Results of Duchenne muscular dystrophy family screening in practice: leaks rather than cascades?

McGowan R, Challoner BR, Ross S, Holloway S, Joss S, Wilcox D, Holden ST, Tolmie J, Longman C. Results of Duchenne muscular dystrophy family screening in practice: leaks rather than cascades? Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease caused by mutations in the gene that encodes the protein dystrophin. Approximately 2 of 3 affected boys inherit their mutation from their carrier mother whereupon other female relatives are at risk of carrying the mutation. Female carriers are also at risk of developing cardiomyopathy and regular cardiac screening is recommended. Clinical genetics services offer genetic counselling and carrier tests for consenting relatives of DMD patients known as ‘cascade screening’. We retrospectively analysed data from two genetics centres, West of Scotland and South East Thames where the latter centre operated a computer‐held DMD register. Over the period, 1971–2008, a total of 843 potential carriers, in 195 West of Scotland families, were tested: 16% of 1st degree relatives and 48% of 2nd degree and more distant relatives were not tested. In South East Thames, a total of 1223 potential carriers in 349 families were tested: 49% of 1st degree and 65% of 2nd degree and more distant relatives were not tested. These data are similar to Becker muscular dystrophy/DMD carrier screening results recently reported from the Netherlands. Retrospective results from three countries indicate that despite efforts to offer extended cascade screening, significant numbers of potential carriers of DMD remain unaware of their reproductive and health risks.     

Illness and infection in elite full-contact football-code sports: A systematic review

ObjectivesFull-contact football-code team sports offer a unique environment for illness risk. During training and match-play, players are exposed to high-intensity collisions which may result in skin-on-skin abrasions and transfer of bodily fluids. Understanding the incidence of all illnesses and infections and what impact they cause to time-loss from training and competition is important to improve athlete care within these sports. This review aimed to systematically report, quantify and compare the type, incidence, prevalence and count of illnesses across full-contact football-code team sports.Design/methodsA systematic search of Cochrane Library, MEDLINE, SPORTDiscus, PsycINFO and CINAHL electronic databases was performed from inception to October 2019; keywords relating to illness, athletes and epidemiology were used. Studies were excluded if they did not quantify illness or infection, involve elite athletes, investigate full-contact football-code sports or were review articles.ResultsTwenty-eight studies met the eligibility criteria. Five different football-codes were reported: American football (n = 10), Australian rules football (n = 3), rugby league (n = 2), rugby sevens (n = 3) and rugby union (n = 9). One multi-sport study included both American football and rugby union. Full-contact football-code athletes are most commonly affected by respiratory system illnesses. There is a distinct lack of consensus of illness monitoring methodology.ConclusionsFull-contact football-code team sport athletes are most commonly affected by respiratory system illnesses. Due to various monitoring methodologies, illness incidence could only be compared between studies that used matching incidence exposure measures. High-quality illness surveillance data collection is an essential component to undertake effective and targeted illness prevention in athletes.     

Dosimetric consequences of seed placement accuracy in permanent breast seed implant brachytherapy

PurposeThis study quantifies the dosimetric impact of implant accuracy and derives a quantitative relationship relating implant accuracy to target dosimetry.Methods and MaterialsA framework was developed to simulate multiple implants for error combinations. Spherical clinical target volumes (CTVs) were modeled with volumes 1.4 cm³, 9.2 cm³, and 20.6 cm³, representing the range seen clinically. Each CTV was expanded 10 mm isotropically to create a planning target volume (PTV).. Random and systematic seed placement errors were simulated by shifting needles from their planned positions. Implant errors were simulated over the range of clinically practical errors in permanent breast seed implant. The relative effect on target coverage was evaluated. Regression analysis was performed to derive relationships between CTV dosimetry and the magnitude of implant accuracy. The validity of the clinically used 10 mm PTV margin for each of the CTVs was assessed.ResultsIntroducing practical implant errors resulted in CTV V_90% median (10th and 90th percentile) of 97.7% (85.9% and 100%), 96.2% (86.8% and 99.7%), and 100% (77.8% and 100%) for the typical, large, and small CTV, respectively. All CTVs show similar trends in target coverage. Polynomials were derived relating seed placement accuracy to median (R² = 0.82) and 10th percentile (R² = 0.78) CTV V_90%._.ConclusionsThis work quantitatively describes the relationship between implant accuracy and CTV coverage. Based on simulations, the 10 mm PTV margin is adequate to maintain target coverage. These equations can be used with institutional seed placement accuracy to estimate coverage.     

Determinations of new psychoactive substances in biological matrices with focus on microextraction techniques: a review of fundamentals and state-of-the-art extraction methods

Purpose

This review article provides a detailed discussion of studies in which microextraction techniques are applied for the determination of new psychoactive substances (NPS) in biological samples. Definitions and classifications of NPS are highlighted as well as the fundamentals of the microextraction techniques used in their analyses.

Methods

A complete literature search was carried out with PubMed, Scopus and the World Wide Web using relevant keywords, e.g., NPS, microextraction and biological fluids.

Results

The determinations of NPS in biological samples remain a challenge for analytical laboratories due to its wide diversity of compounds. The utilization of microextraction techniques in this context is still not many. However, the 96 deep well plate for microextraction and microextraction by packed sorbent (MEPS) can be highlighted as the most explored configurations. Microextraction approaches have the potential to be further improved and optimized to provide rapid and low-cost analyses with reliable results.

Conclusions

There is a wide scope of microextraction techniques to be explored in the field of toxicology and NPS determinations. These techniques are compatible with recent trends of automation and miniaturization, which can enable a straightforward workflow for NPS analyses.

     

Recurrent deletion of 3p13 targets multiple tumour suppressor genes and defines a distinct subgroup of aggressive ERG fusion‐positive prostate cancers

Deletion of 3p13 has been reported from about 20% of prostate cancers. The clinical significance of this alteration and the tumour suppressor gene(s) driving the deletion remain to be identified. We have mapped the 3p13 deletion locus using SNP array analysis and performed fluorescence in situ hybridization (FISH) analysis to search for associations between 3p13 deletion, prostate cancer phenotype and patient prognosis in a tissue microarray containing more than 3200 prostate cancers. SNP array analysis of 72 prostate cancers revealed a small deletion at 3p13 in 14 (19%) of the tumours, including the putative tumour suppressors FOXP1, RYBP and SHQ1. FISH analysis using FOXP1‐specific probes revealed deletions in 16.5% and translocations in 1.2% of 1828 interpretable cancers. 3p13 deletions were linked to adverse features of prostate cancer, including advanced stage (p < 0.0001), high Gleason grade (p = 0.0125), and early PSA recurrence (p = 0.0015). In addition, 3p13 deletions were linked to ERG⁺ cancers and to PTEN deletions (p < 0.0001 each). A subset analysis of ERG⁺ tumours revealed that 3p13 deletions occurred independently from PTEN deletions (p = 0.3126), identifying tumours with 3p13 deletion as a distinct molecular subset of ERG⁺ cancers. mRNA expression analysis confirmed that all 3p13 genes were down regulated by the deletion. Ectopic over‐expression of FOXP1, RYBP and SHQ1 resulted in decreased colony‐formation capabilities, corroborating a tumour suppressor function for all three genes. In summary, our data show that deletion of 3p13 defines a distinct and aggressive molecular subset of ERG⁺ prostate cancers, which is possibly driven by inactivation of multiple tumour suppressors. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Ridgecounter: A program for obtaining semi-automated finger ridge counts

Finger ridge count is a valuable quantitative phenotype used in a wide range of biological and anthropological research. However, the scoring of the phenotype is both labour intensive and error prone. This paper describe a freely available software program, RIDGECOUNTER, that can be used to obtain ridge counts from digitized prints (either collected using a digital fingerprint scanner or scanned from an inked print). The program yields semi-automated ridge counts and logs the location of the user-selected core and delta points to aid in the training of new researchers and ensure the repeatability of count. In a validity study of 451 prints, the semi-automated ridge counts of digital prints showed good agreement (r?=?0.957) with traditional manual counts of inked-rolled prints (which were obtained 2 years apart and counted by different researchers). In a reliability study of 200 prints, semi-automated ridge counts derived from digital prints collected at two different time points also showed good agreement (r?=?0.962) (the prints were obtained 2 years apart and counted by the same researcher). Although designed for use with fingerprints, the program is suitable for use with palm, foot or toe prints using user-defined landmarks.     

A Basomedial Amygdala to Intercalated Cells Microcircuit Expressing PACAP and Its Receptor PAC1 Regulates Contextual Fear

Trauma can cause dysfunctional fear regulation leading some people to develop disorders, such as post-traumatic stress disorder (PTSD). The amygdala regulates fear, whereas PACAP (pituitary adenylate activating peptide) and PAC1 receptors are linked to PTSD symptom severity at genetic/epigenetic levels, with a strong link in females with PTSD. We discovered a PACAPergic projection from the basomedial amygdala (BMA) to the medial intercalated cells (mICCs) in adult mice. In vivo optogenetic stimulation of this pathway increased CFOS expression in mICCs, decreased fear recall, and increased fear extinction. Selective deletion of PAC1 receptors from the mICCs in females reduced fear acquisition, but enhanced fear generalization and reduced fear extinction in males. Optogenetic stimulation of the BMA-mICC PACAPergic pathway produced EPSCs in mICC neurons, which were enhanced by the PAC1 receptor antagonist, PACAP 6-38. Our findings show that mICCs modulate contextual fear in a dynamic and sex-dependent manner via a microcircuit containing the BMA and mICCs, and in a manner that was dependent on behavioral state.SIGNIFICANCE STATEMENT Traumatic stress can affect different aspects of fear behaviors, including fear learning, generalization of learned fear to novel contexts, how the fear of the original context is recalled, and how fear is reduced over time. While the amygdala has been studied for its role in regulation of different aspects of fear, the molecular circuitry of this structure is quite complex. In addition, aspects of fear can be modulated differently in males and females. Our findings show that a specific circuitry containing the neuropeptide PACAP and its receptor, PAC1, regulates various aspects of fear, including acquisition, generalization, recall, and extinction in a sexually dimorphic manner, characterizing a novel pathway that modulates traumatic fear.     

Glutamate Signaling via the AMPAR Subunit GluR4 Regulates Oligodendrocyte Progenitor Cell Migration in the Developing Spinal Cord

Oligodendrocyte progenitor cells (OPCs) are specified from discrete precursor populations during gliogenesis and migrate extensively from their origins, ultimately distributing throughout the brain and spinal cord during early development. Subsequently, a subset of OPCs differentiates into mature oligodendrocytes, which myelinate axons. This process is necessary for efficient neuronal signaling and organism survival. Previous studies have identified several factors that influence OPC development, including excitatory glutamatergic synapses that form between neurons and OPCs during myelination. However, little is known about how glutamate signaling affects OPC migration before myelination. In this study, we use in vivo, time-lapse imaging in zebrafish in conjunction with genetic and pharmacological perturbation to investigate OPC migration and myelination when the GluR4A ionotropic glutamate receptor subunit is disrupted. In our studies, we observed that gria4a mutant embryos and larvae displayed abnormal OPC migration and altered dorsoventral distribution in the spinal cord. Genetic mosaic analysis confirmed that these effects were cell-autonomous, and we identified that voltage-gated calcium channels were downstream of glutamate receptor signaling in OPCs and could rescue the migration and myelination defects we observed when glutamate signaling was perturbed. These results offer new insights into the complex system of neuron-OPC interactions and reveal a cell-autonomous role for glutamatergic signaling in OPCs during neural development.SIGNIFICANCE STATEMENT The migration of oligodendrocyte progenitor cells (OPCs) is an essential process during development that leads to uniform oligodendrocyte distribution and sufficient myelination for central nervous system function. Here, we demonstrate that the AMPA receptor (AMPAR) subunit GluR4A is an important driver of OPC migration and myelination in vivo and that activated voltage-gated calcium channels are downstream of glutamate receptor signaling in mediating this migration.     

Transcranial direct current stimulation for post-stroke dysphagia: a systematic review and meta-analysis of randomized controlled trials

Journal of Neurology - Transcranial direct current stimulation (tDCS) has been investigated as a tool for dysphagia recovery after stroke in several single-center randomized controlled trials...