Pathological features and inhaled corticosteroid response of eosinophilic and non-eosinophilic asthma

Background

Non‐eosinophilic asthma is a potentially important clinicopathological phenotype since there is evidence that it responds poorly to inhaled corticosteroid therapy. However, little is known about the underlying airway immunopathology and there are no data from placebo‐controlled studies examining the effect of inhaled corticosteroids.

Methods

Airway immunopathology was investigated using induced sputum, bronchial biopsies, bronchial wash and bronchoalveolar lavage in 12 patients with symptomatic eosinophilic asthma, 11 patients with non‐eosinophilic asthma and 10 healthy controls. The patients with non‐eosinophilic asthma and 6 different patients with eosinophilic asthma entered a randomised, double‐blind, placebo‐controlled crossover study in which the effects of inhaled mometasone 400 μg once daily for 8 weeks on airway responsiveness and asthma quality of life were investigated.

Results

Patients with non‐eosinophilic asthma had absence of eosinophils in the mucosa (median 4.4 cells/mm² vs 23 cells/mm² in eosinophilic asthma and 0 cells/mm² in normal controls; p = 0.03) and normal subepithelial layer thickness (5.8 μm vs 10.3 μm in eosinophilic asthma and 5.1 μm in controls, p = 0.002). Non‐eosinophilic and eosinophilic asthma groups had increased mast cell numbers in the airway smooth muscle compared with normal controls (9 vs 8 vs 0 cells/mm², p = 0.016). Compared with placebo, 8 weeks of treatment with inhaled mometasone led to less improvement in methacholine PC₂₀ (0.5 vs 5.5 doubling concentrations, 95% CI of difference 1.1 to 9.1; p = 0.018) and asthma quality of life (0.2 vs 1.0 points, 95% CI of difference 0.27 to 1.43; p = 0.008).

Conclusions

Non‐eosinophilic asthma represents a pathologically distinct disease phenotype which is characterised by the absence of airway eosinophilia, normal subepithelial layer thickness and a poor short‐term response to treatment with inhaled corticosteroids.Clinicians have long regarded asthma as a heterogeneous disease,^1,2 although detailed clinicopathological studies have tended to emphasise the similarities in the underlying airway pathology and disordered function between patients.^3,4 The development of safe non‐invasive induced sputum techniques has provided the opportunity to study airway inflammation in a diverse range of patients. Using this technique, we and a number of other groups have identified a subset of adults who have clear physiological evidence of asthma but no induced sputum evidence of eosinophilic airway inflammation.^5,6,7 This asthma phenotype is potentially clinically important since several uncontrolled studies have suggested that it is associated with a poor short‐term and longer‐term response to inhaled corticosteroid.^5,8,9Non‐eosinophilic asthma is present in 53% of patients presenting to an adult respiratory clinic with symptomatic asthma.⁹ Other investigators have reported the absence of a sputum eosinophilia in up to 50% of patients with refractory asthma,⁹ patients studied during an asthma exacerbation¹⁰ and patients taking high doses of inhaled corticosteroids.⁶ In a recent longitudinal study of patients with severe asthma, the absence of sputum eosinophils has been reported to be a stable feature in a number of patients observed over 12 months;¹¹ another study showed that it was present in untreated symptomatic patients as well as those receiving inhaled corticosteroid therapy.⁹ These observations suggest that, in some patients at least, non‐eosinophilic asthma is a stable phenotype that is not solely explained by the effects of corticosteroid therapy.Several studies have noted that an airway neutrophilia is often present in patients with non‐eosinophilic asthma, and Wenzel et al⁷ reported a predominantly neutrophilic airway inflammatory response with an absence of eosinophils and normal basement membrane thickness in a subgroup of patients with refractory asthma from whom bronchial biopsy specimens were taken. These findings support the concept that non‐eosinophilic asthma is a pathologically distinct entity, although the extent to which these findings reflect the effects of treatment remains unclear.The aim of this study was to compare the immunopathology of eosinophilic and non‐eosinophilic asthma with normal controls in patients with symptomatic asthma who were not treated with inhaled corticosteroids. We also set out to compare the response to 8 weeks of treatment with the inhaled corticosteroid mometasone in a prospective randomised, double‐blind, placebo‐controlled crossover trial in patients with non‐eosinophilic asthma and in a subgroup with eosinophilic asthma.     

Injection pain of the inferior alveolar nerve block in patients with irreversible pulpitis.

OBJECTIVE: The purpose of this retrospective analysis was to determine the pain associated with needle insertion, placement, and solution deposition for the conventional inferior alveolar nerve (IAN) block in patients with irreversible pulpitis. STUDY DESIGN: One hundred two emergency patients with irreversible pulpitis received IAN block injections using 2% lidocaine with 1:100,000 epinephrine. The patients recorded pain of the 3 injection stages on a Heft-Parker visual analog scale (VAS). RESULTS: Moderate-to-severe pain may occur 57% to 89% of the time with the IAN block. Needle placement was significantly more painful than needle insertion for men and significantly more painful than either insertion or deposition for women (P < .03). There was no statistical difference between the pain for men or women with respect to needle insertion, placement, or deposition pain (P > .05). Deposition of 0.2 to 0.4 mL anesthetic during placement did not significantly reduce placement pain for either gender (P = .753). CONCLUSION: In conclusion, 57% to 89% of patients presenting with irreversible pulpitis have the potential for moderate to severe pain with the IAN block.     

The Impact of Financial Conflict of Interest on Surgical Research: An Observational Study of Published Manuscripts

Background

Substantial discrepancies exist between industry-reported and self-reported conflicts of interest (COI). Although authors with relevant, self-reported financial COI are more likely to write studies favorable to industry sponsors, it is unknown whether undisclosed COI have the same effect. We hypothesized that surgeons who fail to disclose COI are more likely to publish findings that are favorable to industry than surgeons with no COI.

Methods

PubMed was searched for articles in multiple surgical specialties. Financial COI reported by surgeons and industry were compared. COI were considered to be relevant if they were associated with the product(s) mentioned by an article. Primary outcome was favorability, which was defined as an impression favorable to the product(s) discussed by an article and was determined by 3 independent, blinded clinicians for each article. Primary analysis compared incomplete self-disclosure to no COI. Ordered logistic multivariable regression modeling was used to assess factors associated with favorability.

Results

Overall, 337 articles were reviewed. There was a high rate of discordance in the reporting of COI (70.3%). When surgeons failed to disclose COI, their conclusions were significantly more likely to favor industry than surgeons without COI (RR 1.2, 95% CI 1.1–1.4, p < 0.001). On multivariable analysis, any COI (regardless of relevance, disclosure, or monetary amount) were significantly associated with favorability.

Conclusions

Any financial COI (disclosed or undisclosed, relevant or not relevant) significantly influence whether studies report findings favorable to industry. More attention must be paid to improving research design, maximizing transparency in medical research, and insisting that surgeons disclose all COI, regardless of perceived relevance.

     

Effects of Adult Romantic Attachment and Social Support on Resilience and Depression in Individuals with Spinal Cord Injuries

Background:

Spinal cord injury (SCI) can cause psychological consequences that negatively affect quality of life. It is increasingly recognized that factors such as resilience and social support may produce a buffering effect and are associated with improved health outcomes. However the influence of adult attachment style on an individual’s ability to utilize social support after SCI has not been examined.

Objective:

The purpose of this study was to examine relationships between adult romantic attachment perceived social support depression and resilience in individuals with SCI. In addition we evaluated potential mediating effects of social support and adult attachment on resilience and depression.

Methods:

Participants included 106 adults with SCI undergoing inpatient rehabilitation. Individuals completed measures of adult attachment (avoidance and anxiety) social support resilience and depression. Path analysis was performed to assess for presence of mediation effects.

Results:

When accounting for the smaller sample size support was found for the model (comparative fit index = .927 chi square = 7.86 P = .01 β = -0.25 standard error [SE] = -2.93 P < .05). The mediating effect of social support on the association between attachment avoidance and resilience was the only hypothesized mediating effect found to be significant (β = -0.25 SE = -2.93 P < .05).

Conclusion:

Results suggest that individuals with SCI with higher levels of attachment avoidance have lower perceived social support which relates to lower perceived resilience. Assessing attachment patterns during inpatient rehabilitation may allow therapists to intervene to provide greater support.     

Prehospital triage and survival of major trauma patients in a Dutch regional trauma system: relevance of trauma registry

Background and aims Since 1999, the Dutch trauma care has been regionalized into ten trauma systems. This study is the first to review such a trauma system. The aim was to examine the sensitivity of prehospital triage criteria [triage revised trauma score (T-RTS)] in identifying major trauma patients and to evaluate the current level of trauma care of a regionalized Dutch trauma system for major trauma patients.Patients and methods Major trauma patients (n=511) (June 2001–December 2003) were selected from a regional trauma registry database. The prehospital T-RTS was computed and standardized W scores (Ws) were generated to compare observed vs expected survival based on contemporary US- and UK-norm databases.Results The T-RTS showed low sensitivity for the prehospital identification of major trauma patients [34.1% (T-RTS≤10)]. Nevertheless, 78.0% of all major trauma patients were directly managed by the trauma center. These patients were more severely injured than their counterparts at non-trauma-center hospitals (p<0.001). No significant difference emerged between the mortality rates of both groups. The Ws {−0.46 calculated on the US model [95% confidence interval (CI) ranging from −1.99 to 1.07]} [0.60 calculated on the UK model (95% CI ranging from −1.25 to 2.44)] did not differ significantly from zero.Conclusion The trauma center managed most of the major trauma patients in the trauma system but the triage criteria need to be reconsidered. The level of care of the regional trauma system was shown to measure up to US and UK benchmarks.     

A Prospective,Randomized, Double-Blind Comparison of 2% Lidocaine With 1?:?100,000 Epinephrine, 4% Prilocaine With 1?:?200,000 Epinephrine,and 4% Prilocaine for Maxillary Infiltrations

The purpose of this prospective, randomized, double-blind crossover study was to evaluate the anesthetic efficacy of 2% lidocaine with 1 : 100,000 epinephrine, 4% prilocaine with 1 : 200,000 epinephrine, and 4% prilocaine in maxillary lateral incisors and first molars. Sixty subjects randomly received, in a double-blind manner, maxillary lateral incisor and first molar infiltrations of 1.8 mL of 2% lidocaine with 1 : 100,000 epinephrine, 1.8 mL of 4% prilocaine with 1 : 200,000 epinephrine, and 1.8 mL of 4% prilocaine, at 3 separate appointments spaced at least 1 week apart. The teeth were pulp-tested in 3-minute cycles for a total of 60 minutes. Anesthetic success (ie, obtaining 2 consecutive 80 readings with the electric pulp tester) and onset of pulpal anesthesia were not significantly different between 2% lidocaine with 1 : 100,000 epinephrine, 4% prilocaine with 1 : 200,000 epinephrine, and 4% prilocaine for the lateral incisor and first molar. For both lateral incisor and first molar, 4% prilocaine with 1 : 200,000 epinephrine and 2% lidocaine with 1 : 100,000 epinephrine were equivalent for incidence of pulpal anesthesia. However, neither anesthetic agent provided an hour of pulpal anesthesia. For both lateral incisor and first molar, 4% prilocaine provided a significantly shorter duration of pulpal anesthesia compared with 2% lidocaine with 1 : 100,000 epinephrine and 4% prilocaine with 1 : 200,000 epinephrine.     

Oxidative stress and neurodegeneration in penile ischaemia

OBJECTIVE

To seek markers of oxidative stress and examine neural structural integrity in chronic penile ischaemia using a rabbit model of arteriogenic erectile dysfunction (ED), as the role of ischaemia in penile neuropathy and the oxidative mechanism of neurodegeneration in ED remains unknown.

MATERIALS AND METHODS

A rabbit model of atherosclerosis‐induced ED was developed by partial balloon de‐endothelialization of the iliac arteries. After 10 weeks, intracavernosal blood flow and erectile function in the arteriogenic ED group were compared with age‐matched controls. Erectile tissues were processed for analysis of oxidative stress markers and nerve fibre density using enzyme immunoassay and immunohistochemical staining, respectively. Oxidative stress‐sensitive genes were determined with quantitative real‐time polymerase chain reaction. Tissue ultrastructure was examined by transmission electron microscopy.

RESULTS

Significant erectile tissue ischaemia, erectile dysfunction, increased levels of oxidative products, and marked nitrotyrosine immunoreactivity was evident in the ED group. Oxidative stress‐sensitive genes encoding hypoxia inducible factor‐1α (HIF‐1α), superoxide dismutase (SOD), aldose reductase (AR) and nerve growth factor (NGF) were up‐regulated in the ischaemic erectile tissue. These changes were associated with collapsed axonal and Schwann cell profiles, neurodegeneration, mitochondrial structural damage, increased caveolae, loss of endothelium, and sporadic vacuolization.

CONCLUSIONS

Neuropathy appears to follow the vascular insult in arteriogenic ED. Neural injury in penile ischaemia involves a neurovascular phenomenon mediated by oxidative free radicals. Mitochondrial structural damage and increased HIF‐1α gene expression may be early signals of oxidative stress and neurodegeneration in ED. Up‐regulation of SOD, AR and NGF may be a coordinated defensive reaction to oxidative radicals that seems to fail to prevent neural injury in the ischaemic penis. Our study introduces the concept of oxidative neurodegeneration in the pathophysiology of arteriogenic ED. Therapeutic strategies to protect penile nerves from free radical incursion may enhance the efficacy of surgical and pharmacological interventions in arteriogenic ED.     

Anterior lumbar interbody fusion using two standard cylindrical threaded cages, a single mega-cage, or dual nested cages: a biomechanical comparison

Our purpose was: (1) to compare the biomechanical properties of an interbody reconstruction using two standard threaded cages (18-mm diameter), a reconstruction using a single mega-cage (24-mm diameter), and a reconstruction using dual nested cages (22-mm diameter); and (2) to quantify the surface area of the cancellous bone bed exposed by reaming for the cages. Each motion segment was tested according to a nondestructive biomechanical loading sequence (compression, flexion, extension, lateral bending, axial torsion). Load was applied first to the intact motion segment and again after the insertion of cages, and stiffness values were calculated at each step. After the testing, each specimen was bisected through the disc and the surface area of the vascular bed was calculated. Comparison of the biomechanical properties of the three reconstructions showed that the dual nested cages produced the stiffest reconstruction. However, when the standard cages were compared with the nested cages, there was no significant difference, and compared with the mega-cage, the only difference was in flexion. The surface area of cancellous bone exposed by reaming for each of the three reconstructions showed the greatest value with the dual nested cages. These findings, together with the improved safety afforded by the nested or mega-cage, suggest that they are appropriate alternatives to the standard dual threaded cage reconstruction. Received: May 16, 2000 / Accepted: October 25, 2000