RESUMO
Two complementary approaches were used in search of the intracellular targets of the toxic PR poly-dipeptide encoded by the repeat sequences expanded in the C9orf72 form of amyotrophic lateral sclerosis. The top categories of PRn-bound proteins include constituents of non-membrane invested cellular organelles and intermediate filaments. PRn targets are enriched for the inclusion of low complexity (LC) sequences. Evidence is presented indicating that LC sequences represent the direct target of PRn binding and that interaction between the PRn poly-dipeptide and LC domains is polymer-dependent. These studies indicate that PRn-mediated toxicity may result from broad impediments to the dynamics of cell structure and information flow from gene to message to protein.
Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Dipeptídeos/metabolismo , Demência Frontotemporal/metabolismo , Peptídeos/metabolismo , Proteínas/metabolismo , Esclerose Lateral Amiotrófica/genética , Proteína C9orf72 , Expansão das Repetições de DNA , Dipeptídeos/química , Dipeptídeos/genética , Demência Frontotemporal/genética , Células HeLa , Humanos , Proteínas de Filamentos Intermediários/metabolismo , Peptídeos/química , Peptídeos/genética , Domínios Proteicos , Proteínas/genéticaRESUMO
BACKGROUND: As countries move towards or achieve measles elimination status, serosurveillance is an important public health tool. However, a major challenge of serosurveillance is finding a feasible, accurate, cost-effective, and high throughput assay to measure measles antibodyâ¯concentrationsâ¯and estimate susceptibility in a population. We conducted a systematic review to assess, characterize, and - to the extent possible - quantify the performance of measles IgG enzyme-linked assays (EIAs) compared to the gold standard, plaque reduction neutralization tests (PRNT). METHODS: We followed the PRISMA statement for a systematic literature search and methods for conducting and reporting systematic reviews and meta-analyses recommended by the Cochrane Screening and Diagnostic Tests Methods Group. We identified studies through PubMed and Embase electronic databases and included serologic studies detecting measles virus IgG antibodies among participants of any age from the same source population that reported an index (any EIA or multiple bead-based assays, MBA) and reference test (PRNT) using sera, whole blood, or plasma. Measures of diagnostic accuracy with 95% confidence intervals (CI) were abstracted for each study result, where reported. RESULTS: We identified 550 unique publications and identified 36 eligible studies for analysis. We classified studies as high, medium, or low quality; results from high quality studies are reported. Because most high quality studies used the Siemens Enzygnost EIA kit, we generate individual and pooled diagnostic accuracy estimates for this assay separately. Median sensitivity of the Enzygnost EIA was 92.1% [IQR = 82.3, 95.7]; median specificity was 96.9 [93.0, 100.0]. Pooled sensitivity and specificity from studies using the Enzygnost kit were 91.6 (95%CI: 80.7,96.6) and 96.0 (95%CI: 90.9,98.3), respectively. The sensitivity of all other EIA kits across high quality studies ranged from 0% to 98.9% with median (IQR) = 90.6 [86.6, 95.2]; specificity ranged from 58.8% to 100.0% with median (IQR) = 100.0 [88.7, 100.0]. CONCLUSIONS: Evidence on the diagnostic accuracy of currently available measles IgG EIAs is variable, insufficient, and may not be fit for purpose for serosurveillance goals. Additional studies evaluating the diagnostic accuracy of measles EIAs, including MBAs, should be conducted among diverse populations and settings (e.g., vaccination status, elimination/endemic status, age groups).
Assuntos
Sarampo , Humanos , Testes de Neutralização/métodos , Técnicas Imunoenzimáticas , Vírus do Sarampo , Sensibilidade e Especificidade , Anticorpos Antivirais , Imunoglobulina GRESUMO
Adults living with intellectual and developmental disabilities are often prescribed psychotropic medication on an "as needed" basis (PRN) in response to behavioural challenges. In the present study we conducted a retrospective analysis of medication administration records in the 6-months preceding and following discharge of 11 adults with intellectual and developmental disabilities to community settings from forensic inpatient units within a mental health hospital. We found a significant reduction in the frequency of PRN usage after discharge. We propose potential reasons for the difference in PRN administration across settings and make suggestions for future research.
Assuntos
Pacientes Internados , Deficiência Intelectual , Adulto , Humanos , Pacientes Internados/psicologia , Estudos Retrospectivos , Deficiência Intelectual/tratamento farmacológico , Alta do Paciente , Psicotrópicos/uso terapêuticoRESUMO
Low Earth Orbit (LEO) satellites have stronger received signals and more rapid geometry changes than Global Navigation Satellite System (GNSS) satellites, making them attractive for positioning, navigation, and timing (PNT) applications. Due to the low altitude, the LEO constellation requires more satellites to cover the entire globe and more Pseudo Random Noise (PRN) codes to realize Code Division Multiple Access (CDMA), which means greater receiver storage resources and receiver acquisition time. In this paper, different from the traditional methods that assign a unique PRN code to each satellite, we propose a novel method in which several satellites share the same PRN code, and simply demonstrate the feasibility and benefits of this method. To determine the minimum number of PRN codes needed for a constellation, we build a mathematical model. After the algorithm comparison, we improve the recursive largest first (RLF) algorithm so that it has a higher running speed and a smaller approximate optimal solution within a certain time period. By studying polar-orbiting and walker constellations, we find that if other satellite parameters remain the same, the higher the orbital altitude is, the more PRN codes are needed, and no matter what the orbital inclination is, the minimum number of PRN codes remains the same. Overall, it is feasible and meaningful for several satellites sharing the same PRN code to save storage resources and reduce the satellite acquisition time of the receiver. If this new technology is applied, the storage resources and the average satellite acquisition time of the receiver will be, at most, one-third of previous ones.
RESUMO
Recent reemergence of pertussis (whooping cough) in highly vaccinated populations and rapid expansion of Bordetella pertussis strains lacking pertactin (PRN), a common acellular vaccine antigen, have raised the specter of vaccine-driven evolution and potential return of what was once the major killer of children. The discovery that most circulating B. pertussis strains in the United States have acquired new and independent disruptive mutations in PRN is compelling evidence of strong selective pressure. However, the other 4 antigens included in acellular vaccines do not appear to be selected against so rapidly. We consider 3 aspects of PRN that distinguish it from other vaccine antigens, which might, individually or collectively, explain why only this antigen is being precipitously eliminated. An understanding of the increase in PRN-deficient strains should provide useful information for the current search for new protective antigens and provide broader lessons for the design of improved subunit vaccines.
Assuntos
Bordetella pertussis , Coqueluche , Proteínas da Membrana Bacteriana Externa , Criança , Humanos , Vacina contra Coqueluche , Fatores de Virulência de BordetellaRESUMO
BACKGROUND: In this quality improvement project, we set out to study the effectiveness and feasibility of using music as an adjunct or replacement for pharmacologic agitation management on an inpatient psychiatric unit. We hypothesized music intervention would not only assist in de-escalation/calming of agitated patients, but also reduce overall administration of PRN medications on the unit. METHOD: The project included 172 volunteer participants over 6 months: Three months without music available and 3 months with a music de-escalation option. During the latter period, patients were given the option of selecting a preferred music genre and provided with wireless headphones for up to 30 min. The number of as needed (PRN) medications administered for agitation and anxiety (including oral, sublingual, and intramuscular routes) was compiled from raw data using pharmacy records. Patients and nurses were provided with self-report surveys regarding the music intervention. RESULTS: The average weekly PRN medication administrations decreased significantly during the 3 months with music for both haloperidol (8.46 [+/- 1.79, p < 0.05] to 5.00 [+/- 1.44, p < 0.05] administrations/week) and olanzapine (9.69 [+/- 2.32, p < 0.05] to 4.62 [+/- 1.51, p < 0.05] administrations/week), compared to the 3 months prior to music implementation. There was a non-significant increase in administration of lorazepam (3.23 [+/- 1.09, p < 0.05] to 6.38 [+/- 2.46, p < 0.05] average administrations/week). The patient survey responses were 96% positive (non-neutral; either agree or strongly agree with calming effect). Nurses agreed that the project was easy to implement; 56% agreed that music helped to calm patients down. Other exploratory outcomes included observed reductions in average length of hospital stay and number of seclusion events. CONCLUSION: Music may play a significant role in reducing the utilization of PRN agitation medications on acute inpatient psychiatric units. More studies are needed to expand on these findings and explore the effect of PRN music on other therapeutic outcomes. TRIAL REGISTRATION: Protocol registration NCT04514432 , retrospectively registered on 08/13/2020.
Assuntos
Pacientes Internados , Música , Ansiedade , Estudos de Viabilidade , Haloperidol/uso terapêutico , Humanos , Agitação Psicomotora/tratamento farmacológicoRESUMO
BACKGROUND: To compare the efficacy of one initial intravitreal injection of conbercept (IVC) versus three monthly IVCs in patients with macular edema (ME) after branch retinal vein occlusion (BRVO). Both options were followed by a pro re nata (PRN) retreatment regimen. METHODS: This study retrospectively investigated and followed 60 patients with acute ME secondary to BRVO for over a year. 30 subjects received one initial injection (1 + PRN group); while, 30 received three monthly injections (3 + PRN group). The functional and anatomic outcomes were assessed during each follow-up. RESULTS: The general characteristics of the 60 subjects were as follows: mean [SD] age, 57.43 [13.06] years; 33 [55%] female; 36 [60%] non-ischemic form. Both groups showed a stable gain in visual acuity (VA) with similar logMAR (mean ± SD) (1 + PRN group 0.308 ± 0.399, 3 + PRN group 0.34 ± 0.352) during the first 12 months. Additionally, both groups exhibited a significant reduction in central foveal thickness (CFT) with no statistically significant difference between them (1 + PRN group 222.1 µm ± 197.1 µm, 3 + PRN group 228.4 µm ± 200.2 µm). Both treatment groups had similar improvements in logMAR and anatomic outcomes over time. The stratified analysis showed that patients with the non-ischemic form and those with the ischemic form had similar improvements in VA (0.346 ± 0.366 VS 0.29 ± 0.39, P = 0.575) during the 12 months follow-ups. The number of injections was lower in the 1 + PRN group (4.0 ± 1.6) than in the 3 + PRN group (4.7 ± 1.3) (P = 0.068). No adverse effects or unexpected safety issues were reported in either group. CONCLUSIONS: Conbercept yielded significant improvements in VA and CFT among patients with BRVO induced ME, independent of their retinal ischemia status. The results showed that the 3 + PRN regimen do not lead to better functional outcomes or lower treatment needs in clinical practice as compared to the 1 + PRN regimen.
Assuntos
Edema Macular/tratamento farmacológico , Proteínas Recombinantes de Fusão/administração & dosagem , Oclusão da Veia Retiniana/complicações , Tomografia de Coerência Óptica/métodos , Acuidade Visual , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Seguimentos , Humanos , Injeções Intravítreas , Edema Macular/diagnóstico , Edema Macular/etiologia , Masculino , Pessoa de Meia-Idade , Oclusão da Veia Retiniana/diagnóstico , Oclusão da Veia Retiniana/tratamento farmacológico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Intravitreal injections are a mandatory treatment for macular edema due to nAMD, DME and RVO. These chronic diseases usually need chronic treatment using intravitreal injections with anti-VEGF agents. Thus, many trials were performed to define the best treatment interval using pro re nata regimes (PRN), fixed regimes or treat-and-extend regimes (TE). However, real-world studies reveal a high rate of losing patients within a 2-year interval of treatment observation causing worse results. In this study we analyzed retrospectively 2 years of real-world experience with an individualized treat-and-extend injection scheme. METHODS: Since 2015 our treatment scheme for intravitreal injections has been switched from PRN to TE. Out of 102 patients 59 completed a follow up time of 2 years. Every patient received visual acuity testing, SD-OCT and slit lamp examination prior to every injection. At each visit an injection was performed and the treatment interval was adjusted mainly on SD-OCT based morphologic changes by increasing or reducing in 2-week steps. Individual changes of the treatment protocol by face-to-face communication between physician and patient were possible. RESULTS: After 1 year of treatment visual acuity gain in nAMD was 7.4 ± 2.2 ETDRS letters (n = 34; injection frequency: 7.4 ± 0.4) respectively 6.1 ± 4.7 in DME (n = 9; injection frequency: 8.4 ± 1.1) and 9.7 ± 4.5 in RVO (n = 16; injection frequency: 7.6 ± 0.5). After 2 years of treatment results were as following: nAMD: visual acuity gain 6.9 ± 2.1 (injection frequency: 12.6 ± 0.7); DME: 11.1 ± 5.1 (injection frequency: 14.0 ± 1.0); RVO: 7.5 ± 5.0 (injection frequency: 11.2 ± 0.9). Planned treatment exit after 2 year was achieved in 29.4% of patients in nAMD (0% after 1 year); 0% in DME (0% after 1 year); and 31.3% in RVO (0% after 1 year). Patients' persistence was 94.1% during the follow-up. CONCLUSION: Using a consequent and individualized TE regime in daily practice may lead to a high patients' persistence and visual acuity gains nearly comparable to those of large prospective clinical trials. Crucial factors are face-to-face communication with the patient as well as a stringent management regime. At this time TE may be the only instrument for proactive therapy which should therefore be regarded as a first-line tool in daily practice.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Neovascularização de Coroide/tratamento farmacológico , Retinopatia Diabética/tratamento farmacológico , Edema Macular/tratamento farmacológico , Oclusão da Veia Retiniana/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Degeneração Macular Exsudativa/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Bevacizumab/uso terapêutico , Neovascularização de Coroide/diagnóstico por imagem , Neovascularização de Coroide/fisiopatologia , Protocolos Clínicos , Retinopatia Diabética/diagnóstico por imagem , Retinopatia Diabética/fisiopatologia , Feminino , Seguimentos , Humanos , Injeções Intravítreas , Edema Macular/diagnóstico por imagem , Edema Macular/fisiopatologia , Masculino , Pessoa de Meia-Idade , Medicina de Precisão , Ranibizumab/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Oclusão da Veia Retiniana/diagnóstico por imagem , Oclusão da Veia Retiniana/fisiopatologia , Retratamento , Estudos Retrospectivos , Tomografia de Coerência Óptica , Resultado do Tratamento , Acuidade Visual/fisiologia , Degeneração Macular Exsudativa/diagnóstico por imagem , Degeneração Macular Exsudativa/fisiopatologiaRESUMO
The toxic proline:arginine (PRn) poly-dipeptide encoded by the (GGGGCC)n repeat expansion in the C9orf72 form of heritable amyotrophic lateral sclerosis (ALS) binds to the central channel of the nuclear pore and inhibits the movement of macromolecules into and out of the nucleus. The PRn poly-dipeptide binds to polymeric forms of the phenylalanine:glycine (FG) repeat domain, which is shared by several proteins of the nuclear pore complex, including those in the central channel. A method of chemical footprinting was used to characterize labile, cross-ß polymers formed from the FG domain of the Nup54 protein. Mutations within the footprinted region of Nup54 polymers blocked both polymerization and binding by the PRn poly-dipeptide. The aliphatic alcohol 1,6-hexanediol melted FG domain polymers in vitro and reversed PRn-mediated enhancement of the nuclear pore permeability barrier. These data suggest that toxicity of the PRn poly-dipeptide results in part from its ability to lock the FG repeats of nuclear pore proteins in the polymerized state. Our study offers a mechanistic interpretation of PRn poly-dipeptide toxicity in the context of a prominent form of ALS.
Assuntos
Transporte Ativo do Núcleo Celular , Proteína C9orf72/farmacologia , Expansão das Repetições de DNA/genética , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Poro Nuclear/metabolismo , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Animais , Biopolímeros , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Dipeptídeos/genética , Dipeptídeos/metabolismo , Dipeptídeos/farmacologia , Feminino , Glicóis/farmacologia , Humanos , Microscopia Confocal , Poro Nuclear/química , Poro Nuclear/efeitos dos fármacos , Poro Nuclear/ultraestrutura , Complexo de Proteínas Formadoras de Poros Nucleares/química , Complexo de Proteínas Formadoras de Poros Nucleares/ultraestrutura , Oócitos/ultraestrutura , Permeabilidade/efeitos dos fármacos , Ligação Proteica , Domínios Proteicos , Aglutininas do Germe de Trigo/metabolismo , Aglutininas do Germe de Trigo/farmacologia , Xenopus laevisRESUMO
The autocorrelation function (ACF) of the Binary Offset Carrier modulation (BOC) signal for Global Navigation Satellite System (GNSS) has multiple peaks, ambiguity is easily generated during the synchronization of the baseband signal. Some methods have been proposed to remove the ambiguity, but the performance is not suitable for high-order BOC signals or does not maintain narrow correlation characteristics. This paper proposes a sub-function reconstruction synchronization algorithm to solve this problem, of which the key is to design a new local auxiliary code: the local Pseudo-Random Noise (PRN) code is divided into several new codes with different delays. The auxiliary code performs a coherent integration operation with the received signal. Then, a correlation function without any positive side peaks is obtained by multiplying the two correlation results to make the acquisition/tracking completely unambiguous. The paper gives a design scheme of navigation signal acquisition/tracking and deduces the theoretical analysis of detection performance. The phase discrimination function is provided. The performance of the method is analyzed from both theoretical and simulation aspects. Compared with the Binary phase shift keying-like (BPSK-LIKE) method, Subcarrier Phase Cancellation (SCPC) method and the Autocorrelation Side-Peak Cancellation Technique (ASPeCT) method, the proposed method has the best detection probability for the acquisition, which is 0.5 dB-Hz better than ASPeCT. For tracking, the proposed method performs best in terms of phase-detection curve, anti-multipath performance, and anti-noise performance. For high-order BOC signals, the SRSA technique successfully removes the false lock points, and there is only one multipath error envelope, and the code tracking error is almost the same as the ASPeCT method.
RESUMO
During the 2008-2012 pertussis epidemic in Australia, pertactin (Prn)-negative Bordetella pertussis emerged. We analyzed 78 isolates from the 2013-2017 epidemic and documented continued expansion of Prn-negative ptxP3 B. pertussis strains. We also detected a filamentous hemagglutinin-negative and Prn-negative B. pertussis isolate.
Assuntos
Adesinas Bacterianas/genética , Proteínas da Membrana Bacteriana Externa/genética , Bordetella pertussis/genética , Fatores de Virulência de Bordetella/genética , Coqueluche/epidemiologia , Coqueluche/microbiologia , Adesinas Bacterianas/imunologia , Alelos , Austrália/epidemiologia , Proteínas da Membrana Bacteriana Externa/imunologia , Bordetella pertussis/classificação , Bordetella pertussis/imunologia , História do Século XXI , Humanos , Vacina contra Coqueluche/administração & dosagem , Vacina contra Coqueluche/imunologia , Filogenia , Fatores de Virulência de Bordetella/imunologia , Coqueluche/história , Coqueluche/prevenção & controleRESUMO
PURPOSE: To compare treatment efficacy of anti-VEGF medications following pro re nata (PRN, "as needed", monthly injections only in case of active disease) or treat and extend (T&E, progressive extension of treatment intervals up to 12 weeks depending on the clinical findings) treatment protocols in real-world conditions. METHODS: Retrospective, observational study. Patients diagnosed with age-related macular degeneration and without pre-treatment undergoing routine anti-VEGF treatment in one eye clinic in Switzerland were included. Treatment was performed according to local practices, using ranibizumab or aflibercept, and following T&E or PRN regimens. Changes in logMAR and injection intervals (time between two injections) for specific treatment periods were evaluated descriptively and using mixed models. RESULTS: In total, 1071 patients with 1332 treated eyes (ranibizumab/PRN 722, ranibizumab/T&E 191, aflibercept/T&E 419) were included in the analyses. At baseline, logMAR (mean ± SD) was similar in both ranibizumab treatment groups (PRN 0.63 ± 0.43, T&E 0.57 ± 0.42). In the ranibizumab/PRN group, logMAR was about 0.1 lower for all time intervals in the initial and maintenance phases in comparison with baseline, indicating an improvement in VA. By comparison, logMAR improved more strongly in the ranibizumab/T&E group (16 to < 22 months, - 0.19 [- 0.23-0.15]) in comparison with baseline. Comparing ranibizumab/T&E vs. aflibercept/T&E groups, improvements in logMAR were similar over time. In the maintenance phase, the rate of patients with a clinically relevant improvement in visual acuity (> 0.2 logMAR) was higher in both T&E groups compared with the ranibizumab/PRN group. Injection intervals in the maintenance phase in ranibizumab/T&E group gradually expanded over time; whereas in the aflibercept/T&E group, injection intervals remained relatively stable. CONCLUSIONS: Ranibizumab used according to T&E protocol yielded a stronger improvement in logMAR, compared with PRN protocol with longer injection intervals than aflibercept/T&E. This large real-world data assessment supports previous data on the superiority of T&E treatment.
Assuntos
Macula Lutea/patologia , Ranibizumab/administração & dosagem , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Acuidade Visual , Degeneração Macular Exsudativa/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Injeções Intravítreas , Masculino , Pessoa de Meia-Idade , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Estudos Retrospectivos , Tomografia de Coerência Óptica , Resultado do Tratamento , Degeneração Macular Exsudativa/diagnósticoRESUMO
OBJECTIVE: Insomnia is a prevalent complaint on acute psychiatric units. When not addressed by primary treating teams, patients request sleep aids "as needed," leading to increased burden on on-call residents and decreased individualized treatment. The authors implemented a new educational curriculum and computer order set for inpatient insomnia management, and examined changes in residents' comfort level in its management and in inpatient sleep medication ordering patterns. METHODS: In this IRB-approved quality improvement project, the authors identified best practices for insomnia management, developed a new curriculum for psychiatry residents, and created a "Sleep Order set" in the electronic medical record (EMR). Residents were surveyed and EMR queried for sleep medication orders for 6 months pre- and post-intervention. RESULTS: The level of comfort of the residents in ordering a variety of sleep medications increased significantly. Sleep medication orders placed by primary teams surged from 938 during the pre-intervention period to 1801 post-intervention (p < 0.001), while those placed by on-call teams fell considerably. CONCLUSION: Education on insomnia management boosted residents' confidence in handling inpatient sleep disorders. Implementation of the new resident-developed "Sleep Order set" greatly reduced the work load of on-call residents, in terms of "as needed" sleep medication orders.
Assuntos
Educação de Pós-Graduação em Medicina , Medicina Interna , Distúrbios do Início e da Manutenção do Sono , Currículo , Registros Eletrônicos de Saúde , Humanos , Pacientes Internados , Medicina Interna/educação , Melhoria de Qualidade , Sono , Distúrbios do Início e da Manutenção do Sono/terapia , Carga de TrabalhoRESUMO
ADP-ribosyltransferase activities have been observed in many prokaryotic and eukaryotic species and viruses and are involved in many cellular processes, including cell signalling, DNA repair, gene regulation and apoptosis. In a number of bacterial toxins, mono ADP-ribosyltransferase is the main cause of host cell cytotoxicity. Several approaches have been used to analyse this biological system from measuring its enzyme products to its functions. By using a mono ADP-ribose binding protein we have now developed an ELISA method to estimate native pertussis toxin mono ADP-ribosyltransferase activity and its residual activities in pertussis vaccines as an example. This new approach is easy to perform and adaptable in most laboratories. In theory, this assay system is also very versatile and could measure the enzyme activity in other bacteria such as Cholera, Clostridium, E. coli, Diphtheria, Pertussis, Pseudomonas, Salmonella and Staphylococcus by just switching to their respective peptide substrates. Furthermore, this mono ADP-ribose binding protein could also be used for staining mono ADP-ribosyl products resolved on gels or membranes.
Assuntos
ADP Ribose Transferases/análise , ADP Ribose Transferases/metabolismo , Ensaios Enzimáticos/métodos , Ensaio de Imunoadsorção Enzimática , Toxina Pertussis/metabolismo , Vacinas Conjugadas/metabolismo , ADP Ribose Transferases/antagonistas & inibidores , Cromatografia Líquida de Alta Pressão , Clostridium/enzimologia , Escherichia coli/enzimologia , Escherichia coli/metabolismo , Humanos , Peptídeos/química , Peptídeos/metabolismo , Toxina Pertussis/análise , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Especificidade por Substrato , Vacinas Conjugadas/análiseRESUMO
PURPOSE: Current algorithms for automated computer interpretation of optical coherence tomography (OCT) imaging of patients suffering from neovascular age-related macular degeneration (AMD) mostly rely on fluid detection. However, fluid detection itself and correct interpretation of the fluid currently limits diagnostic accuracy. We therefore performed a detailed analysis of the requirements that would have to be met for fluid detection approaches. We further investigated if monitoring retinal volume would be a viable alternative to detect disease activity. METHODS: Retrospective analysis and manual grading of 764 OCT volume scans of 44 patients with exudative AMD treated with intravitreal anti-VEGF injections at a pro-re-nata (PRN) treatment regimen for at least 24 months. RESULTS: Detection of subretinal fluid (SRF) or intraretinal fluid (IRF) alone is not sufficient for disease detection. A combination of SRF and IRF can detect disease activity with a sensitivity of 98.6% and a specificity of 82%. With further characterization of IRF into exudative and degenerative cysts, specificity can be increased to 100%. However, correct characterization is currently not achieved by published fluid detection approaches. Change of macular retinal volume (MRV) can depict disease activity with sensitivity of 88.4% and specificity of 89.6%. Combination with the detection of SRF can further improve diagnostic accuracy to a specificity of 93.3% and sensitivity of 93.9% without relying on IRF or IRF characterization. CONCLUSION: Fluid detection without further characterization is not sufficient for AMD monitoring. Either further distinction between exudative and degenerative cysts is necessary, or other activity markers have to be taken into account. MRV offers good potential to fill this diagnostic gap and might become an important monitoring marker.
Assuntos
Biomarcadores , Neovascularização de Coroide/diagnóstico , Retina/patologia , Tomografia de Coerência Óptica/métodos , Degeneração Macular Exsudativa/diagnóstico , Idoso , Inibidores da Angiogênese/uso terapêutico , Bevacizumab/uso terapêutico , Neovascularização de Coroide/tratamento farmacológico , Feminino , Humanos , Injeções Intravítreas , Masculino , Ranibizumab/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Retina/diagnóstico por imagem , Estudos Retrospectivos , Sensibilidade e Especificidade , Líquido Sub-Retiniano/diagnóstico por imagem , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Degeneração Macular Exsudativa/tratamento farmacológicoRESUMO
In previous studies with Pseudomonas chlororaphis G05, two operons (phzABCDEFG and prnABCD) were confirmed to respectively encode enzymes for biosynthesis of phenazine-1-carboxylic acid and pyrrolnitrin that mainly contributed to suppression of some fungal phytopathogens. Although some regulators were identified to govern their expression, it is not known how two operons coordinately interact. By constructing the phz- or/and prn- deletion mutants, we found that in comparison with the wild-type strain G05, phenazine-1-carboxylic acid production in the mutant G05Δprn obviously decreased in GA broth in the absence of prn, and pyrrolnitrin production in the mutant G05Δphz remarkably declined in the absence of phz. By generating the phzA and prnA transcriptional and translational fusions with a truncated lacZ on shuttle vector or on the chromosome, we found that expression of the phz or prn operon was correspondingly increased in the presence of the prn or phz operon at the post-transcriptional level, not at the transcriptional level. These results indicated that the presence of one operon would promote the expression of the other one operon between the phz and prn. This reciprocal enhancement would keep the strain G05 producing more different antifungal compounds coordinately and living better with growth suppression of other microorganisms.
Assuntos
Antifúngicos/metabolismo , Proteínas de Bactérias/genética , Regulação Bacteriana da Expressão Gênica , Óperon/genética , Pseudomonas chlororaphis/genética , Antifúngicos/análise , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , Mutação , Fenazinas/análise , Fenazinas/metabolismo , Pseudomonas chlororaphis/enzimologia , Pseudomonas chlororaphis/metabolismo , Pirrolnitrina/análise , Pirrolnitrina/metabolismoRESUMO
In the recent years, molecular modeling and substrate docking, coupled with biochemical and genetic analyses have identified the substrate-binding residues of several amino acid transporters of the yeast amino acid transporter (YAT) family. These consist of (a) residues conserved across YATs that interact with the invariable part of amino acid substrates and (b) variable residues that interact with the side chain of the amino acid substrate and thus define specificity. Secondary structure sequence alignments showed that the positions of these residues are conserved across YATs and could thus be used to predict the specificity of YATs. Here, we discuss the potential of combining molecular modeling and structural alignments with intra-species phylogenetic comparisons of transporters, in order to predict the function of uncharacterized members of the family. We additionally define some orphan branches which include transporters with potentially novel, and to be characterized specificities. In addition, we discuss the particular case of the highly specific l-proline transporter, PrnB, of Aspergillus nidulans, whose gene is part of a cluster of genes required for the utilization of proline as a carbon and/or nitrogen source. This clustering correlates with transcriptional regulation of these genes, potentially leading to the efficient coordination of the uptake of externally provided l-Pro via PrnB and its enzymatic degradation in the cell.
Assuntos
Sistemas de Transporte de Aminoácidos/genética , Evolução Molecular , Redes e Vias Metabólicas/genética , Filogenia , Sequência de Aminoácidos/genética , Aspergillus nidulans/genética , Aspergillus nidulans/metabolismo , Transporte Biológico/genética , Regulação Fúngica da Expressão Gênica , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Relação Estrutura-AtividadeRESUMO
AIM: To evaluate the safety, tolerability, and pharmacokinetics/pharmacodynamics of PRN1008, a novel Bruton's tyrosine kinase (BTK) inhibitor, in healthy volunteers, and thus determine the dose range for future clinical studies. METHODS: This was a two-part randomized, placebo controlled study in healthy volunteers using a liquid formulation. Part I was a single ascending dose design with dose levels of 50-1200 mg (n = 6 active, two placebos per cohort); Part II was a multiple ascending dose design, with dose regimens ranging from 300 to 900 mg daily, either four times or twice daily for 10 days. Plasma pharmacokinetics, adverse events, vital signs, electrocardiograms and laboratory parameters were assessed. BTK occupancy in peripheral blood mononuclear cells was evaluated as a marker of target engagement. RESULTS: PRN1008 was rapidly absorbed following oral administration, and was safe and well tolerated in all dose regimens evaluated in both single and multiple doses. PRN1008 demonstrated a large volume of distribution, and a half-life of approximately 3-4 h. BTK occupancy of >90% was observed within 4 h after dosing in both single and multiple dose regimens, and was closely linked to maximum plasma concentration. BTK occupancy decay was slow (-1.6% h-1 ), and occupancy was sustained despite drug concentrations being undetectable. No severe or serious adverse events occurred, and the most common adverse events were gastrointestinal in nature. CONCLUSIONS: PRN1008 was safe and well-tolerated following oral administration, and achieved high, sustained levels of BTK occupancy in peripheral blood mononuclear cells.
Assuntos
Leucócitos Mononucleares/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Administração Oral , Adulto , Tirosina Quinase da Agamaglobulinemia , Doenças Autoimunes/tratamento farmacológico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Meia-Vida , Voluntários Saudáveis , Humanos , Inflamação/tratamento farmacológico , Masculino , Placebos , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/metabolismo , Adulto JovemRESUMO
PURPOSE: To evaluate prospectively the efficacy and safety of a fixed bimonthly ranibizumab treatment regimen (RABIMO) in eyes with neovascular age-related macular degeneration (nAMD) and to compare these results with a pro re nata (PRN) treatment scheme. METHODS: This was a 12-month, phase IV, single center, randomised, non-inferiority study. Following three initial monthly injections, patients were randomised to receive either ranibizumab bimonthly (RABIMO group) or ranibizumab PRN (PRN group) (n = 20 each). Main outcome measures were best-corrected visual acuity (BCVA), central retinal thickness (CRT), number of injections, and adverse events (AEs). RESULTS: BCVA [median (interquartile range, IQR)] increased significantly in both groups after 12 months [RABIMO group +8.5 (14); PRN group +6.5 (16) ETDRS letters] when compared to baseline (p < 0.0001; p = 0.0085). At month 12, the RABIMO treatment regimen was non-inferior to the PRN scheme (∆BCVA = 3.5 ETDRS letters; p < 0.0001). CRT was significantly reduced in both groups after the 12-month study period (p < 0.0001 each), with no significant difference between groups (p = 0.6772). Number of overall injections [median (IQR)] was 8 (0) in the RABIMO versus 4 (5) in the PRN group (p = 0.0037). Three patients in the RABIMO group received one additional unscheduled injection. We observed no significant differences between groups in the number of patients with reported SAEs/AEs (RABIMO group n = 6/15; PRN group n = 7/13) (p = 0.7357/p = 0.4902). CONCLUSIONS: We found no evidence of significant functional or anatomical differences between the RABIMO and PRN treatment regimens. However, the RABIMO group's number of injections was twice as high as the PRN group's (protocol-driven). In light of potential side effects, the fixed bimonthly treatment regimen might not be advisable for routine clinical care, but it might be a worthwhile treatment option if monthly monitoring is not possible. Eudra-CT number: 2009-017324-11.
Assuntos
Macula Lutea/patologia , Ranibizumab/administração & dosagem , Tomografia de Coerência Óptica/métodos , Acuidade Visual , Degeneração Macular Exsudativa/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/administração & dosagem , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Seguimentos , Humanos , Injeções Intravítreas , Masculino , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento , Degeneração Macular Exsudativa/diagnóstico , Degeneração Macular Exsudativa/fisiopatologiaRESUMO
In order to enhance the positioning capability of terrestrial networks, a novel communication and navigation fusion signal is proposed. The novel signal multiplexes the communication and navigation signal in the same frequency band, and the navigation system is superimposed on the original communication system. However, the application of pseudorandom noise (PRN) sequences in the navigation system is limited by the communication clock period. Taking the application of PRN sequences limited by the clock period as objects, the present study analyzes truncated PRN (TPRN) sequences. PRN sequences with a TPRN sequence as the navigation signal can overcome the communication system clock period limitation. Then, a matched filter algorithm with double detection (MFADD) is proposed to acquire the novel signal. The matched filter method is applied to the proposed algorithm to determine the start code phase of TPRN. Monte Carlo simulations and real data tests demonstrate the effectiveness of the proposed algorithm for the designed signal.