A novel TASK channel antagonist nasal spray reduces sleep apnea severity in physiological responders: a randomized, blinded, trial.

Preclinical and human physiological studies indicate that topical, selective TASK 1/3 K+ channel antagonism increases upper airway dilator muscle activity and reduces pharyngeal collapsibility during anesthesia and nasal breathing during sleep. The primary aim of this study was to determine the effects of BAY2586116 nasal spray on obstructive sleep apnea (OSA) severity and whether individual responses vary according to differences in physiological responses and route of breathing. Ten people (5 females) with OSA [apnea-hypopnea index (AHI) = 47 ± 26 events/h (means ± SD)] who completed previous sleep physiology studies with BAY2586116 were invited to return for three polysomnography studies to quantify OSA severity. In random order, participants received either placebo nasal spray (saline), BAY2586116 nasal spray (160 µg), or BAY2586116 nasal spray (160 µg) restricted to nasal breathing (chinstrap or mouth tape). Physiological responders were defined a priori as those who had improved upper airway collapsibility (critical closing pressure ≥2 cmH2O) with BAY2586116 nasal spray (NCT04236440). There was no systematic change in apnea-hypopnea index (AHI3) from placebo versus BAY2586116 with either unrestricted or nasal-only breathing versus placebo (47 ± 26 vs. 43 ± 27 vs. 53 ± 33 events/h, P = 0.15). However, BAY2586116 (unrestricted breathing) reduced OSA severity in physiological responders compared with placebo (e.g., AHI3 = 28 ± 11 vs. 36 ± 12 events/h, P = 0.03 and ODI3 = 18 ± 10 vs. 28 ± 12 events/h, P = 0.02). Morning blood pressure was also lower in physiological responders after BAY2586116 versus placebo (e.g., systolic blood pressure = 137 ± 24 vs. 147 ± 21 mmHg, P < 0.01). In conclusion, BAY2586116 reduces OSA severity during sleep in people who demonstrate physiological improvement in upper airway collapsibility. These findings highlight the therapeutic potential of this novel pharmacotherapy target in selected individuals.NEW & NOTEWORTHY Preclinical findings in pigs and humans indicate that blocking potassium channels in the upper airway with topical nasal application increases pharyngeal dilator muscle activity and reduces upper airway collapsibility. In this study, BAY2586116 nasal spray (potassium channel blocker) reduced sleep apnea severity in those who had physiological improvement in upper airway collapsibility. BAY2586116 lowered the next morning's blood pressure. These findings highlight the potential for this novel therapeutic approach to improve sleep apnea in certain people.

Co-morbid insomnia and sleep apnea (COMISA): recent research and future directions.

PURPOSE OF REVIEW: Insomnia and obstructive sleep apnea have previously been viewed as completely independent conditions. However, there is now increasing recognition that insomnia and sleep apnea frequently co-occur. Co-morbid insomnia and sleep apnea (COMISA) is a highly prevalent condition that is associated with impairment of sleep, daytime function, mental health and physical health outcomes, and mortality risk. This review aims to provide an update on COMISA prevalence, consequences, treatment approaches, and future research directions. RECENT FINDINGS: People with COMISA experience worse sleep, mental health, physical health, quality of life and longevity compared to people with neither condition, and often compared to those with insomnia alone and sleep apnea alone. Emerging evidence suggests that cognitive behavioral therapy for insomnia is an effective treatment in the presence of treated and untreated sleep apnea, that may also improve manifestations and subsequent management of sleep apnea. Future research is required to understand the etiology of COMISA, and to develop and implement tailored treatment approaches. SUMMARY: It is important for sleep and respiratory technicians, researchers and clinicians to be aware of the high co-morbidity rates, consequences, and treatment requirements of patients with co-morbid insomnia and sleep apnea.

Stepwise Add-On and Endotype-informed Targeted Combination Therapy to Treat Obstructive Sleep Apnea: A Proof-of-Concept Study.

Rationale: Oral appliance therapy (OAT) is an effective treatment for many people with obstructive sleep apnea (OSA). However, OSA pathogenesis is heterogeneous, and, in ∼50% of cases, OAT does not fully control OSA. Objectives: This study aimed to control OSA in individuals with an incomplete response to OAT alone by using additional targeted therapies informed by OSA endotype characterization. Methods: Twenty-three people with OSA (apnea-hypopnea index [AHI], 41 ± 19 events/h) not fully resolved (AHI, >10 events/h) with OAT alone were prospectively recruited. OSA endotypes were characterized pretherapy during a detailed physiology study night. Initially, an expiratory positive airway pressure (EPAP) valve and supine avoidance device therapy were added to target the impaired anatomical endotype. Those with residual OSA (AHI, >10 events/h) then received one or more nonanatomical interventions based on endotype characterization. This included O2 (4 L/min) to reduce high loop gain (unstable respiratory control) and 80/5 mg atomoxetine-oxybutynin to increase pharyngeal muscle activity. Finally, if required, OAT was combined with EPAP and continuous positive airway pressure (CPAP) therapy. Results: Twenty participants completed the study. OSA was successfully controlled (AHI, <10 events/h) with combination therapy in all but one participant (17 of 20 without CPAP). OAT plus EPAP and supine avoidance therapy treated OSA in 10 (50%) participants. OSA was controlled in five (25%) participants with the addition of O2 therapy, one with atomoxetine-oxybutynin, and one required O2 plus atomoxetine-oxybutynin. Two participants required CPAP for their OSA, and another was CPAP intolerant. Conclusions: These novel prospective findings highlight the potential of precision medicine to inform targeted combination therapy to treat OSA. Clinical trial registered with the Australian New Zealand Clinical Trials Registry (ACTRN12618001995268).

Topical Potassium Channel Blockage Improves Pharyngeal Collapsibility: A Translational, Placebo-Controlled Trial.

BACKGROUND: Potassium (K+) channel inhibition has been identified in animal models as a potential target to increase pharyngeal dilator muscle activity and to treat OSA. However, these findings have not yet been translated to humans. RESEARCH QUESTION: Does a novel, potent, tandem of P domains in a weak inward rectifying K+ channel (TWIK)-related acid-sensitive K+ (TASK) 1/3 channel antagonist, BAY2586116, improve pharyngeal collapsibility in pigs and humans, and secondarily, what is the optimal dose and method of topical application? STUDY DESIGN AND METHODS: In the preclinical study, pharyngeal muscle activity and upper-airway collapsibility via transient negative pressure application was quantified in 13 anesthetized pigs during administration of placebo, 0.3 µg, 3 µg, and 30 µg nasal drops of BAY2586116. In the clinical study, 12 people with OSA instrumented with polysomnography equipment, an epiglottic pressure catheter, pneumotachograph, and nasal mask to monitor sleep and breathing performed up to four detailed upper airway sleep physiology studies. Participants received BAY2586116 (160 µg) or placebo nasal spray before sleep via a double-masked, randomized, crossover design. Most participants also returned for three additional overnight visits: (1) nasal drops (160 µg), (2) half-dose nasal spray (80 µg), and (3) direct endoscopic application (160 µg). The upper-airway critical closing pressure (Pcrit) during sleep was quantified at each visit. RESULTS: Consistent and sustained improvements in pharyngeal collapsibility to negative pressure were found with 3 and 30 µg of BAY2586116 vs placebo in pigs. Similarly, BAY2586116 improved pharyngeal collapsibility by an average of approximately 2 cm H2O vs placebo, regardless of topical application method and dose (P < .008, mixed model) in participants with OSA. INTERPRETATION: Acute topical application of BAY2586116 improves upper-airway collapsibility in anesthetized pigs and sleeping humans with OSA. These novel physiologic findings highlight the therapeutic potential to target potassium channel mechanisms to treat OSA. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT04236440; URL: www. CLINICALTRIALS: gov.

The Combination of Betahistine and Oxybutynin Increases Respiratory Control Sensitivity (Loop Gain) in People with Obstructive Sleep Apnea: A Randomized, Placebo-Controlled Trial.

Rationale: There are widespread histaminergic projections throughout the brain, including hypoglossal nuclei, that modulate pharyngeal muscle tone and respiratory control. Hence, histaminergic stimulation pharmacologically may increase pharyngeal muscle tone and stabilize respiratory control (loop gain) to reduce obstructive sleep apnea (OSA) severity. Antimuscarinics also increase REM pharyngeal muscle tone in rats. Thus, a combination of histaminergic and anti-muscarinic drugs may be a novel target for OSA pharmacotherapy. However, this has not been investigated. Accordingly, we aimed to test the effects of betahistine (Beta), an H3-autoreceptor antagonist which thereby increases histamine levels, in combination with the antimuscarinic oxybutynin (Oxy), on OSA severity, OSA endotypes, polysomnography parameters and next-day sleepiness and alertness. Methods: Thirteen adults with OSA received either Beta-Oxy (96-5mg) or placebo according to a randomized, crossover, double-blind design, prior to polysomnography. Participants completed the Karolinska Sleep Scale and Leeds Sleep Evaluation Questionnaire and a driving simulation task to quantify next-day sleepiness and alertness. OSA endotypes were estimated through validated algorithms using polysomnography. Results: Compared to placebo, Beta-Oxy increased respiratory control sensitivity (loop gain) (0.52[0.24] vs 0.60[0.34], median [IQR], P = 0.021) without systematically changing OSA severity (34.4±17.2 vs 40.3±27.3 events/h, mean±SD, P = 0.124), sleep efficiency, arousal index or markers of hypoxemia. Beta-Oxy was well tolerated and did not worsen next-day sleepiness/alertness. Conclusion: Rather than stabilize breathing during sleep, Beta-Oxy increases loop gain, which is likely to be deleterious for most people with OSA. However, in certain conditions characterized by blunted respiratory control (eg, obesity hypoventilation syndrome), interventions to increase loop gain may be beneficial.

Regional genioglossus reflex responses to negative pressure pulses in people with obstructive sleep apnea.

Tongue and upper airway dilator muscle movement patterns during quiet breathing vary in people with obstructive sleep apnea (OSA). Many patients have inadequate or counterproductive responses to inspiratory negative airway pressure that likely contributes to their OSA. This may be due, at least in part, to inadequate or nonhomogeneous reflex drive to different regions of the largest upper airway dilator, genioglossus. To investigate potential regional heterogeneity of genioglossus reflex responses in OSA, brief suction pulses were applied via a nasal breathing mask and an electromyogram (EMG) was recorded in four regions (anterior oblique, anterior horizontal, posterior oblique, and posterior horizontal) using intramuscular fine wire electrodes in 15 people with OSA. Genioglossus short-latency reflex excitation amplitude had regional heterogeneity (horizontal vs. oblique regions) when expressed in absolute units but homogeneity when normalized as a percentage of the immediate (100 ms) prestimulus EMG. Regional variability in reflex morphology (excitation and inhibition) was present in one-third of the participants. The minimum cross-sectional area (CSA) of the pharyngeal airway was quantified using MRI and may be related to the amplitude of the short-latency reflex response to negative pressure as we found that people with a smaller CSA tended to have a greater reflex amplitude (e.g., horizontal region r2 = 0.41, P = 0.01). These findings highlight the complexity of genioglossus reflex control, the potential for regional heterogeneity, and the functional importance of upper airway anatomy in mediating genioglossus reflex responses to rapid changes in negative pressure in OSA.NEW & NOTEWORTHY Our findings indicate that 30% of participants had regional heterogeneity in reflex morphology (excitation/inhibition) to brief pulses of negative upper-airway pressure across anterior oblique, anterior horizontal, posterior oblique, and posterior horizontal regions of the genioglossus muscle. Reflex excitation amplitude was proportional to prestimulus drive, with increased activation in oblique compared with horizontal regions of the posterior tongue. People with narrower upper-airway anatomy tended to have increased genioglossus reflex amplitude to negative pressure pulses during wakefulness.

Impaired pharyngeal reflex responses to negative pressure: a novel cause of sleep apnea in multiple sclerosis.

Obstructive sleep apnea (OSA) is common in people with multiple sclerosis (MS). However, people with MS often do not have "typical" anatomical risk factors (i.e., nonobese and female predominance). Accordingly, nonanatomical factors such as impaired upper-airway muscle function may be particularly important for OSA pathogenesis in MS. Therefore, this study aimed to investigate genioglossus (largest upper-airway dilator muscle) reflex responses to brief pulses of upper-airway negative pressure in people with OSA and MS. Eleven people with MS and OSA and 10 OSA controls without MS matched for age, sex, and OSA severity were fitted with a nasal mask, pneumotachograph, choanal and epiglottic pressure sensors, and intramuscular electrodes into genioglossus. Approximately 60 brief (250 ms) negative pressure pulses (approximately -12 cmH2O mask pressure) were delivered every 2-6 breaths at random during quiet nasal breathing during wakefulness to determine genioglossus electromyogram (EMGgg) reflex responses (timing, amplitude, and morphology). Where available, recent clinical MRI brain scans were evaluated for the number, size, and location of brainstem lesions in the group with MS. When present, genioglossus reflex excitation responses were similar between MS participants and controls (e.g., peak excitation amplitude = 229 ± 85% vs. 282 ± 98% baseline, P = 0.17). However, ∼30% of people with MS had either an abnormal (predominantly inhibition) or no protective excitation reflex. Participants with MS without a reflex had multiple brainstem lesions including in the hypoglossal motor nucleus which may impair sensory processing and/or efferent output. Impaired pharyngeal reflex function may be an important contributor to OSA pathogenesis for a proportion of people with MS.NEW & NOTEWORTHY This study investigated the function of an important reflex that helps protect the upper airway from closing during negative (suction) pressure in people with and without multiple sclerosis (MS) and obstructive sleep apnea (OSA). We found that ∼30% of people with MS had either no protective reflex or an abnormal reflex response. These findings indicate that impaired upper-airway reflex function may be an important contributor to OSA for a substantial proportion of people with MS.

Bi-directional relationships between co-morbid insomnia and sleep apnea (COMISA).

Insomnia and obstructive sleep apnea (OSA) commonly co-occur. Approximately 30-50% of patients with OSA report clinically significant insomnia symptoms, and 30-40% of patients with chronic insomnia fulfil diagnostic criteria for OSA. Compared to either insomnia or OSA alone, co-morbid insomnia and sleep apnea (COMISA) is associated with greater morbidity for patients, complex diagnostic decisions for clinicians, and reduced response to otherwise effective treatment approaches. Potential bi-directional causal relationships between the mechanisms and manifestations of insomnia and OSA could play an integral role in the development and management of COMISA. A greater understanding of these relationships is required to guide personalized diagnostic and treatment approaches for COMISA. This review summarizes the available evidence of bi-directional relationships between COMISA, including epidemiological research, case studies, single-arm treatment studies, randomized controlled treatment trials, and objective sleep study data. This evidence is integrated into a conceptual model of COMISA to help refine the understanding of potential bi-directional causal relationships between the two disorders. This theoretical framework is essential to help guide future research, improve diagnostic tools, determine novel therapeutic targets, and guide tailored sequenced and multi-faceted treatment approaches for this common, complex, and debilitating condition.

An assessment of a simple clinical technique to estimate pharyngeal collapsibility in people with obstructive sleep apnea.

STUDY OBJECTIVES: Quantification of upper airway collapsibility in obstructive sleep apnea (OSA) could help inform targeted therapy decisions. However, current techniques are clinically impractical. The primary aim of this study was to assess if a simple, novel technique could be implemented as part of a continuous positive airway pressure (CPAP) titration study to assess pharyngeal collapsibility. METHODS: A total of 35 participants (15 female) with OSA (mean ± SD apnea-hypopnea index = 35 ± 19 events/h) were studied. Participants first completed a simple clinical intervention during a routine CPAP titration, where CPAP was transiently turned off from the therapeutic pressure for ≤5 breaths/efforts on ≥5 occasions during stable non-rapid eye movement (non-REM) sleep for quantitative assessment of airflow responses (%peak inspiratory flow [PIF] from preceding 5 breaths). Participants then underwent an overnight physiology study to determine the pharyngeal critical closing pressure (Pcrit) and repeat transient drops to zero CPAP to assess airflow response reproducibility. RESULTS: Mean PIF of breaths 3-5 during zero CPAP on the simple clinical intervention versus the physiology night were similar (34 ± 29% vs. 28 ± 30% on therapeutic CPAP, p = 0.2; range 0%-90% vs. 0%-95%). Pcrit was -1.0 ± 2.5 cmH2O (range -6 to 5 cmH2O). Mean PIF during zero CPAP on the simple clinical intervention and the physiology night correlated with Pcrit (r = -0.7 and -0.9, respectively, p < 0.0001). Receiver operating characteristic curve analysis indicated significant diagnostic utility for the simple intervention to predict Pcrit < -2 and < 0 cmH2O (AUC = 0.81 and 0.92), respectively. CONCLUSIONS: A simple CPAP intervention can successfully discriminate between patients with and without mild to moderately collapsible pharyngeal airways. This scalable approach may help select individuals most likely to respond to non-CPAP therapies.

Changes in pharyngeal collapsibility and genioglossus reflex responses to negative pressure during the respiratory cycle in obstructive sleep apnoea.

KEY POINTS: Impaired pharyngeal anatomy and increased airway collapsibility is a major cause of obstructive sleep apnoea (OSA) and a mediator of its severity. Upper airway reflexes to changes in airway pressure provide important protection against airway closure. This study shows increased pharyngeal collapsibility and attenuated genioglossus reflex responses during expiration in people with OSA. ABSTRACT: Upper airway collapse contributes to obstructive sleep apnoea (OSA) pathogenesis. Pharyngeal dilator muscle activity varies throughout the respiratory cycle and may contribute to dynamic changes in pharyngeal collapsibility. However, whether upper airway collapsibility and reflex responses to changes in airway pressure vary throughout the respiratory cycle in OSA is unclear. Thus, this study quantified differences in upper airway collapsibility and genioglossus electromyographic (EMG) activity and reflex responses during different phases of the respiratory cycle. Twelve middle-aged people with OSA (2 female) were fitted with standard polysomnography equipment: a nasal mask, pneumotachograph, two fine-wire intramuscular electrodes into the genioglossus, and a pressure catheter positioned at the epiglottis and a second at the choanae (the collapsible portion of the upper airway). At least 20 brief (∼250 ms) pressure pulses (∼-11 cmH2 O at the mask) were delivered every 2-10 breaths during four conditions: (1) early inspiration, (2) mid-inspiration, (3) early expiration, and (4) mid-expiration. Mean baseline genioglossus EMG activity 100 ms prior to pulse delivery and genioglossus reflex responses were quantified for each condition. The upper airway collapsibility index (UACI), quantified as 100 × (nadir choanal - epiglottic pressure)/nadir choanal pressure during negative pressure pulses, varied throughout the respiratory cycle (early inspiration = 43 ± 25%, mid-inspiration = 29 ± 19%, early expiration = 83 ± 19% and mid-expiration = 95 ± 11% (mean ± SD) P < 0.01). Genioglossus EMG activity was lower during expiration (e.g. mid-expiration vs. mid-inspiration = 76 ± 23 vs. 127 ± 41% of early-inspiration, P < 0.001). Similarly, genioglossus reflex excitation was delayed (39 ± 11 vs. 23 ± 7 ms, P < 0.001) and reflex excitation amplitude attenuated during mid-expiration versus early inspiration (209 ± 36 vs. 286 ± 80%, P = 0.009). These findings may provide insight into the physiological mechanisms of pharyngeal collapse in OSA.

Upper airway collapsibility measured using a simple wakefulness test closely relates to the pharyngeal critical closing pressure during sleep in obstructive sleep apnea.

STUDY OBJECTIVES: A collapsible or crowded pharyngeal airway is the main cause of obstructive sleep apnea (OSA). However, quantification of airway collapsibility during sleep (Pcrit) is not clinically feasible. The primary aim of this study was to compare upper airway collapsibility using a simple wakefulness test with Pcrit during sleep. METHODS: Participants with OSA were instrumented with a nasal mask, pneumotachograph and two pressure sensors, one at the choanae (PCHO), the other just above the epiglottis (PEPI). Approximately 60 brief (250 ms) pulses of negative airway pressure (~ -12 cmH2O at the mask) were delivered in early inspiration during wakefulness to measure the upper airway collapsibility index (UACI). Transient reductions in the continuous positive airway pressure (CPAP) holding pressure were then performed during sleep to determine Pcrit. In a subset of participants, the optimal number of replicate trials required to calculate the UACI was assessed. RESULTS: The UACI (39 ± 24 mean ± SD; range = 0%-87%) and Pcrit (-0.11 ± 2.5; range: -4 to +5 cmH2O) were quantified in 34 middle-aged people (9 female) with varying OSA severity (apnea-hypopnea index range = 5-92 events/h). The UACI at a mask pressure of approximately -12 cmH2O positively correlated with Pcrit (r = 0.8; p < 0.001) and could be quantified reliably with as few as 10 replicate trials. The UACI performed well at discriminating individuals with subatmospheric Pcrit values [receiver operating characteristic curve analysis area under the curve = 0.9 (0.8-1), p < 0.001]. CONCLUSIONS: These findings indicate that a simple wakefulness test may be useful to estimate the extent of upper airway anatomical impairment during sleep in people with OSA to direct targeted non-CPAP therapies for OSA.

Obstructive sleep apnea: current perspectives.

The prevalence of obstructive sleep apnea (OSA) continues to rise. So too do the health, safety, and economic consequences. On an individual level, the causes and consequences of OSA can vary substantially between patients. In recent years, four key contributors to OSA pathogenesis or "phenotypes" have been characterized. These include a narrow, crowded, or collapsible upper airway "anatomical compromise" and "non-anatomical" contributors such as ineffective pharyngeal dilator muscle function during sleep, a low threshold for arousal to airway narrowing during sleep, and unstable control of breathing (high loop gain). Each of these phenotypes is a target for therapy. This review summarizes the latest knowledge on the different contributors to OSA with a focus on measurement techniques including emerging clinical tools designed to facilitate translation of new cause-driven targeted approaches to treat OSA. The potential for some of the specific pathophysiological causes of OSA to drive some of the key symptoms and consequences of OSA is also highlighted.

Effect of tranilast in comparison with beclomethasone in chronic murine model of asthma.

AIM OF THE STUDY: The current investigation was taken to scrutinize the action of tranilast on the airway remodeling in chronic asthma in mice. MATERIALS AND METHODS: Intraperitoneal injection of ovalbumin was applied to mice for sensitization and subsequent inhalation of 1% ovalbumin three times week for 10 weeks for challenge. Beclomethasone or tranilast were given daily for the 10 week challenge period. At the end of the study, lung weight index, total collagen content, bronchoalveolar lavage level of total and differential cell counts, interleukin-13, in addition to lung tissue nitrate/nitrite and transforming growth beta-1 were measured. Also, histological analysis was done. RESULTS: Asthmatic mice demonstrated apparent fibrotic changes. Significant airway fibrosis was demonstrated by hyperplasia of goblet cells and thickening of airway epithelium, increased content of lung collagen, lung and bronchoalveolar lavage of transforming growth factor beta-1 and interleukin-13 mutually accompanied by reduction in nitrate/nitrite generation. CONCLUSIONS: Beclomethasone influence on airway remodeling was mediated mainly via suppression of eosinophilic recruitment into the airways and reduction of interleukin-13 cytokine levels. Whereas, tranilast effects on airway remodeling was found to be mainly mediated via its inhibitory effect on transforming growth beta-1. Both beclomethasone and tranilast influence airway remodeling by different degrees and mechanisms.

Airway Inflammatory Biomarker: Could It Tailor the Right Medications for the Right Asthmatic Patient?

Asthma is a heterogeneous disease, in which asthmatic patients present with different clinical phenotypes, variable endotypes, and different response to asthma medicines. Thus, we are faced with an asthma paradox; asthma is diagnosed subjectively by clinical history and treated with biologically active drugs. To solve this paradox, we need objective airway biomarkers to tailor the proper medications to the proper patient. Biomarkers should have one or more of the following characteristics:1) A biomarker that could differentiate poor symptoms perceivers from over perceivers, 2) A biomarker that could predict disease activity and hence disease outcome, 3) A biomarker that could clarify responders from non-responders asthma phenotypes, and finally 4) A biomarker that could characterize different clinical asthma phenotypes. In conclusion, we have conducted a review of literature trying to apply those four parameters to different airway inflammatory biomarkers. We found that FeNO fulfilled the four proposed clinical parameters of airway inflammatory biomarkers whereas; serum periostin was the single best systemic biomarker of airway luminal and tissue eosinophilia in severe uncontrolled TH2 asthma phenotype. Thus, this may be considered a trial towards tailoring the proper medication to the proper patient. However, application of biomarkers in clinical practice requires easier and cheaper techniques together with standardized methods for sample collection and analysis.

Montelukast as an add-on treatment in steroid dependant nephrotic syndrome, randomised-controlled trial.

BACKGROUND: The underlying mechanisms of nephrotic syndrome (NS) are still under debate and the need for more effective and less toxic treatment is challenging. We aimed to evaluate the efficacy of montelukast, a leukotriene receptor antagonist as an add-on therapy, and to explore the leukotriene (LT) biology in steroid-dependent nephrotic syndrome (SDNS). METHODS: A randomized controlled trial was conducted including 32 patients with SDNS who were randomly assigned to receive standard steroid treatment only [low-dose steroid (LDS) group] or standard steroid therapy plus montelukast (Montelukast group). Urine protein/creatinine ratio, serum albumin, creatinine, cholesterol, and plasma LTs (LTB4/C4/D4/E4) were evaluated in all patients before and after treatment. RESULTS: After treatment, both groups showed a significant decrease of LTB4 and LTC4/D4/E4. Further, the Montelukast group showed a significant decrease in serum creatinine and a significant increase in diastolic blood pressure and protein/creatinine ratio. It also showed a marked decrease in plasma LTC4/D4/E4 compared to the LDS group, although not statistically significant. CONCLUSIONS: Our findings highlight the effect of montelukast on renal function, but suggest that the clinical and laboratory efficacy of the addition of montelukast to steroids in maintenance treatment of SDNS is debatable.

Unilateral Emphysema in Infancy, a Rare Presentation of Aberrant Bronchial Artery: Case Report and Review of Literature.

Aberrant bronchial arteries are rarely seen and may originate from various vascular structures. Hemoptysis is the most common clinical presentation of cases with anomalous bronchial artery. We report a case of a 1-month-old infant presented with respiratory distress and left lung emphysema. Radiologic investigations and bronchoscopy revealed that the cause is an aberrant left bronchial artery compressing the left main bronchus. Surgical division of the aberrant vessel was performed with gradual improvement of the emphysema and respiratory distress. Unilateral emphysema due to vascular compression was previously reported. However, to the best of our knowledge, this is the first reported case of aberrant bronchial artery presenting with external compression of a main bronchus and unilateral emphysema. Also, this is the youngest reported case with an aberrant bronchial artery.

Clinical asthma phenotyping: A trial for bridging gaps in asthma management.

Asthma is a common disease affecting millions of people worldwide and exerting an enormous strain on health resources in many countries. Evidence is increasing that asthma is unlikely to be a single disease but rather a series of complex, overlapping individual diseases or phenotypes, each defined by its unique interaction between genetic and environmental factors. Asthma phenotypes were initially focused on combinations of clinical characteristics, but they are now evolving to link pathophysiological mechanism to subtypes of asthma. Better characterization of those phenotypes is expected to be most useful for allocating asthma therapies. This article reviews different published researches in terms of unbiased approaches to phenotype asthma and emphasizes how the phenotyping exercise is an important step towards proper asthma treatment. It is structured into three sections; the heterogeneity of asthma, the impact of asthma heterogeneity on asthma management and different trials for phenotyping asthma.

Endobronchial inflammatory pseudotumor: a rare cause of a pneumothorax in children.

Inflammatory pseudotumors of the lung are a group of non-neoplastic tumors, which are mainly of parenchymal origin and rarely endobronchial. We report a case of a 9-year-old girl who presented with left-sided tension pneumothorax and subcutaneous emphysema. After emergency management, chest computed tomography revealed an ill-defined left lung mass. Rigid bronchoscopy revealed a mass occluding the left main bronchus at the origin of the left upper lobe bronchus. Initially, the mass was thought to be a foreign body granuloma. Few weeks later, the child presented with recurrence of the same clinical, radiologic, and bronchoscopic outcomes. Histologic examination after the repeat bronchoscopic excision revealed the lesion to be consistent with inflammatory pseudotumor. Left upper lobectomy was performed with a complete resolution of symptoms and no recurrence was observed during the 2 years of follow-up. To the best of our knowledge, this is the first reported case of inflammatory pseudotumor presenting with tension pneumothorax.