Disease-modifying effects of edasalonexent,an NF-κB inhibitor,in young boys with Duchenne muscular dystrophy: Results of the MoveDMD phase 2 and open label extension trial

Chronic activation of NF-κB is a key driver of muscle degeneration and suppression of muscle regeneration in Duchenne muscular dystrophy. Edasalonexent (CAT-1004) is an orally-administered novel small molecule that covalently links two bioactive compounds (salicylic acid and docosahexaenoic acid) that inhibit NF-κB. This placebo-controlled, proof-of-concept phase 2 study with open-label extension in boys ≥4-<8 years old with any dystrophin mutation examined the effect of edasalonexent (67 or 100 mg/kg/day) compared to placebo or off-treatment control. Endpoints were safety/tolerability, change from baseline in MRI T₂ relaxation time of lower leg muscles and functional assessment, as well as pharmacodynamics and biomarkers. Treatment was well-tolerated and the majority of adverse events were mild, and most commonly of the gastrointestinal system (primarily diarrhea). There were no serious adverse events in the edasalonexent groups. Edasalonexent 100 mg/kg was associated with slowing of disease progression and preservation of muscle function compared to an off-treatment control period, with decrease in levels of NF-κB-regulated genes and improvements in biomarkers of muscle health and inflammation. These results support investigating edasalonexent in future trials and have informed the design of the edasalonexent phase 3 clinical trial in boys with Duchenne.     

A CO-FISH assay to assess sister chromatid segregation patterns in mitosis of mouse embryonic stem cells

Sister chromatids contain identical DNA sequence but are chiral with respect to both their helical handedness and their replication history. Emerging evidence from various model organisms suggests that certain stem cells segregate sister chromatids nonrandomly to either maintain genome integrity or to bias cellular differentiation in asymmetric cell divisions. Conventional methods for tracing of old vs. newly synthesized DNA strands generally lack resolution for individual chromosomes and employ halogenated thymidine analogs with profound cytotoxic effects on rapidly dividing cells. Here, we present a modified chromosome orientation fluorescence in situ hybridization (CO-FISH) assay, where identification of individual chromosomes and their replication history is achieved in subsequent hybridization steps with chromosome-specific DNA probes and PNA telomere probes. Importantly, we tackle the issue of BrdU cytotoxicity and show that our method is compatible with normal mouse ES cell biology, unlike a recently published related protocol. Results from our CO-FISH assay show that mitotic segregation of mouse chromosome 7 is random in ES cells, which contrasts previously published results from our laboratory and settles a controversy. Our straightforward protocol represents a useful resource for future studies on chromatid segregation patterns of in vitro-cultured cells from distinct model organisms.     

Directional genomic hybridization for chromosomal inversion discovery and detection

Chromosomal rearrangements are a source of structural variation within the genome that figure prominently in human disease, where the importance of translocations and deletions is well recognized. In principle, inversions—reversals in the orientation of DNA sequences within a chromosome—should have similar detrimental potential. However, the study of inversions has been hampered by traditional approaches used for their detection, which are not particularly robust. Even with significant advances in whole genome approaches, changes in the absolute orientation of DNA remain difficult to detect routinely. Consequently, our understanding of inversions is still surprisingly limited, as is our appreciation for their frequency and involvement in human disease. Here, we introduce the directional genomic hybridization methodology of chromatid painting—a whole new way of looking at structural features of the genome—that can be employed with high resolution on a cell-by-cell basis, and demonstrate its basic capabilities for genome-wide discovery and targeted detection of inversions. Bioinformatics enabled development of sequence- and strand-specific directional probe sets, which when coupled with single-stranded hybridization, greatly improved the resolution and ease of inversion detection. We highlight examples of the far-ranging applicability of this cytogenomics-based approach, which include confirmation of the alignment of the human genome database and evidence that individuals themselves share similar sequence directionality, as well as use in comparative and evolutionary studies for any species whose genome has been sequenced. In addition to applications related to basic mechanistic studies, the information obtainable with strand-specific hybridization strategies may ultimately enable novel gene discovery, thereby benefitting the diagnosis and treatment of a variety of human disease states and disorders including cancer, autism, and idiopathic infertility.     

Uncertainties surrounding the choice of surgical treatment for ‘bone on bone’ medial compartment osteoarthritis of the knee

A number of different surgical interventions can be used for treating antero-medial osteoarthritis (AMOA) of the knee and this choice can present challenges for patient's decision-making. Patients with AMOA can undergo Total Knee Replacement (TKR), Unicompartmental Knee Replacement (UKR) or High Tibial Osteotomy (HTO) for the same pathology. However many uncertainties still exist as to deciding which operation is best for individual patients and the Orthopaedic community has failed to systematically compare treatment options. The relative lack of scientifically based evidence has impacted on the ability to provide clear guidelines on treatment choice, patient suitability and direct patient preference for treatment. This paper, using available evidence, discusses the issue and offers some suggestions for future development.     

Prevalence Rates and Correlates of Likely Post-Traumatic Stress Disorder in Residents of Fort McMurray 6 Months After a Wildfire

On May 3, 2016, mandatory evacuation order was declared for Fort McMurray region as wildfire threatened. Over 90,000 residents were evacuated and firefighters from Canada and abroad worked constantly to protect the municipality. Overall, fire consumed about 2400 homes and over 200,000 ha of forest, reaching into Saskatchewan. The evacuation order was lifted with residents returning to the Municipality in phases from June 1, 2016. The aim of this study is to assess likely prevalence of PTSD in residents of Fort McMurray 6 months after a wildfire and to determine the predictors of likely PTSD in the respondents. A quantitative cross-sectional survey was used to collect data through self-administered paper-based questionnaires to determine likely PTSD. The PTSD Checklist for DSM 5 Part 3 was used to assess the presence or absence of likely PTSD in respondents randomly selected from a variety of natural settings in Fort McMurray. Data were analyzed with SPSS version 20 using univariate analysis with the chi-squared test and binary logistic regression analysis. One-month prevalence rate among adult residents for likely PTSD 6 months after the disaster was 12.8% (14.9% for females and 8.7% for males). While controlling for other factors in the logistic regression model, corresponding odds ratios included 9.51 and 4.88 for those who received no or only limited support respectively from friends/family, 8.00 for those who had history of an anxiety disorder before the wildfire, and 4.01 for those who received counseling after the wildfire. Respondents who presented with likely PTSD were significantly more likely to self-report increased drug abuse, but not increased alcohol use, after the fire. Our study has established that while support from family/friends following wildfires may be protective against likely PTSD, a prior diagnosis of an anxiety disorder significantly increased risk for developing PTSD. Further studies are needed to explore whether receiving counseling after a wild fire alters the likelihood of individuals presenting with PTSD.

     

Chronically elevated depressive symptoms interact with acute increases in inflammation to predict worse neurocognition among people with HIV

Journal of NeuroVirology - We examined the joint effects of depressive symptoms (Beck Depression Inventory-II (BDI-II)) and systemic inflammation (plasma C-reactive protein (CRP)) on longitudinal...