Improved responsiveness to change in joint space width over 24-month follow-up: comparison of 3D JSW on weight-bearing CT vs 2D JSW on radiographs in the MOST study.

OBJECTIVE: Radiographic joint space width (JSW) has been a standard for measuring knee osteoarthritis (OA) structural change. Limitations in the responsiveness of this approach might be overcome by instead measuring 3D JSW on weight-bearing CT (WBCT). This study compared the responsiveness of 3D JSW measurements using WBCT with the responsiveness of radiographic 2D JSW. DESIGN: Standing, fixed-flexion knee radiographs (XR) and WBCT were acquired ancillary to the 144- and 168-month Multicenter Osteoarthritis Study visits. Tibiofemoral JSW was measured on both XR and WBCT. Responsiveness to change was defined by the standardized response mean (SRM) for change in JSW (1) at predetermined mediolateral locations (JSWx) on both modalities and (2) in the following subregions measured on WBCT images: central medial and lateral femur (CMF/CLF) and tibia (CMT/CLT), and anterior and posterior tibia (AMT/ALT, PMT/MLT). RESULTS: Baseline and 24-month follow-up JSWx measurements were completed for 265 participants (58.1% women). Responsiveness of 3D JSWx for medial tibiofemoral compartment on coronal WBCT (SRM range: -0.18, -0.24) exceeded that for 2D JSWx (-0.10, -0.16). Responsiveness of 3D JSW subregional mean (-0.06, -0.36) and maximal (-1.14, -1.75) CMF and CMT and maximal CLF/CLT 3D JSW changes were statistically significantly greater in comparison with respective medial and lateral 2D JSWx (P ≤ 0.002). CONCLUSIONS: Subregional 3D JSW on WBCT is substantially more responsive to 24-month changes in tibiofemoral joint structure compared to radiographic measurements. Use of subregional 3D JSW on WBCT could enable improved detection of OA structural progression over a 24-month duration in comparison with measurements made on XR.

Differential executive functioning performance by phase of bipolar disorder.

OBJECTIVE: This study examined the influence of illness phase on executive functioning performance using factor-derived cognitive scores in a cross-sectional design. METHODS: Healthy control (HC) subjects (n = 57), and euthymic (E-BD) (n = 117), depressed (D-BD) (n = 73), and hypomanic/mixed (HM/M-BD) (n = 26) patients with bipolar disorder (BD) were evaluated using executive functioning measures (Wisconsin Card Sorting Test, Trail Making Test-Parts A and B, Verbal Fluency, Parametric Go/No-Go, Stroop, and Digit Symbol) comprising Conceptual Reasoning and Set-Shifting (CRSS), Processing Speed with Interference Resolution (PSIR), Verbal Fluency and Processing Speed (VFPS), and Inhibitory Control (IC) factor scores. RESULTS: Two of the four executive functioning factors were significantly different between groups based upon phase of illness. The HM/M group was significantly worse than both of the other BD groups and the HC group in IC. The VFPS factor was sensitive to the active phase of BD, with the HM/M-BD and D-BD groups worse than HC. Extending our prior work, the PSIR factor, and now the CRSS factor were significantly worse in BD relative to HC, irrespective of phase of illness. CONCLUSIONS: Phase of illness had differential cognitive profiles in executive functioning factors, even after considering and excluding the impact of clinical features, illness characteristics, medications, and demographics. Consolidating executive functioning tasks into reliable factor scores provides unique information to measure and define cognitive deficiencies throughout phases of BD, and to measure intermediate phenotypes in BD, and may aid in tracking and clarifying treatment focus.

Impact of obesity on the severity and therapeutic responsiveness of acute episodes of asthma.

BACKGROUND: It has been suggested that obesity adversely influences both the severity and the therapeutic responsiveness of chronic asthma. However, it is unclear if it also impacts acute situations. METHODS: To determine whether adiposity worsens the clinical and physiological manifestations of acute asthma and limits therapeutic effectiveness of standard treatment, we contrasted signs, symptoms, medication use, arterial oxygen saturation, peak expiratory flow rate, and the bronchodilator response to standard doses of albuterol in 90 non-obese and 90 obese asthmatics as they presented for urgent care. Treatment and clinical decisions were systematized using published care paths and the peak flow was measured with standard techniques. Body mass index (BMI) was calculated according to consensus criteria. RESULTS: Other than BMI (p < .001), there were no between-group differences in age, gender, race, signs, symptoms, pulse oximetry, or pre-presentation medication use. The pretreatment peak flow in the obese population was 22.4% higher on average (p = .007), but there were no differences in the distribution of severity (p = .38), the response to albuterol (p = .61), or admission-discharge ratios (p = .62). CONCLUSIONS: Obesity does not adversely influence the severity or the resolution of acute episodes of asthma.

Critical comparisons of the clinical performance of oxygen-conserving devices.

RATIONALE: Clinical testing of oxygen-conserving devices is not mandated before marketing. Consequently, little is known about individual or comparative therapeutic effectiveness. OBJECTIVES: To relate oxygen delivery from prototypical instruments to physiological performance. METHODS: Thirteen subjects with obstructive lung disease performed progressive treadmill exercise while inhaling either room air, 2 L O(2)/min, or bolus oxygen from four commercially available conserving devices at regulator settings of 2, 5, and continuous. The devices were studied blindly in random order after first being tested to determine performance characteristics. Pulse oximetry, oxygen delivery, and nasal and oral ventilations were monitored at rest and with exertion. MEASUREMENTS AND MAIN RESULTS: At a setting of 2 at rest, all conservers maintained saturation greater than 90%, but there were significant differences in oxygenation between systems. Only one equaled 2 L O(2)/min. With exertion, saturation decreased with all conservers but not with 2 L O(2)/min. One device did not perform any better than room air. Two systems provided less oxygen than predicted, one more, and in one the expected and actual amounts were equal only at rest. Breath-by-breath performance was highly variable, with irregular activation and inconsistent oxygen bolus size delivery. Increasing oxygen pulse volume to the point of eradicating conservation with the continuous setting did not eliminate all disparities. CONCLUSIONS: The mechanical and clinical performances of current oxygen conservers are highly variable and in some instances actually contribute to limitations in exercise ability. Seemingly equivalent technical features do not guarantee equivalent therapeutic functionality.

Coronary plaque burden in patients with stable and unstable coronary artery disease using multislice CT coronary angiography.

PURPOSE: We evaluated the multislice computed tomography (MSCT) coronary plaque burden in patients with stable and unstable angina pectoris. MATERIALS AND METHODS: Twenty-one patients with stable and 20 with unstable angina pectoris scheduled for conventional coronary angiography (CCA) underwent MSCT-CA using a 64-slice scanner offering a fast rotation time (330 ms) and higher X-ray tube output (900 mAs). To determine the MSCT coronary plaque burden, we assessed the extent (number of diseased segments), size (small or large), type (calcific, noncalcific, mixed) of plaque, its anatomic distribution and angiographic appearance in all available ≥2-mm segments. In a subset of 15 (seven stable, eight unstable) patients, the detection and classification of coronary plaques by MSCT was verified by intracoronary ultrasound (ICUS). RESULTS: Sensitivity and specificity of MSCT compared with ICUS to detect significant plaques (defined as ≥1-mm plaque thickness on ICUS) was 83% and 87%. Overall, 473 segments were examined, resulting in 11.6±1.5 segments per patient. Plaques were present in 62% of segments and classified as large in 47% of diseased segments. Thirty-two percent were noncalcific, 25% calcific and 43% mixed. Plaques were most frequently located in the proximal and mid segments. Plaque was found in 33% of segments classified as normal on CCA. Unstable patients had significantly more noncalcific plaques when compared with stable patients (45% vs. 21%, p<0.05). CONCLUSIONS: MSCT-CA provides important information regarding the coronary plaque burden in patients with stable and unstable angina.

Comparison of primary angioplasty and pre-hospital fibrinolysis in acute myocardial infarction (CAPTIM) trial: a 5-year follow-up.

AIMS: The CAPTIM (Comparison of primary Angioplasty and Pre-hospital fibrinolysis In acute Myocardial infarction) study found no evidence that a strategy of primary angioplasty was superior in terms of 30-day outcomes to a strategy of pre-hospital fibrinolysis with transfer to an interventional facility in patients managed early at the acute phase of an acute myocardial infarction. The present analysis was designed to compare both strategies at 5 years. METHODS AND RESULTS: The CAPTIM study included 840 patients managed in a pre-hospital setting within 6 h of an acute ST-segment elevation myocardial infarction. Patients were randomized to either a primary angioplasty (n = 421) or a pre-hospital fibrinolysis (rt-PA) with immediate transfer to a centre with interventional facilities (n = 419). Long-term follow-up was obtained in blinded fashion from 795 patients (94.6%). Using an intent-to-treat analysis, all-cause mortality at 5 years was 9.7% in the pre-hospital fibrinolysis group when compared with 12.6% in the primary angioplasty group [HR 0.75 (95% CI, 0.50-1.14); P = 0.18]. For patients included within 2 h, 5 year mortality was 5.8% in the pre-hospital fibrinolysis group when compared with 11.1% in the primary angioplasty group [HR 0.50 (95% CI, 0.25-0.97); P = 0.04], whereas it was, respectively, 14.5 and 14.4% in patients included after 2 h [HR 1.02, (95% CI 0.59-1.75), P = 0.92]. CONCLUSION: The 5-year follow-up is consistent with the 30-day outcomes of the trial, showing similar mortality for primary percutaneous coronary intervention and a policy of pre-hospital lysis followed by transfer to an interventional center. In addition, for patients treated within 2 h of symptom onset, 5-year mortality was lower with pre-hospital lysis.

Bronchoconstrictor effects of leukotriene C in humans.

Maximum expiratory flow rate at 30 percent of vital capacity above residual volume served as an index of airway obstruction in comparing the effects of leukotriene C and histamine administered by aerosol to five normal persons. Leukotriene C was 600 to 9500 times more potent than histamine on a molar basis in producing an equivalent decrement in the residual volume. The leukotriene C response was slow in onset and prolonged, reminiscent of the effects of aerosol allergen challenge in asthmatic allergic subjects.

Does the association between self-rated health and mortality vary by social class?

Self-rated health (SRH) predicts future mortality. Individuals in different social classes with similar physical health status may have different reference levels and criteria against which they judge their health, therefore the SRH-mortality relationship may vary according to social class. We examine the relationship between SRH and mortality by occupational social class in a prospective study of 22,457 men and women aged 39-79 years, without prevalent disease, living in the general community in Norfolk, United Kingdom, recruited using general practice age-sex registers in 1993-1997 and followed up for an average of 10 years. As expected, SRH was related to subsequent mortality. The age and sex adjusted hazard ratio for mortality for those with poor compared to those with excellent SRH was 4.35 (95% confidence interval 3.38-5.59, P<0.001). The prevalence of poor or moderate SRH was higher in manual than in non-manual classes. However, SRH was similarly related to mortality in manual and non-manual classes: when non-manual classes are compared with manual classes for each category of SRH, the 95% confidence intervals for the mortality hazard ratios overlap. There was no evidence of an interaction between social class and SRH in either men or women. Thus in this population, SRH appears to predict mortality in a similar manner in non-manual and manual classes.

Observations on the physiological interactions between obesity and asthma.

To explore whether asthma and obesity share overlapping pathogenic features, we examined the impact of each alone, and in combination, on multiple aspects of lung function. We reasoned that if they influenced the lungs through similar mechanisms, the individual physiological manifestations in the comorbid state should interact in a complex fashion. If not, then the abnormalities should simply add. We measured specific conductance, spirometry, lung volumes, and airway responsiveness to adrenergic and cholinergic agonists in 52 normal, 53 asthmatic, 52 obese, and 53 asthmatic and obese patients using standard techniques. Six-minute walks were performed in subsets from each group. Asthma significantly lowered specific conductance and the spirometric variables while increasing airway reactivity and residual volume. Obesity also reduced the spirometric variables as well as total lung capacity and functional residual capacity. Residual volume, specific conductance, and airway responsivity were unaltered. With comorbidity, the disease-specific derangements added algebraically. Features that existed in isolation appeared unchanged in the combination, whereas shared ones either added or subtracted depending on the individual directional changes. Synergistic interactions were not observed. Body mass index weakly correlated with spirometry and lung volumes in asthma, but not with specific conductance or bronchial reactivity. Exercise performance did not aid in differentiation. Our findings indicate asthma and obesity appear to influence the respiratory system through different processes.

Randomized controlled trial of honey versus mupirocin to decolonize patients with nasal colonization of meticillin-resistant Staphylococcus aureus.

BACKGROUND: Mupirocin is used specifically for the eradication of nasal meticillin-resistant Staphylococcus aureus (MRSA), but increasing mupirocin resistance restricts its repeated use. The antibacterial effects of manuka honey have been established in vitro; antibacterial activity of other honeys has also been reported. AIM: To describe the learning experience from a randomized controlled trial (RCT) comparing the efficacy of medical-grade honey (MGH) with mupirocin 2% for the eradication of nasal MRSA. METHODS: Patients colonized in the nose with MRSA and age ≥18 years were recruited. Participants received either one or two courses of MGH or mupirocin 2%, three times per day for five consecutive days. FINDINGS: The proportion of patients who were decolonized after one or two courses of treatment was not significantly different between MGH [18/42; 42.8%; 95% confidence interval (CI): 27.7-59.0] and mupirocin 2% (25/44; 56.8%; 95% CI: 41.0-71.7). Non-nasal MRSA colonization was significantly associated with persistent nasal colonization (odds ratio: 5.186; 95% CI: 1.736-5.489; P = 0.003). The rate of new acquisition of mupirocin resistance was 9.75%. CONCLUSION: Although not significant, a decolonization rate of 42.8% for MGH was impressive. Our findings suggest that this strategy, which has the potential to combat antimicrobial resistance, should be assessed in similar but larger studies.

Airway cooling and rewarming. The second reaction sequence in exercise-induced asthma.

To determine if a relationship exists among the magnitude and rate of airway rewarming, and the severity of bronchial obstruction in thermally induced asthma, we had seven subjects perform three- to four-point stimulus response curves with isocapnic hyperventilation of frigid air with and without pretreatment with inhaled norepinephrine. The latter was employed to alter the heat supplied to the airway walls by producing vasoconstriction. 1-s forced expiratory volume (FEV1) was measured before and 5 min after the cessation of each bout of hyperpnea and before and after norepinephrine. On a separate day, the subjects repeated the above challenges while the temperatures of the airstream in the intrathoracic airways were measured. Prenorepinephrine, FEV1 progressively decreased in a stimulus response fashion as ventilation rose, while norepinephrine shifted this curve to the right. As the level of ventilation increased, the size of the temperature difference between the cooling of hyperpnea and the rewarming of recovery followed suit, and their magnitude was linearly related to the severity of bronchial narrowing. Reducing the mucosal blood supply of the airways with norepinephrine limited rewarming and attenuated the obstructive response. These data demonstrate that the airway narrowing that develops following hyperpnea and the magnitude of the thermal differences are related, and that alterations in blood supply directly affect bronchial heat flux and influence obstruction.

Acute effects of inhaled isoproterenol on the mechanical characteristics of the lungs in normal man.

We investigated the effects of isoproterenol on the pulmonary mechanics of eight healthy male subjects. We measured the flow-volume, pressure-volume, resistance-volume, and pressure-flow relationships of the lungs of our subjects in addition to the forced expiratory volume (FEV(1)). The results of this study confirm earlier observations that isoproterenol produces a considerable decrease in airway resistance but only small changes in maximum expiratory flow. Measurements of static pressure-volume curves showed that isoproterenol caused a temporary decrease in the elastic recoil pressure of the lungs. In five men there were mean falls in recoil pressure of 4.1 cm H(2)O at 85% total lung capacity (TLC), 2.6 cm H(2)O at 75% TLC, and 1.5 cm H(2)O at 50% TLC. We postulate that the reason for the relatively small increments in maximum expiratory flow after isoproterenol is primarily that the effects of airway dilatation are in large part negated by the reduction in lung recoil pressure, which results in a fall in the maximum effective driving force for expiratory air flow, and secondly that there is an increase in the compliance of the flow-limiting airways. These studies emphasize that tests of maximum flow and of airway resistance should not be regarded as invariably interchangeable in the assessment of airway reactions or mild disease of the airways.

Intraairway thermal profiles during exercise and hyperventilation in normal man.

When large volumes of air are inhaled at rapid rates of ventilation, substantial segments of the tracheobronchial tree become involved in the conditioning process and the inspirate does not reach body conditions of temperature and humidity until it passes well into the peripheral bronchi. To determine if the manner in which ventilation is elevated is an important factor in producing this response, we measured the temperature of the airstream at six points in the tracheobronchial tree from the pharynx to the subsegmental bronchi during 5 min of exercise and voluntary hyperventilation in seven normal subjects while they inhaled frigid air. Minute ventilation and respiratory frequency were recorded at minute intervals and intrathoracic temperatures were measured continuously. With both forms of hyperpnea, airway temperature fell dramatically, and there were no significant differences between exercise and hyperventilation. These results demonstrate that the thermal events that occur within the lung during short, moderately intense degrees of exercise can be readily simulated by voluntary hyperventilation when ventilation and inspired air conditions are matched. Our data also indicate that this form of exercise does not result in an increase in airstream temperature and raise the possibility that the bronchial blood supply may be determined by the local thermal needs of the airways to recover heat and water independent of, at least moderate, increases in cardiac output.

Postexertional airway rewarming and thermally induced asthma. New insights into pathophysiology and possible pathogenesis.

To determine if postexercise thermal events play a role in exercise-induced asthma (EIA), nine normal and eight asthmatic subjects on three occasions exercised while they inhaled frigid air. During the recovery period, either cold air, air at room temperature and humidity, or air at body conditions was administered in a random fashion. On a fourth occasion, body-condition air was given during exercise. Pulmonary mechanics were measured before and after each challenge. No changes in mechanics developed when air at body conditions was inhaled during exercise, however, increasing the heat content of the air during recovery produced progressively greater obstruction in both groups. On a separate occasion, seven asthmatics hyperventilated frigid air and either recovered spontaneously or had their ventilation slowly reduced. Controlling ventilation markedly attenuated the obstructive response. These data demonstrate that the severity of EIA is dependent not only on airway cooling but also upon the rapidity and magnitude of airway rewarming postchallenge.

A critical assessment of the roles of circulating hydrogen ion and lactate in the production of exercise-induced asthma.

To evaluate the roles of circulating hydrogen ion and lactate in the production of exercise-induced asthma, two experiments were performed. In the first, we exercised six asthmatic subjects to exhaustion on a bicycle ergometer while recording arterial pH at periodic intervals. Multiple aspects of pulmonary mechanics were measured before and after the work load. After recovery, the identical procedures were repeated, but sufficient quantities of sodium bicarbonate were infused to keep the pH at the pre-exercise level. In both experiments, statistically identical attacks of asthma were induced. To study the effect of lactate, five subjects were exercised on several occasions in order to determine the lowest level of work, and hence arterial lactate, that was reproducibly associated with an acute asthma attack. When this was known, sufficient quantities of sodium lactate were infused into the resting subjects so as to equal or exceed the amount produced with exercise. Pulmonary mechanics were not altered with this intervention. These findings demonstrate that lactic acidemia is not the cause of exercise-induced asthma.

Relative contributions of large and small airways to flow limitation in normal subjects before and after atropine and isoproterenol.

Bronchodilatation was produced in normal subjects by the inhalation of atropine, a parasympatholytic agent, and isoproterenol, a beta adrenergic stimulator. Density dependence of maximal expiratory flow (Vmax), expressed as a ratio of Vmax with an 80% helium-20% oxygen gas mixture to Vmax with air at isolung volumes, indicated that the predominant flow regimes across upstream airways changed differently after each agent was given separately. After atropine Vmax increased, elastic recoil pressure did not change, and density dependence decreased. Utilizing the equal pressure points analysis which defines upstream and downstream segments of the intrathoracic airways at flow limitation, these results suggest a greater relative dilatation of the larger upstream airways such that more of the driving pressure is dissipated across the smaller airways in which flow is less dependent upon gas density. After isoproterenol Vmax increased, elastic recoil pressure did not change, and density dependence increased. This suggests a preferential dilatation of the smaller and more peripheral airways with less density-dependent flow regimes such that more of the driving pressure would be dissipated in the larger airways in which flow is more dependent upon gas density. Systematic decreases after isoproterenol lead independently to the same conclusion. After both agents together, Vmax increased and density dependence and critical alveolar pressures did not change from control, suggesting a relatively uniform dilatation of all the airways comprising the upstream segment.

A critical assessment of the mechanism by which hyperoxia attenuates exercise-induced asthma.

Recent data demonstrate that the magnitude of the heat loss that occurs from the respiratory tract during exercise correlates with the degree of post-exertional obstruction that develops in asthmatics. Respiratory heat loss relates directly to the minute ventilation and heat capacity of the inspired gas and inversely to its water content and temperature. Because it has been shown that inhaling 100% oxygen during exercise blunts the obstructive response, we wondered if this effect could be accounted for by differing values of heat exchange with air and oxygen breathing. To examine this question, we studied 10 asthmatics by measuring multiple aspects of pulmonary mechanics before and after four bouts of exhausting leg work during which the subjects inhaled either air or oxygen conditioned to provide widely differing thermal burdens on their airways. Under all inspired gas conditions, oxygen breathing produced significantly less obstruction than air. Minute ventilation was also significantly less with oxygen as was the total heat lost. As the latter fell, so did the magnitude of the postexercise obstruction. When the differences in ventilation and respiratory heat loss between air and oxygen were eliminated by eucapnic hyperventilation, the differences in the obstructive responses also disappeared. Thus, the effects of hyperoxia on exercise-induced asthma can be accounteed for solely by alterations in heat exchange.

Direct recordings of the temperatures in the tracheobronchial tree in normal man.

In an effect to determine how far inspired air could penetrate into the respiratory tract before being brought to body conditions, we measured the temperature in the airways of the anterior basilar segment of the right lower lobe in five normal subjects while they breathed air at subfreezing and ambient conditions. During quiet breathing, most of the heating of the incoming gas took place in the upper airways as expected. However, as the thermal burden was increased by rapid inspirations, frigid air, and hyperventilation, the temperature of the distal airways progressively fell and the point at which the incoming air reached body conditions moved deep into the periphery of the lung. These findings demonstrate that heat and water transfer is not localized to one region, but rather is a continuous process that begins the moment the air enters the body and involves as much of the respiratory tract as necessary to complete the task.

Evaluation of role played by mediators of immediate hypersensitivity in exercise-induced asthma.

To determine whether mediators of immediate hypersensitivity played a role in the pathogenesis of exercise-induced asthma, we measured the concentration of histamine and neutrophil-chemotactic activity present in systemic arterial blood during thermal challenges in five asymptomatic asthmatics. Because exercise-induced asthma has been shown to be a result of respiratory heat loss and because respiratory heat loss during isocapnic hyperventilation has been shown to give identical responses, we chose the latter provocational method in order to minimize increases in cardiac output that might interfere with the interpretation of mediator concentrations in arterial blood. Multiple aspects of pulmonary mechanics were also recorded before and after provocation. The results of these studies were then compared with the effects observed when the same subjects inhaled aerosols of specific antigens on the same day. Each challenge produced identical alterations in lung function, and neither was associated with consistent changes in arterial histamine. However, antigen provocation evoked a sustained and prolonged release of neutrophil chemotactic activity in each subject, whereas isocapnic hyperventilation with cold air was without effect. These data strongly suggest that mast-cell derived mediators are not involved in the development or maintenance of the bronchial obstruction that follows exercise in asthmatics.

Productive infection of isolated human alveolar macrophages by respiratory syncytial virus.

Respiratory syncytial virus (RSV) is a significant cause of lower respiratory tract disease in children and individuals with cell-mediated immunodeficiencies. Airway epithelial cells may be infected with RSV, but it is unknown whether other cells within the lung permit viral replication. We studied whether human alveolar macrophages supported RSV replication in vitro. Alveolar macrophages exposed to RSV demonstrated expression of RSV fusion gene, which increased in a time-dependent manner and correlated with RSV protein expression. RSV-exposed alveolar macrophages produced and released infectious virus into supernatants for at least 25 d after infection. Viral production per alveolar macrophage declined from 0.053 plaque-forming units (pfu)/cell at 24 h after infection to 0.003 pfu/cell by 10 d after infection and then gradually increased. The capability of alveolar macrophages to support prolonged RSV replication may have a role in the pulmonary response to RSV infection.