Summary
Background
Most people with psoriasis have limited disease that could be treated with topicals, but topical efficacy is limited by low short‐term adherence. Psoriasis is a chronic disease, ...and long‐term adherence is an even bigger problem.
Objectives
To determine how well medication is used in the long‐term topical treatment of psoriasis and to assess the potential of an internet‐based reporting intervention to improve treatment adherence and outcomes.
Methods
An investigator‐blinded, prospective study evaluated topical fluocinonide adherence in 40 patients with mild‐to‐moderate psoriasis over 12 months. Subjects were randomized in a 1 : 1 ratio to standard‐of‐care or internet‐based reporting group. Adherence was objectively monitored with Medication Event Monitoring System® caps.
Results
Fifty per cent of subjects discontinued the treatment. Greater adherence was seen in the intervention group compared with the standard‐of‐care group (50% vs. 35%, P = 0·08). Psoriasis Area and Severity Index improved more in the intervention group at month 1 (1·61 vs. −0·12, P = 0·003), month 3 (2·50 vs. 0·79, P = 0·025) and month 12 (3·32 vs. 0·34, P = 0·038) than in the standard‐of‐care group.
Conclusions
This study likely underestimates the challenge of long‐term adherence, as adherence tends to be better in research studies than in clinical practice. This study also did not fully account for primary nonadherence. Adherence to topical treatment is low in the short term and decreased further in the long term, a considerable challenge for dermatologists to address. A reporting intervention may be one of the ways we can improve our patients’ treatment outcomes.
What's already known about this topic?
We already know that short‐term adherence to topical medication is poor, but there is too little information about patients’ long‐term use of treatment.
Understanding long‐term adherence to topical treatment of chronic skin diseases is essential.
What does this study add?
Long‐term adherence to topical treatment is abysmal and measures that physicians can take to improve adherence have the potential to provide major improvements in patients’ treatment outcomes.
A reporting intervention can have large effects on short‐term adherence, but effects on long‐term adherence attenuate over time.
Plain language summary available online
Most proteomic studies to date have attempted to identify changes in protein levels without considering the effects of post-translational modifications (PTM). However, characteristic changes of PTM ...such as phosphorylation could be biologically informative, as these can give insights into disease and drug mechanisms of action at the functional level. With this in mind, we have conducted a comparative proteomic and phosphoproteomic analysis of blood sera from 20 antipsychotic-naïve schizophrenia patients and 20 matched healthy controls. We used immobilised metal ion affinity chromatography (IMAC) for enrichment of phosphoproteins combined with label-free liquid chromatography-mass spectrometry (LC-MSE) for identification and measurement of protein and phosphoprotein levels. The LC-MSE analysis of both IMAC-fractions resulted in identification of 35 proteins with altered levels in schizophrenia. Analysis of the enriched fraction resulted in identification of 72 phosphoproteins with altered phosphorylation patterns. Of these, 59 showed changes in phosphorylation only, with no overall change in protein levels. This study provided evidence that schizophrenia patients feature serum abnormalities in phosphorylation of proteins involved in acute phase response and coagulation pathways. Further studies of such phosphorylation-specific changes could lead to a better understanding of the molecular aetiology of schizophrenia, and provide a means of biomarker identification for clinical studies. This article is part of a Special Issue entitled: Integrated omics.
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► Combination of depletion, IMAC and nanoLC-MSE was used to analyse serum samples. ► Non-pooled serum samples from 20 schizophrenia patients and 20 controls were investigated individually. ► Identification of 72 phosphoproteins with altered phosphorylation patterns. ► Most showed altered phosphorylation, without change in protein concentration. ► Specific examples of clinical use of changed phosphoproteins.
Tree mortality can fundamentally affect soils, which in turn shape forest regeneration and dynamics. Here, we quantify the dynamics of soil volumes associated with tree mortality, parsing effects by ...mode of tree death (broken vs uprooted) and species. The concept of ecosystem biogeomorphic succession was also tested. We used repeated tree censuses carried out in ten European and North American forests, differing in species composition, climate, and disturbance regimes. Development of more than 172,000 individual trees was recorded over periods of up to 48 years, during which more than one-third of the trees died. Biogeomorphic impact of deaths was modeled using allometry and field measurements. Tree uprooting-related soil volumes accounted annually for 0.01–13.5 m
3
ha
−1
, reaching maximum values on sites with infrequent strong windstorms (European mountains). The redistribution of soils related to trees that died standing ranged annually between 0.17 and 20.7 m
3
ha
−1
and were highest in the presence of non-stand-replacing fire (Yosemite National Park, USA). Comparison of the results with known long-term erosion rates suggests that on certain sites over the last few millennia, tree uprooting may represent a significant driver of landscape erosion. Despite the key role of severe disturbances, the data showed potential for future increases in the intensity of biogeomorphic processes. The high biogeomorphic potential in some USA sites that has not yet been realized can be activated by external changes in the disturbance regime. Forests in Central Europe, on the other hand, are more sensitive to changes in biogeomorphic processes due to species turnover.
The process of protein phosphorylation in cells is well studied in the context of a wide range of biologic functions such as signalling, cell cycle, cell growth and differentiation, and others. In ...contrast, little progress has been made in the investigation of protein phosphorylation specifically in blood. Here, we focussed on the phosphoproteome in human blood serum to study its extent and characteristics, and to explore the potential clinical utility.
Immobilised metal ion affinity chromatography (IMAC) for the enrichment of intact phosphorylated proteins and label-free liquid chromatography–mass spectrometry (LC–MSE) were used for the molecular analysis of a large number of serum samples. To obtain high-confidence results, phosphorylated peptides had to be detected in at least 2 out of 3 technical replicates per sample and in >70% of the serum samples drawn from 80 volunteers. Individual analysis of these 80 non-pooled samples resulted in the detection of 5825 unique phosphorylated peptides after filtering, which corresponded to 502 unique proteins.
The results provided evidence that blood serum may be an untapped source of phosphoproteins suitable for potential use in understanding disease pathophysiology and for identification of disease and drug response biomarkers. This article is part of a Special Issue entitled: Integrated omics.
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► We used IMAC and nanoLC-ESI-QTOF to analyse serum samples. ► Non-pooled serum samples from 80 volunteers were investigated individually. ► Peptides had to be detected in 2/3 technical replicates and in >70% of all samples. ► Just under 6000 phosphopeptides corresponding to >500 proteins detected. ► Specific examples of clinical use of phosphoproteins given.
In order to exploit human blood as a source of protein disease biomarkers, robust analytical methods are needed to overcome the inherent molecular complexity of this bio-fluid. We present the ...coupling of label-free SAX chromatography and IMAC to a data-independent nanoLC–MS/MS (nanoLC–MS
E) platform for analysis of blood plasma and serum proteins. The methods were evaluated using protein standards added at different concentrations to two groups of samples. The results demonstrate that both techniques enable accurate protein quantitation using low sample volumes and a minimal number of fractions. Combining both methods, 883 unique proteins were identified, of which 423 proteins showed high reproducibility. The two approaches resulted in identification of unique molecular signatures with an overlap of approximately 30%, thus providing complimentary information on sub-proteomes. These methods are potentially useful for systems biology, biomarker discovery, and investigation of phosphoproteins in blood.
Nicotinic acetylcholine receptors (nAChRs) have been implicated in a number of neurological disorders. 5-Iodo-3-2(S)-2-azetidinylmethoxypyridine (5-I-A-85380) is a novel nAChR marker, binding ...predominantly to the alpha4beta2 subtype. This in vitro autoradiography study describes the distribution of 5-(125)I-A-85380 binding in post-mortem brain tissue from normal elderly individuals and from cases with age-associated dementias of both neurodegenerative and vascular types. The binding distribution of 5-(125)I-A-85380 in normal brain tissue was found to be consistent with the reported distribution of other high-affinity nicotinic ligands. In addition to high thalamic and moderate striatal and temporal cortex density, moderate 5-(125)I-A-85380 binding was also seen in white matter tracts in cingulate, occipital, and temporal areas, indicating the presence of nAChRs along nerve fiber tracts, which has not been reported in other high-affinity nicotinic agonist distribution studies. In Parkinson's disease (PD), loss of striatal 5-(125)I-A-85380 binding closely parallels the loss of nigrostriatal dopaminergic markers previously observed. In dementia with Lewy bodies (DLB) reduced striatal 5-(125)I-A-85380 binding density, comparable to that in PD, may be a marker of early degeneration in nigrostriatal inputs, while in Alzheimer's disease (AD) reduced striatal 5-(125)I-A-85380 binding could be related to reduced cortical inputs. The reductions of nAChRs seen in AD, DLB, and PD were not apparent in vascular dementia (VaD). In conclusion, 5-I-A-85380 is clearly a useful ligand for both in vitro and in vivo single photon emission tomography human studies investigating disease symptoms and progression, response to acetylcholinesterase-inhibiting drugs and in differentiating primary degenerative dementia from VaD.
Dementia with Lewy bodies (DLB) is a neuropsychiatric disease associated with extrapyramidal features which differ from those of Parkinson's disease, including reduced effectiveness of L-dopa and ...severe sensitivity reactions to neuroleptic drugs. Distinguishing Alzheimer's disease from DLB is clinically relevant in terms of prognosis and appropriate treatment. Dopaminergic activities have been investigated at coronal levels along the rostrocaudal striatal axis from a post-mortem series of 25 DLB, 14 Parkinson's disease and 17 Alzheimer's disease patients and 20 elderly controls. 3HMazindol binding to the dopamine uptake site was significantly reduced in the caudal putamen in DLB compared with controls (57%), but not as extensively as in Parkinson's disease (75%), and was unchanged in Alzheimer's disease. Among three dopamine receptors measured (D1, D2 and D3), the most striking changes were apparent in relation to D2. In DLB, 3Hraclopride binding to D2 receptors was significantly reduced in the caudal putamen (17%) compared with controls, and was significantly lower than in Parkinson's disease at all levels. D2 binding was significantly elevated at all coronal levels in Parkinson's disease compared with controls, most extensively in the rostral putamen (71%). There was no change from the normal pattern of D2 binding in Alzheimer's disease. The only significant alteration in D1 binding (3HSCH23390) in the groups examined was an elevation (30%) in the caudal striatum in Parkinson's disease. There were no differences in D3 binding, measured using 3H7-OH-DPAT, in DLB compared with controls. A slight, significant decrease in D3 binding in the caudal striatum of Parkinson's disease (13%) patients and an increase in Alzheimer's disease (20%) in the dorsal striatum at the level of the nucleus accumbens were found. The concentration and distribution of dopamine were disrupted in both DLB and Parkinson's disease, although in the caudate nucleus the loss of dopamine in DLB was uniform whereas in Parkinson's disease the loss was greater caudally. In the caudal putamen, dopamine was reduced by 72% in DLB and by 90% in Parkinson's disease. The homovanillic acid : dopamine ratio, a metabolic index, indicated compensatory increased turnover in Parkinson's disease, which was absent in DLB despite the loss of substantia nigra neurons (49%), dopamine and uptake sites. These differences between DLB, Parkinson's disease and Alzheimer's disease may explain some characteristics of the extrapyramidal features of DLB and its limited response to L-dopa and severe neuroleptic sensitivity. The distinct changes in the rostrocaudal pattern of expression of dopaminergic parameters are relevant to the interpretation of the in vivo imaging and diagnosis of DLB.
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