Spectrally Sharp Near-Field Thermal Emission: Revealing Some Disagreements between a Casimir-Polder Sensor and Predictions from Far-Field Emittance.

Near-field thermal emission largely exceeds blackbody radiation, owing to spectrally sharp emission in surface polaritons. We turn the Casimir-Polder interaction between Cs(7P_{1/2}) and a sapphire interface into a sensor sharply filtering, at 24.687 THz, the near-field sapphire emission at ∼24.5 THz. The temperature evolution of the sapphire mode is demonstrated. The Cs sensor, sensitive to both dispersion and dissipation, suggests the polariton to be redshifted and sharper, as compared, up to 1100 K, to predictions from far-field sapphire emission, affected by birefringence and multiple resonances.

Linear Probing of Molecules at Micrometric Distances from a Surface with Sub-Doppler Frequency Resolution.

We report on precision spectroscopy of subwavelength confined molecular gases. This was obtained by rovibrational selective reflection of NH_{3} and SF_{6} gases using a quantum cascade laser at λ≈10.6 µm. Our technique probes molecules at micrometric distances (≈λ/2π) from the window of a macroscopic cell with submegahertz resolution, allowing molecule-surface interaction spectroscopy. We exploit the linearity and high resolution of our technique to gain novel spectroscopic information on the SF_{6} greenhouse gas, useful for enriching molecular databases. The natural extension of our work to thin cells will allow compact frequency references and improved measurements of the Casimir-Polder interaction with molecules.

Surface response around a sharply resonant surface polariton mode is simply a Lorentzian.

At the planar interface between a material and vacuum, the complex surface response S(ω)=[ε(ω)-1]/[ε(ω)+1], with ε(ω) being the relative complex dielectric permittivity of the material, exhibits resonances typical of the surface polariton modes, when ε(ω)∼-1. We show that for a moderately sharp resonance, S(ω) is satisfactorily described with a mere (complex) Lorentzian, independent of the details affecting the various bulk resonances describing ε(ω). Remarkably, this implies a quantitative correlation between the resonant behaviors of ℜe[S(ω)] and ℑm[S(ω)], respectively, associated to the dispersive and dissipative effects in the surface near-field. We show that this "strong resonance" approximation easily applies and discuss its limits, based on published data for sapphire, CaF2, and BaF2. An extension to interfaces between two media or to a non-planar interface is briefly considered.

A prospective whole-mixture approach to assess risk of the food and chemical exposome.

Many widely used chemicals result in ubiquitous human exposure from multiple sources, including diet. Legislation mainly deals with the toxicological evaluation of single substances owing to a methodological and conceptual lack of alternatives, and does so within defined silos subject to over 40 distinct regulations in the EU alone. Furthermore, much of the research and many of the initiatives concerned with the assessment and evaluation of chemical mixtures and their potential effects on human health rely on retrospective analysis. Here we propose an approach for the prospective identification, assessment and regulation of mixtures relevant to human health. We address two distinct aspects of toxicology-which chemicals actually do occur together, and how potential mixture-related health hazards can be predicted-with an adapted concept of the exposome and large-scale hazard screens. The proactive use of the likelihood of co-exposure, together with the new approach of methods-based testing, may be a timely and feasible way of identifying those substances and mixtures where hazards may have been overlooked and regulatory action is needed. Ideally, we would generate co-exposure patterns for specific consumer groups, depending on lifestyle and dietary habits, to assess the specific risk of identified mixtures.

Safety and efficacy of retreatment with a bioengineered hyaluronate for painful osteoarthritis of the knee: results of the open-label Extension Study of the FLEXX Trial.

OBJECTIVE: To evaluate the safety of repeated intra-articular (IA) injections of Euflexxa® (1% sodium hyaluronate; IA--BioHA) for painful knee osteoarthritis (OA). DESIGN: Participants who completed the randomized, double-blind, 26-week FLEXX Trial comparing IA-BioHA to IA saline (IA-SA) for knee OA(1) received three weekly IA-BioHA injections in a 26-week Extension Study. Adverse events (AEs) were recorded and the effect of treatment on knee pain was measured immediately following a 50-foot walk test using a 100 mm visual analog scale (VAS). Responder rate, Medical Outcomes Study Short Form 36 scores, Patient's Global Assessment, and intake of rescue medication were also evaluated. RESULTS: The Extension Study included 433 subjects, 219 who received IA-BioHA and 214 who received IA-SA during the FLEXX Trial. Safety results from the Extension Study indicated that 43.4% (188/433) of subjects had AEs, of which 4.8% (21/433) were deemed treatment-related AEs. Two AEs in the Extension Study led to discontinuation, and no joint effusion was reported. Patients who continued with IA-BioHA in the Extension Study maintained their improvement from baseline, with an average reduction in pain in the VAS score of -3.5 mm. Patients initially treated with IA-SA in the FLEXX Trial also had a reduction in VAS score of -9.0 mm. Secondary efficacy variables also improved during the Extension Study. CONCLUSIONS: Repeat injections of IA-BioHA were effective, safe, well tolerated, and not associated with an increase in AEs, such as synovial effusions. Additional symptom improvements were noted for subjects who received either IA-BioHA or IA-SA in the FLEXX Trial. CLINICAL TRIAL REGISTRATION NUMBER: NCT00379236.

Safety issues in the development of treatments for osteoarthritis: recommendations of the Safety Considerations Working Group.

OBJECTIVE: The symptomatic treatment of osteoarthritis (OA) remains to be improved, as many patients do not respond well to current palliative therapies and/or suffer unacceptable adverse events. Given the unmet need for innovative, effective and well-tolerated therapies, it is important to develop the means to estimate the ongoing safety profile of novel therapeutic agents over short- and longer term use. DESIGN: Methods are presented to estimate the number of serious adverse events (SAEs) of interest considered as "acceptable" per 1000 patient-years exposure and to estimate the numbers of patient-years needed in a randomized controlled trial (RCT) to meet objectives. As exposure is increased, more evidence is accrued that the overall risk is within study limits. It is equally important that requirements for delineating the safety of promising new therapies not create barriers that would preclude their development. Therefore, ongoing surveillance of occurrence of SAEs of interest during clinical development is proposed, for example after every incremental 500 patient-years exposure are accrued. RESULTS: This paper and others in this special issue focus on identification of safety signals for symptomatic treatments of OA. Much less information is available for agents aimed at slowing/preventing structural progression but it is expected that a higher risk profile might be considered acceptable in the context of more promising benefit. CONCLUSION: This paper provides a proposal and supporting data for a comprehensive approach for assessing ongoing safety during clinical development of both palliative and disease-modifying therapies for OA.

Study of redox potential in cytochrome c covalently bound to terminal oxidase of alkaliphilic Bacillus pseudofirmus FTU.

Spectroelectrochemistry was used to determine the midpoint redox potentials of heme cofactors of the caa3-type cytochrome oxidase from the alkaliphilic bacterium Bacillus pseudofirmus FTU. The apparent midpoint potentials (E(m)(app)) for the most prominent transitions of hemes a and a3 (+193 and +334 mV, respectively) were found to be similar to the values reported for other enzymes with high homology to the caa3-type oxidase. In contrast, the midpoint potential of the covalently bound cytochrome c (+89 mV) was 150-170 mV lower than in cytochromes c, either low molecular weight or covalently bound to the caa3 complex in all known aerobic neutralophilic and thermo-neutralophilic bacteria. Such an unusually low redox potential of the covalently bound cytochrome c of the caa3-type oxidase of alkaliphilic bacteria, together with high redox potentials of hemes a and a3, ensures more than twice higher difference in redox potentials inside the respiratory complex compared to the homologous mitochondrial enzyme. The energy released during this redox transition might be stored in the transmembrane H+ gradient even under low Deltap in the alkaline environment of the bacteria at the expense of a significant increase in DeltaG of the coupled redox reaction.

Responsiveness, effect size, and smallest detectable difference of Magnetic Resonance Imaging in knee osteoarthritis.

OBJECTIVE: The aim of this study was to determine the responsiveness, effect size (ES) and smallest detectable difference (SDD) of two Magnetic Resonance Imaging (MRI) measures for osteoarthritis (OA) of the knee: a whole-organ semiquantitative evaluation and cartilage volume. DESIGN: This analysis was performed on a dataset from a randomized, double-blind trial (Roche NI-15713) conducted in 1998 of a novel therapy in subjects with mild-moderate knee OA, with MRI at baseline and 6-month follow-up. The trial measurements included (1) cartilage volume measured using a proprietary software method; and (2) semiquantitative scoring of other parameters important for "whole organ" evaluation of OA knee joint pathology, using the Whole-Organ MRI Score (WORMS). The analysis initially examined the distributional characteristics of WORMS items, such as cartilage morphology. Standardized response mean (SRM), ES, and SDD between baseline and 6-month follow-up were then calculated in the whole group and the placebo group alone. RESULTS: In general, the differences were small and this was reflected in the small ESs and SRMs. There was also a suggestion of a treatment effect with reduction in differences between baseline and follow-up in the treatment group. CONCLUSION: Of the MRI semiquantitative measures, cartilage morphology, synovitis and osteophytes appeared to be responsive to change and the focus of repeat measures should highlight these articular features. In general, the ESs and SRMs were small.

Effect of reproductive factors and postmenopausal hormone use on the risk of Parkinson disease.

OBJECTIVE: Parkinson disease (PD) is less common in women possibly because of hormonal or reproductive influences. The objective of this study was to evaluate the associations of reproductive factors and postmenopausal hormone use with the risk of PD among postmenopausal women. METHODS: Incident cases (n = 178) and randomly selected age-matched controls (n = 189) who were members of the Kaiser Permanente Medical Care Program (KPMCP) of Northern California participated in the study conducted during the years 1994 to 1995. Statistical analyses were carried out using logistic regression. RESULTS: The association of postmenopausal hormone use with PD risk depended on the type of menopause. Among women with history of a hysterectomy with or without an oophorectomy, estrogen use alone was associated with a 2.6-fold increased risk (adjusted odds ratio (OR) 2.6, 95% CI: 1.1 to 6.1) and significant trends in the risk of PD were observed with increasing duration of estrogen use, but disease risk was not influenced by recency of use. In contrast, among women with natural menopause, no increased risk of PD was observed with hormone use (estrogen alone or a combined estrogen-progestin regimen). Early age at final menstrual period (44 years or younger) was associated with reduction in risk (adjusted OR 0.5, 95% CI: 0.3 to 1.0). Age at menarche and parity were not associated with the risk of PD. CONCLUSION: Postmenopausal use of estrogen alone may increase the risk of Parkinson disease (PD) among women with a hysterectomy. Among women with natural menopause for whom the usual treatment is combined estrogen-progestin therapy, no increased risk of PD was observed.

Endovascular repair or surveillance of patients with small AAA.

OBJECTIVE: To compare the outcome of patients with small abdominal aortic aneurysms (AAA) treated in a prospective trial of endovascular aneurysm repair (EVAR) to patients randomized to the surveillance arm of the UK Small Aneurysm Trial. METHOD: All patients with small AAA (< or = 5.5 cm diameter) treated with a stent graft (EVARsmall) in the multicenter AneuRx clinical trial from 1997 to 1999 were reviewed with follow up through 2003. A subgroup of patients (EVARmatch) who met the age (60-76 years) and aneurysm size (4.0-5.5 cm diameter) inclusion criteria of the UK Small Aneurysm Trial were compared to the published results of the surveillance patient cohort (UKsurveil) of the UK Small Aneurysm Trial (NEJM 346:1445, 2002). Endpoints of comparison were aneurysm rupture, fatal aneurysm rupture, operative mortality, aneurysm related death and overall mortality. The total patient years of follow-up for EVAR patients was 1369 years and for UK patients was 3048 years. Statistical comparisons of EVARmatch and UKsurveil patients were made for rates per 100 patient years of follow up (/100 years) to adjust for differences in follow-up time. RESULTS: The EVARsmall group of 478 patients comprised 40% of the total number of patients treated during the course of the AneuRx clinical trial. The EVARmatch group of 312 patients excluded 151 patients for age < 60 or > 76 years and 15 patients for AAA diameter < 4 cm. With the exception of age, there were no significant differences between EVARsmall and EVARmatch in pre-operative factors or post-operative outcomes. In comparison to the UKsurveil group of 527 patients, the EVARmatch group was slightly older (70 +/- 4 vs. 69 +/- 4 years, p = 0.009), had larger aneurysms (5.0 +/- 0.3 vs. 4.6 +/- 0.4 cm, p < 0.001), fewer women (7 vs. 18%, p < 0.001), and had a higher prevalence of diabetes and hypertension and a lower prevalence of smoking at baseline. Ruptures occurred in 1.6% of EVARmatch patients and 5.1% of UKsurveil patients; this difference was not significant when adjusted for the difference in length of follow up. Fatal aneurysm rupture rate, adjusted for follow up time, was four times higher in UKsurveil (0.8/100 patient years) than in EVARmatch (0.2/100 patient years, p < 0.001); this difference remained significant when adjusted for difference in gender mix. Elective operative mortality rate was significantly lower in EVARmatch (1.9%) than in UKsurveil (5.9%, p < 0.01). Aneurysm-related death rate was two times higher in UKsurveil (1.6/100 patient years) than in EVARmatch (0.8/100 patient years, p = 0.03). All-cause mortality rate was significantly higher in UKsurveil (8.3/100 patient years) than in EVARmatch (6.4/100 patient years, p = 0.02). CONCLUSIONS: It appears that endovascular repair of small abdominal aortic aneurysms (4.0-5.5 cm) significantly reduces the risk of fatal aneurysm rupture and aneurysm-related death and improves overall patient survival compared to an ultrasound surveillance strategy with selective open surgical repair.

Energetics of alkalophilic representatives of the genus Bacillus.

Cytochrome and lipid composition of membranes is considered as the attributes required for adaptation of the alkalophiles to alkaline conditions. Respiratory chains of alkalophilic representatives of the genus Bacillus are discussed. Special attention is paid to the features of the Na(+)-cycle of these bacteria and to the features determining halo- and alkalotolerant phenotype, which have been reported due to recent achievements in genomics.

Meniscal tear and extrusion are strongly associated with progression of symptomatic knee osteoarthritis as assessed by quantitative magnetic resonance imaging.

BACKGROUND: The relation between knee meniscal structural damage and cartilage degradation is plausible but not yet clearly proven. OBJECTIVES: To quantitate the cartilage volume changes in knee osteoarthritis using magnetic resonance imaging (MRI), and determine whether meniscal alteration predicts cartilage volume loss over time. METHODS: 32 patients meeting ACR criteria for symptomatic knee osteoarthritis were studied. MRI knee acquisitions were done every six months for two years. The cartilage volumes of different knee regions were measured. Three indices of structural change in the medial and lateral menisci were evaluated--degeneration, tear, and extrusion--using a semiquantitative scale. RESULTS: 24 patients (75%) had mild to moderate or severe meniscal damage (tear or extrusion) at baseline. A highly significant difference in global cartilage volume loss was observed between severe medial meniscal tear and absence of tear (mean (SD), -10.1 (2.1)% v -5.1 (2.4)%, p = 0.002). An even greater difference was found between the medial meniscal changes and medial compartment cartilage volume loss (-14.3 (3.0)% in the presence of severe tear v -6.3 (2.7)% in the absence of tear; p<0.0001). Similarly, a major difference was found between the presence of a medial meniscal extrusion and loss of medial compartment cartilage volume (-15.4 (4.1)% in the presence of extrusion v -4.5 (1.7)% with no extrusion; p<0.001). CONCLUSIONS: Meniscal tear and extrusion appear to be associated with progression of symptomatic knee osteoarthritis.

Measurement of structural progression in osteoarthritis of the hip: the Barcelona consensus group.

OBJECTIVE: To outline the best available method of measurement for detecting progression of osteoarthritis (OA) of the hip especially in therapeutic trials. METHOD: A Medline search of articles related to progression of hip OA was performed. A group of experts met over a 1.5-day session to review available literature and new research. Specific questions were addressed in order to reach a consensus on measuring progression of OA of the hip. RESULTS: Of the available surrogate measures, a single yearly standing or reclined antero-posterior plain radiograph of the pelvis with feet internally rotated 15-20 degrees, can be evaluated with the use of an atlas for joint space width (JSW, interbone distance). There should be a minimum JSW upon baseline screening that may be 1 or 2 mm. Digitization of films offers a slight reduction in variability of measurements. Progression of OA can be calculated by measurement of the JSW on paired and blinded films. A reduction of > or = 0.5 mm is greater than the 'minimum perceptible difference' as well as the variation of most imaging techniques, and represents a clinically relevant and significant reduction in the JSW. Narrowing of the superomedial or superolateral JSW may tend to progress more rapidly than other changes. In clinical trials, patients who discontinue the study treatment need to be followed after discontinuation, and an imputation strategy which provides unbiased estimates of both the treatment effect and its variance is an appropriate technique for intent-to-treat analysis. CONCLUSION: For the development of new agents intended to prevent, retard, stabilize or reverse the progress of OA of the hip, the radiographic methodology presently available is adequate to detect changes in hip JSW of OA.

Mitochondrial DNA and microsatellite variation in the eider duck (Somateria mollissima) indicate stepwise postglacial colonization of Europe and limited current long-distance dispersal.

To unravel the postglacial colonization history and the current intercolony dispersal in the common eider, Somateria mollissima, we analysed genetic variation at a part of the mitochondrial control region and five unlinked autosomal microsatellite loci in 175 eiders from 11 breeding colonies, covering the entire European distribution range of this species. As a result of extreme female philopatry, mitochondrial DNA differentiation is substantial both among local colonies and among distant geographical regions. Our study further corroborates the previous hypothesis of a single Pleistocene refugium for European eiders. A nested clade analysis on mitochondrial haplotypes suggests that (i) the Baltic Sea eider population is genetically closest to a presumably ancestral population and that (ii) the postglacial recolonization progressed in a stepwise fashion via the North Sea region and the Faroe Islands to Iceland. Current long-distance dispersal is limited. Differentiation among colonies is much less pronounced at microsatellite loci. The geographical pattern of this nuclear genetic variation is to a large extent explained by isolation by distance. As female dispersal is very limited, the geographical pattern of nuclear variation is probably explained by male-mediated gene flow among breeding colonies. Our study provides genetic evidence for the assumed prominent postglacial colonization route shaping the present terrestrial fauna of the North Atlantic islands Iceland and the Faroes. It suggests that this colonization had been a stepwise process originating in continental Europe. It is the first molecular study on eider duck populations covering their entire European distribution range.

Reliability of a quantification imaging system using magnetic resonance images to measure cartilage thickness and volume in human normal and osteoarthritic knees.

OBJECTIVE: The aim of this study was to evaluate the reliability of a software tool that assesses knee cartilage volumes using magnetic resonance (MR) images. The objectives were to assess measurement reliability by: (1) determining the differences between readings of the same image made by the same reader 2 weeks apart (test-retest reliability), (2) determining the differences between the readings of the same image made by different readers (between-reader agreement), and (3) determining the differences between the cartilage volume readings obtained from two MR images of the same knee image acquired a few hours apart (patient positioning reliability). METHODS: Forty-eight MR examinations of the knee from normal subjects, patients with different stages of symptomatic knee osteoarthritis (OA), and a subset of duplicate images were independently and blindly quantified by three readers using the imaging system. The following cartilage areas were analyzed to compute volumes: global cartilage, medial and lateral compartments, and medial and lateral femoral condyles. RESULTS: Between-reader agreement of measurements was excellent, as shown by intra-class correlation (ICC) coefficients ranging from 0.958 to 0.997 for global cartilage (P<0.0001), 0.974 to 0.998 for the compartments (P<0.0001), and 0.943 to 0.999 for the condyles(P<0.0001). Test-retest reliability of within-reader data was also excellent, with Pearson correlation coefficients ranging from 0.978 to 0.999 (P<0.0001). Patient positioning reliability was also excellent, with Pearson correlation coefficients ranging from 0.978 to 0.999 (P<0.0001). CONCLUSIONS: The results of this study establish the reliability of this MR imaging system. Test-retest reliability, between-reader agreement, and patient positioning reliability were all extremely high. This study represents a first step in the overall validation of an imaging system designed to follow progression of human knee OA.

Assessment of low-flow CSF drainage as a treatment for AD: results of a randomized pilot study.

OBJECTIVE: This prospective, randomized, controlled study was designed to investigate the safety, feasibility, and preliminary efficacy of long-term CSF drainage via a low-flow ventriculoperitoneal shunt in subjects suffering from AD. METHODS: Twenty-nine subjects selected for probable AD (National Institute of Neurological and Communicative Diseases and Stroke-Alzheimer's Disease and Related Dementias Association criteria) were screened to exclude normal pressure hydrocephalus or other etiologies of dementia and randomized to treatment (shunt) or no treatment groups. The study endpoint was the comparison of group performance on psychometric testing at quarterly intervals for 1 year. Shunted subjects had CSF withdrawn for MAP-tau and Abeta((1-42)) assays at the same time intervals. RESULTS: There was no mortality from the surgical procedure, and no patient sustained a subdural hematoma. Five notable postoperative adverse events, which resolved without permanent neurologic deficit, were reported in the shunt group. Group mean Mattis Dementia Rating Scale total scores showed little change over the year in the shunt-treatment group, in contrast to a decline in the control group (p = 0.06). Mini-Mental State Examination mean scores supported a trend in favor of shunt treatment (p = 0.1). There was a concomitant decrease in ventricular CSF concentrations of AD biomarkers MAP-tau and Abeta((1-42)). CONCLUSIONS: The surgical procedure and the device are reasonably safe. Adverse events were consistent with shunt procedures for hydrocephalus in this older population. The endpoint data show a trend in favor of the treated group. A larger, randomized, double-blinded, controlled, clinical trial is underway.

Fetal ear length measurement: a useful predictor of aneuploidy?

OBJECTIVE: To determine the usefulness of short ear length (EL) measurement in the prenatal detection of fetuses with chromosomal abnormalities. DESIGN: Fetal EL measurements, routine biometry and complete anatomic survey for fetal abnormalities were prospectively performed by antenatal sonography. SUBJECTS: One thousand eight hundred and forty-eight patients with singleton pregnancies undergoing genetic amniocentesis in the second or third trimester. METHODS: Complete data for EL, biometry and anatomic survey for major structural abnormalities and minor sonographic markers of chromosomal abnormality were available in 1311 fetuses. Of these, 48 (3.7%) had an abnormal karyotype and 1263 (96.3%) had a normal karyotype. Using an EL measurement of < or = 10th percentile for corresponding gestational age in normal fetuses as abnormal cut-off values, detection rates for chromosomal abnormalities by short EL were determined. RESULTS: Among the 48 abnormal karyotypes, 34 were considered significant, and 11 of these 34 (32.4%) fetuses had short EL. In 14 cases, the karyotypic abnormality was considered non-significant and fetal EL was normal in all cases. Of the 34 fetuses with significant chromosomal abnormalities, six (17.6%) on antenatal sonography had no detectable abnormal findings, other than short EL. An increased biparietal diameter (BPD)/EL ratio of > or = 4.0 was also noted in fetuses with an abnormal karyotype, but the sensitivity and predictive value of increased BPD/EL ratio alone or increased BPD/EL ratio in combination with short EL was no better than the sensitivity and predictive value of short EL alone. A combination of short EL and abnormal ultrasound, however, gave a much higher positive predictive value (46%) for significant chromosomal abnormalities. CONCLUSIONS: Our findings suggest that in women at high risk for fetal chromosomal abnormality, a short fetal EL measurement on prenatal ultrasound, either alone or in combination with other sonographically detectable structural abnormalities, may be a useful parameter in predicting fetal aneuploidy.

The influence of parental relatedness on reproductive success.

The relationship between fitness and parental similarity has been dominated by studies of how inbreeding depression lowers fecundity in incestuous matings. A widespread implicit assumption is that adult fitness (reproduction) of individuals born to parents who are not unusually closely related is more or less equal. Examination of three long-lived vertebrates, the long-finned pilot whale, the grey seal and the wandering albatross reveals significant negative relationships between parental similarity and genetic estimates of reproductive success. This effect could, in principle, be driven by a small number of low quality, inbred individuals. However, when the data are partitioned into individuals with above average and below average parental similarity, we find no evidence that the slopes differ, suggesting that the effect is more or less similar across the full range of parental similarity values. Our results thus uncover a selective pressure that favours not only inbreeding avoidance, but also the selection of maximally dissimilar mates.