Atomic clock performance enabling geodesy below the centimetre level.

The passage of time is tracked by counting oscillations of a frequency reference, such as Earth's revolutions or swings of a pendulum. By referencing atomic transitions, frequency (and thus time) can be measured more precisely than any other physical quantity, with the current generation of optical atomic clocks reporting fractional performance below the 10-17 level1-5. However, the theory of relativity prescribes that the passage of time is not absolute, but is affected by an observer's reference frame. Consequently, clock measurements exhibit sensitivity to relative velocity, acceleration and gravity potential. Here we demonstrate local optical clock measurements that surpass the current ability to account for the gravitational distortion of space-time across the surface of Earth. In two independent ytterbium optical lattice clocks, we demonstrate unprecedented values of three fundamental benchmarks of clock performance. In units of the clock frequency, we report systematic uncertainty of 1.4 × 10-18, measurement instability of 3.2 × 10-19 and reproducibility characterized by ten blinded frequency comparisons, yielding a frequency difference of [-7 ± (5)stat ± (8)sys] × 10-19, where 'stat' and 'sys' indicate statistical and systematic uncertainty, respectively. Although sensitivity to differences in gravity potential could degrade the performance of the clocks as terrestrial standards of time, this same sensitivity can be used as a very sensitive probe of geopotential5-9. Near the surface of Earth, clock comparisons at the 1 × 10-18 level provide a resolution of one centimetre along the direction of gravity, so the performance of these clocks should enable geodesy beyond the state-of-the-art level. These optical clocks could further be used to explore geophysical phenomena10, detect gravitational waves11, test general relativity12 and search for dark matter13-17.

Faraday-Shielded dc Stark-Shift-Free Optical Lattice Clock.

We demonstrate the absence of a dc Stark shift in an ytterbium optical lattice clock. Stray electric fields are suppressed through the introduction of an in-vacuum Faraday shield. Still, the effectiveness of the shielding must be experimentally assessed. Such diagnostics are accomplished by applying high voltage to six electrodes, which are grounded in normal operation to form part of the Faraday shield. Our measurements place a constraint on the dc Stark shift at the 10^{-20} level, in units of the clock frequency. Moreover, we discuss a potential source of error in strategies to precisely measure or cancel nonzero dc Stark shifts, attributed to field gradients coupled with the finite spatial extent of the lattice-trapped atoms. With this consideration, we find that Faraday shielding, complemented with experimental validation, provides both a practically appealing and effective solution to the problem of dc Stark shifts in optical lattice clocks.

Hyperpolarizability and Operational Magic Wavelength in an Optical Lattice Clock.

Optical clocks benefit from tight atomic confinement enabling extended interrogation times as well as Doppler- and recoil-free operation. However, these benefits come at the cost of frequency shifts that, if not properly controlled, may degrade clock accuracy. Numerous theoretical studies have predicted optical lattice clock frequency shifts that scale nonlinearly with trap depth. To experimentally observe and constrain these shifts in an ^{171}Yb optical lattice clock, we construct a lattice enhancement cavity that exaggerates the light shifts. We observe an atomic temperature that is proportional to the optical trap depth, fundamentally altering the scaling of trap-induced light shifts and simplifying their parametrization. We identify an "operational" magic wavelength where frequency shifts are insensitive to changes in trap depth. These measurements and scaling analysis constitute an essential systematic characterization for clock operation at the 10^{-18} level and beyond.

Development of Theoretical Descriptors for Cytotoxicity Evaluation of Metallic Nanoparticles.

Motivated by the recent development of quantitative structure-activity relationship (QSAR) methods in the area of nanotoxicology, we proposed an approach to develop additional descriptors based on results of first-principles calculations. For the evaluation of the biochemical activity of metallic nanoparticles, we consider two processes: ion extraction from the surface of a specimen to aqueous media and water dissociation on the surface. We performed calculations for a set of metals (Al, Fe, Cu, Ag, Au, and Pt). Taking into account the diversity of atomic structures of real metallic nanoparticles, we performed calculations for different models such as (001) and (111) surfaces, nanorods, and two different cubic nanoparticles of 0.6 and 0.3 nm size. Significant energy dependence of the processes from the selected model of nanoparticle suggests that for the correct description we should combine the calculations for several representative models. In addition to the descriptors of chemical activity of the metallic nanoparticles for the two studied processes, we propose descriptors for taking into account the dependence of chemical activity from the size and shape of nanoparticles. Routes to minimization of computational costs for these calculations are also discussed.

Coenzyme Q10 in combination with steroid therapy for treatment of sudden sensorineural hearing loss: a controlled prospective study.

OBJECTIVE: To evaluate the therapeutic efficacy of coenzyme Q10 added to systemic steroid in patients with idiopathic sudden sensorineural hearing loss. DESIGN: A controlled prospective study. SETTING: Asan medical center, University of Ulsan College of Medicine. PARTICIPANTS: Between August 2007 and October 2008, the first 60 patients diagnosed with sudden sensorineural hearing loss were managed with systemic steroid treatment for 2 weeks including 5-day hospitalisation. And the second 60 patients were managed with coenzyme Q10 for 2 weeks added to previous management. MAIN OUTCOME MEASURES: We evaluated auditory function by pure tone audiometry and speech discrimination score. Auditory evaluations were performed before and 3 months after treatment using Siegel's criteria. The degree of improvement in four-tone average hearing and speech discrimination score was calculated from the results before and after treatment. RESULTS: The total hearing improvement rate after the treatment was 75.0% (90/120 patients) in this study. Although 47 patients (78.3%) of coenzyme Q10 group showed better hearing improvement than 43 patients (71.7%) of control group, there was no significant difference. However, the coenzyme Q10 group showed significantly higher improvement in speech discrimination score. CONCLUSION: From this study, we suggest that coenzyme Q10 may have beneficial effects in the treatment of sudden sensorineural hearing loss.

Multivariate statistical analysis for selecting optimal descriptors in the toxicity modeling of nanomaterials.

The present study is based on the application of a multivariate statistical analysis approach for the selection of optimal descriptors of nanomaterials with the objective of robust qualitative modeling of their toxicity. A novel data mining protocol has been developed for the selection of an optimal subset of descriptors of nanomaterials by using the well-known multivariate method principal component analysis (PCA). The selected subsets of descriptors were validated for qualitative modeling of the toxicity of nanomaterials in the PC space. The analysis and validation of the proposed schemes were based on five decisive nanomaterial toxicity data sets available in the published literature. Optimal descriptors were selected on the basis of the maximum loading criteria and using a threshold value of cumulative variance ≤90% on PC directions. A maximum inter-class separation(B) and the minimum intra-classes separation(A) were obtained for toxic vs. nontoxic nanomaterials in the PC space with the selected subsets of optimal descriptors compared to their other combinations for each of the datasets.

Template-free synthesis of monolithic carbon xerogels with hierarchical porosity from resorcinol and formaldehyde via hydrothermal reaction.

Monolithic carbon xerogels with hierarchical porosity were prepared from resorcinol (R) and formaldehyde (F) via a base-catalysed hydrothermal polycondensation reaction, without a template and supercritical drying. First, an aqueous solution of resorcinol, formaldehyde and sodium carbonate was prepared by varying R/W (25-45) and R/C (1-10k) ratios to produce monolithic RF gels. The reaction was carried out in a pressurized Teflon mould at 100 °C for 6 h to give a co-continuous pore structure via spinodal decomposition and a tenacious gel to avoid supercritical drying. Next, the RF gels were dried for 42 h at 60 °C and another 6 h at 100 °C to produce RF xerogels without cracks, followed by pyrolysis in a tube furnace at 900 °C for 2 h under N2 flow, and then activation at 1000 °C for 2, 4 or 6 h under CO2 flow. Finally, the carbon xerogels were characterized by SEM and N2 adsorption-desorption measurements. Monolithic RF gels were obtained from all combinations of R/W and R/C, but the gels from R/W = 45 exhibited a co-continuous large-pore structure, providing a specific surface area (SSA) of ∼650 m2 g-1, which increased to 3311 m2 g-1 (for R/C = 10k) at 6 h of CO2 activation without exhibiting cracks. N2 isotherms demonstrated that micro- and meso-pores were introduced via activation, forming hierarchical porosity in combination with large pores from spinodal decomposition without using a template.

The enhanced cellular uptake of very-low-density lipoprotein enriched in apolipoprotein E.

We have recently reported an increased clearance of plasma very-low-density lipoprotein (VLDL) after intravenous injection of apolipoprotein (apo) E in Watanabe heritable hyperlipidemic (WHHL) rabbits. In the present study, we have investigated the cellular uptake of VLDL enriched in apo E (VLDL-E) which had been incubated with purified rabbit apo E. VLDL-E was taken up approx. 2-fold more than VLDL in human skin fibroblast, human monocyte-derived macrophage and Hep G2 cell and its degradation was least in macrophage. To characterize the binding of VLDL-E, we performed a binding assay using hepatic endosome isolated from estradiol-treated rats and we observed both increased EDTA-sensitive and -resistant binding of VLDL-E on endosome. Ligand blotting of hepatic endosome demonstrated two major bands of LDL receptor (130 and 260 kDa protein) and a minor band of LDL receptor-related protein (580 kDa protein) with a ligand of VLDL-E. These results suggested that VLDL-E was endocytosed in liver through a similar pathway among three cell types, and enrichment of apo E in VLDL enhanced the uptake of VLDL not only via an EDTA-sensitive binding site (classical LDL receptor) but also via other binding sites including an EDTA-resistant binding site and an LDL receptor-related protein.

The relationship between body mass index and the prevalence of obesity-related diseases based on the 1995 National Health Interview Survey in Korea.

This study estimated the body mass index (BMI) distribution of Koreans and examined the relationship between BMI and obesity-related diseases, in particular hypertension and diabetes mellitus. We also attempted to provide primary data to determine suitable BMI cut-off points for obesity in Korea. The 1995 National Health Interview Study (NHIS) data were used to estimate BMI and the prevalence of hypertension and diabetes mellitus. A random sample of 5750 Koreans (15-69 years of age) were investigated. BMI was calculated by self-reported weights and heights. The diagnoses of hypertension and diabetes mellitus were obtained from self-reported conditions specified in response to consultations with physicians. The mean BMI was 22.6+/-2.6 kg m(-2) for males and 21.7+/-4.8 kg m(-2) for females. The prevalence of hypertension and diabetes mellitus increased with BMI. The odds ratios of the third quartile of BMI (21.9-23.8 kg m(-2)) for hypertension and diabetes mellitus compared with the first quartile were 6.04 and 3.22, respectively. The odds ratio of the fourth quartile (>23.8 kg m(-2)) of BMI was not significantly different from that of the third quartile. The risk of hypertension and diabetes mellitus increased at the third quartile of BMI (21.9-23.8 kg m(-2)), this quartile being much lower than both the current World Health Organization (WHO) BMI cut-off point of overweight of 25.0 kg m(-2), and the 90th percentile proposed in the Monica project, BMI 26.4 kg m(-2). This finding was notable considering the fact that both hypertension and diabetes mellitus occur in Koreans with lower BMIs than whites. Further studies are necessary to identify the BMI cut-off point for obesity in Korea.

Characterization of monoclonal anti-rabbit apolipoprotein E antibodies and chemical composition of lipoproteins separated by anti-apolipoprotein E immuno-affinity chromatography.

Six mouse monoclonal antibodies against rabbit apolipoprotein E (apo E) have been developed. Of these monoclonal antibodies, clone 5 revealed a high affinity for purified apo E, very low density lipoprotein (VLDL) and beta-VLDL. This monoclonal antibody was used to prepare an immunoaffinity column. Coupled to Sepharose 4B, this antibody allowed complete removal of lipoproteins containing apo E from plasma of New Zealand white (NZW) rabbits; 62, 46, 14, and 3% of VLDL-, IDL-, LDL-, and HDL-protein, respectively, were bound to the anti-apo E affinity column. The bound VLDL was significantly rich in free cholesterol (FC) and cholesteryl esters (CE) relative to the unbound VLDL, whereas bound IDL, LDL and HDL were significantly rich in FC only. All of the bound fractions were characterized by significantly increased ratios of FC/phospholipids (PL). These results indicate that the two lipoprotein populations with and without apo E have different lipid compositions. The relatively high content of cholesterol in lipoproteins containing apo E suggests a contribution of apo E to plasma cholesterol transport.

Systemic vasculitis: a temporal bone histopathologic study.

Systemic vasculitis includes a broad spectrum of disorders that may involve blood vessels of any size in any organ system. Systemic vasculitis is associated with immunopathogenic mechanisms. Sixteen temporal bones from eight persons were studied to determine histopathologic changes that occur in systemic vasculitis. Three persons had Wegener's granulomatosis, two had polyarteritis nodosa, and three had systemic lupus erythematosus. Otitis media was seen in 15 ears, with ten ears showing chronic middle ear changes and two showing fibrotic inner ear changes. In Wegener's granulomatosis, granulation tissue was observed around the eustachian tube and protympanum, and in polyarteritis nodosa, inflammatory cell infiltrate and thickened blood vessels were observed around the facial nerve. Although sensorineural hearing loss has been described clinically in systemic lupus erythematosus, the present report describes findings in temporal bones, including severe fibrosis and new bone formation throughout the inner ear.

Histopathology of sudden hearing loss.

Eleven temporal bones from eight patients who had clinical histories of sudden hearing loss (SHL) were studied to assess the possible etiopathogenesis. The origin of SHL in seven ears from five patients was obscure, but appeared to be due to multiple causes. Common histopathologic changes in the cochlea, although complex, included atrophy of the organ of Corti and loss of cochlear neurons. Loss of cochlear neurons was the main finding in ears of viral infection. Labyrinthine fibrosis and formation of new bone were seen in two ears associated with vascular insult and in two ears of autoimmune disease. Different histopathologic findings causing SHL were observed even in cases with the same etiology. A case of SHL showing endolymphatic hydrops as the main histopathologic finding is described.

Symptomatic versus asymptomatic endolymphatic hydrops: a histopathologic comparison.

One of the unanswered questions in Meniere's disease research is the pathophysiology by which the classic symptoms are produced. A histopathological study was undertaken to identify the pathological features of symptomatic endolymphatic hydrops and their relationship to these symptoms. Two groups of temporal bones were examined, compared, and described. The first group was from patients with symptoms of Meniere's disease (n = 29). Temporal bones in the second group were chosen for the presence of endolymphatic hydrops and the absence of otologic symptoms (n = 13). Significant differences were noted in the severity of hydrops, the frequency of membrane ruptures, the endolymphatic duct, and coexistent pathologic conditions. Ruptures were seen in 38% of temporal bones from symptomatic patients and in only 8% of temporal bones from patients with asymptomatic endolymphatic hydrops. Based on this study and a review of the literature, the authors believe that the symptoms and findings of Meniere's disease are explained best on the basis of both chemical and physical mechanisms being operational intermittently and together.

Temporal bone histopathology in chronically infected ears with intact and perforated tympanic membranes.

Chronic suppurative otitis media has been clinically defined as a chronic discharge from the middle ear in the presence of a perforation of the tympanic membrane. However, irreversible tissue pathology in the middle ear or mastoid can occur behind an intact tympanic membrane. One hundred forty-four human temporal bones with chronic otitis media were divided into two groups: those with perforated (28) and those with nonperforated (116) tympanic membranes. The histopathological findings of their middle ears were compared. Granulation tissue in various degrees was the most prominent pathological feature. It was observed in 96% of temporal bones with perforation of the tympanic membrane, and in 97% of those without perforation. Also found were ossicular bony changes (96% with perforation; 90.5% without), middle ear effusion (93% with perforation; 89% without), cholesterol granuloma (21% with perforation; 12% without), cholesteatoma (36% with perforation; 4% without), and tympanosclerosis (43% with perforation; 20% without). This study shows that the histopathological changes of the middle ear are similar in temporal bones with and without perforation of the tympanic membrane. The clinician should, therefore, be aware that an intact tympanic membrane does not necessarily preclude the presence of gross pathological changes of the middle ear cleft.

Age-related morphologic changes in the human tympanic membrane. A light and electron microscopic study.

To our knowledge, the normal changes that occur in the tympanic membrane after birth have not been described, despite several reports that their otoscopic appearance in healthy, full-term infants is different from that in adults. To provide such a description, the tympanic membranes of 54 temporal bones that had no pathologic evidence of otologic diseases, from patients aged 33 weeks' gestation to 91 years, were examined with light or electron microscopy. The changes encountered in thickness, cellularity, vascularity, collagen, and elastin indicated beyond the first year of life and into old age.

A micromachined silicon depth probe for multichannel neural recording.

A process of making a new type of silicon depth-probe microelectrode array is described using a combination of plasma and wet etch. The plasma etch, which is done using a low temperature oxide (LTO) mask, enables probe thickness to be controlled over a range from 5 to 90 mu. Bending tests show that the probe's mechanical strength depends largely on shank thickness. More force can be applied to thicker shanks while thinner shanks are more flexible. One can then choose a thickness and corresponding mechanical strength using the process developed. The entire probe shaping process is performed only at low temperature, and thus is consistent with the standard CMOS fabrication. Using the probe in recording from rat's somatosensory cortex, we obtained four channel simultaneous recordings which showed clear independence among channels with a signal-to-noise ratio performance comparable with that obtained using other devices.

Clinical experience with transurethral microwave thermotherapy for chronic nonbacterial prostatitis and prostatodynia.

Chronic prostatitis and prostatodynia are troublesome disorders that are not responsive to any kind of treatment. Patients with treatment-resistant chronic nonbacterial prostatitis (n = 61) or prostatodynia (n = 17) for longer than 3 years underwent a single 1-hour session of transurethral microwave thermotherapy (TUMT) using the Prostatron. Complete symptom disappearance was obtained in 23% of patients and a partial response in 43%. Of the patients with prostatitis, 46% showed normalization and 31% an improvement of the leukocyte count in expressed prostatic secretion. In patients with prostatodynia, the corresponding figures were 35% and 41%. Most complications were temporary, but there was one case of epididymitis and one of reduction in the volume of the ejaculate. TUMT is well tolerated and safe, and it is effective in relieving the symptoms of many patients with nonbacterial prostatitis or prostatodynia. The possible adverse effects on fertility and urinary continence require further study.

Otosclerosis involving the vestibular aqueduct and Menière's disease.

The coexistence of otosclerosis and endolymphatic hydrops in the temporal bone have been described; however, the mechanism for the development of endolymphatic hydrops in otosclerosis remains unknown. Among 128 temporal bones with otosclerosis, involvement of the vestibular aqueduct by otosclerosis was observed in four temporal bones from two patients. In all four, the vestibular aqueduct was filled with active otosclerotic foci; the lumen of the endolymphatic duct and sac was narrowed as a result of fibrosis, and endolymphatic hydrops, more severe in the pars inferior than the pars superior, was observed. Collapse of the ductus reuniens and dilated saccule was seen in three temporal bones. Our study indicates that otosclerotic obstruction of the vestibular aqueduct may create a disturbance of the outflow and/or absorption of endolymph, leading to the development of endolymphatic hydrops and Meniere's disease, thus supporting the theory of longitudinal flow of endolymph.

Otologic histopathology of Fabry's disease.

Fabry's disease is a rare progressive X-linked recessive disorder of glycosphingolipid metabolism. The accumulation of glycosphingolipids occurs in virtually all areas of the body, including the endothelial, perithelial, and smooth-muscle cells of blood vessels, the ganglion cells of the autonomic nervous system, and the glomeruli and tubules of the kidney. Although otologic symptoms have been described in these patients, to our knowledge there have been no temporal bone histopathologic reports. We describe the clinical histories, audiometric results, and temporal bone findings of two patients with this rare disorder. Both patients demonstrated a bilateral sloping sensorineural hearing loss audiometrically. Middle ear findings of seropurulent effusions and hyperplastic mucosa were seen in all four temporal bones. Strial and spiral ligament atrophy in all turns, and hair cell loss mainly in the basal turns, were also common findings. The number of spiral ganglion cells was reduced in all temporal bones; however, evidence of glycosphingolipid accumulation was not observed in the spiral ganglia.

Cellular changes in Reissner's membrane in endolymphatic hydrops.

A quantitative morphologic study of the cellular changes in human Reissner's membrane (RM) was performed under light microscopy on 30 normal temporal bones from 15 subjects, and on 20 temporal bones from 10 subjects with endolymphatic hydrops. The cellular density of the epithelial and mesothelial layers of normal RMs decreased with increasing age. In endolymphatic hydrops, cellular proliferation and decreased cellular density of a distended RM were observed, and these changes occurred more remarkably in epithelial cells. Decreased cellular density in RM was correlated to the degree of endolymphatic hydrops. These findings indicate an involvement of the epithelial cellular changes in the pathogenesis of endolymphatic hydrops. Our results suggest that cellular changes in RM may cause dysfunction of radial flow leading to ionic disturbance of endolymph, which provides a possible mechanism of hearing loss in endolymphatic hydrops.