Picosecond kilohertz-class cryogenically cooled multistage Yb-doped chirped pulse amplifier.

A multistage cryogenic chirped pulse amplifier has been developed, utilizing two different Yb-doped gain materials in subsequent amplifier stages. A Yb:GSAG regenerative amplifier followed by a Yb:YAG power amplifier is able to deliver pulses with a broader bandwidth than a system using only one of these two gain media throughout. We demonstrate 90 mJ of pulse energy (113 W of average power) uncompressed and 67 mJ (84 W of average power) compressed at 1.25 kHz pulse repetition frequency, 3.0 ps FWHM Gaussian pulse width, and near-diffraction-limited (M2<1.3) beam quality.

Immune function and brain abnormalities in patients with systemic lupus erythematosus without overt neuropsychiatric manifestations.

OBJECTIVE: This study examined the relationship between immune, cognitive and neuroimaging assessments in subjects with systemic lupus erythematosus (SLE) without histories of overt neuropsychiatric (NP) disorders. METHODS: In total, 84 subjects with nonNPSLE and 37 healthy controls completed neuropsychological testing from the American College of Rheumatology SLE battery. Serum autoantibody and cytokine measures, volumetric magnetic resonance imaging, and magnetic resonance spectroscopy data were collected on a subset of subjects. RESULTS: NonNPSLE subjects had lower scores on measures of visual/complex attention, visuomotor speed and verbal memory compared with controls. No clinically significant differences between nonNPSLE patients and controls were found on serum measures of lupus anticoagulant, anticardiolipin antibodies, beta 2-glycoproteins, or pro-inflammatory cytokines (interleukin (IL)-1, IL-6, interferon alpha (IFN-alpha), and interferon gamma (IFN-gamma)). Higher scores on a global cognitive impairment index and a memory impairment index were correlated with lower IFN-alpha. Few associations between immune functions and neuroimaging parameters were found. CONCLUSIONS: Results indicated that nonNPSLE patients demonstrated cognitive impairment but not immune differences compared with controls. In these subjects, who were relatively young and with mild disease, no relationship between cognitive dysfunction, immune parameters, or previously documented neuroimaging abnormalities were noted. Immune measures acquired from cerebrospinal fluid instead of serum may yield stronger associations.

Memory impairment associated with neurometabolic abnormalities of the hippocampus in patients with non-neuropsychiatric systemic lupus erythematosus.

OBJECTIVE: Memory impairment is common in patients with systemic lupus erythematosus (SLE). This study examined hippocampal volumes and neurometabolic alterations in relation to memory function in SLE patients without a history of neuropsychiatric syndromes (nonNPSLE). METHODS: Subjects included 81 nonNPSLE patients and 34 healthy controls. Volumetric magnetic resonance imaging and magnetic resonance spectroscopy of the right and left hippocampal areas (RH, LH) were performed. Verbal and visual memory tests were administered and a memory impairment index (MII) was derived from standardized tests. RESULTS: Higher memory impairment (MII) was correlated with lower RH glutamate + glutamine/creatine (p = 0.009) and lower RH N-acetylaspartic acid/creatine (p = 0.012) in nonNPSLE patients. A trend for a negative correlation between RH and LH volumes and MII was evident for absolute hippocampal volumes. Lower RH glutamate + glutamine/creatine was also correlated with worse performance in a mean visual memory index (p = 0.017). CONCLUSIONS: An association between reduced memory and lower N-acetylaspartic acid/creatine in the RH suggests neuronal damage in nonNPSLE patients with very mild and early disease. Alterations in glutamate + glutamine/creatine further indicate early metabolic changes in nonNPSLE are related to memory impairment, a finding that might suggest that memory impairment relates to presynaptic glutamatergic dysfunction in the hippocampus.

Critical velocity for superfluid flow across the BEC-BCS crossover.

Critical velocities have been observed in an ultracold superfluid Fermi gas throughout the BEC-BCS crossover. A pronounced peak of the critical velocity at unitarity demonstrates that superfluidity is most robust for resonant atomic interactions. Critical velocities were determined from the abrupt onset of dissipation when the velocity of a moving one-dimensional optical lattice was varied. The dependence of the critical velocity on lattice depth and on the inhomogeneous density profile was studied.

Evidence for superfluidity of ultracold fermions in an optical lattice.

The study of superfluid fermion pairs in a periodic potential has important ramifications for understanding superconductivity in crystalline materials. By using cold atomic gases, various models of condensed matter can be studied in a highly controllable environment. Weakly repulsive fermions in an optical lattice could undergo d-wave pairing at low temperatures, a possible mechanism for high temperature superconductivity in the copper oxides. The lattice potential could also strongly increase the critical temperature for s-wave superfluidity. Recent experimental advances in bulk atomic gases include the observation of fermion-pair condensates and high-temperature superfluidity. Experiments with fermions and bosonic bound pairs in optical lattices have been reported but have not yet addressed superfluid behaviour. Here we report the observation of distinct interference peaks when a condensate of fermionic atom pairs is released from an optical lattice, implying long-range order (a property of a superfluid). Conceptually, this means that s-wave pairing and coherence of fermion pairs have now been established in a lattice potential, in which the transport of atoms occurs by quantum mechanical tunnelling and not by simple propagation. These observations were made for interactions on both sides of a Feshbach resonance. For larger lattice depths, the coherence was lost in a reversible manner, possibly as a result of a transition from superfluid to insulator. Such strongly interacting fermions in an optical lattice can be used to study a new class of hamiltonians with interband and atom-molecule couplings.

Observation of strong quantum depletion in a gaseous Bose-Einstein condensate.

We studied quantum depletion in a gaseous Bose-Einstein condensate. An optical lattice enhanced the atomic interactions and modified the dispersion relation resulting in strong quantum depletion. The depleted fraction was directly observed as a diffuse background in the time-of-flight images. Bogoliubov theory provides a semiquantitative description for our observations of depleted fractions in excess of 50%.

Coherent molecular optics using ultracold sodium dimers.

Coherent molecular optics is performed using two-photon Bragg scattering. Molecules were produced by sweeping an atomic Bose-Einstein condensate through a Feshbach resonance. The spectral width of the molecular Bragg resonance corresponded to an instantaneous temperature of 20 nK, indicating that atomic coherence was transferred directly to the molecules. An autocorrelating interference technique was used to observe the quadratic spatial dependence of the phase of an expanding molecular cloud. Finally, atoms initially prepared in two momentum states were observed to cross pair with one another, forming molecules in a third momentum state. This process is analogous to sum-frequency generation in optics.

Multimedia quality of life assessment: advances with FLAIR.

Assessing impact of functional dependency on quality of life (QOL) among older adults can provide an in-depth understanding of health preferences. Utilities as a measure of preferences are necessary in conducting cost-effectiveness evaluations of healthcare interventions designed to improve overall QOL. We describe further development of a multimedia utility elicitation instrument that is highly portable and easily accessible. An earlier version, FLAIR1, introduced features designed for older adult, computer inexperienced users. FLAIR2 includes modifications such as migration to a web-based platform, consistency checks, audio/visual updates, and more response methods. As compared with FLAIR1, more FLAIR2 respondents (n=318) preferred using the computer and found the computer program to be enjoyable, easy to use, and easily understood. There were also fewer inconsistencies among FLAIR2 respondents. FLAIR2 enhancements have increased portability, minimized invariance and inconsistency, and produced a more user friendly design.

Formation of quantum-degenerate sodium molecules.

Ultracold sodium molecules were produced from an atomic Bose-Einstein condensate by ramping an applied magnetic field across a Feshbach resonance. More than 10(5) molecules were generated with a conversion efficiency of approximately 4%. Using laser light resonant with an atomic transition, the remaining atoms could be selectively removed, preventing fast collisional relaxation of the molecules. Time-of-flight analysis of the pure molecular sample yielded an instantaneous phase-space density greater than 20.

Quality of life assessment software for computer-inexperienced older adults: multimedia utility elicitation for activities of daily living.

Functional status as measured by dependencies in the Activities of Daily Living (ADLs) is an important indicator of overall health for older adults. Methodologies for outcomes-based medical-decision-making for public policy, such as decision modeling and cost-effectiveness analysis, require utilities for outcome health states. Utilities have been reported for many disease states, but have not been indexed by functional status, which is a strong predictor of outcome in geriatrics. We describe here a utility elicitation program developed specifically for use with computer-inexperienced older adults: Functional Limitation And Independence Rating (FLAIR1). FLAIR1 design features address common physical problems of the aged and computer attitudes of inexperienced users that could impede computer acceptance. We interviewed 400 adults ages 65 years and older with FLAIR1. In exit interviews with 154 respondents, 118 (76%) found FLAIR1 easy to use. Design features in FLAIR1 can be applied to other software for older adults

A longitudinal study of brain atrophy in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG).

OBJECTIVE: To determine if progressive brain atrophy could be detected over 1- and 2-year intervals in relapsing MS, based on annual MR studies from the Multiple Sclerosis Collaborative Research Group (MSCRG) trial of interferon beta-1a (Avonex). METHODS: All subjects had mild to moderate disability, with baseline expanded disability status scores ranging from 1.0 to 3.5, and at least two relapses in the 3 years before study entry. Atrophy measures included third and lateral ventricle width, brain width, and corpus callosum area. RESULTS: Significant increases were detected in third ventricle width at year 2 and lateral ventricle width at 1 and 2 years. Significant decreases in corpus callosum area and brain width were also observed at 1 and 2 years. Multiple regression analyses suggested that the number of gadolinium-enhancing lesions at baseline was the single significant contributor to change in third ventricle width. Atrophy over 1 and 2 years as indicated by enlargement of the third and lateral ventricle and shrinkage of the corpus callosum was greater for patients entering the trial with enhancing lesions. Greater disability increments over 1 and 2 years were associated with more severe third ventricle enlargement. CONCLUSION: In patients with relapsing MS and only mild to moderate disability, significant cerebral atrophy is already developing that can be measured over periods of only 1 to 2 years. The course of cerebral atrophy in MS appears to be influenced by prior inflammatory disease activity as indicated by the presence of enhancing lesions. Brain atrophy measures are important markers of MS disease progression because they likely reflect destructive and irreversible pathologic processes.

Increased levels of transforming growth factor-beta in HIV-associated nephropathy.

BACKGROUND: Human immunodeficiency virus-associated nephropathy (HIVAN) is a renal disease of unknown pathogenesis. Recent evidence suggests that the fibrogenic cytokine transforming growth factor-beta (TGF-beta) might be involved. We hypothesized that overproduction of TGF-beta in the kidney might be involved in the pathogenesis of HIVAN. METHODS: The mRNA and protein expression of TGF-beta isoforms, TGF-beta 1, TGF-beta 2, and TGF beta 3, deposition of matrix proteins induced by TGF-beta, and levels of HIV Tat protein were studied in HIVAN. Controls included normal and diseased kidneys from HIV-positive and -negative patients. The ability of Tat to induce production of TGF-beta and matrix proteins was also studied in human mesangial cells. RESULTS: Normal kidneys, thin basement membrane nephropathy, and minimal change disease were negative for the three TGF-beta isoforms and Tat. In HIVAN, levels of TGF-beta isoforms and Tat were significantly increased, along with the expression of TGF-beta mRNA and deposition of matrix proteins stimulated by TGF-beta. Increased levels of TGF-beta isoforms, but not Tat, were also found in other glomerular diseases characterized by matrix accumulation. HIV infection, in the absence of HIVAN, was not associated with an increase in TGF-beta or Tat expression. Tat stimulated the expression and production of TGF-beta 1 and matrix proteins by human mesangial cells. CONCLUSIONS: Our findings suggest that overproduction of TGF-beta is involved in the pathogenesis of HIVAN.

The murine Fhit gene is highly similar to its human orthologue and maps to a common fragile site region.

The human FHIT gene is a putative tumor suppressor gene that maps to human chromosome band 3p14.2 in a region that is frequently deleted in cancers. It exhibits both genomic deletions and aberrant transcripts in a variety of tumors and spans the common fragile site FRA3B. This fragile site extends over a broad region of several hundred kb within the FHIT gene and may account for its instability in tumors. As one test of this hypothesis, we isolated the murine Fhit gene and asked whether it also contains a common fragile site and if it is unstable in mouse tumors or tumor cell lines. The Fhit gene was isolated, and the sequence was found to be 87.5% identical to that of the human FHIT gene in the open reading frame. Using fluorescence in situ hybridization, Fhit was assigned to mouse chromosome band 14A2, in a region that was previously shown to contain an aphidicolin-inducible mouse fragile site. Fluorescence in situ hybridization with genomic clones containing Fhit and flanking sequences demonstrated that gaps and breaks in the fragile site occur over a broad region within and proximal to the Fhit locus. Thus, the physical relationship of Fhit to a common fragile site is similar to that observed with the orthologous human FHIT gene and FRA3B.

A mutation of the atrial natriuretic peptide (guanylyl cyclase-A) receptor results in a constitutively hyperactive enzyme.

Mutation of an invariant glutamate residue found within the catalytic domain of guanylyl cyclases resulted in a dramatic 14-fold increase in the activity of the guanylyl cyclase-A receptor. Even in the presence of Mn2+/Triton X-100, a treatment previously thought to yield hormone-independent and maximum cyclase activity, the mutant enzyme remained 7-fold more active; to our knowledge, this is the first example of a protein modification or of an added agent that significantly increases cyclase activity in the presence of Mn2+/Triton X-100. Intracellular concentrations of cGMP in cells expressing the mutant (E974A) cyclase were only marginally elevated by the addition of atrial natriuretic peptide, and in broken-cell preparations, the mutant enzyme also was relatively insensitive to ligand/regulatory nucleotide. The marked increase in cyclase activity was not due to a relief of protein kinase domain inhibition, since the point mutation caused 7- to 13-fold elevations in guanylyl cyclase-A activity when the protein kinase homology domain was deleted. The E974A mutation also altered the kinetics from positive cooperative to linear with respect to MnGTP, suggesting disruption of subunit-subunit interactions. Thus, a single point mutation within the catalytic domain of a guanylyl cyclase results in a constitutively hyperactive enzyme that is independent of protein kinase domain regulation.

Frequent deletions of FHIT and FRA3B in Barrett's metaplasia and esophageal adenocarcinomas.

The FHIT gene, which spans the common fragile site FRA3B, has been shown to produce aberrant transcripts in a variety of tumor types. Homozygous deletions within the FHIT locus have been detected only in tumor-derived cell lines and LOH has been described in numerous primary tumors. Based on these findings and its location on 3p, FHIT has been proposed as a tumor suppressor gene. To further study the relationship of FRA3B to the findings regarding the FHIT gene and to determine the extent of FHIT mRNA alterations in early stages of tumor development, the status of the FHIT gene was evaluated in the premalignant condition of Barrett's esophagus and associated esophageal adenocarcinomas. FHIT expression was investigated by RT-PCR in normal esophageal, Barrett's metaplasia and adenocarcinoma tissues from 15 patients. Alterations of FHIT transcripts were observed in 12/14 (86%) of Barrett's metaplasia and in 14/15 (93%) of the adenocarcinomas from the same patients. Characterization of the altered transcripts revealed FHIT mRNA lacking one or more exons, with deletion of exons 5-7 being most frequent. Analysis of genomic DNA from 20 patients showed homozygous deletions involving exon 5 of FHIT in 4/20 (20%) esophageal adenocarcinomas, and 7/20 (35%) tumors demonstrated hemizygous loss. Genomic deletions also involved the BE758-6 locus, indicating that a large region is deleted. Fluorescence in situ hybridization (FISH) analysis demonstrated that this region of deletion is localized within FRA3B. Our results extend the range of tumor types in which altered FHIT transcripts have been demonstrated and show that these alterations can be seen in the premalignant stage of esophageal tumor development. These results indicate that the fragility and recombination-prone nature of FRA3B is related to tumor-specific chromosomal instability affecting the FHIT gene in esophageal adenocarcinoma development.

Isolation of human and murine homologues of the Drosophila minibrain gene: human homologue maps to 21q22.2 in the Down syndrome "critical region".

The presence of an extra copy of human chromosome 21 (trisomy 21), especially region 21q22.2, causes many phenotypes in Down syndrome, including mental retardation. To study genes potentially responsible for some of these phenotypes, we cloned a human candidate gene (DYRK) from 21q22.2 and its murine counterpart (Dyrk) that are homologous to the Drosophila minibrain (mnb) gene required for neurogenesis and to the rat Dyrk gene (dual specificity tyrosine phosphorylation regulated kinase). The three mammalian genes are highly conserved, >99% identical at the protein level over their 763-amino-acid (aa) open reading frame; in addition, the mammalian genes are 83% identical over 414 aa to the smaller 542-aa mnb protein. The predicted human DYRK and murine Dyrk proteins both contain a nuclear targeting signal sequence, a protein kinase domain, a putative leucine zipper motif, and a highly conserved 13-consecutive-histidine repeat. Fluorescence in situ hybridization and regional mapping data localize DYRK between markers D21S336 and D21S337 in the 21q22.2 region. Northern blot analysis indicated that both human and murine genes encode approximately 6-kb transcripts. PCR screening of cDNA libraries derived from various human and murine tissues indicated that DYRK and Dyrk are expressed both during development and in the adult. In situ hybridization of Dyrk to mouse embryos (13, 15, and 17 days postcoitus) indicates a differential spatial and temporal pattern of expression, with the most abundant signal localized in brain gray matter, spinal cord, and retina. The observed expression pattern is coincident with many of the clinical findings in trisomy 21. Its chromosomal locus (21q22. 2), its homology to the mnb gene, and the in situ hybridization expression patterns of the murine Dyrk combined with the fact that transgenic mice for a YAC to which DYRK maps are mentally deficient suggest that DYRK may be involved in the abnormal neurogenesis found in Down syndrome.