Montelukast and Neuropsychiatric Events in Children with Asthma: A Nested Case-Control Study.

OBJECTIVE: To examine the association between montelukast prescription and neuropsychiatric events in children with asthma. STUDY DESIGN: A matched, nested case-control design was used to identify cases and controls from a cohort of children aged 5-18 years with physician-diagnosed asthma from 2004 to 2015, in Ontario, Canada, prescribed an asthma maintenance medication. Cases were children with a hospitalization or emergency department visit for a neuropsychiatric event. Cases were matched to up to 4 controls on birth year, year of asthma diagnosis, and sex. The exposures were dispensed prescriptions for montelukast (yes/no) and number of dispensed montelukast prescriptions in the year before the index date. Conditional logistic regression was used to measure the unadjusted OR and aOR and 95% CIs for montelukast prescription and neuropsychiatric events. Covariates in the adjusted model included sociodemographic factors and measures of asthma severity. RESULTS: In total, 898 cases with a neuropsychiatric event and 3497 matched controls were included. Children who experienced a new-onset neuropsychiatric event had nearly 2 times the odds of having been prescribed montelukast, compared with controls (OR 1.91, 95% CI 1.15-3.18; P = .01). Most cases presented for anxiety (48.6%) and/or sleep disturbance (26.1%). CONCLUSIONS: Children with asthma who experienced a new-onset neuropsychiatric event had nearly twice the odds of having been prescribed montelukast in the year before their event. Clinicians should be aware of the association between montelukast and neuropsychiatric events in children with asthma, to inform prescribing practices and clinical follow-up.

Treatment of renal pruritus with dupilumab monotherapy: A case report.

Chronic kidney disease-associated pruritus leads to decreased quality of life and is an independent risk factor for mortality. There is limited evidence for treatment of chronic kidney disease-associated pruritus, with only one on-label treatment approved by the FDA and Health Canada. We present a case of a 69-year-old female with a history of chronic kidney disease, who presented to clinic with a several-year history of diffuse, intense pruritus. There were no primary lesions. She was started on dupilumab 600 mg loading dose, then 300 mg subcutaneously every 2 weeks. At her follow-up appointment 5 months after initiation of dupilumab, she reported her pruritus as 1/10, with no interruptions in her sleep. Her creatinine remained elevated and was stable throughout the follow-up period. This case demonstrates sustained improvement in chronic kidney disease-associated pruritus with dupilumab. Further research is required to quantify the efficacy of dupilumab for treatment of chronic kidney disease-associated pruritus.

Erratum to uncontrolled and under-diagnosed asthma in a Damascus shelter during the Syrian crisis.

[This corrects the article DOI: 10.21037/jtd.2017.08.86.].

Uncontrolled and under-diagnosed asthma in a Damascus shelter during the Syrian crisis.

Background: Studies have shown that poor shelter or dwelling conditions may lead to deteriorations in health. Those with asthma may be more susceptible to compromised living conditions and stress leading to a higher risk of asthma exacerbations. To describe the asthma control and quality of life of individuals with diagnosed asthma living in a shelter in Damascus, Syria and estimate the prevalence of respiratory symptoms in shelter dwellers without diagnosed asthma. Methods: In this cross-sectional study, all individuals 5 years and older living in Al-Herjalleh shelter with diagnosed asthma were recruited to complete a questionnaire, which included items related to their respiratory symptoms, asthma exacerbations, exposure to asthma triggers, medication use, and health-related quality of life before and since entering the shelter. A representative sample of shelter dwellers without diagnosed asthma also completed a questionnaire to establish their demographics, respiratory symptoms, environment and chronic disease co-morbidities, in order to identify factors associated with under-diagnosed asthma. All participants underwent spirometry to measure their lung function. Descriptive statistics were calculated, and chi-square tests and Student's t-tests were used to compare individuals with asthma before and since entering the shelter, as well as to compare those with under-diagnosed asthma and individuals without asthma. Results: The prevalence of asthma at the Al-Herjalleh shelter in those aged 5 years and older was approximately 8.5%. Nearly 70% of the asthma group felt their asthma had worsened since entering the shelter, and there was a significant drop in the proportion of individuals using inhaled corticosteroids (ICS), with only 4.3% using daily ICS in the shelter (P<0.0001). The proportion of individuals experiencing a severe asthma attack did not change after entering the shelter (P=0.97), but almost all individuals with asthma (94.4%) reported worsening in their health-related quality of life. In the non-asthma group, 44.2% of participants reported episodes of wheezing, coughing and breathlessness at night, consistent with under-diagnosed asthma. A higher proportion of those with under-diagnosed asthma had allergic rhinitis (57.1%), symptoms of post-traumatic stress disorder (PTSD) (35.1%), and abnormal spirometry (60.0%), compared to those without asthma. Conclusions: The findings of our study highlight the need for asthma programs in Syrian shelters as significant gaps exist in both the screening and management of chronic respiratory diseases to minimize asthma deterioration in Syrian shelter dwellers.

Angiotensin II regulates testicular peritubular cell function via AT1 receptor: a specific situation in male infertility.

We observed that peritubular myoid cells in the human testis are immunoreactive for angiotensin II (AngII) receptors (AT1R) and explored AngII actions in cultured human testicular peritubular cells (HTPCs). In response to AngII they contracted within minutes. The AT1R-blocker losartan blocked contraction, implying involvement of AngII and AT1R in intratesticular sperm transport. AngII also significantly increased IL-6 mRNA levels and IL-6 secretion within hours and losartan again prevented this action. This suggests involvement in inflammatory processes, which may play a role in male infertility. AngII can be generated locally by mast cell (MC)-derived chymase (CHY), which cleaves AngI. In testicular biopsies from infertile men we found abundant MCs, which express CHY, within the wall of seminiferous tubules. In contrast, CHY-positive MCs are hardly found in normal human testis. Testicular inflammatory events may fuel processes resulting in impaired spermatogenesis. Therefore therapeutic interference with MCs, CHY or AT1R might be novel options in male infertility.

The Ca2+-activated, large conductance K+-channel (BKCa) is a player in the LH/hCG signaling cascade in testicular Leydig cells.

In Leydig cells, hormonal stimulation by LH/hCG entails increased intracellular Ca(2+) levels and steroid production, as well as hyperpolarization of the cell membrane. The large-conductance Ca(2+)-activated K(+)-channel (BK(Ca)) is activated by raised intracellular Ca(2+) and voltage and typically hyperpolarizes the cell membrane. Whether BK(Ca) is functionally involved in steroid production of Leydig cells is not known. In order to explore this point we first investigated the localization of BK(Ca) in human and hamster testes and then used a highly specific toxin, the BK(Ca) blocker iberiotoxin (IbTx), to experimentally dissect a role of BK(Ca). Immunohistochemistry and RT-PCR revealed that adult Leydig cells of both species are endowed with these channels. Ontogeny studies in hamsters indicated that BK(Ca) becomes strongly detectable in Leydig cells only after they acquire the ability to produce androgens. Using purified Leydig cells from adult hamsters, membrane potential changes in response to hCG were monitored. HCG hyperpolarized the cell membrane, which was prevented by the selective BK(Ca) blocker IbTx. Steroidogenic acute regulatory (StAR) mRNA expression and testosterone production were not affected by IbTx under basal conditions but markedly increased when hCG, in submaximal and maximal concentration or when db-cAMP was added to the incubation media. A blocker of K(V)4-channels, expressed by Leydig cells, namely phrixotoxin-2 (PhTx-2) was not effective. In summary, the data reveal BK(Ca) as a crucial part of the signaling cascade of LH/hCG in Leydig cells. The hyperpolarizing effect of BK(Ca) in the Leydig cell membrane appears to set in motion events limiting the production of testosterone evoked by stimulatory endocrine mechanisms.

Partial loss of contractile marker proteins in human testicular peritubular cells in infertility patients.

Fibrotic remodelling of the testicular tubular wall is common in human male infertility caused by impaired spermatogenesis. We hypothesized that this morphological change bears witness of an underlying fundamentally altered state of the cells building this wall, that is, peritubular smooth muscle-like cells. This could include a loss of the contractile abilities of these cells and thus be a factor in male infertility. Immune cells are increased in the tubular wall in these cases, hence local immune cell-related factors, including a prostaglandin (PG) metabolite may be involved. To explore these points in the human, we used testicular biopsies, in which tubules with normal spermatogenesis and impaired spermatogenesis are next to each other [mixed atrophy (MA)], normal biopsies and cultured human testicular peritubular cells. Proteins essential for contraction, myosin heavy chain (MYH11), calponin (Cal) and relaxation, cGMP-dependent protein kinase 1 (cGKI), were readily detected by immunohistochemistry and were equally distributed in all peritubular cells of biopsies with normal spermatogenesis. In all biopsies, vascular smooth muscle cells also stained and served as important intrinsic controls, which showed that in MA samples when spermatogenesis was impaired, staining was restricted to only few peritubular cells or was absent. When spermatogenesis was normal, regular peritubular staining became obvious. This pattern suggests complex regulatory influences, which in face of the identical systemic hormonal situation in MA patients, are likely caused by the local testicular micromilieu. The PG metabolite 15dPGJ2 may represent such a factor and it reduced Cal protein levels in peritubular cells from patients with/without impaired spermatogenesis. The documented phenotypic switch of peritubular, smooth muscle-like cells in MA patients may impair the abilities of the afflicted seminiferous tubules to contract and relax and must now be considered as a part of the complex events in male infertility.