hardware constraints is acceptable: with 8-bit weights, updated probabilistically and with a simplified output error criterion, the error rate increases by no more than 7% when compared with weight perturbation implemented with full 32-bit precision.
Asunto(s)
Inteligencia Artificial , Computadores Analógicos , Redes Neurales de la Computación , Algoritmos , Bases de Datos Factuales , Neuronas , Robótica/instrumentación , SinapsisRESUMEN
School attendance and school achievement were the parameters studied to assess the pediatric cancer patient's ability to learn and keep pace with their peers. Effects of CNS prophylaxis, as either intrathecal methotrexate (IT) alone or intrathecal methotrexate given in addition to cranial radiation (CRT), were studied in two groups. A third group of cancer patients who received no CNS prophylaxis, and two comparison groups, siblings and a matched sample of children, also participated in the study. Impairment in central nervous system function was measured by means of psychological testing, neurological examination, and computer-assisted tomography. Patients who received central nervous system prophylactic treatments at an early age had poorer performance on verbal IQ scores, with comprehension and arithmetic subscores being most affected. Patients who received both cranial radiotherapy plus intrathecal methotrexate showed a decrease in six out of seven categories of instruction when grades from the year prior to diagnosis were compared to those obtained 3 years after diagnosis. The combined groups of patients with leukemia had a lower grade point average and poorer school attendance than did the comparison groups.
Asunto(s)
Neoplasias Encefálicas/terapia , Neoplasias/terapia , Pruebas Psicológicas , Logro , Adolescente , Encéfalo/diagnóstico por imagen , Neoplasias Encefálicas/psicología , Niño , Preescolar , Femenino , Humanos , Pruebas de Inteligencia , Masculino , Neoplasias/psicología , Examen Neurológico , Tomografía Computarizada por Rayos XRESUMEN
A urinary assay (17 kgs/creatinine) was used to measure compliance in 31 acute lymphocytic leukemia patients under 15 years of age receiving oral prednisone. Demographic data and psychological test responses of patients and their parents were correlated with the urinary assays. Results indicated that while the rate of compliance was the same for boys and girls, the psychological correlates were very different. Parental personality traits and attitudes were more involved with boy's compliance than with girl's. Some of the parent variables associated with compliance in boys were hostility, anxiety, and obsessive-compulsive behavior. Parents described compliant boys as vulnerable. These traits usually are considered maladaptive but in this case appear to facilitate boy's compliance. For girls, far fewer parent variables were associated with compliance. Parents seemed to have less worry and concern about their daughters and presumably give them the responsibility for their own medication. It was the girl's own anxiety which predicted compliance.
Asunto(s)
Cooperación del Paciente , Adolescente , Adulto , Niño , Preescolar , Creatinina/análisis , Femenino , Humanos , Leucemia Linfoide/tratamiento farmacológico , MMPI , Masculino , Relaciones Padres-Hijo , Inventario de Personalidad , Pruebas Psicológicas , Factores Sexuales , Orina/análisisAsunto(s)
Crecimiento , Acontecimientos que Cambian la Vida , Privación Materna , Neoplasias/psicología , Desnutrición Proteico-Calórica/etiología , Relaciones entre Hermanos , Adulto , Aniversarios y Eventos Especiales , Niño , Preescolar , Muerte , Femenino , Humanos , Lactante , Masculino , Desnutrición Proteico-Calórica/psicologíaRESUMEN
Several developing behaviors of a single infant are tracked via direct and continuous measurement through the period of acquisition and decay of these behaviors. Changes in frequency and duration are reported for four motor behaviors, and frequency changes for speech and nonspeech sounds. The relationship of changes in vocal behavior as motor skills are emerging is also explored.
Asunto(s)
Desarrollo del Lenguaje , Destreza Motora , Psicología Infantil , Factores de Edad , Humanos , Lactante , Recién Nacido , MasculinoRESUMEN
Twice a week observation of five infants' vocalizations during the first 30 weeks of life showed that hearing impaired infants displayed different language patterns than normally hearing infants. Developmental differences in vocal activity were observed by six weeks of age, suggesting that hearing impaired infants may differ from unimpaired infants earlier than has been believed.
Asunto(s)
Lenguaje Infantil , Desarrollo del Lenguaje , Llanto , Sordera/psicología , Femenino , Trastornos de la Audición/psicología , Humanos , Lactante , Estudios Longitudinales , Masculino , HablaRESUMEN
Infant development scales provide a one time measure of the number of scale items an infant performs and his standing relative to his age group. Repeated assessment indicates how many more items he can perform and whether his relative status has altered but does not measure actual changes in the same behaviors as development progresses. This paper discusses the importance of continuously measuring the same behavior over time as an alternative strategy. The developmental information is exemplified by the behavioral records of two infants observed over a 25-week period for changes in frequency and duration of three prone position motor responses.