A 28-day clinical trial of aerosolized hyaluronan in alpha-1 antiprotease deficiency COPD using desmosine as a surrogate marker for drug efficacy

A previous 2-week clinical trial of aerosolized hyaluronan (HA) in COPD showed a rapid reduction in lung elastic fiber breakdown, as measured by sputum levels of the unique elastin crosslinks, desmosine and isodesmosine (DID). To further assess the therapeutic efficacy of HA and the utility of DID as surrogate markers for the development of pulmonary emphysema, we have conducted a 28-day randomized, double-blind, placebo-controlled, phase 2 trial of HA involving 27 subjects with alpha-1 antiprotease deficiency COPD.The study drug consisted of a 3 ml inhalation solution containing 0.03% HA with an average molecular weight of 150 kDa that was self-administered twice daily. DID levels were measured in urine, sputum, and plasma using tandem mass spectrometry.Free urine DID in the HA group showed a significant negative correlation with time between days 14 and 35 (r = -1.0, p = 0.023) and was statistically significantly decreased from baseline at day 35 (15.4 vs 14.2 ng/mg creatinine, p = 0.035). A marked decrease in sputum DID was also seen in the HA group between days 1 and 28 (0.96 vs 0.18 ng/mg protein), but the difference was not significant, possibly due to the small number of adequate specimens. Plasma DID remained unchanged following HA treatment and no significant reductions in urine, sputum, or plasma DID were seen in the placebo group.The results support additional clinical trials to further evaluate the therapeutic effect of HA and the use of DID as a real-time marker of drug efficacy.•Aerosolized hyaluronan (HA) was given to alpha-1 antiprotease deficient COPD patients for 28 days without significant adverse effects.•Treatment with HA (but not placebo) significantly decreased free desmosine in urine, consistent with reduced lung elastic fiber injury.•The findings support further investigation of the therapeutic effect of HA in COPD and the use of desmosine as a biomarker for drug efficacy

The History of Mum and Dad: Recent Historical Research on Parenting in England from the 16th to 20th centuries

Parenting has a complex but only recently examined history. This article surveys this scholarship, which is driven by the histories of gender, emotions, medicine, bodies, material culture, class and deviance to uncover how parenting is socially and culturally constructed and therefore changes over time. It traces several significant arguments. First, shifting gender constructions have reshaped expectations about mothers' and fathers' roles. Thus, while paternal breadwinning and maternal care is always important, at times fathers have been commended for caring for infants and mothers for economic provision of offspring. Secondly, the material aspects of life have powerfully affected parenting. Until relatively recently, parents struggled against implacably high rates of infant and child mortality: nursing children, preparing them for death and the afterlife, and coping with grief. Therefore, although the depth of feeling over this remained consistent, varying emotional regimes have influenced forms of parental expression and practice. Parents' responsibilities for their children's health at times of inadequate medical treatment often left them physically and mentally exhausted and woefully disempowered. Other limitations or freedoms were imposed on mothering and fathering by the objects and spaces associated with bringing up children. Thirdly, levels of wealth and social class affect parenting, with working-class, poor and lone parents especially vulnerable to family disruption due to poverty, ill-health and under- or unemployment. Fourthly, the parameters of bad parenting shift over time, and even those mothers and fathers who killed their children were viewed differently over time and place as cultural sensibilities shifted. Finally, the article concludes with some suggestions for the further development of this exciting new field

GPCR Theme Editorial

This themed section of BJP includes 11 reviews on the biology of G-protein coupled receptors (GPCRs) and the drug targets that these present, 21 research papers on the pharmacology of a range of GPCRs and Commentaries on four of the papers

Diffusion tensor imaging of the hippocampus and verbal memory performance: The RUN DMC Study

Background: Cerebral small vessel disease (SVD) and hippocampal atrophy are related to verbal memory failures and may ultimately result in Alzheimer's disease. However, verbal memory failures are often present before structural changes on conventional MRI appear. Changes in microstructural integrity of the hippocampus, which cannot be detected with conventional MRI, may be the underlying pathological substrate. With diffusion tensor imaging (DTI), we investigated the relation between the microstructural integrity of the hippocampus and verbal memory performance in 503 nondemented elderly with SVD. Methods: The Radboud University Nijmegen Diffusion tensor and Magnetic resonance imaging Cohort study is a prospective cohort study among 503 nondemented elderly with cerebral SVD aged between 50 and 85 years. All participants underwent T1 MPRAGE, fluid-attenuated inversion recovery, DTI scanning and the Rey Auditory Verbal Learning Test. After manual segmentation of the hippocampi, we calculated the mean diffusivity (MD) and fractional anisotropy in both hippocampi. The relation between memory performance and hippocampal DTI parameters was adjusted for age, sex, education, depressive symptoms, hippocampal, and white-matter lesions volume and lacunar infarcts. Results: We found inverse relations between hippocampal MD and verbal memory performance (β = −0.22; P < 0.001), immediate recall (β = −0.22; P < 0.001), delayed recall (β = −0.20; P < 0.001), and forgetting rate (β = −0.13; P = 0.025), most pronounced in participants with a normal hippocampal volume. Conclusion: Microstructural integrity of the hippocampus assessed by DTI is related to verbal memory performance in elderly with SVD, also in participants with an intact appearing hippocampus. Changes in hippocampal microstructure may be an early marker of underlying neurodegenerative disease, before macrostructural (i.e., volumetric) changes occur. Hum Brain Mapp, 201