BACKGROUND/OBJECTIVE: To integrate new evidence into the Canadian Asthma Management Continuum diagram, encompassing both pediatric and adult asthma. METHODS: The Canadian Thoracic Society Asthma Committee members, comprised of experts in pediatric and adult respirology, allergy and immunology, emergency medicine, general pediatrics, family medicine, pharmacoepidemiology and evidence-based medicine, updated the continuum diagram, based primarily on the 2008 Global Initiative for Asthma guidelines, and performed a focused review of literature pertaining to key aspects of asthma diagnosis and management in children six years of age and over, and adults. RESULTS: In patients six years of age and over, management of asthma begins with establishing an accurate diagnosis, typically by supplementing medical history with objective measures of lung function. All patients and caregivers should receive self-management education, including a written action plan. Inhaled corticosteroids (ICS) remain the first-line controller therapy for all ages. When asthma is not controlled with a low dose of ICS, the literature supports the addition of long-acting beta2-agonists in adults, while the preferred approach in children is to increase the dose of ICS. Leukotriene receptor antagonists are acceptable as second-line monotherapy and as an alternative add-on therapy in both age groups. Antiimmunoglobulin E therapy may be of benefit in adults, and in children 12 years of age and over with difficult to control allergic asthma, despite high-dose ICS and at least one other controller. CONCLUSIONS: The foundation of asthma management is establishing an accurate diagnosis based on objective measures (eg, spirometry) in individuals six years of age and over. Emphasis is placed on the similarities and differences between pediatric and adult asthma management approaches to achieve asthma control.

Smooth ocular tracking of a moving visual stimulus comprises a range of responses that encompass the ocular following response (OFR), a pre-attentive, short-latency mechanism, and smooth pursuit, which directs the retinal fovea at the moving stimulus. In order to determine how interdependent these two forms of ocular tracking are, we studied vertical OFR in progressive supranuclear palsy (PSP), a parkinsonian disorder in which vertical smooth pursuit is known to be impaired. We measured eye movements of 9 patients with PSP and 12 healthy control subjects. Subjects viewed vertically moving sine-wave gratings that had a temporal frequency of 16.7 Hz, contrast of 32%, and spatial frequencies of 0.17, 0.27 or 0.44 cycles/ degrees . We measured OFR amplitude as change in eye position in the 70 - 150 ms, open-loop interval following stimulus onset. Vertical smooth pursuit was studied as subjects attempted to track a 0.27 cycles/ degrees grating moving sinusoidally through several cycles at frequencies between 0.1 - 2.5 Hz. We found that OFR amplitude, and its dependence on spatial frequency, was similar in PSP patients (group mean 0.10(o)) and control subjects (0.11(o)), but the latency to onset of OFR was greater for PSP patients (group mean 99 ms) than control subjects (90 ms). When OFR amplitude was re-measured, taking into account the increased latency in PSP patients, there was still no difference from control subjects. We confirmed that smooth pursuit was consistently impaired in PSP; group mean tracking gain at 0.7 Hz was 0.29 for PSP patients and 0.63 for controls. Neither PSP patients nor control subjects showed any correlation between OFR amplitude and smooth-pursuit gain. We propose that OFR is spared because it is generated by low-level motion processing that is dependent on posterior cerebral cortex, which is less affected in PSP. Conversely, smooth pursuit depends more on projections from frontal cortex to the pontine nuclei, both of which are involved in PSP. The accessory optic pathway, which is heavily involved in PSP, seems unlikely to contribute to the OFR in humans.

PURPOSE: During locomotion, head perturbations, consisting of rotations and translations (linear movements), occur with predominant frequencies of 0.5-5.0 Hz. The vestibular reflexes act at short latency to safeguard clear vision and stable posture during locomotion. Much is known about the angular vestibulo-ocular reflex (aVOR) in response to head rotations, which depend on the semicircular canals of the vestibular labyrinth. However, the means to test reliably the linear or translational vestibulo-ocular reflex (tVOR), which depends on the otolithic organs, has only become available more recently. METHODS: We used a moving platform to translate normal human subjects vertically at frequencies similar to those occurring during locomotion, under ambient illumination. RESULTS: Our findings suggested that, whereas aVOR is concerned with stabilizing images of visual targets on the retina to optimize visual acuity, tVOR seems best suited to minimize retinal image motion between objects lying in different depth planes, in order to optimize motion parallax information. We then asked whether the tVOR functioned abnormally in patients with two neurological disorders that often cause falls: progressive supranuclear palsy (PSP) and cerebellar ataxia. We found that patients with PSP cannot adjust tVOR responses appropriately during viewing of near objects, nor converge their eyes. Vestibular-evoked myogenic potentials (VEMPs), an otolith-spinal reflex, are also impaired in PSP patients. Patients with cerebellar ataxia also lack the ability to adjust tVOR for near viewing, even though they may be able to converge. CONCLUSIONS: Taken together, our studies suggest that abnormal otolithic vestibular reflexes contribute to postural instability in PSP and cerebellar ataxia, and deserve further investigation.

The inferior olivary nuclei clearly play a role in creating oculopalatal tremor, but the exact mechanism is unknown. Oculopalatal tremor develops some time after a lesion in the brain that interrupts inhibition of the inferior olive by the deep cerebellar nuclei. Over time the inferior olive gradually becomes hypertrophic and its neurons enlarge developing abnormal soma-somatic gap junctions. However, results from several experimental studies have confounded the issue because they seem inconsistent with a role for the inferior olive in oculopalatal tremor, or because they ascribe the tremor to other brain areas. Here we look at 3D binocular eye movements in 15 oculopalatal tremor patients and compare their behaviour to the output of our recent mathematical model of oculopalatal tremor. This model has two mechanisms that interact to create oculopalatal tremor: an oscillator in the inferior olive and a modulator in the cerebellum. Here we show that this dual mechanism model can reproduce the basic features of oculopalatal tremor and plausibly refute the confounding experimental results. Oscillations in all patients and simulations were aperiodic, with a complicated frequency spectrum showing dominant components from 1 to 3 Hz. The model's synchronized inferior olive output was too small to induce noticeable ocular oscillations, requiring amplification by the cerebellar cortex. Simulations show that reducing the influence of the cerebellar cortex on the oculomotor pathway reduces the amplitude of ocular tremor, makes it more periodic and pulse-like, but leaves its frequency unchanged. Reducing the coupling among cells in the inferior olive decreases the oscillation's amplitude until they stop (at approximately 20% of full coupling strength), but does not change their frequency. The dual-mechanism model accounts for many of the properties of oculopalatal tremor. Simulations suggest that drug therapies designed to reduce electrotonic coupling within the inferior olive or reduce the disinhibition of the cerebellar cortex on the deep cerebellar nuclei could treat oculopalatal tremor. We conclude that oculopalatal tremor oscillations originate in the hypertrophic inferior olive and are amplified by learning in the cerebellum.

BACKGROUND AND PURPOSE: We aimed to determine if ischemia involving Broca area predicts Broca aphasia more reliably in acute or chronic stroke. METHODS: We included consecutive right-hand-dominant patients with left hemisphere ischemic stroke (<48 hours from onset for acute stroke or >6 months after stroke for chronic stroke). MRI scans were analyzed for ischemic lesions or hypoperfusion in Broca area (Brodmann areas 44 and 45). Patients were scored on the Western Aphasia Battery to classify aphasia syndromes; chi(2) tests were used to identify significant associations. RESULTS: The presence of infarct involving any part of Broca area and the presence of Broca or global aphasia was much stronger in acute (chi(2)=38.1; df1; P<0.0001) than in chronic stroke (chi(2)=0.54; df1; P=0.46; not significant). The association between infarct or hypoperfusion covering all of Broca area and the presence of Broca or global aphasia was much stronger in acute (chi(2)=35.8; df1; P<0.0001) than in chronic stroke (chi(2)=1.2; df1; p=0.27; not significant). In a subset of 20 patients studied longitudinally, the associations were significant only acutely, not chronically (chi(2)=20; df1; P<0.0001 vs. chi(2)=0; df1; p=1; not significant for ischemia involving part of Broca area, and chi(2)=16.4; df1; P<0.0001 vs chi(2)=3.2; df1; p=0.08; not significant for ischemia covering all of Broca area). CONCLUSIONS: Broca aphasia is more reliably associated with infarct/ hypoperfusion of Broca area in acute stroke. Many chronic stroke patients with damage to part or all of Broca area had neither Broca nor global aphasia. Broca or global aphasia was sometimes present initially in these patients but resolved by 6 months. Our results indicate that the acute aphasia syndrome may allow the clinician to predict the compromised vascular territory, even when structural imaging shows only a small (or no) infarct.

BACKGROUND: Combining inhaled corticosteroids with long-acting beta(2)-agonists results in improved asthma symptom control and fewer asthma exacerbations compared with those seen after inhaled corticosteroids alone. However, there are limited data as to whether these beneficial effects are due to enhanced anti-inflammatory actions or whether such combination therapies affect airway remodeling in patients with asthma. OBJECTIVE: We sought to determine the effects of inhaled budesonide/formoterol combination therapy versus inhaled budesonide alone or inhaled placebo on allergen-induced airway responses, airway inflammation, and airway remodeling. METHODS: Fourteen asthmatic subjects with dual responses after allergen inhalation were included in this prospective, randomized, double-blind, 3-period crossover study. Outcomes included early and late asthmatic responses, changes in airway responsiveness, sputum eosinophilia measured before and after allergen challenge, numbers of airway submucosal myofibroblasts, and smooth muscle area measured before and after study treatment. RESULTS: Allergen-induced sputum eosinophilia was significantly reduced by combination treatment to a greater extent than by budesonide alone. Allergen inhalation resulted in a significant increase in submucosal tissue myofibroblast numbers and produced a significant decrease in percentage smooth muscle area. Combination therapy, but not budesonide monotherapy, significantly attenuated these changes in myofibroblast numbers and smooth muscle area. CONCLUSIONS: The effects on allergen-induced changes in sputum eosinophils, airway myofibroblast numbers, and smooth muscle seen with combination therapy suggest that the benefits associated with this treatment might relate to effects on airway inflammation and remodeling. The attenuation of early asthmatic responses and airway hyperresponsiveness by combination treatment was likely due to the known functional antagonistic effect of formoterol.

BACKGROUND: Contrast acuity (identification of low-contrast letters on a white background) is frequently reduced in patients with demyelinating optic neuropathy associated with multiple sclerosis (MS), even when high-contrast (Snellen) visual acuity is normal. Since visual evoked potentials (VEPs) induced with high-contrast pattern-reversal stimuli are typically increased in latency in demyelinating optic neuropathy, we asked if VEPs induced with low-contrast stimuli would be more prolonged and thus helpful in identifying demyelinating optic neuropathy in MS. METHODS: We studied 15 patients with clinically definite MS and 15 age-matched normal controls. All subjects underwent a neuro-ophthalmologic assessment, including measurement of high-contrast visual acuity and low-contrast acuities with 25%, 10%, 5%, 2.5%, and 1.25% contrast Sloan charts. In patients with MS, peripapillary retinal nerve fiber layer (RNFL) thickness was determined using optical coherence tomography. Monocular VEPs were induced using pattern-reversal checkerboard stimuli with 100% and 10% contrast between checks, at 5 spatial frequencies (8-130 minutes of arc). RESULTS: VEP latencies were significantly increased in response to low- compared with high-contrast stimuli in both groups. VEP latencies were significantly greater in patients with MS than controls for both high- and low-contrast stimuli. VEP latencies correlated with high- and low-contrast visual acuities and RNFL thickness. VEPs were less likely to be induced with low- than with high-contrast stimuli in eyes with severe residual visual loss. CONCLUSIONS: Visual evoked potentials obtained in patients with multiple sclerosis using low-contrast stimuli are increased in latency or absent when compared with those obtained using high-contrast stimuli and, thus, may prove to be helpful in identifying demyelinating optic neuropathy.

Glucocorticoids are widely used to treat various inflammatory lung diseases. Acting via the glucocorticoid receptor (GR), they exert clinical effects predominantly by modulating gene transcription. This may be to either induce (transactivate) or repress (transrepress) gene transcription. However, certain individuals, including those who smoke, have certain asthma phenotypes, chronic obstructive pulmonary disease (COPD) or some interstitial diseases may respond poorly to the beneficial effects of glucocorticoids. In these cases, high dose, often oral or parental, glucocorticoids are typically prescribed. This generally leads to adverse effects that compromise clinical utility. There is, therefore, a need to enhance the clinical efficacy of glucocorticoids while minimizing adverse effects. In this context, a long-acting beta(2)-adrenoceptor agonists (LABA) can enhance the clinical efficacy of an inhaled corticosteroid (ICS) in asthma and COPD. Furthermore, LABAs can augment glucocorticoid-dependent gene expression and this action may account for some of the benefits of LABA/ICS combination therapies when compared to ICS given as a montherapy. In addition to metabolic genes and other adverse effects that are induced by glucocorticoids, there are many other glucocorticoid-inducible genes that have significant anti-inflammatory potential. We therefore advocate a move away from the search for ligands of GR that dissociate transactivation from transrepression. Instead, we submit that ligands should be functionally screened by virtue of their ability to induce or repress biologically-relevant genes in target tissues. In this review, we discuss pharmacological methods by which selective GR modulators and "add-on" therapies may be exploited to improve the clinical efficacy of glucocorticoids while reducing potential adverse effects.

Epstein-Barr virus (EBV) is best known as the organism responsible for the syndrome of acute infectious mononucleosis. Transmission of EBV most commonly occurs through oral secretions. EBV has also been isolated from the female genital tract, where its role is poorly understood. This article reviews the available literature and data regarding EBV in the female genital tract and discusses areas of consensus and controversy. The primary manifestation of EBV seems to be vulvar ulcers, which are underrecognized. Diagnosis relies on appropriate serologic testing. Management includes local care and may require pain and corticosteroid medications. Although EBV is present elsewhere in the female genital tract, its pathogenic role in the cervix, uterus, fallopian tubes, and ovaries is poorly understood.