Temperature-controlled Laminar Airflow (TLA) in symptomatic severe asthma - a post hoc analysis of severe exacerbations, quality of life and health economics.

PURPOSE: Uncontrolled severe asthma constitutes a major economic burden to society. Add-ons to standard inhaled treatments include inexpensive oral corticosteroids and expensive biologics. Nocturnal treatment with Temperature-controlled Laminar Airflow (TLA; Airsonett®) could be an effective, safe and cheaper alternative. The potential of TLA in reducing severe asthma exacerbations was addressed in a recent randomised placebo-controlled trial (RCT) in patients with severe asthma (Global Initiative for Asthma (GINA) step 4/5), but the results were inconclusive. We re-analysed the RCT with severe exacerbations stratified by the level of baseline asthma symptoms and Quality of Life. METHODS: More uncontrolled patients, defined by Asthma Control Questionnaire 7 (ACQ7) > 3, EuroQoL 5-Dimension Questionnaire Visual Analogue Scale (EQ5D-VAS) ≤ 65 and Asthma Quality of Life Questionnaire (AQLQ) ≤ 4 were selected for re-analysis. The rates of severe asthma exacerbations, changes in QoL and health-economics were analysed and compared between TLA and placebo. RESULTS: The study population included 226 patients (113 TLA / 113 placebo.) The rates of severe asthma exacerbations were reduced by 33, 31 and 25% (p = 0.083, 0.073, 0.180) for TLA compared to placebo, dependent on selected control measures (ACQ7, EQ5D-VAS, AQLQ, respectively). For patients with less control defined by AQLQ≤4, the difference in mean AQLQ0-12M between TLA and placebo was 0.31, 0.33, 0.26 (p = 0.085, 0.034, 0.150), dependent on selected covariate (AQLQ, EQ5D-VAS, ACQ7, respectively). For patients with poor control defined by ACQ7 > 3, the difference in EQ5D-5 L utility scores between TLA and placebo was significant at 9 and 12 months with a cost-effective ICER. The results from the original study did not demonstrate these differences. CONCLUSION: This post hoc analysis demonstrated an effect of TLA over placebo on severe exacerbations, asthma control and health economics in a subgroup of patients with more symptomatic severe allergic asthma. The results are consistent with the present recommendations for TLA. However, these differences were not demonstrated in the full study. Several explanations for the different outcomes have been outlined, which should be addressed in future studies. FUNDING: NIHR Health Technology Assessment Programme and Portsmouth Hospitals NHS Trust.

Long Sun-Exposures Influencing High Sub-Cutaneous Synthesis of Vitamin-D3 may be Associated with Exacerbation of Symptoms in Allergic-Asthma.

OBJECTIVES: Does excessive sun-exposure, non-use of sunscreen and/or high doses of vitamin-D3 supplements provoke exacerbation of asthma? DESIGN: Clinical examinations, retrospective records-access and questionnaire surveys were distributed to a convenience sample of allergic-asthma patient (n=183). SETTING: Patients (19-89 years) attending the outpatient respiratory clinics at Maidstone Hospital were enrolled. RESULTS: 90.3% of patients (total IgE levels ≥75 kU/L ; n=103) exposed to direct sunlight of ≥ 15 minutes per day continuously for 6-7 days presented with wheeze (χ2(1) = 7.46; p< 0.05) compared to only 9.7% patients of similar atopy-status, presenting with wheeze if exposed to sunlight of < 15 minutes per day for 6-7 days. 68.9% patients (with IgE levels ≥ 75 kU/L ; n=103), non-users of sunscreen (SPF 30 and above), exposed to direct sunlight of ≥ 15 minutes per day continuously for 6-7 days developed a wheeze, compared to fewer users of sunscreen (9.7%, n=103), exposed to the same duration of sunlight who developed asthma symptoms (p< 0.05). Vitamin-D3 supplementation in asthma-patients with clinical signs of hypovitaminosis-D (n=21), produced symptoms of morning chest-tightness (76.2%), allergic rhinitis (61.9%) and wheeze (100%), 2 weeks after initiation of treatment. CONCLUSIONS: Our results advocate direct sunlight exposure < 15 minutes per day and use of sunscreen as a novel approach to preventing atopic-asthma symptoms in allergic-asthma patients.. Activated vitamin-D3 is well-recognised to shift the immune-balance towards Th2 predominance, favouring allergic asthma. These results suggest that limiting subcutaneous synthesis of vitamin-D3 in asthma patients and re-addressing dosage of vitamin-D3 supplementation is necessary may contribute to prevent exacerbation of symptoms.

Molecular motors in the heart.

The contractile apparatus of muscle is a highly efficient and adaptable mechanism for producing movement and is exploited throughout the animal kingdom. Molecular biology is yielding important insights into the intricate functioning of muscular contraction, especially in the heart, and in explaining the genesis of inherited myopathies. Mutational analyses of the sarcomeric-protein genes in conjunction with clinical assessment have shown that certain mutations indicate a more serious prognosis in HCM. Detecting these mutations in individuals is important for screening other family members for the disease. Understanding the contractile apparatus at the molecular level could contribute to the design of more effective drugs for treatment of cardiac diseases.

Expression of factor I-resistant mutants of the human complement component C3 in heterologous systems.

Complement plays a major role in hyperacute rejection of xenografts. In order to overcome this, we are developing, by minimal mutagenesis, a modified C3 molecule that, like cobra venom factor (CVF), escapes normal complement regulatory processes and inhibits complement-mediated responses by systemic depletion of C3. Unlike CVF, this protein should have little or no immunogenicity and be suitable for repeat administrations. As an initial step in this process, we have modified human C3 to make it resistant to inactivation by factor I. The factor I resistant C3 is capable of forming an active C3 convertase. Preincubation with normal human serum abrogated subsequent complement-mediated cytolysis by both the classical and alternative pathways, while wild-type (wt) C3 was inactive. The modified human C3 also blocked complement activity of guinea-pig serum. For economical and rapid production, we have developed expression of recombinant C3 wt and mutant proteins in the Baculovirus system. Large quantities are also being produced from stably transfected CHO cell lines. In addition, we have developed a fast C3 purification method by engineering a 6XHIS tag into the C3a portion of the molecule, thereby avoiding the need for subsequent separation of the tag from active C3b molecules.