Cerebral blood flow quantification using vessel-encoded arterial spin labeling.
Arterial spin labeling (ASL) techniques are gaining popularity for visualizing and quantifying cerebral blood flow (CBF) in a range of patient groups. However, most ASL methods lack vessel-selective information, which is important for the assessment of collateral flow and the arterial supply to lesions. In this study, we explored the use of vessel-encoded pseudocontinuous ASL (VEPCASL) with multiple postlabeling delays to obtain individual quantitative CBF and bolus arrival time maps for each of the four main brain-feeding arteries and compared the results against those obtained with conventional pseudocontinuous ASL (PCASL) using matched scan time. Simulations showed that PCASL systematically underestimated CBF by up to 37% in voxels supplied by two arteries, whereas VEPCASL maintained CBF accuracy since each vascular component is treated separately. Experimental results in healthy volunteers showed that there is no systematic bias in the CBF estimates produced by VEPCASL and that the signal-to-noise ratio of the two techniques is comparable. Although more complex acquisition and image processing is required and the potential for motion sensitivity is increased, VEPCASL provides comparable data to PCASL but with the added benefit of vessel-selective information. This could lead to more accurate CBF estimates in patients with a significant collateral flow.


Ocean acidification has little effect on the biochemical composition of the coccolithophore Emiliania huxleyi.
Owing to the hierarchical organization of biology, from genomes over transcriptomes and proteomes down to metabolomes, there is continuous debate about the extent to which data and interpretations derived from one level, e.g. the transcriptome, are in agreement with other levels, e.g. the metabolome. Here, we tested the effect of ocean acidification (OA; 400 vs. 1000 μatm CO2) and its modulation by light intensity (50 vs. 300 μmol photons m-2 s-1) on the biomass composition (represented by 75 key metabolites) of diploid and haploid life-cycle stages of the coccolithophore Emiliania huxleyi (RCC1216 and RCC1217) and compared these data with interpretations from previous physiological and gene expression screenings. The metabolite patterns showed minor responses to OA in both life-cycle stages. Whereas previous gene expression analyses suggested that the observed increased biomass buildup derived from lipid and carbohydrate storage, this dataset suggests that OA slightly increases overall biomass of cells, but does not significantly alter their metabolite composition. Generally, light was shown to be a more dominant driver of metabolite composition than OA, increasing the relative abundances of amino acids, mannitol and storage lipids, and shifting pigment contents to accommodate increased irradiance levels. The diploid stage was shown to contain vastly more osmolytes and mannitol than the haploid stage, which in turn had a higher relative content of amino acids, especially aromatic ones. Besides the differences between the investigated cell types and the general effects on biomass buildup, our analyses indicate that OA imposes only negligible effects on E. huxleyi´s biomass composition.


How well do patients' assessments of their diabetes self-management correlate with actual glycemic control and receipt of recommended diabetes services?
Although patient diabetes self-management is a key determinant of health outcomes, there is little evidence on whether patients' own assessments of their self-management correlates with glycemic control and key aspects of high-quality diabetes care. We explored these associations in a nationwide sample of Veterans' Affairs (VA) patients with diabetes. We abstracted information on achieved level of glycemic control (HbA(1c)) and diabetes processes of care (receipt of HbA(1c) test, eye examination, and nephropathy screen) from medical records of 1032 diabetic patients who received care from 21 VA facilities and had answered the Diabetes Quality Improvement Program survey in 2000. The survey included sociodemographic measures and a five-item scale assessing the patients' diabetes self-management (medication use, blood glucose monitoring, diet, exercise, and foot care [alpha = 0.68]). Using multivariable regression, we examined the associations of patients' reported self-management with HbA(1c) level and receipt of each diabetes process of care. We adjusted for diabetes severity and comorbidities, insulin use, age, ethnicity, income, education, use of VA services, and clustering at the facility level. Higher patient evaluations of their diabetes self-management were significantly associated with lower HbA(1c) levels (P < 0.01) and receipt of diabetes services. Those in the 95th percentile for self-management had a mean HbA(1c) level of 7.3 (95% CI 6.4-8.3), whereas those in the 5th percentile had mean levels of 8.3 (7.4-9.2). For every 10-point increase in patients' ratings of their diabetes self-management, even after adjusting for number of outpatient visits, the odds of receiving an HbA(1c) test in the past year increased by 15% (4-27%), of receiving an eye examination increased by 16% (7-27%), and of receiving a nephropathy screen increased by 13% (2-26%). In this sample, patients' assessments of their diabetes self-care using a simple five-question instrument were significantly associated both with actual HbA(1c) control and with receiving recommended diabetes services. These findings reinforce the usefulness of patient evaluations of their own self-management for understanding and improving glycemic control. The mechanisms by which those patients who are more actively engaged in their diabetes self-care are also more likely to receive necessary services warrant further study.


Antibiotic-specific differences in the response of Staphylococcus aureus to treatment with antimicrobials combined with manuka honey.
Skin infections caused by antibiotic resistant Staphylococcus aureus are a significant health problem worldwide; often associated with high treatment cost and mortality rate. Complex natural products like New Zealand (NZ) manuka honey have been revisited and studied extensively as an alternative to antibiotics due to their potent broad-spectrum antimicrobial activity, and the inability to isolate honey-resistant S. aureus. Previous studies showing synergistic effects between manuka-type honeys and antibiotics have been demonstrated against the growth of one methicillin-resistant S. aureus (MRSA) strain. We have previously demonstrated strong synergistic activity between NZ manuka-type honey and rifampicin against growth and biofilm formation of multiple S. arueus strains. Here, we have expanded our investigation using multiple S. aureus strains and four different antibiotics commonly used to treat S. aureus-related skin infections: rifampicin, oxacillin, gentamicin, and clindamycin. Using checkerboard microdilution and agar diffusion assays with S. aureus strains including clinical isolates and MRSA we demonstrate that manuka-type honey combined with these four antibiotics frequently produces a synergistic effect. In some cases when synergism was not observed, there was a significant enhancement in antibiotic susceptibility. Some strains that were highly resistant to an antibiotic when present alone become sensitive to clinically achievable concentrations when combined with honey. However, not all of the S. aureus strains tested responded in the same way to these combinational treatments. Our findings support the use of NZ manuka-type honeys in clinical treatment against S. aureus-related infections and extend their potential use as an antibiotic adjuvant in combinational therapy. Our data also suggest that manuka-type honeys may not work as antibiotic adjuvants for all strains of S. aureus, and this may help determine the mechanistic processes behind honey synergy.


Biotemplated synthesis of PZT nanowires.
Piezoelectric nanowires are an important class of smart materials for next-generation applications including energy harvesting, robotic actuation, and bioMEMS. Lead zirconate titanate (PZT), in particular, has attracted significant attention, owing to its superior electromechanical conversion performance. Yet, the ability to synthesize crystalline PZT nanowires with well-controlled properties remains a challenge. Applications of common nanosynthesis methods to PZT are hampered by issues such as slow kinetics, lack of suitable catalysts, and harsh reaction conditions. Here we report a versatile biomimetic method, in which biotemplates are used to define PZT nanostructures, allowing for rational control over composition and crystallinity. Specifically, stoichiometric PZT nanowires were synthesized using both polysaccharide (alginate) and bacteriophage templates. The wires possessed measured piezoelectric constants of up to 132 pm/V after poling, among the highest reported for PZT nanomaterials. Further, integrated devices can generate up to 0.820 μW/cm(2) of power. These results suggest that biotemplated piezoelectric nanowires are attractive candidates for stimuli-responsive nanosensors, adaptive nanoactuators, and nanoscale energy harvesters.


CpG island hypermethylation and repetitive DNA hypomethylation in premalignant lesion of extrahepatic cholangiocarcinoma.
Biliary intraepithelial neoplasia (BilIN) is the premalignant lesion of extrahepatic cholangiocarcinoma (EHC), and there are no published data regarding epigenetic changes throughout disease progression from normal biliary epithelia to BilIN to EHC. The objective of this study was to identify the occurrence of CpG island hypermethylation and repetitive DNA hypomethylation in BilIN. A total of 50 EHCs, 31 BilINs, and 31 normal cystic duct samples were analyzed for their methylation status in seven genes and two repetitive DNA elements. The number of methylated genes increased with disease progression (normal bile duct, 0.6; BilIN, 2.0; EHC, 3.6; P < 0.001). The methylation level of examined genes was significantly higher in BilIN than in normal samples (TMEFF2, HOXA1, NEUROG1, and RUNX3, P < 0.05) and in EHC than in BilIN samples (TMEFF2, HOXA1, NEUROG1, RUNX3, RASSF1A, and APC, P < 0.05). Long interspersed nucleotide element-1 (LINE-1) and juxtacentromeric satellite 2 (SAT2) methylation levels were markedly lower in EHC than in normal duct and BilIN samples, and BilIN samples showed a decrease of SAT2 methylation levels but no decrease of LINE-1 methylation levels compared to normal samples. These findings suggest that most of cancer-specific CpG island hypermethylation occur in the stage of BilIN and that CpG island hypermethylation seems to occur earlier than repetitive DNA element hypomethylation.


Effect of water-soluble silicon supplementation on bone status and balance of calcium and magnesium in male mice.
Silicon (Si) is important for the growth and development of bone and connective tissues. Several studies have reported that Si supplementation improved bone mineral density (BMD) in female ovarectomized rats. However, few studies have investigated the effects of Si supplementation on bone status and bone metabolism in male animals. The purpose of this study was to investigate the effects of Si supplementation on BMD and balance of calcium (Ca) and magnesium (Mg) in adult male mice. Si was administrated orally through demineralized water containing different contents of Si as a form of sodium metasilicate (0 %, control; 0.025 %, Si50; 0.050 %, Si100; and 0.075 %, Si150) to 9-week-old male mice for 4 weeks. Si supplementation did not alter weight gain or BMD of femur and tibia in male mice. However, a high level of Si (0.05 and 0.075 %) supplementation significantly decreased Mg retention without changing Ca retention. Serum alkaline phosphatase of Si-supplemented groups significantly decreased compared with that of the control. According to these results, short-term Si supplementation did not affect BMD but showed a possible effect on increasing the need for Mg in adult male mice.


Cracking the code of oscillatory activity.
Neural oscillations are ubiquitous measurements of cognitive processes and dynamic routing and gating of information. The fundamental and so far unresolved problem for neuroscience remains to understand how oscillatory activity in the brain codes information for human cognition. In a biologically relevant cognitive task, we instructed six human observers to categorize facial expressions of emotion while we measured the observers' EEG. We combined state-of-the-art stimulus control with statistical information theory analysis to quantify how the three parameters of oscillations (i.e., power, phase, and frequency) code the visual information relevant for behavior in a cognitive task. We make three points: First, we demonstrate that phase codes considerably more information (2.4 times) relating to the cognitive task than power. Second, we show that the conjunction of power and phase coding reflects detailed visual features relevant for behavioral response--that is, features of facial expressions predicted by behavior. Third, we demonstrate, in analogy to communication technology, that oscillatory frequencies in the brain multiplex the coding of visual features, increasing coding capacity. Together, our findings about the fundamental coding properties of neural oscillations will redirect the research agenda in neuroscience by establishing the differential role of frequency, phase, and amplitude in coding behaviorally relevant information in the brain.


Kinetic host defense of the mice infected with Aspergillus Fumigatus.
Aim:Aspergillus fumigatus is one of the most common opportunistic fungi that can cause invasive infection. To profile the kinetic variation of immune cells and cytokines after exposure to A. fumigatus thoroughly, we established a pulmonary A. fumigatus infection model in temporarily immunosuppressed mice. Materials & methods: Systematic and kinetic studies of different immune cells and cytokines were performed. Results: We observed that the granulocytes and macrophages recruited to the site of infection played an important role in the infectious phase. There was a significant increase in the cytokines IFN-γ, IL-6, TNF-α as well as the chemokines CXCL1, MIP-1α, MIP-2 and CCL5 after infection. IL-10 was found to participate in balancing the anti-inflammatory response in the recovery phases. The immune response mediated by T cells was mainly presented by the Th1-type on day 7 after exposure with a high proportion of IFN-γ+ CD4+ T cells and CD4+CD44highCD62Llow effector T cells. Conclusion: These kinetic parameters of the immune response might provide diagnostic clues for A. fumigatus infection.


Age-Related Differences in Vehicle Control and Eye Movement Patterns at Intersections: Older and Middle-Aged Drivers.
Older drivers are at increased risk of intersection crashes. Previous work found that older drivers execute less frequent glances for detecting potential threats at intersections than middle-aged drivers. Yet, earlier work has also shown that an active training program doubled the frequency of these glances among older drivers, suggesting that these effects are not necessarily due to age-related functional declines. In light of findings, the current study sought to explore the ability of older drivers to coordinate their head and eye movements while simultaneously steering the vehicle as well as their glance behavior at intersections. In a driving simulator, older (M = 76 yrs) and middle-aged (M = 58 yrs) drivers completed different driving tasks: (1) travelling straight on a highway while scanning for peripheral information (a visual search task) and (2) navigating intersections with areas potential hazard. The results replicate that the older drivers did not execute glances for potential threats to the sides when turning at intersections as frequently as the middle-aged drivers. Furthermore, the results demonstrate costs of performing two concurrent tasks, highway driving and visual search task on the side displays: the older drivers performed more poorly on the visual search task and needed to correct their steering positions more compared to the middle-aged counterparts. The findings are consistent with the predictions and discussed in terms of a decoupling hypothesis, providing an account for the effects of the active training program.


Activities of daily living in dementia: revalidation of the E-ADL Test and suggestions for further development.
The everyday practical capabilities of dementia patients have a direct influence on a patient's independence and thus on the person's quality of life and on the amount of care needed. These capabilities are therefore important as therapeutic goals and are also important from a health-economic point of view. To date, no economical and valid performance test is available. The E-ADL-Test developed by Gräβel et al. in 2009 is a short performance test that has, however, only been validated on a small sample thus far. The objective of the present study is to re-validate the E-ADL-Test and explore possibilities for further development. The data were obtained from an RCT with a sample of 139 dementia patients in 5 nursing homes in Bavaria (Germany). The internal consistency was calculated as a measure of reliability. An item analysis was performed for the sample and subgroups with various degrees of dementia. Criterion and construct validity were tested based on five hypotheses. For validation, the residents' capabilities were examined using the Barthel-Index (BI), the Nurses' Observation Scale for Geriatric Patients (NOSGER), the Alzheimer's Disease Assessment Scale (ADAS), and the Mini-Mental Status Examination (MMSE). The internal consistency was .68 for the sample and .73 for the subgroup with severe dementia. The item analysis yielded good difficulty indices and discrimination power for moderate and severe dementia. The tasks were found to be too easy for mild dementia. The predictive criterion-related validity was confirmed by a correlation of r = .54 with the care level after 22 months and significant mean differences in the E-ADL-Test between persons with and without an increase in the care level. A differentiated correlation profile supported the three hypotheses on construct validity. The E-ADL-Test in its current form is a valid and reliable instrument for assessing the ADL capabilities of patients with moderate and severe dementia. More difficult items should be developed for use with mild dementia. http://www.isrctn.com Identifier: ISRCTN87391496.


Antithrombin III deficiency in Indian patients with deep vein thrombosis: identification of first India based AT variants including a novel point mutation (T280A) that leads to aggregation.
Antithrombin III (AT) is the main inhibitor of blood coagulation proteases like thrombin and factor Xa. In this study we report the identification and characterization of several variants of AT for the first time in Indian population. We screened 1950 deep vein thrombosis (DVT) patients for AT activity and antigen levels. DNA sequencing was further carried out in patients with low AT activity and/or antigen levels to identify variations in the AT gene. Two families, one with type I and the other with type II AT deficiency were identified. Three members of family I showed an increase in the coagulation rates and recurrent thrombosis in this family was solely attributed to the rs2227589 polymorphism. Four members of family II spanning two generations had normal antigen levels and decreased AT activity. A novel single nucleotide insertion, g.13362_13363insA in this family in addition to g.2603T>C (p.R47C) mutation were identified. AT purified from patient's plasma on hi-trap heparin column showed a marked decrease in heparin affinity and thrombin inhibition rates. Western blot analysis showed the presence of aggregated AT. We also report a novel point mutation at position g.7549 A>G (p.T280A), that is highly conserved in serpin family. Variant protein isolated from patient plasma indicated loss of regulatory function due to in-vivo polymerization. In conclusion this is the first report of AT mutations in SERPINC1 gene in Indo-Aryan population where a novel point mutation p.T280A and a novel single nucleotide insertion g.13362_13363insA are reported in addition to known variants like p.R47C, p.C4-X and polymorphisms of rs2227598, PstI and DdeI.


Branding your medical practice.
Branding is the process of differentiating your medical practice from all other practices in the industry. Branding takes into account the "look and feel" of your office, you and your staff your materials, and every other detail that gives your patients clues as to who you are and what you value. This article will review the strategies that go into building your own solid brand so your existing patients, as well as prospective ones, are attracted and loyal to you and your brand.


Surgical resection improves survival in pancreatic cancer patients without vascular invasion- a population based study.
To investigate the effect of surgery on overall survival (measured from the time of diagnosis) in pancreatic cancer without vascular invasion (stage 1, 2A and 2B). We also sought to investigate factors that predict survival in patients who elected to undergo surgery and factors that affect the decision to undergo surgery. The Surveillance Epidemiology and End Results (SEER) database was queried for microscopically confirmed cases of stage 1,2A and 2B pancreatic ductal adenocarcinoma diagnosed between 1973-2009. Survival analysis was carried out by univariate and multivariate analysis. Logistic regression was employed to identify factors that predict decision to undergo surgery. 1,759 patients with microscopically confirmed pancreatic cancer with stage 1-2B at the time of diagnosis were recorded in the SEER database. 92.6% patients underwent pancreatic cancer-directed surgery. Patients undergoing surgery had a significantly lower mean age at the time of diagnosis (65.8 vs. 69.9 years, P=0.002) and a longer median survival (18 vs. 7 months) compared to those who did not undergo surgery. Surgical resection was a significant predictor of overall survival upon both univariate and multivariate analysis. Younger age at the time of diagnosis, non-white, non-black race, tumor size <40 mm and tumor located in the tail of the pancreas were factors significantly associated with a chance of pancreatic cancer-directed surgery. Surgery improves survival in pancreatic cancer patients where the tumor has not involved the vasculature. Younger patients, those with smaller tumors located in the tail of the pancreas were most likely to undergo surgical resection.


Calculated tabulations of H(2)O line broadening by H(2)O, N(2), O(2), and CO(2) at high temperature.
We present calculations of the temperature dependence of H(2)O pressure broadening parameters by H(2)O, CO(2), N(2), and O(2). They were made for Q-lines with a theoretical model which provides a correct treatment of close collisions and has been widely tested. The results should be useful for Raman spectra calculations. A simple law is proposed to deduce halfwidths of P- and R-lines from the Q-line results. The accuracy of this law at high temperature is demonstrated. A simple analytical representation of a constant halfwidth approximation is also given.


Effect of glucosamine HCl on dissolution and solid state behaviours of piroxicam upon milling.
Piroxicam is a non-steroidal anti-inflammatory drug that is characterised by low solubility and high permeability. In order to improve the drug dissolution rate, the co-grinding method was used as an approach to prepare piroxicam co-ground in the carriers such as glucosamine hydrochloride. As, this amino sugar (glucosamine HCl) has been shown to decrease pain and improve mobility in osteoarthritis in joints, therefore, the incorporation of glucosamine in piroxicam formulations would be expected to offer additional benefits to patients. The effect of the order of grinding on the dissolution of piroxicam was also investigated. Co-ground drug and glucosamine were prepared in different ratios using a ball mill. The samples were then subjected to different grinding times. In order to investigate the effect of the grinding process on the dissolution behaviour of piroxicam, the drug was ground separately in the absence of glucosamine. Mixtures of ground piroxicam and unground D-glucosamine HCl were prepared. Physical mixtures of piroxicam and glucosamine were also prepared for comparison. The properties of prepared co-ground systems and physical mixtures were studied using a dissolution tester, FTIR, SEM, XRPD and DSC. These results showed that the presence of glucosamine HCl can increase dissolution rate of piroxicam compared to pure piroxicam. Generally, all dissolution profiles showed the fastest dissolution rate when ground piroxicam was mixed with unground glucosamine. This was closely followed by the co-grinding of piroxicam with glucosamine where lower grinding times showed the fastest dissolution. The solid state studies showed that the grinding of piroxicam for longer times had no effect on polymorphic form of piroxicam, whereas mixtures of piroxicam-glucosamine ground for longer times (60 min) converted piroxicam polymorph II to polymorph I.


Observed to expected lung area to head circumference ratio in the prediction of survival in fetuses with isolated diaphragmatic hernia.
To assess the value of antenatally determined observed to expected fetal lung area to head circumference ratio (LHR) in the prediction of postnatal survival in isolated, congenital diaphragmatic hernia (CDH). Two groups of fetuses were examined. The first group included 650 normal fetuses at 12-32 weeks' gestation, and the data collected were used to establish a normal range of observed to expected LHR with gestational age. The second group included the data of a retrospective multicenter study of 354 fetuses with isolated CDH in which the LHR was measured on one occasion at 18-38 weeks' gestation. The patients were divided into those with left-sided CDH with and without intrathoracic herniation of the liver and right-sided CDH. Regression analysis was used to determine the significant predictors of postnatal survival. In both the normal fetuses and those with CDH the LHR increased but the observed to expected LHR did not change significantly with gestational age. In normal fetuses the mean observed to expected LHR in the left lung was 100% (95% CI, 61-139%) and in the right lung it was 100% (95% CI, 67-133%). In fetuses with CDH the mean observed to expected LHR was 39% (range 7-79%). Regression analysis demonstrated that significant predictors of survival were the observed to expected LHR (odds ratio (OR) 1.09, 95% CI, 1.06-1.12), side of CDH (left side OR 11.14, 95% CI, 3.41-36.39) and gestational age at delivery (OR 1.18, 95% CI, 1.02-1.36). In CDH, the LHR increases while observed to expected LHR is independent of gestational age. In fetuses with both left- and right-sided CDH, measurement of the observed to expected LHR provides a useful prediction of subsequent survival.


Treatment of classic Kaposi sarcoma with a nicotine dermal patch: a phase II clinical trial.
Kaposi sarcoma (KS), a malignancy of dermal endothelial cells that is caused by human herpesvirus 8 (HHV8) infection, is sensitive to perturbations of immunity. Nicotine might be effective against KS because of its immunologic and vascular effects and because smoking is associated with a low risk of KS. We conducted a masked, randomized phase 2 clinical trial of transdermal nicotine and placebo patches to assess the safety and efficacy of nicotine against classic KS (cKS). Three cKS lesions, predominantly nodules, in each of 24 non-smoking patients were randomly assigned to 15 weeks continuous treatment with nicotine patch (escalated to 7 mg), identical masked placebo patch or no patch. Changes in lesion area and elevation from baseline through six follow-up visits, by direct measurement and by two independent readers using digital photographs of the lesions, were compared using non-parametric and regression methods. Changes in longitudinal levels of HHV8 antibodies and DNA in blood cells were similarly assessed. There were no systemic or serious adverse events, and compliance was good. One patient resumed smoking and discontinued patches, and two patients withdrew at week 12 for unrelated indications. Six (29%) of the remaining 21 suspended use of patches to relieve local skin irritation; four of these six completed the trial at reduced dose. Treatment assignment was not associated with significant or consistent changes in cKS lesion area or elevation, HHV8 viral load or antibodies. Transdermal nicotine and placebo patches caused no serious toxicities but had no demonstrable effect on nodular cKS lesions or HHV8 levels.


SHP-1-mediated inhibitory signals promote responsiveness and anti-tumour functions of natural killer cells.
Natural killer (NK) cells are cytotoxic innate lymphoid cells that are involved in immune defense. NK cell reactivity is controlled in part by MHC class I recognition by inhibitory receptors, but the underlying molecular mechanisms remain undefined. Using a mouse model of conditional deletion in NK cells, we show here that the protein tyrosine phosphatase SHP-1 is essential for the inhibitory function of NK cell MHC class I receptors. In the absence of SHP-1, NK cells are hyporesponsive to tumour cells in vitro and their early Ca(2+) signals are compromised. Mice without SHP-1 in NK cells are unable to reject MHC class I-deficient transplants and to control tumours in vivo. Thus, the inhibitory activity of SHP-1 is needed for setting the threshold of NK cell reactivity.


Direct assessment of CXCR4 mutant conformations reveals complex link between receptor structure and G(alpha)(i) activation.
Ligand binding to G protein-coupled receptors (GPCRs) is thought to induce changes in receptor conformation that translate into activation of downstream effectors. The link between receptor conformation and activity is still insufficiently understood, as current models of GPCR activation fail to take an increasing amount of experimental data into account. To elucidate structure-function relationships in GPCR activation, we used bioluminescence resonance energy transfer to directly assess the conformation of mutants of the chemokine receptor CXCR4. We analyzed substitutions in the arginine cage DRY motif and in the conserved asparagine N(3.35)119, which are pivotal molecular switches for receptor conformation and activation. G(alpha)(i) activation of the mutants was either similar to wild-type CXCR4 (D133N, Y135A, and N119D) or resulted in loss of activity (R134A and N119K). Mutant N119S was constitutively active but further activated by agonist. Bioluminescence resonance energy transfer analysis suggested no simple correlation between conformational changes in response to ligand binding and activation of G(alpha)(i) by the mutants. Different conformations of active receptors were detected (for wild-type CXCR4, D133N, and N119S), suggesting that different receptor conformations are able to trigger G(alpha)(i) activity. Several conformations were also found for inactive mutants. These data provide biophysical evidence for different receptor conformations being active with respect to a single readout. They support models of GPCR structure-activity relationships that take this conformational flexibility of active receptors into account.


Changes in Doppler echocardiographic indexes of left ventricular function as potential markers of acute cardiac rejection.
Changes in left ventricular filling and ejection as potential markers of cardiac allograft rejection were evaluated by serial Doppler echocardiography performed in 23 normal volunteers and within 24 hr of endomyocardial biopsy in 22 patients aged 14 to 53 years (mean 37). Peak aortic velocity, left ventricular ejection time index (ETI), isovolumic relaxation time (IVRT), mitral valve pressure half-time (PHT), peak early mitral flow velocity (M1), and velocity following donor atrial systole (M2) were measured without prior knowledge of endomyocardial biopsy findings. Biopsy specimens were graded histologically as: no rejection, mild rejection (cellular infiltrate), and moderate rejection (myocyte necrosis). A total of 120 biopsy-correlated Doppler echocardiographic studies were performed during 16 weeks after cardiac transplantation. Heart rate and mean arterial pressure were significantly higher in transplant recipients than in normal subjects. IVRT and PHT were significantly longer, while M1 and M2 were similar. Peak aortic velocity was higher in normal subjects than in transplant recipients, while ejection time was similar. Rejection of increasing severity was associated with a progressive shortening of IVRT and PHT and with an increase in M1 (p less than .0005 for all comparisons). Peak aortic velocity and ejection time index did not change significantly with rejection. These data indicate that acute cardiac rejection is accompanied by alteration in left ventricular filling dynamics detectable by Doppler echocardiography, without measureable changes in systolic function. These changes may provide noninvasive markers for surveillance of rejection.


Clinical and radiographic findings that lead to intervention in diabetic patients with foot ulcers. A nationwide survey of primary care physicians.
To determine which elements of clinical history, physical examination, and diagnostic tests are important to primary care physicians in their management of foot ulcers in diabetic patients. We conducted a national mail survey of 600 primary care physicians to determine which patient characteristics and diagnostic test results were important in their decisions to seek radiographic studies, surgical referrals, and hospitalization for diabetic patients with foot ulcers. The case characteristics most likely to influence physicians to order advanced diagnostic or therapeutic interventions are the presence of osteomyelitis on plain radiographs, the failure of the ulcer to improve with conservative therapy, and the presence of visible bone, crepitus, or necrosis within the ulcer (P < 0.001). Information from the initial clinical history was less likely to influence physicians to order advanced diagnostic or therapeutic interventions (P < 0.001) than was information from the physical examination. We conclude that 1) the patient's history is relatively unimportant to primary care physicians in their management of diabetic foot ulcers; 2) the failure of conservative management is a major reason that primary care physicians order surgical referral, hospitalization, or radiographic testing for diabetic patients with foot ulcers; and 3) primary care physicians rely heavily on plain X ray of the foot, a test with poor sensitivity and specificity, in deciding whether to order further interventions for their diabetic patients with foot ulcers.


2015 AMCLC Open-Microphone Session: Improving the IQ (Information Quality) of What We Do.
Each year an open-microphone session is hosted by the Council Steering Committee. The committee invited an expert panel to discuss the use of effective communication in appropriate procedure selection and methods and resources to communicate the results of procedures performed in an actionable and clear manner to referring clinicians and patients, as well as downstream data systems. The ACR is actively encouraging radiologists to leverage existing and new technologies to increase their visibility in the health care system. Key features in Imaging 3.0 are results reporting through actionable reports, decision support for results reporting, guidelines for recommendations, tools for actionable reports, and tracking a radiologist's recommendations. The final radiology report is an essential product of our service, but it is increasingly clear that the noninterpretive components of our profession will add the most value to patient care. The radiology report is not the only evidence of our work. Nonetheless, the information quality and content of the radiology report can and must be improved so that it can add value and clinical usefulness toward excellent patient care. We must use appropriate tools and "best knowledge" to deliver actionable and value-added high-quality reports.


Carbon nanodots interference with lactate dehydrogenase assay in human monocyte THP-1 cells.
Carbon nanodots (CD), a new class of carbon nanomaterials with sizes below 10 nm, have recently attracted wide attention due to their superiority in water solubility, chemical inertness, and resistance to photobleaching. As a result, CD has found important and wide applications in energy, catalysis, biological labeling, bioimaging and drug delivery. On the other hand, due to the lack of available toxicity data, there is a growing concern regarding the potential risks of CD. Hence, accurate assessment of the cytotoxicity of CD has become more important than ever before. The lactate dehydrogenase (LDH) assay is widely used to detect cytotoxicity of various nanoparticles including CD. Many recent studies used LDH assay to study the CD toxicity in various cells. However, these studies failed to further examine whether the CD were interfering with the LDH assay which would alter their findings. This study investigated the possible interference of carbon nanodots on the LDH assay in human monocyte THP-1 cells. Monocytes are known to be involved in inflammable vascular diseases, and have been suggested to be the targets for CD exposure. In this study, the cytotoxicity of CD in concentrations ranging from 0.075 to 0.60 mg/mL, was determined by using the LDH assay. To validate the results of LDH assay, the cell counting method with trypan blue staining was used. With 24 hours incubation time, the cell viability of THP-1 was significantly decreased according to the trypan blue staining method. Whereas, in the LDH assay, the CD was found to interfere in a dose-dependent manner with the NADH absorbance measurements at 340 nm. This study represents the first report on the negative interference of CD on LDH assay, and caution should be observed when evaluating the cytotoxicity of CD.


H2AX deficiency is associated with erythroid dysplasia and compromised haematopoietic stem cell function.
Myelodysplastic syndromes (MDS) are clonal disorders of haematopoiesis characterised by dysplastic changes of major myeloid cell lines. However, the mechanisms underlying these dysplastic changes are poorly understood. Here, we used a genetically modified mouse model and human patient data to examine the physiological roles of H2AX in haematopoiesis and how the loss of H2AX contributes to dyserythropoiesis in MDS. H2AX knockout mice showed cell-autonomous anaemia and erythroid dysplasia, mimicking dyserythropoiesis in MDS. Also, dyserythropoiesis was increased in MDS patients with the deletion of chromosome 11q23, where H2AX is located. Although loss of H2AX did not affect the early stage of terminal erythropoiesis, enucleation was decreased. H2AX deficiency also led to the loss of quiescence of hematopoietic stem and progenitor cells, which dramatically compromised their bone marrow engraftment. These results reveal important roles of H2AX in late-stage terminal erythropoiesis and hematopoietic stem cell function.


Hepatic differentiation potential of commercially available human mesenchymal stem cells.
The ready availability and low immunogenicity of commercially available mesenchymal stem cells (MSC) render them a potential cell source for the development of therapeutic products. With cell source a major bottleneck in hepatic tissue engineering, we investigated whether commercially available human MSC (hMSC) can transdifferentiate into the hepatic lineage. Based on previous studies that find rapid gain of hepatic genes in bone marrow-derived stem cells cocultured with liver tissue, we used a similar approach to drive hepatic differentiation by coculturing the hMSC with rat livers treated or untreated with gadolinium chloride (GdCl(3)). After a 24-hour coculture period with liver tissue injured by GdCl(3) in a Transwell configuration, approximately 34% of the cells differentiated into albumin-expressing cells. Cocultured cells were subsequently maintained with growth factors to complete the hepatic differentiation. Cocultured cells expressed more hepatic gene markers, and had higher metabolic functions and P450 activity than cells that were only differentiated with growth factors. In conclusion, commercially available hMSC do show hepatic differentiation potential, and a liver microenvironment in culture can provide potent cues to accelerate and deepen the differentiation. The ability to generate hepatocyte-like cells from a commercially available cell source would find interesting applications in liver tissue engineering.


Revision decompression and collagen nerve wrap for recurrent and persistent compression neuropathies of the upper extremity.
Recurrent or persistent compression neuropathies of the upper extremity, including carpal and cubital tunnel syndrome, present a difficult treatment challenge to the hand or peripheral nerve surgeon. Collagen conduits have been used successfully for decades in nerve injury repair, but have not been studied in the treatment of compression neuropathy. Patients with recurrent or persistent compression neuropathies treated with a repeat decompression and collagen wrap from a 5-year period were retrieved from the Computerized Patient Record System database and 15 patient records were identified. A systematic review was performed for all articles from 1946 to 2012 on secondary carpal and cubital tunnel syndrome. The mean age of the 15 patients treated was 63.3 years and ranged from 35 to 86 years. The patients with revision carpal tunnel decompression had an 89% subjective response rate, whereas those with revision cubital tunnel decompression had an 83% resolution or improvement of symptoms. Visual analog scale decreased from a preoperative mean 2.47 to 0.47 postoperatively and the mean number of opiate medications decreased from 0.67 to 0.40. We identified 32 papers using various treatment strategies for recurrent carpal tunnel syndrome with success rates ranging from 53% to 100%. We identified 18 papers on recurrent cubital tunnel syndrome, with success rates ranging from 33% to 100%, with a weighted success of 78.1% overall but 71.7% in the submuscular transposition group. Here we report on the novel technique of using a collagen matrix wrap in recurrent compression neuropathies with good success. The collagen wrap allows nerve gliding, protection from perineural scar formation, and a favorable microenvironment. Submuscular transposition seems to be no better than other methods of decompression for recurrent cubital tunnel syndrome in contrary to traditional teaching.


Community-Based Healthy Living Interventions.
In an environment in which most people have lifestyles that increase risk for initial or recurrent cardiovascular disease (CVD) events, community-based healthy lifestyle initiatives are highly effective in providing programs, education and support to reduce associated CVD risk factors and improve outcomes. Pioneering programs, such as the Stanford Three Community and Five Cities studies, and the North Karelia project in Finland, served as prototypes for current initiatives. These include partnerships with national organizations (e.g., YMCA DPP) and faith-based programs. Training may be provided by healthcare professionals and/or community healthcare workers; initiatives include exercise-based and weight-reduction programs, smoking cessation interventions, dietary counseling and education, and medication adherence. Contemporary technologies and home-based programs provide alternatives to those who might not otherwise have access to center-based programs. Community-based initiatives, particularly those with state or national support, have the potential to enhance the delivery and effectiveness of CVD prevention at low cost.


EPS8L2 is a new causal gene for childhood onset autosomal recessive progressive hearing loss.
More than 70 % of the cases of congenital deafness are of genetic origin, of which approximately 80 % are non-syndromic and show autosomal recessive transmission (DFNB forms). To date, 60 DFNB genes have been identified, most of which cause congenital, severe to profound deafness, whereas a few cause delayed progressive deafness in childhood. We report the study of two Algerian siblings born to consanguineous parents, and affected by progressive hearing loss. After exclusion of GJB2 (the gene most frequently involved in non-syndromic deafness in Mediterranean countries), we performed whole-exome sequencing in one sibling. A frame-shift variant (c.1014delC; p.Ser339Alafs*15) was identified in EPS8L2, encoding Epidermal growth factor receptor Pathway Substrate 8 L2, a protein of hair cells' stereocilia previously implicated in progressive deafness in the mouse. This variant predicts a truncated, inactive protein, or no protein at all owing to nonsense-mediated mRNA decay. It was detected at the homozygous state in the two clinically affected siblings, and at the heterozygous state in the unaffected parents and one unaffected sibling, whereas it was never found in a control population of 150 Algerians with normal hearing or in the Exome Variant Server database. Whole-exome sequencing allowed us to identify a new gene responsible for childhood progressive hearing loss transmitted on the autosomal recessive mode.


Human neural stem cells restore spatial memory in a transgenic Alzheimer's disease mouse model by an immunomodulating mechanism.
Stem cells are a promising therapeutic in Alzheimer's disease (AD) given the complex pathophysiologic pathways involved. However, the therapeutic mechanisms of stem cells remain unclear. Here, we used spatial transcriptomics to elucidate therapeutic mechanisms of human neural stem cells (hNSCs) in an animal model of AD. hNSCs were transplanted into the fimbria fornix of the hippocampus using the 5XFAD mouse model. Spatial memory was assessed by Morris water maze. Amyloid plaque burden was quantified. Spatial transcriptomics was performed and differentially expressed genes (DEGs) identified both globally and within the hippocampus. Subsequent pathway enrichment and ligand-receptor network analysis was performed. hNSC transplantation restored learning curves of 5XFAD mice. However, there were no changes in amyloid plaque burden. Spatial transcriptomics showed 1061 DEGs normalized in hippocampal subregions. Plaque induced genes in microglia, along with populations of stage 1 and stage 2 disease associated microglia (DAM), were normalized upon hNSC transplantation. Pathologic signaling between hippocampus and DAM was also restored. hNSCs normalized many dysregulated genes, although this was not mediated by a change in amyloid plaque levels. Rather, hNSCs appear to exert beneficial effects in part by modulating microglia-mediated neuroinflammation and signaling in AD.


Mendelian inheritance, genetic linkage, and genotypic disequilibrium for nine microsatellite loci in Cariniana estrellensis (Raddi) Kuntze (Lecythidaceae).
Cariniana estrellensis is one of the largest trees found in Brazilian tropical forests. The species is typical of advanced stages of succession, characteristic of climax forests, and essential in genetic conservation and environmental restoration plans. In this study, we assessed Mendelian inheritance, genetic linkage, and genotypic disequilibrium in nine microsatellite loci for a C. estrellensis population. We sampled and genotyped 285 adult trees and collected seeds from 20 trees in a fragmented forest landscape in Brazil. Based on maternal genotypes and their seeds, we found no deviation from the expected 1:1 Mendelian segregation and no genetic linkage between pairwise loci. However, for adults, genotypic disequilibrium was detected for four pairs of loci, suggesting that this result was not caused by genetic linkage. Based on these results, we analyzed microsatellite loci that are suitable for use in population genetic studies assessing genetic diversity, mating system, and gene flow in C. estrellensis populations.


Intracellular Abeta and cognitive deficits precede beta-amyloid deposition in transgenic arcAbeta mice.
The brain pathology of Alzheimer's disease is characterized by abnormally aggregated Abeta in extracellular beta-amyloid plaques and along blood vessel walls, but the relation to intracellular Abeta remains unclear. To address the role of intracellular Abeta deposition in vivo, we expressed human APP with the combined Swedish and Arctic mutations in mice (arcAbeta mice). Intracellular punctate deposits of Abeta occurred concomitantly with robust cognitive impairments at the age of 6 months before the onset of beta-amyloid plaque formation and cerebral beta-amyloid angiopathy. beta-Amyloid plaques from arcAbeta mice had distinct dense-core morphologies with blood vessels appearing as seeding origins, suggesting reduced clearance of Abeta across blood vessels in arcAbeta mice. The co-incidence of intracellular Abeta deposits with behavioral deficits support an early role of intracellular Abeta in the pathophysiological cascade leading to beta-amyloid formation and functional impairment.


Garlic-Derived Organic Polysulfides and Myocardial Protection.
For centuries, garlic has been shown to exert substantial medicinal effects and is considered to be one of the best disease-preventative foods. Diet is important in the maintenance of health and prevention of many diseases including cardiovascular disease (CVD). Preclinical and clinical evidence has shown that garlic reduces risks associated with CVD by lowering cholesterol, inhibiting platelet aggregation, and lowering blood pressure. In recent years, emerging evidence has shown that hydrogen sulfide (H2S) has cardioprotective and cytoprotective properties. The active metabolite in garlic, allicin, is readily degraded into organic diallyl polysulfides that are potent H2S donors in the presence of thiols. Preclinical studies have shown that enhancement of endogenous H2S has an impact on vascular reactivity. In CVD models, the administration of H2S prevents myocardial injury and dysfunction. It is hypothesized that these beneficial effects of garlic may be mediated by H2S-dependent mechanisms. This review evaluates the current knowledge concerning the cardioprotective effects of garlic-derived diallyl polysulfides.


Stability of red blood cell folate in whole blood and haemolysate.
Folate, a water soluble B vitamin, is necessary for normal cell growth and DNA synthesis. A deficiency leads to megaloblastic anaemia and possible neurological sequelae. Since we receive samples from distant clinics and experience problems due to the long transit times to our laboratory, we carried out a folate stability study. Fasting blood samples were drawn from 40 healthy volunteers. We determined the baseline red blood cell (RBC) folate in duplicate on each sample. Half the sample was then stored at various temperatures prior to haemolysate formation and RBC folate was determined regularly to determine sample stability. The other half was haemolysed, the haemolysate stored at various temperatures and analysed regularly to determine haemolysate stability. A statistical test of equivalence was applied using 18% as a pre-defined limit. We found that whole blood was stable at 4 degrees C up to 72 hours. At room temperature stability has been proven up to 24 hours. Results of additional experiments with haemolysate support stability under all conditions for 12 hours. Samples for RBC folate determination transported from distant clinics are stable for up to 72 hours at 4 degrees C or at room temperature for at least 24 hours. The prepared haemolysates may be stored at -20 degrees C. Our experiments show that sample transportation at higher temperature does not affect folate stability within our predefined limits.


Genome-Wide Association Study Meta-Analysis of Stroke in 22 000 Individuals of African Descent Identifies Novel Associations With Stroke.
Stroke is a complex disease with multiple genetic and environmental risk factors. Blacks endure a nearly 2-fold greater risk of stroke and are 2× to 3× more likely to die from stroke than European Americans. The COMPASS (Consortium of Minority Population Genome-Wide Association Studies of Stroke) has conducted a genome-wide association meta-analysis of stroke in >22 000 individuals of African ancestry (3734 cases, 18 317 controls) from 13 cohorts. In meta-analyses, we identified one single nucleotide polymorphism (rs55931441) near the HNF1A gene that reached genome-wide significance (P=4.62×10-8) and an additional 29 variants with suggestive evidence of association (P<1×10-6), representing 24 unique loci. For validation, a look-up analysis for a 100 kb region flanking the COMPASS single nucleotide polymorphism was performed in SiGN (Stroke Genetics Network) Europeans, SiGN Hispanics, and METASTROKE (Europeans). Using a stringent Bonferroni correction P value of 2.08×10-3 (0.05/24 unique loci), we were able to validate associations at the HNF1A locus in both SiGN (P=8.18×10-4) and METASTROKE (P=1.72×10-3) European populations. Overall, 16 of 24 loci showed evidence for validation across multiple populations. Previous studies have reported associations between variants in the HNF1A gene and lipids, C-reactive protein, and risk of coronary artery disease and stroke. Suggestive associations with variants in the SFXN4 and TMEM108 genes represent potential novel ischemic stroke loci. These findings represent the most thorough investigation of genetic determinants of stroke in individuals of African descent, to date.


Pain and psychological well-being among people with dementia in long-term care.
To examine the relationship between self-reported pain and psychological well-being of people with dementia (PWD) living in residential long-term care as indicated by displays of observed emotional expression over the daytime period. Secondary analysis using repeated measures of self-report and observational data. A total of 177 PWD were included from 17 nursing homes and six assisted living facilities in Michigan and Pennsylvania. Negative emotional expression was used as an indicator of reduced psychological well-being. Pain was assessed through PWD's response to a question about presence of pain obtained at each observation. Cognitive impairment was assessed using the Mini-Mental Status Examination. Linear mixed models were used that accounted for correlation of negative emotional expression measurements over time for each participant and between participants within the same facility. Among 171 participants who were able to express their pain, 44% of PWD reported pain once or more during the daytime period. Severity of cognitive impairment was related to expression of negative emotion. PWD with pain displayed more negative emotional expression than PWD without pain. Routine pain assessment is feasible among PWD with moderate to severe dementia and positive report of pain is associated with greater observed negative emotional expression, an indicator of reduced psychological well-being. Improving pain management holds potential for enhancing psychological well-being among PWD living in residential long-term care.


Endocrinopathies in celiac disease: When the endocrinologist sees what is invisible to the gastroenterologist.
Celiac disease (CD) is a systemic, immune mediated and genetically determined small intestinal disorder characterized by intolerance to dietary gluten that generally presents with gastrointestinal symptoms in young children and extra-intestinal manifestations. Furthermore, there is close association between CD and endocrine diseases, including diabetes, autoimmune thyroid diseases, growth and pubertal disorders, etc. probably due to the presence of a common genetic predisposition. The present review aims to highlight and give more insight to the endocrine changes in CD, especially when there are few or no gastrointestinal symptoms and to emphasize on screening opportunities in some endocrine diseases.


Cognitive reserve and Alzheimer's disease biomarkers are independent determinants of cognition.
The objective of this study was to investigate how a measure of educational and occupational attainment, a component of cognitive reserve, modifies the relationship between biomarkers of pathology and cognition in Alzheimer's disease. The biomarkers evaluated quantified neurodegeneration via atrophy on magnetic resonance images, neuronal injury via cerebral spinal fluid t-tau, brain amyloid-β load via cerebral spinal fluid amyloid-β1-42 and vascular disease via white matter hyperintensities on T2/proton density magnetic resonance images. We included 109 cognitively normal subjects, 192 amnestic patients with mild cognitive impairment and 98 patients with Alzheimer's disease, from the Alzheimer's Disease Neuroimaging Initiative study, who had undergone baseline lumbar puncture and magnetic resonance imaging. We combined patients with mild cognitive impairment and Alzheimer's disease in a group labelled 'cognitively impaired' subjects. Structural Abnormality Index scores, which reflect the degree of Alzheimer's disease-like anatomic features on magnetic resonance images, were computed for each subject. We assessed Alzheimer's Disease Assessment Scale (cognitive behaviour section) and mini-mental state examination scores as measures of general cognition and Auditory-Verbal Learning Test delayed recall, Boston naming and Trails B scores as measures of specific domains in both groups of subjects. The number of errors on the American National Adult Reading Test was used as a measure of environmental enrichment provided by educational and occupational attainment, a component of cognitive reserve. We found that in cognitively normal subjects, none of the biomarkers correlated with the measures of cognition, whereas American National Adult Reading Test scores were significantly correlated with Boston naming and mini-mental state examination results. In cognitively impaired subjects, the American National Adult Reading Test and all biomarkers of neuronal pathology and amyloid load were independently correlated with all cognitive measures. Exceptions to this general conclusion were absence of correlation between cerebral spinal fluid amyloid-β1-42 and Boston naming and Trails B. In contrast, white matter hyperintensities were only correlated with Boston naming and Trails B results in the cognitively impaired. When all subjects were included in a flexible ordinal regression model that allowed for non-linear effects and interactions, we found that the American National Adult Reading Test had an independent additive association such that better performance was associated with better cognitive performance across the biomarker distribution. Our main conclusions included: (i) that in cognitively normal subjects, the variability in cognitive performance is explained partly by the American National Adult Reading Test and not by biomarkers of Alzheimer's disease pathology; (ii) in cognitively impaired subjects, the American National Adult Reading Test, biomarkers of neuronal pathology (structural magnetic resonance imaging and cerebral spinal fluid t-tau) and amyloid load (cerebral spinal fluid amyloid-β1-42) all independently explain variability in general cognitive performance; and (iii) that the association between cognition and the American National Adult Reading Test was found to be additive rather than to interact with biomarkers of Alzheimer's disease pathology.


Implanted Nanosensors in Marine Organisms for Physiological Biologging: Design, Feasibility, and Species Variability.
In recent decades, biologists have sought to tag animals with various sensors to study aspects of their behavior otherwise inaccessible from controlled laboratory experiments. Despite this, chemical information, both environmental and physiological, remains challenging to collect despite its tremendous potential to elucidate a wide range of animal behaviors. In this work, we explore the design, feasibility, and data collection constraints of implantable, near-infrared fluorescent nanosensors based on DNA-wrapped single-wall carbon nanotubes (SWNT) embedded within a biocompatible poly(ethylene glycol) diacrylate (PEGDA) hydrogel. These sensors are enabled by Corona Phase Molecular Recognition (CoPhMoRe) to provide selective chemical detection for marine organism biologging. Riboflavin, a key nutrient in oxidative phosphorylation, is utilized as a model analyte in in vitro and ex vivo tissue measurements. Nine species of bony fish, sharks, eels, and turtles were utilized on site at Oceanogràfic in Valencia, Spain to investigate sensor design parameters, including implantation depth, sensor imaging and detection limits, fluence, and stability, as well as acute and long-term biocompatibility. Hydrogels were implanted subcutaneously and imaged using a customized, field-portable Raspberry Pi camera system. Hydrogels could be detected up to depths of 7 mm in the skin and muscle tissue of deceased teleost fish ( Sparus aurata and Stenotomus chrysops) and a deceased catshark ( Galeus melastomus). The effects of tissue heterogeneity on hydrogel delivery and fluorescence visibility were explored, with darker tissues masking hydrogel fluorescence. Hydrogels were implanted into a living eastern river cooter ( Pseudemys concinna), a European eel ( Anguilla anguilla), and a second species of catshark ( Scyliorhinus stellaris). The animals displayed no observable changes in movement and feeding patterns. Imaging by high-resolution ultrasound indicated no changes in tissue structure in the eel and catshark. In the turtle, some tissue reaction was detected upon dissection and histopathology. Analysis of movement patterns in sarasa comet goldfish ( Carassius auratus) indicated that the hydrogel implants did not affect swimming patterns. Taken together, these results indicate that this implantable form factor is a promising technique for biologging using aquatic vertebrates with further development. Future work will tune the sensor detection range to the physiological range of riboflavin, develop strategies to normalize sensor signal to account for the optical heterogeneity of animal tissues, and design a flexible, wearable device incorporating optoelectronic components that will enable sensor measurements in moving animals. This work advances the application of nanosensors to organisms beyond the commonly used rodent and zebrafish models and is an important step toward the physiological biologging of aquatic organisms.


SOME QUESTIONS RELATING TO THE VIRULENCE OF MICRO-ORGANISMS WITH PARTICULAR REFERENCE TO THEIR IMMUNIZING POWERS.
The virulent cholera spirillum possesses a greater number of bacteriolytic and agglutinable haptophore groups, or these groups are endowed with a greater avidity for uni- and amboceptors than the avirulent. The number or the avidity of the bacteriolytic receptors possessed by a bacterium is directly proportional to its virulence. However, the agglutinable receptors do not follow this law, i.e., the agglutinable haptophore groups are not necessarily present in the same proportion as the bactericidal ones. While the energy of growth is a very important factor in relation to virulence, other phenomena must also be considered. The virulent organism possesses a greater number of toxic haptophore groups than the avirulent. The binding power of the free receptors of the organisms for bacteriolytic amboceptors in vitro is proportional to the bactericidal immunity produced in animals by each, which latter is in turn proportional to the virulence of the organisms from which the receptors were extracted. The binding power in vitro of the dead micro-organisms of different virulence for bacteriolytic amboceptors is not in proportion to their toxicity. The bactericidal immunity obtained by means of the inoculation with the dead organisms of different virulence, or their extracts obtained by autolytic digestion, is proportional to the virulence of the living strains of the bacteria employed. With the living organisms, while the bactericidal immunity obtained from the inoculation of animals with the virulent organism is greater than that produced with the avirulent, such immunity is not in direct proportion to the virulence of the bacteria introduced. These conclusions apply to the two strains of cholera spirilk employed in the foregoing experiments. Whether they will also hold good with other strains of this spirillum or for micro organisms in general, must be decided by further experimenta work.


Creating an academy of medical educators: how and where to start.
While most faculty members want to improve as teachers, they neither know where their educational strengths and weaknesses lie nor where or how to begin to effect a change in their teaching abilities. The lack of actionable, directed and specific feedback, and sensible and sensitive metrics to assess performance and improvement complicates the attainment of educational excellence. The purpose of this article was to outline a series of specific steps that medical education programs can take to enhance the quality of teaching, promote teaching excellence, elevate the status and value of medical educators, and stimulate the creation of innovative teaching programs and curricula. To achieve these goals at the Hospital for Special Surgery, the Academy of Rheumatology Medical Educators was formed. The academy had the following goals: (1) create within our institution a mission which advances and supports educators, (2) establish a membership composed of distinguished educators, (3) create a formal organizational structure with designated leadership, (4) dedicate resources that fund mission-related initiatives and research, and (5) establish a plan for promoting teachers as well as enhancing and advancing educational scholarship. The Hospital for Special Surgery Academy of Rheumatology Medical Educators was recently formed to address these goals by promoting teaching and learning of musculoskeletal skills in an environment that is supportive to educators and trainees and provides much needed resources for teachers. The development of a pilot academy of medical educators represents one of the high-priority goals of those institutions that wish to elevate and enrich their teaching through a structured, proven approach.


Terahertz-rate optical pulse generation from a passively mode-locked semiconductor laser diode.
We report what is to our knowledge the first demonstration of terahertz-rate optical pulse generation by harmonic passive mode locking in a distributed-Bragg-reflector laser diode. Along with the fundamental repetition rate of 38.8 GHz, we observed 400-GHz, 800-GHz, and 1.54-THz harmonics, depending on the bias condition of gain section. The pulse envelope for 1.54-THz pulses was in good agreement with a calculation from the Fourier transformation of the optical spectrum, indicating that the output pulses are transform limited.


Characteristics of human erythrocyte insulin receptors.
Highly specific insulin receptors have been identified on human erythrocytes. A modification of the monocyte insulin radioreceptor technique permitted distinct separation of human erythrocytes with their bound insulin from the free insulin. When incubated with 80 pg. per milliliter of 125I-insulin (pH 8.0, 3.5 hours, 15 degrees C.), erythrocytes from 17 normal volunteers specifically bound 10 per cent (+/- 1.450 S.D.) of the total 125I-insulin. Less than 15 per cent of the total 125I-insulin bound was nonspecific. Binding of 125I-insulin to human erythrocytes was dependent on pH and temperature. Less than 5 per cent of the insulin available to the plasma membrane was degraded. Both calcium and magnesium enhanced 125I-insulin binding by 100 per cent but had no synergistic effect when mixed in a 1:1 molar ratio. Scatchard analysis of the binding data resulted in a curvilinear plot with characteristics typical of negative cooperative interactions between receptor sites and with an unoccupied site affinity constant of 0.1 X 10(8) M-1. Human erythrocytes have 2,000 insulin binding sites per erythrocyte with 14 sites per square micrometer of surface area. The readily available human erythrocyte, thus, has both specific insulin binding sites and binding characteristics similar to other human cell types. These studies have provided the basis for further clinical investigation of polypeptide hormone receptors on human erythrocytes.


What is community integration anyway?: defining meaning following traumatic brain injury.
Full community integration, or participation in society, is the ultimate goal of rehabilitation and of research conducted in the field of rehabilitation for persons with traumatic brain injury (TBI). Community integration has been traditionally defined by 3 main areas: employment or other productive activity, independent living, and social activity. However, these have not always received equal weighting and attention in clinical or research efforts. Significant gaps remain in our understanding of factors that impact community integration and in our ability to intervene to improve participation for persons with TBI. This article describes 3 main challenges for researchers and rehabilitation professionals. First, a comprehensive meaning of community integration is needed, which includes the viewpoints and preferences of persons with TBI. Second, cultural competence in measurement and intervention is needed. Third, a thorough assessment of environmental factors impacting participation is needed and should be incorporated into research and treatment planning.


Head-neck domain of Arabidopsis myosin XI, MYA2, fused with GFP produces F-actin patterns that coincide with fast organelle streaming in different plant cells.
The cytoskeletal mechanisms that underlie organelle transport in plants are intimately linked to acto-myosin function. This function is mediated by the attachment of myosin heads to F-actin and the binding of cargo to the tails. Acto-myosin also powers vigorous cytoplasmic streaming in plant cells. Class XI myosins exhibit strikingly fast velocities and may have extraordinary roles in cellular motility. Studies of the structural basis of organelle transport have focused on the cargo-binding tails of myosin XI, revealing a close relationship with the transport of peroxisomes, mitochondria, and Golgi-vesicles. Links between myosin heads and F-actin-based motility have been less investigated. To address this function, we performed localization studies using the head-neck domain of AtMYA2, a myosin XI from Arabidopsis. We expressed the GFP-fused head-neck domain of MYA2 in epidermal cells of various plant species and found that it associated with F-actin. By comparison to other markers such as fimbrin and talin, we revealed that the myosin-labeled F-actin was of a lower quality and absent from the fine microfilament arrays at the cell cortex. However, it colocalized with cytoplasmic (transvacuolar) F-actin in areas coinciding with the tracks of fast organelles. This observation correlates well with the proposed function of myosin XI in organelle trafficking. The fact that organelle streaming was reduced in cells expressing the GFP-MYA2-head6IQ indicated that the functionless motor protein inhibits endogenous myosins. Furthermore, co-expression of the GFP-MYA2-head6IQ with other F-actin markers disrupted its attachment to F-actin. In nuclei, the GFP-myosin associated with short bundles of F-actin. The localization of the head of MYA2 in living plant cells, as investigated here for the first time, suggests a close linkage between this myosin XI and cytoplasmic microfilaments that support the rapid streaming of organelles such as peroxisomes. Potential roles of MYA2 may also exist in the cell nucleus. Whether the low quality of the F-actin-labeling by MYA2-head6IQ compared to other F-actin-binding proteins (ABPs) signifies a weak association of the myosin with actin filaments remains to be proven by other means than in vivo. Clues for the mode of contact between the myosin molecules and F-actin so far cannot be drawn from sequence-related data.


Mechanisms of metal toxicity in plants.
Metal toxicity in plants is still a global problem for the environment, agriculture and ultimately human health. This review initially addresses the current state of the environmental/agricultural problem, and then discusses in detail the occurrence, mechanisms and relevance of toxicity of selected trace metals (Cd, Cu, Fe, Hg, Ni, and Zn). When discussing the mechanisms, special emphasis is laid on a critical review of their environmental/agricultural relevance, because even now many studies in this field of research are performed under highly artificial lab conditions. The main problems outlined in published studies are artificially high metal concentrations (which never occur even in highly polluted sites) combined with too short treatment times, as well as environmentally and agriculturally irrelevant growth conditions (e.g. constant light and submerged cultivation of seedlings). Furthermore, wherever possible an attempt is made to link the mechanisms published to date in terms of discussing which mechanisms are a direct cause of the observed disturbance of plant function and which are rather a consequence of the primary mechanisms, leading to a complicated toxicity phenotype and ultimately to diminished growth or even death of the plants.


Photolabile coumarins with improved efficiency through azetidinyl substitution.
Azetidinyl substituents have been recently used to improve the fluorescence quantum yield of several classes of fluorophores. Herein, we demonstrate that other useful photochemical processes can be modulated using this strategy. In particular, we prepared and measured the quantum yield of photorelease of a series of 7-azetidinyl-4-methyl coumarin esters and compared it to their 7-diethylamino and julolidine-fused analogues. The efficiency of the photorelease reactions of the azetidinyl-substituted compounds was 2- to 5-fold higher than the corresponding diethylamino coumarins. We investigated the origin of this effect in model fluorophores and in the photoactivatable esters, and found that H-bonding with the solvent seems to be the prominent deactivation channel inhibited upon substitution with an azetidinyl ring. We anticipate that this substitution strategy could be used to modulate other photochemical processes with applications in chemical biology, catalysis and materials science.


Transcribed dark matter: meaning or myth?
Genomic tiling arrays, cDNA sequencing and, more recently, RNA-Seq have provided initial insights into the extent and depth of transcribed sequence across human and other genomes. These methods have led to greatly improved annotations of protein-coding genes, but have also identified transcription outside of annotated exons. One resultant issue that has aroused dispute is the balance of transcription of known exons against transcription outside of known exons. While non-genic 'dark matter' transcription was found by tiling arrays to be pervasive, it was seen to contribute only a small percentage of the polyadenylated transcriptome in some RNA-Seq experiments. This apparent contradiction has been compounded by a lack of clarity about what exactly constitutes a protein-coding gene. It remains unclear, for example, whether or not all transcripts that overlap on either strand within a genomic locus should be assigned to a single gene locus, including those that fail to share promoters, exons and splice junctions. The inability of tiling arrays and RNA-Seq to count transcripts, rather than exons or exon pairs, adds to these difficulties. While there is agreement that thousands of apparently non-coding loci are present outside of protein-coding genes in the human genome, there is vigorous debate of what constitutes evidence for their functionality. These issues will only be resolved upon the demonstration, or otherwise, that organismal or cellular phenotypes frequently result when non-coding RNA loci are disrupted.


On Psychology and Psychiatry in Diabetes.
Managing diabetes requires dealing with diet, medications, and self-monitoring, besides other pressures of daily living. It, therefore, requires collaboration among individuals with diabetes, their families, and significant others including the social milieu in which they reside. Psychological stress plays critical role in the cause and course of diabetes, particularly in mastering various self-management skills, which are essential for adequate management of diabetes. It is possible to measure and to resolve such stressors. Besides the patient and the family, the built environment which the person occupies must be conducive for healthy living. This is a key component in providing an appropriate physical and psychosocial environment. Lacunae in any of the built environmental parameters compromise social and psychological well-being. Psychiatric conditions are also common in diabetes. Both depression and distress are bi-directionally associated with diabetes. The presence of one condition increases the risk of developing the other. In addition, medications used for the treatment of psychiatric conditions have adverse effects on body weight and insulin sensitivity. One must carefully weigh the risk and benefit of the drug class with potential adverse effects. Therefore, identification and management of psychological and psyciatric aspects in subjects with diabetes is an integral and critical component in treating subjects with diabetes.


Can global variation of nasopharynx cancer be retrieved from the combined analyses of IARC Cancer Information (CIN) databases?
The international nasopharynx cancer (NPC) burdens are masked due to the lack of integrated studies that examine epidemiological data based on up-to-date international disease databases such as the Cancer Information (CIN) databases provided by the International Agency for Research on Cancer (IARC). By analyzing the most recently updated NPC epidemiological data available from IARC, we tried to retrieve the worldwide NPC burden and patterns from combined analysis with GLOBOCAN2008 and the Cancer Incidence in Five Continents (CI5) databases. We provide age-standardized rates (ASR) for NPC mortality in 20 highest cancer registries from GLOBOCAN2008 and the World Health Organization (WHO) mortality databases, respectively. However, NPC incidence data can not be retrieved since it is not individually listed in CI5 database. The trend of NPC mortality was investigated with Joinpoint analysis in the selected countries/regions with high ASR. GLOBOCAN 2008 revealed that the highest NPC incidence rates in 2008 were in registries from South-Eastern Asia, Micronesia and Southern Africa with Malaysia, Indonesia and Singapore ranking the top 3. WHO mortality database analysis revealed that China Hong Kong, Singapore and Malta ranks the top 3 regions with the highest 5-year mortality rates. NPC mortality rate is about 2-3 times higher in male than that in female, and shows decrease tendency in those selected countries/regions during the analyzed periods. However, the integrated analyses of the current IARC CIN databases may not be suitable to retrieve epidemiological data of NPC. Much effort is required to improve the local cancer entry and regional death-reporting systems so as to aid similar studies.


Neural correlates of delicate sadness: an fMRI study based on the neuroaesthetics of Noh masks.
Although the role of the amygdala in processing facial expressions of fear is well established, its role in the processing of other emotions, such as sadness, remains unclear. We hypothesized that the amygdala would respond to a negative emotion such as sadness, when sadness was represented by a theatrical mask. In the traditional Japanese Noh theater, performers use masks to indicate many of the mental states of the characters they portray. Here, we report a functional MRI study, in which participants' brains were scanned while viewing Noh masks, whose faces appeared delicately sad. Among seventy standard Noh masks previously rated by the individual participants, we chose six top-rated sad masks and six neutral masks to study the neural correlates of such delicate sadness. Results based on a region of interest analysis indicated the activation of the right amygdala while viewing sad masks. We suggest the fact that such delicate sad masks could activate the amygdala, and it could possibly be because of an underlying similarity to emotions such as fear and disgust.


Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL): an overview of presentation and pathogenesis and guidelines for pathological diagnosis and management.
Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an uncommon complication associated largely with textured implants. It is important that the symptoms associated with BIA-ALCL are recognised and that robust pathways are in place to establish the diagnosis. The aim of this paper is to review what is known of the incidence of the disease, current thoughts on pathogenesis, patterns of presentation and pathological features to provide standard guidelines for its diagnosis. Systematic review of the literature via PubMed covering cases series, modes of presentation, cytological, histological and immunohistochemical features and disease outcome. Since 1997, 518 cases throughout 25 countries have been registered on the American Society of Plastic Surgeons PROFILE registry, with an estimated risk for women with an implant of one to three per million per year. It most frequently presents as a late-onset accumulation of seroma fluid, sometimes as a mass lesion. The neoplastic cells are highly atypical, consistently strongly positive for CD30, with 43-90% also positive for EMA, and all are ALK-negative. Behaviour is best predicted using a staging system for solid tumours. BIA-ALCL is a rare but important complication of breast implants. While characterised by CD30-positive neoplastic cells this must be interpreted with care, and we provide pathological guidelines for the robust diagnosis of this lesion as well as the most appropriate staging system and management strategies. Finally, in order to generate more accurate data on incidence, we recommend mechanisms for the routine central reporting of all cases.


Preoperative sizing in breast augmentation.
Implant size selection in breast augmentation patients is one of many variables to be determined before surgery. Few methods exist today that allow the patient to participate in this process and accurately determine optimal size. The authors describe a simple method of preoperative sizing using silicone implant samples. A total of 567 patients underwent breast augmentation: 297 had surgery before implementation of preoperative sizing and 270 patients were sized preoperatively. Sizing consisted of fitting the patients with various size silicone implants in a larger bra at least twice before surgery to determine desired size. Surveys were sent to both groups to inquire about overall satisfaction, how many preferred a different size postoperatively, and how many ultimately underwent size change surgery. One hundred two responses (34.3 percent) were obtained from the control group and 142 (52.6 percent) were obtained from the sized group. Sized patients received smaller implants (average, 276.6 cc nonsized versus 246.4 cc sized; p < 0.001). Four patients (1.4 percent) in the control group underwent a size change procedure compared with none in the sized group. In the sized cohort, 69 percent believe they are the size that the process predicted, 21 percent are smaller, 9 percent are larger, and 1 percent did not answer the question. Sized patients were more satisfied than controls and fewer were interested in having a different size implant postoperatively. Sized patients indicated that preoperative sizing was both helpful and reasonably accurate in predicting final breast size.


Differentially expressed microRNAs in the aqueous humor of patients with exfoliation glaucoma or primary open-angle glaucoma.
Both exfoliation glaucoma (XFG) and primary open-angle glaucoma (POAG) have been linked to decreased conventional outflow of aqueous humor (AH). To better understand the molecular changes in the AH content under such conditions, we analyzed the miRNA profiles of AH samples from patients with POAG and XFG compared to non-glaucoma controls. Individual AH samples (n = 76) were collected from POAG and XFG patients and age-matched controls during surgical procedure. After RNA extraction, the miRNA profiles were individually determined in 12 POAG, 12 XFG and 11 control samples. We identified 205, 295 and 195 miRNAs in the POAG, XFG and control samples, respectively. Our differential expression analysis identified three miRNAs (miR-125b-5p, miR-302d-3p and miR-451a) significantly different between POAG and controls, five miRNAs (miR-122-5p, miR-3144-3p, miR-320a, miR-320e and miR-630) between XFG and controls and one miRNA (miR-302d-3p) between POAG and XFG. While none of these miRNAs have been previously linked to glaucoma, miR-122-5p may target three glaucoma-associated genes: OPTN, TMCO1 and TGF-ß1. Pathway analysis revealed that these miRNAs are involved in potential glaucoma pathways, including focal adhesion, tight junctions, and TGF-ß signaling. Comparison of the miRNA profile in AH to unrelated human serum (n = 12) exposed potential relationships between these two fluids, although they were not significantly correlated. In summary, we have successfully profiled the miRNA expression without amplification in individual human AH samples and identified several POAG or XFG-associated miRNAs. These miRNAs may play a role in pathways previously implicated in glaucoma and act as biomarkers for disease pathogenesis.


Use of alternative medicine by Saudi liver disease patients attending a tertiary care center: prevalence and attitudes.
Complementary alternative medicine (CAM) covers many types of treatments and procedures that are usually not included in conventional medicine and are used in addition to physician-prescribed drugs to "complement" treatment. Although liver disease is prevalent in Saudi Arabia, not much is known about CAM use among Saudi liver disease patients. Thus, this study aimed to assess the prevalence of CAM use in these patients and their attitudes toward it. Patients were recruited randomly from a tertiary care hepatology clinic at King Khalid University Hospital (KKUH), Riyadh, Saudi Arabia from February 4 to March 20, 2012. A four-page questionnaire was used to interview patients. Of all the 232 participants surveyed, 55.6% have used or are using CAM to treat their liver disease with 45.0% of CAM users stating that they believe it has a positive effect on their treatment. Honey was the most used CAM treatment among the participants (39.0%). Herb use was represented by 31.8% of all users, while 13.5% used bloodletting as a treatment. Cautery was the least used CAM method (3.4%). Nearly 76.6% of CAM users were satisfied with using alternative treatments to help control their disease. Nearly 69.4% of users and nonusers stated that they believe CAM treatments to have numerous beneficial effects. Nearly 60.5% of CAM users stated that their physician had no knowledge of their CAM use. Of the factors included in linear multivariate regression analysis (including: Age, gender, and family CAM use, among other socioeconomic factors) only family CAM use was considered a significant independent factor affecting participants CAM use (Beta = 0.582, 95% CI: 0.372-0.754, P = 0.0001). More than half of the patients have reported CAM use. Overall, more than two-thirds of the entire sample believed that CAM treatments have numerous health benefits.


Peak match speed and maximal sprinting speed in young soccer players: effect of age and playing position.
This study assessed the relationship between peak match speed (PMS) and maximal sprinting speed (MSS) in regard to age and playing positions. MSS and absolute PMS (PMSAbs) were collected from 180 male youth soccer players (U13-U17, 15.0 ± 1.2 y, 161.5 ± 9.2 cm, and 48.3 ± 8.7 kg). The fastest 10-m split over a 40-m sprint was used to determine MSS. PMSAbs was recorded using a global positioning system and was also expressed as a percentage of MSS (PMSRel). Sprint data were compared between age groups and between playing positions. Results showed that regardless of age and playing positions, faster players were likely to reach higher PMSAbs and possibly lower PMSRel. Despite a lower PMSAbs than in older groups (eg, 23.4 ± 1.8 vs 26.8 ± 1.9 km/h for U13 and U17, respectively, ES = 1.9 90%, confidence limits [1.6;2.1]), younger players reached a greater PMSRel (92.0% ± 6.3% vs. 87.2% ± 5.7% for U13 and U17, respectively, ES = -0.8 90% CL [-1.0;-0.5]). Playing position also affected PMSAbs and PMSRel, as strikers were likely to reach higher PMSAbs (eg, 27.0 ± 2.7 vs 23.6 ± 2.2 km/h for strikers and central midfielders, respectively, ES = 2.0 [1.7;2.2]) and PMSRel (eg, 93.6% ± 5.2% vs 85.3% ± 6.5% for strikers and central midfielders, respectively, ES = 1.0 [0.7;1.3]) than all other positions. The findings confirm that age and playing position affect the absolute and relative intensity of speed-related actions during matches.


Sexual counseling and cardiovascular disease: practical approaches.
Patients with cardiovascular disease and their partners expect health care providers to provide sexual counseling to assist them in maintaining sexual quality of life. Evidence suggests however, that there is a gap in integrating evidence into practice and that relatively few cardiac patients receive sexual counseling. This can result in negative psychological, physical, and quality of life outcomes for couples who may needlessly decide sexual activity is too risky and cease all sexual activity. Two scientific statements now exist that provide ample guidance to health care providers in discussing this important topic. Using a team approach that includes physicians, nurses, physical therapists, rehabilitation staff, and others is important to ensure that sexual counseling occurs throughout recovery. In addition, several trials using interventional approaches for sexual counseling provide insight into successful approaches for sexual counseling in practice. This article provides practical strategies and evidence-based approaches for assessment and sexual counseling for all cardiac patients and their partners, and specific counseling for those with ischemic conditions, heart failure, and implanted devices.


Study design of the man and machine trial: a prospective international controlled noninferiority trial comparing manual with robotic catheter ablation for treatment of atrial fibrillation.
Pulmonary vein isolation (PVI) has become the cornerstone procedure for the treatment of symptomatic drug-resistant atrial fibrillation (AF). At the present time, circumferential PVI (CPVI) using irrigated radiofrequency (RF) is the mostly used ablation technique. However, for CPVI, precise catheter navigation and excellent catheter stability is crucial thereby requiring experienced operators. Robotic navigation systems have been introduced to facilitate catheter navigation and to improve catheter stability, therefore potentially increasing procedural success and making CPVI accessible to less experienced operators. To date, no prospective randomized trial has evaluated the efficacy and safety of CPVI using RNS compared to manually performed ablation. In this prospective international multicenter noninferiority trial, 258 patients with either paroxysmal or short-standing persistent AF will be randomized for comparison of PVI using either manual or robotic ablation. In all patients, CPVI will be performed using irrigated RF ablation in combination with a 3D mapping system. The primary endpoint of the trial is the absence of AF or atrial tachycardia without antiarrhythmic drug therapy during 12-month follow-up. Secondary endpoints will be evaluation of periprocedural complications and procedural data such as procedure time, fluoroscopy time, as well as the incidence of esophageal injury assessed by endoscopy within 48 hours after the procedure. The "Man and Machine Trial" is the first prospective international randomized controlled multicenter noninferiority trial to compare manually performed CPVI with robotically navigated CPVI, evaluating both the safety and efficacy of the 2 techniques during a 12-month follow-up period.


Cadmium-113 NMR studies on homoleptic complexes containing thioether ligands: the crystal structures of [Cd([12]aneS4)2](ClO4)2, [Cd([18]aneS4N2)](PF6)2 and [Cd([9]aneS3)2](PF6)2.
We report the measurement of 113Cd NMR chemical shift data for homoleptic thioether and related aza and mixed aza/thiacrown complexes. In a series of Cd(II) complexes containing trithioether to hexathioether ligands, we observe solution 113Cd NMR chemical shifts in the range of 225 to 731 ppm. Upfield chemical shifts in these NMR spectra are seen whenever: (a) the number of thioether sulfur donors in the complex is decreased, (b) a thioether sulfur donor is replaced by a secondary nitrogen donor, or (c) the size of the macrocycle ring increases without a change in the nature or number of the donor atoms. Changes in the identity of non-coordinating anions such as perchlorate or hexafluorophosphate have little effect upon the 113Cd NMR chemical shift in solution. We report the X-ray structure of the complex [Cd([12]aneS4)2](ClO4)2 ([12]aneS4 = 1,4,7,10-tetrathiacyclododecane) (1) which shows the first example of octakis(thioether) coordination of a metal ion, forming an unusual eight-coordinate square antiprismatic structure. We report the X-ray structure of the complex [Cd([9]aneS3)2](PF6)2 ([9]aneS3 = 1,4,7-trithiacyclononane) (3a) which shows hexakis(thioether) coordination to form a distorted octahedral structure. We have also prepared and characterized the Cd(II) complex of a mixed azathiacrown, [Cd([18]aneS4N2)](PF6)2 ([18]aneS4N2 = 1,4,10,13-tetrathia-7,16-diazacyclooctadecane) (6). Its X-ray structure shows a distorted octahedral S4N2 environment around the Cd(II) with the ligand coordinated in the rac fashion. We observe a solvent- and temperature-dependent 14N-1H coupling in the 1H NMR spectrum of the complex which is not present in analogous complexes with this ligand.


Evidence for tumour necrosis factor/cachectin production in cancer.
Labile tumour-necrosis-factor-like (TNF) activity was detected by means of an enzyme-linked immunosorbent assay in 50% of 226 freshly obtained serum samples from cancer patients with active disease. In contrast, only 3% of 32 samples from normal subjects and 18% of 39 samples from cancer patients with no clinically evident disease were positive for this factor, with low levels of activity. Greater proportions of serum samples from patients with ovarian or oat-cell carcinoma were positive (69% and 63%) than those from patients with lymphoma (26%). RNA preparations from peripheral-blood mononuclear cells and solid tumours were probed with TNF complementary DNA; evidence of TNF messenger RNA was found in 8 of 11 samples of peripheral-blood mononuclear cells from cancer patients, but only 1 of 8 normal subjects, and in 2 of 6 colorectal tumours. As yet the inducing stimulus and the clinical significance of TNF production in cancer are not understood.


Codon-Driven Translational Efficiency Is Stable across Diverse Mammalian Cell States.
Whether codon usage fine-tunes mRNA translation in mammals remains controversial, with recent papers suggesting that production of proteins in specific Gene Ontological (GO) pathways can be regulated by actively modifying the codon and anticodon pools in different cellular conditions. In this work, we compared the sequence content of genes in specific GO categories with the exonic genome background. Although a substantial fraction of variability in codon usage could be explained by random sampling, almost half of GO sets showed more variability in codon usage than expected by chance. Nevertheless, by quantifying translational efficiency in healthy and cancerous tissues in human and mouse, we demonstrated that a given tRNA pool can equally well translate many different sets of mRNAs, irrespective of their cell-type specificity. This disconnect between variations in codon usage and the stability of translational efficiency is best explained by differences in GC content between gene sets. GC variation across the mammalian genome is most likely a result of the interplay between genome repair and gene duplication mechanisms, rather than selective pressures caused by codon-driven translational rates. Consequently, codon usage differences in mammalian transcriptomes are most easily explained by well-understood mutational biases acting on the underlying genome.


Sex differences in device therapy for heart failure: utilization, outcomes, and adverse events.
Multiple studies of heart failure patients demonstrated significant improvement in exercise capacity, quality of life, cardiac left ventricular function, and survival from cardiac resynchronization therapy (CRT), but the underenrollment of women in these studies is notable. Etiological and pathophysiological differences may result in different outcomes in response to this treatment by sex. The observed disproportionate representation of women suggests that many women with heart failure either do not meet current clinical criteria to receive CRT in trials or are not properly recruited and maintained in these studies. We performed a systematic literature review through May 2014 of clinical trials and registries of CRT use that stratified outcomes by sex or reported percent women included. One-hundred eighty-three studies contained sex-specific information. Ninety percent of the studies evaluated included ≤ 35% women. Fifty-six articles included effectiveness data that reported response with regard to specific outcome parameters. When compared with men, women exhibited more dramatic improvement in specific parameters. In the studies reporting hazard ratios for hospitalization or death, women generally had greater benefit from CRT. Our review confirms women are markedly underrepresented in CRT trials, and when a CRT device is implanted, women have a therapeutic response that is equivalent to or better than in men, while there is no difference in adverse events reported by sex.