A functional link between lariat debranching enzyme and the intron-binding complex is defective in non-photosensitive trichothiodystrophy.

The pre-mRNA life cycle requires intron processing; yet, how intron-processing defects influence splicing and gene expression is unclear. Here, we find that TTDN1/MPLKIP, which is encoded by a gene implicated in non-photosensitive trichothiodystrophy (NP-TTD), functionally links intron lariat processing to spliceosomal function. The conserved TTDN1 C-terminal region directly binds lariat debranching enzyme DBR1, whereas its N-terminal intrinsically disordered region (IDR) binds the intron-binding complex (IBC). TTDN1 loss, or a mutated IDR, causes significant intron lariat accumulation, as well as splicing and gene expression defects, mirroring phenotypes observed in NP-TTD patient cells. A Ttdn1-deficient mouse model recapitulates intron-processing defects and certain neurodevelopmental phenotypes seen in NP-TTD. Fusing DBR1 to the TTDN1 IDR is sufficient to recruit DBR1 to the IBC and circumvents the functional requirement for TTDN1. Collectively, our findings link RNA lariat processing with splicing outcomes by revealing the molecular function of TTDN1.

Cholecystectomy clip-induced biliary stone: Case report and literature review.

ABSTRACT: Migration of cholecystectomy surgical clip into the common bile duct with subsequent stone formation is a rare phenomenon, one which may lead to complications including obstruction, pain, nausea, vomiting and fever. The mechanism of migration is largely unknown but may result from a combination of factors including necrosis, intra-abdominal pressure or poor surgical technique with migrated clip serving as a nidus for stone formation. We present a 55-year-old woman with clip-induced stone impacted at the distal common bile duct 12 years post-cholecystectomy and a review of the literature related to cholecystectomy clip stone formation. In addition, we reviewed relevant English language case reports and literature reviews by searching PubMed using search terms 'stone', 'clip', 'cholecystectomy' and 'biliary'. There was no limit to the date of publication. Our study found 68 unduplicated cases of clip-induced stones which had a wide range of onset and presenting systems. Further research is needed to identify risk factors, methods of prevention and benefits of early detection screening.

Moving past neonicotinoids and honeybees: A systematic review of existing research on other insecticides and bees.

Synthetic pesticides (e.g. herbicides, fungicides and insecticides) are used widely in agriculture to protect crops from pests, weeds and disease. However, their use also comes with a range of environmental concerns. One key concern is the effect of insecticides on non-target organisms such as bees, who provide pollination services for crops and wild plants. This systematic literature review quantifies the existing research on bees and insecticides broadly, and then focuses more specifically on non-neonicotinoid insecticides and non-honeybees. We find that articles on honeybees (Apis sp.) and insecticides account for 80% of all research, with all other bees combined making up 20%. Neonicotinoids were studied in 34% of articles across all bees and were the most widely studied insecticide class for non-honeybees overall, with almost three times as many studies than the second most studied class. Of non-neonicotinoid insecticide classes and non-honeybees, the most studied were pyrethroids and organophosphates followed by carbamates, and the most widely represented bee taxa were bumblebees (Bombus), followed by leaf-cutter bees (Megachile) and mason bees (Osmia). Research has taken place across several countries, with the highest numbers of articles from Brazil and the US, and with notable gaps from countries in Asia, Africa and Oceania. Mortality was the most studied effect type, while sub-lethal effects such as on behaviour were less studied. Few studies tested how the effect of insecticides were influenced by multiple pressures, such as climate change and co-occurring pesticides (cocktail effects). As anthropogenic pressures do not occur in isolation, we suggest that future research also addresses these knowledge gaps. Given the changing global patterns in insecticide use, and the increasing inclusion of both non-honeybees and sub-lethal effects in pesticide risk assessment, there is a need for expanding research beyond its current state to ensure a strong scientific evidence base for the development of risk assessment and associated policy.

Closing the Osteoporotic-Fracture Care Gap for Frail Older Persons.

Aim To implement standardised fracture risk assessment in the frail older person. Methods Frail older patients underwent opportunistic screening for fracture risk. Roadblocks to standardised assessment were identified. An Integrated Care Team for older persons (ICT) trained in fracture risk assessment using FRAX. Clinical assessment was via a locally agreed algorithm. Data was entered onto Excel. The SQUIRE guidelines for quality improvement programmes were used to report the results. Results Of 96 patients opportunistically screened, the average age was 84 years. FRAX was completed for 19% (n=18). 89% (n=16) met the pharmacotherapy threshold. Nine were recommended pharmacotherapy. Of sixteen patients recommended for DXA, just 31% (n=5) were booked. Following implementation of a quality improvement project, 100 patients were assessed, and average age was 80 years. FRAX was completed for 62% (n=63) and 95% (n=60) required pharmacotherapy. 24% (n=14) had untreated prior fracture. All had pharmacotherapy prescribed. 59% (n=59) required DXA scanning. 70% (n=41) had DXA ordered. Conclusion ICT ownership increased FRAX assessment 3-fold and point of contact prescribing to 100%.

Management referral triaging process pilot study: a 'telephone first' approach.

BACKGROUND: In this Occupational Health Department (OHD), a 'telephone first' approach was introduced to triage management referrals with potential to convert to Telephone Independent Medical Assessment (TIMA). Telephone consultation has been widely used in the UK's NHS in the occupational health setting. AIMS: To evaluate TIMA effectiveness and efficiency of OHD resources; comparing the outcome of a triage call compared to previous default allocation of next available appointment, percentage of telephone triage calls converted to TIMA and appointment waiting times. To assess use of OHD resources arising from TIMA. To evaluate service user satisfaction following TIMA. To examine service user characteristics. METHODS: As management referrals were received, service users were given a telephone contact. Data were collected and anonymized regarding service users, who also consented to receive feedback questionnaire. Cross-sectional analysis of this management referral cohort was carried out. RESULTS: Two hundred and sixty-one management referrals were received in the specified period. Eighty per cent had a TIMA carried out (n = 208); 64% of management referrals with TIMA had a report issued (n = 166). Response rate to feedback questionnaire was 38% (n = 70); 94% of survey participants found TIMA acceptable going forward for management referrals (n = 66). CONCLUSIONS: Introduction of a 'telephone first' approach resulted in improved efficiency of this OHD, allowing maximum workforce planning, and positive service user feedback.

The role of the mussel Mytilus spp. in the transmission of ostreid herpesvirus-1 microVar.

The Pacific oyster Crassostrea gigas contributes significantly to global aquaculture; however, C. gigas culture has been affected by ostreid herpesvirus-1 (OsHV-1) and variants. The dynamics of how the virus maintains itself at culture sites is unclear and the role of carriers, reservoirs or hosts is unknown. Both wild and cultured mussels Mytilus spp. (Mytilus edulis, Mytilus galloprovincialis and hybrids) are commonly found at C. gigas culture sites. The objective of this study was to investigate if Mytilus spp. can harbour the virus and if viral transmission can occur between mussels and oysters. Mytilus spp. living at oyster trestles, 400-500 m higher up the shore from the trestles and up to 26 km at non-culture sites were screened for OsHV-1 and variants by all the World Organization for Animal Health (OIE) recommended diagnostic methods including polymerase chain reaction (PCR), quantitative PCR (qPCR), histology, in situ hybridization and confirmation using direct sequencing. The particular primers that target OsHV-1 and variants, including OsHV-1 microVar (µVar), were used in the PCR and qPCR. OsHV-1 µVar was detected in wild Mytilus spp. at C. gigas culture sites and more significantly the virus was detected in mussels at non-culture sites. Cohabitation of exposed wild mussels and naïve C. gigas resulted in viral transmission after 14 days, under an elevated temperature regime. These results indicate that mussels can harbour OsHV-1 µVar; however, the impact of OsHV-1 µVar on Mytilus spp. requires further investigation.

Madarosis: a qualitative study to assess perceptions and experience of Australian patients with early breast cancer treated with taxane-based chemotherapy.

PURPOSE: Eyebrow and eyelash loss (madarosis) is a common and distressing side effect of chemotherapy for which no protective strategies have yet been developed. The purpose of this study was to develop an overview of perceptions and experiences of women undergoing taxane-based treatment for early breast cancer. METHODS: A total of 25 women with a diagnosis of invasive early breast cancer participated in a focus group (n = 5), ages ranging from 35 to 64 (median 50), all had completed therapy with a taxane-based chemotherapy treatment. This focus group used targeted questions to explore participants' perceptions and experience of madarosis during and following chemotherapy and identified issues associated with impact of madarosis on quality of life (QoL). Thematic analysis was conducted to identify important issues experienced by participants. RESULTS: Seven themes emerged from the data: (1) timing of regrowth and permanent changes, (2) meaning/importance of eyebrow/eyelashes, (3) preparedness/information given, (4) impact of the hair loss of self, (5) impact of hair loss on others, (6) physiological side effects of loss of eyebrows/eyelashes, and (7) management of loss of eyebrows/eyelashes. In addition, participants noted physical symptoms of eye irritation during their treatment that they attributed to madarosis. CONCLUSION: This study highlights the significant impact of madarosis on patients, providing the first published analysis of patient's attitude and perception of eyelash and eyebrow loss during chemotherapy. Further research in this area is required and will be benefitted from the development of a dedicated instrument/questionnaire that can capture and measure the impact of madarosis on QoL and allow development of clinical trial strategies.

Evidence of degradation of hair corticosterone in museum specimens.

Researchers increasingly rely on non-invasive physiological indices, such as glucocorticoid (GC) levels, to interpret how vertebrates respond to changes in their environment. Recently, hair GCs have been of particular interest, because they are presumed stable over long periods of storage, which may facilitate the study of large-scale spatial and temporal patterns of stress in mammals. In the current study, we evaluated the stability of hair corticosterone levels in museum specimens, and the potential effects of different museum curation treatments. Using deer mouse (Peromyscus maniculatus) specimens collected from Vancouver Island (11 sites, 82 individuals) over 76 years, we found that specimens collected earlier in the 20th century had lower hair corticosterone than more recently collected specimens. These results suggest that hair hormone levels may not be stable over decades of storage time. We then subjected hair samples collected from white-footed mouse (Peromyscus leucopus, n = 36) to 3 different museum curation treatments, and found that borax lowered hair corticosterone levels relative to control samples, but air drying samples, or treating them with turpentine had no effect. Our results present a source of concern for the use of museum specimens for hair hormone analysis, and for studying long term trends in glucocorticoid levels.

Role of the intertidal predatory shore crab Carcinus maenas in transmission dynamics of ostreid herpesvirus-1 microvariant.

Ostreid herpesvirus-1 microVar (OsHV-1 µVar) has been responsible for significant mortalities globally in the Pacific oyster Crassostrea gigas. While the impact of this virus on the Pacific oyster has been significant, this pathogen may have wider ecosystem consequences. It has not been definitively determined how the virus is sustaining itself in the marine environment and whether other species are susceptible. The shore crab Carcinus maenas is a mobile predator and scavenger of C. gigas, commonly found at Pacific oyster culture sites. The aim of this study was to investigate the role of the crab in viral maintenance and transmission to the Pacific oyster. A field trial took place over 1 summer at different shore heights at 2 Irish Pacific oyster culture sites that are endemic for OsHV-1 µVar. Infection of OsHV-1 µVar in tissues of C. maenas at both shore heights of both sites was detected by polymerase chain reaction (PCR), quantitative PCR (qPCR), in situ hybridization and direct Sanger sequencing. In addition, a laboratory trial demonstrated that transmission of the virus could occur to naïve C. gigas within 4 d, from C. maenas previously exposed to the virus in the wild. These findings provide some insight into the possibility that the virus can be transmitted through marine food webs. The results also suggest viral plasticity in the hosts required by the virus and potential impacts on a range of crustacean species with wider ecosystem impacts if transmission to other species occurs.

A highly prevalent equine glycogen storage disease is explained by constitutive activation of a mutant glycogen synthase.

BACKGROUND: Equine type 1 polysaccharide storage myopathy (PSSM1) is associated with a missense mutation (R309H) in the glycogen synthase (GYS1) gene, enhanced glycogen synthase (GS) activity and excessive glycogen and amylopectate inclusions in muscle. METHODS: Equine muscle biochemical and recombinant enzyme kinetic assays in vitro and homology modelling in silico, were used to investigate the hypothesis that higher GS activity in affected horse muscle is caused by higher GS expression, dysregulation, or constitutive activation via a conformational change. RESULTS: PSSM1-affected horse muscle had significantly higher glycogen content than control horse muscle despite no difference in GS expression. GS activity was significantly higher in muscle from homozygous mutants than from heterozygote and control horses, in the absence and presence of the allosteric regulator, glucose 6 phosphate (G6P). Muscle from homozygous mutant horses also had significantly increased GS phosphorylation at sites 2+2a and significantly higher AMPKα1 (an upstream kinase) expression than controls, likely reflecting a physiological attempt to reduce GS enzyme activity. Recombinant mutant GS was highly active with a considerably lower Km for UDP-glucose, in the presence and absence of G6P, when compared to wild type GS, and despite its phosphorylation. CONCLUSIONS: Elevated activity of the mutant enzyme is associated with ineffective regulation via phosphorylation rendering it constitutively active. Modelling suggested that the mutation disrupts a salt bridge that normally stabilises the basal state, shifting the equilibrium to the enzyme's active state. GENERAL SIGNIFICANCE: This study explains the gain of function pathogenesis in this highly prevalent polyglucosan myopathy.

Combined use of modulated ultrasound and electric current stimulation for diabetic foot ulcers: a case series.

OBJECTIVE: Diabetic foot ulcers (DFUs) are a significant challenge in wound care practice. Our aim was to evaluate the combined use of of two therapies, ultrasound and electrostimulation, in the treatment of DFUs. METHOD: This study employed a prospective, non-comparative, case series design, undertaken in a podiatry-led diabetic foot clinic, in an acute hospital setting, in an urban location in Ireland. We recruited patinets with hard-to-heal DFUs who were treated twice a week with combined modulated ultrasound and electric current stimulation. RESULTS: We recruited seven patients with eight chronic DFUs. A mean wound size reduction of 71% was achieved and there were no adverse reactions to the therapy. CONCLUSION: The results of this small case series indicate that combined modulated ultrasound and electric current stimulation offers promise as an adjunct therapy for DFUs. Further large scale trials are now warranted.

A point mutation in the glutamate-gated chloride channel of Plutella xylostella is associated with resistance to abamectin.

The diamondback moth, Plutella xylostella, is a global pest of cruciferous vegetables. Abamectin resistance in a field population of P. xylostella was introgressed into the susceptible Roth strain. The resulting introgression strain Roth-Abm showed 11 000-fold resistance to abamectin compared with Roth. An A309V substitution at the N-terminus of the third transmembrane helix (M3) of the glutamate-gated chloride channel of P. xylostella (PxGluCl) was identified in Roth-Abm. The frequency of the V309 allele of PxGluCl was 94.7% in Roth-Abm, whereas no such allele was detected in Roth. A subpopulation of Roth-Abm was kept without abamectin selection for 20 generations to produce a revertant strain, Roth-Abm-D. Abamectin resistance in Roth-Abm-D declined to 1150-fold compared with Roth, with the V309 allele frequency decreased to 9.6%. After treatment of the Roth-Abm-D strain with 80 mg/l abamectin the V309 allele frequency in the survivors increased to 55%. This demonstrates that the A309V mutation in PxGluCl is strongly associated with a 10-fold increase in abamectin resistance in Roth-Abm relative to Roth-Abm-D. Homology modelling and automated ligand docking results suggest that the A309V substitution allosterically modifies the abamectin-binding site, as opposed to directly eliminating a key binding contact. Other resistance mechanisms to abamectin in Roth-Abm are discussed besides the A309V mutation of PxGluCl.

Chaperone-mediated native folding of a ß-scorpion toxin in the periplasm of Escherichia coli.

BACKGROUND: Animal neurotoxin peptides are valuable probes for investigating ion channel structure/function relationships and represent lead compounds for novel therapeutics and insecticides. However, misfolding and aggregation are common outcomes when toxins containing multiple disulfides are expressed in bacteria. METHODS: The ß-scorpion peptide toxin Bj-xtrIT from Hottentotta judaica and four chaperone enzymes (DsbA, DsbC, SurA and FkpA) were co-secreted into the oxidizing environment of the Escherichia coli periplasm. Expressed Bj-xtrIT was purified and analyzed by HPLC and FPLC chromatography. Its thermostability was assessed using synchrotron radiation circular dichroism spectroscopy and its crystal structure was determined. RESULTS: Western blot analysis showed that robust expression was only achieved when cells co-expressed the chaperones. The purified samples were homogenous and monodisperse and the protein was thermostable. The crystal structure of the recombinant toxin confirmed that it adopts the native disulfide connectivity and fold. CONCLUSIONS: The chaperones enabled correct folding of the four-disulfide-bridged Bj-xtrIT toxin. There was no apparent sub-population of misfolded Bj-xtrIT, which attests to the effectiveness of this expression method. GENERAL SIGNIFICANCE: We report the first example of a disulfide-linked scorpion toxin natively folded during bacterial expression. This method eliminates downstream processing steps such as oxidative refolding or cleavage of a fusion-carrier and therefore enables efficient production of insecticidal Bj-xtrIT. Periplasmic chaperone activity may produce native folding of other extensively disulfide-reticulated proteins including animal neurotoxins. This work is therefore relevant to venomics and studies of a wide range of channels and receptors.

Review of Time to Surgical Decompression in Traumatic Spinal Cord Injured Patients.

Interventions which may improve neurological outcomes, including time to surgical decompression, in traumatic spinal cord injury (TSCI) evoke much interest. The majority of TSCI patients in Ireland are managed acutely at the National Spinal Injuries Unit (NSIU). A retrospective review of healthcare records of TSCI patients, who had surgical management there, in 2010, 2011, 2012, was performed. From the information gathered, the duration of each stage of the patient pathway was calculated. Median duration between onset of injury and time of arrival at local hospital was 1 hour 25 minutes, between arrival at local hospital and referral to NSIU was 4 hours 17 minutes, between referral to and arrival at NSIU was 6 hours 25 minutes, between onset of injury and arrival at NSIU was 13 hours 7 minutes, between onset of injury and surgical decompression was 27 hours. A number of factors have been identified which could influence these time durations.

Systematic review: work-related stress and the HSE management standards.

BACKGROUND: The Health and Safety Executive (HSE) has defined six management standards representing aspects of work that, if poorly managed, are associated with lower levels of employee health and productivity, and increased sickness absence. The HSE indicator tool aims to measure organizations' performance in managing the primary stressors identified by the HSE management standards. AIMS: The aims of the study are to explore how the HSE indicator tool has been implemented within organizations and to identify contexts in which the tool has been used, its psychometric properties and relationships with alternative measures of well-being and stress. METHODS: Studies that matched specific criteria were included in the review. Abstracts were considered by two researchers to ensure a reliable process. Full texts were obtained when abstracts met the inclusion criteria. RESULTS: Thirteen papers were included in the review. Using factor analysis and measures of reliability, the studies suggest that the HSE indicator tool is a psychometrically sound measure. The tool has been used to measure work-related stress across different occupational groups, with a clear relationship between the HSE tool and alternative measures of well-being. Limitations of the tool and recommendations for future research are discussed. CONCLUSIONS: The HSE indicator tool is a psychometrically sound measure of organizational performance against the HSE management standards. As such it can provide a broad overview of sources of work-related stress within organizations. More research is required to explore the use of the tool in the design of interventions to reduce stress, and its use in different contexts and with different cultural and gender groups.

Revision of the Australian endemic ant genera Pseudonotoncus and Teratomyrmex (Hymenoptera: Formicidae: Formicinae).

The Australian endemic formicine ant genera Pseudonotoncus and Teratomyrmex are revised and their distributions and biologies reviewed. Both genera are limited to forested areas along the east coast of Australia. Pseudonotoncus is known from two species, P. eurysikos (new species) and P hirsutus (= P. turneri, new synonym), while Teratomyrmex is known from three species, T. greavesi, T. substrictus (new species) and T. tinae (new species). Distribution modelling was used to examine habitat preferences within the Pseudonotoncus species.