Defining the Maximum Outcome Improvement of the Modified Harris Hip Score, the Nonarthritic Hip Score, the Visual Analog Scale For Pain, and the International Hip Outcome Tool-12 in the Arthroscopic Management for Femoroacetabular Impingement Syndrome and Labral Tear.
To determine the respective percent thresholds for achieving the maximal outcome improvement (MOI) for the modified Harris Hip Score (mHHS), the Nonarthritic Hip Score (NAHS), the visual analog scale (VAS) for pain, and the International Hip Outcome Tool-12 (iHOT-12) that were associated with satisfaction following hip arthroscopy for femoroacetabular impingement syndrome and labral tear, and to identify preoperative predictors of reaching the mHHS, NAHS, VAS, and the iHOT-12 thresholds for achieving the MOI. An anchor question was provided to patients who underwent hip arthroscopy between April 2008 and April 2019. Patients were included if they answered the anchor question and had minimum 1-year follow-up. Patients were excluded if they had a previous ipsilateral hip surgery, a Tönnis grade >1, hip dysplasia, or a previous hip condition. Receiver operating characteristic analysis was used to determine the thresholds for the percentage of the MOI predictive of satisfaction. Multivariate logistic regression was used to determine predictors of achieving the MOI threshold. In total, 407 hips (375 patients) were included, with 279 female patients (68.6%). The average age, body mass index, and follow-up time were 38.8 ± 13.7 years, 26.6 ± 5.8, and 51.8 ± 33.2 months, respectively. Satisfaction with the current state of their hip was reported in 77.9% (317) of the cases. It was determined that 54.8%, 52.5%, 55.5%, and 55.8% of MOI were the thresholds for maximal predictability of satisfaction for mHHS, NAHS, VAS, and iHOT-12, respectively. Predictors of achieving MOI were not identified. Following hip arthroscopy in the context of femoroacetabular impingement syndrome and labral tear, the thresholds for achieving the MOI for the mHHS, NAHS, VAS for pain, and iHOT-12 were 54.8%, 52.5%, 55.5%, and 55.8% respectively. No preoperative predictors of achieving the MOI were identified. IV, case-series.


VASP is a CXCR2-interacting protein that regulates CXCR2-mediated polarization and chemotaxis.
Chemotaxis regulates the recruitment of leukocytes, which is integral for a number of biological processes and is mediated through the interaction of chemokines with seven transmembrane G-protein-coupled receptors. Several studies have indicated that chemotactic signaling pathways might be activated via G-protein-independent mechanisms, perhaps through novel receptor-interacting proteins. CXCR2 is a major chemokine receptor expressed on neutrophils. We used a proteomics approach to identify unique ligand-dependent CXCR2-interacting proteins in differentiated neutrophil-like HL-60 cells. Using this approach, vasodilator-stimulated phosphoprotein (VASP) was identified as a CXCR2-interacting protein. The interaction between CXCR2 and VASP is direct and enhanced by CXCL8 stimulation, which triggers VASP phosphorylation via PKA- and PKCdelta-mediated pathways. The interaction between CXCR2 and VASP requires free F-actin barbed ends to recruit VASP to the leading edge. Finally, knockdown of VASP in HL-60 cells results in severely impaired CXCR2-mediated chemotaxis and polarization. These data provide the first demonstration that direct interaction of VASP with CXCR2 is essential for proper CXCR2 function and demonstrate a crucial role for VASP in mediating chemotaxis in leukocytes.


Challenges and controversies in the diagnosis of malignant mesothelioma: Part 2. Malignant mesothelioma subtypes, pleural synovial sarcoma, molecular and prognostic aspects of mesothelioma, BAP1, aquaporin-1 and microRNA.
Pleural malignant mesothelioma (MM) includes several unusual and even rare but distinctive histological subtypes, in addition to the usual subdivision into epithelioid, biphasic and sarcomatoid MM. Criteria for discrimination between fibrous pleuritis versus desmoplastic mesothelioma include evidence of neoplastic invasion for diagnosis of desmoplastic MM, but this histological assessment is complicated by the recently-described 'fake fat phenomenon' in cases of fibrous pleuritis. The distinction between biphasic and monophasic synovial sarcoma of the pleura versus biphasic and sarcomatoid MM can be problematical and is most cogently based upon molecular detection of the t(X;18) translocation, whereas a clear diagnosis of MM for a pleural tumour histologically resembling synovial sarcoma is favoured by a negative result for this translocation and, probably, microRNA evidence supportive of a diagnosis of MM. Aquaporin-1 (AQP1) is a molecule involved in the growth of MM cells, and yet is a factor reported to correlate with improved survival rates for MM with an epithelioid component, in comparison to AQP1-poor MM, as assessed from AQP1 expression by epithelioid MM cells only (apart from co-expression by stromal endothelial cells in addition to the tumour cells). Recent reports have also focused upon germline mutations in the BRCA1-associated protein 1 (BAP1), not only in cases of familial mesothelioma, but also BAP1 deletion in sporadic MM. Prognostic factors for MM include not only the histological subtypes, but other independent variables that include (among others), AQP1 expression by mesothelioma cells, the clinical status of the patient, the serum neutrophil:lymphocyte ratio and blood thrombocytosis.


Investigation of the utility of feces and hair as non-invasive measures of glucocorticoids in wild black-tailed prairie dogs (Cynomys ludovicianus).
Non-invasive measures of glucocorticoid (GC) hormones and their metabolites, particularly in feces and hair, are gaining popularity as wildlife management tools, but species-specific validations of these tools remain rare. We report the results of a validation on black-tailed prairie dogs (Cynomys ludovicianus), a highly social engineer of the grasslands ecosystem that has experienced recent population declines. We captured adult female prairie dogs and brought them into temporary captivity to conduct an adrenocorticotropic hormone (ACTH) stimulation test, assessing the relationship between plasma GC and fecal glucocorticoid metabolite (FGM) levels following a single injection of a low (4 IU/kg) or high dose (12 IU/kg) of ACTH, compared to a single injection of saline. We also gave repeated injections of ACTH to adult females to assess whether this would result in an increase of hair cortisol concentrations, compared with control individuals repeatedly injected with saline. A single injection of ACTH at either low or high dose peaked plasma cortisol levels after 30 min, and thereafter the cortisol levels declined until 120 min, where they returned to pre-treatment levels comparable to those of the saline injected group. Despite the significant elevation of plasma cortisol in the treatment groups following ACTH injection, the elevation of FGM levels in the treatment groups were not significantly different from those in the control group over the following 12 h. Repeated injection of a high dose of ACTH failed to increase hair cortisol concentration in treatment animals. Instead, hair cortisol levels remained comparable to the pre-treatment mean, despite an increase in post-treatment hair cortisol levels seen in the saline-injected group. The magnitude of increase in the saline control group was comparable to natural seasonal variation seen in unmanipulated individuals. These results highlight that while measurement of GCs and their metabolites in feces and hair are potentially valuable conservation tools for black-tailed prairie dogs, further validation work is required before these matrices can be to real-world conservation applications.


Antibody-mediated targeting of iron oxide nanoparticles to the folate receptor alpha increases tumor cell association in vitro and in vivo.
Active molecular targeting has become an important aspect of nanoparticle development for oncology indications. Here, we describe molecular targeting of iron oxide nanoparticles (IONPs) to the folate receptor alpha (FOLRα) using an engineered antibody fragment (Ffab). Compared to control nanoparticles targeting the non-relevant botulinum toxin, the Ffab-IONP constructs selectively accumulated on FOLRα-overexpressing cancer cells in vitro, where they exhibited the capacity to internalize into intracellular vesicles. Similarly, Ffab-IONPs homed to FOLRα-positive tumors upon intraperitoneal administration in an orthotopic murine xenograft model of ovarian cancer, whereas negative control particles showed no detectable tumor accumulation. Interestingly, Ffab-IONPs built with custom 120 nm nanoparticles exhibited lower in vitro targeting efficiency when compared to those built with commercially sourced 180 nm nanoparticles. In vivo, however, the two Ffab-IONP platforms achieved equivalent tumor homing, although the smaller 120 nm IONPs were more prone to liver sequestration. Overall, the results show that Ffab-mediated targeting of IONPs yields specific, high-level accumulation within cancer cells, and this fact suggests that Ffab-IONPs could have future utility in ovarian cancer diagnostics and therapy.


[The association between adverse events and nursing care: measurement problems].
The association between adverse events and nursing care: measurement problems. Staffing of RNs below target levels has been associated with increased adverse events, included mortality. Some events may be directly associated to lack of surveillance or care, others occur as a result of neglected care and cannot be associated to the shift with levels of nurses below the target. However, a close look to negative events, neglecting positive events provides an incomplete view. Such studies have been criticized because they have not shown a direct link between the level of staffing and individual patient experiences, often did not control for sill mix and did not explore in depth what nurses do and what are their priorities when there is an higher workload. Often these studies present data with mean values ignoring that nurse staffing is not the same across an entire hospital and nursing care is delivered in geographically-based units, with wide variation in staffing levels. A future challenge of research is to combine a descriptive-quantitative approach with the collection of more qualitative data and prospective designs.


Prognostic Value of N-Terminal Pro-B-Type Natriuretic Peptide Levels in Heart Failure Patients With and Without Atrial Fibrillation.
Patients with heart failure (HF) and atrial fibrillation (AF) have higher circulating levels of NT-proBNP (N-terminal pro-B-type natriuretic peptide) than HF patients without AF. There is uncertainty about the prognostic importance of a given concentration of NT-proBNP in HF patients with and without AF. We investigated this question in a large cohort of patients with HF and reduced ejection fraction. We studied 14 737 patients with HF and reduced ejection fraction and a measurement of NT-proBNP at time of screening, enrolled in either the PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) or the ATMOSPHERE trial (Aliskiren Trial to Minimize Outcomes in Patients With Heart Failure), of whom 3575 (24%) had AF on their baseline ECG. Median (Q1, Q3) levels of NT-proBNP were 1817 pg/mL (1095-3266 pg/mL) in those with AF and 1271 pg/mL (703-2569 pg/mL) in those without (P<0.0001). Patients with AF were older (67 versus 62 years), had worse New York Heart Association class (III/IV; 36% versus 24%), and experienced fewer previous HF hospitalizations (52% versus 61%) or myocardial infarction (30% versus 46%); all P<0.001. We categorized patients with and without AF into 5 NT-proBNP bands: <400, 400 to 999 (reference), 1000 to 1999, 2000 to 2999, and ≥3000 pg/mL. For the primary composite outcome of cardiovascular death or HF hospitalization, event rates differed for patients with and without AF in the lowest band (<400 pg/mL; 8.2 versus 5.0 per 100 patient-years), but not for the higher bands (400-999 pg/mL, 7.4 versus 7.7 per 100 patient-years; 1000-1999 pg/mL, 9.8 versus 11.4 per 100 patient-year; 2000-2999 pg/mL, 13.5 versus 13.4 per 100 patient-years; ≥3000 pg/mL, 22.7 versus 23.0 per 100 patient-years). These findings were consistent whether NT-proBNP was examined as a categorical or continuous variable and before and after adjustment for other prognostic variables. We found similar results for the components of the composite outcome and all-cause mortality. HF and reduced ejection fraction patients with AF had higher NT-proBNP than those without AF. However, above a concentration of 400 pg/mL (representing most patients in each group), NT-proBNP had similar predictive value for adverse cardiovascular outcomes, irrespective of AF status. URL: https://www.clinicaltrials.gov. Unique identifier NCT00853658 (ATMOSPHERE) and NCT01035255 (PARADIGM-HF).


The effect of differing Gleason scores at biopsy on the odds of upgrading and the risk of death from prostate cancer.
The GS is an established prostate cancer prognostic factor. Whether the presence of differing GSs at biopsy (eg, 4+3 and 3+3), which we term ComboGS, improves the prognosis that would be predicted based on the highest GS (eg, 4+3) because of decreased upgrading is unknown. Therefore, we evaluated the odds of upgrading at time of radical prostatectomy (RP) and the risk of PCSM when ComboGS was present versus absent. Logistic and competing risks regression were performed to assess the effect that ComboGS had on the odds of upgrading at time of RP in the index (n = 134) and validation cohorts (n = 356) and the risk of PCSM after definitive therapy in a long-term cohort (n = 666), adjusting for known predictors of these end points. We calculated and compared the area under the curve using a receiver operating characteristic analysis when ComboGS was included versus excluded from the upgrading models. ComboGS was associated with decreased odds of upgrading (index: adjusted odds ratio [AOR], 0.14; 95% confidence interval [CI], 0.04-0.50; P = .003; validation: AOR, 0.24; 95% CI, 0.11-0.51; P < .001) and added significantly to the predictive value of upgrading for the in-sample index (P = .02), validation (P = .003), and out-of-sample prediction models (P = .002). ComboGS was also associated with a decreased risk of PCSM (adjusted hazard ratio, 0.40; 95% CI, 0.19-0.85; P = .02). Differing biopsy GSs are associated with a lower odds of upgrading and risk of PCSM. If validated, future randomized noninferiority studies evaluating deescalated treatment approaches in men with ComboGS could be considered.


When males and hermaphrodites coexist: a review of androdioecy in animals.
Androdioecy (populations consisting of males and hermaphrodites) is a rare mating system in plants and animals: up to 50 plants and only 36 animals have been described as being androdioecious, with most of the latter being crustaceans. To date, a thorough comparative analysis of androdioecy in animals has not been undertaken. Herein we present such an analysis. Androdioecy has only been extensively surveyed in 2 animal taxa: the nematode Caenorhabditis and the clam shrimp Eulimnadia. The other major taxon having androdioecious species is the Cirripedia (barnacles), but there are only limited studies on androdioecy in this group. In animals, androdioecy is found either in species that have morphologically and ecologically distinct sexes (that is, hermaphrodites and small, "complemental" males) that are derived from hermaphroditic ancestors (that is, the barnacles) or in species that have similarly-sized males and hermaphrodites that have been derived from dioecious ancestors (the remaining androdioecious species). We suggest that the barnacles have evolved a sexual specialization in the form of these complemental males that can more efficiently use the constrained habitats that these barnacles often experience. For the remaining species, we suggest that androdioecy has evolved as a response to reproductive assurance in species that experience episodic low densities. Additionally, we hypothesize that the development of mechanisms allowing reproductive assurance in species with a number of sexually differentiated traits is most likely to result in androdioecy rather than gynodioecy (mixtures of females and hermaphrodites), and that these species may be developmentally constrained to stay androdioecious rather than being capable of evolving into populations solely consisting of efficient, self-compatible hermaphrodites. We conclude by suggesting several areas in need of further study to understand more completely the evolution and distribution of this interesting mating system in animals.


Prediction of non-muscle invasive bladder cancer recurrence using machine learning of quantitative nuclear features.
Non-muscle invasive bladder cancer (NMIBC) generally has a good prognosis; however, recurrence after transurethral resection (TUR), the standard primary treatment, is a major problem. Clinical management after TUR has been based on risk classification using clinicopathological factors, but these classifications are not complete. In this study, we attempted to predict early recurrence of NMIBC based on machine learning of quantitative morphological features. In general, structural, cellular, and nuclear atypia are evaluated to determine cancer atypia. However, since it is difficult to accurately quantify structural atypia from TUR specimens, in this study, we used only nuclear atypia and analyzed it using feature extraction followed by classification using Support Vector Machine and Random Forest machine learning algorithms. For the analysis, 125 patients diagnosed with NMIBC were used; data from 95 patients were randomly selected for the training set, and data from 30 patients were randomly selected for the test set. The results showed that the support vector machine-based model predicted recurrence within 2 years after TUR with a probability of 90% and the random forest-based model with probability of 86.7%. In the future, the system can be used to objectively predict NMIBC recurrence after TUR.


Transmissibility of the Ice Bucket Challenge among globally influential celebrities: retrospective cohort study.
To estimate the transmissibility of the Ice Bucket Challenge among globally influential celebrities and to identify associated risk factors. Retrospective cohort study. Social media (YouTube, Facebook, Twitter, Instagram). David Beckham, Cristiano Ronaldo, Benedict Cumberbatch, Stephen Hawking, Mark Zuckerberg, Oprah Winfrey, Homer Simpson, and Kermit the Frog were defined as index cases. We included contacts up to the fifth generation seeded from each index case and enrolled a total of 99 participants into the cohort. Basic reproduction number R0, serial interval of accepting the challenge, and odds ratios of associated risk factors based on fully observed nomination chains; R0 is a measure of transmissibility and is defined as the number of secondary cases generated by a single index in a fully susceptible population. Serial interval is the duration between onset of a primary case and onset of its secondary cases. Based on the empirical data and assuming a branching process we estimated a mean R0 of 1.43 (95% confidence interval 1.23 to 1.65) and a mean serial interval for accepting the challenge of 2.1 days (median 1 day). Higher log (base 10) net worth of the participants was positively associated with transmission (odds ratio 1.63, 95% confidence interval 1.06 to 2.50), adjusting for age and sex. The Ice Bucket Challenge was moderately transmissible among a group of globally influential celebrities, in the range of the pandemic A/H1N1 2009 influenza. The challenge was more likely to be spread by richer celebrities, perhaps in part reflecting greater social influence.


Effects of flow patterns on the localization and expression of VE-cadherin at vascular endothelial cell junctions: in vivo and in vitro investigations.
Atherosclerosis occurs preferentially at vascular curvature and branch sites where the vessel walls are exposed to fluctuating shear stress and have high endothelial permeability. Endothelial permeability is modulated by intercellular adhesion molecules such as VE-cadherin. This study was designed to elucidate the effects of different flow patterns on the localization and expression of VE-cadherin in endothelial cells (ECs) both in vivo and in vitro. VE-cadherin staining at EC borders was much stronger in the descending thoracic aorta and abdominal aorta, where the pulsatile flow has a strong net forward component than in the aortic arch and the poststenotic dilatation site beyond an experimental constriction, where the flow near the wall is complex and reciprocating with little net flow. With the use of flow chambers the effects of pulsatile flow (12 +/- 4 dyn/cm2 at 1 Hz) and reciprocating flow (0.5 +/- 4 dyn/cm2 at 1 Hz) on VE-cadherin organization in endothelial monolayers were studied in vitro. VE-cadherin staining was continuous along cell borders in static controls. Following 6 h of either pulsatile or reciprocating flow, the VE-cadherin staining at cell borders became intermittent. When the pulsatile flow was extended to 24, 48 or 72 h the staining around the cell borders became continuous again, but the staining was still intermittent when the reciprocating flow was similarly extended. Exposure to pulsatile or reciprocating flow for 6 and 24 h neither change the expression level of VE-cadherin nor its distribution between membrane and cytosol fractions as determined by Western blot and compared with static controls. These findings suggest that the cell junction remodeling induced by different flow patterns may result from a redistribution of VE-cadherin within the cell membrane. Both the in vivo and in vitro data indicate that pulsatile and reciprocating flow patterns have different effects on cell junction remodeling. The lack of junction reorganization in regions of reciprocating flow in vivo and in vitro may provide a mechanistic basis for the high permeability and the preferential localization of atherosclerosis in regions of the arterial stress with complex flow patterns and fluctuating shear stress.


Selective tyrosine hyperphosphorylation of cytoskeletal and stress proteins in primary human breast cancers: implications for adjuvant use of kinase-inhibitory drugs.
Small-molecule growth factor receptor inhibitors block cell growth in vitro and downstream signaling in vivo, but controlled trials in patients with advanced solid tumors have yielded disappointing response rates. To clarify this discrepancy, we compared the patterns of tyrosine phosphoprotein expression in human cancer cells and primary tumors. Immunoaffinity chromatography, two-dimensional electrophoresis, and antiphosphotyrosine immunoblotting were combined with mass spectrometry to determine the phosphoproteomic signatures of 40 matched normal and malignant tissues from patients with breast or liver cancer. The identities and abundance of the detected tyrosine phosphoproteins were compared with those of ligand-responsive A431 cells. Patterns of tyrosine-phosphorylated proteins are similar among normal tissues of the same origin but vary markedly between different tissues. Primary breast tumors exhibit a strikingly homogeneous tyrosine phosphorylation profile, whereas liver cancers display greater phosphoproteomic diversity. The main breast-tumor-specific tyrosine phosphoproteins are cytoskeletal molecules (actin, tubulin, and vimentin) and molecular chaperones (Hsp70, Hsc71, and Grp75). In contrast, control studies in ligand-stimulated A431 human cancer cells revealed an additional phosphorylated subset of promitogenic phosphoproteins (Grb2, Shc, Jnk2, phospholipase C-gamma, and phosphatidylinositol 3'-kinase). Identification of cytoskeletal and stress proteins as the most abundant tyrosine phosphoproteins in breast tumors implicates these molecules, rather than promitogenic effectors, as the prime stoichiometric substrates for kinase-inhibitory anticancer drugs in vivo. Because phosphorylated cytoskeletal proteins and chaperones mediate cell motility and apoptotic resistance, respectively, these data raise the intriguing possibility that small-molecule tyrosine kinase inhibitors may be of greatest value either as adjuvant antimetastatic/-invasive drugs or as chemo-/radiosensitizers.


Modulation of hippocampal acetylcholine release: a potent central action of interleukin-2.
The potential of the T-cell growth factor interleukin-2 (IL-2) to modulate the release of ACh from rat hippocampus was studied in vitro, as a means to investigate the possible functional significance of this cytokine in the CNS. Hippocampal slices were superfused with Krebs' buffer medium, and endogenous ACh released into the superfusate was measured using a radioenzymatic assay. Recombinant human IL-2 present during a stimulation with 25 mM KCl altered, in a concentration-dependent manner, the evoked transmitter release. At a concentration of 15 U/ml (< or = 1 nM), IL-2 inhibited ACh release by more than 50% of the control level (evoked ACh release from the untreated contralateral hemispheres). Inhibition was observed within 20 min of tissue exposure to IL-2 and lasted for up to 1 hr. The inhibitory effect of IL-2 was reversible since transient tissue exposure to IL-2 did not affect subsequent evoked ACh release. IL-2 at this concentration also significantly decreased evoked ACh in frontal cortical slices, but was ineffective in the parietal cortex and striatum, revealing that IL-2 selectively modulates the release of ACh from certain, but not all, cholinergic nerve terminals in the CNS. At very low concentrations (1.5 mU/ml, < or = 0.1 pM), IL-2 transiently increased hippocampal evoked ACh release, resulting in a biphasic dose-response profile with no significant effect observed at 0.015 mU/ml (< or = 1 fM). Other cytokines (IL-1 alpha, IL-3, IL-5, IL-6, interferon alpha), tested in hippocampal slice incubations, failed to modulate ACh release.(ABSTRACT TRUNCATED AT 250 WORDS)


Safety and efficacy of multipotent adult progenitor cells in acute ischaemic stroke (MASTERS): a randomised, double-blind, placebo-controlled, phase 2 trial.
Multipotent adult progenitor cells are a bone marrow-derived, allogeneic, cell therapy product that modulates the immune system, and represents a promising therapy for acute stroke. We aimed to identify the highest, well-tolerated, and safest single dose of multipotent adult progenitor cells, and if they were efficacious as a treatment for stroke recovery. We did a phase 2, randomised, double-blind, placebo-controlled, dose-escalation trial of intravenous multipotent adult progenitor cells in 33 centres in the UK and the USA. We used a computer-generated randomisation sequence and interactive voice and web response system to assign patients aged 18-83 years with moderately severe acute ischaemic stroke and a National Institutes of Health Stroke Scale (NIHSS) score of 8-20 to treatment with intravenous multipotent adult progenitor cells (400 million or 1200 million cells) or placebo between 24 h and 48 h after symptom onset. Patients were ineligible if there was a change in NIHSS of four or more points during at least a 6 h period between screening and randomisation, had brainstem or lacunar infarct, a substantial comorbid disease, an inability to undergo an MRI scan, or had a history of splenectomy. In group 1, patients were enrolled and randomly assigned in a 3:1 ratio to receive 400 million cells or placebo and assessed for safety through 7 days. In group 2, patients were randomly assigned in a 3:1 ratio to receive 1200 million cells or placebo and assessed for safety through the first 7 days. In group 3, patients were enrolled, randomly assigned, and stratified by baseline NIHSS score to receive 1200 million cells or placebo in a 1:1 ratio within 24-48 h. Patients, investigators, and clinicians were masked to treatment assignment. The primary safety outcome was dose-limiting toxicity effects. The primary efficacy endpoint was global stroke recovery, which combines dichotomised results from the modified Rankin scale, change in NIHSS score from baseline, and Barthel index at day 90. Analysis was by intention to treat (ITT) including all patients in groups 2 and 3 who received the investigational agent or placebo. This study is registered with ClinicalTrials.gov, number NCT01436487. The study was done between Oct 24, 2011, and Dec 7, 2015. After safety assessments in eight patients in group 1, 129 patients were randomly assigned (67 to receive multipotent adult progenitor cells and 62 to receive placebo) in groups 2 and 3 (1200 million cells). The ITT populations consisted of 65 patients who received multipotent adult progenitor cells and 61 patients who received placebo. There were no dose-limiting toxicity events in either group. There were no infusional or allergic reactions and no difference in treatment-emergent adverse events between the groups (64 [99%] of 65 patients in the multipotent adult progenitor cell group vs 59 [97%] of 61 in the placebo group). There was no difference between the multipotent adult progenitor cell group and placebo groups in global stroke recovery at day 90 (odds ratio 1·08 [95% CI 0·55-2·09], p=0·83). Administration of multipotent adult progenitor cells was safe and well tolerated in patients with acute ischaemic stroke. Although no significant improvement was observed at 90 days in neurological outcomes with multipotent adult progenitor cells treatment, further clinical trials evaluating the efficacy of the intervention in an earlier time window after stroke (<36 h) are planned. Athersys Inc.


Assessment of insulin resistance by a 13C glucose breath test: a new tool for early diagnosis and follow-up of high-risk patients.
Insulin resistance (IR) plays an important role in the pathogenesis of diabetes and non-alcoholic fatty liver disease (NAFLD). Current methods for insulin resistance detection are cumbersome, or not sensitive enough for early detection and follow-up. The BreathID system can continuously analyse breath samples in real-time at the point-of-care. Here we determined the efficacy of the BreathID using the 13C-Glucose breath test (GBT) for evaluation of insulin resistance. Twenty healthy volunteers were orally administered 75 mg of 13C-glucose 1-13C. An oral glucose tolerance test (OGTT) was performed immediately; followed by serum glucose and insulin level determinations using GBT. GBT and OGTT were repeated following exercise, which alters insulin resistance levels. Within-subject correlations of GBT parameters with serum glucose and serum insulin levels were high. Before and after exercise, between-subjects correlations were high between the relative insulin levels and the % dose recoveries at 90 min (PDR 90), and the cumulative PDRs at 60 min (CPDR 60). Pairwise correlations were identified between pre-exercise Homeostasis Model Assessment (HOMA) IR at 90 min and PDR 90; HOMA B (for beta cell function) 120 and CPDR 30; HOMA IR 60 and peak time post-exercise; and HOMA B 150 with PDR 150. The non-invasive real-time BreathID GBT reliably assesses changes in liver glucose metabolism, and the degree of insulin resistance. It may serve as a non-invasive tool for early diagnosis and follow up of patients in high-risk groups.


Technique for designing and evaluating probe caps used in optical topography of infants using a real head model based on three dimensional magnetic resonance images.
We have developed an effective technique for aiding the design and evaluating the performance of the probe caps used to perform optical topography (OT) on infants. To design and evaluate a probe cap, it is necessary to determine the measurement positions for conducting OT on the brain surface of subjects. One technique for determining these positions on the brain surface is to find their three-dimensional (3D) coordinates using a 3D magnetic space digitizer, which consists of a 3D magnetic source and a 3D magnetic sensor. The problem with this technique is that it takes a long time to determine all the measurement points on the subject's head and it is difficult to use with infants. It is a particular problem with infants who cannot support their own heads. Therefore, we have developed a real model of an infant subject's head based on 3D magnetic resonance (MR) images. The model is made from an optical-curable resin using 3D computer-aided-format coordinate data taken from 3D MR image-format coordinate data. We have determined the measurement positions on the surface of the model corresponding to a scalp using a 3D magnetic space digitizer and displayed the positions on a 3D MR image of the infant's brain. Using this technique, we then determined the actual 72 measurement positions located over the entire brain surface area for use with our new whole-head probe cap for neonates and infants. This method is useful for evaluating the performance of and designing probe caps.


Total parathyroidectomy alone or with autograft for renal hyperparathyroidism?
Seventy-six patients underwent parathyroidectomy for renal hyperparathyroidism. There were 10 subtotal parathyroidectomies, 49 total parathyroidectomies with implantation of part of one gland as an autograft, nine total parathyroidectomies with no autograft, and eight patients in whom only three parathyroid glands were found. In 34 dialysis patients who underwent total parathyroidectomy with an autograft there was a high rate of recurrent hyperparathyroidism after 6 years in those remaining on dialysis. Fifty per cent had asymptomatic recurrent hyperparathyroidism and 30 per cent required partial autograft excision for symptomatic hyperparathyroidism. In contrast, recurrent hyperparathyroidism was rare in renal transplant recipients with good renal function. This favourable outcome did not depend upon whether parathyroid surgery was performed before or after transplantation, or on the type of parathyroidectomy. Total parathyroidectomy without an autograft was performed in nine dialysis patients without any short-term adverse effects, and with clinical and pathological improvement in bone disease. In summary, the results of surgery for renal hyperparathyroidism were excellent in patients who received a successful renal transplant. However, there was a high incidence of recurrent hyperparathyroidism in patients who remained on long-term dialysis. Total parathyroidectomy without an autograft may be the treatment of choice in patients unlikely to receive a renal transplant.


Seasonal dynamics of Atlantic herring (Clupea harengus L.) populations spawning in the vicinity of marginal habitats.
Gillnet sampling and analyses of otolith shape, vertebral count and growth indicated the presence of three putative Atlantic herring (Clupea harengus L.) populations mixing together over the spawning season February-June inside and outside an inland brackish water lake (Landvikvannet) in southern Norway. Peak spawning of oceanic Norwegian spring spawners and coastal Skagerrak spring spawners occurred in March-April with small proportions of spawners entering the lake. In comparison, spawning of Landvik herring peaked in May-June with high proportions found inside the lake, which could be explained by local adaptations to the environmental conditions and seasonal changes of this marginal habitat. The 1.85 km(2) lake was characterized by oxygen depletion occurring between 2.5 and 5 m depth between March and June. This was followed by changes in salinity from 1-7‰ in the 0-1 m surface layer to levels of 20-25‰ deeper than 10 m. In comparison, outside the 3 km long narrow channel connecting the lake with the neighboring fjord, no anoxic conditions were found. Here salinity in the surface layer increased over the season from 10 to 25‰, whereas deeper than 5 m it was stable at around 35‰. Temperature at 0-5 m depth increased significantly over the season in both habitats, from 7 to 14 °C outside and 5 to 17 °C inside the lake. Despite differences in peak spawning and utilization of the lake habitat between the three putative populations, there was an apparent temporal and spatial overlap in spawning stages suggesting potential interbreeding in accordance with the metapopulation concept.


A collaboration with local Aboriginal communities in rural New South Wales, Australia to determine the oral health needs of their children and develop a community-owned oral health promotion program.
As part of an oral health service for Aboriginal people in central northern New South Wales (NSW), Australia, oral health promotion was identified as a priority by the local Aboriginal community. The objective of this study was to collaborate with local Aboriginal communities to determine (1) the oral health needs of Aboriginal children aged 5-12 years, (2) the oral health knowledge and attitudes towards oral health of parents/guardians and (3) the perceived barriers and enablers towards oral health promotion for school children by local school staff and community health workers. The results of this collaboration will inform a community-owned oral health promotion program. Aboriginal children aged 5-12 years enrolled in local schools received a dental screening by a single examiner. The number of decayed, missing and filled teeth of primary and permanent dentition (dmft/DMFT), plaque and gingivitis were recorded. Children completed a questionnaire assessing current oral hygiene practices, dental history and information on their diet. Parents/guardians completed a questionnaire assessing oral health knowledge and attitudes towards oral health. School staff and community health workers completed a questionnaire assessing attitudes, barriers and enablers towards implementing an oral health promotion program in schools. Eighty-eight children, representing 94% of those eligible, were screened, and 78 (82%) completed a questionnaire. The mean dmft/DMFT score was 5.3. Risk factors for dental caries identified included lack of toothbrush ownership (35%), minimal fluoride toothpaste use (24%), limited daily tooth brushing (51%) and frequent consumption of sugary foods (72%) and soft drinks (64%). Questionnaires were completed by 32 parents/guardians and 39 school and community health workers. Parents/guardians had limited oral health knowledge. School and health staff were willing to support a health promotion program to improve dental health of children. Aboriginal children living in rural and remote communities in NSW experience high rates of dental caries. Oral health promotion is urgently required to reduce the burden of dental caries and should address oral hygiene behaviours, fluoride use and access to healthy foods and drinks. Note: This article uses the term 'Aboriginal people' when referring to the first peoples of Australia. This term is inclusive of Australian Aboriginal and Torres Strait Islander people.


Leukemoid reaction resulting from multiple cytokine production in metastatic mucoepidermoid carcinoma with central necrosis.
We report a male patient with metastatic high-grade mucoepidermoid carcinoma and associated leukemoid reaction. The patient was transferred to our hospital due to persistent spiking fever, marked granulocytosis, and suspected liver abscess. After thorough bacteriological studies, including cultures of blood and material aspirated from the "liver abscess", no evidence of infection was documented. The patient suffered from persistent spiking fever for more than 4 weeks in spite of empirical antibiotic treatment, and repeated aspiration of the presupposed liver abscess. He underwent exploratory laparotomy for intended surgical evacuation of the liver abscess and bacteriological diagnosis. The operative findings were compatible with metastatic carcinoma with multiple liver and retroperitoneal lymph node involvement and tumor necrosis. The pathology report indicated high-grade mucoepidermoid carcinoma. Immunohistochemistry showed positive staining for interleukin-1 alpha (IL-1 alpha) and IL-6. Elevation of cytokine levels in the necrotic tumor fluid, including IL-1 alpha, IL-6, granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor was confirmed by ELISA test. This case shows that multiple cytokine production from a metastatic tumor and its central necrotic area in the liver can produce a febrile leukemoid reaction mimicking a pyogenic liver abscess.


Two-photon time-lapse microscopy of BODIPY-cholesterol reveals anomalous sterol diffusion in chinese hamster ovary cells.
Cholesterol is an important membrane component, but our knowledge about its transport in cells is sparse. Previous imaging studies using dehydroergosterol (DHE), an intrinsically fluorescent sterol from yeast, have established that vesicular and non-vesicular transport modes contribute to sterol trafficking from the plasma membrane. Significant photobleaching, however, limits the possibilities for in-depth analysis of sterol dynamics using DHE. Co-trafficking studies with DHE and the recently introduced fluorescent cholesterol analog BODIPY-cholesterol (BChol) suggested that the latter probe has utility for prolonged live-cell imaging of sterol transport. We found that BChol is very photostable under two-photon (2P)-excitation allowing the acquisition of several hundred frames without significant photobleaching. Therefore, long-term tracking and diffusion measurements are possible. Two-photon temporal image correlation spectroscopy (2P-TICS) provided evidence for spatially heterogeneous diffusion constants of BChol varying over two orders of magnitude from the cell interior towards the plasma membrane, where D ~ 1.3 μm2/s. Number and brightness (N&B) analysis together with stochastic simulations suggest that transient partitioning of BChol into convoluted membranes slows local sterol diffusion. We observed sterol endocytosis as well as fusion and fission of sterol-containing endocytic vesicles. The mobility of endocytic vesicles, as studied by particle tracking, is well described by a model for anomalous subdiffusion on short time scales with an anomalous exponent α ~ 0.63 and an anomalous diffusion constant of Dα = 1.95 x 10-3 μm2/sα. On a longer time scale (t > ~5 s), a transition to superdiffusion consistent with slow directed transport with an average velocity of v ~ 6 x 10-3 μm/s was observed. We present an analytical model that bridges the two regimes and fit this model to vesicle trajectories from control cells and cells with disrupted microtubule or actin filaments. Both treatments reduced the anomalous diffusion constant and the velocity by ~40-50%. The mobility of sterol-containing vesicles on the short time scale could reflect dynamic rearrangements of the cytoskeleton, while directed transport of sterol vesicles occurs likely along both, microtubules and actin filaments. Spatially varying anomalous diffusion could contribute to fine-tuning and local regulation of intracellular sterol transport.


Hemophagocytic Lymphohistiocytosis in a Patient With Acute Respiratory Distress Syndrome Secondary to SARS-CoV-2 Infection.
Hemophagocytic lymphohistiocytosis (HLH) is a potentially life-threatening entity resulting from the dysregulated activation of T-lymphocytes. Secondary HLH (sHLH) complicates various medical conditions. Similar to 2009 H1N1 influenza, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection appears to trigger a cytokine storm in a subset of individuals. The patient of 64 years old presented himself in the emergency department with cough and fever, and was subjected to the nasopharyngeal swab and tested positive for SARS-CoV-2, as expected from epidemiological data. Hospitalized in cohort isolation, he initially presented a multi-organ impairment and specifically a worsening of his renal function, initial coagulopathy, lymphopenia modest thrombocytopenia and systemic inflammatory commitment. During the course of the 6th day, a picture of a probable cytokine storm and clear multiple organ failure (MOF) was evident. Therefore a clinical diagnosis was made according to HScore criteria of secondary hemophagocytic lymphohistiocytosis. We started high-dose steroid therapy (dexamethasone 8 mg bid). And after 36 h, the patient was significantly improved: alert, oriented, weaned from non-invasive ventilation (NIV) and stable blood chemistry. In conclusion, in coronavirus disease 2019 (COVID-19) positive patients with evidence of cytokine storm and acute respiratory distress syndrome (ARDS), the levels of blood triglycerides and ferritin are useful and often decisive to comfort the diagnosis of sHLH if cytopenia of one or more lines is revealed.


Outbreak of invasive methicillin-resistant Staphylococcus aureus infection associated with acupuncture and joint injection.
To describe an outbreak of invasive methicillin-resistant Staphylococcus aureus (MRSA) infection after percutaneous needle procedures (acupuncture and joint injection) performed by a single medical practitioner. A medical practitioner's office and 4 hospitals in Perth, Western Australia. Eight individuals who developed invasive MRSA infection after acupuncture or joint injection performed by the medical practitioner. We performed a prospective and retrospective outbreak investigation, including MRSA colonization surveillance, environmental sampling for MRSA, and detailed molecular typing of MRSA isolates. We performed an infection control audit of the medical practitioner's premises and practices and administered MRSA decolonization therapy to the medical practitioner. Eight cases of invasive MRSA infection were identified. Seven cases occurred as a cluster in May 2004; another case (identified retrospectively) occurred approximately 15 months earlier in February 2003. The primary sites of infection were the neck, shoulder, lower back, and hip: 5 patients had septic arthritis and bursitis, and 3 had pyomyositis; 3 patients had bacteremia, including 1 patient with possible endocarditis. The medical practitioner was found to be colonized with the same MRSA clone [ST22-MRSA-IV (EMRSA-15)] at 2 time points: shortly after the first case of infection in March 2003 and again in May 2004. After the medical practitioner's premises and practices were audited and he himself received MRSA decolonization therapy, no further cases were identified. This outbreak most likely resulted from a breakdown in sterile technique during percutaneous needle procedures, resulting in the transmission of MRSA from the medical practitioner to the patients. This report demonstrates the importance of surveillance and molecular typing in the identification and control of outbreaks of MRSA infection.


The additional prognostic value of morphometric nuclear arrangement and DNA-ploidy to other morphometric and stereologic features in endometrial hyperplasias.
Earlier studies have shown that morphometric analysis of nuclear size and shape features and stereologic analysis of gland architecture in endometrial hyperplasia are useful to predict the risk of progression to cancer. A multivariate discriminatory D-score using these features has a higher sensitivity than qualitative microscopic characteristics (nuclear atypicality and glandular complexity) when an appropriate threshold is chosen. In the present study, the (additional) prognostic value of morphometric features related to the arrangement of nuclei in glands (distance of nuclear centroids to basal membrane, angle of longest nuclear axis with basal membrane) and DNA-ploidy (determined by flow cytometry) has been analyzed in 39 cases of endometrial hyperplasia, seven (18%) of which have progressed to cancer. Variation in stratification of nuclei has prognostic value, in contrast to DNA-ploidy. Multivariate analysis selects the outer surface density of the glands, mean distance, volume percentage of lumen and the coefficient of variation of nuclear axes as having separate and additional value. A multivariate rule called HYPER-score results from these features. With this score a high-risk (score value >/=0.20, nine cases, 78% progressed) and a low-risk group (score value <0.20, 30 cases, none progressed) can be discerned. The prognostic value, sensitivity and specificity of the hyper-score greatly exceeds that of any of the previously described prognostic factors in endometrial hyperplasias. An additional clinical advantage is that with the HYPER-score two groups (instead of four groups as with Kurman's method(1)) with a high sensitivity and specificity can be discerned. The morphometric and stereologic features agree well with the usual qualitative predictors but have much stronger prognostic value.


Comparison between Effects of Retroactivity and Resource Competition upon Change in Downstream Reporter Genes of Synthetic Genetic Circuits.
Reporter genes have contributed to advancements in molecular biology. Binding of an upstream regulatory protein to a downstream reporter promoter allows quantification of the activity of the upstream protein produced from the corresponding gene. In studies of synthetic biology, analyses of reporter gene activities ensure control of the cell with synthetic genetic circuits, as achieved using a combination of in silico and in vivo experiments. However, unexpected effects of downstream reporter genes on upstream regulatory genes may interfere with in vivo observations. This phenomenon is termed as retroactivity. Using in silico and in vivo experiments, we found that a different copy number of regulatory protein-binding sites in a downstream gene altered the upstream dynamics, suggesting retroactivity of reporters in this synthetic genetic oscillator. Furthermore, by separating the two sources of retroactivity (titration of the component and competition for degradation), we showed that, in the dual-feedback oscillator, the level of the fluorescent protein reporter competing for degradation with the circuits' components is important for the stability of the oscillations. Altogether, our results indicate that the selection of reporter promoters using a combination of in silico and in vivo experiments is essential for the advanced design of genetic circuits.


Peripheral eosinophilia in the diagnosis of chronic rhinosinusitis.
To determine the relationship between peripheral blood eosinophilia and chronic rhinosinusitis. A retrospective review was conducted of consecutive operative cases during 1 calendar year. The preoperative complete blood count (CBC) were tabulated for three groups of patients: those undergoing endoscopic sinus surgery, those undergoing septoplasty with turbinate reduction alone, and a nonrhinologic control group. Statistical analysis was performed to determine differences in the components of the CBC among these three groups of patients and to identify significant associations between abnormal peripheral eosinophil counts and these diagnoses. A total of 87, 32, and 92 patients were identified for the endoscopic sinus surgery (ESS), septoplasty, and control groups, respectively. Significant differences in the percentages of eosinophils, lymphocytes, and neutrophils were noted among the three groups (P <.05). Comparison among groups indicated that ESS patients had significantly higher percent peripheral eosinophilia when compared with both the control group and septoplasty group (P <.001 and P =.010, respectively); no significant difference was noted between the septoplasty group and the control group (P =.627). The sensitivity and specificity of the peripheral eosinophil count for chronic sinusitis were 49.4% and 84.7%, respectively. The peripheral eosinophil count in chronic sinusitis is elevated compared with both a nonrhinologic control group and a group of patients with septal deviation. Furthermore, abnormally elevated eosinophil counts are associated with chronic sinusitis but not chronic rhinitis alone. However, this association is not strong enough to be used in the diagnosis of chronic sinusitis because of poor sensitivity.


Reference PMHS Sled Tests to Assess Submarining.
Sled tests focused on pelvis behavior and submarining can be found in the literature. However, they were performed either with rigid seats or with commercial seats. The objective of this study was to get reference tests to assess the submarining ability of dummies in more realistic conditions than on rigid seat, but still in a repeatable and reproducible setup. For this purpose, a semi-rigid seat was developed, which mimics the behavior of real seats, although it is made of rigid plates and springs that are easy to reproduce and simulate with an FE model. In total, eight PMHS sled tests were performed on this semirigid seat to get data in two different configurations: first in a front seat configuration that was designed to prevent submarining, then in a rear seat configuration with adjusted spring stiffness to generate submarining. All subjects sustained extensive rib fractures from the shoulder belt loading. No pelvis fractures and no submarining were observed in the front seat configuration, but two subjects sustained lumbar vertebrae fractures. In the rear seat configuration, all subjects sustained pelvic fractures and demonstrated submarining. Corridors were constructed for the external forces and the PMHS kinematics. They are provided in this paper as new reference tests to assess the biofidelity of human surrogates in different configurations that either result in submarining or do not. In future, it is intended to analyze further seat and restraint system configurations to be able to define a submarining predictor.


Site-specific differences in T cell frequencies and phenotypes in the blood and gut of HIV-uninfected and ART-treated HIV+ adults.
Gastrointestinal T lymphocytes are critical for mucosal immunity and HIV pathogenesis, yet little is known about normal T cell numbers and phenotypes in different regions of the gut, or the degree to which ART can restore levels to those of HIV-uninfected individuals. To investigate these questions, we measured T cell frequencies and markers of memory, activation, anergy, and homing in the blood, ileum, and rectum of HIV- and ART-suppressed HIV+ adults. In HIV- individuals, T cell frequencies and phenotypes differed significantly between sites. Compared to HIV- adults, HIV+ adults had lower absolute CD4+T cell counts in the ileal lamina propria and lower relative CD4+T cell counts in the blood and ileum. In the gut, HIV+ adults had a higher proportion of CD38+ CD4+T cells, a lower proportion of terminally-differentiated effector cells, and, in the rectum, a higher proportion of CTLA-4+ CD4+T cells. In HIV+ individuals, relative CD4+T cell numbers in the ileum correlated with the proportion of CTLA-4+ CD4+T cells, whereas in the rectum, they tended to correlate with the proportion of circulating CD4+T cells expressing α4β7 or CCR6. Mechanisms of T cell reconstitution may differ throughout the gut, with homing contributing more in the rectum while ileal reconstitution is associated with mucosal CD4+T cell anergy.


DNA Methylation of Enhancer Elements in Myeloid Neoplasms: Think Outside the Promoters?
Gene regulation through DNA methylation is a well described phenomenon that has a prominent role in physiological and pathological cell-states. This epigenetic modification is usually grouped in regions denominated CpG islands, which frequently co-localize with gene promoters, silencing the transcription of those genes. Recent genome-wide DNA methylation studies have challenged this paradigm, demonstrating that DNA methylation of regulatory regions outside promoters is able to influence cell-type specific gene expression programs under physiologic or pathologic conditions. Coupling genome-wide DNA methylation assays with histone mark annotation has allowed for the identification of specific epigenomic changes that affect enhancer regulatory regions, revealing an additional layer of complexity to the epigenetic regulation of gene expression. In this review, we summarize the novel evidence for the molecular and biological regulation of DNA methylation in enhancer regions and the dynamism of these changes contributing to the fine-tuning of gene expression. We also analyze the contribution of enhancer DNA methylation on the expression of relevant genes in acute myeloid leukemia and chronic myeloproliferative neoplasms. The characterization of the aberrant enhancer DNA methylation provides not only a novel pathogenic mechanism for different tumors but also highlights novel potential therapeutic targets for myeloid derived neoplasms.


Arrestins as signaling molecules involved in apoptotic pathways: a real eye opener.
Recent data suggest that internalized receptor and arrestin complexes are actively involved in signal transduction. Miller and Lefkowitz discuss evidence from the Drosophila visual system that suggests that intracellular rhodopsin and arrestin2 complexes induce apoptosis. Experiments with activated mammalian G protein-coupled receptor and arrestin complexes point to a mechanism by which proliferative or proapoptotic signals can be mediated largely independent from G protein activation.


Neutrophils, lymphocytes, and monocytes exhibit diverse behaviors in transendothelial and subendothelial migrations under coculture with smooth muscle cells in disturbed flow.
Atherosclerosis develops at regions of the arterial tree exposed to disturbed flow. The early stage of atherogenesis involves the adhesion of leukocytes (white blood cells [WBCs]) to and their transmigration across endothelial cells (ECs), which are located in close proximity to smooth muscle cells (SMCs). We investigated the effects of EC/SMC coculture and disturbed flow on the adhesion and transmigration of 3 types of WBCs (neutrophils, peripheral blood lymphocytes [PBLs], and monocytes) using our vertical-step flow (VSF) chamber, in which ECs were cocultured with SMCs in collagen gels. Such coculture significantly increased the adhesion and transmigration of neutrophils, PBLs, and monocytes under VSF, particularly in the reattachment area, where the rolling velocity of WBCs and their transmigration time were decreased, as compared with the other areas. Neutrophils, PBLs, and monocytes showed different subendothelial migration patterns under VSF. Their movements were more random and shorter in distance in the reattachment area. Coculture of ECs and SMCs induced their expressions of adhesion molecules and chemokines, which contributed to the increased WBC adhesion and transmigration. Our findings provide insights into the mechanisms of WBC interaction with the vessel wall (composed of ECs and SMCs) under the complex flow environments found in regions of prevalence for atherogenesis.


Predicting novel binding modes of agonists to β adrenergic receptors using all-atom molecular dynamics simulations.
Understanding the binding mode of agonists to adrenergic receptors is crucial to enabling improved rational design of new therapeutic agents. However, so far the high conformational flexibility of G protein-coupled receptors has been an obstacle to obtaining structural information on agonist binding at atomic resolution. In this study, we report microsecond classical molecular dynamics simulations of β(1) and β(2) adrenergic receptors bound to the full agonist isoprenaline and in their unliganded form. These simulations show a novel agonist binding mode that differs from the one found for antagonists in the crystal structures and from the docking poses reported by in silico docking studies performed on rigid receptors. Internal water molecules contribute to the stabilization of novel interactions between ligand and receptor, both at the interface of helices V and VI with the catechol group of isoprenaline as well as at the interface of helices III and VII with the ethanolamine moiety of the ligand. Despite the fact that the characteristic N-C-C-OH motif is identical in the co-crystallized ligands and in the full agonist isoprenaline, the interaction network between this group and the anchor site formed by Asp(3.32) and Asn(7.39) is substantially different between agonists and inverse agonists/antagonists due to two water molecules that enter the cavity and contribute to the stabilization of a novel network of interactions. These new binding poses, together with observed conformational changes in the extracellular loops, suggest possible determinants of receptor specificity.


Loss of apoptosis repressor with caspase recruitment domain (ARC) worsens high fat diet-induced hyperglycemia in mice.
Apoptosis repressor with caspase recruitment domain (ARC) is an endogenous inhibitor of cell death signaling that is expressed in insulin-producing β cells. ARC has been shown to reduce β-cell death in response to diabetogenic stimuli in vitro, but its role in maintaining glucose homeostasis in vivo has not been fully established. Here we examined whether loss of ARC in FVB background mice exacerbates high fat diet (HFD)-induced hyperglycemia in vivo over 24 weeks. Prior to commencing 24-week HFD, ARC-/- mice had lower body weight than wild type (WT) mice. This body weight difference was maintained until the end of the study and was associated with decreased epididymal and inguinal adipose tissue mass in ARC-/- mice. Non-fasting plasma glucose was not different between ARC-/- and WT mice prior to HFD feeding, and ARC-/- mice displayed a greater increase in plasma glucose over the first 4 weeks of HFD. Plasma glucose remained elevated in ARC-/- mice after 16 weeks of HFD feeding, at which time it had returned to baseline in WT mice. Following 24 weeks of HFD, non-fasting plasma glucose in ARC-/- mice returned to baseline and was not different from WT mice. At this final time point, no differences were observed between genotypes in plasma glucose or insulin under fasted conditions or following intravenous glucose administration. However, HFD-fed ARC-/- mice exhibited significantly decreased β-cell area compared to WT mice. Thus, ARC deficiency delays, but does not prevent, metabolic adaptation to HFD feeding in mice, worsening transient HFD-induced hyperglycemia.


Moa diet fits the bill: virtual reconstruction incorporating mummified remains and prediction of biomechanical performance in avian giants.
The moa (Dinornithiformes) are large to gigantic extinct terrestrial birds of New Zealand. Knowledge about niche partitioning, feeding mode and preference among moa species is limited, hampering palaeoecological reconstruction and evaluation of the impacts of their extinction on remnant native biota, or the viability of exotic species as proposed ecological 'surrogates'. Here we apply three-dimensional finite-element analysis to compare the biomechanical performance of skulls from five of the six moa genera, and two extant ratites, to predict the range of moa feeding behaviours relative to each other and to living relatives. Mechanical performance during biting was compared using simulations of the birds clipping twigs based on muscle reconstruction of mummified moa remains. Other simulated food acquisition strategies included lateral shaking, pullback and dorsoventral movement of the skull. We found evidence for limited overlap in biomechanical performance between the extant emu (Dromaius novaehollandiae) and extinct upland moa (Megalapteryx didinus) based on similarities in mandibular stress distribution in two loading cases, but overall our findings suggest that moa species exploited their habitats in different ways, relative to both each other and extant ratites. The broad range of feeding strategies used by moa, as inferred from interspecific differences in biomechanical performance of the skull, provides insight into mechanisms that facilitated high diversities of these avian herbivores in prehistoric New Zealand.


Development of heart block in children of SSA/SSB-autoantibody-positive women is associated with maternal age and displays a season-of-birth pattern.
Congenital heart block may develop in the fetuses of Ro/SSA-positive and La/SSB-positive mothers. Recurrence rates of only 10-20% despite persisting maternal antibodies indicate that additional factors are critical for the establishment of heart block. The authors investigated the influence of other maternal and fetal factors on heart block development in a Swedish population-based cohort. The influence of fetal gender, maternal age, parity and time of birth on heart block development was analysed in 145 families, including Ro/La-positive (n=190) and Ro/La-negative (n=165) pregnancies. There was a recurrence rate of 12.1% in Ro/La-positive women, and no recurrence in Ro/La-negative women. Fetal gender and parity did not influence the development of heart block in either group. Maternal age in Ro/La-positive pregnancies with a child affected by heart block was, however, significantly higher than in pregnancies resulting in babies without heart block (p<0.05).Seasonal timing of pregnancy influenced the outcome. Gestational susceptibility weeks 18-24 occurring during January-March correlated with a higher proportion of children with heart block and lower vitamin D levels during the same period in a representative sample of Swedish women and a corresponding higher proportion of children with heart block born in the summer (p<0.02). Maternal age or seasonal timing of pregnancy did not affect the outcome in Ro/La-negative pregnancies. This study identifies maternal age and seasonal timing of pregnancy as novel risk factors for heart block development in children of Ro/La-positive women. These observations may be useful for counselling when pregnancy is considered.


Electromagnetic fields stress living cells.
Electromagnetic fields (EMF), in both ELF (extremely low frequency) and radio frequency (RF) ranges, activate the cellular stress response, a protective mechanism that induces the expression of stress response genes, e.g., HSP70, and increased levels of stress proteins, e.g., hsp70. The 20 different stress protein families are evolutionarily conserved and act as 'chaperones' in the cell when they 'help' repair and refold damaged proteins and transport them across cell membranes. Induction of the stress response involves activation of DNA, and despite the large difference in energy between ELF and RF, the same cellular pathways respond in both frequency ranges. Specific DNA sequences on the promoter of the HSP70 stress gene are responsive to EMF, and studies with model biochemical systems suggest that EMF could interact directly with electrons in DNA. While low energy EMF interacts with DNA to induce the stress response, increasing EMF energy in the RF range can lead to breaks in DNA strands. It is clear that in order to protect living cells, EMF safety limits must be changed from the current thermal standard, based on energy, to one based on biological responses that occur long before the threshold for thermal changes.


Radiographic and MRI findings in ochronosis.
Ochronotic arthropathy is the articular manifestation of alkaptonuria, a rare hereditary metabolic disease that leads to the deposition of homogentisic acid particularly in the joints where it causes articular degeneration and inflammation. We studied the radiological patterns of the disorder using both traditional X-rays both MRI and comparing the results obtained with the two techniques. The study included five patients (4 males, 1 female, mean age 51 years); we studied the most frequently affected sites, the knee, the shoulder and the spine. As regards the conventional study we used a radiographic score which considered the state of the articular space and the presence of calcifications. MRI of the peripheral joints was performed on the most symptomatic site or, if asymptomatic, on the most severely affected site as established by radiography; in all cases T1- and T2-weighted sequences in the axial, sagittal and coronal planes were acquired. Both the X-ray and MRI study revealed the typical alterations of ochronosis in the cases with a known diagnosis: articular space narrowing up to osseous ankylosis, calcifications, osteophytosis, reactive sclerosis of the articular surfaces; MRI was however more accurate in identifying the alterations and revealing lesions not visible at conventional radiology, such as ligament lesions. In the case of newly diagnosed ochronotic arthropathy MRI proved valuable for its ability to detect alterations that are poorly appreciable at conventional radiology. Modern diagnostic imaging, above all MRI, allowed us to identify the peculiar characteristic features of ochronosis and is fundamental both for the diagnosis and for differentiating ochronosis from other articular disorders.


Analysis of cyclooxygenase 2 (COX-2) expression during malignant melanoma progression.
Cyclooxygenase 2 (COX-2) is an inducible enzyme involved in the production of prostaglandins and thromboxanes during inflammation. There are now several lines of evidence indicating that increased expression of COX-2 plays a functional role in the development and progression of malignant epithelial cancers. However, there is only limited data regarding the role of COX-2 in melanoma pathogenesis. In the present work, we retrospectively examined lesions through out the development of melanoma and metastatic disease (dysplastic nevi n = 10, melanoma in situ n = 4, stage II melanoma n = 10, stage III n = 4, stage IV n = 3, stage V n = 2, melanoma metastasis lymph nodes n = 13 metastasis to other sites n = 3). COX-2 was consistently observed in keratinocytes, dermal fibroblasts, and inflammatory cells in regions adjacent to benign evi and primary cutaneous melanomas. However, no COX-2 staining was detected in the nevi nor in the primary skin melanoma cells. In addition, COX-2 was undetected in all vertical and radial growth phase cases Interestingly, 13 out of 13 of the lymph node metastasis expressed extremely high levels of COX-2 in overlying epithelium and inflammatory cells, and COX-2 was strongly detected in the metastatic cancer cells per se. For additional information on the expression of COX-2 in malignant melanoma, we determined the expression of COX-2 protein in several different melanoma cell lines. We found that 3We found that 5 out of 7 of the melanoma cells over expressed COX-2 compared to normal melanocytes. Collectively, these data suggest that COX-2 may play a functional role in metastases of melanoma, and treatment with COX-2 inhibitors may be efficacious for malignant melanoma.


Inactivation of endotoxin by polymyxin B.
The limulus gelation assay was utilized to investigate endotoxin inactivation by a number of antibiotics in vitro. Endotoxin activity was sharply reduced by polymyxin B and sodium colistimethate. The effect of the polymyxin was not significantly inhibited by 0.001 M calcium or 90% serum. Crude endotoxins from a variety of aerobic gram-negative bacteria, including several not previously studied, could be inactivated 1 or more logs by as little as 1 mug of polymyxin B per ml, whereas Bacteroides fragilis endotoxin was poorly detoxified. A 10,000-fold range in the relative susceptibility of different endotoxins to inactivation by polymyxin B was found. The endotoxin most susceptible to polymyxin B was derived from an organism resistant to polymyxin B by disk sensitivity testing, suggesting that the bacteriocidal and endotoxin detoxifying properties of polymyxin need not be directly related.


Highly Efficient Removal of Neonicotinoid Insecticides by Thioether-Based (Multivariate) Metal-Organic Frameworks.
Circumventing the impact of agrochemicals on aquatic environments has become a necessity for health and ecological reasons. Herein, we report the use of a family of five eco-friendly water-stable isoreticular metal-organic frameworks (MOFs), prepared from amino acids, as adsorbents for the removal of neonicotinoid insecticides (thiamethoxam, clothianidin, imidacloprid, acetamiprid, and thiacloprid) from water. Among them, the three MOFs containing thioether-based residues show remarkable removal efficiency. In particular, the novel multivariate MOF {SrIICuII6[(S,S)-methox]1.5[(S,S)-Mecysmox]1.50(OH)2(H2O)}·36H2O (5), featuring narrow functional channels decorated with both -CH2SCH3 and -CH2CH2SCH3 thioalkyl chains-from l-methionine and l-methylcysteine amino acid-derived ligands, respectively-stands out and exhibits the higher removal efficiency, being capable to capture 100% of acetamiprid and thiacloprid in a single capture step under dynamic solid-phase extraction conditions-less than 30 s. Such unusual combination of outstanding efficiency, high stability in environmental conditions, and low-cost straightforward synthesis in 5 places this material among the most attractive adsorbents reported for the removal of this type of contaminants.


Constraint randomised non-negative factor analysis (CRNNFA): an alternate chemometrics approach for analysing the biochemical data sets.
The present work introduces an alternate chemometrics approach constraint randomised non-negative factor analysis (CRNNFA) for analysing the bioanalytical data sets. The CRNNFA algorithm provides the outputs that are easy to interpret and correlate with the real chromatograms. The CRNNFA algorithm achieves termination when the iteration limit is reached circumventing the premature convergence. Theoretical and computational aspects of the proposed method are also described. The analytical and computational potential of CRNNFA are successfully tested by analysing the complex chromatograms of the peptidoglycan samples belonging to the Alphaproteobacterium members. The obtained results clearly show that CRNNFA can easily trace the compositional variability of the peptidoglycan samples. In summary, the proposed method in general can be a potential alternate approach for analysing the data sets obtained from different analytical and clinical fields.


A PN-type quantum barrier for InGaN/GaN light emitting diodes.
In this work, InGaN/GaN light-emitting diodes (LEDs) with PN-type quantum barriers are comparatively studied both theoretically and experimentally. A strong enhancement in the optical output power is obtained from the proposed device. The improved performance is attributed to the screening of the quantum confined Stark effect (QCSE) in the quantum wells and improved hole transport across the active region. In addition, the enhanced overall radiative recombination rates in the multiple quantum wells and increased effective energy barrier height in the conduction band has substantially suppressed the electron leakage from the active region. Furthermore, the electrical conductivity in the proposed devices is improved. The numerical and experimental results are in excellent agreement and indicate that the PN-type quantum barriers hold great promise for high-performance InGaN/GaN LEDs.


Career choices in dermatology.
Reforms to both undergraduate and postgraduate training have resulted in limited exposure to clinical dermatology, and therefore we need to target advice and clinical attachments to the most appropriate stages of training to ensure that dermatology is considered as a career option by medical students. A questionnaire survey was undertaken to determine when and how doctors chose their career in dermatology. An electronic questionnaire was sent to 709 dermatologists (response rate 44%). Of the respondents, 49% considered dermatology after medical school attachment and 61% were influenced by the jobs they had done as a pre-registration house officer (PRHO) or senior house officer (SHO). Careers advice was lacking, with only 11% receiving it while at medical school and 29% during their PRHO/SHO years. Contact with an inspiring clinician was the most influential factor in choosing dermatology. Both medical students and junior doctors, should have opportunities to learn from and work with clinical dermatologists.


The tumour microenvironment links complement system dysregulation and hypoxic signalling.
The complement system is an innate immune pathway typically thought of as part of the first line of defence against "non-self" species. In the context of cancer, complement has been described to have an active role in facilitating cancer-associated processes such as increased proliferation, angiogenesis and migration. Several cellular members of the tumour microenvironment express and/or produce complement proteins locally, including tumour cells. Dysregulation of the complement system has been reported in numerous tumours and increased expression of complement activation fragments in cancer patient specimens correlates with poor patient prognosis. Importantly, genetic or pharmacological targeting of complement has been shown to reduce tumour growth in several cancer preclinical models, suggesting that complement could be an attractive therapeutic target. Hypoxia (low oxygen) is frequently found in solid tumours and has a profound biological impact on cellular and non-cellular components of the tumour microenvironment. In this review, we focus on hypoxia since this is a prevailing feature of the tumour microenvironment that, like increased complement, is typically associated with poor prognosis. Furthermore, interesting links between hypoxia and complement have been recently proposed but never collectively reviewed. Here, we explore how hypoxia alters regulation of complement proteins in different cellular components of the tumour microenvironment, as well as the downstream biological consequences of this regulation.


[3H]ouabain binding of red blood cells in whites and blacks.
In a previous study, we demonstrated that the red blood cell Na+ concentration and Na+,K+-ATPase activity are sex-dependent and race-dependent: a higher intracellular Na+ concentration in blacks and men was associated with a lower Na+,K+-ATPase activity. To examine whether the low Na+,K+-ATPase activity is due to a decreased number of enzyme units, altered structure of the enzyme, or the presence of an endogenous digoxinlike substance, ouabain binding studies were performed on the same subject group. The measurements included displacement of [3H]ouabain from its specific binding sites by unlabeled ouabain or potassium. The results demonstrate that groups with lower enzyme activity manifest lower numbers of total specific ouabain binding sites on the surface of the red blood cell (mean +/- SD: blacks, 654 +/- 24.4; whites, 806 +/- 18.3; women, 806 +/- 26.9; men, 728 +/- 21.2). Other kinetic parameters of [3H]ouabain displacement appear to be the same among the groups. The respective red blood cell Na+ and K+ concentrations were negatively and positively correlated with the number of ouabain binding sites. Our findings suggest that the lower activity of red blood cell Na+,K+-ATPase in blacks and men is a function of a lower number of Na+-K+ pump units. The results also indicate that sex and race should be considered when red blood cell ouabain binding is examined.


Corticosterone selectively targets endo-cortical surfaces by an osteoblast-dependent mechanism.
The pathogenesis of glucocorticoid-induced osteoporosis remains ill defined. In this study, we examined the role of the osteoblast in mediating the effects of exogenous glucocorticoids on cortical and trabecular bone, employing the Col2.3-11βHSD2 transgenic mouse model of osteoblast-targeted disruption of glucocorticoid signalling. Eight week-old male transgenic (tg) and wild-type (WT) mice (n=20-23/group) were treated with either 1.5 mg corticosterone (CS) or placebo for 4 weeks. Serum tartrate-resistant acid phosphatase 5b (TRAP5b) and osteocalcin (OCN) were measured throughout the study. Tibiae and lumbar vertebrae were analysed by micro-CT and histomorphometry at endpoint. CS suppressed serum OCN levels in WT and tg mice, although they remained higher in tg animals at all time points (p<0.05). Serum TRAP5b levels increased in WT mice only. The effect of CS on cortical bone differed by site: At the endosteal surface, exposure to CS significantly increased bone resorption and reduced bone formation, resulting in a larger bone marrow cavity cross-sectional area (p<0.01). In contrast, at the pericortical surface bone resorption was significantly decreased accompanied with a significant increase in pericortical cross-sectional area (p<0.05) while bone formation remained unaffected. Vertebral cortical thickness and area were reduced in CS treatment mice. Tg mice were partially protected from the effects of exogenous CS, both on a cellular and structural level. At the CS doses used in this study, trabecular bone remained largely unaffected. Endocortical osteoblasts appear to be particularly sensitive to the detrimental actions of exogenous glucocorticoids. The increase in tibial pericortical cross-sectional area and the according changes in pericortical circumference suggest an anabolic bone response to GC treatment at this site. The protection of tg mice from these effects indicates that both catabolic and anabolic action of glucocorticoids are, at least in part, mediated by osteoblasts.


Nutritional quality of eggs from hens fed distillers dried grains with solubles.
A feeding trial was conducted with laying hens where either 10% or 20% regular-fat distiller's dried grains with solubles (R-DDGS) or low-fat DDGS (L-DDGS) were incorporated into the feed. Production parameters and the effect of DDGS on egg nutritional quality, focusing on yolk lipids, were evaluated. Neither R-DDGS nor L-DDGS at up to 20% of laying hen feeds had a statistically significant impact on hen weight gain, egg production, feed intake, feed efficiency, egg mass, or egg weight. Specific gravity was slightly lower for eggs from hens fed 10% R-DDGS or 20% L-DDGS. Eggs from layers fed DDGS had enhanced levels of tocopherols, tocotrienols, and xanthophylls in the yolk, as well as also increased yolk yellow and red color. Eggs from L-DDGS diet had higher tocopherol content, but eggs from R-DDGS diets had higher xanthophylls. Fatty acid composition in eggs was slightly altered by DDGS, but the ratio of saturated to unsaturated fatty acids was very similar. Feeding DDGS to layer hens had no effect on lecithin or cholesterol content of the eggs. Thus, inclusion of DDGS in the diet of laying hens resulted in increases of several beneficial lipophilic nutrients in egg yolks with no apparent detrimental effects.


Integrating plant ecological responses to climate extremes from individual to ecosystem levels.
Climate extremes will elicit responses from the individual to the ecosystem level. However, only recently have ecologists begun to synthetically assess responses to climate extremes across multiple levels of ecological organization. We review the literature to examine how plant responses vary and interact across levels of organization, focusing on how individual, population and community responses may inform ecosystem-level responses in herbaceous and forest plant communities. We report a high degree of variability at the individual level, and a consequential inconsistency in the translation of individual or population responses to directional changes in community- or ecosystem-level processes. The scaling of individual or population responses to community or ecosystem responses is often predicated upon the functional identity of the species in the community, in particular, the dominant species. Furthermore, the reported stability in plant community composition and functioning with respect to extremes is often driven by processes that operate at the community level, such as species niche partitioning and compensatory responses during or after the event. Future research efforts would benefit from assessing ecological responses across multiple levels of organization, as this will provide both a holistic and mechanistic understanding of ecosystem responses to increasing climatic variability.This article is part of the themed issue 'Behavioural, ecological and evolutionary responses to extreme climatic events'.


Malignant Bowel Obstruction in Relapsed Ovarian Cancer With Peritoneal Carcinomatosis: An Occlusive State.
The aim of this study was to describe the clinical and oncological outcomes of women with malignant bowel obstruction (MBO) for relapsed ovarian cancer and peritoneal carcinomatosis. A retrospective cohort study was performed in all consecutive patients admitted at Instituto Valenciano de Oncología, Valencia, Spain, between July 2013 and July 2016 with MBO for relapsed ovarian cancer and peritoneal carcinomatosis. All patients underwent the same protocol of conservative management. Surgical treatment was indicated only in selected cases. There were a total of 22 patients presenting 59 episodes of MBO; 17 (77.2%) of those patients presented more than 1 episode of MBO. All patients had serous epithelial ovarian cancer; 18 (81.8%) were high grade, and 4 (18.2%) low-grade tumors. The median (range) number of episodes per patient was 3 (range, 1-7) with a mean length of hospitalization of 13 (SD, 13.6) days. The median time interval between episodes of MBO (54 episodes in 17 patients) was 17 days (range, 1-727 days). Twenty of 22 patients died with a median overall survival time from the first episode of MBO of 95 days (95% confidence interval, 49-124 days). Patients with MBO due to relapsed epithelial ovarian cancer in the peritoneal carcinomatosis setting have a short life expectancy, presenting a median of 3 episodes of MBO until death, with a short time interval between episodes. These findings show that bowel obstruction can represent a constant status over time until death.


Dermatological uses of high-dose intravenous immunoglobulin.
High-dose intravenous immunoglobulin (hdIVIg) is increasingly used to treat a range of inflammatory and autoimmune diseases. The current dermatological uses of hdIVIg include the treatment of dermatomyositis and the autoimmune bullous disorders, epidermolysis bullosa acquisita, pemphigoid, and pemphigus. Numerous immunomodulatory mechanisms for hdIVIg have been proposed, and they are discussed alongside treatment protocols and adverse effects. Increasing use of this therapy has helped to establish its excellent safety record, without the many adverse effects of steroids and other immunosuppressive agents. This safety record makes hdIVIg an attractive therapeutic option; however, in view of the time required to administer the infusions, the cost, and the urgent need for controlled trials of hdIVIg in patients with specific dermatological disorders such as pemphigus, patients must be carefully selected. Unfortunately, current dermatological uses of hdIVIg have been limited to either uncontrolled trials or anecdotal case reports, except for a single controlled trial of hdIVIg as adjunctive therapy in patients with dermatomyositis, which documented a significant benefit. Further trials in dermatomyositis should be established to confirm these data and to clarify the dose and frequency of therapy required for patients with dermatomyositis. When using hdIVIg, liaison between the dermatologist and the immunologist is helpful because it allows the use of both the nursing and the medical expertise of an existing immunotherapy unit. If appropriate, the patient may be entered into an hdIVIg home therapy training program, such as the one that exists for primary immunodeficiency and some neurologic indications, with clear benefits in quality of life and inpatient costs.


Management of Junctional Hemorrhage in Tactical Combat Casualty Care: TCCC Guidelines?Proposed Change 13-03.
The vast majority of combat casualties who die from their injuries do so prior to reaching a medical treatment facility. Although most of these deaths result from nonsurvivable injuries, efforts to mitigate combat deaths can still be directed toward primary prevention through modification of techniques, tactics, and procedures and secondary prevention through improvement and use of personal protective equipment. For deaths that result from potentially survivable injuries, mitigation efforts should be directed toward primary and secondary prevention as well as tertiary prevention through medical care with an emphasis toward prehospital care as dictated by the fact that the preponderance of casualties die in the prehospital environment. Since the majority of casualties with potentially survivable injuries died from hemorrhage, priority must be placed on interventions, procedures, and training that mitigate death from truncal, junctional, and extremity exsanguination. In response to this need, multiple novel and effective junctional tourniquets have recently been developed.


Integrating Simultaneous Motor Imagery and Spatial Attention for EEG-BCI Control.
EEG-based brain-computer interfaces (BCI) are non-invasive approaches for replacing or restoring motor functions in impaired patients, and direct brain-to-device communication in the general population. Motor imagery (MI) is one of the most used BCI paradigms, but its performance varies across individuals and certain users require substantial training to develop control. In this study, we propose to integrate a MI paradigm simultaneously with a recently proposed Overt Spatial Attention (OSA) paradigm, to accomplish BCI control. We evaluated a cohort of 25 human subjects' ability to control a virtual cursor in one- and two-dimensions over 5 BCI sessions. The subjects used 5 different BCI paradigms: MI alone, OSA alone, MI and OSA simultaneously towards the same target (MI+OSA), and MI for one axis while OSA controls the other (MI/OSA and OSA/MI). Our results show that MI+OSA reached the highest average online performance in 2D tasks at 49% Percent Valid Correct (PVC), and statistically outperforms both MI alone (42%) and OSA alone (45%). MI+OSA had a similar performance to each subject's best individual method between MI alone and OSA alone (50%) and 9 subjects reached their highest average BCI performance using MI+OSA. Integrating MI and OSA leads to improved performance over both individual methods at the group level and is the best BCI paradigm option for some subjects. This work proposes a new BCI control paradigm that integrates two existing paradigms and demonstrates its value by showing that it can improve users' BCI performance.


Risk Factors for Non-Contact Injury in Adolescent Cricket Pace Bowlers: A Systematic Review.
Adolescent cricket pace bowlers are prone to injury. Recognising the risk factors for non-contact injury in this population will aid future injury prevention strategies. To identify the risk factors for non-contact injury in adolescent cricket pace bowlers. We systematically searched PubMed, Cochrane Library, PEDro, SPORTDiscus, Embase, and the South African Journal of Sports Medicine to identify all experimental and observational studies reporting risk factors for non-contact injuries in pace bowlers (aged 12-19 years). The search syntax included terms relevant to cricket bowling, injury, and known risk factors for injury. The Newcastle-Ottawa Quality Assessment Scale and a modified Newcastle-Ottawa Quality Assessment Scale were used to assess the risk of bias in the cohort and cross-sectional studies, respectively. Sixteen studies (five cross-sectional studies, 11 cohort studies) comprising 687 participants (96% male, 75% playing cricket in Australia) met the selection criteria and were included for qualitative synthesis. Three cross-sectional studies were rated as high risk of bias and two as very high risk of bias. For the cohort studies, three were rated as low risk of bias, and eight as high risk of bias. Injury was associated with bowling biomechanics (excessive lateral trunk flexion and pelvis/hip kinematics), reduced trunk endurance, poor lumbo-pelvic-hip movement control, and early signs of lumbar bone stress. Conflicting results were found by studies examining the mixed technique, bowling workload and quadratus lumborum asymmetry. The current systematic review identified a number bowling biomechanics and various neuromuscular deficiencies as risk factors for non-contact injury in adolescent pace bowlers. These factors may provide a useful target for future interventional research aiming to prevent injury in this population. Future studies should utilise prospective cohort designs, and ensure that participants are injury-free at baseline, confounding factors are well controlled and attrition rates are reported. This systematic review was registered a priori (PROSPERO, CRD42016043956).


Altered responses of human macrophages to lipopolysaccharide by hydroperoxy eicosatetraenoic acid, hydroxy eicosatetraenoic acid, and arachidonic acid. Inhibition of tumor necrosis factor production.
The regulation of allergic and autoimmune inflammatory reactions by polyunsaturated fatty acids and their metabolic products (eicosanoids) continues to be of major interest. Our data demonstrate that arachidonic acid 5,8,11,14-eicosatetraenoic acid (20:4n-6) and its hydroxylated derivatives 15(s)-hydroxy-5,8,11,13-eicosatetraenoic acid (15-HETE) and 15(s)-hydroperoxy-5,8,11,13-eicosatetraenoic acid (15-HPETE) regulate agonist-induced tumor necrosis factor alpha (TNF) production, a cytokine that plays a role in inflammatory diseases. Although 20:4n-6 and 15-HETE caused a reduction in production of TNF in mononuclear leukocytes stimulated with phytohaemagglutinin, pokeweed mitogen, concanavalin A, and Staphylococcus aureus, 15-HPETE was far more active. 15-HPETE was also found to dramatically depress the ability of bacterial lipopolysaccharide to induce TNF production in monocytes and the monocytic cell line Mono Mac 6. These fatty acids depressed the expression of TNF mRNA in Mono Mac 6 cells stimulated with LPS; 15-HPETE was fivefold more active than 20:4n-6 and 15-HETE. While 15-HPETE treatment neither affected LPS binding to Mono Mac 6 cells nor caused a decrease in CD14 expression, the fatty acid significantly reduced the LPS-induced translocation of PKC (translocation of alpha, betaI, betaII, and epsilon isozymes), suggesting that 15-HPETE acts by abrogating the early signal transduction events. The findings identify another molecule that could form the basis for development of antiinflammatory pharmaceuticals.


Relative roles of genetic factors, dietary deficiency, and infection in anaemia in Vanuatu, South-West Pacific.
Hypochromic anaemia is very common among the island populations of Vanuatu in the South-West Pacific. Results of a large-scale survey show that, unexpectedly, this form of anaemia is seldom due to iron deficiency or coexistent parasitic disease. Rather, it results from a previously unsuspected high incidence of alpha-thalassaemia which has been identified only by application of DNA analysis to the populations studied. These findings suggest that hypochromic anaemia in tropical or subtropical populations should not necessarily be attributed to iron deficiency; detailed studies of iron status should be carried out before major dietary changes or fortification of food with iron are implemented.


Action potential energy efficiency varies among neuron types in vertebrates and invertebrates.
The initiation and propagation of action potentials (APs) places high demands on the energetic resources of neural tissue. Each AP forces ATP-driven ion pumps to work harder to restore the ionic concentration gradients, thus consuming more energy. Here, we ask whether the ionic currents underlying the AP can be predicted theoretically from the principle of minimum energy consumption. A long-held supposition that APs are energetically wasteful, based on theoretical analysis of the squid giant axon AP, has recently been overturned by studies that measured the currents contributing to the AP in several mammalian neurons. In the single compartment models studied here, AP energy consumption varies greatly among vertebrate and invertebrate neurons, with several mammalian neuron models using close to the capacitive minimum of energy needed. Strikingly, energy consumption can increase by more than ten-fold simply by changing the overlap of the Na(+) and K(+) currents during the AP without changing the APs shape. As a consequence, the height and width of the AP are poor predictors of energy consumption. In the Hodgkin-Huxley model of the squid axon, optimizing the kinetics or number of Na(+) and K(+) channels can whittle down the number of ATP molecules needed for each AP by a factor of four. In contrast to the squid AP, the temporal profile of the currents underlying APs of some mammalian neurons are nearly perfectly matched to the optimized properties of ionic conductances so as to minimize the ATP cost.


Evolutionary genomics. Evolutionary changes in promoter and enhancer activity during human corticogenesis.
Human higher cognition is attributed to the evolutionary expansion and elaboration of the human cerebral cortex. However, the genetic mechanisms contributing to these developmental changes are poorly understood. We used comparative epigenetic profiling of human, rhesus macaque, and mouse corticogenesis to identify promoters and enhancers that have gained activity in humans. These gains are significantly enriched in modules of coexpressed genes in the cortex that function in neuronal proliferation, migration, and cortical-map organization. Gain-enriched modules also showed correlated gene expression patterns and similar transcription factor binding site enrichments in promoters and enhancers, suggesting that they are connected by common regulatory mechanisms. Our results reveal coordinated patterns of potential regulatory changes associated with conserved developmental processes during corticogenesis, providing insight into human cortical evolution.