Current models of evoked otoacoustic emissions explain the striking periodicity in their frequency spectra by suggesting that it originates through the reflection of forward-traveling waves by a ...corresponding spatial corrugation in the mechanics of the cochlea. Although measurements of primate cochlear anatomy find no such corrugation, they do indicate a considerable irregularity in the arrangement of outer hair cells. It is suggested that evoked emissions originate through a novel reflection mechanism, representing an analogue of Bragg scattering in nonuniform, disordered media. Forward-traveling waves reflect off random irregularities in the micromechanics of the organ of Corti. The tall, broad peak of the traveling wave defines a localized region of coherent reflection that sweeps along the organ of Corti as the frequency is varied monotonically. Coherent scattering occurs off irregularities within the peak with spatial period equal to half the wavelength of the traveling wave. The phase of the net reflected wave rotates uniformly with frequency at a rate determined by the wavelength of the traveling wave in the region of its peak. Interference between the backward-traveling wave and the stimulus tone creates the observed spectral periodicity. Ear-canal measurements are related to cochlear mechanics by assuming that the transfer characteristics of the middle ear vary slowly with frequency compared to oscillations in the emission spectrum. The relationship between cochlear mechanics at low sound levels and the frequency dependence of evoked emissions is made precise for one-dimensional models of cochlear mechanics. Measurements of basilar-membrane motion in the squirrel monkey are used to predict the spectral characteristics of their emissions. And conversely, noninvasive measurements of evoked otoacoustic emissions are used to predict the width and wavelength of the peak of the traveling wave in humans.
Summary Background A systematic assessment of potential disease-modifying compounds for Parkinson's disease concluded that pioglitazone could hold promise for the treatment of patients with this ...disease. We assessed the effect of pioglitazone on the progression of Parkinson's disease in a multicentre, double-blind, placebo-controlled, futility clinical trial. Methods Participants with the diagnosis of early Parkinson's disease on a stable regimen of 1 mg/day rasagiline or 10 mg/day selegiline were randomly assigned (1:1:1) to 15 mg/day pioglitazone, 45 mg/day pioglitazone, or placebo. Investigators were masked to the treatment assignment. Only the statistical centre and the central pharmacy knew the treatment name associated with the randomisation number. The primary outcome was the change in the total Unified Parkinson's Disease Rating Scale (UPDRS) score between the baseline and 44 weeks, analysed by intention to treat. The primary null hypothesis for each dose group was that the mean change in UPDRS was 3 points less than the mean change in the placebo group. The alternative hypothesis (of futility) was that pioglitazone is not meaningfully different from placebo. We rejected the null if there was significant evidence of futility at the one-sided alpha level of 0·10. The study is registered at ClinicalTrials.gov , number NCT01280123. Findings 210 patients from 35 sites in the USA were enrolled between May 10, 2011, and July 31, 2013. The primary analysis included 72 patients in the 15 mg group, 67 in the 45 mg group, and 71 in the placebo group. The mean total UPDRS change at 44 weeks was 4·42 (95% CI 2·55–6·28) for 15 mg pioglitazone, 5·13 (95% CI 3·17–7·08) for 45 mg pioglitazone, and 6·25 (95% CI 4·35–8·15) for placebo (higher change scores are worse). The mean difference between the 15 mg and placebo groups was −1·83 (80% CI −3·56 to −0·10) and the null hypothesis could not be rejected (p=0·19). The mean difference between the 45 mg and placebo groups was −1·12 (80% CI −2·93 to 0·69) and the null hypothesis was rejected in favour of futility (p=0·09). Planned sensitivity analyses of the primary outcome, using last value carried forward (LVCF) to handle missing data and using the completers' only sample, suggested that the 15 mg dose is also futile (p=0·09 for LVCF, p=0·09 for completers) but failed to reject the null hypothesis for the 45 mg dose (p=0·12 for LVCF, p=0·19 for completers). Six serious adverse events occurred in the 15 mg group, nine in the 45 mg group, and three in the placebo group; none were thought to be definitely or probably related to the study interventions. Interpretation These findings suggest that pioglitazone at the doses studied here is unlikely to modify progression in early Parkinson's disease. Further study of pioglitazone in a larger trial in patients with Parkinson's disease is not recommended. Funding National Institute of Neurological Disorders and Stroke.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Immune nonresponder (INR) HIV-1-infected subjects are characterized by their inability to reconstitute the CD4+ T cell pool after antiretroviral therapy. This is linked to poor clinical outcome. ...Mechanisms underlying immune reconstitution failure are poorly understood, although, counterintuitively, INRs often have increased frequencies of circulating CD4+ T cells in the cell cycle. While cycling CD4+ T cells from healthy controls and HIV+ patients with restored CD4+ T cell numbers complete cell division in vitro, cycling CD4+ T cells from INRs do not. Here, we show that cells with the phenotype and transcriptional profile of Tregs were enriched among cycling cells in health and in HIV infection. Yet there were diminished frequencies and numbers of Tregs among cycling CD4+ T cells in INRs, and cycling CD4+ T cells from INR subjects displayed transcriptional profiles associated with the impaired development and maintenance of functional Tregs. Flow cytometric assessment of TGF-β activity confirmed the dysfunction of Tregs in INR subjects. Transcriptional profiling and flow cytometry revealed diminished mitochondrial fitness in Tregs among INRs, and cycling Tregs from INRs had low expression of the mitochondrial biogenesis regulators peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1α) and transcription factor A for mitochondria (TFAM). In vitro exposure to IL-15 allowed cells to complete division, restored the expression of PGC1α and TFAM, and regenerated mitochondrial fitness in the cycling Tregs of INRs. Our data suggest that rescuing mitochondrial function could correct the immune dysfunction characteristic of Tregs in HIV-1-infected subjects who fail to restore CD4+ T cells during antiretroviral therapy.
Objectives/Hypothesis Trauma and surgery are the most common causes of cerebrospinal fluid (CSF) rhinorrhea. Surgical repair is recommended for patients with CSF leaks that do not respond to ...conservative measures, traumatic CSF leaks that require transcranial surgery for associated brain injuries, and iatrogenic defects that are discovered intraoperatively. The purpose of our study was to ascertain the outcome after transnasal endoscopic repair of CSF leaks and to identify factors regarding the patient, CSF fistula, and treatment that may influence the results of the repair.
Methods We performed a meta‐analysis of all studies published in English between 1990 and 1999 that reported a minimum of five patients with CSF fistulae that were repaired using an endoscopic approach. We analyzed data that included type of graft and technique used during the repair, surgical complications, the use of packing, and the use of lumbar drains and antibiotics. The success rate was monitored and correlated with the other variables. The meta‐analysis database was compared with and added to a database comprising our own patients.
Results Fourteen studies comprising 289 CSF fistulae met the inclusion criteria. Endoscopic repair of CSF leaks was successful in 90% (259/289) of the cases after a first attempt. Seventeen of 30 persistent leaks (52%) were closed after a second attempt. Thus ultimately 97% (276/289) of the leaks were repaired using an endoscopic approach. The success rate of repairs using any of the reported techniques and materials was high and not statistically different. The incidence of major complications such a meningitis, subdural hematoma, and intracranial abscess was less than 1% for each complication.
Conclusion The endoscopic approach is highly effective and is associated with low morbidity. The literature supports the endoscopic approach using a variety of techniques and materials for the repair of CSF leaks.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Evaluate tryptophan and thymine (TT) impact on carcinogenesis and intravesical BCG bladder cancer treatment.
After identification of TT in vitro inhibitory effect in multiple cancer cell cultures, ...bladder cancer animal model was induced by MNU intravesical instillations and randomized into four groups: Control (n = 9), BCG (n = 9), TT (n = 7), and BCG + TT (n = 8). BCG groups received intravesical 10
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CFU BCG in 0.2 ml saline for 6 consecutive weeks and TT groups received 1 g/kg (1:1) of TT via daily gavage. After 15 wk of protocol, animals were euthanized and the urinary bladders submitted to histopathology, immunohistochemistry, and Western blotting.
Urothelial cancer was identified in 100%, 85.7%, 44.5%, and 37.5% of Control, TT, BCG, and BCG + TT groups, respectively. Cell proliferation marked by nuclear Ki-67 was higher in the Control compared to animals in the other groups (P = 0.03). BCG, TT, and BCG + TT groups showed proliferative cell decline and TLR4/5 labeling increase in the urothelium. BCG decreased the urothelial VEGF labeling, even in TT association.
TT inhibit urothelial carcinogenesis and potentiate the intravesical BCG in the treatment of bladder cancer by reducing cell proliferation and activating TLRs.
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DOBA, IJS, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK, VSZLJ
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