The natural history of subjective tinnitus in adults: a systematic review and meta-analysis of ‘no-intervention’ periods in controlled trials

Objectives Tinnitus is a prevalent condition, but little has been published regarding the natural history of the condition. One technique for evaluating the long-term progression of the disease is to examine what happens to participants in the no-intervention control arm of a clinical trial. The aim of this study was to examine no-intervention or waiting-list data reported in trials, in which participants on the active arm received any form of tinnitus intervention. Data Sources CINAHL, PsychINFO, EMBASE, ASSIA, PubMed, Web of Science, Science Direct, EBSCO Host, and Cochrane. Methods Inclusion criteria followed the PICOS principles: Participants, adults with tinnitus; Intervention, none; Control, any intervention for alleviating tinnitus; Outcomes, a measure assessing tinnitus symptoms using a multi-item patient-reported tinnitus questionnaire. Secondary outcome measures included multi-item patient-reported questionnaires of mood and health-related quality of life and measures that quantified change in tinnitus loudness; Study design, randomized controlled trials or observational studies utilizing a no-intervention or waiting-list control group. Data were extracted and standardized mean difference was calculated for each study to enable meta-analysis. Results The evidence strongly favored a statistically significant decrease in the impact of tinnitus over time, though there was significant heterogeneity and clinical significance cannot be interpreted. Outcome data regarding secondary measures did not demonstrate any clinically significant change. Conclusions Participants allocated to the no-intervention or waiting-list control arm of clinical trials for a tinnitus intervention show a small but significant improvement in self-reported measures of tinnitus with time; the clinical significance of this finding is unknown. There is, however, considerable variation across individuals. These findings support previous work and can cautiously be used when counseling patients

Purification and biochemical/molecular characterisation of antimicrobial peptides produced by Saccharomyces cerevisiae and evaluation of their mode of action

Tese apresentada para obtenção do Grau de Doutor em Engenharia AlimentarABSTRACT: The antagonistic effect exerted by Saccharomyces cerevisiae against other microbial species during wine fermentations was recently ascribed to its capacity to secrete antimicrobial peptides (AMPs). The main goal of the present work was to purify, identify and characterize those AMPs. Firstly, the AMPs were purified by means of chromatographic techniques (size-exclusion and ion-exchange) and then characterized regarding their amino acid sequence, codifying genes and antimicrobial/biochemical properties. Analysis of the purified AMPs by mass spectrometry revealed that the natural biocide is mainly composed by two peptides (AMP1 and AMP2/3) derived from the isoenzymes of the glycolytic protein glyceraldehyde 3-phosphate dehydrogenase (GAPDH). The spectrum of action of the naturally-excreted AMPs, which we named saccharomycin, is wide and includes several wine-related non-Saccharomyces yeasts, such as Hanseniaspora guilliermondii, Torulaspora delbrueckii, Kluyveromyces marxianus, Lachancea thermotolerans and Dekkera bruxellensis, as well as bacteria such as Oenococcus oeni. The antimicrobial effect of saccharomycin is significantly higher than that of synthetic analogues (AMP1 and AMP2/3) and depends on their complementary action and relative proportion. The mode of action of the AMPs was evaluated against sensitive yeast cells. The AMPs induce cell membrane permeabilization, loss of pH homeostasis and increase/decrease of H+-influx/-efflux. They also induce cell molecular markers typical of death by apoptosis in H. guilliermondii. Our work also revealed the accumulation of these GAPDH-derived peptides on the surface of stationary-grown (48 h) cells of S. cerevisiae, which induce death of non-Saccharomyces yeasts (H. guilliermondii and L. thermotolerans) by direct cell-cell contact. Finally, S. cerevisiae strains over-expressing these AMPs prevented growth of D. bruxellensis in co-fermentations, decreasing the levels of sulphur dioxide needed to control wine spoilage. Thus, the potential of these AMPs to be used as biopreservative in wine seems promising.RESUMO: O efeito antagónico de Saccharomyces cerevisiae contra outras espécies microbianas durante fermentações vínicas foi recentemente atribuído à sua capacidade de excretar péptidos antimicrobianos (PAMs). O principal objetivo do presente estudo foi purificar, identificar e caracterizar estes PAMs. Primeiramente, os PAMs foram purificados por técnicas cromatográficas (exclusão molecular e permuta iónica) e posteriormente caracterizados quanto à sua sequência de aminoácidos, aos genes que os codificam e às suas propriedades antimicrobianas/bioquímicas. Os PAMs purificados foram, em seguida, analisados por espectrometria de massa, revelando que o biocida natural é composto maioritariamente por dois PAMs (PAM1 e PAM2/3) originários das três isoenzimas da proteína glicolítica gliceraldeído-3-fosfato desidrogenase. O espectro de ação dos PAMs naturais, os quais designámos por saccharomycin, é amplo e inclui várias leveduras vínicas, tais como Hanseniaspora guilliermondii, Torulaspora delbrueckii, Kluyveromyces marxianus, Lachancea thermotolerans e Dekkera bruxellensis, assim como a bactéria vínica Oenococcus oeni. O efeito antimicrobiano de saccharomycin é bastante mais acentuado do que o efeito dos análogos quimicamente sintetizados (PAM1 e PAM2/3) e depende da sua ação complementar, assim como da sua proporção relativa. O modo de ação dos PAMs foi analisado em leveduras sensíveis, verificando-se que estes induzem permeabilização da membrana celular, perda da homeostase do pH e aumento/decréscimo do influxo/efluxo de H+. Verificou-se igualmente, que os PAMs induzem morte por apoptose em H. guilliermondii. Descobrimos, ainda, que estes PAMs se acumulam na superfície de células estacionárias (48 h) de S. cerevisiae, as quais são capazes de induzir a morte de leveduras não-Saccharomyces (H. guilliermondii e L. thermotolerans) por contacto celular direto. Por fim, uma estirpe laboratorial de S. cerevisiae foi manipulada geneticamente de forma a sobre-expressar cada um dos PAMs, verificando-se que as estirpes manipuladas apresentaram um elevado efeito antimicrobiano contra D. bruxellensis, o que permitiu reduzir os níveis de dióxido de enxofre normalmente aplicados em vinhos. Assim, a utilização destes PAMs como um bioconservante alternativo no vinho parece promissora.N/

A neutral atom frequency reference in the deep UV with 10^(-15) range uncertainty

We present an assessment of the (6s^{2})1S0 -> (6s7s)3P0 clock transition frequency in 199Hg with an uncertainty reduction of nearly three orders of magnitude and demonstrate an atomic quality factor, Q, of ~10^(14). The 199Hg atoms are confined in a vertical lattice trap with light at the newly determined magic wavelength of 362.5697 +/-0.0011 nm and at a lattice depth of 20Er. The atoms are loaded from a single stage magneto-optical trap with cooling light at 253.7 nm. The high Q factor is obtained with an 80 ms Rabi pulse at 265.6 nm. The frequency of the clock transition is found to be 1 128 575 290 808 162.0 +/-6.4 (sys.) +/-0.3 (stat.) Hz (fractional uncertainty = 5.7x10^(-15)). Neither an atom number nor second order Zeeman dependence have yet to be detected. Only three laser wavelengths are used for the cooling, lattice trapping, probing and detection.Comment: 5 pages, 6 figure

Laser locking to the 199Hg clock transition with 5.4x10^(-15)/sqrt(tau) fractional frequency instability

With Hg atoms confined in an optical lattice trap in the Lamb-Dicke regime, we obtain a spectral line at 265.6 nm in which the full-width at half-maximum is <15Hz. Here we lock an ultrastable laser to this ultranarrow clock transition and achieve a fractional frequency stability of 5.4x10^(-15)/sqrt(tau) for tau<=400s. The highly stable laser light used for the atom probing is derived from a 1062.6 nm fiber laser locked to an ultrastable optical cavity that exhibits a mean drift rate of -6.0x10^(-17) s^(-1) (or -16.9 mHz.s^(-1) at 282 THz) over a five month period. A comparison between two such lasers locked to independent optical cavities shows a flicker noise limited fractional frequency instability of 4x10^(-16) per cavity