Small Airways Dysfunction in Asthma: Evaluation and Management to Improve Asthma Control

The small airways have been neglected for many years, but interest in the topic has been rekindled with recent advances in measurement techniques to assess this region and also the ability to deliver therapeutics to the distal airways. Current levels of disease control in asthmatic patients remain poor and there are several contributory factors including; poor treatment compliance, heterogeneity of asthma phenotypes and associated comorbidities. However, the proposition that we may not be targeting all the inflammation that is present throughout the whole respiratory tree may also be an important factor. Indeed decades ago, pathologists and physiologists clearly identified the importance of small airways dysfunction in asthmatic patients. With improved inhaler technology to deliver drug to target the whole respiratory tree and more sensitive measures to assess the distal airways, we should certainly give greater consideration to treating the small airway region when seeing our asthmatic patients in clinic. The aim of this review is to address the relevance of small airways dysfunction in the daily clinical management of patients with asthma. In particular the role of small particle aerosols in the management of patients with asthma will be explored.     

Role of Bruton's tyrosine kinase in myeloma cell migration and induction of bone disease

Myeloma cells typically grow in bone, recruit osteoclast precursors and induce their differentiation and activity in areas adjacent to tumor foci. Bruton's tyrosine kinase (BTK), of the TEC family, is expressed in hematopoietic cells and is particularly involved in B‐lymphocyte function and osteoclastogenesis. We demonstrated BTK expression in clinical myeloma plasma cells, interleukin (IL)?6– or stroma–dependent cell lines and osteoclasts. SDF‐1 induced BTK activation in myeloma cells and BTK inhibition by small hairpin RNA or the small molecule inhibitor, LFM‐A13, reduced their migration toward stromal cell‐derived factor‐1 (SDF‐1). Pretreatment with LFM‐A13 also reduced in vivo homing of myeloma cells to bone using bioluminescence imaging in the SCID‐rab model. Enforced expression of BTK in myeloma cell line enhanced cell migration toward SDF‐1 but had no effect on short‐term growth. BTK expression was correlated with cell‐surface CXCR4 expression in myeloma cells (n = 33, r = 0.81, P < 0.0001), and BTK gene and protein expression was more profound in cell‐surface CXCR4‐expressing myeloma cells. BTK was not upregulated by IL‐6 while its inhibition had no effect on IL‐6 signaling in myeloma cells. Human osteoclast precursors also expressed BTK and cell‐surface CXCR4 and migrated toward SDF‐1. LFM‐A13 suppressed migration and differentiation of osteoclast precursors as well as bone‐resorbing activity of mature osteoclasts. In primary myeloma‐bearing SCID‐rab mice, LFM‐A13 inhibited osteoclast activity, prevented myeloma‐induced bone resorption and moderately suppressed myeloma growth. These data demonstrate BTK and cell‐surface CXCR4 association in myeloma cells and that BTK plays a role in myeloma cell homing to bone and myeloma‐induced bone disease. Am. J. Hematol. 88:463–471, 2013. © 2013 Wiley Periodicals, Inc.     

Predictors of successful labor induction with oral or vaginal misoprostol

Objective: To identify independent predictors of successful labor induction with oral or vaginal misoprostol.

Methods: Women enrolled in four previous randomized trials involving oral or vaginal misoprostol for cervical ripening and labor induction were included in the present cohort study, with dosing of 25–50?μg every 4 to 6?h vaginally (n?=?574) or 50?μg every 4?h orally (n?=?207). Multiple logistic regression was performed to identify factors independently associated with successful labor induction – defined as vaginal delivery within 12?h, vaginal delivery within 24?h and spontaneous vaginal delivery. Predictors of Cesarean birth and the need for only one dose of misoprostol were also identified. Variables included in the models were maternal age, weight, height, parity, gravidity, membrane status, route of misoprostol, gestational age, birth weight, and Bishop score and its individual components.

Results: Maternal age, height, weight, parity, birth weight, dilatation, effacement and cervical station were associated with vaginal delivery within 24?h of induction. Maternal age, height, weight, nulliparity, birth weight and route of misoprostol were associated with Cesarean birth, with oral misoprostol being associated with a lower rate of Cesarean birth. The need for only one dose of misoprostol was predicted by maternal height, weight, parity, gestational age, Bishop score and route of misoprostol.

Conclusion: Characteristics of the woman (height, weight, parity), the fetus (birth weight) and some of the individual components of the Bishop score, were associated with successful labor induction, with oral misoprostol being associated with a lower rate of Cesarean birth.     

Chronic Idiopathic Cough: A Discrete Clinical Entity?

STUDY OBJECTIVES: Despite the success of specialist cough clinics, there is increasing recognition of a subgroup of chronic coughers in whom a diagnosis cannot be made even after thorough, systematic investigation. We call this condition chronic idiopathic cough (CIC). The aim of this study is to compare the clinical characteristics of CIC patients with those of coughers in whom a diagnosis has been established (non-CIC) to see if there is a recognizable clinical pattern that distinguishes CIC from non-CIC. DESIGN: Retrospective analysis of the medical records of chronic cough patients. SETTING: The Royal Brompton Hospital Chronic Cough Clinic, London. PATIENTS: One hundred patients with chronic cough referred to the Royal Brompton Hospital Cough Clinic between October 2000 and February 2004. RESULTS: Seventy-one percent of all patients were female. Median age was 57 years (range, 19 to 81 years), with a median duration of symptoms of 48 months (range, 2 to 384 months). The primary diagnoses were CIC (42%), postnasal drip syndromes (22%), gastroesophageal reflux disease (16%), asthma (7%), and others (13%). In CIC patients, the median age at referral, age at onset of cough, and proportion of females did not differ significantly from non-CIC patients. CIC patients had a longer median duration of cough (72 months vs 24 months, p = 0.002), were more likely to report an upper respiratory tract infection (URTI) as the initial trigger of their cough (48% vs 24%, p = 0.0014), and had a significantly lower cough threshold in response to capsaicin (log concentration of capsaicin required to induce five or more coughs, - 0.009 vs 0.592, p = 0.032) than non-CIC patients. CONCLUSIONS: Patients with CIC commonly describe a URTI that initiates their cough, which then lasts for many years, and they demonstrate an exquisitely sensitive cough reflex. We believe that CIC may be a distinct clinical entity with an as-yet unidentified underlying pathology.     

Low incidence of left atrial or left atrial appendage thrombus in patients with paroxysmal atrial fibrillation and normal EF who present for pulmonary vein antrum isolation procedure

Introduction: The incidence of left atrial appendage (LAA) thrombus in patients with paroxysmal atrial fibrillation (PAF) who present for pulmonary vein antrum isolation procedure (PVAI) is unknown.
Methods and Results: All consecutive patients from January 2000 to June 2004 who underwent a PVAI received a computed tomography (CT) to evaluate LAA thrombus before the procedure and 3 months post-PVAI. All patients were followed prospectively. One thousand two hundred twenty-one patients received a PVAI during the study dates. All patients received a CT pre-PVAI at 3 months, and 601 (49%) received a transesophageal echocardiography (TEE) pre-PVAI. Per protocol, all patients who had CT scans that were positive for LAA thrombus received a TEE. There were 9 patients who had LAA thrombus on CT scan, but only 3 had LAA thrombus on TEE. Using TEE as the gold standard, only 3 patients had an LAA thrombus before PVAI; of these patients, 2 had chronic AF with average ejection fraction (EF) of 48% and 1 patient had PAF with EF 25%. No patients with PAF and normal EF had LAA thrombus. Patients with LAA thrombus pre-PVAI had lower EF than patients without LAA thrombus (40% vs. 53%, P = 0.007) but had similar LA size (5.0 vs. 4.5 cm, P = 0.77). No other differences in baseline characteristics were noted.
Conclusions: In this registry of 1,221 patients, we did not observe LA thrombus in PAF patients with normal EF who present for PVAI. Prescreening CT alone is likely to be sufficient in paroxysmal AF patients with normal EF, and the use of TEE may not be needed.     

Low-dose versus high-dose aspirin after percutaneous coronary intervention: analysis from the guthrie health off-label StenT (GHOST) registry

Background: The optimal dose of aspirin therapy after percutaneous coronary intervention (PCI) remains unclear. We sought to compare the effectiveness and safety of low and high doses of aspirin in preventing adverse outcomes after PCI. Methods: We studied 2,820 consecutive patients who underwent coronary stenting for stable or unstable coronary artery disease (excluding cardiogenic shock) discharged alive without any complications between 2001 and 2007. Patients were categorized based on the discharge aspirin dose into low‐dose (81 mg/day, N = 313) or high‐dose (162–325 mg/day, N = 2,507) groups. The primary end‐points (adjusted using Cox Proportional Hazard and propensity scores) were major adverse cardiovascular events (MACE; a composite of death, myocardial infarction [MI], stent thrombosis [ST], or target vessel revascularization) and net adverse clinical events (NACE; a composite of MACE and thrombolysis in myocardial infarction [TIMI][major or minor] bleeding) at 1 year. Results: In the low‐dose versus high‐dose groups, MACE occurred in 8.6 versus 9.2% (log rank P = 0.71) and NACE in 11 versus 10% (log rank P = 0.58). In multivariable analysis, low‐dose aspirin was not associated with worse outcomes (adjusted HR [95% CI] 0.74 [0.49–1.14] for MACE; 1.03 [0.71–1.50] for NACE). Conclusion: Low‐dose aspirin, as prescribed in this study of routine practice, was not associated with worse outcomes compared to high‐dose aspirin. (J Interven Cardiol 2011;24:307–314)     

Molecular characterization of human factor XSan Antonio

Enzymatic amplification technique was used to isolate all eight exons and sequences around the splice junctions, putative promoter, and polyadenylation sites of human factor X DNA from a patient with factor X deficiency. Two genetic changes in factor X have been observed in this patient. The patient is most likely a compound heterozygote since there is only 14% activity associated with factor X. A point mutation that resulted in the substitution of cysteine (TGC) for arginine (CGC) at amino acid 366 was found in exon VIII of one allele of the factor X gene. This mutation, which occurs in the catalytic domain, can affect the formation of a disulfide bridge and thus could result in a reduction in factor X activity. Sequencing all the regions revealed a second mutation: a deletion of one nucleotide (TCCT to TCT) in exon VII that would cause a frame shift at amino acid 272 followed by termination. We have also shown that the point mutation in exon VIII creates an ApaL1 restriction site and destroys the HinP1 site. Enzymatic DNA amplification followed by restriction digestion provides a quick, reliable, and sensitive method for carrier detection and antenatal diagnosis in affected kindreds. This is the first characterization of factor X deficiency at the molecular level. We propose to name this mutation Factor XSan Antonio.     

Effect of adrenomedullin on the cerebral circulation: relevance to primary headache disorders

Adrenomedullin (ADM) is closely related to calcitonin gene-related peptide, which has a known causative role in migraine. Animal studies have strongly suggested that ADM has a vasodilatory effect within the cerebral circulation. For these reasons, ADM is also likely to be involved in migraine. However, the hypothetical migraine-inducing property and effect on human cerebral circulation of ADM have not previously been investigated. Human ADM (0.08 µg kg⁻¹ min⁻¹) or placebo (saline 0.9%) was administered as a 20-min intravenous infusion to 12 patients suffering from migraine without aura in a crossover double-blind study. The occurrence of headache and associated symptoms were registered regularly 24 h post infusion. Cerebral blood flow (CBF) was measured by ¹³³Xenon single-photon emission computed tomography, mean blood flow velocity in the middle cerebral artery (V_MCA) by transcranial Doppler and the diameter of peripheral arteries by transdermal ultrasound (C-scan). ADM did not induce significantly more headache or migraine compared with placebo ( P  = 0.58). CBF was unaffected by ADM infusion (global CBF, P  = 0.32 and rCBF_MCA, P  = 0.38) and the same applied for the V_MCA ( P  = 0.18). The superficial temporal artery dilated compared with placebo ( P  < 0.001), and facial flushing was seen after ADM administration ( P  = 0.001). In conclusion, intravenous ADM is not a mediator of migraine headache and does not dilate intracranial arteries.     

Reduction of serum matrix metalloproteinase 1 and matrix metalloproteinase 3 in rheumatoid arthritis patients following anti- tumour necrosis factor-alpha (cA2) therapy

Matrix metalloproteinase (MMP)-1 and MMP-3 levels were measured in serum samples from rheumatoid arthritis (RA) patients undergoing a double-blinded placebo-controlled trial with the chimaeric anti-tumour necrosis factor (TNF)-alpha antibody cA2. Both MMP-1 (P < 0.015), but to a larger extent MMP-3 (P < 0.001) levels were elevated in all RA patients prior to the commencement of the trial compared with normal control sera. Following cA2 therapy, MMP-1 and MMP-3 levels were assessed in the placebo, and 1 and 10 mg/kg cA2-treated groups at 7, 14, 21 and 28 days. In both the 1 and the 10 mg/kg cA2-treated groups, a significant decrease in serum MMP-3 levels at all time points was observed, reducing maximally to 41% of pre-infusion values at day 7. MMP-1 levels were also reduced, but less dramatically than MMP-3, to 85% of pre-infusion values after 14 days in the 10 mg/kg cA2 treated group. In a separate non-placebo-controlled study, we also evaluated the tissue inhibitor of metalloproteinase (TIMP)-1 levels in plasma following cA2 infusion. Pre-infusion TIMP-1 levels were above the normal control range, but were significantly reduced (P < 0.035) 14 days after infusion to 72% of pre-infusion values. This study confirms previous reports that MMP-3 levels are elevated and correlate with measures of inflammation in RA, and furthermore demonstrate that serum MMP-3 and MMP-1 levels are downmodulated following anti-TNF-alpha antibody therapy. Whilst serum MMP-3 levels correlated with C-reactive protein (CRP) both prior to and following anti-TNF-alpha antibody therapy, it remains to be demonstrated that serum MMP-3 and/or MMP-1 levels reflect the cartilage and bone resorptive processes which are evident in this disease.      

Systemic lupus erythematosus, thrombocytopenia, microangiopathic haemolytic anaemia and anti-CD36 antibodies [clinical conference]

Thrombocytopenia in patients with acute systemic lupus erythematosus (SLE) frequently presents the clinician with considerable diagnostic and therapeutic difficulties. In this Grand Round, we present a 48-yr- old woman with a 7 yr history of lupus, who presented with acute proliferative glomerulonephritis and nephrotic syndrome, pneumonia, profound hypocomplementaemia and a severe microangiopathic haemolytic anaemia with associated thrombocytopenia. Her thrombocytopenia proved initially refractory to conventional immunosuppressive therapy, and corticosteroids, and resolved only with plasma exchange and repeated fresh frozen plasma infusions. Serological testing revealed high-titre antinuclear antibodies (ANA) and markedly raised antibodies to double- stranded (ds) DNA, but no significant elevation in anticardiolipin antibodies. Platelet-associated IgG and IgM and antibodies to the CD36 glycoprotein antigen, expressed on platelets and endothelium, were detected in the serum. We address some of the difficult diagnostic and management issues raised by this complex patient and the possible immunopathological links between antibodies to CD36, immune-mediated red cell destruction, thrombocytopenia and thrombotic microangiopathic haemolytic anaemia.