Can knowledge of the molecular structure of allergens improve immunotherapy?

Conventional immunotherapy may be associated with the development of adverse reactions, including anaphylaxis, due to the use of increasing doses of allergen. Standardization of extracts is necessary in order to assess the correct amount of allergen administered. In recent years, increased knowledge on the molecular structure of allergens has allowed the development of novel alternatives for immunotherapy. Initially, allergens were cloned and expressed as recombinant proteins in eukaryotic and prokaryotic systems. Crystallization of the purified proteins led to the elucidation of the tertiary structure of the allergen. Molecular biology techniques were used to construct modified allergens whose new IgE binding properties were studied. IgE antibody mapping combined with molecular modeling has allowed the recognition of IgE binding sites on the surface of the molecule. This information has been applied to the engineering of new modified allergens, with and without adjuvants, that retain immunogenicity but with reduced allergenicity. The use of these molecules for immunotherapy should allow the administration of greater doses of allergen, without the undesired side effects characteristic of conventional immunotherapy.     

Can we rely on the best trial? A comparison of individual trials and systematic reviews

Background

The ideal evidence to answer a question about the effectiveness of treatment is a systematic review. However, for many clinical questions a systematic review will not be available, or may not be up to date. One option could be to use the evidence from an individual trial to answer the question?

Methods

We assessed how often (a) the estimated effect and (b) the p-value in the most precise single trial in a meta-analysis agreed with the whole meta-analysis. For a random sample of 200 completed Cochrane Reviews (January, 2005) we identified a primary outcome and extracted: the number of trials, the statistical weight of the most precise trial, the estimate and confidence interval for both the highest weighted trial and the meta-analysis overall. We calculated the p-value for the most precise trial and meta-analysis.

Results

Of 200 reviews, only 132 provided a meta-analysis of 2 or more trials, with a further 35 effect estimates based on single trials. The average number of trials was 7.3, with the most precise trial contributing, on average, 51% of the statistical weight to the summary estimate from the whole meta-analysis. The estimates of effect from the most precise trial and the overall meta-analyses were highly correlated (rank correlation of 0.90).There was an 81% agreement in statistical conclusions. Results from the most precise trial were statistically significant in 60 of the 167 evaluable reviews, with 55 of the corresponding systematic reviews also being statistically significant. The five discrepant results were not strikingly different with respect to their estimates of effect, but showed considerable statistical heterogeneity between trials in these meta-analyses. However, among the 101 cases in which the most precise trial was not statistically significant, the corresponding meta-analyses yielded 31 statistically significant results.

Conclusions

Single most precise trials provided similar estimates of effects to those of the meta-analyses to which they contributed, and statistically significant results are generally in agreement. However, "negative" results were less reliable, as may be expected from single underpowered trials. For systematic reviewers we suggest that: (1) key trial(s) in a review deserve greater attention (2) systematic reviewers should check agreement of the most precise trial and the meta analysis. For clinicians using trials we suggest that when a meta-analysis is not available, a focus on the most precise trial is reasonable provided it is adequately powered.

     

Instruments to assess the quality of health information on the World Wide Web: what can our patients actually use?

OBJECTIVE: To find and assess quality-rating instruments that can be used by health care consumers to assess websites displaying health information. DATA SOURCES: Searches of PubMed, the World Wide Web (using five different search engines), reference tracing from identified articles, and a review of the of the American Medical Informatics Association's annual symposium proceedings. REVIEW METHODS: Sources were examined for availability, number of elements, objectivity, and readability. RESULTS: A total of 273 distinct instruments were found and analyzed. Of these, 80 (29%) made evaluation criteria publicly available and 24 (8.7%) had 10 or fewer elements (items that a user has to assess to evaluate a website). Seven instruments consisted of elements that could all be evaluated objectively. Of these seven, one instrument consisted entirely of criteria with acceptable interobserver reliability (kappa> or =0.6); another instrument met readability standards. CONCLUSIONS: There are many quality-rating instruments, but few are likely to be practically usable by the intended audience.     

Why do we need to use a zero reference? Reference influences on the ERPs of audiovisual effects

Using ERPs in the audiovisual stimulus, the current study is the first to investigate the influence of the reference on experimental effects (between two conditions). Three references, the average reference (AR), the mean mastoid (MM), and a new infinity zero reference (IR), were comparatively investigated via ERPs, statistical parametric scalp mappings (SPSM), and LORETA. Specifically, for the N1 (170–190 ms), the SPSM results showed an anterior distribution for MM, a posterior distribution for IR, and both anterior and posterior distributions for AR. However, the circumstantial evidence provided by LORETA is consistent with SPSM of IR. These results indicated that the newly developed IR could provide increased accuracy; thus, we recommend IR for future ERP studies.     

How accurate and safe is the diagnosis of hazelnut allergy by means of commercial skin prick test reagents?

BACKGROUND: Allergy to tree nuts, like hazelnuts, ranks among the most frequently observed food allergies. These allergies can start at early childhood and are, in contrast to other food allergies, not always outgrown by the patient. Tree nut allergy is frequently associated with severe reactions. Diagnosis partially relies on in vivo testing by means of a skin prick test (SPT) using commercially available SPT reagents. METHODS: Protein and allergen composition of nine commercial SPT solutions was evaluated using standard protein detection methods and specific immunoassays for measurement of five individual allergens. Diagnostic performance was assessed by SPT in 30 hazelnut-allergic subjects, of which 15 were provocation proven. RESULTS: Protein concentrations ranged from 0.2-14 mg/ml. SDS-PAGE/silver staining revealed clear differences in protein composition. The major allergen Cor a 1 was present in all extracts but concentrations differed up to a factor 50. An allergen associated with severe symptoms, Cor a 8 (lipid transfer protein), was not detected on immunoblot in three products, and concentrations varied by more than a factor 100 as was shown by RAST inhibition. Similar observations were made for profilin, thaumatin-like protein and a not fully characterized 38-kD allergen. Ratios of individual allergens were variable among the nine extracts. SPT showed significant difference, and 6/30 patients displayed false-negative results using 3/9 products. CONCLUSION: Variability in the composition of products for the diagnosis of hazelnut allergy is extreme. Sometimes, allergens implicated in severe anaphylaxis are not detected by immunoblotting. These shortcomings in standardisation and quality control can potentially cause a false-negative diagnosis in subjects at risk of severe reactions to hazelnuts.     

Haematology patients and the internet – The use of on-line health information and the impact on the patient–doctor relationship

Objective

Patients access on-line health information (OHI) to better understand their health. We aimed to determine which demographic factors influence OHI use. We also explored how OHI is used and subsequent implications to the patient–doctor relationship.

Methods

We distributed a self-administered questionnaire to 202 haematology out-patients.

Results

62.3% used the internet and 54.3% used OHI. Higher education, (P < 0.001, OR 34.62, 95% CI 5.20–230.66) and household incomes of £15 000–25 000 (P = 0.023 OR 4.8 95% CI 1.236–18.59) were positively associated with OHI use.Those reassured after reading OHI had improved trust in their specialist (P < 0.001, OR 52.1, 95% CI 12.3–221.1), improved confidence during consultations, (P < 0.001, OR 23.0, 95% CI 2.8–188.2) and were improved decisions makers (P = 0.008, OR 13.6, 95% CI 4.1–45.7). Those with increased trust in their haematologist also had improved confidence (P < 0.001, OR 6.2, 95% CI 2.2–17.3) and improved decision making ability (P < 0.001, OR 13.6, 95% CI 4.7–39.4). 74.6% of patients did not share OHI with their haematologist.

Conclusions

Two-thirds of participants were exposed directly or indirectly to OHI. OHI affects patients’ view of their health and influences behaviour during consultations.

Practice implications

Haematologists could facilitate patients using OHI by recommending high quality websites and act supportively when patients share OHI.     

Can we rely on pathologic parameters to define conservative treatment of papillary thyroid carcinoma?

Papillary thyroid carcinoma is the most common malignant tumor of the thyroid and usually behaves in an indolent fashion. At most institutions these tumors are treated by near-total or total thyroidectomy followed by radioactive iodine ablation. The 2 main reasons for this extensive treatment include high rate of multicentricity in papillary carcinoma and difficulty in ablating large thyroid remnants with radioactive iodine after partial thyroidectomy. Some authors believe, however, that this treatment protocol may not be justified in all cases of papillary carcinoma. We analyzed 253 total thyroidectomies performed for papillary thyroid carcinoma for the following pathologic variables: tumor size, presence of tumor capsular and/or vascular invasion, intrathyroidal spread, tumor in the contralateral lobe, and lymph node metastases. Tumors measuring less than 1 cm and those with extrathyroidal soft tissue extension were excluded from this study. Among 253 cases (197 females, 56 males, age range 14-88 years), the primary tumor size ranged from 1-9.5 cm; 162 cases were completely encapsulated. Tumor capsule invasion was seen in 139 (86%) and vascular invasion was present in 32 (13%) cases; of these 27 (11% of the total) patients showed both tumor capsule and vascular invasion. Seventy-four (29%) patients showed tumor in the contralateral lobe; in 35 (47%) of these cases the contralateral tumor measured less than 1.0 cm. Lymph nodes were sampled in 106 cases, metastases were present in 67 (67/106 = 63%) and only 16 cases with lymph node metastases showed contralateral tumors. No significant correlation was noted between tumor size, occurrence of contralateral tumors, and lymph node metastases. Seventy-one percent of cases included in this study failed to show contralateral tumors. Hence, pathologic parameters such as lack of vascular invasion and lack of multifocality may be used to identify patients who can benefit from conservative therapy alone.     

Can we predict the success of a parasite to colonise an invasive host?

Parasitology Research - To understand whether a parasite can exploit a novel invasive host species, we measured reproductive performance (number of eggs per female per day, egg size, development...     

Are we really what we eat? Nutrition and its role in the onset of rheumatoid arthritis

Accumulating research evidence suggests that individual dietary factors and dietary patterns might be implicated in the risk of development of rheumatoid arthritis (RA). This narrative review aims to present this evidence and provide nutritional recommendations for reducing RA risk in susceptible individuals. Overall, a ‘Western’ type diet rich in energy intake, total and saturated fat, an unbalanced ratio of n-3 to n-6 fatty acids, high in refined carbohydrates and sugar and low in fiber and antioxidants might increase the risk of RA both directly through increasing inflammation and indirectly through increasing insulin resistance and obesity, with the latter being a known risk factor for RA. On the contrary, consumption of long-chain omega-3 polyunsaturated fatty acids, derived from fish and fish oil, is associated with a reduced risk of RA probably due to their anti-inflammatory properties. The Mediterranean diet (MD), rich in plant-based foods such as wholegrains, legumes, fruit, vegetables, extra-virgin olive oil and low in red meat consumption, might have the potential to reduce the risk of RA. Based on current research evidence, it is suggested that adherence to the MD enhanced with an increased consumption of fatty fish, reduced consumption of sugar-sweetened drinks and maintenance of a normal body weight, contributes to reducing the risk of RA. Further research on RA susceptibility will allow for more specific dietary recommendations to be made.     

Growth and sexual dimorphism of the hyoid bone and its relationship to the mandible from birth to 19 years: A three-dimensional computed tomography study

The hyoid bone and the hyomandibular complex subserve the functions of respiration, deglutition, and speech. This study quantified the growth of the hyoid bone and the hyomandibular relationships in males and females from birth to 19 years. Using 97 computed tomography (CT) scans, from a previous study (Kelly et al., 2017) on mandibular growth from 49 individuals (16 with longitudinal scans), landmarks were placed on 3D CT models and used to calculate four distance, and three angular measurements. A general increase in growth trend was observed in hyoid bone linear measurements—length, width, and depth—as well as relational mandible-to-hyoid distance, throughout the developmental ages examined in both males and females, with most variables having larger measurements for females up to age 10 years. A general decrease in all three angular measurements was observed in both males and females up to approximately age 12 years, at which time male angular measurements gradually increased with significant sexual dimorphism emerging after age 15 years. As expected, postpubertal males had greater hyoid angle than females; they also had greater hyoid angle of inclination than mandible body inclination (with inclination relative to the anterior–posterior nasal plane), likely related to hyo-laryngeal descent. This study contributes to normative data on hyoid bone and hyomandibular relational growth in typically developing individuals and provides a baseline against which structural and functional influences on anatomic growth may be examined by clinical disciplines that address the aerodigestive and speech functions, as well as the fields of anatomy, forensics, and anthropology.     

Can we extrapolate the outcomes of in vitro studies on murine endothelium to studies of human platelet-endothelium interactions? A technical note

Introduction

Interactions between vascular endothelium and blood platelets play a crucial role in cardiovascular diseases. Ex vitro models which use endothelial cells and platelets were the essential tools to investigate these interactions and their impact on haemostasis. The impaired interplay between vascular endothelium, blood platelets and leukocytes is believed to contribute to the development of cardiovascular disease. In this study we compared the ability of human (HUVECs) and murine (HECa10) endothelial cells to inhibit human platelet function and reactivity under in vitro conditions.

Material and methods

The aliquots of platelet-rich plasma obtained from 20 healthy donors were incubated with murine endothelial cell line HECa10 or human umbilical vein endothelial cells (HUVECs) (10 min, 37°C) prior to agonizing platelets with 5 µM ADP and monitoring platelet reactivity for 10 min using optical aggregation.

Results

Significant reduction in ADP-induced platelet aggregation in the presence of endothelial cell cultures remained independent of cell count. HUVECs appeared much more effective in the inhibition of platelet aggregation compared to HECa10 (35.2 ±2.3 AU vs. 43.7 ±2.0 AU, p= 0.025).

Conclusions

HECa10 cells have much lower potential to inhibit platelet aggregation than HUVECs. This implies that these two cell lines may not be freely used interchangeably in in vitro experiments. These findings clearly indicate that the outcomes of in vitro studies performed with murine EC lines cannot be unreservedly extrapolated to human platelet-endothelium interactions.