Correlations between FEV1 and patient-reported outcomes: A pooled analysis of 23 clinical trials in patients with chronic obstructive pulmonary disease.

BACKGROUND: In clinical trials of inhaled bronchodilators, chronic obstructive pulmonary disease (COPD) guidelines recommend that patient-reported outcomes (PROs) are assessed alongside lung function. How these endpoints are related is unclear. METHODS: Pooled longitudinal data from 23 randomised controlled COPD studies were analyzed (N = 23,213). Treatments included long-acting ß2 agonists, long-acting muscarinic antagonists (LABAs or LAMAs) and the LABA/LAMA combination QVA149. Outcome measures were Transition Dyspnoea Index (TDI) and St. George's Respiratory Questionnaire (SGRQ) scores, COPD exacerbation frequency and rescue medication use. Relationships between changes in trough forced expiratory volume in one second (ΔFEV1) and outcomes following treatment were assessed using correlations of data summaries and model-based analysis: generalized linear mixed-effect regression modelling to determine if ΔFEV1 could predict patient outcomes with different treatments. RESULTS: Mean age was 64 years, 73% were male, and most had moderate (45%) or severe (52%) disease. Statistically significant correlations were observed between ΔFEV1 and each outcome measure (exacerbations Rs = 0.05; rescue medication, SGRQ, TDI, r = 0.11-0.16; all p < .001). Patients with greater improvements in trough FEV1 had on average better SGRQ and TDI scores, fewer exacerbations, and used less rescue medication. For SGRQ and TDI scores, minimal clinically important differences were observed over the range of pooled ΔFEV1 values. Model-based predictions confirmed the treatment effect was partly explained by changes in FEV1 from baseline with improvements in PROs observed across all treatments when trough FEV1 improved. Across all endpoints active treatments were better than placebo (p < .0001), and LABA/LAMA treatment resulted in numerically better treatment outcomes than either monocomponent. CONCLUSIONS: These data suggest that FEV1 improvements post-bronchodilation correlate with PRO improvements. Further improvements in patient outcomes may be expected by maximizing lung function improvements. TRIAL REGISTRATION: Registration details for the 23 randomised controlled studies used in this pooled analysis are supplied in Additional File 4.

Simultaneous conduction mapping and intracellular membrane potential recording in isolated atria.

We describe a novel approach for simultaneously determining regional differences in action potential (AP) morphology and tissue electrophysiological properties in isolated atria. The epicardial surface of rat atrial preparations was placed in contact with a multi-electrode array (9 × 10 silver chloride electrodes, 0.1 mm diameter and 0.1 mm pitch). A glass microelectrode (100 MΩ) was simultaneously inserted into the endocardial surface to record intracellular AP from either of 2 regions (A, B) during pacing from 2 opposite corners of the tissue. AP duration at 80% of repolarisation and its restitution curve was significantly different only in region A (p < 0.01) when AP was initiated at different stimulation sites. Alternans in AP duration and AP amplitude, and in conduction velocity were observed during 2 separate arrhythmic episodes. This approach of combining microelectrode array and intracellular membrane potential recording may provide new insights into arrhythmogenic mechanisms in animal models of cardiovascular disease.

A modeling-derived hypothesis on chronicity in respiratory diseases: desensitized pathogen recognition secondary to hyperactive IRAK/TRAF6 signaling.

Several chronic respiratory diseases exhibit hyperactive immune responses in the lung: abundant inflammatory mediators; infiltrating neutrophils, macrophages, lymphocytes and other immune cells; and increased level of proteases. Such diseases include cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD) and severe/neutrophilic asthma. Paradoxically, patients with these diseases are also susceptible to detrimental bacterial infection and colonization. In this paper, we seek to explain how a positive feedback mechanism via IL-8 could lead to desensitization of epithelial cells to pathogen recognition thus perpetuating bacterial colonization and chronic disease states in the lung. Such insight was obtained from mathematical modeling of the IRAK/TRAF6 signaling module, and is consistent with existing clinical evidence. The potential implications for targeted treatment regimes for these persistent respiratory diseases are explored.

Integrin beta6 mediates phospholipid and collectin homeostasis by activation of latent TGF-beta1.

Surfactant lines the alveolar surface and prevents alveolar collapse. Derangements of surfactant cause respiratory failure and interstitial lung diseases. The collectins, surfactant proteins A and D, are also important in innate host defense. However, surfactant regulation in the postnatal lung is poorly understood. We found that the epithelial integrin, alphavbeta6, regulates surfactant homeostasis in vivo by activating latent transforming growth factor (TGF)-beta. Adult mice lacking the beta-subunit of alphavbeta6 (Itgb6-/-) developed increased bronchoalveolar lavage phospholipids and surfactant proteins A and D, and demonstrated abnormal-appearing alveolar macrophages, reminiscent of the human disease pulmonary alveolar proteinosis. Using lung-specific expression of constitutively active TGF-beta1 in Itgb6-/- mice, we found that TGF-beta1 was sufficient to normalize these abnormalities. Tgfbeta1-deficient mice also demonstrated increased phospholipids and surfactant proteins A and D, but mice lacking the key TGF-beta signaling molecule, SMAD3, did not. Therefore, integrin-mediated activation of latent TGF-beta1 regulates surfactant constituents independent of intracellular SMAD3. In vivo increases in surfactant protein A and D were not associated with increases in mRNA for these proteins in alveolar tissue from Itgb6-/- mice. On the other hand, isolated alveolar macrophages from Itgb6-/- mice were defective in processing phospholipids in vitro, suggesting that reduced surfactant clearance contributes to altered surfactant homeostasis in these mice in vivo. These findings show that alphavbeta6 and TGF-beta1 regulate homeostasis of phospholipids and collectins in adult mouse lungs and may have implications for anti-fibrotic therapeutics that inhibit active TGF-beta in the lung.

Pulmonary emphysema: when more is less.

Pulmonary emphysema results from the loss of intricate alveolar architecture and progressive simplification of small and highly effective gas-exchanging units into large, inefficient cyst-like spaces. Because of the loss of alveolar gas-exchanging units and the capillary bed within them, blood oxygen levels eventually fall and pressures within the pulmonary circulation rise. Recent insights from genetically manipulated mouse models have refined our understanding of the molecular events that prevent or promote the development of pulmonary emphysema. Capitalizing on an improved molecular understanding of emphysema with improved therapeutics has the potential to enhance both the survival and quality of life of patients with this common lung disease.

Discs large (Dlg1) complexes in lymphocyte activation.

T cell antigen recognition involves the formation of a structured interface between antigen-presenting and T cells that facilitates the specific transmission of activating and desensitizing stimuli. The molecular machinery that organizes the signaling molecules and controls their disposition in response to activation remains poorly understood. We show here that in T cells Discs large (Dlg1), a PDZ domain-containing protein, is recruited upon activation to cortical actin and forms complexes with early participants in T cell activation. Transient overexpression of Dlg1 attenuates basal and Vav1-induced NFAT reporter activation. Reduction of Dlg1 expression by RNA interference enhances both CD3- and superantigen-mediated NFAT activation. Attenuation of antigen receptor signaling appears to be a complex, highly orchestrated event that involves the mutual segregation of important elements of the early signaling complex.

Tetrameric dichloro(trimethylammonio-p-toluenesulfonamidate)mercury(II).

In the title compound, hexa-micro-chloro-dichlorotetrakis(N-trimethylammonio-p-toluenesulfonamidate-kappa(2)N,O)tetramercury(II), [Hg[Me(3)N(+)N(-)SO(2)C(6)H(4)CH(3)-p]Cl(2)](4) or [Hg(4)Cl(8)(C(10)H(16)N(2)O(2)S)(4)], four nearly linear and parallel Cl-Hg-Cl units associate through pairwise Hg.Cl interactions of 3.1-3.2 A. Each Hg atom is also coordinated through N and O atoms to a ylide molecule. The available structural data indicate that coordination of a sulfonyl-stabilized nitrogen ylide to a metal atom (Hg or Ag) has no detectable effect on its geometry.

4-Chloro-N-(trimethylammonio)benzamide chloride monohydrate.

The structure of the cation in the ylide hydrochloride [Me(3)NNHC(O)C(6)H(4)-Cl-p]Cl.H(2)O, or C(10)H(14)ClN(2)O(+).Cl(-).H(2)O, is compared with that of the free ylide. Protonation lengthens the N-C(O) bond but shortens the C=O and N-N bonds by approximately 0.03 A and increases the dihedral angle between the phenyl and ylide planes.

Sarcoidosis following HIV infection: evidence for CD4+ lymphocyte dependence.

BACKGROUND: The chronic granulomatous inflammation of sarcoidosis has been hypothesized to depend on the CD4+ T-helper lymphocyte. HIV infection, which depletes these cells, has been reported to attenuate the manifestations of sarcoidosis. STUDY OBJECTIVES: We asked whether the development of symptomatic sarcoidosis in the context of preexisting HIV infection was dependent on the CD4+ lymphocyte count. DESIGN: We performed a retrospective standardized chart review of all patients who developed granulomatous inflammation following HIV infection at an urban academic referral center. MEASUREMENTS: We identified seven patients with sarcoidosis within this cohort and compared their CD4+ lymphocyte count to that in a cohort of 16 patients in whom similar granulomatous inflammation was found but who did not have sarcoidosis. We then compared our cases to all reported cases using a systematic literature review. RESULTS: The CD4+ lymphocyte count was > 200 cells/ microL in all of our patients with HIV infection when they developed subsequent sarcoidosis. In contrast, specific etiologies for granulomatous inflammation were found in all 10 HIV-infected patients who presented with granulomatous inflammation and a CD4+ lymphocyte count of < 200 cells/ microL, with infectious etiologies found in 8 patients. Similarly, there was relative preservation of the CD4+ lymphocyte count in previously reported cases, with 14 of 19 patients (74%) having an absolute CD4+ lymphocyte count of > 200 cells/ microL. CONCLUSIONS: We conclude that the development of the chronic granulomatous inflammation of sarcoidosis appears to depend on the preservation or restoration of the peripheral CD4+ lymphocyte count and that in most cases the CD4+ lymphocyte count exceeds 200 cells/ microL. Furthermore, alternative specific etiologies of granulomatous inflammation are generally identifiable in HIV-infected patients with peripheral CD4+ lymphocyte counts of < 200 cells/ microL.

Self-recognition and hydrogen bonding by polycyclic bridgehead monoalcohols.

Our interest in the relationship between the hydrogen bonding motifs displayed by monoalcohols and the properties of the solids which contain these motifs has led us to determine the crystal structures of three polycyclic bridgehead monoalcohols. One C10H16O isomer crystallises in the space group P2(1)2(1)2(1) but the three molecules which comprise the asymmetric unit are related approximately by the operations of a 3(1) screw axis. They are linked by hydrogen bonds to form an infinite helix. A second C10H16O isomer forms rings containing four molecules joined by cooperative hydrogen bonds. The chiral space group P4(1)2(1)2 accommodates molecules of the S,S and R,R enantiomers in the molar ratio 92:8 (ee 84%) owing to disorder. A related C9H14O2 keto-alcohol forms infinite chains by C-OH...O = C hydrogen bonding. These hydrogen bond motifs are shown to be typical for 45 tertiary monoalcohols, CmHnOH, present in the Cambridge Structural Database. Tertiary monoalcohols display in a more pronounced form the strong preferences for trigonal and tetragonal space groups and for asymmetric units containing several molecules which are established features of the crystallochemistry of monoalcohols.

1,1-bis(phenylsulfonyl)-1-(pyridinio)methanide.

The title disulfonyl-stabilized pyridinium ylide, C(5)H(5)N(+)-C(-)(SO(2)C(6)H(5))(2) or C(18)H(15)NO(4)S(2), contains a near planar NCS(2) core. The structure suggests that the formal negative charge of the ylide C atom is delocalized to the S atoms rather than the N atom. Structural features of pyridinium ylides are briefly discussed.

(2RS)-5,6:7,8-Dibenzobicyclo[2.2.2]octan-2-ol.

The racemic form of the title secondary monoalcohol, C(16)H(14)O, forms crystals in which the molecules are linked into chains by hydrogen bonding. The chain architecture is unusual; adjacent molecules are related pseudosymmetrically, by either a pseudo-diad or a pseudo-glide plane, while alternate molecules are related exactly by a crystallographic glide plane.

Loss of integrin alpha(v)beta6-mediated TGF-beta activation causes Mmp12-dependent emphysema.

Integrins are heterodimeric cell-surface proteins that regulate cell growth, migration and survival. We have shown previously that the epithelial-restricted integrin alpha(v)beta6 has another critical function; that is, it binds and activates latent transforming growth factor-beta (TGF-beta). Through a global analysis of pulmonary gene expression in the lungs of mice lacking this integrin (Itgb6 null mice) we have identified a marked induction of macrophage metalloelastase (Mmp12)--a metalloproteinase that preferentially degrades elastin and has been implicated in the chronic lung disease emphysema. Here we report that Itgb6-null mice develop age-related emphysema that is completely abrogated either by transgenic expression of versions of the beta6 integrin subunit that support TGF-beta activation, or by the loss of Mmp12. Furthermore, we show that the effects of Itgb6 deletion are overcome by simultaneous transgenic expression of active TGF-beta1. We have uncovered a pathway in which the loss of integrin-mediated activation of latent TGF-beta causes age-dependent pulmonary emphysema through alterations of macrophage Mmp12 expression. Furthermore, we show that a functional alteration in the TGF-beta activation pathway affects susceptibility to this disease.

Effectiveness of medical resident education in mechanical ventilation.

Specific methods of mechanical ventilation management reduce mortality and lower health care costs. However, in the face of a predicted deficit of intensivists, it is unclear whether residency programs are training internists to provide effective care for patients who require mechanical ventilation. To evaluate these educational outcomes, we administered a validated 19-item case-based test and survey to resident physicians at 31 diverse U.S. internal medicine residency programs nationwide. Of 347 senior residents, 259 (75%) responded. The mean test score was 74% correct (SD, 14%; range, 37 to 100%). Important items representing evidence-based standards of critical care answered incorrectly were as follows: use of appropriate tidal volume in the acute respiratory distress syndrome (48% incorrect), identifying a patient ready for a weaning trial (38% incorrect), and recognizing indication for noninvasive ventilation (27% incorrect). Most accurately identified pneumothorax (86% correct) and increased intrathoracic positive end-expiratory pressure (93% correct). Better scores were associated with "closed" versus "open" intensive care unit organization (76 versus 71% correct, p = 0.001), resident perception of greater versus lesser ventilator knowledge (79 versus 71% correct, p = 0.001), and graduation from a U.S. versus international medical school (75 versus 69% correct, p = 0.033). Although overall training satisfaction correlated strongly with program use of learning objectives (r = 0.89, p < 0.0001), only 46% reported being satisfied with their mechanical ventilation training. We conclude that senior residents may not be gaining essential evidence-based knowledge needed to provide effective care for patients who require mechanical ventilation. Residency programs should emphasize evidence-based learning objectives to guide mechanical ventilation instruction.

The low-temperature phase transition of 9-methylfluoren-9-ol: comparison of the crystal structures at 100 and 200 K.

Crystals of 9-methylfluoren-9-ol, C(14)H(12)O, undergo a reversible phase transition at 176 (2) K. The structure of the high-temperature alpha form at 200 K is compared with that of the low-temperature beta form at 100 K. Both polymorphs crystallize in space group P1 with Z = 4 and contain discrete hydrogen-bonded R(4)(4)(8) ring tetramers arranged around crystallographic inversion centres. The most obvious changes observed on cooling the crystals to below 176 K are an abrupt increase of ca 0.5 A in the shortest lattice translation, and a thermal transition with deltaH = 1 kJ mol(-1).

Effect of alcohol addition on the movement of petroleum hydrocarbon fuels in soil.

Groundwater contamination by fuel spills from aboveground and underground storage tanks has been of growing concern in recent years. This problem has been magnified by the addition of oxygenates, such as ethanol and methyl-tertiary-butyl ether (MTBE) to fuels to reduce vehicular emissions to the atmosphere. These additives, although beneficial in reducing atmospheric pollution, may, however, increase groundwater contamination due to the co-solvency of petroleum hydrocarbons and by the provision of a preferential substrate for microbial utilisation. With the introduction of ethanol to diesel fuel imminent and the move away from MTBE use in many states of the USA, the environmental implications associated with ethanol additive fuels must be thoroughly investigated. Diesel fuel movement was followed in a 1-m soil column and the effect of ethanol addition to diesel fuel on this movement determined. The addition of 5% ethanol to diesel fuel was found to enhance the downward migration of the diesel fuel components, thus increasing the risk of groundwater contamination. A novel method using soil packed HPLC columns allowed the influence of ethanol on individual aromatic hydrocarbon movement to be studied. The levels of ethanol addition investigated were at the current additive level (approx. 25%) for ethanol additive fuels in Brazil and values above (50%) and below (10%) this level. An aqueous ethanol concentration above 10% was required for any movement to occur. At 25% aqueous ethanol, the majority of hydrocarbons were mobilised and the retention behaviour of the soil column lessened. At 50% aqueous ethanol, all the hydrocarbons were found to move unimpeded through the columns. The retention behaviour of the soil was found to change significantly when both organic matter content and silt/clay content was reduced. Unexpectedly, sandy soil with low organic matter and low silt/clay was found to have a retentive behaviour similar to sandy subsoil with moderate silt/clay, but little organic matter. It was concluded that sand grains might have a more important role in the adsorption of petroleum hydrocarbons than first realised. This method has shown that soil packed HPLC columns can be used to provide a quick estimate of petroleum hydrocarbon, and possibly other organic contaminant, movement in a variety of different soil types.