A Fermi-degenerate three-dimensional optical lattice clock.

Strontium optical lattice clocks have the potential to simultaneously interrogate millions of atoms with a high spectroscopic quality factor of 4 × 1017 Previously, atomic interactions have forced a compromise between clock stability, which benefits from a large number of atoms, and accuracy, which suffers from density-dependent frequency shifts. Here we demonstrate a scalable solution that takes advantage of the high, correlated density of a degenerate Fermi gas in a three-dimensional (3D) optical lattice to guard against on-site interaction shifts. We show that contact interactions are resolved so that their contribution to clock shifts is orders of magnitude lower than in previous experiments. A synchronous clock comparison between two regions of the 3D lattice yields a measurement precision of 5 × 10-19 in 1 hour of averaging time.

Systematic evaluation of an atomic clock at 2 × 10(-18) total uncertainty.

The pursuit of better atomic clocks has advanced many research areas, providing better quantum state control, new insights in quantum science, tighter limits on fundamental constant variation and improved tests of relativity. The record for the best stability and accuracy is currently held by optical lattice clocks. Here we take an important step towards realizing the full potential of a many-particle clock with a state-of-the-art stable laser. Our (87)Sr optical lattice clock now achieves fractional stability of 2.2 × 10(-16) at 1 s. With this improved stability, we perform a new accuracy evaluation of our clock, reducing many systematic uncertainties that limited our previous measurements, such as those in the lattice ac Stark shift, the atoms' thermal environment and the atomic response to room-temperature blackbody radiation. Our combined measurements have reduced the total uncertainty of the JILA Sr clock to 2.1 × 10(-18) in fractional frequency units.

An optical lattice clock with accuracy and stability at the 10(-18) level.

Progress in atomic, optical and quantum science has led to rapid improvements in atomic clocks. At the same time, atomic clock research has helped to advance the frontiers of science, affecting both fundamental and applied research. The ability to control quantum states of individual atoms and photons is central to quantum information science and precision measurement, and optical clocks based on single ions have achieved the lowest systematic uncertainty of any frequency standard. Although many-atom lattice clocks have shown advantages in measurement precision over trapped-ion clocks, their accuracy has remained 16 times worse. Here we demonstrate a many-atom system that achieves an accuracy of 6.4 × 10(-18), which is not only better than a single-ion-based clock, but also reduces the required measurement time by two orders of magnitude. By systematically evaluating all known sources of uncertainty, including in situ monitoring of the blackbody radiation environment, we improve the accuracy of optical lattice clocks by a factor of 22. This single clock has simultaneously achieved the best known performance in the key characteristics necessary for consideration as a primary standard-stability and accuracy. More stable and accurate atomic clocks will benefit a wide range of fields, such as the realization and distribution of SI units, the search for time variation of fundamental constants, clock-based geodesy and other precision tests of the fundamental laws of nature. This work also connects to the development of quantum sensors and many-body quantum state engineering (such as spin squeezing) to advance measurement precision beyond the standard quantum limit.

Comparison of two independent Sr optical clocks with 1×10(-17) stability at 10(3) s.

Many-particle optical lattice clocks have the potential for unprecedented measurement precision and stability due to their low quantum projection noise. However, this potential has so far never been realized because clock stability has been limited by frequency noise of optical local oscillators. By synchronously probing two ^{87}Sr lattice systems using a laser with a thermal noise floor of 1×10(-15), we remove classically correlated laser noise from the intercomparison, but this does not demonstrate independent clock performance. With an improved optical oscillator that has a 1×10(-16) thermal noise floor, we demonstrate an order of magnitude improvement over the best reported stability of any independent clock, achieving a fractional instability of 1×10(-17) in 1000 s of averaging time for synchronous or asynchronous comparisons. This result is within a factor of 2 of the combined quantum projection noise limit for a 160 ms probe time with ~10(3) atoms in each clock. We further demonstrate that even at this high precision, the overall systematic uncertainty of our clock is not limited by atomic interactions. For the second Sr clock, which has a cavity-enhanced lattice, the atomic-density-dependent frequency shift is evaluated to be -3.11×10(-17) with an uncertainty of 8.2×10(-19).

Measurement of optical Feshbach resonances in an ideal gas.

Using a narrow intercombination line in alkaline earth atoms to mitigate large inelastic losses, we explore the optical Feshbach resonance effect in an ultracold gas of bosonic (88)Sr. A systematic measurement of three resonances allows precise determinations of the optical Feshbach resonance strength and scaling law, in agreement with coupled-channel theory. Resonant enhancement of the complex scattering length leads to thermalization mediated by elastic and inelastic collisions in an otherwise ideal gas. Optical Feshbach resonance could be used to control atomic interactions with high spatial and temporal resolution.

Improved pain, physical functioning and health status in patients with rheumatoid arthritis treated with CP-690,550, an orally active Janus kinase (JAK) inhibitor: results from a randomised, double-blind, placebo-controlled trial.

OBJECTIVES: To determine the efficacy of CP-690,550 in improving pain, function and health status in patients with moderate to severe active rheumatoid arthritis (RA) and an inadequate response to methotrexate or a tumour necrosis factor alpha inhibitor. METHODS: Patients were randomised equally to placebo, CP-690,550 5, 15 or 30 mg twice daily for 6 weeks, with 6 weeks' follow-up. The patient's assessment of arthritis pain (pain), patient's assessment of disease activity, Health Assessment Questionnaire-Disability Index (HAQ-DI) and Short Form-36 (SF-36) were recorded. RESULTS: At week 6, significantly more patients in the CP-690,550 5, 15 and 30 mg twice-daily groups experienced a 50% improvement in pain compared with placebo (44%, 66%, 78% and 14%, respectively), clinically meaningful reductions in HAQ-DI (> or =0.3 units) (57%, 75%, 76% and 36%, respectively) and clinically meaningful improvements in SF-36 domains and physical and mental components. CONCLUSIONS: CP-690,550 was efficacious in improving the pain, function and health status of patients with RA, from week 1 to week 6.

New drug therapies for the pediatric rheumatic diseases.

Such developments as the introduction of whole new drug classes, as well as the general increase in pediatric drug trials, have led to a revolution in pediatric rheumatology care. For example, selective cyclooxygenase-2 inhibitors can provide the same symptomatic relief as nonselective nonsteroidal anti-inflammatory agents without the same concerns over significant gastrointestinal toxicity. Biologic agents, notably the tumor necrosis factor inhibitors, have effected dramatic improvements in many patients with severe disease who previously were often significantly disabled. New immunosuppressives, such as mycophenolate mofetil, also have promise for ameliorating systemic lupus and vasculitic conditions, perhaps with reduced toxicity compared with other agents. New strategies for the use of older agents have also been further substantiated, such as intra-articular steroid and alternate-day high-dose steroid in chronic arthritis, and broader use of sulfasalazine. Evidence for the use of these therapies is discussed, as are potential toxicities.

Development of diabetes mellitus during etanercept therapy in a child with systemic-onset juvenile rheumatoid arthritis.

Although clinical trials of etanercept in adult and juvenile rheumatoid arthritis have generally revealed few adverse events, significant concern has arisen over the potential evolution of secondary autoimmune disease due to modulation of tumor necrosis factor. There have been few reports of such diseases developing, and none in children receiving this therapy. Reported herein is the case of a 7-year-old girl with a 3-year history of systemic-onset juvenile rheumatoid arthritis with a polyarticular course, in whom type 1 diabetes mellitus developed 5 months after the initiation of etanercept therapy.

Soluble adhesion molecules in juvenile rheumatoid arthritis.

OBJECTIVE: To determine serum levels of soluble (s) adhesion molecules in patients with juvenile rheumatoid arthritis (JRA), and to determine whether differences exist in these levels among the 3 subtypes of JRA, and whether levels of these molecules correlate with other measures of disease activity. METHODS: Serum levels of soluble forms of intercellular adhesion molecule-1 (ICAM-1), ICAM-3, vascular (V) CAM-1, L-selectin, and E-selectin were determined by sandwich ELISA in 16 patients with JRA (6 systemic, 6 polyarticular, 4 pauciarticular). Differences in levels among JRA subtypes were determined by ANOVA, and correlations between levels and the following clinical variables were assessed by linear regression analysis: erythrocyte sedimentation rate (ESR), total white blood cell count (WBC), hematocrit (HCT), platelet count (PLT), and total swollen joint count (JC). RESULTS: sE-selectin levels were significantly higher in patients with systemic disease compared to other subtypes (p<0.04). Furthermore, there was a trend toward higher levels of sICAM-1 in systemic disease, which did not reach statistical significance. Significant correlations were found between sE-selectin and ESR (r = 0.68, p<0.006), WBC (r = 0.70, p<0.003), and PLT (r = 0.54, p<0.05) and between sL-selectin and WBC (r = 0.55, p<0.03). CONCLUSION: Because of the small number of patients studied, and the lack of age matched control data, our results must be interpreted with caution. Nonetheless, levels of sE-selectin, and possibly ICAM-1 appear to be relatively elevated in systemic JRA, and may indicate cytokine induction and endothelial cell activation in that subtype. Several molecules, especially sE-selectin, correlate with hematologic variables in JRA. These results suggest that serum levels of these molecules may provide a useful additional marker for disease activity in certain patients.

Lack of Borrelia burgdorferi DNA in synovial samples from patients with antibiotic treatment-resistant Lyme arthritis.

OBJECTIVE: To determine whether Borrelia burgdorferi DNA may be detected in synovial tissue from patients with Lyme arthritis who have persistent synovial inflammation after antibiotic treatment. METHODS: Synovial specimens obtained at synovectomy from 26 patients with antibiotic treatment-resistant Lyme arthritis and from 10 control subjects were tested for B burgdorferi DNA using 3 primer-probe sets that target genes encoding outer surface proteins A or B or a flagellar protein (P41) of the spirochete. RESULTS: The 26 patients with Lyme arthritis, who had received antibiotic therapy for a mean total duration of 8 weeks prior to synovectomy, and the 10 control subjects each had negative polymerase chain reaction (PCR) results in synovial samples. When the samples were spiked with approximately 1-10 B burgdorferi, all but 1 had positive PCR results, suggesting that spirochetal DNA could have been detected in most of the unspiked samples if it had been present. CONCLUSION: These results indicate that synovial inflammation may persist in some patients with Lyme arthritis after the apparent eradication of the spirochete from the joint with antibiotic therapy.

Felty syndrome complicating juvenile rheumatoid arthritis.

PURPOSE: To describe a case of Felty syndrome (FS) in a child with (JRA) and review the previous literature on this rare entity. METHODS: Review of clinical data including results of serial blood counts, bone marrow aspirate, human leukocyte antigen (HLA)-typing, and abdominal sonography. RESULTS: Serial blood counts over 2 years revealed persistent leukopenia and thrombocytopenia. Bone marrow aspirate showed normal trilineage hematopoiesis, abdominal sonography demonstrated an enlarged spleen, but normal liver and portal circulation. HLA-typing was most significant for positivity of the DR 1 allele. CONCLUSION: This is only the third child, and the first preadolescent, to be reported with FS complicating juvenile rheumatoid arthritis. This condition needs to be considered in the differential diagnosis when leukopenia, thrombocytopenia, or both develop in patients with JRA.

Fibrin D-dimer as a marker of disease activity in systemic onset juvenile rheumatoid arthritis.

OBJECTIVE: To study the prevalence of coagulation abnormalities in children with systemic juvenile rheumatoid arthritis (JRA) using a sensitive marker of fibrin degradation, and to determine whether serial levels of this variable parallel disease activity or predict response to medications in this disease. METHODS: Levels of d-dimer were determined in 24 consecutive patients with systemic JRA in conjunction with complete blood counts, erythrocyte sedimentation rate, maximum fever, duration of morning stiffness, and swollen joint count. Serial levels were then obtained in 11 patients. Linear regression analyses were done to determine any correlations between d-dimer and the other variables; and paired t test was used to compare levels before and after treatment interventions. Levels of d-dimer were also compared against concurrent clinical events such as pericarditis. RESULTS: Elevated levels of d-dimer were found in 23/24 of the patients (96%). When serial levels were analyzed, there were correlations between levels of d-dimer and fever (p = 0.03) and total leukocyte count (p = 0.04), but not with other variables. There was a significant reduction in levels before and after treatment in patients deemed to be clinical responders to immunomodulatory agents (p = 0.02). Elevated levels were also indicative of severe disease over the remainder of followup; lack of d-dimer indicated a benign disease course. CONCLUSION: With the use of a sensitive and specific marker of fibrinolysis known as d-dimer, coagulation abnormalities were more prevalent in children with systemic JRA than previously reported, and are frequently found during periods of active disease. Furthermore, serial levels of d-dimer appear to parallel response to disease modifying agents, and may predict outcome over a short followup period. Fibrin d-dimer may represent a novel marker that, when used in combination with known variables, could enhance that assessment of disease activity and response to medications in children with systemic onset JRA.

Neurocognitive abnormalities in children after classic manifestations of Lyme disease.

BACKGROUND: In adults a subtle encephalopathy characterized primarily by memory impairment, irritability and somnolence may occur months to years after classic manifestations of Lyme disease. However, only limited information is available about whether there is an equivalent disorder in children. METHODS: Case series of five children seen in a Lyme disease clinic in a university referral center for evaluation of neurocognitive symptoms that developed near the onset of infection or months after classic manifestations of Lyme disease. The diagnosis was based on clinical symptoms, serologic reactivity to Borrelia burgdorferi and intrathecal antibody production to the spirochete. Evaluation included detailed neuropsychologic testing. After evaluation the children were treated with intravenous ceftriaxone for 2 or 4 weeks. Follow-up was done in the clinic and a final assessment was made by telephone 2 to 7 years after treatment. RESULTS: Along with or months after erythema migrans, cranial neuropathy or Lyme arthritis, the five children developed behavioral changes, forgetfulness, declining school performance, headache or fatigue and in two cases a partial complex seizure disorder. All five patients had IgG antibody responses to B. burgdorferi in serum as well as intrathecal IgG antibody production to the spirochete. Two patients had CSF pleocytoses and three did not. Despite normal intellectual functioning the five children had mild to moderate deficits in auditory or visual sequential processing. After ceftriaxone therapy, the four children in whom follow-up information was available experienced gradual improvement in symptoms. CONCLUSIONS: Children may develop neurocognitive symptoms along with or after classic manifestations of Lyme disease. This may represent an infectious or postinfectious encephalopathy related to B. burgdorferi infection.

Detection of Borrelia burgdorferi DNA by polymerase chain reaction in cerebrospinal fluid in Lyme neuroborreliosis.

A polymerase chain reaction (PCR) assay that detects Borrelia burgdorferi DNA in cerebrospinal fluid (CSF) was evaluated as a diagnostic test for acute or chronic Lyme neuroborreliosis. In one laboratory, 102 samples were tested blindly, and 40 samples were retested in a second laboratory. In the first laboratory, B. burgdorferi DNA was detected in CSF samples in 6 (38%) of 16 patients with acute neuroborreliosis, 11 (25%) of 44 with chronic neuroborreliosis, and none of 42 samples from patients with other illnesses. There was a significant correlation between PCR results and the duration of previous intravenous antibiotic therapy. The overall frequency of positive results was similar in the second laboratory, but concordance between the laboratories and among primer-probe sets was limited because many samples were positive with only one primer-probe set. Thus, PCR testing can sometimes detect B. burgdorferi DNA in CSF in patients with acute or chronic neuroborreliosis, but with current methods, the sensitivity of the test is limited.

Bicipital synovial cysts in juvenile rheumatoid arthritis: clinical description and sonographic correlation.

OBJECTIVE: To describe the presentation and clinical course of bicipital synovial cysts in 6 patients with juvenile rheumatoid arthritis (JRA) and to elucidate their anatomy using ultrasonography. METHODS: A clinical description of the cyst, JRA subtype, activity of concurrent arthritis, systemic disease features, and erythrocyte sedimentation rate was recorded for each patient. Ultrasonographic examination of the cyst was performed for each patient. RESULTS: Bicipital cysts generally presented as a sudden painless swelling on the flexor aspect of the upper arm, but on was in the forearm. Five of 6 patients had systemic disease. All patients had active arthritis when the cysts developed. Five of 6 cysts resolved spontaneously in less than 12 weeks. Ultrasonography confirmed a cystic structure in all patients, and in all cases was associated with thickening of the biceps tendon. Fluid was found within or adjacent to the biceps tendon in all cases. CONCLUSION: Bicipital synovial cysts should be considered a cause of acute arm swelling in patients with JRA, especially those with systemic disease. Ultrasonography is a useful diagnostic adjunct in this condition. This condition is generally self-resolving.

von Willebrand factor in juvenile dermatomyositis.

OBJECTIVE: To evaluate whether plasma von Willebrand factor (vWF) levels are a useful indicator of disease activity in juvenile dermatomyositis (DM). METHODS: Serum vWF levels were prospectively measured in 15 patients with juvenile DM and were compared to serum muscle enzyme levels, muscle strength, and presence of extramuscular manifestations. RESULTS: 6/15 active disease periods were accompanied by an increase in vWF; 9 were not. Elevated vWF levels did not relate to the presence of active skin disease or calcinosis. vWF was not consistently related to muscle strength, CPK, or aldolase in the study group. Two patients had elevations of vWF in association with viral infections while their DM was quiescent. CONCLUSION: An elevated vWF level is often indicative of a disease exacerbation in DM, and thus may be helpful in managing difficult cases. However, it is not consistently elevated in, nor specific for active disease in DM. It therefore cannot be recommended as a routine test in patients with DM. When used, results should be interpreted with caution.