Airway hyperresponsiveness (AHR) is a clinical feature of asthma and is often in proportion to the underlying severity of the disease. To understand AHR and the mechanisms that contribute to these ...processes, it is helpful to divide the airway components that affect this feature of asthma into "persistent" and "variable" categories. The persistent component of AHR represents structural changes in the airway, whereas the variable feature relates to inflammatory events. Insight into how these interrelated components of AHR can contribute to asthma is gained by studying treatment effects and models of asthma provocation.
Allergy and asthma Bochner, Bruce S.; Busse, William W.
Journal of Allergy and Clinical Immunology,
05/2005, Letnik:
115, Številka:
5
Journal Article
Recenzirano
Initiation and regulation of allergic inflammation is influenced by many factors, including cell type, membrane receptors, and mediators generated. Furthermore, the altered response of targeted ...tissues (ie, airway smooth muscle) becomes important to the eventual expression of asthma. Finally, the genetic regulation and association of genetic polymorphisms has enhanced our understanding of host susceptibility. In this review key findings published in 2004 issues of the
Journal of Allergy and Clinical Immunology are highlighted to demonstrate recent advances in these areas.
Summary Eosinophilia is an established marker of asthma-related inflammation. We assessed the effect of omalizumab on peripheral blood eosinophil counts using a pooled analysis of data from five ...randomized, double-blind, placebo-controlled studies in patients with moderate-to-severe persistent allergic asthma receiving moderate-to-high-dose inhaled corticosteroids (omalizumab, n = 1136; placebo, n = 1100). Relationships between omalizumab, peripheral blood eosinophils, serum free IgE concentrations and clinical outcomes were explored. Baseline mean eosinophil counts were similar in each treatment group. Post-treatment eosinophil counts were significantly reduced from baseline in the omalizumab group ( p < 0.0001) but were not significantly different in the placebo group. Greater reductions in eosinophil counts were observed in patients who had post-treatment free IgE levels <50 ng/mL. Three studies included steroid-stable and steroid-reduction phases. At the end of each phase in these studies, a significantly greater reduction in eosinophil counts was achieved in the omalizumab group compared with the placebo group ( p < 0.0001). A consistent pattern of improved clinical outcomes/decreased eosinophils and worsened clinical outcomes/increased eosinophils was observed for both omalizumab and placebo treatment groups. The findings from our analysis of a large patient population are consistent with earlier reports of the inhibitory effect of omalizumab on eosinophils.
In patients with vasodilatory shock, plasma concentrations of angiotensin I (ANG I) and II (ANG II) and their ratio may reflect differences in the response to severe vasodilation, provide novel ...insights into its biology, and predict clinical outcomes. The objective of these protocol prespecified and subsequent post hoc analyses was to assess the epidemiology and outcome associations of plasma ANG I and ANG II levels and their ratio in patients with catecholamine-resistant vasodilatory shock (CRVS) enrolled in the Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) study.
We measured ANG I and ANG II levels at baseline, calculated their ratio, and compared these results to values from healthy volunteers (controls). We dichotomized patients according to the median ANG I/II ratio (1.63) and compared demographics, clinical characteristics, and clinical outcomes. We constructed a Cox proportional hazards model to test the independent association of ANG I, ANG II, and their ratio with clinical outcomes.
Median baseline ANG I level (253 pg/mL interquartile range (IQR) 72.30-676.00 pg/mL vs 42 pg/mL IQR 30.46-87.34 pg/mL in controls; P < 0.0001) and median ANG I/II ratio (1.63 IQR 0.98-5.25 vs 0.4 IQR 0.28-0.64 in controls; P < 0.0001) were elevated, whereas median ANG II levels were similar (84 pg/mL IQR 23.85-299.50 pg/mL vs 97 pg/mL IQR 35.27-181.01 pg/mL in controls; P = 0.9895). At baseline, patients with a ratio above the median (≥1.63) had higher ANG I levels (P < 0.0001), lower ANG II levels (P < 0.0001), higher albumin concentrations (P = 0.007), and greater incidence of recent (within 1 week) exposure to angiotensin-converting enzyme inhibitors (P < 0.00001), and they received a higher norepinephrine-equivalent dose (P = 0.003). In the placebo group, a baseline ANG I/II ratio <1.63 was associated with improved survival (hazard ratio 0.56; 95% confidence interval 0.36-0.88; P = 0.01) on unadjusted analyses.
Patients with CRVS have elevated ANG I levels and ANG I/II ratios compared with healthy controls. In such patients, a high ANG I/II ratio is associated with greater norepinephrine requirements and is an independent predictor of mortality, thus providing a biological rationale for interventions aimed at its correction.
ClinicalTrials.gov identifier NCT02338843. Registered 14 January 2015.
Increasing body mass index (BMI) has been associated with less fractional exhaled nitric oxide (Fe(NO)). This may be explained by an increase in the concentration of asymmetric dimethyl arginine ...(ADMA) relative to L-arginine, which can lead to greater nitric oxide synthase uncoupling.
To compare this mechanism across age of asthma onset groups and determine its association with asthma morbidity and lung function.
Cross-sectional study of participants from the Severe Asthma Research Program, across early- (<12 yr) and late- (>12 yr) onset asthma phenotypes.
Subjects with late-onset asthma had a higher median plasma ADMA level (0.48 μM, interquartile range (IQR), 0.35-0.7 compared with early onset, 0.37 μM IQR, 0.29-0.59, P = 0.01) and lower median plasma l-arginine (late onset, 52.3 IQR, 43-61 compared with early onset, 51 μM IQR 39-66; P = 0.02). The log of plasma L-arginine/ADMA was inversely correlated with BMI in the late- (r = -0.4, P = 0.0006) in contrast to the early-onset phenotype (r = -0.2, P = 0.07). Although Fe(NO) was inversely associated with BMI in the late-onset phenotype (P = 0.02), the relationship was lost after adjusting for L-arginine/ADMA. Also in this phenotype, a reduced L-arginine/ADMA was associated with less IgE, increased respiratory symptoms, lower lung volumes, and worse asthma quality of life.
In late-onset asthma phenotype, plasma ratios of L-arginine to ADMA may explain the inverse relationship of BMI to Fe(NO). In addition, these lower L-arginine/ADMA ratios are associated with reduced lung function and increased respiratory symptom frequency, suggesting a role in the pathobiology of the late-onset phenotype.
Mentoring is and always will be part of our learning and, to a large extent, a determinant of what we do, how we do it, and the benefit, satisfaction, and success that ensues, and is particularly ...recognizable and related to career development in medicine, including our specialty. Given the importance of mentoring to career development, an awareness of opportunities to participate in this lifecycle journey can provide pivotal and directive contributions to the eventual growth of our specialty and members (Fig 1). Harking back to events in early decisions to become a physician, we should be aware of these early and impressionable encounters with our patients and plant the seed early into the formidable young person about medicine as well as allergy and immunology. Exposure to Allergy and Immunology during medical school and residency training is limited for most students and house staff.
IMPORTANCE: Harms and benefits of opioids for chronic noncancer pain remain unclear. OBJECTIVE: To systematically review randomized clinical trials (RCTs) of opioids for chronic noncancer pain. DATA ...SOURCES AND STUDY SELECTION: The databases of CENTRAL, CINAHL, EMBASE, MEDLINE, AMED, and PsycINFO were searched from inception to April 2018 for RCTs of opioids for chronic noncancer pain vs any nonopioid control. DATA EXTRACTION AND SYNTHESIS: Paired reviewers independently extracted data. The analyses used random-effects models and the Grading of Recommendations Assessment, Development and Evaluation to rate the quality of the evidence. MAIN OUTCOMES AND MEASURES: The primary outcomes were pain intensity (score range, 0-10 cm on a visual analog scale for pain; lower is better and the minimally important difference MID is 1 cm), physical functioning (score range, 0-100 points on the 36-item Short Form physical component score SF-36 PCS; higher is better and the MID is 5 points), and incidence of vomiting. RESULTS: Ninety-six RCTs including 26 169 participants (61% female; median age, 58 years interquartile range, 51-61 years) were included. Of the included studies, there were 25 trials of neuropathic pain, 32 trials of nociceptive pain, 33 trials of central sensitization (pain present in the absence of tissue damage), and 6 trials of mixed types of pain. Compared with placebo, opioid use was associated with reduced pain (weighted mean difference WMD, −0.69 cm 95% CI, −0.82 to −0.56 cm on a 10-cm visual analog scale for pain; modeled risk difference for achieving the MID, 11.9% 95% CI, 9.7% to 14.1%), improved physical functioning (WMD, 2.04 points 95% CI, 1.41 to 2.68 points on the 100-point SF-36 PCS; modeled risk difference for achieving the MID, 8.5% 95% CI, 5.9% to 11.2%), and increased vomiting (5.9% with opioids vs 2.3% with placebo for trials that excluded patients with adverse events during a run-in period). Low- to moderate-quality evidence suggested similar associations of opioids with improvements in pain and physical functioning compared with nonsteroidal anti-inflammatory drugs (pain: WMD, −0.60 cm 95% CI, −1.54 to 0.34 cm; physical functioning: WMD, −0.90 points 95% CI, −2.69 to 0.89 points), tricyclic antidepressants (pain: WMD, −0.13 cm 95% CI, −0.99 to 0.74 cm; physical functioning: WMD, −5.31 points 95% CI, −13.77 to 3.14 points), and anticonvulsants (pain: WMD, −0.90 cm 95% CI, −1.65 to −0.14 cm; physical functioning: WMD, 0.45 points 95% CI, −5.77 to 6.66 points). CONCLUSIONS AND RELEVANCE: In this meta-analysis of RCTs of patients with chronic noncancer pain, evidence from high-quality studies showed that opioid use was associated with statistically significant but small improvements in pain and physical functioning, and increased risk of vomiting compared with placebo. Comparisons of opioids with nonopioid alternatives suggested that the benefit for pain and functioning may be similar, although the evidence was from studies of only low to moderate quality.
Breaking Up Mucus Plugs in Asthma Busse, William W.; Jarjour, Nizar N
American journal of respiratory and critical care medicine,
08/2024
Journal Article
OBJECTIVE:Acute kidney injury requiring renal replacement therapy in severe vasodilatory shock is associated with an unfavorable prognosis. Angiotensin II treatment may help these patients by ...potentially restoring renal function without decreasing intrarenal oxygenation. We analyzed the impact of angiotensin II on the outcomes of acute kidney injury requiring renal replacement therapy.
DESIGN:Post hoc analysis of the Angiotensin II for the Treatment of High-Output Shock 3 trial.
SETTING:ICUs.
PATIENTS:Patients with acute kidney injury treated with renal replacement therapy at initiation of angiotensin II or placebo (n = 45 and n = 60, respectively).
INTERVENTIONS:IV angiotensin II or placebo.
MEASUREMENTS AND MAIN RESULTS:Primary end pointsurvival through day 28; secondary outcomes included renal recovery through day 7 and increase in mean arterial pressure from baseline of ≥ 10 mm Hg or increase to ≥ 75 mm Hg at hour 3. Survival rates through day 28 were 53% (95% CI, 38%–67%) and 30% (95% CI, 19%–41%) in patients treated with angiotensin II and placebo (p = 0.012), respectively. By day 7, 38% (95% CI, 25%–54%) of angiotensin II patients discontinued RRT versus 15% (95% CI, 8%–27%) placebo (p = 0.007). Mean arterial pressure response was achieved in 53% (95% CI, 38%–68%) and 22% (95% CI, 12%–34%) of patients treated with angiotensin II and placebo (p = 0.001), respectively.
CONCLUSIONS:In patients with acute kidney injury requiring renal replacement therapy at study drug initiation, 28-day survival and mean arterial pressure response were higher, and rate of renal replacement therapy liberation was greater in the angiotensin II group versus the placebo group. These findings suggest that patients with vasodilatory shock and acute kidney injury requiring renal replacement therapy may preferentially benefit from angiotensin II.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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