A concept for integrated care pathways for atopic dermatitis-A GA2 LEN ADCARE initiative

INTRODUCTION: The integrated care pathways for atopic dermatitis (AD-ICPs) aim to bridge the gap between existing AD treatment evidence-based guidelines and expert opinion based on daily practice by offering a structured multidisciplinary plan for patient management of AD. ICPs have the potential to enhance guideline recommendations by combining interventions and aspects from different guidelines, integrating quality assurance, and describing co-ordination of care. Most importantly, patients can enter the ICPs at any level depending on AD severity, resources available in their country, and economic factors such as differences in insurance reimbursement systems. METHODS: The GA2 LEN ADCARE network and partners as well as all stakeholders, abbreviated as the AD-ICPs working group, were involved in the discussion and preparation of the AD ICPs during a series of subgroup workshops and meetings in years 2020 and 2021, after which the document was circulated within all GAL2 EN ADCARE centres. RESULTS: The AD-ICPs outline the diagnostic procedures, possible co-morbidities, different available treatment options including differential approaches for the pediatric population, and the role of the pharmacists and other stakeholders, as well as remaining unmet needs in the management of AD. CONCLUSION: The AD-ICPs provide a multidisciplinary plan for improved diagnosis, treatment, and patient feedback in AD management, as well as addressing critical unmet needs, including improved access to care, training specialists, implementation of educational programs, assessment on the impact of climate change, and fostering a personalised treatment approach. By focusing on these key areas, the initiative aims to pave the way for a brighter future in the management of AD

Functional interdependence of BRD4 and DOT1L in MLL leukemia.

Targeted therapies against disruptor of telomeric silencing 1-like (DOT1L) and bromodomain-containing protein 4 (BRD4) are currently being evaluated in clinical trials. However, the mechanisms by which BRD4 and DOT1L regulate leukemogenic transcription programs remain unclear. Using quantitative proteomics, chemoproteomics and biochemical fractionation, we found that native BRD4 and DOT1L exist in separate protein complexes. Genetic disruption or small-molecule inhibition of BRD4 and DOT1L showed marked synergistic activity against MLL leukemia cell lines, primary human leukemia cells and mouse leukemia models. Mechanistically, we found a previously unrecognized functional collaboration between DOT1L and BRD4 that is especially important at highly transcribed genes in proximity to superenhancers. DOT1L, via dimethylated histone H3 K79, facilitates histone H4 acetylation, which in turn regulates the binding of BRD4 to chromatin. These data provide new insights into the regulation of transcription and specify a molecular framework for therapeutic intervention in this disease with poor prognosis

Investigating causal relationships between genetically determined increased risk of attention-deficit/hyperactivity disorder (ADHD) and atopic dermatitis (AD): A Mendelian randomization analysis

Atopic dermatitis (AD) is a chronic, inflammatory skin condition with a huge disease burden. Attention-deficit/hyperactivity disorder (ADHD) is often diagnosed in children, and is associated with symptoms of inattention, hyperactivity and impulsive behaviour. Observational studies have demonstrated associations between AD and ADHD. However, to date, there has been no formal assessment of causal relationship between the two. We aim to evaluate causal relationships between genetically increased risk of AD and ADHD using Mendelian randomization (MR) approach. Two-sample bi-directional MR was conducted to elucidate potential causal relationships between genetically increased risk of AD and ADHD, using the largest and most recent genome-wide association study datasets for AD and ADHD-EArly Genetics & Lifecourse Epidemiology AD consortium (21 399 cases and 95 464 controls) and Psychiatric Genomics Consortium (20 183 cases and 35 191 controls). Genetically determined increased risk of AD is not associated with ADHD based on genetic information: odds ratio (OR) of 1.02 (95% CI -0.93 to 1.11; p = 0.705). Similarly, genetic determined increased risk of ADHD is not associated with an increased risk of AD: OR of 0.90 (95% CI -0.76 to 1.07; p = 0.236). Horizontal pleiotropy was not observed from the MR-Egger intercept test (p = 0.328) Current MR analysis showed no causal relationship between genetically increased risk of AD and ADHD in either direction in individuals of European descent. Any observed associations between AD and ADHD in previous population studies could possibly be due to confounding lifestyle factors such as psychosocial stress and sleeping habits.Published versio

Specialist pediatric dialysis nursing improves outcomes in children on chronic peritoneal dialysis

10.1007/s00467-010-1581-3Pediatric Nephrology1-

Why tocotrienols work better: insights into the in vitro anti-cancer mechanism of vitamin E

The selective constraint of liver uptake and the sustained metabolism of tocotrienols (T3) demonstrate the need for a prompt detoxification of this class of lipophilic vitamers, and thus the potential for cytotoxic effects in hepatic and extra-hepatic tissues. Hypomethylated (γ and δ) forms of T3 show the highest in vitro and in vivo metabolism and are also the most potent natural xenobiotics of the entire vitamin E family of compounds. These stimulate a stress response with the induction of detoxification and antioxidant genes. Depending on the intensity of this response, these genes may confer cell protection or alternatively they stimulate a senescence-like phenotype with cell cycle inhibition or even mitochondrial toxicity and apoptosis. In cancer cells, the uptake rate and thus the cell content of these vitamers is again higher for the hypomethylated forms, and it is the critical factor that drives the dichotomy between protection and toxicity responses to different T3 forms and doses. These aspects suggest the potential for marked biological activity of hypomethylated “highly metabolized” T3 that may result in cytoprotection and cancer prevention or even chemotherapeutic effects. Cytotoxicity and metabolism of hypomethylated T3 have been extensively investigated in vitro using different cell model systems that will be discussed in this review paper as regard molecular mechanisms and possible relevance in cancer therapy