A Novel Group Cognitive Behavioral Therapy Approach to Adult Non-rapid Eye Movement Parasomnias

Copyright © 2021 O’Regan, Nesbitt, Biabani, Drakatos, Selsick, Leschziner, Steier, Birdseye, Duncan, Higgins, Kumari, Stokes, Young and Rosenzweig. Background: Following the success of Cognitive Behavioral Therapy (CBT) for insomnia, there has been a growing recognition that similar treatment approaches might be equally beneficial for other major sleep disorders, including non-rapid eye movement (NREM) parasomnias. We have developed a novel, group-based, CBT-program for NREM parasomnias (CBT-NREMP), with the primary aim of reducing NREM parasomnia severity with relatively few treatment sessions. Methods: We investigated the effectiveness of CBT-NREMP in 46 retrospectively-identified patients, who completed five outpatient therapy sessions. The outcomes pre- and post- CBT-NREMP treatment on clinical measures of insomnia (Insomnia Severity Index), NREM parasomnias (Paris Arousal Disorders Severity Scale) and anxiety and depression (Hospital Anxiety and Depression Scale), were retrospectively collected and analyzed. In order to investigate the temporal stability of CBT-NREMP, we also assessed a subgroup of 8 patients during the 3 to 6 months follow-up period. Results: CBT-NREMP led to a reduction in clinical measures of NREM parasomnia, insomnia, and anxiety and depression severities [pre- vs. post-CBT-NREMP scores: P (Insomnia Severity Index) = 0.000054; P (Paris Arousal Disorders Severity Scale) = 0.00032; P (Hospital Anxiety and Depression Scale) = 0.037]. Improvements in clinical measures of NREM parasomnia and insomnia severities were similarly recorded for a subgroup of eight patients at follow-up, demonstrating that patients continued to improve post CBT-NREMP. Conclusion: Our findings suggest that group CBT-NREMP intervention is a safe, effective and promising treatment for NREM parasomnia, especially when precipitating and perpetuating factors are behaviorally and psychologically driven. Future randomized controlled trials are now required to robustly confirm these findings.National Institute for Health Research (NIHR) Biomedical Research Centre at South London; Maudsley NHS Foundation Trust and King's College London; National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College Londo

Effect of ABCB1 and ABCC3 Polymorphisms on Osteosarcoma Survival after Chemotherapy: A Pharmacogenetic Study

Background: Standard treatment for osteosarcoma patients consists of a combination of cisplatin, adriamycin, and methotrexate before surgical resection of the primary tumour, followed by postoperative chemotherapy including vincristine and cyclophosphamide. Unfortunately, many patients still relapse or suffer adverse events. We examined whether common germline polymorphisms in chemotherapeutic transporter and metabolic pathway genes of the drugs used in standard osteosarcoma treatment may predict treatment response. Methodology/Principal Findings: In this study we screened 102 osteosarcoma patients for 346 Single Nucleotide Polymorphisms (SNPs) and 2 Copy Number Variants (CNVs) in 24 genes involved in the metabolism or transport of cisplatin, adriamycin, methotrexate, vincristine, and cyclophosphamide. We studied the association of the genotypes with tumour response and overall survival. We found that four SNPs in two ATP-binding cassette genes were significantly associated with overall survival: rs4148416 in ABCC3 (per-allele HR = 8.14, 95%CI = 2.73-20.2, p-value = 5.1×10 -5), and three SNPs in ABCB1, rs4148737 (per-allele HR = 3.66, 95%CI = 1.85-6.11, p-value = 6.9×10 -5), rs1128503 and rs10276036 (r 2 = 1, per-allele HR = 0.24, 95%CI = 0.11-0.47 p-value = 7.9×10 -5). Associations with these SNPs remained statistically significant after correction for multiple testing (all corrected p-values [permutation test] ≤0.03). Conclusions: Our findings suggest that these polymorphisms may affect osteosarcoma treatment efficacy. If these associations are independently validated, these variants could be used as genetic predictors of clinical outcome in the treatment of osteosarcoma, helping in the design of individualized therapyThis work was supported by the AECC (Asociación Española contra el Cáncer), FIS (Fondo de Investigación Sanitaria-Instituto de Salud Carlos III) and the ‘‘Inocente Inocente’’ Foundatio

Pharmacogenetics: data, concepts and tools to improve drug discovery and drug treatment

Variation in the human genome is a most important cause of variable response to drugs and other xenobiotics. Susceptibility to almost all diseases is determined to some extent by genetic variation. Driven by the advances in molecular biology, pharmacogenetics has evolved within the past 40 years from a niche discipline to a major driving force of clinical pharmacology, and it is currently one of the most actively pursued disciplines in applied biomedical research in general. Nowadays we can assess more than 1,000,000 polymorphisms or the expression of more than 25,000 genes in each participant of a clinical study – at affordable costs. This has not yet significantly changed common therapeutic practices, but a number of physicians are starting to consider polymorphisms, such as those in CYP2C9, CYP2C19, CYP2D6, TPMT and VKORC1, in daily medical practice. More obviously, pharmacogenetics has changed the practices and requirements in preclinical and clinical drug research; large clinical trials without a pharmacogenomic add-on appear to have become the minority. This review is about how the discipline of pharmacogenetics has evolved from the analysis of single proteins to current approaches involving the broad analyses of the entire genome and of all mRNA species or all metabolites and other approaches aimed at trying to understand the entire biological system. Pharmacogenetics and genomics are becoming substantially integrated fields of the profession of clinical pharmacology, and education in the relevant methods, knowledge and concepts form an indispensable part of the clinical pharmacology curriculum and the professional life of pharmacologists from early drug discovery to pharmacovigilance

Structural basis for the initiation of eukaryotic transcription-coupled DNA repair

Eukaryotic transcription-coupled repair (TCR) is an important and well-conserved sub-pathway of nucleotide excision repair that preferentially removes DNA lesions from the template strand that block translocation of RNA polymerase II (Pol II). Cockayne syndrome group B (CSB, also known as ERCC6) protein in humans (or its yeast orthologues, Rad26 in Saccharomyces cerevisiae and Rhp26 in Schizosaccharomyces pombe) is among the first proteins to be recruited to the lesion-arrested Pol II during the initiation of eukaryotic TCR. Mutations in CSB are associated with the autosomal-recessive neurological disorder Cockayne syndrome, which is characterized by progeriod features, growth failure and photosensitivity1. The molecular mechanism of eukaryotic TCR initiation remains unclear, with several long-standing unanswered questions. How cells distinguish DNA lesion-arrested Pol II from other forms of arrested Pol II, the role of CSB in TCR initiation, and how CSB interacts with the arrested Pol II complex are all unknown. The lack of structures of CSB or the Pol II–CSB complex has hindered our ability to address these questions. Here we report the structure of the S. cerevisiae Pol II–Rad26 complex solved by cryo-electron microscopy. The structure reveals that Rad26 binds to the DNA upstream of Pol II, where it markedly alters its path. Our structural and functional data suggest that the conserved Swi2/Snf2-family core ATPase domain promotes the forward movement of Pol II, and elucidate key roles for Rad26 in both TCR and transcription elongation

PREVALENCE OF RESTLESS LEGS SYNDROME IN PATIENTS WITH RESISTANT HYPERTENSION: A CROSS-SECTIONAL, BI-CENTRIC COHORT STUDY

Objective: Though obstructive sleep apnea syndrome (OSAS) is common in patients with resistant hypertension (RH), the prevalence of other sleep disorders, such as restless legs syndrome (RLS) is unknown. We aimend at investigating the prevalence of OSAS and RLS in a cohort of patients with RH recruited in two centres. Design and method: By using the ESC/ESH definition we consecutively recruited 63 patients with RH (age 63 ± 12 years, BMI 32 ± 6 kg/mq, 24% women, 31% patients with previous CV events, 31% diabetic), undergoing a polisomnographic study. RLS rating scale, Epworth Sleepiness Scale (ESS), past medical history and office BP were obtained. Sleep stages were scored according to 2007 AASM modified criteria. Results: Moderate-severe OSAS (AHI>15/h) was diagnosed in 34 RH patients (54%), RLS in 26 (41%): 13 patients presented both conditions. Only 16 patients (25%) had neither OSAS nor RLS. Periodic limb movements (PLM Index>15/h) were present in 31% of the studied population. OSAS+RLS- and OSAS+RLS+ patients were older than OSAS-RLS- and OSAS-RLS+. None among OSAS-RLS- had diabetes. OSAS+RLS- patients had a reduced total sleep time, sleep and REM latency and sleep efficiency in comparison to OSAS-RLS-. Conversely, slow wave sleep was reduced only in OSAS+RLS+. PLM index was increased in OSAS-RLS+ [18 (0–36)] but not in OSAS+RLS+ [2 (0–25), p < 0.05]. Conclusions: OSAS and RLS are common in RH patients, often co-occurring. BMI or daily sleepiness are not useful to identify RH patients with sleep disorders, suggesting that all RH patients should undergo polisomnography. Diabetes seems to be a feature of RH patients with sleep disorders. When coexisting with OSAS, RLS is not associated with PLM, suggesting a different pathophysiology. However, the presence of OSAS together with RLS is associated with shorter slow wave sleep, a phenomenon that can possibly lead to severe cardiovascular and cognitive complications in this subgroup