Three-dimensional vortices generated by self-replication in stably stratified rotating shear flows.

A previously unknown instability creates space-filling lattices of 3D vortices in linearly stable, rotating, stratified shear flows. The instability starts from an easily excited critical layer. The layer intensifies by drawing energy from the background shear and rolls up into vortices that excite new critical layers and vortices. The vortices self-similarly replicate to create lattices of turbulent vortices. The vortices persist for all time. This self-replication occurs in stratified Couette flows and in the dead zones of protoplanetary disks where it can destabilize Keplerian flows.

The CHOICE survey: high rates of persistent and uncontrolled asthma in the United States.

BACKGROUND: Surveys have consistently shown that many patients with asthma do not have their disease well controlled. OBJECTIVES: The CHOICE (Comprehensive Survey of Healthcare Professionals and Asthma Patients Offering Insight on Current Treatment Gaps and Emerging Device Options) survey was designed to evaluate the current status of inhalation devices used in asthma treatment, but questions also were included about asthma severity and control. METHODS: A total of 1,000 patients with asthma were interviewed about their use of inhalation devices and asthma-related burden, medication use, and hospital/emergency care. Based on the responses to these questions, asthma severity and control were categorized using methods established in the Expert Panel Report III (EPR 3). RESULTS: Almost half (490) of the patients with asthma participating in the CHOICE survey were not using controller medications. Most of those not using controllers (79%) had persistent asthma; 47% had either mild or moderate persistent asthma. Of those on controllers (510), only 14.3% were well controlled. Acute care utilization was greater for patients with persistent asthma than those with intermittent asthma and for patients with not well and poorly controlled asthma than those with well-controlled asthma. CONCLUSION: The CHOICE survey is particularly pertinent clinically, because it demonstrates for the first time, using EPR 3 methods, the current extent of poor asthma control in the United States. This situation falls far short of national asthma management targets.

In vitro analysis of virus particle subpopulations in candidate live-attenuated influenza vaccines distinguishes effective from ineffective vaccines.

Two effective (vac+) and two ineffective (vac-) candidate live-attenuated influenza vaccines (LAIVs) derived from naturally selected genetically stable variants of A/TK/OR/71-delNS1[1-124] (H7N3) that differed only in the length and kind of amino acid residues at the C terminus of the nonstructural NS1 protein were analyzed for their content of particle subpopulations. These subpopulations included total physical particles (measured as hemagglutinating particles [HAPs]) with their subsumed biologically active particles of infectious virus (plaque-forming particles [PFPs]) and different classes of noninfectious virus, namely, interferon-inducing particles (IFPs), noninfectious cell-killing particles (niCKPs), and defective interfering particles (DIPs). The vac+ variants were distinguished from the vac- variants on the basis of their content of viral subpopulations by (i) the capacity to induce higher quantum yields of interferon (IFN), (ii) the generation of an unusual type of IFN-induction dose-response curve, (iii) the presence of IFPs that induce IFN more efficiently, (iv) reduced sensitivity to IFN action, and (v) elevated rates of PFP replication that resulted in larger plaques and higher PFP and HAP titers. These in vitro analyses provide a benchmark for the screening of candidate LAIVs and their potential as effective vaccines. Vaccine design may be improved by enhancement of attributes that are dominant in the effective (vac+) vaccines.

Effects of respiratory cycle and body position on quantitative pulmonary perfusion by MRI.

PURPOSE: To evaluate the performance of lung perfusion imaging using two-dimensional (2D) first pass perfusion MRI and a quantitation program based on model-independent deconvolution algorithm. MATERIALS AND METHODS: In eight healthy volunteers 2D first pass lung perfusion was imaged in coronal planes using a partial Fourier saturation recovery stead state free precession (SSFP) technique with a temporal resolution of 160 ms per slice acquisition. The dynamic signal in the lung was measured over time and absolute perfusion calculated based on a model-independent deconvolution program. RESULTS: In the supine position mean pulmonary perfusion was 287 ± 106 mL/min/100 mL during held expiration. It was significantly reduced to 129 ± 68 mL/min/100 mL during held inspiration. Similar differences due to respiration were observed in prone position with lung perfusion much greater during expiration than during inspiration (271 ± 101 versus 99 ± 38 mL/min/100 mL (P < 0.01)). There was a linear increase in pulmonary perfusion from anterior to posterior lung fields in supine position. The perfusion gradient reversed in the prone position with the highest perfusion in anterior lung and the lowest in posterior lung fields. CONCLUSION: Lung perfusion imaging using a 2D saturation recovery SSFP perfusion MRI coupled with a model-independent deconvolution algorithm demonstrated physiologically consistent dynamic heterogeneity of lung perfusion distribution.

Strength through defects: A novel Bayesian approach for the optimization of architected materials.

We use a previously unexplored Bayesian optimization framework, "evolutionary Monte Carlo sampling," to systematically design the arrangement of defects in an architected microlattice to maximize its strain energy density before undergoing catastrophic failure. Our algorithm searches a design space with billions of 4 × 4 × 5 3D lattices, yet it finds the global optimum with only 250 cost function evaluations. Our optimum has a normalized strain energy density 12,464 times greater than its commonly studied defect-free counterpart. Traditional optimization is inefficient for this microlattice because (i) the design space has discrete, qualitative parameter states as input variables, (ii) the cost function is computationally expensive, and (iii) the design space is large. Our proposed framework is useful for architected materials and for many optimization problems in science and elucidates how defects can enhance the mechanical performance of architected materials.

Dynamics of biologically active subpopulations of influenza virus: plaque-forming, noninfectious cell-killing, and defective interfering particles.

The dynamic changes in the temporal appearance and quantity of a new class of influenza virus, noninfectious cell-killing particles (niCKP), were compared to defective interfering particles (DIP). After a single high-multiplicity passage in MDCK cells of an egg-derived stock that lacked detectable niCKP or DIP, both classes of particles appeared in large numbers (>5 x 10(8)/ml), and the plaque-forming particle (PFP) titer dropped approximately 60-fold. After two additional serial high-multiplicity passages the DIP remained relatively constant, the DIP/niCKP ratio reached 10:1, and the PFP had declined by about 10,000-fold. Together, the niCKP and DIP subpopulations constituted ca. 20% of the total hemagglutinating particle population in which these noninfectious biologically active particles (niBAP) were subsumed. DIP neither killed cells nor interfered with the cell-killing (apoptosis-inducing) activity of niCKP or PFP (infectious CKP), even though they blocked the replication of PFP. Relative to the UV-target of approximately 13,600 nucleotides (nt) for inactivation of PFP, the UV target for niCKP was approximately 2,400 nt, consistent with one of the polymerase subunit genes, and that for DIP was approximately 350 nt, consistent with the small DI-RNA responsible for DIP-mediated interference. Thus, niCKP and DIP are viewed as distinct particles with a propensity to form during infection at high multiplicities. These conditions are postulated to cause aberrations in the temporally regulated replication of virus and its packaging, leading to the production of niBAP. DIP have been implicated in the virulence of influenza virus, but the role of niCKP is yet unknown.

Prediction of a global climate change on Jupiter.

Jupiter's atmosphere, as observed in the 1979 Voyager space craft images, is characterized by 12 zonal jet streams and about 80 vortices, the largest of which are the Great Red Spot and three White Ovals that had formed in the 1930s. The Great Red Spot has been observed continuously since 1665 and, given the dynamical similarities between the Great Red Spot and the White Ovals, the disappearance of two White Ovals in 1997-2000 was unexpected. Their longevity and sudden demise has been explained however, by the trapping of anticyclonic vortices in the troughs of Rossby waves, forcing them to merge. Here I propose that the disappearance of the White Ovals was not an isolated event, but part of a recurring climate cycle which will cause most of Jupiter's vortices to disappear within the next decade. In my numerical simulations, the loss of the vortices results in a global temperature change of about 10 K, which destabilizes the atmosphere and thereby leads to the formation of new vortices. After formation, the large vortices are eroded by turbulence over a time of approximately 60 years--consistent with observations of the White Ovals-until they disappear and the cycle begins again.

Clonogenic assay of type a influenza viruses reveals noninfectious cell-killing (apoptosis-inducing) particles.

Clonogenic (single-cell plating) assays were used to define and quantify subpopulations of two genetically closely related variants of influenza virus A/TK/OR/71 that differed primarily in the size of the NS1 gene product; they expressed a full-size (amino acids [aa] 1 to 230) or truncated (aa 1 to 124) NS1 protein. Monolayers of Vero cells were infected with different amounts of virus, monodispersed, and plated. Cell survival curves were generated from the fraction of cells that produced visible colonies as a function of virus multiplicity. The exponential loss of colony-forming capacity at low multiplicities demonstrated that a single virus particle sufficed to kill a cell. The ratios of cell-killing particles (CKP) to plaque-forming particles (PFP) were 1:1 and 7:1 in populations of variants NS1(1-124) and NS1(1-230), respectively. This study revealed a new class of particles in influenza virus populations-noninfectious CKP. Both infectious and noninfectious CKP were 6.3 times more resistant to UV radiation than PFP activity. Based on UV target theory, a functional polymerase subunit was implicated in a rate-limiting step in cell killing. Since influenza viruses kill cells by apoptosis (programmed cell death), CKP are functionally apoptosis-inducing particles. Noninfectious CKP are present in excess of PFP in virus populations with full-size NS1 and induce apoptosis that is temporally delayed and morphologically different than that initiated by infectious CKP present in the virus population expressing truncated NS1. The identification and quantification of both infectious and noninfectious CKP defines new phenotypes in influenza virus populations and presents a challenge to determine their role in regulating infectivity, pathogenesis, and vaccine efficacy.

Development and validation of the Chronic Obstructive Pulmonary Disease Assessment Questionnaire (COPD-AQ).

AIMS: To develop a practical patient-completed chronic obstructive pulmonary disease assessment questionnaire (COPD-AQ) to improve COPD assessment and management in primary care, based on the concept of COPD stability. METHODS: An Expert Working Group defined parameters of COPD stability and a 10-item Physician's Global Assessment was established. A 21-item COPD-AQ was developed and validated in a cross-sectional, non-randomised study of patients with COPD (n=395). Items most discriminative of stability status (stable/unstable) were selected to produce a 5-item COPD-AQ, which was then validated. RESULTS: In the development sample, internal consistency reliability of the 5-item COPD-AQ was 0.74 (n=296). The COPD-AQ discriminated between stability groups based on physician assessment (F=44.26; p<0.0001) and post-bronchodilator spirometry measures (F=2.92; p<0.05). A questionnaire score >20 (range: 5.0-25.0) had a specificity of 82.9% and sensitivity of 64.7%. CONCLUSIONS: The 5-item COPD-AQ proved a practical tool for assessing COPD status and was sufficiently simple for routine clinical use. However, overall validation was limited by small numbers of patients in the validation sample. Difficulties also existed over using the term 'stability' to define COPD status. COPD-AQ was not progressed further, but this work will prove valuable in the future development of a global questionnaire to improve COPD management in primary care.

The Israel Family Court - Therapeutic jurisprudence and jurisprudential therapy from the start.

Based on the recommendations of a commission set up to review the handling of Family Law cases in Israel, the Family Courts Law 5755-1995 included a revolutionary provision - that a Social Services Unit, staffed by senior social workers, would be an integral part of each Family Court. Their mandate includes giving assessment, advice and assistance services to litigants and to the court, and this provision has been broadly interpreted, to include mediation and referrals for therapy. The activities of the Unit are confidential and free of charge to the parties. More recently the Units were given the task of seeing children whose future is the subject of litigation, to find out their needs and views; and also to serve as the agency which parties who want to start proceedings are required to attend, in order to receive information about the effect of proceedings on their children and advice about alternative dispute resolution to avoid litigation. The resulting synergy between the social workers and the Judges ensures that the needs of all those involved are met in a therapeutic fashion where this is necessary and possible, alongside the judicial powers to make orders as needed. Thus unnecessary suffering can be mitigated.

Super-sentinel chickens and detection of low-pathogenicity influenza virus.

Chicken interferon-alpha administered perorally in drinking water acts on the oropharyngeal mucosal system as an adjuvant that causes chickens to rapidly seroconvert after natural infection by low-pathogenicity Influenza virus. These chickens, termed super sentinels, can serve as sensitive early detectors of clinically inapparent infections.

Incorporating anti-IgE (omalizumab) therapy into pulmonary medicine practice: practice management implications.

Despite aggressive therapy, many asthma patients cannot achieve optimal control, and it is recognized that a small number of patients, generally those with severe persistent asthma, are the most difficult to control and are responsible for a large segment of the costs of asthma. These patients demonstrate a need for additional therapeutic options to achieve enhanced asthma control. Omalizumab should be considered a second-line therapy for patients with moderate-to-severe persistent allergic asthma not fully controlled on standard therapy. This article should not be considered a complete guide to incorporating this therapy into practice but serve as an introduction and a basic review of the practice management aspects of therapy for physicians practicing in the United States.

A tribute to Dr. Theodore T. Puck (September 24, 1916-November 6, 2005).

Dr. Theodore T. Puck, a pioneer in mammalian cell culture, somatic cell genetics, and the study of human genetic diseases, passed away in 2005. In tribute to Dr. Puck, In Vitro Cellular and Developmental Biology-Animal presents invited remembrances from four colleagues whose associations with Dr. Puck spanned 51 years.

The role of nebulized inhaled corticosteroid therapy in adult patients with asthma and chronic obstructive pulmonary disease.

Conventional metered-dose inhalers and dry powder inhalers are used by most adult patients with asthma and chronic obstructive pulmonary disease who receive inhaled corticosteroid therapy. There are circumstances, however, in which nebulized inhaled corticosteroid delivery may provide greater clinical benefit to these patients. This review discusses the efficacy and safety of nebulized inhaled corticosteroid therapy in adult patients with asthma or chronic obstructive pulmonary disease for whom nebulized therapy may be preferable.

Intrapatient symptom variability in adults and children with asthma: results of a survey.

The objective of this survey was to evaluate variability of symptoms in adult and pediatric patients with persistent asthma. Prospective participants from a US database of patients with asthma were invited to complete an Internet-based survey designed to assess the occurrence of asthma symptoms during the past year. A total of 1311 adult patients and 491 caregivers of pediatric patients were surveyed. Adult patients (18%-30%) and pediatric patients (8%-20%) experienced a variety of symptoms on a daily basis. At least 50% of patients receiving treatment experienced variability in 1 or more symptoms during the previous year. The most common treatment recommendation when asthma symptoms were experienced included changing the number of medication (reliever or controller) inhalations (48% and 55% of adult and pediatric patients, respectively) or adding another medication (31% and 39%). This survey indicates that adult patients and caregivers of pediatric patients report variability in asthma symptoms over time, even when asthma medications are taken.

In vivo assessment of NS1-truncated influenza virus with a novel SLSYSINWRH motif as a self-adjuvanting live attenuated vaccine.

Mutants of influenza virus that encode C-terminally truncated NS1 proteins (NS1-truncated mutants) characteristically induce high interferon responses. The dual activity of interferon in blocking virus replication and enhancing the development of adaptive immune responses makes these mutants promising as self-adjuvanting live-attenuated influenza vaccine (LAIV) candidates. Yet, among the NS1-truncated mutants, the length of NS1 is not directly correlated with the interferon-inducing efficiency, the level of attenuation, or effectiveness as LAIV. Using quantitative in vitro biologically active particle subpopulation analysis as a tool to identify potential LAIV candidates from a pool of NS1-truncated mutants, we previously predicted that a NS1-truncated mutant pc2, which was less effective as a LAIV in chickens, would be sufficiently effective as a LAIV in mammalian hosts. In this study, we confirmed that pc2 protected mice and pigs against heterologous virus challenge in terms of preventing clinical signs and reducing virus shedding. pc2 expresses a unique SLSYSINWRH motif at the C-terminus of its truncated NS1. Deletion of the SLSYSINWRH motif led to ~821-fold reduction in the peak yield of type I interferon induced in murine cells. Furthermore, replacement of the SLSYSINWRH motif with the wildtype MVKMDQAIMD sequence did not restore the interferon-inducing efficiency. The diminished interferon induction capacity in the absence of the SLSYSINWRH motif was similar to that observed in other mutants which are less effective LAIV candidates. Remarkably, pc2 induced 16-fold or more interferon in human lung and monkey kidney cells compared to the temperature-sensitive, cold-adapted Ann Arbor virus that is currently used as a master backbone for LAIVs such as FluMist. Although the mechanism by which the SLSYSINWRH motif regulates the vaccine properties of pc2 has not been elucidated, this motif has potential use in engineering self-adjuvanting NS1-truncated-based LAIVs.

Jupiter's Great Red Spot and zonal winds as a self-consistent, one-layer, quasigeostrophic flow.

We present the point of view that both the vortices and the east-west zonal winds of Jupiter are confined to the planet's shallow weather layer and that their dynamics is completely described by the weakly dissipated, weakly forced quasigeostrophic (QG) equation. The weather layer is the region just below the tropopause and contains the visible clouds. The forcing mimics the overshoot of fluid from an underlying convection zone. The late-time solutions of the weakly forced and dissipated QG equations appear to be a small subset of the unforced and undissipated equations and are robust attractors. We illustrate QG vortex dynamics and attempt to explain the important features of Jupiter's Great Red Spot and other vortices: their shapes, locations with respect to the extrema of the east-west winds, stagnation points, numbers as a function of latitude, mergers, break-ups, cloud morphologies, internal distributions of vorticity, and signs of rotation with respect to both the planet's rotation and the shear of their surrounding east-west winds. Initial-value calculations in which the weather layer starts at rest produce oscillatory east-west winds. Like the Jovian winds, the winds are east-west asymmetric and have Karman vortex streets located only at the west-going jets. From numerical calculations we present an empirically derived energy criterion that determines whether QG vortices survive in oscillatory zonal flows with nonzero potential vorticity gradients. We show that a recent proof that claims that all QG vortices decay when embedded in oscillatory zonal flows is too restrictive in its assumptions. We show that the asymmetries in the cloud morphologies and numbers of cyclones and anticyclones can be accounted for by a QG model of the Jovian atmosphere, and we compare the QG model with competing models.

Influenza virus subpopulations: interferon induction-suppressing particles require expression of NS1 and act globally in cells; UV irradiation of interferon-inducing particles blocks global shut-off and enhances interferon production.

Influenza virus populations contain several subpopulations of noninfectious biologically active particles that are measured by the unique phenotypes they express. Two of these subpopulations were studied: (1) interferon (IFN)-inducing particles (IFP) and (2) IFN induction-suppressing particles (ISP). ISP are dominant in cells coinfected with one or more IFP; they completely suppress IFN production in cells otherwise programmed to induce it. Influenza virus ISP were shown to act in host cells in a nonspecific and global manner, suppressing IFN induction independent of the family of viruses serving as IFN inducers. ISP must be present within the first 3 h of coinfection with IFP to be maximally effective; by 7 hpi IFN induction/production is refractory to the action of superinfecting ISP. UV target and thermal inactivation analyses revealed that ISP activity was dependent solely on the expression of the NS gene. Low doses of UV radiation enhanced by ∼10-fold the already high IFN-inducing capacity of a virus that expressed truncated NS1. There was no change in the number of IFP, implying that the production of IFN/cell had increased. We postulated that preventing degradation of cellular RNA pol II by viral polymerase prolonged the transcription of cellular mRNA, including IFN mRNA, to enhance the IFN-inducing capacity of the cell without any increase in the number of IFP. These studies point to the dueling roles of IFP and ISP in modulating IFN induction/production, the former activity being critical to the efficacy of live attenuated influenza vaccines.

Influenza virus subpopulations: exchange of lethal H5N1 virus NS for H1N1 virus NS triggers de novo generation of defective-interfering particles and enhances interferon-inducing particle efficiency.

Reassortment of influenza A viruses is known to affect viability, replication efficiency, antigenicity, host range, and virulence, and can generate pandemic strains. In this study, we demonstrated that the specific exchange of the NS gene segment from highly pathogenic A/HK/156/97 (H5N1) [E92 or E92D NS1] virus for the cognate NS gene segment of A/PR/834(H1N1) [D92 NS1] virus did not cause a significant change in the sizes of infectious particle subpopulations. However, it resulted in 2 new phenotypic changes: (1) de novo generation of large subpopulations of defective-interfering particles (DIPs); and (2) enhancement of interferon (IFN)-inducing particle efficiency leading to an order of magnitude or higher quantum (peak) yield of IFN in both avian and mammalian cells. These changes were attributed to loss of function of the H5N1-NS gene products. Most notably, the NS exchange obliterated the usual IFN-induction-suppressing capacity associated with expression of full-size NS1 proteins, and hence functionally mimicked deletions in the NS1 gene. The loss of NS1-mediated suppression of IFN induction, de novo generation of DIPs, and the concomitant enhancement of IFN-inducing particle efficiency suggest that in an attenuated background, the H5N1-NS could be used to formulate a self-adjuvanting live attenuated influenza vaccine similar to viruses with deletions in the NS1 gene.