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Non-susceptibility of Escherichia coli, Klebsiella spp., Pseudomonas spp., Streptococcus pneumoniae and Staphylococcus aureus in the UK: temporal trends in England, Northern Ireland, Scotland and Wales. - The Journal of antimicrobial chemotherapy
To monitor and compare trends in the non-susceptibility of bloodstream isolates of pathogens to key antibiotics in the constituent countries of the UK between 2010 and 2014.Routinely generated antibiotic susceptibility test results for bloodstream isolates of Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Pseudomonas spp., Streptococcus pneumoniae and Staphylococcus aureus were collected from hospital microbiology laboratories in each country.With the exception of a decrease in the proportion of S. aureus that were MRSA, non-susceptibility to key antibiotics among the pathogens studied remained largely unchanged over the 5 year study period, with any increases in non-susceptibility being small. Although some intercountry variation in the proportions of non-susceptible isolates was seen, apart from MRSA, the differences were generally small (<5%) and fluctuated from year to year, with no country showing consistently higher or lower rates of resistance.Collaboration between the constituent countries of the UK allows an integrated approach to nationwide surveillance of antibiotic resistance.Â© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: email@example.com.
Angiogenic gene signature in human pancreatic cancer correlates with TGF-beta and inflammatory transcriptomes. - Oncotarget
Pancreatic ductal adenocarcinomas (PDACs) are hypovascular, but overexpress pro-angiogenic factors and exhibit regions of microvasculature. Using RNA-seq data from The Cancer Genome Atlas (TCGA), we previously reported that ~12% of PDACs have an angiogenesis gene signature with increased expression of multiple pro-angiogenic genes. By analyzing the recently expanded TCGA dataset, we now report that this signature is present in ~35% of PDACs but that it is mostly distinct from an angiogenesis signature present in pancreatic neuroendocrine tumors (PNETs). These PDACs exhibit a transcriptome that reflects active TGF-Î² signaling, and up-regulation of several pro-inflammatory genes, and many members of JAK signaling pathways. Moreover, expression of SMAD4 and HDAC9 correlates with endothelial cell abundance in PDAC tissues. Concomitantly targeting the TGF-Î² type I receptor (TÎ²RI) kinase with SB505124 and JAK1-2 with ruxolitinib suppresses JAK1 phosphorylation and blocks proliferative cross-talk between human pancreatic cancer cells (PCCs) and human endothelial cells (ECs), and these anti-proliferative effects were mimicked by JAK1 silencing in ECs. By contrast, either inhibitor alone does not suppress their enhanced proliferation in 3D co-cultures. These findings suggest that targeting both TGF-Î² and JAK1 signaling could be explored therapeutically in the 35% of PDAC patients whose cancers exhibit an angiogenesis gene signature.
Athletes Doing Arabesques: Important Considerations in the Care of Young Dancers. - Current sports medicine reports
Dance is as much a sport as an art form. Sports medicine clinicians seeing dancers in their practice will need to be familiar with the unique characteristics of dance in order to provide proper care. Dance encompasses different forms, which vary in equipment and terminology. The epidemiology of dance injuries has historically focused on ballet, but there is increasing research on other dance forms. Lower extremity and back injuries predominate. Injury prevention, both primary and secondary, is at the heart of dance medicine. Primary prevention includes preseason conditioning, identifying risk factors for injury, and recognizing the female athlete triad. Secondary prevention includes a comprehensive approach to injury rehabilitation, an appreciation for the unique demands of dance, and an understanding of the particulars of the injury being treated. Dancers may have difficulty accessing medical care or following prescribed advice; the proactive clinician will anticipate these situations.
Analysis of crystallization data in the Protein Data Bank. - Acta crystallographica. Section F, Structural biology communications
The Protein Data Bank (PDB) is the largest available repository of solved protein structures and contains a wealth of information on successful crystallization. Many centres have used their own experimental data to draw conclusions about proteins and the conditions in which they crystallize. Here, data from the PDB were used to reanalyse some of these results. The most successful crystallization reagents were identified, the link between solution pH and the isoelectric point of the protein was investigated and the possibility of predicting whether a protein will crystallize was explored.
Motor and Sensory Deficits in the teetering Mice Result from Mutation of the ESCRT Component HGS. - PLoS genetics
Neurons are particularly vulnerable to perturbations in endo-lysosomal transport, as several neurological disorders are caused by a primary deficit in this pathway. In this report, we used positional cloning to show that the spontaneously occurring neurological mutation teetering (tn) is a single nucleotide substitution in hepatocyte growth factor-regulated tyrosine kinase substrate (Hgs/Hrs), a component of the endosomal sorting complex required for transport (ESCRT). The tn mice exhibit hypokenesis, muscle weakness, reduced muscle size and early perinatal lethality by 5-weeks of age. Although HGS has been suggested to be essential for the sorting of ubiquitinated membrane proteins to the lysosome, there were no alterations in receptor tyrosine kinase levels in the central nervous system, and only a modest decrease in tropomyosin receptor kinase B (TrkB) in the sciatic nerves of the tn mice. Instead, loss of HGS resulted in structural alterations at the neuromuscular junction (NMJ), including swellings and ultra-terminal sprouting at motor axon terminals and an increase in the number of endosomes and multivesicular bodies. These structural changes were accompanied by a reduction in spontaneous and evoked release of acetylcholine, indicating a deficit in neurotransmitter release at the NMJ. These deficits in synaptic transmission were associated with elevated levels of ubiquitinated proteins in the synaptosome fraction. In addition to the deficits in neuronal function, mutation of Hgs resulted in both hypermyelinated and dysmyelinated axons in the tn mice, which supports a growing body of evidence that ESCRTs are required for proper myelination of peripheral nerves. Our results indicate that HGS has multiple roles in the nervous system and demonstrate a previously unanticipated requirement for ESCRTs in the maintenance of synaptic transmission.
PA18â€…Heart of gold. integrating cross boundary care across different sectors with patients at the heart of care - a population-based public health perspective. - BMJ supportive & palliative care
In response to the growing challenge of over-hospitalisation and fragmentation of care for people nearing the end-of-life, a key factor is to develop an integrated cross-boundary care approach to meet the population's needs. Gold Standards Framework (GSF) quality improvement programmes are widely used in the UK in primary care, care homes, hospitals, domiciliary care and hospices. By working together to a common plan, GSF can help be a vehicle for improvement with patients at the heart of care.To explore using GSF programmes in different settings to develop an integrated whole-system approach, with patients at the heart of care - the 'heart of gold' projects.A description of GSF used in different settings as a common language to develop better integrated cross-boundary care, with peoples' wishes and preferences at the heart of care. GSF improves the early identification, Advance Care Planning discussions and coordination of care reducing unnecessary hospital admissions.Findings from different sectors are presented from each setting, looking at whole-systems, and practical and qualitative measures of progress.Real improvements are being seen across whole areas using GSF as a vehicle for better co-ordinated care. 'Gold patients' and their families feel many benefits and there is greater openness and 'cultural change' in end-of-life-care, especially for the frail elderly. GSF can be part of the solution in developing such integrated care by developing a common 'vocabulary' of care for all people in any setting with any condition in the final years of life.Â© 2015, Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Distinct effects of ubiquitin overexpression on NMJ structure and motor performance in mice expressing catalytically inactive USP14. - Frontiers in molecular neuroscience
Ubiquitin-specific protease 14 (USP14) is a major deubiquitinating enzyme and a key determinant of neuromuscular junction (NMJ) structure and function. We have previously reported dramatic ubiquitin depletion in the nervous systems of the USP14-deficient ataxia (ax (J) ) mice and demonstrated that transgenic ubiquitin overexpression partially rescues the ax (J) neuromuscular phenotype. However, later work has shown that ubiquitin overexpression does not correct the ax (J) deficits in hippocampal short term plasticity, and that transgenic expression of a catalytically inactive form of USP14 in the nervous system mimics the neuromuscular phenotype observed in the ax (J) mice, but causes a only a modest reduction of free ubiquitin. Instead, increased ubiquitin conjugates and aberrant activation of pJNK are observed in the nervous systems of the USP14 catalytic mutant mice. In this report, we demonstrate that restoring free ubiquitin levels in the USP14 catalytic mutant mice improved NMJ structure and reduced pJNK accumulation in motor neuron terminals, but had a negative impact on measures of NMJ function, such as motor performance and muscle development. Transgenic expression of ubiquitin had a dose-dependent effect on NMJ function in wild type mice: moderate levels of overexpression improved NMJ function while more robust ubiquitin overexpression reduced muscle development and motor coordination. Combined, these results suggest that maintenance of free ubiquitin levels by USP14 contributes to NMJ structure, but that USP14 regulates NMJ function through a separate pathway.
TCGA data and patient-derived orthotopic xenografts highlight pancreatic cancer-associated angiogenesis. - Oncotarget
Pancreatic ductal adenocarcinomas (PDACs) overexpress pro-angiogenic factors but are not viewed as vascular. Using data from The Cancer Genome Atlas we demonstrate that a subset of PDACs exhibits a strong pro-angiogenic signature that includes 37 genes, such as HDAC9, that are overexpressed in PDAC arising in KRC mice, which express mutated Kras and lack RB. Moreover, patient-derived orthotopic xenografts can exhibit tumor angiogenesis, whereas conditioned media (CM) from KRC-derived pancreatic cancer cells (PCCs) enhance endothelial cell (EC) growth and migration, and activate canonical TGF-Î² signaling and STAT3. Inhibition of the type I TGF-Î² receptor with SB505124 does not alter endothelial activation in vitro, but decreases pro-angiogenic gene expression and suppresses angiogenesis in vivo. Conversely, STAT3 silencing or JAK1-2 inhibition with ruxolitinib blocks CM-enhanced EC proliferation. STAT3 disruption also suppresses endothelial HDAC9 and blocks CM-induced HDAC9 expression, whereas HDAC9 re-expression restores CM-enhanced endothelial proliferation. Moreover, ruxolitinib blocks mitogenic EC/PCC cross-talk, and suppresses endothelial p-STAT3 and HDAC9, and PDAC progression and angiogenesis in vivo, while markedly prolonging survival of KRC mice. Thus, targeting JAK1-2 with ruxolitinib blocks a final pathway that is common to multiple pro-angiogenic factors, suppresses EC-mediated PCC proliferation, and may be useful in PDACs with a strong pro-angiogenic signature.
Orthostatic Intolerance and Autonomic Dysfunction in Youth With Persistent Postconcussion Symptoms: A Head-Upright Tilt Table Study. - Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine
To explore head-upright tilt table (HUT) signs of autonomic dysfunction in a cohort of youth with persistent postconcussion symptoms (PCSs) that include light-headedness and to correlate repeat tilt table results with symptom improvements for those patients found to have postural tachycardia syndrome (POTS) on initial testing.Prospective cohort design.Nationwide Children's Hospital, Neurology Clinic.Thirty-four patients (13-18 years of age) with persistent PCSs.All patients underwent at least 1 tilt table test. The PCS Interview (PCS-I) and patient ratings of light-headedness and vertigo were used to measure symptom burden. Patients found to have POTS were asked to repeat tilt table testing when PCSs improved or 3 to 6 months after the initial test if symptoms persisted.Twenty-four of the 34 (70.6%) patients had abnormal tilt table results with patients categorized as normal (n = 10), isolated syncope (n = 10), and POTS (n = 14). Patients with POTS had higher PCS-I scores than normal patients (P < 0.001) and higher ratings of light-headedness than both normal patients (P = 0.015) and syncope patients (P = 0.04). Twelve POTS patients underwent repeat tilt table testing, and 9 of 12 (75%) no longer met POTS diagnostic criteria. All patients with resolution of POTS had corresponding improvements in PCSs, including light-headedness and vertigo.Our study demonstrates a high rate of tilt table abnormalities among youth with persistent PCSs. Several patients with POTS had normalization of tilt table testing when PCSs improved. These findings warrant further research of autonomic dysfunction related to concussion.Our study is the first to prospectively characterize autonomic dysfunction in patients with persistent PCSs using HUT testing and to show that the tilt test abnormalities normalize in some patients as PCSs improve.
The failing heart: a bad case of the 'flu'. - BMJ case reports
A 24-year-old Nepali man presented to hospital with a short history of feeling unwell with a flu-like illness. He subsequently went into acute renal failure requiring several sessions of renal replacement therapy by haemofiltration. The underlying aetiology of his renal failure was unclear. His renal function recovered following haemofiltration and he was discharged home with a plan for outpatient follow-up and investigations. He re-presented to hospital 6 days later with severe fluid overload. Echocardiogram was suggestive of impaired left ventricular systolic function; subsequent cardiac MRI confirmed this and was indicative of a dilated cardiomyopathy. A diagnosis of dilated cardiomyopathy with cardiorenal syndrome was made, most likely secondary to viral myocarditis in view of his initial presentation. He was diuresed and treated with prognostic medications for heart failure. His symptoms resolved and on subsequent outpatient review he was feeling well.2015 BMJ Publishing Group Ltd.
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