Deformation versus Sphericity in the Ground States of the Lightest Gold Isotopes.

The changes in mean-squared charge radii of neutron-deficient gold nuclei have been determined using the in-source, resonance-ionization laser spectroscopy technique, at the ISOLDE facility (CERN). From these new data, nuclear deformations are inferred, revealing a competition between deformed and spherical configurations. The isotopes ^{180,181,182}Au are observed to possess well-deformed ground states and, when moving to lighter masses, a sudden transition to near-spherical shapes is seen in the extremely neutron-deficient nuclides, ^{176,177,179}Au. A case of shape coexistence and shape staggering is identified in ^{178}Au which has a ground and isomeric state with different deformations. These new data reveal a pattern in ground-state deformation unique to the gold isotopes, whereby, when moving from the heavy to light masses, a plateau of well-deformed isotopes exists around the neutron midshell, flanked by near-spherical shapes in the heavier and lighter isotopes-a trend hitherto unseen elsewhere in the nuclear chart. The experimental charge radii are compared to those from Hartree-Fock-Bogoliubov calculations using the D1M Gogny interaction and configuration mixing between states of different deformation. The calculations are constrained by the known spins, parities, and magnetic moments of the ground states in gold nuclei and show a good agreement with the experimental results.

Utility of 3D printed models as adjunct in acetabular fracture teaching for Orthopaedic trainees.

OBJECTIVE: To evaluate the use of 3-D printed models as compared to didactic lectures in the teaching of acetabular fractures for Orthopaedic trainees. METHODS: This was a randomised prospective study conducted in a tertiary hospital setting which consisted of 16 Orthopaedic residents. Ten different cases of acetabular fracture patterns were identified and printed as 3-D models. The baseline knowledge of orthopaedic residents regarding acetabular fracture classification and surgical approach was determined by an x-ray based pre-test. Trainees were then randomly assigned into two groups. Group I received only lectures. Group II were additionally provided with 3-D printed models during the lecture. Participants were then assessed for comprehension and retention of teaching. RESULTS: Sixteen trainees participated in the trial. Both Group 1 and 2 improved post teaching with a mean score of 2.5 and 1.9 to 4.4 and 6 out of 10 respectively. The post test score for fracture classification and surgical approach were significantly higher for 3-D model group (p < 0.05). Trainees felt that the physical characteristics of the 3-D models were a good representation of acetabular fracture configuration, and should be used routinely for teaching and surgical planning. CONCLUSION: 3-D printed model of real clinical cases have significant educational impact compared to lecture-based learning towards improving young trainees' understanding of complex acetabular fractures.

Accuracy of contrast-enhanced CT and predictive factors for extracapsular spread in unknown primary head and neck squamous cell cancer.

AIM: To determine the accuracy of contrast-enhanced computed tomography (CECT) for nodal extracapsular spread (ECS) and identify predictive radiological signs and clinicopathological features for ECS in unknown-primary head and neck squamous cell cancer (UPHNSCC). MATERIALS AND METHODS: The CECT imaging of patients who underwent primary neck dissection for UPHNSCC during 2011-2015 was analysed. The largest pathological-looking node at each radiologically involved level was evaluated in consensus by two head and neck radiologists. Parameters included longest diameter, margin sharpness, haziness in adjacent fat, necrosis, and loss of fat plane with adjacent structures. Independent assessment was also made regarding the presence/absence of ECS. Findings and clinicopathological parameters were correlated with histopathology. RESULTS: Thirty-one patients with 39 neck levels had metastatic nodal involvement determined on CECT. Confirmed ECS was found at 26 levels in 23 patients. Sensitivity of radiological assessment for ECS by nodal level was 81-85% (95% confidence interval [CI]=65-93%) and specificity 46-54% (95% CI=19-81%); kappa 0.87. On univariate analysis based on the largest involved node per patient, longest diameter being ≥30 mm (p=0.007), haziness in adjacent fat (p=0.023), increasing age (p=0.006), and more advanced pathological nodal status (p=0.027) were statistically significantly associated with ECS. Haziness and increasing age were independent predictors on multivariate analysis (odds ratio [OR]=26.4 and 1.24). CONCLUSION: Expert assessment of ECS on CECT had good sensitivity with excellent interobserver agreement. A longest nodal diameter of ≥30 mm, haziness in the surrounding fat on CECT, advanced pathological nodal status, and advancing patient age were significantly associated with ECS in UPHNSCC patients, findings not previously reported.

Exploring men's perceptions of a community-based men's shed programme in England.

Background: Sheds have been used in Australia for decades as an intervention to try and promote 'health by stealth' among men by providing a social space for those who may be particularly vulnerable to poor mental health. Little is known about the impact of men's sheds in England. Methods: Members of 19 sheds from one local authority area were invited to participate in focus groups to explore their perceptions of their shed. In total, 32 men participated in five focus groups which were analysed using applied thematic analysis. Results: While some sheds run activities, the main driving factor of sheds was the social aspect, with many coming along for nothing more than a chat and a cup of tea, allowing men to recapture lost social networks from their working days. However, it was felt that there could be more formal links forged between individual groups, which may result in a better range of activities on offer. Conclusions: This study indicates that the shed can be an effective way of reducing social isolation in older men. However, further work is needed to understand what impact the shed has on physical and mental well-being.

Divergence in ectomycorrhizal communities with foreign Douglas-fir populations and implications for assisted migration.

Assisted migration of forest trees has been widely proposed as a climate change adaptation strategy, but moving tree populations to match anticipated future climates may disrupt the geographically based, coevolved association suggested to exist between host trees and ectomycorrhizal fungal (EMF) communities. We explored this issue by examining the consistency of EMF communities among populations of 40 year-old Douglas-fir (Pseudotsuga menziesii var. menziesii) trees in a common-garden field trial using four provenances from contrasting coastal climates in southwestern British Columbia. Considerable variation in EMF community composition within test sites was found, ranging from 0.38 to 0.65 in the mean similarity index, and the divergence in EMF communities from local populations increased with site productivity. Clinal patterns in colonization success were detected for generalist and specialist EMF species on only the two productive test sites. Host population effects were limited to EMF species abundance rather than species loss, as richness per site averaged 15.0 among provenances and did not differ by transfer extent (up to 450 km), while Shannon's diversity index declined slightly. Large differences in colonization rates of specialist fungi, such as Tomentella stuposa and Clavulina cristata, raise the possibility that EMF communities maladapted to soil conditions contributed to the inferior growth of some host populations on productive sites. The results of the study suggest locally based specificity in host-fungal communities is likely a contributing factor in the outcome of provenance trials, and should be a consideration in analyzing seed-transfer effects and developing strategies for assisted migration.

Integrin signalling: a new Cas(t) of characters enters the stage.

Cellular morphology is determined by the organization of the intracellular actin cytoskeleton, which is influenced by external and internal cues. Focal adhesions are sites at which the actin cytoskeleton is linked to the extracellular matrix by integrin receptor complexes. In addition to providing structural tethering points for cells, integrin receptor complexes transduce signals that influence a broad range of cellular processes, including migration, proliferation, transformation and apoptosis. The Cas proteins (p130Cas, HEF1/Cas-L and Efs/Sin), a family of docking proteins containing multiple interaction domains, are important components of integrin receptor signalling and have been implicated in all of these processes.

Receptor for motilin identified in the human gastrointestinal system.

Motilin is a 22-amino acid peptide hormone expressed throughout the gastrointestinal (GI) tract of humans and other species. It affects gastric motility by stimulating interdigestive antrum and duodenal contractions. A heterotrimeric guanosine triphosphate-binding protein (G protein)-coupled receptor for motilin was isolated from human stomach, and its amino acid sequence was found to be 52 percent identical to the human receptor for growth hormone secretagogues. The macrolide antibiotic erythromycin also interacted with the cloned motilin receptor, providing a molecular basis for its effects on the human GI tract. The motilin receptor is expressed in enteric neurons of the human duodenum and colon. Development of motilin receptor agonists and antagonists may be useful in the treatment of multiple disorders of GI motility.

Tamoxifen treatment promotes phosphorylation of the adhesion molecules, p130Cas/BCAR1, FAK and Src, via an adhesion-dependent pathway.

Reports that the adhesion-associated molecule p130Cas/BCAR1 promotes resistance to tamoxifen suggested that adhesion-mediated signalling may be altered by tamoxifen treatment. We find that p130Cas/BCAR1 phosphorylation is enhanced in tamoxifen-treated estrogen receptor (ER)-positive MCF-7 breast cancer cells. The effects of estrogen and tamoxifen were assessed independently and in combination, and the results demonstrate that tamoxifen antagonizes estrogen regulation of p130Cas/BCAR1 phosphorylation. Phosphorylation correlates with tamoxifen ER antagonist effects, as phosphorylation effects are replicated by the pure antiestrogen ICI 182, 780. Correspondingly, phosphorylation is not changed in ER-negative cells exposed to tamoxifen. We show that deletion of the p130Cas/BCAR1 substrate domain substantially reduces tamoxifen-induced phosphorylation of p130Cas/BCAR1 and confers enhanced sensitivity to tamoxifen. P130Cas/BCAR1 forms a phosphorylation-dependent signalling complex with focal adhesion kinase (FAK) and Src kinase that promotes adhesion-mediated cell survival. Therefore, we examined the kinetics of p130Cas/BCAR1, Src and FAK phosphorylation over a 14-day time course and find sustained phosphorylation of these molecules after 7 days exposure to tamoxifen. Inhibition of Src kinase is shown to reduce tamoxifen-promoted p130Cas/BCAR1 phosphorylation and reduce cell viability. Stimulation of the Src/FAK/p130Cas/BCAR1 adhesion signalling pathway in tamoxifen-treated MCF-7 cells does not cause increased migration; however, there is Src-dependent phosphorylation of the cell survival molecule Akt. Correspondingly, Akt inhibition reduces cell viability in cells treated with tamoxifen. We propose that prolonged activation of adhesion-dependent signalling may confer a survival advantage in response to additional cellular insults or alternatively, may poise cells to develop a migratory phenotype in response to additional cellular cues.

Suppression of niacin-induced vasodilation with an antagonist to prostaglandin D2 receptor subtype 1.

Niacin (nicotinic acid) reduces cardiovascular events in patients with dyslipidemia. However, symptoms associated with niacin-induced vasodilation (e.g., flushing) have limited its use. Laropiprant is a selective antagonist of the prostaglandin D(2) receptor subtype 1 (DP1), which may mediate niacin-induced vasodilation. The aim of this proof-of-concept study was to evaluate the effects of laropiprant (vs placebo) on niacin-induced cutaneous vasodilation. Coadministration of laropiprant 30, 100, and 300 mg with extended-release (ER) niacin significantly lowered flushing symptom scores (by approximately 50% or more) and also significantly reduced malar skin blood flow measured by laser Doppler perfusion imaging. Laropiprant was effective after multiple doses in reducing symptoms of flushing and attenuating the increased malar skin blood flow induced by ER niacin. In conclusion, the DP1 receptor antagonist laropiprant was effective in suppressing both subjective and objective manifestations of niacin-induced vasodilation.

Proteolysis of the docking protein HEF1 and implications for focal adhesion dynamics.

The dynamic regulation of focal adhesions is implicated in cellular processes of proliferation, differentiation, migration, and apoptosis. The focal adhesion-associated docking protein HEF1 is cleaved by caspases during both mitosis and apoptosis. Common to both of these cellular processes is the loss of focal adhesions, transiently during mitosis and permanently during apoptosis. The proteolytic processing of HEF1 during both mitosis and apoptosis therefore posits a general role for HEF1 as a sensor of altered adhesion states. In this study, we find that HEF1 undergoes proteolytic processing specifically in response to cellular detachment, while HEF1 proteolysis is prevented by specific integrin receptor ligation and focal adhesion formation. We show that overexpression of a C-terminal caspase-derived 28-kDa HEF1 peptide causes cellular rounding that is demonstrably separable from apoptosis. Mutation of the divergent helix-loop-helix motif found in 28-kDa HEF1 significantly reduces the induction of apoptosis by this peptide, while deletion of the amino-terminal 28 amino acids of 28-kDa HEF1 completely abrogates the induction of apoptosis. Conversely, these mutations have no effect on the rounding induced by 28-kDa HEF1. Finally, we detect a novel focal adhesion targeting domain located in the C terminus of HEF1 and show that this activity is necessary for HEF1-induced cell spreading. Together, these data suggest that proteolytic and other posttranslational modifications of HEF1 in response to loss of adhesion serve to modulate the disassembly of focal adhesions.

The docking protein HEF1 is an apoptotic mediator at focal adhesion sites.

HEF1 (human enhancer of filamentation 1) is a member of a docking protein family that includes p130(Cas) and Efs. Through assembly of multiple protein interactions at focal adhesion sites, these proteins activate signaling cascades in response to integrin receptor binding of the extracellular matrix. The HEF1 protein is cell cycle regulated, with full-length forms cleaved in mitosis at a caspase consensus site to generate an amino-terminal 55-kDa form that localizes to the mitotic spindle. The identification of a caspase cleavage site in HEF1 led us to investigate whether HEF1 belongs to a select group of caspase substrates cleaved in apoptosis to promote the morphological changes characteristic of programmed cell death. Significantly, inducing expression of HEF1 in MCF-7 or HeLa cells causes extensive apoptosis, as assessed by multiple criteria. Endogenous HEF1 is cleaved into 65- and 55-kDa fragments and a newly detected 28-kDa form in response to the induction of apoptosis, paralleling cleavage of poly(ADP-ribose) polymerase and focal adhesion kinase (FAK); the death-promoting activity of over-expressed HEF1 is associated with production of the 28-kDa form. While the generation of the cleaved HEF1 forms is caspase dependent, the accumulation of HEF1 forms is further regulated by the proteasome, as the proteasome inhibitors N-acetyl-L-leucinyl-L-leucinyl-L-norleucinyl and lactacystin enhance their stability. Finally, the induction of HEF1 expression also increases Jun N-terminal protein kinase (JNK) activation, and activated JNK colocalizes with HEF1, implicating this pathway in HEF1 action. Based on these results, we propose that dysregulation of HEF1 and its family members along with FAK may signal the destruction of focal adhesion sites and regulate the onset of apoptosis.

The effect of physical fatigue on oscillatory dynamics of the sensorimotor cortex.

AIM: While physical fatigue is known to arise in part from supraspinal mechanisms within the brain, exactly how brain activity is modulated during fatigue is not well understood. Therefore, this study examined how typical neural oscillatory responses to voluntary muscle contractions were affected by fatigue. METHODS: Eleven healthy adults (age 27 ± 4 years) completed two experimental sessions in a randomized crossover design. Both sessions first assessed baseline maximal voluntary isometric wrist-flexion force (MVFb ). Participants then performed an identical series of fourteen test contractions (2 × 100%MVFb , 10 × 40%MVFb , 2 × 100%MVFb ) both before and after one of two interventions: forty 12-s contractions at 55%MVFb (fatigue intervention) or 5%MVFb (control intervention). Magnetoencephalography (MEG) was used to characterize both the movement-related mu and beta decrease (MRMD and MRBD) and the post-movement beta rebound (PMBR) within the contralateral sensorimotor cortex during the 40%MVFb test contractions, while the 100%MVFb test contractions were used to monitor physical fatigue. RESULTS: The fatigue intervention induced a substantial physical fatigue that endured throughout the post-intervention measurements (28.9-29.5% decrease in MVF, P < 0.001). Fatigue had a significant effect on both PMBR (anova, session × time-point interaction: P = 0.018) and MRBD (P = 0.021): the magnitude of PMBR increased following the fatigue but not the control interventions, whereas MRBD was decreased post-control but not post-fatigue. Mu oscillations were unchanged throughout both sessions. CONCLUSION: Physical fatigue resulted in an increased PMBR, and offset attenuations in MRBD associated with task habituation.

Cyclin-dependent kinase 7 is a therapeutic target in high-grade glioma.

High-grade glioma (HGG) is an incurable brain cancer. The transcriptomes of cells within HGG tumors are highly heterogeneous. This renders the tumors unresponsive or able to adapt to therapeutics targeted at single pathways, thereby causing treatment failure. To overcome this, we focused on cyclin-dependent kinase 7 (CDK7), a ubiquitously expressed molecule involved in two major drivers of HGG pathogenesis: cell cycle progression and RNA polymerase-II-based transcription. We tested the activity of THZ1, an irreversible CDK7 inhibitor, on patient-derived primary HGG cell lines and ex vivo HGG patient tissue slices, using proliferation assays, microarray analysis, high-resolution respirometry, cell cycle analysis and in vivo tumor orthografts. The cellular processes affected by CDK7 inhibition were analyzed by reverse transcriptase-quantitative PCR, western blot, flow cytometry and immunofluorescence. THZ1 perturbed the transcriptome and disabled CDK activation, leading to cell cycle arrest at G2 and DNA damage. THZ1 halted transcription of the nuclear-encoded mitochondrial ribosomal genes, reducing mitochondrial translation and oxidative respiration. It also inhibited the expression of receptor tyrosine kinases such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor-α (PDGFR-α), reducing signaling flux through the AKT, extracellular-signal-regulated kinase 1/2 (ERK1/2) and signal transducer and activator of transcription 3 (STAT3) downstream pathways. Finally, THZ1 disrupted nucleolar, Cajal body and nuclear speckle formation, resulting in reduced cytosolic translation and malfunction of the spliceosome and thus leading to aberrant mRNA processing. These findings indicate that CDK7 is crucial for gliomagenesis, validate CDK7 as a therapeutic target and provide new insight into the cellular processes that are affected by THZ1 and induce antitumor activity.

Irish-1 and Irish-2: UK epidemic meticillin-resistant Staphylococcus aureus strains associated with Northern Ireland.

Since 1998, an increasing number of meticillin-resistant Staphylococcus aureus (MRSA) isolates with one of two characteristic phage patterns have been referred to the authors' laboratory from Northern Ireland. These strains were designated 'Irish-1' and 'Irish-2'. Analysis of 956 submitted isolates classified as Irish-1 or Irish-2 showed that 97% of the former and 95% of the latter were from Northern Ireland. Only 0.2% and 3%, respectively, were from England. Eleven Irish-2 isolates had been referred from Western Australia as representatives of an epidemic strain originally isolated there in 1994. Ninety isolates with the Irish-1 phage pattern and 91 isolates with the Irish-2 phage pattern, from numerous hospitals, were characterized by SmaI pulsed-field gel electrophoresis (PFGE), toxin gene carriage and antibiotic susceptibility. PFGE showed that, within each collection, a few isolates represented unrelated strains, but the majority were within six band differences of the most common profiles. Half of the Irish-1 isolates were homogeneous, with 22 DNA profiles among the remainder. Irish-2 isolates had two common profiles, D1 and D2, equally divided between one-third of the isolates and differing from each other by two bands; the remaining isolates shared 31 DNA profiles. Cluster analysis showed some overlap in DNA profiles between the Irish-1 and Irish-2 strains, but clear separation from other epidemic MRSA strains. There was no obvious correlation between PFGE profile and either antibiotic resistance pattern or toxin gene possession. All but three Irish-1 isolates possessed only the staphylococcal enterotoxin A (sea) gene, whereas almost all Irish-2 isolates were negative for all 12 enterotoxin genes. Sixty-nine percent of Irish-2 isolates were resistant to ciprofloxacin, erythromycin, kanamycin, neomycin and streptomycin, while 90% of Irish-1 isolates were resistant to all these plus gentamicin and mupirocin. All isolates were sensitive to quinupristin/dalfopristin, teicoplanin and vancomycin. Urease production was negative in both strains. The results suggest that Irish-1 and Irish-2 are distinct epidemic strains, identifiable by phage typing, DNA profiles, antibiotic resistance and toxin gene carriage.

Expression of prostaglandin G/H synthase-1 and -2 protein in human colon cancer.

Prostaglandin G/H synthase (PGHS), a key enzyme leading to the formation of prostaglandins, is the target of nonsteroidal antiinflammatory drugs. Two forms of the enzyme have been identified, PGHS-1 and PGHS-2. Epidemiological evidence has suggested that aspirin and other nonsteroidal antiinflammatory drugs may reduce the risk of colorectal cancer. We examined by immunoblot analyses the expression of human PGHS-1 and PGHS-2 protein in 25 matched colon cancer and nontumor tissues, 4 premalignant polyps, 5 control colon tissues from noncancer patients, and 3 matched normal and cancerous breast tissue samples. PGHS-1 was detected in all normal and tumor tissue. In contrast, PGHS-2 was not detected in 23 of 25 normal colon tissues but was detected in 19 of 25 colon tumors. PGHS-2 protein was not observed in four human premalignant polyp samples, control colon from noncancer patients, or matched normal or cancerous breast tissues. These results suggest that the beneficial effects of nonsteroidal antiinflammatory drugs in colon cancer may be mediated by inhibition of PGHS-2.

Frequent loss of estrogen receptor-beta expression in prostate cancer.

The role of estrogen and its receptors in the etiology and progression of prostate cancer (PC) is poorly understood. In normal and malignant human prostate, estrogen receptor-alpha is expressed only in the stroma, whereas estrogen receptor-beta (ERbeta) is present in both normal stroma and epithelium. Because loss of ERbeta expression is associated with prostate hyperplasia in ERbeta-null mice, this study determined patterns of ERbeta expression in normal, hyperplastic, and malignant human prostate and associations with clinical outcome. Five normal prostates from organ donors and 159 radical prostatectomy specimens from patients with clinically localized PC were assessed for ERbeta expression using immunohistochemistry. ERbeta-positivity was defined as > or =5% of cells demonstrating nuclear immunoreactivity. All of the five normal prostates showed strong ERbeta-nuclear staining in >95% of the epithelium and 35% of the stromal cells. The number of ERbeta-positive cases declined to 24.2% (38/157) in hyperplasia adjacent to carcinoma and 11.3% (18/159) in PCs. ERbeta-positivity was related to decreased relapse-free survival (log-rank P = 0.04). Thus, loss of ERbeta expression is associated with progression from normal prostate epithelium to PC, whereas those cancers that retained ERbeta expression were associated with a higher rate of recurrence. These data identify the need to further investigate the potential role of ERbeta in the regulation of prostate epithelial cell proliferation and the functional consequences of decreased ERbeta expression in the evolution of PC.

Calf Compartment Syndrome associated with the Use of an Intra-osseous Line in an Adult Patient: A Case Report.

We present a case of a lower limb compartment syndrome associated with the use of an intra-osseous line inserted into the proximal tibia in an adult patient. An unconscious 59-year old male with multiple injuries presented to our Emergency Department after a road traffic accident. Bilateral proximal tibial intra osseous-lines were inserted due to poor venous access. After resuscitation his left leg was noted to be tense and swollen with absent pulses. Acute compartment syndrome was diagnosed both clinically and with compartment pressure measurement. Two incision fasciotomy on his left lower leg was performed. Intra osseous-lines in the proximal tibia are increasingly used in adult patients in the pre-hospital setting by paramedics and emergency physicians. Their use, along with the possible complications of these devices, such as the development of compartment syndrome or osteomyelitis leading to amputation, is well reported in the paediatric literature. To the best of our knowledge, there have not been any previous reports of complications in the adult patient. We present a case of lower leg compartment syndrome developing from the use of an intra-osseous line in the proximal tibia in an adult patient. With the increasing use of intra-osseous lines in adult patients, clinicians should be aware of the possibility of developing compartment syndrome which may lead to disability or amputation in severe cases.

A Coproduction Community Based Approach to Reducing Smoking Prevalence in a Local Community Setting.

Research highlights that asset-based community development where local residents become equal partners in service development may help promote health and well-being. This paper outlines baseline results of a coproduction evaluation of an asset-based approach to improving health and well-being within a small community through promoting tobacco control. Local residents were recruited and trained as community researchers to deliver a smoking prevalence survey within their local community and became local health champions, promoting health and well-being. The results of the survey will be used to inform health promotion activities within the community. The local smoking prevalence was higher than the regional and national averages. Half of the households surveyed had at least one smoker, and 63.1% of children lived in a smoking household. Nonsmokers reported higher well-being than smokers; however, the differences were not significant. Whilst the community has a high smoking prevalence, more than half of the smokers surveyed would consider quitting. Providing smoking cessation advice in GP surgeries may help reduce smoking prevalence in this community. Work in the area could be done to reduce children's exposure to smoking in the home.