Evaluation of cofactor responsiveness

The response to cofactor therapy in inborn errors of metabolism may be dramatic with complete resolution of the clinical illness but more commonly the response is absent or partial. When assessing cofactor responsiveness clinical and biochemical findings as well as the natural history of the disorder must be taken into account.     

Dissociation between airway responsiveness to methacholine and responsiveness to antigen.

Repeated aerosolized antigen challenges to brown Norway (BN) rats generate nonspecific airway hyperresponsiveness (AHR). On the other hand, some studies have demonstrated that repeated antigen challenge could attenuate antigen-specific AHR in BN rats. The authors questioned whether such dissociation in airway responses actually occurs when assessed in a single study in the same animals. The authors simultaneously measured AHR to methacholine and antigen-specific AHR in rats that were repeatedly exposed to aerosolized ovalbumin (OA) for 1 or 3 months after sensitization. Four days after the last challenge, airway responses to methacholine and OA, morphometry of the airways, the cell profile in bronchoalveolar lavage fluid, and cytokine messenger ribonucleic acid (mRNA) expression in the lungs were evaluated. The two types of AHR were modulated in opposite directions by repeated antigen challenges. The AHR to methacholine was significantly increased in the rats receiving antigen challenges compared with the control rats receiving saline challenges after sensitization; whereas, the antigen-specific AHR was significantly decreased. The number of alveolar macrophages in lavaged fluid and the expression of transforming growth factor-beta1 mRNA in lung tissue was significantly different between the antigen-challenged rats and the control rats. In conclusion, dissociation between nonspecific airway hyperresponsiveness and antigen-specific airway hyperresponsiveness in brown Norway rats after repeated antigen challenges was demonstrated. Sustained airway inflammation with macrophages and/or upregulation of transforming growth factor-beta1 messenger ribonucleic acid in the lung tissue may be responsible for this dissociation.     

Laboratory evaluation of aspirin responsiveness

Aspirin is the most commonly used antiplatelet medication. Laboratory monitoring of aspirin response has recently become a topic of interest due to potential impacts on patient management and clinical outcomes. This article summarizes available laboratory testing of aspirin response with focus on technical issues, limitations, and current opinion on the utility of routine patient testing. Am. J. Hematol., 2010. © 2010 Wiley‐Liss, Inc.     

Desensitisation of calcitonin gene-related peptide responsiveness but not adrenomedullin responsiveness in vascular smooth muscle cells

Adrenomedullin (ADM) and calcitonin gene-related peptide (CGRP) are distantly related peptides. Both act through G protein-coupled receptors on vascular smooth muscle cells to increase intracellular cAMP concentrations, causing vasorelaxation. Recent evidence suggests that both peptides bind to a common heptahelical receptor, with specificity for each peptide being determined by a receptor activity modifying protein (RAMP). This hypothesis predicts that each peptide should desensitise the cellular response to subsequent stimulation by the other. We have studied the patterns of desensitisation of ADM/CGRP receptors in rat aortic vascular smooth muscle cells. Cells were incubated for 20 min in either serum free medium (SFM), alone (control) or in SFM containing vasoactive agonist (e.g. ADM 10(-8) M, CGRP 10(-7) M, angiotensin II 10(-9) M or isoproterenol 10(-6) M). Cells were then washed and incubated for a further 20 min in SFM containing a second agonist and 1 mM isobutyryl methyl xanthine. Cells were harvested and assayed for cAMP. Pre-exposure of cells to CGRP, isoproterenol, angiotensin II or ADM, decreased cAMP generation in response to subsequent stimulation with CGRP by 84% (+/-5), 66% (+/-18), 45% (+/-5) and 60% (+/-10) respectively (mean+/-s.d.). Pre-incubation of cells with 100 nM H-89, a protein kinase A (PKA) inhibitor, abolished the desensitisation of CGRP by itself, implying that this desensitisation was mediated through PKA. In contrast, there was no attenuation of the cAMP response to stimulation with ADM by pre-exposure to ADM and all other agonists tested. Identical results were seen with or without PKA inhibition by H-89. These results indicate that the ADM receptor does not desensitise over this time period in RAVSMCs, in contrast to the CGRP receptor, which is desensitised by pre-exposure to CGRP and other vaso-active agonists. These data also suggest that ADM and CGRP act through separate receptors in these cells.     

Basophil responsiveness in chronic urticaria

Chronic urticaria is a common skin disease without an etiology in the majority of cases. The similarity of symptoms and pathology to allergen-induced skin reactions supports the idea that skin mast cell and blood basophil IgE receptor activation is involved; however, no exogenous allergen trigger has been identified. Recent evidence supports a role for blood basophils in disease expression. Specifically, blood basopenia is noted in active disease with the recruitment of blood basophils to skin lesional sites. In addition, blood basophils display altered IgE receptor-mediated degranulation that reverts in disease remission. In active chronic idiopathic urticaria (CIU) subjects, changes in IgE receptor-signaling molecule expression levels accompany the altered degranulation function in blood basophils. The arrival of therapies targeting IgE has further shown that altered blood basophil degranulation behavior has potential use as a disease biomarker in CIU.     

Firefighting acutely increases airway responsiveness

The acute effects of the products of combustion and pyrolysis on airway responsiveness among firefighters are poorly documented. To study this relationship, spirometry and methacholine challenge testing (MCT) were performed on 18 active Seattle firefighters before and 5 to 24 h after firefighting. Body plethysmography was used to measure changes in specific airway conductance (SGaw), and results of MCT were analyzed using PD35-SGaw, the cumulative dose causing a 35% decrease in SGaw. Subjects who did not react by the end of the protocol were assigned a value of 640 inhalational units, the largest cumulative dose. Fire exposure was defined as the total time (hours) spent without a self-contained breathing apparatus at the firesite and was categorized as mild (less than 1 h, n = 7), moderate (1 to 2 h, n = 5), or severe (greater than 2 h, n = 6). Mean age of the 18 firefighters was 36.7 +/- 6.7 yr (range, 25 to 51), with a mean of 9.1 +/- 7.9 active years in the trade (range, zero to 22). None was known to be asthmatic. After firefighting, FEV1 % predicted (%pred) and FEF25-75 %pred significantly decreased by means of 3.4 +/- 1.1% and 5.6 +/- 2.6%, respectively. The mean decline in PD35-SGaw after firefighting was 184.5 +/- 53.2 units (p = 0.003). This observed decline in PD35-SGaw could not be explained by decrements in prechallenge SGaw, FEV1, or FVC.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sexual responsiveness in diabetic women

Sexual responsiveness in 82 Type 1 (insulin-dependent) diabetic women was compared with that of 47 normal control subjects, using an interview method for rating various aspects of sexual response, and attitude questionnaires. The diabetic women were questioned about symptoms of autonomic neuropathy, and cardiovascular autonomic nerve function tests were performed. There were differences between the two groups in the reports of vaginal lubrication, but in most other respects the groups were similar. The diabetic women were not less orgasmic, and reported significantly fewer unpleasant feelings during sexual intercourse. They saw themselves and their husbands as less 'potent' than did the normal subjects. The possible enhancing effect of diabetes on the marriage of some diabetic women possibly counteracted the relatively mild physiological deficits involved. There was very little difference in sexual response between women with and without symptomatic autonomic neuropathy.     

Prediction of airway responsiveness to allergen from skin sensitivity to allergen and airway responsiveness to histamine

Previous data have indicated that airway responsiveness to allergen, expressed as the provocation concentration causing a 20% FEV1 fall (PC20), was dependent on nonallergic airway responsiveness (histamine PC20) and sensitivity to allergen (skin sensitivity or end-point titration). From retrospective data in 24 subjects, we developed a formula to predict allergen PC20 and examined its accuracy prospectively in 26 new subjects undergoing allergen inhalation test with doubling allergen concentrations. Allergen PC20 (APC20) was predicted from histamine PC20 (HPC20) and skin sensitivity (SS) by the formula: Log10 (APC20) = 0.69 Log10 (HPC20 X SS) + 0.11 (r = 0.85). Allergen PC20 was accurately predicted in 6, and overestimated or underestimated by 1 doubling concentration in 11, by 2 concentrations in 6, by 3 concentrations in 3, and by greater than 3 concentrations in none. From the total of 50 subjects, a new relationship was developed: Log10 (APC10) = 0.68 log10 (HPC20 X SS) (r = 0.82) from which 46 of 50 (92%) of allergen PC20 values fall within 2 doubling concentrations of the regression line (and all within 3). Early airway responsiveness to a given allergen can be predicted within a +/- 8-fold range, which is better than some investigator's test reproducibility of +/- 1 log (10-fold). Allergen inhalation tests to determine early asthmatic responsiveness to different IgE-mediated allergens can probably be replaced by the simpler and safer determinations of allergen sensitivity (SS, RAST) and histamine or methacholine airway responsiveness.     

Vascular responsiveness in obstructed gut

Multiorgan system failure due to hypotension and sepsis is an important cause of death in patients with bowel obstruction. We have investigated the pathophysiology of this entity in an animal model. After 5 days of bowel obstruction, blood flow in the superior mesenteric artery was measured with and without Pitressin and norepinephrine given in separate experiments. In controls, Pitressin in moderate dosages caused a substantial fall in gut blood flow, which was not seen in obstructed animals (blood flow reduction 52 percent vs. 11 percent in sham and obstructed animals respectively, P less than 0.01). Similarly, norepinephrine infusion had less of an effect on gut blood flow in obstructed animals (blood flow reduction 79 percent vs. 58 percent sham vs. obstructed animals (P less than 0.05). Thus, both agents had dose-related effects on gut blood flow, which was maintained at a higher level throughout the drug infusion periods in the bowel of obstructed animals, demonstrating that splanchnic flow is less responsive to vasoactive drug infusion under these experimental conditions. Because splanchnic vasoconstriction is an important feature of normal hemodynamic homeostasis, we suggest that these results may help explain some aspects of the pathophysiology of multiorgan failure caused or worsened by systemic hypotension seen in bowel obstruction.     

Airway responsiveness to inhaled acetaldehyde in subjects with allergic rhinitis: relationship to methacholine responsiveness

BACKGROUND: Asthmatic subjects have an exaggerated airway response to inhaled acetaldehyde, but no information is available on airway responsiveness to this bronchoconstrictor agent in subjects with allergic rhinitis. OBJECTIVE: The aim of this study was to determine the effect of inhaled acetaldehyde on lung function in nonasthmatic subjects with allergic rhinitis. METHODS: A total of 78 adults (43 subjects with allergic rhinitis, 16 asthmatics and 19 healthy subjects) were challenged with increased concentrations of acetaldehyde and methacholine. The response to each bronchoconstrictor agent was measured by the provocative concentration required to produce a 20% fall in FEV(1) (PC(20)). RESULTS: The geometric mean PC(20) acetaldehyde value for asthmatics was 35.5 mg/ml compared with 67.6 mg/ml in subjects with allergic rhinitis and with 80.0 mg/ml in healthy subjects (p < 0.001). The PC(20) acetaldehyde values in the allergic rhinitis group were also significantly lower than in the healthy control group (p = 0.04). All of the subjects with allergic rhinitis and increased responsiveness to acetaldehyde showed airway hyperresponsiveness to methacholine, but 9 patients with hyperresponsiveness to methacholine failed to respond to acetaldehyde. CONCLUSIONS: We conclude that subjects with allergic rhinitis are less responsive to inhaled acetaldehyde than asthmatic subjects, but more than healthy controls. Furthermore, only approximately half the patients with allergic rhinitis and airway hyperresponsiveness to methacholine exhibit bronchoconstriction with inhaled acetaldehyde, thus suggesting that airway hyperresponsiveness to methacholine may not be the sole factor leading to bronchoconstriction in response to acetaldehyde.     

机械通气患者容量反应性评估策略

对于急性循环衰竭患者,特别是感染性休克患者,液体治疗对于血流动力学的稳定、组织器官的血流灌注、纠正细胞缺氧、对抗感染十分重要,但过多增加液体量对危重症患者,特别是脓毒血症和/或肺损伤患者是有害的,如何选取合适的指标指导临床合理输液仍面临许多挑战.评估容量反应性可避免盲目补液,降低补液风险.回顾关于评估容量反应性的指标及临床报道,静态血流动力学参数,如中心静脉压、肺毛细血管楔压,虽常用但受干扰因素多,无法及时准确地评估循环血容量的变化.基于心肺相互作用的功能性血流动力学监测指标,如脉压变异和每搏量变异,虽广泛应用,但因自主呼吸、心律失常、低潮气量或低肺顺应性等局限性,不能用于所有患者.呼气末屏气试验、微量静脉输液、被动抬腿试验成为有自主呼吸运动和/或心律失常情况下评估容量反应性的备选方法,其可靠性及局限性值得进一步研究.     

The responsiveness of the Shoulder Disability Questionnaire

Objective—To evaluate the responsiveness of the Shoulder Disability Questionnaire (SDQ).
Methods—The study was conducted within the framework of an observational study on shoulder disorders in primary care. After first presentation of their complaints to the general practitioner and after one and six months, participants completed the SDQ, a single question on functional status (FSQ), and an ordinal 11 point scale for the severity of pain (PSS). Responsiveness of the SDQ was evaluated compared with that of the FSQ and PSS, by calculating responsiveness ratios and by plotting receiver operating characteristic (ROC) curves. Recovery according to the patient was used as an external criterion for clinically relevant improvement (complete recovery or much improved on a six point Likert scale was denoted as clinically relevant improvement).
Results—A total of 349 consecutive patients with shoulder disorders were enrolled in the observational study. Response rates ranged between 96% and 89%. Responsiveness ratios were slightly higher for the PSS compared with the SDQ (2.53 versus 2.22 at one month, 2.24 versus 1.89 at six months). The area under the ROC curve was 0.84 for both the SDQ and the PSS, and 0.72 for the FSQ.
Conclusion—The results of this study confirm the responsiveness of the SDQ, making it a useful instrument to assess functional disability in longitudinal studies.

Keywords: shoulder; outcome assessment; functional disability; responsiveness     

Genetic determinants of responsiveness to antiplatelet therapy

Antiplatelet drugs are well-established therapies for acute coronary syndromes and for the primary and secondary prevention of coronary artery disease, stroke, and peripheral vascular disease. However, wide interindividual variability exists in the degree of platelet suppression among patients treated with antiplatelet drugs, and many individuals develop atherothrombotic events while on therapy. Although many potential mechanisms may contribute to the response variation observed, there is accumulating evidence that polymorphisms of genes from multiple biologic pathways involved in platelet activation are at least partly responsible for variable platelet responsiveness and potentially responsible for clinical failure of antiplatelet therapy.