Proof of concept pilot study: prevalence of grass virus infection and the potential for effects on the allergenic potency of pollen

Background

Wild plants harbour a variety of viruses and these have the potential to alter the composition of pollen. The potential consequences of virus infection of grasses on pollen-induced allergic disease are not known.

Methods

We have collected pollen from Dactylis glomerata (cocksfoot; a grass species implicated as a trigger of allergic rhino-conjunctivitis) from Wytham Wood, Oxfordshire UK. Extracts were prepared from pollen from uninfected grass, and from grass naturally infected by the Cocksfoot streak potyvirus (CSV). Preparations of pollen from virus-infected and non-infected grasses were employed in skin testing 15 grass pollen-allergic subjects with hayfever. Allergen profiles of extracts were investigated by Western blotting for IgE with sera from allergic subjects.

Results

The prevalence of CSV infection in cocksfoot grasses sampled from the study site varied significantly over an eight-year period, but infection rates of up to 70% were detected. Virus infection was associated with small alterations in the quantities of pollen proteins detected by polyacrylamide gel electrophoresis, and in the patterns of allergens identified by Western blotting with IgE from grass pollen allergic subjects. For individual subjects there were differences in potencies of standardised extracts of pollen from virus-free and virus-infected plants as assessed by skin testing, though a consistent pattern was not established for the group of 15 subjects.

Conclusion

Infection rates for CSV in cocksfoot grass can be high, though variable. Virus-induced alterations in components of grass pollen have the potential to alter the allergenic potency.

     

No evidence of compensatory changes in energy balance,despite reductions in body weight and liver fat,during dapagliflozin treatment in type 2 diabetes mellitus: A randomized,double-blind,placebo-controlled,cross-over trial (ENERGIZE)

Aim

This study assessed the impact of dapagliflozin on food intake, eating behaviour, energy expenditure, magnetic resonance imaging (MRI)-determined brain response to food cues and body composition in patients with type 2 diabetes mellitus (T2D).

Materials and Methods

Patients were given dapagliflozin 10 mg once daily in a randomized, double-blind, placebo-controlled trial with short-term (1 week) and long-term (12 weeks) cross-over periods. The primary outcome was the difference in test meal food intake between long-term dapagliflozin and placebo treatment. Secondary outcomes included short-term differences in test meal food intake, short- and long-term differences in appetite and eating rate, energy expenditure and functional MRI brain activity in relation to food images. We determined differences in glycated haemoglobin, weight, liver fat (by ¹H magnetic resonance spectroscopy) and subcutaneous/visceral adipose tissue volumes (by MRI).

Results

In total, 52 patients (43% were women) were randomized; with the analysis of 49 patients: median age 58 years, weight 99.1 kg, body mass index 35 kg/m², glycated haemoglobin 49 mmol/mol. Dapagliflozin reduced glycated haemoglobin by 9.7 mmol/mol [95% confidence interval (CI) 3.91-16.27, p = .004], and body weight (−2.84 vs. −0.87 kg) versus placebo. There was no short- or long-term difference in test meal food intake between dapagliflozin and placebo [mean difference 5.7 g (95% CI −127.9 to 139.3, p = .933); 15.8 g (95% CI −147.7 to 116.1, p = .813), respectively] nor in the rate of eating, energy expenditure, appetite, or brain responses to food cues. Liver fat (median reduction −4.7 vs. 1.95%), but not subcutaneous/visceral adipose tissue, decreased significantly with 12 weeks of dapagliflozin.

Conclusions

The reduction in body weight and liver fat with dapagliflozin was not associated with compensatory adaptations in food intake or energy expenditure.     

Analysis of nociception, sex and peripheral nerve innervation in the TMEV animal model of multiple sclerosis

Although pain was previously not considered an important element of multiple sclerosis (MS), recent evidence indicates that over 50% of MS patients suffer from chronic pain. In the present study, we utilized the Theiler's murine encephalomyelitis virus (TMEV) model of MS to examine whether changes in nociception occur during disease progression and to investigate whether sex influences the development of nociception or disease-associated neurological symptoms. Using the rotarod assay, TMEV infected male mice displayed increased neurological deficits when compared to TMEV infected female mice, which mimics what is observed in human MS. While both male and female TMEV infected mice exhibited thermal hyperalgesia and mechanical allodynia, female mice developed mechanical allodynia at a faster rate and displayed significantly more mechanical allodynia than male mice. Since neuropathic symptoms have been described in MS patients, we quantified sensory nerve fibers in the epidermis of TMEV-infected and non-infected mice to determine if there were alterations in epidermal nerve density. There was a significantly higher density of PGP9.5 and CGRP-immunoreactive axons in the epidermis of TMEV-infected mice versus controls. Collectively these results indicate that the TMEV model is well suited to study the mechanisms of MS-induced nociception and suggest that alterations in peripheral nerve innervation may contribute to MS pain.     

Thyroid cancer susceptibility polymorphisms: confirmation of loci on chromosomes 9q22 and 14q13, validation of a recessive 8q24 locus and failure to replicate a locus on 5q24

Five single nucleotide polymorphisms (SNPs) associated with thyroid cancer (TC) risk have been reported: rs2910164 (5q24); rs6983267 (8q24); rs965513 and rs1867277 (9q22); and rs944289 (14q13). Most of these associations have not been replicated in independent populations and the combined effects of the SNPs on risk have not been examined. This study genotyped the five TC SNPs in 781 patients recruited through the TCUKIN study. Genotype data from 6122 controls were obtained from the CORGI and Wellcome Trust Case-Control Consortium studies. Significant associations were detected between TC and rs965513A (p=6.35×10(-34)), rs1867277A (p=5.90×10(-24)), rs944289T (p=6.95×10(-7)), and rs6983267G (p=0.016). rs6983267 was most strongly associated under a recessive model (P(GG vs GT + TT)=0.004), in contrast to the association of this SNP with other cancer types. However, no evidence was found of an association between rs2910164 and disease under any risk model (p>0.7). The rs1867277 association remained significant (p=0.008) after accounting for genotypes at the nearby rs965513 (p=2.3×10(-13)) and these SNPs did not tag a single high risk haplotype. The four validated TC SNPs accounted for a relatively large proportion (～11%) of the sibling relative risk of TC, principally owing to the large effect size of rs965513 (OR 1.74).     

Sputum microbiome profiles identify severe asthma phenotypes of relative stability at 12 to 18 months

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Double-blind, placebo-controlled study comparing the efficacy and safety of fexofenadine hydrochloride (120 and 180 mg once daily) and cetirizine in seasonal allergic rhinitis.

BACKGROUND: Fexofenadine hydrochloride (HCl) is a new H(1) antihistamine used twice daily in some countries. OBJECTIVE: A multicenter, double-blind, parallel-group, placebo-controlled trial compared the efficacy and safety of fexofenadine HCl (120 and 180 mg administered once daily) and cetirizine (10 mg once daily) in the treatment of seasonal allergic rhinitis. METHODS: After a 3- to 5-day run-in period, patients meeting entrance criteria were randomized to receive placebo, fexofenadine HCl 120 mg once daily, fexofenadine HCl 180 mg once daily, or cetirizine 10 mg once daily (active control) for 2 weeks. Eight hundred twenty-one patients comprised the intention-to-treat population and 722 patients completed the study. Symptom assessments were conducted 12 hours after the dose for the previous 12 hours and again at 24 hours after the dose for the previous 12 hours. In addition, assessment was made immediately before dosing in the morning for the previous 30 minutes. Total symptom score was calculated as the sum of scores for the 4 individual symptoms: (1) sneezing, (2) rhinorrhea, (3) itchy nose, palate, or throat, and (4) itchy, watery, or red eyes; the nasal congestion score was also recorded. RESULTS: Both doses of fexofenadine HCl were superior to placebo in reducing the total symptom score. Efficacy was maintained for the entire dosing interval (ie, for 24 hours). There were no differences in efficacy between the 2 doses of fexofenadine HCl or between either dose of fexofenadine HCl and cetirizine. There was no major side effect, but the combined incidence of drowsiness or fatigue was greater with ce-tirizine (9%) than with placebo (4%) (P =.07) or fexofenadine (4%) (P =.02). CONCLUSIONS: Once-daily fexofenadine is thus a valuable addition to the nonsedating group of H(1) receptor antagonists currently available for the treatment of seasonal allergic rhinitis.     

99mTc technegas ventilation and perfusion lung scintigraphy for the diagnosis of pulmonary embolus.

Lung scintigraphy is used widely for diagnosis of pulmonary embolus (PE). Technegas ventilation imaging has many advantages over other methods, but little outcome data exists on this technique. The aims of this study were to better define the role of lung scintigraphy in the management of patients with suspected PE and to evaluate technegas ventilation imaging by following patient outcomes. METHODS: A group of 717 out of 834 consecutive patients, referred to a university teaching hospital for lung scintigraphy to confirm or refute the diagnosis of PE, was followed for 18-30 mo to determine clinical outcome. The follow-up endpoints were death as a result of PE, death as a result of hemorrhage after treatment for PE, uncomplicated survival, survival with subsequent PE, nonfatal hemorrhage after treatment for PE and recurrence of PE in treated patients. Ventilation imaging was performed using technegas, and perfusion imaging was performed using intravenous 99mTc macroaggregated albumin. The modified PIOPED (Prospective Investigation of Pulmonary Embolism Diagnosis) diagnostic criterion was used for interpretation of lung scintigraphy. RESULTS: Diagnostic results included 3.5% normal studies, 67.4% assessed as low probability for PE, 10% as moderate probability for PE and 19.1% as high probability for PE. A total of 231 patents received therapy with heparin, followed by warfarin, including those receiving anticoagulation therapy for other conditions. Ninety-six percent of patients with normal and low probability studies (n = 508) had good outcomes, 6 patients died as a result of PE and 12 subsequently developed PE. The odds ratio for death by PE in this group was 0.2. Of the 72 moderate probability studies, 39 patients were untreated. In this group there was 1 death due to PE, and PE subsequently developed in 2 patients. None of the remaining 33 treated patients died, but 4 patients experienced bleeding complications. The odds ratio for death by PE in the moderate probability group was 0.7. In those patients with high-probability studies, there were 8 deaths by PE, 6 deaths by hemorrhage, 11 nonfatal hemorrhages and 7 patients who experienced recurrences of PE. The odds ratios in this group were 6 and 10 for death by PE, or death by PE and the treatment of PE, respectively. CONCLUSION: The use of the modified PIOPED diagnostic classification is valid for technegas lung scintigraphy. Using technegas, normal/low-probability and high-probability results are highly predictive of respective outcomes. Technegas lung scintigraphy reduces the number of indeterminate studies.