Dual bronchodilatory and pulmonary anti-inflammatory activity of RO5024118, a novel agonist at vasoactive intestinal peptide VPAC2 receptors

BACKGROUND AND PURPOSE

Vasoactive intestinal peptide is expressed in the respiratory tract and induces its effects via its receptors, VPAC₁ and VPAC₂. RO5024118 is a selective VPAC₂ receptor agonist derived via chemical modification of an earlier VPAC₂ agonist, RO0251553. In the present studies, we characterized the pharmacological activity of RO5024118.

EXPERIMENTAL APPROACH

Stability of RO5024118 to human neutrophil elastase was assessed. Bronchodilatory activity of RO5024118 was investigated in guinea pig and human isolated airway smooth muscle preparations and in a guinea pig bronchoconstriction model. Pulmonary anti-inflammatory activity of RO5024118 was investigated in a lipopolysaccharide mouse model and in a porcine pancreatic elastase (PPE) rat model.

KEY RESULTS

RO5024118 demonstrated increased stability to neutrophil elastase compared with RO0251553. In human and guinea pig isolated airway preparations, RO5024118 induced bronchodilatory effects comparable with RO0251553 and the long-acting β-agonist salmeterol and was significantly more potent than native vasoactive intestinal peptide and the short-acting β-agonist salbutamol. In 5-HT-induced bronchoconstriction in guinea pigs, RO5024118 exhibited inhibitory activity with similar efficacy as, and longer duration than, RO0251553. In a lipopolysaccharide-mouse model, RO5024118 inhibited neutrophil and CD8⁺ cells and myeloperoxidase levels. In rats, intratracheal instillation of PPE induced airway neutrophilia that was resistant to dexamethasone. Pretreatment with RO5024118 significantly inhibited PPE-induced neutrophil accumulation.

CONCLUSIONS AND IMPLICATIONS

These results demonstrate that RO5024118 induces dual bronchodilatory and pulmonary anti-inflammatory activity and may be beneficial in treating airway obstructive and inflammatory diseases.     

The growth of uterine myomas in untreated women: influence factors and ultrasound monitoring

Purpose

Until now there are no systematic studies about the long-term course of myoma growth. Therefore, the aims of the present study were: (1) ultrasound monitoring of the natural course of growth of uterine leiomyomas; (2) assessment of whether the growth of myomas depends on the age of the patients, the location, or the initial size (possible co-factors/predictor criteria for increase of growth); influence of oral contraceptives (OC).

Methods

Patient records (2010–May 2016) were retrospectively and systematically evaluated in regards to their growth and clinical course. The patients received a follow-up questionnaire by mail about the further history. Linear regression analysis and generalized regression analysis were performed to determine the influence of various factors on the growth of myomas.

Results

Overall, 152 met the further inclusion criteria. Most of the myomas increased in size but 10% of the myomas became smaller without therapy. There is a significant dependency between the initial myoma size, and the first and second measurements, but not between those measures and myoma localization. In regression analysis, there was also a significant association between the growth of the myomas and the initial size but no association with age, complaint symptoms, and use of OC. However, the use of OC waas significantly associated with myoma growth in GEE.

Conclusions

The course of growth of myomas has large variance, so this should not be taken as a sign for a malignant event (sarcoma or the so-called STUMP). The growth takes place with considerable individual variability and ultimately is not predictable.

     

Longitudinal associations of social cognition and substance use in childhood and early adolescence: findings from the Avon Longitudinal Study of Parents and Children

Substance use is associated with impaired social cognition. Experimental studies have shown that acute intoxication of alcohol, tobacco, and cannabis decreases the performance in non-verbal, social communication and theory of mind tasks. However, in epidemiological studies the temporal direction of this association has gone relatively unstudied. We investigated both directions of association within an adolescent birth cohort: the association of social cognition with subsequent substance use, and the association of early substance use with subsequent social cognition. We used data from the Avon Longitudinal Study of Parents and Children, a UK birth cohort. Logistic regression indicated that poor childhood non-verbal communication was associated with decreased odds of adolescent alcohol (OR 0.70, 95% 0.54–0.91), tobacco (OR 0.62, 95% CI 0.47–0.83), and cannabis use (OR 0.62, 95% CI 0.46–0.83). Early adolescent substance use was associated with increased odds of poor social communication (alcohol: OR 1.46, 95% CI 0.99–2.14; tobacco: OR 1.95, 95% CI 1.33–2.86) and poor social reciprocity (alcohol: OR 1.57, 95% CI 1.18–2.09; tobacco: OR 1.92, 95% CI 1.43–2.58; cannabis: OR 1.54, 95% CI 1.16–2.05). Overall, the relationship between social cognition and substance use was different in each temporal direction. Poor non-verbal communication in childhood appeared protective against later substance use, while adolescent substance use was associated with decreased social cognitive performance.     

Comparative effects of ionic and nonionic iodinated low-osmolar contrast media on platelet function with the PFA-100 (platelet function analyzer)

RATIONALE AND OBJECTIVES: This study was designed to (1) compare the effects of ionic (ioxaglate) and nonionic (iodixanol and iohexol) iodinated low-osmolar contrast media (CM) on platelet function in human whole blood by using the new PFA-100trade mark, a "platelet function analyzer"; (2) determine the animal species closest to human with regard to platelet reactivity to CM; and (3) evaluate which element of the ioxaglate solution supports this activity. METHODS: For all studies, platelet adhesion and aggregation were measured using the PFA-100trade mark system with adenosine diphosphate-primed collagen membrane cartridges. Results are shown as the membrane closure time (MCT; the longer the MCT, the greater the antiaggregatory effect) and given as medians. Citrated whole-blood samples from six healthy volunteers were mixed for 1 minute with a 10% (vol/vol) solution of ioxaglate, iodixanol, or iohexol or their respective ionic and nonionic controls (isotonic saline and mannitol). The test solution/control solution ratio for the MCT was calculated for the blood of humans, guinea pigs, rabbits, dogs, and rats. Isotonic saline and iso-osmolar (280 mOsm/kg) and hyperosmolar (560 mOsm/kg) solutions of meglumine hydrochloride, meglumine ioxaglate (560 mOsm/kg), and sodium ioxaglate (600 mOsm/kg) were tested under similar conditions. RESULTS: All three CM caused significant prolongation of MCT when compared with their respective controls (ioxaglate: 300 seconds, ie, "no closure" on the PFA-100trade mark system; iodixanol: 179 seconds; iohexol: 171 seconds; saline: 115 seconds; mannitol: 118 seconds). The antiplatelet effect of ioxaglate was higher than that of iodixanol and iohexol (P < 0.05). The animal species tested did not differ significantly from the human species with regard to an effect of their blood on MCT. Both ioxaglic acid salts caused a higher prolongation of MCT when compared with saline (sodium salt: 259 seconds; meglumine salt: 212 seconds; P < 0.05 vs. saline) but not versus the ioxaglate commercial solution. Conversely, both iso- and hyperosmolar solutions of meglumine hydrochloride (108 and 128 seconds, respectively) did not lengthen MCT versus saline, but their MCTs were shorter than that of the commercial solution of ioxaglate (P < 0.05). CONCLUSIONS: The ionic CM ioxaglate displayed a greater antiaggregatory effect on human platelets than did both iso-osmolar (iodixanol) and hyperosmolar (iohexol) nonionic CM. This effect seems to be linked to the ioxaglic moiety, because neither osmolality nor sodium or meglumine appeared to play a significant role.     

Immunisation with a polyvalent pneumococcal vaccine. Effect of respiratory mortality in children living in the New Guinea highlands

In Tari, in the southern highlands of Papua New Guinea, each child experienced, on average, two acute lower respiratory tract infections (ALRTI) between birth and age 5 years. The yearly mortality rate from ALRTI was 30 per 1000 in infants, and 4 per 1000 in children aged between 1 and 4 years. A double-blind trial of a 14-valent pneumococcal polysaccharide vaccine was carried out on 871 children from this community who were aged between 6 months and 5 years. Morbidity from ALRTI was lower (by 37%) in children given the vaccine provided they were at least 17 months of age at the time of immunisation. There were 8 deaths from ALRTI in the placebo group, but only 1 death in the vaccine group.     

Dairy product intake and mortality in a cohort of 70-year-old Swedes: a contribution to the Nordic diet discussion

Introduction

Conflicting results in the literature exist on the role of dairy products in the context of a Nordic Healthy Diet (NHD). Two recent Swedish studies indicate both negative and positive associations with total mortality when comparing key dairy products. There is no consensus about how to include these foods into the NHD.

Purpose

To study consumption of cheese and milk products (milk, sour milk and unsweetened yoghurt) by 70-year-old Swedes in relation to all-cause mortality.

Methods

Cox proportional hazard models, adjusted for potential confounders and stratified by follow-up duration, were used to assess the prediction of all-cause mortality by the above foods. The associations of fat from cheese and milk products with mortality were tested in separate models.

Results

Cheese intake inversely predicted total mortality, particularly at high protein intakes, and this association decreased in strength with increasing follow-up time. Milk products predicted increased mortality with stable HRs over follow-up. The association between milk products and mortality was strongly influenced by the group with the highest consumption. Fat from cheese mirrored the protective association of cheese intake with mortality, whereas fat from milk products predicted excess mortality, but only in an energy-adjusted model.

Conclusion

Based on our results, it may be argued that the role of dairy products in the context of a Nordic healthy diet should be more clearly defined by disaggregating cheese and milk products and not necessarily focusing on dairy fat content. Future epidemiological research should consider dairy products as disaggregated food items due to their great diversity in health properties.

     

Quality improvement strategies for organizational change: a multiphase observational study to increase insight into nonparticipating organizations

Background

The scope of implementation research is often restricted to the analysis of organizations that participate voluntarily in implementation interventions. The recruitment of participants for a quality improvement collaborative increases awareness of the specific innovation. The objective of this multiphase observational study was to identify differences between organizations that participated in a large-scale implementation project aiming to improve perioperative care, functional recovery, and length of hospital stay after gynecologic surgery and organizations that did not participate. A secondary objective was to explore how perioperative practice changed among nonparticipants.

Methods

Of the seven gynecology departments of nonparticipating Dutch hospitals, five agreed to participate in a retrospective analysis. Baseline data of participating hospitals’ (N?=?19) characteristics, time to functional recovery, and length of hospital stay were compared. Outcome measures for the subsequent pre-post awareness study in the five nonparticipating hospitals were: (1) overall adherence to predefined evidence-based perioperative elements; and (2) change in functional recovery and length of hospital stay. Multivariable regression models, adjusted for baseline characteristics, were used for analysis.

Results

In retrospect, nonparticipating and participating hospitals did not differ in baseline characteristics, functional recovery, and length of hospital stay. In three of the five nonparticipating hospitals, adherence to the selected evidence-based perioperative elements increased significantly after awareness of the trial (overall mean difference 9.7%, 95% CI 6.9 to 12.5%, p?<? 0.001). Linear regression models revealed no statistically significant or clinically relevant differences in time to functional recovery (mean difference???0.2?days, 95% CI -0.7 to 0.2, p?=?0.319) or length of hospital stay (mean difference???0.4?days, 95% CI -1.3 to 0.5, p?=?0.419) in the nonparticipating hospitals. None of these hospitals managed to reduce time to functional recovery or length of hospital stay significantly.

Conclusions

No differences in perioperative outcomes between the nonparticipating and participating hospitals were identified at baseline. Despite the statistically significant improvement in overall evidence-based perioperative care, the awareness raised by recruitment activities alone was not enough to reduce time to functional recovery and length of hospital stay in nonparticipating hospitals. Insight into the trends of nonparticipants is valuable to existing implementation effectiveness research.

     

Hematological Diagnostic Markers of Acute Appendicitis in Children

Background

White blood cell (WBC) and platelet indices are useful biomarkers in many inflammatory diseases. A study was made of possible WBC and platelet indices in children with acute appendicitis.

Methods

We reviewed the results of the complete blood count tests made on admission of 150 children with acute appendicitis (94 boys, 56 girls) and those of 74 healthy children (46 boys, 28 girls). We compared the WBC and platelet indices between the children with acute appendicitis and healthy children and between the complicated and uncomplicated cases of appendicitis.

Results

The children with acute appendicitis had higher WBC, neutrophil count, neutrophil percentage and neutrophil/ lymphocyte ratio and lower lymphocyte count and lymphocyte percentage than the healthy children. Cases of appendicitis with complications had lower lymphocyte count, lymphocyte percentage and higher neutrophil to lymphocyte ratio than those without complications. In girls WBC, neutrophil count and neutrophil percentage were higher in complicated acute appendicitis. WBC, neutrophil count, neutrophil percentage, lymphocyte percentage and a neutrophil/lymphocyte ratio >2.5 were accurate markers for acute appendicitis in children, but not for detecting complicated cases. Girls with acute appendicitis had lower platelet distribution width than healthy girls, with high sensitivity and positive predictive value at platelet distribution width <12.4%, but moderate specificity and negative predictive value.

Conclusions

The Neutrophil/lymphocyte ratio can be used as an additional diagnostic marker of acute appendicitis in children, but cannot detect complications, and platelet distribution width can be an additional marker for confirming, but not excluding, acute appendicitis in girls.