COgnitive behavioural therapy vs standardised medical care for adults with Dissociative non-Epileptic Seizures (CODES): a multicentre randomised controlled trial protocol

Background The evidence base for the effectiveness of psychological interventions for patients with dissociative non-epileptic seizures (DS) is currently extremely limited, although data from two small pilot randomised controlled trials (RCTs), including from our group, suggest that Cognitive Behavioural Therapy (CBT) may be effective in reducing DS occurrence and may improve aspects of psychological status and psychosocial functioning. Methods/Design The study is a multicentre, pragmatic parallel group RCT to evaluate the clinical and cost-effectiveness of specifically-tailored CBT plus standardised medical care (SMC) vs SMC alone in reducing DS frequency and improving psychological and health-related outcomes. In the initial screening phase, patients with DS will receive their diagnosis from a neurologist/epilepsy specialist. If patients are eligible and interested following the provision of study information and a booklet about DS, they will consent to provide demographic information and fortnightly data about their seizures, and agree to see a psychiatrist three months later. We aim to recruit ~500 patients to this screening stage. After a review three months later by a psychiatrist, those patients who have continued to have DS in the previous eight weeks and who meet further eligibility criteria will be told about the trial comparing CBT + SMC vs SMC alone. If they are interested in participating, they will be given a further booklet on DS and study information. A research worker will see them to obtain their informed consent to take part in the RCT. We aim to randomise 298 people (149 to each arm). In addition to a baseline assessment, data will be collected at 6 and 12 months post randomisation. Our primary outcome is monthly seizure frequency in the preceding month. Secondary outcomes include seizure severity, measures of seizure freedom and reduction, psychological distress and psychosocial functioning, quality of life, health service use, cost effectiveness and adverse events. We will include a nested qualitative study to evaluate participants’ views of the intervention and factors that acted as facilitators and barriers to participation. Discussion This study will be the first adequately powered evaluation of CBT for this patient group and offers the potential to provide an evidence base for treating this patient group. Trial registration Current Controlled Trials ISRCTN05681227 ClinicalTrials.gov NCT0232554

COgnitive behavioural therapy versus standardised medical care for adults with Dissociative non-Epileptic Seizures (CODES): statistical and economic analysis plan for a randomised controlled trial.

BACKGROUND: Dissociative seizures (DSs), also called psychogenic non-epileptic seizures, are a distressing and disabling problem for many patients in neurological settings with high and often unnecessary economic costs. The COgnitive behavioural therapy versus standardised medical care for adults with Dissociative non-Epileptic Seizures (CODES) trial is an evaluation of a specifically tailored psychological intervention with the aims of reducing seizure frequency and severity and improving psychological well-being in adults with DS. The aim of this paper is to report in detail the quantitative and economic analysis plan for the CODES trial, as agreed by the trial steering committee. METHODS: The CODES trial is a multicentre, pragmatic, parallel group, randomised controlled trial performed to evaluate the clinical effectiveness and cost-effectiveness of 13 sessions of cognitive behavioural therapy (CBT) plus standardised medical care (SMC) compared with SMC alone for adult outpatients with DS. DISCUSSION: The objectives and design of the trial are summarised, and the aims and procedures of the planned analyses are illustrated. The proposed analysis plan addresses statistical considerations such as maintaining blinding, monitoring adherence with the protocol, describing aspects of treatment and dealing with missing data. The formal analysis approach for the primary and secondary outcomes is described, as are the descriptive statistics that will be reported. This paper provides transparency to the planned inferential analyses for the CODES trial prior to the extraction of outcome data. It also provides an update to the previously published trial protocol and guidance to those conducting similar trials. TRIAL REGISTRATION: ISRCTN registry ISRCTN05681227 (registered on 5 March 2014); ClinicalTrials.gov NCT02325544 (registered on 15 December 2014)

Widespread Hypomethylation Occurs Early and Synergizes with Gene Amplification during Esophageal Carcinogenesis

Although a combination of genomic and epigenetic alterations are implicated in the multistep transformation of normal squamous esophageal epithelium to Barrett esophagus, dysplasia, and adenocarcinoma, the combinatorial effect of these changes is unknown. By integrating genome-wide DNA methylation, copy number, and transcriptomic datasets obtained from endoscopic biopsies of neoplastic progression within the same individual, we are uniquely able to define the molecular events associated progression of Barrett esophagus. We find that the previously reported global hypomethylation phenomenon in cancer has its origins at the earliest stages of epithelial carcinogenesis. Promoter hypomethylation synergizes with gene amplification and leads to significant upregulation of a chr4q21 chemokine cluster and other transcripts during Barrett neoplasia. In contrast, gene-specific hypermethylation is observed at a restricted number of loci and, in combination with hemi-allelic deletions, leads to downregulatation of selected transcripts during multistep progression. We also observe that epigenetic regulation during epithelial carcinogenesis is not restricted to traditionally defined “CpG islands,” but may also occur through a mechanism of differential methylation outside of these regions. Finally, validation of novel upregulated targets (CXCL1 and 3, GATA6, and DMBT1) in a larger independent panel of samples confirms the utility of integrative analysis in cancer biomarker discovery

The cystic fibrosis microbiome in an ecological perspective and its impact in antibiotic therapy

The recent focus on the cystic fibrosis (CF) complex microbiome has led to the recognition that the microbes can interact between them and with the host immune system, affecting the disease progression and treatment routes. Although the main focus remains on the interactions between traditional pathogens, growing evidence supports the contribution and the role of emergent species. Understanding the mechanisms and the biological effects involved in polymicrobial interactions may be the key to improve effective therapies and also to define new strategies for disease control. This review focuses on the interactions between microbe-microbe and host-microbe, from an ecological point of view, discussing their impact on CF disease progression. There are increasing indications that these interactions impact the success of antimicrobial therapy. Consequently, a new approach where therapy is personalized to patients by taking into account their individual CF microbiome is suggested.Portuguese Foundation for Science and Technology (FCT), the strategic funding of UID/BIO/04469/2013-CEB and UID/EQU/00511/2013-LEPABE units. This study was also supported by FCT and the European Community fund FEDER, through Program COMPETE, under the scope of the Projects “DNA mimics” PIC/IC/82815/2007, RECI/BBB-EBI/0179/2012 (FCOMP-01-0124-FEDER-027462), “BioHealth—Biotechnology and Bioengineering approaches to improve health quality”, Ref. NORTE-07-0124-FEDER-000027 and NORTE-07-0124-FEDER-000025—RL2_ Environment and Health, co-funded by the Programa Operacional Regional do Norte (ON.2 – O Novo Norte), QREN, FEDER. The authors also acknowledge the grant of Susana P. Lopes (SFRH/BPD/95616/2013) and of the COST-Action TD1004: Theragnostics for imaging and therapy

A Chaperone Trap Contributes to the Onset of Cystic Fibrosis

Protein folding is the primary role of proteostasis network (PN) where chaperone interactions with client proteins determine the success or failure of the folding reaction in the cell. We now address how the Phe508 deletion in the NBD1 domain of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein responsible for cystic fibrosis (CF) impacts the binding of CFTR with cellular chaperones. We applied single ion reaction monitoring mass spectrometry (SRM-MS) to quantitatively characterize the stoichiometry of the heat shock proteins (Hsps) in CFTR folding intermediates in vivo and mapped the sites of interaction of the NBD1 domain of CFTR with Hsp90 in vitro. Unlike folding of WT-CFTR, we now demonstrate the presence of ΔF508-CFTR in a stalled folding intermediate in stoichiometric association with the core Hsps 40, 70 and 90, referred to as a ‘chaperone trap’. Culturing cells at 30 C resulted in correction of ΔF508-CFTR trafficking and function, restoring the sub-stoichiometric association of core Hsps observed for WT-CFTR. These results support the interpretation that ΔF508-CFTR is restricted to a chaperone-bound folding intermediate, a state that may contribute to its loss of trafficking and increased targeting for degradation. We propose that stalled folding intermediates could define a critical proteostasis pathway branch-point(s) responsible for the loss of function in misfolding diseases as observed in CF

Resilience of cereal crops to abiotic stress: A review

In the last century, conventional selection and breeding program proved to be highly effective in improving crops against abiotic stresses. Therefore, breeding for abiotic stress tolerance in crop plants should be given high research priority as abiotic stresses are the main factor negatively affecting crop growth and productivity throughout the globe. Advancement in physiology, genetics and molecular biology, have greatly improved our understanding of plant responses to stresses. Many studies show that salt tolerance is tightly associated with the ability to maintain ion homeostasis under salinity. Na+ transporter SKC1 unloads Na+ from xylem; plasma membrane N+/H+ antiporter SOS1 excludes sodium out of cytosol, and tonoplast Na+/H+ antiporter NHX1 sequesters Na+ into the vacuole. Silicon deposition in exodermis and endodermis of rice root reduces sodium transport through the apoplastic pathway. A number of transcription factors regulate stress-inducible gene expression that leads to initiating stress responses and establishing plant stress tolerance. Over expression of some transcription factors, including DREB/CBF and NAC, enhances salt, drought, and cold tolerance in rice. A variant of one of ERF family genes, Sub1A-1, confers immersion tolerance to lowland rice. These findings and their exploitation will hold promise for engineering breeding to protect crop plants from certain abiotic stresses. Although, cereal crops are also quite sensitive to various abiotic stresses, hence in this short review, we will present recent progresses in adaptation of cereal crops to salinity, drought and cold tolerance are emphasized and the future potentials are highlighted.Keywords: Cereal crops, abiotic stresses, food insecurity, molecular breeding, quantitative trait loci (QTLs), salinity, water stress.African Journal of Biotechnology, Vol 13(29) 2908-292