Basil Elnazir

POSTNATAL DEVELOPMENT OF THE PATTERN OF RESPIRATORY AND CARDIOVASCULAR RESPONSE TO SYSTEMIC HYPOXIA IN THE PIGLET : THE ROLES OF ADENOSINE

1. In 3‐day‐old and 3‐week‐old spontaneously breathing piglets anaesthetized with Saffan, we have studied ventilatory and cardiovascular responses evoked by 5 min periods of hypoxia (breathing 10 and 6% O2). 2. In 3‐day‐old piglets both 10 and 6% O2 evoked an increase followed by a secondary fall in ventilation, a gradual tachycardia and a renal vasoconstriction, with an increase in femoral blood flow that was attributable to femoral vasodilatation. Arterial blood pressure rose initially but fell towards control values by the 5th minute of hypoxia. 3. The stable adenosine analogue 2‐chloroadenosine (2‐CA; 30 mg kg(‐1) i.v.) evoked bradycardia and renal vasoconstriction, but had no effect on femoral vasculature. These responses were blocked by the adenosine receptor antagonist 8‐phenyltheophylline (8‐PT; 8 mg kg(‐1) i.v.). 8‐PT also abolished the secondary fall in ventilation evoked by 10 and 6% O2 and the renal vasoconstriction evoked by 10% O2, but had no effect on the tachycardia, or on the femoral vascular response. 4. By contrast, in 3‐week‐old piglets both 10 and 6% O2 evoked a sustained increase in ventilation, tachycardia and a rise in arterial pressure with renal vasoconstriction, but no change in renal blood flow and substantial femoral vasodilatation with an increase in femoral blood flow. 2‐CA evoked bradycardia and renal vasoconstriction, as in 3‐day‐old piglets, but also evoked pronounced femoral vasodilatation. 8‐PT blocked these responses and the hypoxia‐induced femoral vasodilatation, but had no significant effect on other components of the hypoxia‐induced response. 5. We propose that there is postnatal development of the ventilatory and cardiovascular responses evoked by systemic hypoxia and of the role of locally released adenosine in these responses: at 3 days, adenosine released within the central nervous system and within the kidney is a major contributor to the secondary fall in ventilation and renal vasoconstriction respectively, whereas at 3 weeks, adenosine makes little contribution to the ventilatory response, or renal vasoconstriction, but is largely responsible for hypoxia‐induced vaso‐dilatation in skeletal muscle.

Vitamin D receptor agonists inhibit pro-inflammatory cytokine production from the respiratory epithelium in cystic fibrosis ☆

BACKGROUND 1,25-Dihydroxycholecalciferol (1,25(OH)(2)D(3)) has been shown to mitigate epithelial inflammatory responses after antigen exposure. Patients with cystic fibrosis (CF) are at particular risk for vitamin D deficiency. This may contribute to the exaggerated inflammatory response to pulmonary infection in CF. METHODS CF respiratory epithelial cell lines were exposed to Pseudomonas aeruginosa lipopolysaccharide (LPS) and Pseudomonas conditioned medium (PCM) in the presence or absence of 1,25(OH)(2)D(3) or a range of vitamin D receptor (VDR) agonists. Levels of IL-6 and IL-8 were measured in cell supernatants, and cellular total and phosphorylated IκBα were determined. Levels of human cathelicidin antimicrobial peptide (hCAP18) mRNA and protein were measured in cells after treatment with 1,25(OH)(2)D(3). RESULTS Pretreatment with 1,25(OH)(2)D(3) was associated with significant reductions in IL-6 and IL-8 protein secretion after antigen exposure, a finding reproduced with a range of low calcaemic VDR agonists. 1,25(OH)(2)D(3) treatment led to a decrease in IκBα phosphorylation and increased total cellular IκBα. Treatment with 1,25(OH)(2)D(3) was associated with an increase in hCAP18/LL-37 mRNA and protein levels. CONCLUSIONS Both 1,25(OH)(2)D(3) and other VDR agonists significantly reduce the pro-inflammatory response to antigen challenge in CF airway epithelial cells. VDR agonists have significant therapeutic potential in CF.

Differentiation of the peripherally mediated from the centrally mediated influences of adenosine in the rat during systemic hypoxia

In two groups of Saffan‐anaesthetized, spontaneously breathing rats we have attempted to identify the peripheral influences of adenosine in mediating the responses evoked by hypoxia by using an adenosine receptor antagonist, 8‐sulphophenyltheophylline (8‐SPT, 20 mg kg‐1 i.v., Group 1) and adenosine deaminase (ADA, 500 units in 0.04 ml infused into the tail artery for 10 min, Group 2); neither of these drugs crosses the blood‐brain barrier. Recordings were made of respiration, heart rate, arterial pressure, blood flow and vascular conductance in the femoral artery, with ankle ligated (FBF and FVC, respectively) and in the carotid artery with all branches except the internal carotid ligated (CBF and CVC, respectively, Group 1 only) in order to indicate responses in skeletal muscle and cerebral vasculature. Hypoxia (breathing 8 or 10% O2 for 10 min) evoked an increase followed by a secondary decrease in respiration, tachycardia followed by secondary bradycardia, a fall in arterial pressure, an increase in FVC and CVC and an increase, followed by a decrease, in CBF. Neither 8‐SPT nor ADA had any significant effect on the secondary decrease in respiration. The secondary bradycardia was unaffected by 8‐SPT, but abolished by ADA. Both drugs reduced the fall in arterial pressure and the increase in FVC; 8‐SPT had no significant effect on the increase in CVC, but CBF no longer fell with arterial pressure. We propose that adenosine contributes to the hypoxia‐induced fall in arterial pressure by causing vasodilatation in skeletal muscle and possibly by causing bradycardia by a direct action on the heart; other evidence suggests that adenosine contributes to the secondary decrease in respiration by acting on central respiratory neurones. The possibility that the fall in arterial pressure and the secondary falls in CBF, respiration and heart rate, can become interdependent in a positive feedback manner is discussed.

Vitamin D as an adjunctive therapy in asthma. Part 2: A review of human studies.

Vitamin D deficiency (VDD) is highly prevalent worldwide, with adverse effects on bone health but also potentially other unfavorable consequences. VDD and asthma-incidence/severity share many common risk factors, including winter season, industrialization, poor diet, obesity, dark skin pigmentation, and high latitude. Multiple anatomical areas relevant to asthma contain both the enzyme responsible for producing activated vitamin D and the vitamin D receptor suggesting that activated vitamin D (1,25-dihydroxyvitamin D) may have important local effects at these sites. Emerging evidence suggests that VDD is associated with increased airway hyperresponsiveness, decreased pulmonary function, worse asthma control, and possibly decreased response to standard anti-asthma therapy. However the effect is inconsistent with preliminary evidence from different studies suggesting vitamin D is both beneficial and detrimental to asthma genesis and severity. Current evidence suggests that supplementation with moderate doses of vitamin D may be appropriate for maintenance of bone health in asthmatics, particularly steroid users. However emerging data from an increasing number of randomized, controlled, intervention studies of vitamin D supplementation in pediatric and adult asthma are becoming available and should help determine the importance, if any of vitamin D for asthma pathogenesis. The purpose of this second of a two-part review is to review the current human literature on vitamin D and asthma, discussing the possible consequences of VDD for asthma and the potential for vitamin D repletion as adjunct therapy.

Vitamin D as an adjunctive therapy in asthma. Part 1: A review of potential mechanisms.

Vitamin D deficiency (VDD) is highly prevalent worldwide. The classical role for vitamin D is to regulate calcium absorption form the gastrointestinal tract and influence bone health. Recently vitamin D receptors and vitamin D metabolic enzymes have been discovered in numerous sites systemically supporting diverse extra-skeletal roles of vitamin D, for example in asthmatic disease. Further, VDD and asthma share several common risk factors including high latitude, winter season, industrialization, poor diet, obesity, and dark skin pigmentation. Vitamin D has been demonstrated to possess potent immunomodulatory effects, including effects on T cells and B cells as well as increasing production of antimicrobial peptides (e.g. cathelicidin). This immunomodulation may lead to asthma specific clinical benefits in terms of decreased bacterial/viral infections, altered airway smooth muscle-remodeling and -function as well as modulation of response to standard anti-asthma therapy (e.g. glucocorticoids and immunotherapy). Thus, vitamin D and its deficiency have a number of biological effects that are potentially important in altering the course of disease pathogenesis and severity in asthma. The purpose of this first of a two-part review is to review potential mechanisms whereby altering vitamin D status may influence asthmatic disease.

Vitamin D3 for uncontrolled childhood asthma: A pilot study.

Observational and mechanistic data suggest a role for vitamin D in childhood asthma. However, subsequent interventional trials have been inconsistent. We aimed to assess the effect of 15 weeks of vitamin D3 supplementation compared with placebo (PL) in Irish children with asthma.

Congenital Pulmonary Malformation in Children

Congenital Pulmonary Malformations (CPMs) are a group of rare lung abnormalities affecting the airways, parenchyma, and vasculature. They represent a spectrum of abnormal development rather than discrete pathological entities. They are caused by aberrant embryological lung development which occurs at different stages of intrauterine life.

Respiratory Syncytial Virus Preterm (32-36 Completed Weeks of Gestation) Risk Estimation Measure for RSV Hospitalization in Ireland: A Prospective Study.

Background: In several countries, respiratory syncytial virus prophylaxis is offered to late preterm infants who are at escalated risk of respiratory syncytial virus hospitalization (RSVH). However, targeted prophylaxis should be informed by country-specific data. This study, which uniquely includes 36 weeks of gestational age (GA) infants, aims to establish the risk factors for RSVH in 32–36 weeks of GA infants in Ireland. Methods: A prospective observational study at 13 hospitals of laboratory-confirmed RSVH in nonprophylaxed 32–36 weeks of GA infants was conducted from July 2011 to February 2014. Baseline and first-year clinical data were analyzed by using SPSS software Version 22 (IBM Corp, Armonk, NY). Significant (P < 0.05) variables were entered into multiple logistic regression to determine the independent risk factors for RSVH. Results: Sixty-three percent of eligible infants (1825 of 2877) were recruited. The RSVH rate was 3.6% (65 of 1807 analyzed infant records). There was no RSV-attributable mortality. Twelve infants required intensive care. Of the 15 variables correlating to RSVH, 5 independent risk factors were identified: older siblings [odds ratio (OR): 3.8; 95% confidence interval (CI): 1.97–7.41], being Caucasian (OR: 2.3; 95% CI: 1.04–5.29), neonatal respiratory morbidity (OR: 2.2; 95% CI: 1.28–3.94); birth July 15 to December 15 (OR: 2.1; 95% CI: 1.09–3.92) and family history of asthma (OR: 1.9; 95% CI: 1.01–3.39). Birth from 36 weeks to 36 + 6 days mitigated RSVH risk (relative risk: 0.58; 95% CI: 0.34–0.99); however, risk factors were similar to the 32–35 weeks of GA cohort. Conclusion: Neonatal respiratory morbidity or being Caucasian were the population-specific independent risk factors for RSVH in 32–36 weeks of GA in Ireland, whereas the other identified independent risk factors mirrored those established in previous studies.

Night blindness in a teenager with cystic fibrosis.

This article describes the case of a 16-year-old boy with cystic fibrosis who presented with difficulty seeing in the dark. He had a history of bowel surgery at birth, and he developed cystic fibrosis liver disease and osteopenia during his teenage years. He always had good lung function. When his serum vitamin A level was checked, it was undetectable in sample. He was diagnosed with night blindness and commenced on high-dose vitamin A. His symptoms resolved within 3 days. However, it took over 1 year for his vitamin A level to return to normal. This case emphasizes the importance of monitoring vitamin levels in cystic fibrosis to detect deficiency and prevent long-term consequences, and it highlights the challenges encountered during the course of night blindness treatment.

Emergence of persistent Aspergillus terreus colonisation in a child with cystic fibrosis

Graphical abstract